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danger from pricks by contaminated hypodermic needles is reduced by the configuring of a family of single diameter and multiple diameter syringes that accommodate conventional hypodermic needles but also a variety of universal needle - based guards , shields , and safety needles . the family of syringes has as a common property among all the members of the family — a standardized diameter of that portion of the syringe barrel adjacent the needle . the portion of the syringe barrels in the family having the standardized diameter can accommodate universal safety needles regardless of the volume of the syringe . | the concept of a syringe family having standardized diameters and including multiple diameter syringes is a holistic vision of syringe design in which each individual syringe is a member of a larger and interrelated syringe family . each member of an individual syringe family has a common property , that is , a segment of the syringe barrel is equal in diameter ( length may be the same or may vary somewhat ) between the different members of the family . this common property permits each member of an particular syringe family to be fit with safety devices that are universal in the sense that they are wholly interchangeable so as to fit on any member of the syringe family . the safety devices can be needle - based or syringe - based , and can be of various designs . the innovations involved in the creation of these syringe families permit an institution to implement an overall syringe safety program in which the same universal safety devices will work across the entire line of syringes permitting cost savings and the general use of safety devices . with a syringe family having standardized diameters and including multiple diameter syringes ( i . e ., a multidiameter syringe family ) there is a manufacturing advantage , in that an individual safety device will fit each and every member of the syringe family , greatly reducing the costs of manufacturing safety devices and safety device systems . these new multidiameter syringe families will also permit the use of all conventional needles thus maintaining operator flexibility . the syringes forming a multidiameter syringe family are multipurpose , and can completely supplant conventional syringes without surrendering flexibility while at the same time increasing safety and overall syringe ergonomics . it is anticipated that when an institution wishes to implement a universal safety system , they would buy the entire multidiameter syringe line , and completely dispense with conventional syringes . on the other hand , a customer could buy individual members of the syringe family fitted with syringe - based safety devices , but the cost savings for the manufacturer would be maintained in that the same syringe - based safety device would fit any member of an individual syringe family . thus , only one size of safety device need be manufactured because it would fit all of the syringes . this is a tremendous cost advantage for a manufacturer . the design innovations used to create the multidiameter syringe families also produce individual syringes with greater utility , ergonomics , and specific uses , while maintaining their multipurpose properties . thus , the larger members of a given syringe family have distinct practical advantages over their conventional counterparts in that the multidiameter syringes can be used in narrower operating fields , can approach a target at a more conducive angle , permit the hands to be farther from a dangerous operative site while permitting the use of a larger volume syringe , permit the use of shorter needles or medical instruments ( which are more easily shielded ). they also permit easier filling of the syringe ( in aspiration mode ) from a bottle , a fluid container , or a body cavity , and permit a more ergonomic use of a safety device so that it does not interfere with the use of a syringe . any of the syringes embodied according to the teachings of this invention may also include a reciprocating feature , without detracting in any way from the fundamental strength of the multidiameter syringe family concept . a reciprocating syringe has two or more plungers mechanically connected so that one plunger reciprocates with respect to the other plunger , enabling alternate injection or aspiration by changing only the thumb position . the multidiameter syringe families concept is an important advance in syringe design that promotes universal safety precautions , maintains operator flexibility , permits use of conventional needles if desired , reduces safety device manufacturing costs , permits a manufacturer to market the entire syringe family line as an integrated “ safety system ,” and produces individual members of the syringe family that have special uses , yet maintains the flexibility provided in a mutually compatible syringe family . each syringe in a given family of syringes has a syringe barrel with flanges and a plunger with appropriate stoppers and thumb rest . the syringe barrel has a luer , a luer - lok , or other fitting to connect to a hypodermic needle or other medical device . the syringes of a given family are related to one another by having a portion of the syringe barrel or an effective external portion of the syringe barrel having a diameter that is at or slightly less than a selected standard size . in some instances , the portion ( or effective external portion ) of the syringe barrel has a standardized length throughout the syringe family . one way for individual syringes within a syringe family effect the standard diameter is to have a false barrel surround the real barrel . another way of implementing the standardization of diameter is for some syringes within the syringe family to be re - shaped to be longer or shorter than conventional syringes of the same volume . for larger volume syringes , an effective way to accomplish the standardized diameter is to have a standard diameter narrow portion and a larger diameter non - standarized portion . the larger diameter portion accommodates the desired volume . in this multiple diameter configuration , the plunger may be provided with a second stopper sized and positioned to empty the fluid from the narrow portion of the barrel . more specifically , if the internal diameter of the narrower standard diameter portion of the multiple diameter syringe is constant , then the plunger is modified to have a segment to move fluid in the narrow portion of the barrel and a segment to move fluid in the wider portion of the barrel . the segment of the plunger that moves fluid in the wider portion of the barrel is of a wider lower portion of the plunger with a first stopper at the end . the first stopper is sized for sealable and slidable engagement with the wider portion of the syringe barrel . the segment of the plunger that moves fluid in the narrow portion of the barrel is a narrow upper portion of the plunger with the second stopper at the end . the second stopper is sized for sealable and slidable engagement with the narrow portion of the syringe barrel . the plunger also has a channel , tunnel , grove , or other passage to permit movement of fluid between the narrow and wider compartments of the syringe barrel when the syringe is being operated for either aspiration or injection . alternatively , the second stopper may be omitted in favor of a single stopper plunger . if the internal diameter of the narrow , standardized portion of a multiple diameter syringe is tapering , an appropriate modification to the plunger is for the stopper to include a tapering segment for extending into the narrow , standardized portion of the barrel to move fluid in the narrow compartment . one feature of a syringe family having standardized diameters and including multiple diameter syringes is that the syringes can be embodied so as to include shields in the form of extendable plastic cylinders ( or other shape ) that are capable of being extended from around the standard diameter narrow segment of the syringe barrel outwardly so as to cover a needle or other sharp . the shielded syringe advantageously has a locking or securing mechanism to stabilize the shield in the extended protective position . it is useful to note that shields for use with such syringe families are standardized in diameter and / or length and , thus , can be used on any particular member of the syringe family . needle - based safety devices of various designs including , but not limited to , caps ( with or without handles ) are useful in combination with such a family of syringes , provided that the caps can fit over the diameter of the standard diameter portion of the syringe barrel or over the external diameter of a shield on the barrel . the caps advantageously are interchangeable between the different members of a given multidiameter syringe family . as an example , a multiple diameter syringe according to various embodiments of the present invention has a barrel , a plunger movable inside the barrel , and a fluid conduit at one end of the barrel . the fluid conduit is adapted for a needle , catheter , or other similar structure to connect to the syringe . the barrel has a narrow barrel portion at the end of the barrel near the fluid conduit , and a wide barrel portion at the other end of the barrel . the wide barrel portion has a diameter that is substantially larger than the diameter of the narrow barrel portion . the plunger has a narrow plunger portion and a wide plunger portion . the narrow plunger portion is sized to move within the narrow barrel portion , and the wide plunger portion is sized to move within the wide barrel portion . the multiple diameter syringes disclosed enable standardized or non - standardized syringes to be used in narrow operating fields , to approach a target at a more conducive angle , to permit the hands to be farther from operative site . they also enable the use of shorter needles or medical instruments . the members of a syringe family may include one or more reciprocating syringes that have at least two plungers mechanically connected so that one plunger reciprocates with respect to the other plunger . this reciprocating structure enables use of the syringe to alternately inject or aspirate by changing only the position of the user &# 39 ; s thumb . a multidiameter syringe family integrated with universal safety devices forms a sharps safety system . such a sharps safety system is appropriate for adoption by a health care institution to promote safer use of syringes . accidental sticks that occur from improperly discarded uncapped needles on syringes , accidental sticks that occur from the act of improperly discarding needles on syringes , sticks that occur from attempts to recap the contaminated needle on a syringe , sticks that occur to the operator from an uncapped needle not in immediate use , but still on the equipment tray or in the operating field , sticks that occur in the operating field from a misdirected needle , or the present invention is useful to decrease needle sticks occurring principally from improperly discarded uncapped needles on syringes , recapping injuries , and improper disposal of needles on syringes . although one aspect of the present invention is to provide a family of syringes that have the common property , that is , a syringe barrel portion diameter that is standardized so as to accommodate universal needle safety devices regardless of the volume of the syringe . the standard barrel diameter may be selected to be any diameter . advantageously , the standard diameter is chosen to be in a range appropriate to accommodate the external diameter of a luer - lok device , or other common coupling . as a useful alternative , the standard diameter is chosen to be in a range appropriate to accommodate a luer fitting . however , because of the risk of accidental dislodgment of a needle during a procedure , especially a procedure in which the syringe develops high - pressure , operators would expect the capability of a luer - lok . in this instance , the minimal diameter so as to accommodate a luer - lok is an appropriate selection for the standardized syringe diameter and is preferable over that to accommodate a luer fitting . as a practical matter , since the luer - lok has a larger diameter than a luer , to accommodate a luer - lok device , the external diameter of the narrow portion of the syringe is limited to the external diameter of the luer - lok device or larger . accordingly , a salient aspect of the present invention is to select the standard diameter that will tend to accommodate any safety device . generally , though , a family of syringes could have any standard diameter selected to be compatible with a luer fitting , a luer - lok , a catheter , or some specialized structures . all of structures fulfill useful purposes and are thus suitable choices on which to base a selection of standard diameter . with the foregoing general guidance as to how to select an appropriate standard diameter , it has been found that standardized syringe barrel diameters in the range of from about 0 . 5 cm to about 3 . 0 cm are useful . the members of a family of such syringes each provide a long narrow syringe barrel portion appropriate to accommodate mounting of a safety device and needles ( conventional if desired , or otherwise ). optionally joined to this long narrow syringe barrel portion is a larger diameter barrel to accommodate the volume desired for that syringe . because the syringe is composed of a barrel of either increased length to accommodate greater volume or a barrel with multiple external and internal diameters , plungers having a likewise modified configuration are appropriate . the length of the long narrow portion may be selected in order to accommodate needles of a particular size . for example , if use of longer needles with the syringe family is desired , the length of the standardized portion of the barrel is expanded and the large portion is widened to accommodate greater volume . these syringe modifications have a number of specific advantages independent of their compatibility with other members of a particular syringe family . for larger syringes , since the diameter of the barrel portion close the needle is narrower , the larger volume syringes can be used for fine procedures . that is because the diameter of the proximal portion of the syringe barrel does not interfere , either visually or physically , with close approach to the object . this will improve the technical performance of a number of syringe - based procedures ; especially those used with larger syringes . similarly , in larger syringes , the stroke distance of the plunger will be decreased because the stroke distance will be determined by the length of the largest barrel portion . this will be an advantage with larger syringes where the stroke distance is long , as in a conventional 60 cc syringe . that is because it will be better suited for individuals with small hands who have difficulty accommodating the long stroke distance . it is also because the hand muscles have a greater mechanical advantage when the stroke distance of the plunger is less . although the applied force may need to be greater to generate a greater pressure , but this is overcome by the mechanical advantage of the lesser stroke distance . the basic design of the multidiameter syringe according to a first embodiment is a narrow barrel portion having a standardized diameter selected to accommodate the needle or safety device , and a larger barrel portion having variable length and variable diameter selectable to accommodate a desired fluid volume . one plunger accomplishes movement of fluid in the multidiameter syringe , thus , special consideration is given to the design of the plunger and stopper so that fluid can move freely between the upper narrow diameter syringe barrel portion and the lower wider diameter syringe barrel portion . this can be accomplished by have the internal diameter of the narrow barrel being constant and providing a groove or passage through the plunger to permit passage of fluid between the lower wider chamber and the upper narrower chamber . some small amount of residual fluid will be trapped in the groove or passage in this design . to minimize the amount of residual fluid , the narrow portion of the plunger cannot have empty space ; otherwise a substantial amount of fluid will be trapped within the syringe . if this is permitted to occur , the trapped fluid will prevent movement of both the plunger and the fluid . accordingly , it is useful to have configurations that do not have dead space between the upper and lower portions of the plunger . an example of a multiple diameter syringe according to the first embodiment of the present invention has a common property within a syringe family . the multiple diameter syringe has a barrel , a plunger movable inside the barrel , and a fluid conduit at one end of the barrel . the barrel has a narrow barrel portion at the end of the barrel near the fluid conduit , and a wide barrel portion at the other end of the barrel . the wide barrel portion has a diameter that is substantially larger than the diameter of the narrow barrel portion . the narrow barrel portion having a constant diameter interior profile . the plunger has a narrow plunger portion , a wide plunger portion , a wide resilient stopper , and a narrow resilient stopper . the narrow plunger portion is sized to move within the narrow barrel portion , and the wide plunger portion is sized to move within the wide barrel portion . the wide resilient stopper is located between the narrow plunger portion and the wide plunger portion , and is sized to slidably and sealably engage the inside surface of the wide barrel portion . the narrow resilient stopper is located on the narrow plunger portion , and is sized to slidably and sealably engage the inside surface of the narrow barrel portion . the narrow barrel portion has an outside diameter that is substantially equal to the standard diameter for the syringe family . a fluid flow channel is formed in the the narrow barrel portion so that fluid is free to flow through the fluid flow channel between a lower chamber formed inside the wide barrel portion and an upper chamber formed inside the narrow barrel portion . referring to fig1 a side view of a plunger subassembly of a syringe according to a first embodiment of the present invention is illustrated . the plunger 100 has a smaller upper rubber stopper 110 that can be discrete or continuous with plunger , a groove or tunnel 120 in the upper portion 130 of the plunger to permit movement of fluid through the upper portion 130 of plunger and move into the upper narrow portion of the barrel . the plunger also has a larger lower rubber stopper 140 that can be discrete or continuous with , and disposed between , the upper plunger portion 130 and the lower portion 150 of the plunger . a thumb rest 160 is disposed at the extreme end of the lower portion 150 of the plunger . referring to fig2 a side view of a barrel subassembly of a syringe according to the first embodiment of the present invention is illustrated . the syringe barrel 200 has a hypodermic needle 210 ( or optionally a cannula or nozzle ) with a needle hub 220 with an integrated needle fitting 230 . the needle fitting 230 may be a luer , luer - lok , catheter or other similar , suitable structure . the syringe barrel 200 has an upper narrow barrel portion 240 , a larger diameter lower barrel portion 250 , and finger flanges 260 . referring to fig3 a partial section view of a syringe , according to the first embodiment of the present invention , is illustrated as assembled and in operation . as the plunger 100 is depressed , fluid in the lower chamber 310 flows towards the upper chamber 330 via the grove or tunnel 120 in the upper plunger portion and moves 320 to join fluid in the upper chamber 330 . an example of a multiple diameter syringe according to a second embodiment of the present invention has a barrel , a plunger movable inside the barrel , and a fluid conduit at one end of the barrel . the barrel has a narrow barrel portion at the end of the barrel near the fluid conduit , and a wide barrel portion at the other end of the barrel . the wide barrel portion has a diameter that is substantially larger than the diameter of the narrow barrel portion . the plunger is sized to move within the wide barrel portion and has a resilient stopper located at an end of the stopper that is sized to slidably and sealably engage an inside surface of the wide barrel portion . referring to fig4 a partial section view of a syringe , according to a second embodiment of the present invention , is illustrated in operation . this embodiment is similar to the first embodiment except that the plunger does not have a narrow upper plunger portion . thus , some dead space is left in the narrow upper barrel 410 that harbors some amount of fluid that flows from the larger lower barrel 420 into the narrow upper barrel 410 cannot be cleared from the syringe . however , in larger syringes this volume may be negligible . although each syringe in a family can be utilized independently , the syringes within a family are configured so that a safety system is achievable when the family of multidiameter syringes is adopted by an institution so that universal safety devices are readily utilized on syringes . referring to fig5 a side view of a plunger subassembly of a syringe according to a third embodiment of the present invention is illustrated . the plunger has a rubber stopper with a tapered upper portion 510 and a wide lower portion 520 . the rubber stopper upper portion 510 is tapered to permit movement of fluid along the plunger surface and to correspond to a tapered shape of the syringe barrel . the rubber stopper may be discrete or continuous with lower plunger 530 . a thumb rest 540 is disposed at the bottom end of the lower plunger 530 . referring to fig6 a partial section view of a barrel subassembly of a syringe according to the third embodiment of the present invention is illustrated . a hypodermic needle 610 with a needle hub 620 is shown affixed to the barrel 600 . optionally , a cannula or nozzle may be affixed in place of a needle . the needle hub 620 connects to a needle fitting 630 at the end of the barrel 600 . the needle fitting 630 is optionally configured as a luer , luer - lok , catheter , or other type of fitting as needed . the barrel 600 has a narrow upper portion 640 having a tapered inner surface , and a larger diameter lower portion 650 . finger flanges 660 are disposed at the periphery of the lower end of the barrel 600 . in this third embodiment , no groove or tunnel is necessary for fluid to move from the large diameter chamber to the upper chamber having a tapered diameter . referring to fig7 a partial section view of a syringe , according to the third embodiment of the present invention , is illustrated in operation . as the plunger is depressed , fluid in the lower chamber 710 is forced by the wide lower portion 520 of the stopper to flow upward 720 past the tapered upper portion 510 of the stopper and moves to join fluid in the upper chamber 730 . [ 0087 ] fig8 - 12 portray an exemplary multidiameter syringe family . what unites the members of a syringe family is that they have an upper diameter that is the same as ( or slightly less than ) a standard diameter d . because these devices have a common upper diameter d , they can accommodate a number of standard , interchangeable , or universal safety devices or needles as well as conventional needles . referring to fig8 a partial section view of a 1 ml syringe is illustrated according to the exemplary family of syringes . for the 1 ml syringe 800 , the upper diameter is narrower than the standard diameter d since for such a small volume barrel it is impractical to make it as wide as d . this discrepancy is accommodated by adding a false barrel 810 to the outside of the barrel . the false barrel 810 has a diameter of d . a small volume syringe according to various embodiments of the present invention has a common property within a syringe family . the syringe has has a barrel , a plunger movable inside the barrel , a fluid conduit at one end of the barrel , and a resilient stopper located at the end of the plunger and sized to slidably and sealably engage an inside surface of the barrel . the barrel has an outside diameter that is less than a standard diameter of the syringe family . the syringe also has a false barrel surrounding the barrel and located at the end of the barrel with the fluid conduit . the false barrel has an outside diameter that is substantially equal to the standard diameter for the syringe family . referring to fig9 a partial section view of a 3 ml or 5 ml syringe is illustrated according to the exemplary family of syringes . in certain of the syringes , particularly the 3 , 5 , and 10 - ml versions , varying the length of the syringe , while maintaining the standard diameter d can accommodate the volume requirement . these longer versions can thus accommodate a larger safety device . referring to fig1 , a partial section view of a 5 ml or 10 ml syringe according to the exemplary family of syringes is illustrated . referring to fig1 , a partial section view of a 10 ml , 20 ml , or 30 ml syringe according to the exemplary family of syringes is illustrated . for larger volumes the multidiameter syringe versions are required . referring to fig1 , a partial section view of a 50 ml or 60 ml syringe according to an exemplary family of syringes is illustrated . the length l 1 of the upper narrow segment of the barrel determines the maximum length of the safety device for that syringe . according to another embodiment of the present invention , a syringe family includes at least two syringes . each of the syringes in the family has a different volume capacity that the other syringes . all of the syringes in the family share the common property of having a barrel that has an outside diameter at its needle end that is substantially equal to a standard diameter for the syringe family . reciprocating syringes may utilize this standardization concept to fit within a family of syringes . reciprocating syringes have two or more plungers and one or more dependent or independent barrels , where the plungers are mechanically connected so that they alternate or reciprocate with each cycle of aspiration / injection . referring to fig1 , a partial section view of a shield is illustrated . the shield is useful for integration with a family of syringes arranged according to any of the various embodiments of the present invention . the shield is an example of a standard guard or shield for the multidiameter syringe . of course , practice of the present invention is not limited only to the shield shape illustrated and may take any number of modified configurations . the shield 1300 is composed of a plastic and has a length l s . the shield 1300 has an inside diameter id and an exterior diameter od . the inside diameter id of the shield 1300 is greater than or equal to the standard diameter d of the syringe and / or syringe family . this shield 1300 optionally has intrinsic fasteners that lock the shield in a particular position , either extended or retracted . the locking devices may effect a position lock that is either permanent or temporary . examples of suitable temporary or permanent locking devices are : 1 ) threaded or partially threaded components on the shield and syringe , 2 ) depressible tabs on the syringe which protrude and lock through fenestrations on the shield , 3 ) a series of angled and flexible retaining tabs facing opposite direction which would engage and trap an appropriate surface attached to the syringe , 4 ) a ring or partial ring composed of flexible material or rigid material with a spring or other material with memory that would engage an lock an appropriate retaining grove or space on the guard or shield or vice - versa . other locking or fastening devices may also be utilized . it would be anticipated that the length l s of the shield 1300 would be roughly the same dimension as the lengths of narrow standardized portions of barrels of members of the syringe family ( e . g ., l 1 ), although it could be longer or shorter on individual syringes , and possibly as long as the maximum syringe length l 2 . this shield or guard could be designed specifically for each syringe size , or could be standardized and fit identically on any and all members of a particular syringe family . this shield could also be used in combination with a number of different needle based safety devices , as long as they could accommodate the outside diameter od of the shield or the inside diameter id . a standard shield that would fit on every member of a given syringe family has a salient manufacturing advantage . referring to fig1 , a partial section view of the 1 ml syringe , according to the exemplary family of syringes , is illustrated with a shield in place . on the 1 ml syringe the inside diameter id may be made to correspond to the intrinsic diameter of the syringe but to fit compatibly on the other various members of the syringe family the inside diameter id is selected to correspond to the size of the false barrel 810 . the shield is shown in a retracted positions on the 1 ml syringe . referring to fig1 , a partial section view of the 3 ml or 5 ml syringe , according to the exemplary family of syringes , is illustrated with a shield in place . this shield ( or guard ) is shown in an extended position on the 3 or 5 mil syringe . referring to fig1 , a partial section view of the 5 ml or 10 ml syringe , according to the exemplary family of syringes , is illustrated with a shield in place . the shield is shown in a retracted positions on the 5 or 10 ml syringe . referring to fig1 , a partial section view of the 10 ml , 20 ml , or 30 ml syringe , according to the exemplary family of syringes , is illustrated with a shield in place . the shield is shown in a retracted position on the 10 , 20 , or 30 - ml syringe . referring to fig1 , a partial section view of the 50 ml or 60 ml syringe , according to the exemplary family of syringes , is illustrated with a shield in place . the shield is shown in an extended position on the 50 or 60 ml syringe . needle - based safety devices are useable on these multidiameter syringes and syringe families with or without the shield , although the presence of the shield would naturally affect the design and dimensions of many of the needle - based safety devices . referring to fig1 , a partial section view of a safety cap is illustrated . the safety cap is useful for integration with a family of syringes arranged according to any of the various embodiments of the present invention . the safety cap 1900 is an example of a needle based safety device . the safety cap shown has a handle 1910 . however , the diameter of the medical device that this type of cap can accommodate is limited to a length that is twice the distance r from the central axis of the safety cap to the handle . the length of the handle l h also places a limit on dimensions of the medical device that this type of cap can accommodate . referring to fig2 , a partial section view of a syringe is illustrated for use with a safety cap according to fig1 . in terms of the multidiameter syringe 2000 , the value of two times r must at least be equal or greater than the external diameter d of the standardized portion of the syringe , and the length of the handle l h is limited by the length l b of the standardized portion of the barrel of the syringe 2000 . once the safety device fulfills these constraints it can fit on any member of a given syringe family . referring to fig2 , a partial section view of a syringe is illustrated without a shield and having a safety cap according to fig1 mounted thereon . a safety device designed to fit on the multidiameter syringe with a shield will naturally also fit on non - shielded versions 2100 of these syringes . this safety cap device 1900 is shown only as an example . many other safety devices of many designs could be standardized to fit interchangeably on an entire family of these shielded or non - shielded multidiameter syringes . referring to fig2 , a partial section view of a syringe is illustrated with a shield and having a safety cap according to fig1 mounted thereon . once a shielded version 2200 of this syringe is used however , the safety device parameter of r is adjusted to accommodate the external diameter of the standard shield 1300 , in this case by lengthening the offset dimension a of the handle . such a modified safety device 2210 is seated on a shield syringe 2200 as shown . although the present invention has been described in terms of a number of exemplary embodiments , it will be understood by those of skill in the art that various improvements , modifications , and simplifications may be made to the embodiments disclosed without departing from the scope of the invention . | US-77216304-A |
a method and apparatus for reducing the effects of noise on a system for measuring physiological parameters , such as , for example , a pulse oximeter . the method and apparatus of the invention take into account the physical limitations on various physiological parameters being monitored when weighting and averaging a series of measurements . varying weights are assigned different measurements , measurements are rejected , and the averaging period is adjusted according to the reliability of the measurements . similarly , calculated values derived from analyzing the measurements are also assigned varying weights and averaged over adjustable periods . more specifically , a general class of filters such as , for example , kalman filters , is employed in processing the measurements and calculated values . the filters use mathematical models which describe how the physiological parameters change in time , and how these parameters relate to measurement in a noisy environment . the filters adaptively modify a set of averaging weights to optimally estimate the physiological parameters . | fig1 a shows the flow of data according to one embodiment of the present invention . a separate platform collects the oximetry data ( step 10 ) and passes it to processors 50 and 52 of the present invention . a preferred platform is described in u . s . pat . no . 5 , 348 , 004 assigned to nellcor , the entire disclosure of which is incorporated herein by reference . the data is first pre - processed ( steps 12 and 14 ), and is then passed to a saturation calculation algorithm ( box 50 ). the algorithm described herein employs an improved kalman filter method ( step 24 ). it will be understood that other saturation calculation techniques may be employed . the pulse rate calculation method ( box 52 ) and a cardiac gated averaging technique also using a kalman filter ( step 16 ) are discussed below . according to a preferred embodiment , the processing technique employs the following pre - processing . the natural logarithm of the ir and red wavelength data is taken ( step 12 ), and then the data is band pass filtered with an infinite impulse response ( iir ) filter that has a high pass cutoff frequency at 0 . 5 hz , i . e ., 30 beats per minute , and a low pass rolloff from 10 to 20 hz ( step 14 ). fig2 shows the frequency response of an dr filter employed by a specific embodiment of the invention . after the oximetry data has been filtered , it is processed by a saturation calculation algorithm ( box 50 ). according to a preferred embodiment of the invention depicted in fig1 a , two saturation values are calculated in parallel by saturation calculator 50 . one saturation value is calculated using a harmonic filter 17 and a kalman - filter - based cardiac gated averaging ( cga ) technique ( step 16 ) ( described below ) to obtain a more reliable data stream . kalman cga 16 is gated by triggers based on the pulse rate which are supplied by pulse rate calculator 52 . in a specific embodiment , the data is put through a harmonic filter ( step 17 ) before it is averaged in step 16 . harmonic filter 17 digitally filters the ir and red waveforms such that only energy at integer multiples of the heart rate is allowed through the filter . the response of harmonic filter 17 varies with the heart rate which is supplied by pulse rate calculator 52 to attenuate motion and noise energy not at the heart rate . in one embodiment , only one of the ir and red waveforms is filtered by harmonic filter 17 . in this embodiment , the subsequent filtering by kalman cga 16 and / or the saturation calculation algorithm described below applies the same weighting and averaging to both the ir and red data streams on the basis of the single filtered data stream . both saturation values are calculated in the following manner . the data pulses ( either directly from the band pass filter or from steps 16 and 17 ) are normalized ( step 18 ) and then “ whitened ” ( step 20 ). normalizing downweights large pulse amplitudes so that each pulse has roughly the same average amplitude . normalizing step 18 assumes that from one sample to the next , noise energy should look substantially the same statistically . as a result , samples exhibiting large amounts of noise are down weighted , thus de - emphasizing outliers . whitening step 20 involves taking the derivative of the normalized data , thereby emphasizing the higher harmonics of the pleth so that its energy is more evenly distributed between them . data points resulting in an impossible saturation calculation are rejected ( step 22 ) and the resulting data are used to calculate the saturation values using a kalman filter technique described below ( step 24 ). the best saturation value is then chosen ( step 26 ) according to confidence levels associated with each , and , after some post processing ( step 27 ), the saturation value is output to the display ( step 28 ). post processing 27 , which will be discussed in greater detail below , uses available metrics with regard to the saturation value to determine its reliability and determine whether and how it is to be displayed . in specific preferred embodiments of the present invention , the initial saturation value calculated by each calculation path in saturation calculator 50 may be calculated by the well known classic least squares ( cls ) technique as indicated by step 21 . the use of this technique occurs on initialization of saturation calculator 50 only . the pulse or heart rate is calculated in pulse rate calculator 52 in the following manner . after the pre - processing described above , data from one channel , e . g ., the ir channel , are normalized ( step 29 ) by the downweighting of data corresponding to large pulse amplitudes so that each pulse has roughly the same average amplitude . the data are then sent to two different algorithms for calculation of the patient &# 39 ; s pulse rate . according to one algorithm , the derivative of the data is taken ( step 30 ) as described above , and the fundamental frequency of the pulse rate is tracked using an adaptive comb filter ( acf ) 32 as discussed below . acf 32 supplies its pulse rate directly to harmonic filter 17 as described above . acf 32 also provides the trigger for kalman cga 16 after the data is unwhitened by integration ( step 34 ) and the triggers for kalman cga are generated ( step 36 ). alternatively , the triggers for kalman cga 16 may be derived from , for example , an ecg waveform . acf 32 is a robust pulse rate tracker , but not a good pulse rate finder . therefore , the frequency power spectrum of the normalized data is calculated periodically ( step 38 ) to determine whether acf 32 is tracking the fundamental rather than a super - or subharmonic of the pulse rate . the normalized data is also supplied to a pattern matching algorithm 40 which recognizes sequences of crests and troughs in the data and calculates an average period of the pleth over a set number of samples . this algorithm is preferably used primarily to track the pulse rate for an arrhythmic pulse rate during periods where no motion is detected . a best rate algorithm 42 then arbitrates between the pulse rates calculated by acf 32 ( as updated by frequency power spectrum 38 ) and pattern matching algorithm 40 using confidence levels associated with each , which are based on various metrics . after post processing ( step 44 ), the pulse rate is output to the display ( step 46 ). as with saturation calculator 50 , post processing 44 uses available metrics to determine the reliability of the pulse rate and to determine whether and how it is to be displayed . fig1 b shows the flow of data according to a second embodiment of the present invention . the system operates the same as the system of fig1 a except that after the data is band pass filtered by iir filter 14 , it undergoes an additional processing step in eta correction processor 15 before it is sent to either saturation calculation algorithm 50 or pulse rate calculation algorithm 52 . like other aspects of the present invention already described , eta correction processor 15 serves to reduce the effects of motion and other noise artifact . the operation of eta correction processor 15 is based on an analysis of the signal intensity received for the different wavelengths , without separately measuring the motion signal for each wavelength , without providing feedback to cancel the motion signal , and without attempting to mathematically eliminate the motion signal individually for each wavelength . instead , processor 15 mathematically recognizes the presence of the motion signal and recognizes a few key characteristics of the motion signal . first , although the magnitude of the effect of motion on the signal intensity for each wavelength will be different , the change in the logarithm of the motion component will be approximately the same ( for signals obtained at approximately the same time ). this allows the motion component to be cancelled out in a ratiometric equation . second , it is assumed that the blood pulse signal is not affected by motion . this second assumption is more of an approximation , since the blood pulse signal is somewhat affected by motion , which can actually change the blood volume characteristics at any point in the patient . eta correction processor 15 recognizes that the intensity signal for each of the wavelengths includes a time - varying motion term , and that this time - varying motion term is proportional for each of the wavelengths . in addition , each wavelength signal occurs close enough in time with one another that the motion should not vary noticeably , and can be assumed to be the same for each signal . the output from eta correction processor 15 is an ir or red signal which has significantly less motion noise than the signals fed into processor 15 . if the data include information from a third wavelength , the output of processor 15 is both an ir signal and a red signal depleted of motion noise . a more detailed description of the operation of eta correction processor 15 is described in a commonly assigned , copending u . s . patent application ser . no . 08 / 490 , 315 for method and apparatus for removing artifact and noise from pulse oximetry , filed jun . 14 , 1995 , the entire disclosure of which is incorporated herein by reference . the method for calculation of blood oxygen saturation ( step 24 ) described below uses a kalman filter . the method first transforms the pre - processed data into quantities corresponding to the oxyhemoglobin and total hemoglobin concentrations using appropriate extinction coefficients . the instantaneous ratio of these two transformed quantities gives the saturation . it will be understood from the equation immediately following equation ( 4 ) above that the instantaneous saturation value may be calculated directly by using the extinction coefficients , or from the ratio of ratios as shown in the equation immediately following equation ( 5 ). according to a preferred embodiment , the method does not search for maxima or minima like a pulse searching algorithm ( although maxima or minima could be used and kalman filtered if desired ). using instantaneous ratios ( i . e ., a time based algorithm ) rather than maxima / minima ratios ( i . e ., an event based algorithm ) keeps the code from being event driven and having to qualify data as it arrives . thus , the preferred method of the present invention is simpler to implement than a pulse - searching event - based saturation calculation algorithm . the extinction coefficients are determined with reference to the wavelength or wavelengths being transmitted by the leds in the particular sensor attached to the patient . in a preferred embodiment , the sensor includes a means for generating a signal which corresponds to at least one of the wavelengths being transmitted by the sensor &# 39 ; s leds . the oximeter monitor receives the signal and determines the proper extinction coefficients based on the wavelength or wavelengths indicated by the signal . this avoids the need to recalibrate an oximeter to match the transmission characteristics of a particular probe . in a preferred embodiment , the means for generating the signal is an electrical impedance element such as , for example , a resistor , the value of which corresponds to the wavelengths of the leds . a preferred embodiment of a sensor / oximeter combination is shown in fig3 . oximetry system 60 includes a sensor 61 and an oximeter monitor 62 . sensor 61 includes leds 63 and 64 typically having wavelength emission characteristics in the infrared and red ranges of the spectrum , respectively . photodiode sensor 65 receives the light transmitted by leds 63 and 64 . resistor 66 ( or a similar electrical impedance reference ) is chosen to correspond to a specific wavelength or combination of wavelengths as specified by a table relating impedance values to wavelengths . once decoding means 67 determines the impedance value of resistor 66 , appropriate extinction coefficients are generated which correspond to the transmission characteristics of the particular sensor 61 . thus , the oximeter may be used with a variety of sensors having leds which emit varying wavelengths of light without recalibration . sensor 61 may be detachably coupled to oximeter monitor 62 via connector 68 . an example of such a sensor / oximeter combination is described in commonly assigned u . s . pat . no . 4 , 621 , 643 for calibrated optical oximeter probe , issued on nov . 11 , 1986 ; no . 4 , 700 , 708 for calibrated optical oximeter probe , issued on oct . 20 , 1987 ; and no . 4 , 770 , 179 for calibrated optical oximeter probe , issued on sep . 13 , 1988 , the entire disclosures of which are incorporated herein by reference . kalman filtering allows one to fit parameters in a least squares sense when these parameters are varying in time . traditionally one might employ a classical least squares ( cls ) approach with low - pass filtering or averaging of the estimated quantity . essentially kalman filtering does the same thing , but the kalman filter calculates the optimal amount of averaging . one embodiment employs a kalman filter algorithm derived by r . g . brown and p . y . c . hwang in introduction to random signals and applied kalman filtering ( 1992 ), the disclosure of which is incorporated herein by reference . a simplified general kalman filter is described below . in this example , an estimate of the data average is made as the data are being measured . the measured data also has a gain h to be removed . the k - th measurement is z k and the k - th estimate of the average is x k . the first estimate of the average is just the measurement this may be continued , but after a while becomes inefficient because of the need to store all of the measurements , constantly re - add them all , and divide by the gain and the number of measurements . a more efficient solution uses only the last estimate of the average and the current measurement . with this solution , after the first measurement , the estimate is still where we have used k to simplify the equation notation . the kalman filter uses the same ideas with some extensions : the kalman filter optimally filters noise , and the parameter being estimated can vary in time . a simplified kalman filter employed in one embodiment of the present invention will now be described . the parameter to be estimated ( for example , saturation ) is x which varies in time in some predictable way . if the value of x is known at some sample in time , then in the next sample , x may be expected to have little or no variation from the previous value . q is the valiance of this difference . the parameter x is not measured directly . what is actually measured is a parameter z which equals x times a constant h plus measurement noise . r is the variance of this measurement noise . the ability to estimate the value of x knowing z and the last estimate of x is related to the two noises quantified by r and q . the kalman filter quantifies the two noises in a parameter called the estimation error , p . the kalman filter also uses an intermediate term called the kalman gain , k . p 0 − 1 is initialized with a value of zero . then at each new data point k , the following steps are performed : notice how the estimate x k looks like the sample averaging example . with the kalman filter , the saturation is allowed to vary , and the model is separated into two parts . the first part is that is , the ratio of the transformed pre - processed data is the saturation value except for measurement noise . the spread of the data gives a real - time measurement of the noise variance . the second part says that on average saturation does not change in time , but if it does change the standard deviation of the change is some constant , q 1 / 2 ( 1 . 3 saturation points per second in one embodiment ). that is , the second equation is this second equation gives the kalman filter the ability to recognize that if saturation changes by 10 points in two seconds , for example , it must be due to measurement noise . the kalman filter then averages the calculated saturation more with previous values to bring the change more in line with what is expected from physiology . in contrast , if the change is within bounds the kalman filter will average very little . the value of r is estimated from the difference between v and us over the last n points , where the user specifies the value n . in one embodiment , the kalman model for saturation also gives less weight to the smaller portions of a pulse , more weight to the larger portions , and adds a small incremental value to the actual variance to represent the error inherent in the measurement system ( e . g ., hardware noise ). in another preferred embodiment , a kalman filter limits the changes to the time derivative of saturation . the equations for this filter say that the expected value of the time derivative of saturation should statistically be unchanged with time . where z is the estimate of saturation from the first kalman filter , and x is the estimate of saturation after limiting its time derivative . in this embodiment , the parameter n q is 2 . 5 preferred to be chosen to correspond to 0 . 2 saturation points per second per second , and n p is estimated from the data . in the general form of the kalman filter , these two separate filters could be combined into one filter . by separating them , the need to use matrix algebra is eliminated and each kalman filter is able to be tested separately . the measurement noise is estimated by centering a window around the data values being used . this centering gives a more accurate estimate of the noise , but delays the output of the kalman filter by half the window length . a one second window is preferred under the belief that the filter can respond quickly to motion coming and going , and the one - half second delay in saturation estimation is not clinically significant . the kalman filter employed by the present invention behaves in a very robust manner . although motion can fool the kalman filter , in most instances kalman filtering results in the calculated saturation remaining closer to truth much longer than the cis method and other known prior art methods . fig4 compares the response of a saturation calculation algorithm employing the classic least squares ( cls ) solution ( 70 ) and the kalman filter ( 72 ) saturation algorithm to several artificial changes in saturation which occur at physiologically unbelievable rates . for rapid changes , the kalman filter slows down the response to a specified rate , whereas the cls algorithm quickly changes saturation , going to a value which is clearly erroneous in view of physiological realities . for slow changes , both algorithms track the same saturation change . a further feature of the present invention is the kalman cga processor 16 which again uses kalman filter theory . preferably , kalman cga 16 is used in series with kalman saturation . the data used is after the preprocessing step 17 described above . the kalman cga processor 16 optimally averages successive pleth pulses or waveforms to create an optimally filtered pleth waveform . the first equation following says that the measured pleth shape should equal the averaged pleth wave shape except for measurement noise . the value of q is estimated from the data . the next equation following says the new pulse cannot be more than some percentage ( 10 % or 20 % in two preferred embodiments ) different from the averaged pleth pulse . the kalman cardiac gated averaging model automatically averages more data points if the incoming wave form varies quite a bit , yet has the ability to update quickly if the wave form obeys assumptions based on expected physiological variation . the kalman cardiac gated averaging represents a significant improvement over prior art methods of calculating saturation as used in nellcor oximeter models n200 and n3000 , and as described in u . s . pat . no . 4 , 802 , 486 ; no . 4 , 869 , 254 ; no . 4 , 911 , 167 ; no . 4 , 928 , 692 ; no . 4 , 934 , 372 ; no . 5 , 078 , 136 ; and no . 5 , 351 , 685 all assigned to nellcor , the disclosures of which are all incorporated herein by reference . fig5 shows an example of the inputs and outputs of a kalman filter according to one embodiment of the invention . the trigger waveform 100 is from the r - wave of an ecg or from pulse rate calculation method 52 ( fig1 ). the raw data waveform 102 is at times quite corrupted by motion , yet by variable averaging , the kalman cardiac gated averaging technique is able to keep the filtered waveform 104 looking quite regular . the estimated residual 106 correlates quite well in time with the noise on the measured data . fig6 shows actual data processed by the series combination of the kalman cardiac gated averaging and kalman saturation algorithm ( waveform 108 ) as compared to data processed with only the kalman saturation algorithm ( waveform 110 ). it is believed that there was no true desaturation ( i . e ., saturation below 90 %) over the time period depicted , a fact reflected more accurately by the series combination of kalman cardiac gated averaging and kalman saturation averaging . fig7 illustrates the relationship between the weight applied to the raw optical waveform , and the age of the filtered waveform according one embodiment of the kalman cardiac gated averaging filter . the vertical axis on the left hand side of the graph represents the weighting and is associated with waveform 112 . the right hand side vertical axis represents the age of the filtered waveform and is associated with waveform 114 . it is important to note that as the weight applied to the incoming data decreases , the data employed in calculating the pulse rate ages correlatively . fig8 is a graph illustrating the improvement in saturation calculation gained by employing both the kalman cardiac gated averaging filter and the kalman saturation algorithm ( waveform 116 ) as compared to the nellcor n200 pulse oximetry system mentioned above ( waveform 118 ). during this clinical trial , no true desaturation ( i . e ., saturation below 90 %) is believed to have occurred . in a preferred embodiment , a technique is employed to generate a robust pulse rate from the optical data for use as the kalman cardiac gated averaging triggers instead of the ecg waveform which is typically obtained from impedance measurements . one prior art technique for determining a pulse rate from the optical pleth waveform is to count zero crossings . if there is no motion and no other noise , the optical pleth signal is very clean and a pulse rate can be determined by accurately counting zero crossings . during motion a zero - crossing approach will count transients from the motion and display an artificially high rate . another prior art approach uses a template of the pleth signal corresponding to a single pulse and counts the number of matches with this template . however , during motion the signal may look nothing like the template and as a consequence , no pulse counting occurs . the pulse rate calculator employed by the present invention estimates the frequencies and amplitudes of sinusoids in noise . nehorai developed a procedure to find the frequencies and then the amplitudes and phases of a given number of arbitrary sinusoids in noise ; nehorai , a ., a minimal parameter adaptive notch filter with constrained poles and zeros , volume 33 of the ieee transactions on acoustics , speech , and signal processing ( 1985 ), the disclosure of which is incorporated herein by reference . nehorai and porat extended this approach to specifically look for the fundamental frequency and then the amplitudes and phases of a harmonic signal in noise ; nehorai , a . and porat , b ., adaptive comb filtering for harmonic signal enhancement , volume 34 of the jeff transactions on acoustics , speech , and signal processing ( 1986 ), the disclosure of which is incorporated herein by reference . hendry recognized a numerically more efficient procedure in finding the fundamental frequency based on nehorai and porat &# 39 ; s approach ; hendry , s . d ., computation of harmonic comb filter weights , volume 41 of the ieee transactions on acoustics , speech , and signal processing ( 1993 ), the disclosure of which is incorporated herein by reference . the technique employed by the present invention is referred to herein as adaptive comb filtering ( acf ). the pulse rate is calculated from the optical absorbance signal . when viewed as a spectrogram ( frequency versus time ), the energy in a typical human pleth signal is distributed in a few stable , clearly defined bands corresponding to the harmonics of the pulse rate . the acf first finds the fundamental frequency by defining a comb filter to notch out the energy of the signal , leaving only noise . the number of notches or signal harmonics in the signal is a matter of choice . for normal heart rates , four harmonics are preferred according to one embodiment , but other numbers may be preferred depending on the application , processor , computation power , and the low pass cutoff frequency of the bandpass filter 14 . the acf finds the harmonic frequency that defines the comb filter to cause the output noise outside the fundamental and chosen harmonics to have the smallest energy . the acf searches for the fundamental by working out the first and second derivatives of the squared noise with respect to the fundamental to perform a newton - raphson search ( described below ), which is the classic approach to nonlinear minimization . to formalize the minimization description , let y be the measured signal , x the harmonic signal , and n the noise the parameter ω 0 is the fundamental frequency normalized by the sample rate . each quadratic in the numerator of h introduces a zero on the unit circle at ± kω 0 . with ρ & lt ; 1 , the denominator introduces a pole inside the unit circle at ± kω 0 . the bandwidth of the notches is π ( 1 − ρ ). fig9 shows the frequency response of such a filter . the troughs correspond to a pulse rate of 150 beats per minute ( bpm ). a brief summary of the derivation of the acf follows . the error signal is the energy between the notches in the comb ε ( t )= h ( z − 1 ) y ( t ). if the fundamental frequency is constant , and the error signal is measured for many time samples , a squared error may be defined now the problem is to find the fundamental frequency that minimizes v . this is a nonlinear problem , thus requiring a newton - raphson search . first differentiate the squared error with respect to the fundamental frequency nehorai and porat show how to evaluate this first derivative . this term is set equal to zero to solve for the fundamental frequency , except that a nonlinear relationship still exists . therefore , a taylor series expansion must be taken about the current estimate of the fundamental frequency up to the linear terms in the newton raphson method , the second derivative of the error is typically set to zero because it is often small and complicated to calculate . then solve for the update to the estimated fundamental frequency in practice it is desirable to estimate the fundamental frequency as the data comes in , and allow the frequency to change slowly in time . this approach of using the instantaneous values of the error and its derivatives is called the least mean square ( lms ) approach . in the lms approach , the instantaneous values must be smoothed , otherwise using the update results in erratic behavior in the fundamental frequency update . nehorai and porat proposed using where γ ( t ) is a time varying constant that is always less than one , keeping the update small , and r ( t ) is a low - pass filtered version of ψ 2 ( t ). the derivative of the measurement error is then evaluated with respect to the fundamental frequency . first , it must be noted that the numerator in h can be rewritten as the steps of the acf algorithm according to the present invention follow . first , the a i &# 39 ; s in the vector a are defined . it turns out that given with a 0 = b 0 = 1 . a distinction may also be made between the current error given the last estimate of the fundamental frequency , called the prediction error ε ( t ), and the current error given the current estimate of the fundamental frequency , called the a posteriori prediction error ε ( t ). the difference is subtle , but nehorai found the convergence rate improved with this distinction . the acf algorithm begins with initializing all errors to zero and initializing the filter coefficients with the best guess of the fundamental frequency . in one embodiment , a fixed value of ρ = 0 . 98 is used and the following acf algorithm is iterated the input measurement in this preferred implementation is the derivative of the normalized ir data ( e . g ., from box 18 of fig1 a ). using the derivative emphasizes the higher frequencies so that the noise energy is more evenly distributed , or “ whitened ”, which improves the tracking performance of the adaptive comb filter . 4 . using the notation ∇ i = δa i / δω 0 , update the derivatives of a with the following recursive formula 9 . update the constants used to keep the lms approach stable . in one embodiment , λ 0 = 0 . 98 . 11 . estimate the harmonic signal as the difference between the measured signal and the prediction error corrected for non - unity bandpass gain . when a reliable estimate of the fundamental frequency has been determined , it is preferred to at least occasionally calculate the harmonic amplitudes . a description of a technique for calculating the harmonic amplitudes follows . as will be shown , it is useful to know the amplitudes of the harmonics . the power of each of the first n = 4 harmonics is estimated by taking an rms of the output of a comb filter having only one “ tooth ” tuned to the frequency of that harmonic . this allows the power of the harmonics to be estimated with a minimal number of computations . this process can be performed independently of the adaptive comb filter provided the heart rate estimate is made available to this process . for each harmonic k , the steps in the harmonic estimation are : a 1 =− 2 cos kω 0 , a 0 = a 2 = 1 2 . calculate the output of the “ single toothed ” comb filter at kω 0 3 . estimate the bandpass gain of the “ single toothed ” comb filter at kω k , as the gain at dc 4 . estimate the harmonic signal at kω 0 as the difference between the measured signal and the output of the “ single toothed ” comb filter . 5 . estimate the power ( pwr ) in the harmonic at kω 0 using a cascaded br filter as described above , an improvement is achieved in both the saturation calculation and cardiac gated averaging algorithms with the use of a kalman model to optimally filter updates . therefore , in a particular embodiment , the final pulse rate displayed is also the output of a kalman filter where the input is the change in rate from the above approaches . the kalman model is where n q is the physiologically possible change in rate , n r is the measurement noise , δω 0 is the update from the acf , and δω 0 ′ is the kalman estimate of the update . the standard deviation of n q was modeled to be 5 bpm . according to a preferred embodiment , implementation precision requirements are achieved as follows . given coefficients at 30 bpm , ω 0 is approximately 0 . 055 and the gain of the numerator is approximately 4 . 8e - 8 , with coefficients of a having magnitudes ranging from roughly 1 to 100 . thus a small error in the calculation of one of the coefficients of a can produce a huge error in the gain of the numerator of the filter . it has been observed that about 32 bits of floating point precision are required to calculate a so that the gain is reasonably preserved at 30 bpm . note , however , that if the ω 0 is doubled , the gain increases by 256 - fold , reducing the precision requirement by 8 bits . the precision requirements for the denominator of the comb filter are similar . the effect of not having enough precision is that the comb filter become unstable at these low rates . for one preferred embodiment using an analog - to - digital sampling frequency of approximately 5 mhz , it is preferred to subsample the input by a factor of 2 , which effectively doubles w 0 . using ρ = 0 . 96 with subsampling by a factor of 2 produces a comb filter of equivalent performance to that described above with ρ = 0 . 98 and no subsampling . furthermore , the gain itself can be calculated with greater precision in floating point because it is calculated as a series of multiplications rather than additions . the actual gain of the numerator , or denominator , can also be calculated by adding the coefficients of a . it is preferred to compare the actual and expected gains and adjust the middle coefficient of a by the difference . these two optimizations permit the adaptive comb filter to track rates down to 30 bpm using single precision floating point arithmetic without becoming unstable . there are times when the acf by itself is not sufficient to track a patient &# 39 ; s heart rate this is the case with arrhythmias , where the energy is not concentrated in a few trackable harmonics . also , a patient &# 39 ; s heart rate can change more rapidly than the acf is capable of tracking , or change dramatically during a period of motion in which the acf failed to correctly track the change . an alternative pleth rate calculator is therefore included in the present invention that does not require a harmonic signal , and is not based on an adaptive algorithm . this alternative rate calculator is not as robust during motion as the rate calculator described above , but is intended to be used when the acf cannot track the rate . a feature that is common to all human pulses is that they go up and down and have some minimum period corresponding to about 250 bpm , i . e ., 240 msec . given this model of a human pulse , there is a crest during each pulse such that the current value of the pulse waveform is the maximum value that has been seen for the past 240 msec followed by a trough during that same pulse where the current value is the minimum value that has been seen for the past 240 msec . the pattern matcher of the present invention identifies sequences of crests and troughs that preferably do not trigger any motion detection criterion ( discussed below ), and computes the rate from the average period of all such patterns which have been identified in the past 512 signal samples . according to a preferred embodiment , the optical signal is nominally sampled 57 times each second , 512 samples therefore corresponding to roughly 9 seconds . in one embodiment , the pattern matcher uses a minimum period of 210 msec instead of 240 msec to make allowances for limited motion artifact and an oximeter sampling rate in excess of 57 hz . the pattern matching rate is updated each time such a pattern is identified . in some preferred embodiments , motion detection criterion based on the shape of the pulse have been adapted to reject pulses which are potentially contaminated by motion artifact . according to a preferred embodiment , the motion detection - criterion require the calculation of the maxima , minima , and average for the current and previous detected patterns . motion is detected when any of the following criterion are met : a ) the maximum of the current pattern is significantly farther away from the average of the current pattern than the minimum is ( e . g ., the ratio of differences is greater than 1 . 02 ); b ) criterion a ) failed on the last detected pattern ; c ) the maximum of the current pattern is significantly farther away from the average of the current pattern than the average of the current pattern is from the average of the current and previous minima ; or d ) the difference between the average of the current and previous patterns is greater than half the difference between the current maximum and minimum ( big dc shift ). a motion flag is set whenever any of the motion detection criterion are met and is cleared whenever none are met for two consecutive patterns . in a preferred embodiment , two pattern matching rate calculators are run in parallel . one receives the bandpassed normalized waveform as input . the second receives a filtered form of the first derivative of the pleth . the use of two inputs with different characteristics minimizes the time that motion is incorrectly reported . each pattern matcher stores the proportion of patterns for which its motion metrics indicate motion . the pattern matcher that reports the least motion over the last ten seconds is used for the pattern matching rate . this dual pattern matcher reports that motion is present only when the motion metrics for each of its two pattern matchers indicates motion . as discussed above , the adaptive comb filter ( acf ) employed by the present invention tracks a signal having n harmonics . it sometimes happens that motion artifact causes the acf to track the wrong rate , and when the motion stops , the “ teeth ” on the comb may be on a harmonic rather than the fundamental . for example , the fundamental of the acf could be tracking the second harmonic of the pleth , or the 2nd harmonic for the acf could be tracking the fundamental of the pleth . these situations would cause the acf to report twice or half the correct pulse rate , respectively . this could happen if the acf was initialized to the wrong rate and settled on a harmonic or subharmonic , or if the rate changed more suddenly than the acf could track . in general , the acf is quite stable , and several minutes of prolonged , vigorous motion may be required before it locks onto a harmonic or subharmonic of the pulse rate . however , because of the potential for false reporting , according to a preferred embodiment a number of rules are used to calculate a more accurate rate . a simple model of most plethysmographs , i . e ., pleths , may be compared to a sawtooth - like pattern for which the amplitude of the harmonics of the pleth fall off by a factor of 2 for each harmonic . thus , for most pleths , the falloff is fairly rapid . however , some patients have nearly half the energy of their pulses contained in the second harmonic . other physiological pleth patterns may contain significant amounts of energy at multiples of one - half the pulse rate , while still others may have strong respiratory components at one - half the pulse rate , although the signal at the pulse rate should still be dominant arrhythmias may have no repeating pattern , thus violating the model assumed by the acf . when the acf locks onto a subharmonic , or some superharmonic , the “ tooth ” on the comb that passes the greatest amount of energy will not correspond to the fundamental frequency estimated by the acf . table 1 shows relative harmonic amplitudes for a typical pleth . for most patients , where there is little or no motion , all the energy in the pleth is at the fundamental or a harmonic of the pulse rate . although pulse rates will vary cyclically in response to various mechanisms , plateaus in the pulse rate will be long enough , and frequent enough , that the autocorrelation has a very high value at the fundamental of the pulse rate at these times . where there is significant energy at a subharmonic of the pulse rate , the autocorrelation at the subharmonic may be higher than at the pulse rate , but the autocorrelation function will still have a strong local maxima at the pulse rate . for an arrhythmia with a non - repeating pattern , the autocorrelation may not have any strong local maxima . however , if a patient is not moving , the pleth will be modulated only by the patient &# 39 ; s pulse , and will thus be completely correlated in the ir and red channels . motion artifact , however , causes the ir and red channels to become less correlated . this crosscorrelation can thus be used as a rough indicator of the degree of motion and therefore the reliability of the rate reported by the pattern matching . in view of the foregoing , a concise set of rules is desirable that reliably enables the acf to resume tracking the correct pulse rate when motion has stopped , and which does not increase the chance that acf will track the wrong pulse rate . an “ uncorrelation ” metric is calculated which is defined as : where the crosscorrelation is currently calculated over 512 points of the normalized data . the magnitude of each of the n = 4 harmonics is estimated each second , and the magnitude information is used to calculate a measure of the validity of the pulse . in addition to estimating the pulse rate , the acf also calculates filtered signal and noise waveforms , x and ε using the comb filter , which enables the calculation of a signal to noise ( s / n ) ratio . the s / n ratio is expected to be high for non - arrhythmic patients who are not moving , and low during motion or arrhythmias . it is also low if the fundamental of the heart rate does not match any of the harmonics being tracked by the acf . in various embodiments , the s / n may be calculated using both whitened and unwhitened pleths with the best s / n ratio being used . 1 ) calculate the magnitude of each of the harmonics of the pleth . correct the magnitudes for any bandpass filtering that occurred earlier in the processing chain . normalize the harmonics so that they add up to one , and iir filter with a time constant of 0 . 1 / second . 2 ) take the logarithm of the filtered energy estimate for each harmonic . for each harmonic excluding the fundamental , take the difference between the logarithm for that harmonic and the logarithm for the previous harmonic . bound the difference by ± 1 . 5 . calculate the average of all of these n − 1 differences to estimate the exponential decay rate for the harmonics of the pleth , and iir filter this average with a time constant of 0 . 3 / second . 3 ) while calculating the unfiltered exponential decay rate , also calculate the standard deviation between the exponential decays of the pairs of harmonics and the previous filtered exponential decay rate . iir filter this standard deviation with the same time constant used for the filtered exponential decay ( 0 . 3 / second ). 4 ) subtract the filtered standard deviation from the filtered exponential decay to get the validity measure . the best pleth , according to this validity measure , will have the energy in consecutive harmonics falling off exponentially with a decay rate of at least e 1 . 5 ( about 4 . 5 - fold ). if a majority of the energy in the pleth is calculated to be in one of the harmonics instead of the fundamental , the standard deviation for the exponential decay will probably be large enough to drive the validity measure negative . the validity measurement preferably should have a response time of about 12 - 13 seconds . fig1 shows the validity measure 134 and relative strength of the four harmonics ( 130 - 133 ) of the pleth signal . when the strength of the higher harmonics , e . g ., waveform 130 , goes above lower harmonics , e . g ., waveform 132 , the validity index 134 goes appropriately down . the following mechanisms may be used to assure that the acf is tracking the right rate . every 10 seconds a fast fourier transform ( fft ) ( power spectrum ) may be performed on the ir pleth and each peak in the spectrum may be evaluated prospectively to find the rate which would give the highest confidence measure for the acf ( the formulas used to combine various metrics into a confidence measure for the acf rate are described in a subsequent section of this application ). this is possible because the magnitude of each of the harmonics that would be tracked by the acf at a given rate can be estimated by adding up the energy in several adjacent frequencies of the fft . according to one preferred embodiment , one can use a 512 point fft and model a harmonic as 3 adjacent frequencies . the acf rate is reset to this rate if the following conditions are met : a ) the current acf confidence measure is less than 50 or the acf has not been initialized by this mechanism yet . b ) the prospectively estimated confidence measure for the new rate is at least 50 . c ) the prospectively estimated s / n for the new rate is at least 0 . 7 . d ) the new rate is within 10 bpm of a local maxima on the autocorrelation curve , and that local maxima is positive . e ) the best rate estimated by this method is within 15 % of the best rate estimated by this method 10 seconds ago . note that no acf rate is ever reported until it has been initialized by this mechanism fig1 shows a comparison between the pulse rate 240 calculated by the acf with the additional rules disclosed above as compared to the pulse rate 242 reported by a prior art system . during a period of motion ( 244 ), an inaccurately high pulse rate is reported by the nellcor n200 oximeter . the acf designed according to the present invention which applied these exception handling rules tracked the rate accurately through the motion . in this section , preferred methods of processing and displaying the arterial oxygen saturation and pulse rate for use on a hospital floor are described . given available metrics from the above - described algorithms , confidence levels for the saturation and the heart rate are estimated , thus determining which saturation and which heart rate of the multiple heart rates and multiple saturations ( calculated in the systems of fig1 a and 1 b ) should be considered more reliable , and how long the saturation or heart rate previously selected should be held when a current estimate is not considered sufficiently reliable . the present invention calculates the following values : the acf heart rate , from the adaptive comb filter ; the pattern matching heart rate ; saturation using a kalman filter without cardiac gated averaging ; and saturation using a kalman filter in combination with a kalman - filter - based cardiac gated averaging technique . several metrics are also calculated and can be used to predict the confidence of the saturations and heart rates . these include for the acf heart rate : validity : a heuristic metric based on the strength of harmonics in the pulse , i . e ., the shape of the pulse ; s / n : signal - to - noise ratio ; arrhythmia probability : a function of s / n vs . uncorrelation averaged over 20 - 100 seconds ; and uncorrelation of ir and red : √ 1 − crosscorrelation ( ir , red ) 2 motion flag : set when motion is detected ; and motion percent : percentage of motion corrupted patterns detected in the last ten seconds age : effective averaging period is double this ; and variance : standard deviation of saturation estimate in saturation points for saturation using a kalman filter in combination with kalman - filter - based cardiac gated averaging ( cga ): age : effective averaging period is double this ; and variance : standard deviation of saturation estimate in saturation points several metrics are calculated independent of saturation or heart rate . these include : % ir modulation contact status : from contact electrodes of sensor ( used in a preferred fetal sensor as described in commonly assigned u . s . pat . no . 5 , 247 , 932 , the entire disclosure of which is incorporated herein by reference ); light level ir spectrum : 128 sample points ; and uncorrelation of ir , red : 128 sample points for faster response at 100 % saturation the confidence intervals for the saturation values calculated using only a kalman filter are : when the 50 , 80 , and 95 % confidence lines are plotted in age - variance space , the lines come very close to having a common origin , so that the confidence level can be estimated continuously as a function of the slope of a line from that origin . the 95 - 100 % confidence interval covers a disproportionately large area in the age - variance space , so the confidence interval should be adjusted if it is over 95 %. for lower saturations , the variance is reduced as a function of the saturation by up to 60 % at a saturation of 50 . this reflects the fact that fixed variance in ratio - of - ratios will have an increasing effect on the saturation estimate as the saturation declines . the confidence intervals for saturation values calculated with the kalman - filter - based cardiac gated averaging are the same as above except that age is rust divided by 2 , because the cardiac gated averaging can result in an older but more accurate saturation value . the confidence interval for the acf heart rate is a function of the validity metric and the arrhythmia probability metric . this space divides into several regions in which one or both metrics are the determining factor in how likely the adaptive comb filter is to be tracking the correct rate . for the pattern matching heart rate , the confidence interval is set to 100 % less the motion percent metric . according to a preferred embodiment , if one saturation has a confidence interval at least 10 % higher than the other , it is the best saturation . if the two saturations have confidence intervals within 10 % of each other , the best saturation will be calculated as a linear interpolation between the two saturations , with their variances and ages also being linearly interpolated for recalculation of the confidence interval of the best saturation . if the interpolated saturation has an age greater than 35 seconds , but either the non - cga saturation or the cga saturation has an age less than 35 seconds , the saturations will be re - interpolated so that the interpolated saturation has an age of 35 seconds . the interpolated saturation is then smoothed out with an adaptive filter that looks at the rate of saturation change and results in a slight increment to the age of the interpolated ( best ) saturation . similar criteria are used for interpolation of the heart rates , except that no check needs to be made of the age of the heart rates , as they are generally quite recent , i . e ., less than 10 seconds old . the age and valiance metrics for the saturation algorithms are calculated according to one embodiment of the invention in the following manner . a general algorithm for calculating the age of the output of an iir filter having the form where the age of filtered and raw are known , and filtered ( n ) is the value at sample number n , is described by the following steps : 1 ) increment the age of filtered by the amount of time elapsed since it was last calculated ; and 2 ) age of filtered ( n + 1 )=( 1 +* age of filtered ( n )+ w * age of raw according to the present invention the term w is calculated as follows . in all instances , k represents the gain of the kalman filter . in all instances , w is equal to the amount by which filtered is incremented divided by the difference between filtered and raw . that is , with respect to the saturation algorithms of the present invention , where u and v are transforms of the raw ir and red values such that the instantaneous rawsat = v / u . therefore , filteredsat ( n + 1 )=( 1 − k )* u * filteredsat ( n )+ k * u * rawsat if kalman filtering of the derivative of saturation ( d ( sat )/ dt ) is included in the embodiment , the calculation of saturation age is accomplished according to the following chain of events . initially , the value age is the delay of the bandpass filter , if one is included in the embodiment . age is then passed to the kalman cga ( if included in the embodiment ), which stores the age of each filtered point on the pulse , updates the age of the appropriate point , and sets age to that of the ir and red values output . age is then passed to the normalization routine ( if included in the embodiment ), which buffers and sets age to the value from half a window ago , plus half the window length . age is then passed to the saturation algorithm ( assume kalman saturation algorithm ), which sets age to the age of the saturation estimate . finally , age is passed to the kalman dsat / dt calculator ( if included in the embodiment this provides some incremental smoothing of saturation as well as calculates dsat / dt ), which sets age to the age of the final sat estimate . the calculation of the variance metric for the saturation algorithms is as follows . when the saturation is not changing , the following is true : when saturation is changing , the difference between estimated and actual saturation is : the kalman saturation calculation includes a residual term , r , which is equal to the mean square over some window of : and also includes the term usizebar which is equal to the mean square of u over that window . therefore , since the kalman saturation algorithm is an hr filter , the inputs that contribute to its current saturation estimate cover a longer period of time than that which is covered by the finite window used to calculate r and usizebar . the variance for all of these inputs that are contributing to the saturation estimate is calculated in the same manner as the age of the saturation estimate , that is , according to a preferred embodiment , independent of the confidence metrics for saturation and heart rate , several properties of the incoming oximetry signal are evaluated in order to determine if the signal is actually due to a human pulse and what action the display should take . the possible states include : disconnect : when the sensor is unplugged ; no contact : when the sensor is a fetal sensor and the contact electrodes do not indicate contact with the patient ; pulse lost when the pulse disappears and the sensor is still on the patient ; non - pulse when the oximetry signal comes from a signal other than a human pulse because the sensor has fallen off or is seeing an enormous amount of interference ; pulse present when the oximetry signal comes from a human pulse ; and not sure a waiting period before declaring a disconnect or non - pulse state . the possible actions in response to the occurrence of these various states are to update the display , hold the current values , or clear the display , e . g ., blanks , dashes , zeroes , etc . some additional values are calculated for use in evaluating the states and the possible actions . the maximum and minimum light levels over the past 15 seconds are calculated ( ½ second sampling ) by comparing amplitudes of the signal sample points after they are bandpass filtered by filter 14 , but prior to being normalized . in addition , a value called allen &# 39 ; s threshold is calculated which is a percentage modulation threshold indicative of a sudden loss of pulse . this value is set to zero when the ratio of the maximum and minimum light levels over the past 5 seconds is greater than 1 . 5 . otherwise it is set to ⅙ of the ir percent modulation if that value is greater than the current allen &# 39 ; s threshold . otherwise , allen &# 39 ; s threshold decays with a 5 second response time if the current percent ir modulation is non - zero and is either less than the allen &# 39 ; s threshold or has been less than the allen &# 39 ; s threshold for over 5 seconds . the criteria for the various states are evaluated in the following order : disconnect : the ir light level is zero for two seconds . if the light level has been zero for less than two seconds the not sure state is declared . no contact : the contact electrodes of a sensor indicated that there is no contact with the patient . pulse lost : the % ir modulation is below the allen &# 39 ; s threshold for over 5 seconds , or the criteria for non - pulse are met and the previous state bad been pulse lost . non - pulse : the sum of 125 * uncorrelation ( 128 sample points ) and the percentage of energy about 5 hz in the 128 sample point spectrum is greater than 100 or the percent ir modulation is below 0 . 05 . this criterion has been true for ten seconds continuously . if this criterion has been true for less than ten seconds , the not sure state is declared . pulse present : the state is not one of the above states . the criteria for the various display actions are update when the state is pulse present , hold when the state is not sure or no contact , and clear when the state is disconnect , pulse lost , or non - pulse . the best saturation is displayed when 1 ) the signal state action is update , and 2 ) the best saturation is less than 40 seconds old . saturation is held when 1 ) the conditions for displaying the best saturation are not met , 2 ) the displayed saturation is less than 40 seconds old , and 3 ) the signal state action is not clear . saturation is blanked when 1 ) the conditions for displaying the best saturation are not met , and 2 ) the conditions for holding the saturation are not met . the best heart rate is displayed when 1 ) the best calculated heart rate has a confidence interval & gt ; 50 %, and 2 ) the signal state action is update . the heart rate is held when 1 ) the conditions for displaying the current heart rate are not met , 2 ) the displayed heart rate is less than 40 seconds old , and 3 ) the signal state action is not clear . the heart rate is blanked when 1 ) the conditions for displaying the current heart rate are not met , and 2 ) the conditions for holding the heart rate are not met . while the invention has been particularly shown and described with reference to specific embodiments thereof , it will be understood by those skilled in the art that the foregoing and other changes in the form and details may be made therein without departing from the spirit or scope of the invention . it will be understood that different embodiments of the present invention may employ different combinations of the above - described techniques . for example , in one embodiment , the kalman cardiac gated averaging technique may be used to shape the oximetry data pulses for processing by either a cls saturation calculation technique , the kalman saturation calculation technique , or an alternate technique . either embodiment could use an ecg pulse rate , or a pulse rate generated by the acf as the cardiac gated averaging trigger . other embodiments may employ the kalman saturation calculation technique without the kalman cardiac gated averaging technique . moreover , the technology disclosed in this patent is applicable to many noninvasive medical monitoring technologies . for example , in respiratory gas monitoring like capnography the measured signal is many times driven by regular breathing . in blood pressure monitoring , the sounds in auscultatory measurements , or the pressure variations in oscillometric measurements , are both driven by the beating heart as is the plethysmogram in pulse oximetry . the scope of the invention should therefore be determined not by the specification , but by the following claims . | US-95326210-A |
the present invention provides a contrast agent which ensures 1 ) high contrast performance , 2 ) low toxicity , and 3 ) a simple production process . the present invention provides a contrast agent containing a silsesquioxane represented by general formula , wherein r 1 , the same or different , is a substituent bonded to si through a carbon atom , the substituent having , at its terminal , a group represented by general formula , wherein p represents an integer of from 1 to 5 ; q is the same or different , and represents an integer of from 1 to 5 ; r 2 is the same or different , and represents hydrogen atom , alkyl group , aralkyl group or acyl group , or a group represented by general formula , wherein p , q and r 2 are the same as above . | the present invention is more specifically explained with reference to examples and comparative examples . however , the present invention is not limited to these examples . 800 ml of methanol and 135 ml of a concentrated hydrochloric acid were mixed in a 1 l recovery flask , and 100 ml ( 0 . 427 mol ) of 3 - aminopropyltriethoxysilane was added thereto . the mixture was stirred at room temperature ( 25 ° c .) for 48 hours until a white precipitate was produced . after filtering the precipitate , the obtained residue was washed with methanol to give an amino compound salt ( 18 . 8 g , yield = 30 %) represented by general formula ( iva ) wherein each r 3a represents —( ch 2 ) 3 — nh 3 cl . thereafter , 1 g ( 0 . 852 mmol ) of the obtained amino compound salt , 15 ml ( 0 . 102 mol , 120 equivalents with respect to the amino compound salt ) of dipea , 15 ml ( 0 . 102 mol , 120 equivalents with respect to the amino compound salt ) of tert - butyl bromoacetate and 100 ml of dmf were placed in a 500 ml recovery flask , and the mixture was reacted at 60 ° c . for 16 hours in a nitrogen atmosphere . the resulting reaction liquid was dried under vacuum to give a yellow solid . 100 ml ( 2 . 65 mol ) of a formic acid was placed in the recovery flask containing the yellow solid obtained in step ( 1 ). the flask was heated under reflux for 24 hours to give a reaction liquid ( deprotection step ). after removing the formic acid from the obtained reaction liquid using an evaporator , 200 ml of methanol was added to cause precipitation . after filtering the precipitate , the obtained residue was washed with methanol to give silsesquioxane a ( 240 mg , yield = 16 %) represented by general formula ( ia2 ) wherein each r 1a2 represents the following chemical formula . the 1 h nmr spectrum of the obtained silsesquioxane a is as follows . 1 h nmr ( d 2 o , 400 mhz ) δ 3 . 92 ( s , 32h ), 3 . 33 ( brs , 16h ), 1 . 83 ( brs , 16h ), 0 . 80 ( brs , 16h ): 13 c nmr ( d 2 o , 100 mhz ) δ161 . 3 , 50 . 4 , 48 . 2 , 26 . 4 , 9 . 9 : 29 si nmr ( d 2 o , 80 mhz ) δ − 67 . 2 : maldi - tof [( m + h ) + ] calcd . 1811 . 08 , found 1812 . 01 . 1 g ( 0 . 853 mmol ) of the amino compound salt obtained in example 1 , 15 ml of dipea ( 86 . 1 mmol , 100 equivalents with respect to the amino compound salt ), 9 . 5 ml ( 86 . 1 mmol , 100 equivalents with respect to the amino compound salt ) of ethylbromoacetate and 50 ml of dmf were placed in a 500 ml recovery flask . the mixture was reacted at 60 ° c . for 16 hours in a nitrogen atmosphere to give a reaction liquid . after removing dmf from the reaction liquid using an evaporator , 200 ml of ethyl acetate was added to give a mixed solution . the mixed solution was washed three times with 200 ml of water , and then washed once with 200 ml of a saturated sodium chloride aqueous solution . the organic layer obtained by the washing was concentrated to give a silsesquioxane ( ib1 ) ( 1 . 07 g , 0 . 529 mmol , yield = 62 %) represented by general formula ( ib1 ) wherein p represents 3 , q represents 1 , and r 4b represents — ch 2 ch 3 . thereafter , 200 ml ( 2 . 24 mol ) of ethylenediamine was added , and the silsesquioxane ( ib1 ) and the ethylenediamine were reacted at 60 ° c . for 16 hours in a nitrogen atmosphere to give a reaction liquid . the reaction liquid was dried using a vacuum pump to give an amide compound ( 1 . 3 g , 0 . 523 mmol , yield = 99 %) represented by above general formula ( ivb ) wherein p represents 3 , q represents 1 , and r represents 2 . 1 g ( 0 . 403 mmol ) of the amide compound obtained in step ( 2 ), 15 ml of dipea ( 0 . 102 mol , 250 equivalents with respect to the amide compound ), 15 ml ( 0 . 102 mol , 250 equivalents with respect to the amide compound ) of tert - butyl bromoacetate and 100 ml of dmf were placed in a 500 ml recovery flask . the mixture was reacted at 60 ° c . for 16 hours under a nitrogen atmosphere to give a reaction liquid . the reaction liquid was dried under vacuum to give a silsesquioxane ( ib1 ′) represented by above general formula ( ib1 ′) wherein p represents 3 , q represents 1 , r represents 2 , and r 4b2 represents tert - butyl group . 100 ml ( 2 . 65 mol ) of a formic acid was placed in the recovery flask containing a yellow solid obtained in step ( 3 ). the flask was heated under reflux for 24 hours to give a reaction liquid ( deprotection step ). after removing the formic acid from the obtained reaction liquid using an evaporator , 200 ml of methanol was added to cause precipitation . after filtering the precipitate , the obtained residue was washed with methanol to give silsesquioxane b ( 1 . 05 mg , yield = 60 %) represented by general formula ( ib2 ) wherein p represents 3 , q represents 1 , and r represents 2 . 1 h nmr ( d 2 o , 400 mhz ) δ 3 . 72 ( br , 96h ), 3 . 56 ( brs , 32h ), 3 . 30 ( brs , 32h ), 3 . 20 ( brs , 16h ), 1 . 71 ( brs , 16h ), 0 . 67 ( brs , 16h ): 13 c nmr ( d 2 o , 100 mhz ) δ175 . 1 , 172 . 1 , 61 . 7 , 61 . 2 , 59 . 2 , 51 . 5 , 37 . 5 , 20 . 8 , 10 . 2 : 29 si nmr ( d 2 o , 80 mhz ) δ − 67 . 4 : esi - tof [( m + 3h ) 3 + ] calcd . 1454 . 8 , found 1454 . 8 . 1 . 0 g ( 0 . 403 mmol ) of the amide compound obtained in step ( 2 ) of example 2 , 15 ml of dipea ( 86 . 1 mmol , 215 equivalents with respect to the amide compound ), 9 . 5 ml ( 86 . 1 mmol , 215 equivalents with respect to the amide compound ) of ethylbromoacetate and 50 ml of dmf were placed in a 500 ml recovery flask . the mixture was reacted at 60 ° c . for 16 hours in a nitrogen atmosphere to give a reaction liquid . after concentrating the obtained reaction liquid , 200 ml of ethyl acetate was added thereto to give a mixed solution . the mixed solution was washed three times with 200 ml of water , and then washed once with 200 ml of a saturated sodium chloride aqueous solution . the organic layer obtained by the washing was concentrated to give silsesquioxane ( ib1 ′) ( yellow solid , 548 mg , 0 . 104 mmol , yield - 26 %) represented by above general formula ( ib1 ′) wherein p represents 3 , q represents 1 , r represents 2 and r 4b2 represents ethyl group . then , 200 ml ( 2 . 24 mol ) of ethylenediamine was added , and the silsesquioxane ( ib1 ′) and the ethylenediamine were reacted at 60 ° c . for 16 hours under a nitrogen atmosphere to give a reaction liquid . the reaction liquid was dried under vacuum to give an amide compound ( 589 mg , 0 . 103 mmol , yield = 99 %) represented by above general formula ( ivc ) wherein p represents 3 , q represents 1 , and r represents 2 . 15 ml of dipea ( 0 . 102 mol , 1 , 000 equivalents with respect to the amide compound ), 15 ml ( 0 . 102 mol , 1 , 000 equivalents with respect to the amide compound ) of tert - butyl bromoacetate and 100 ml of dmf were placed in a recovery flask containing the amide compound obtained in step ( 1 ). the mixture was reacted at 60 ° c . for 16 hours in a nitrogen atmosphere to give a reaction liquid . the reaction liquid was dried under vacuum to give silsesquioxane ( ic1 ) ( yellow solid ) represented by above general formula ( ic1 ) wherein p represents 3 , q represents 1 , r represents 2 , and r 4c represents tert - butyl group . 100 ml ( 2 . 65 mol ) of a formic acid was placed in the recovery flask containing the yellow solid obtained in step ( 2 ). the flask was heated under reflux for 24 hours to give a reaction liquid ( deprotection step ). after removing the formic acid from the obtained reaction liquid using an evaporator , 200 ml of methanol was added to cause precipitation . after filtering the precipitate , the obtained residue was washed with methanol to give silsesquioxane c ( 169 mg , yield = 16 %) represented by general formula ( ic2 ), wherein p represents 3 , q represents 1 , and r represents 2 . 1 h nmr ( d 2 o , 400 mhz ) δ 3 . 96 ( s , 224h ), 3 . 82 ( brs , 96h ), 3 . 35 ( brs , 96h ), 3 . 23 ( brs , 16h ), 1 . 72 ( brs , 16h ), 0 . 65 ( brs , 16h ): 13 c nmr ( d 2 o , 100 mhz ) δ165 . 5 , 164 . 1 , 164 . 0 , 51 . 9 , 51 . 2 , 50 . 9 , 48 . 7 , 46 . 6 , 45 . 7 , 42 . 7 , 36 . 9 , 28 . 9 , 10 . 7 : 29 si nmr ( d 2 o , 80 mhz ) δ − 67 . 3 : esi - tof [( m + 7h ) 7 + ] calcd . 1342 . 1 , found 1342 . 2 . under a temperature of 298k , changes in heat quantity during titration of 1 mm of gd 3 + into the silsesquioxane a aqueous solution ( concentration : 100 μm ) obtained in example 1 were measured using an isothermal titration calorimetry ( itc ). through the curve fitting with the obtained spectra , the coordination number of gd 3 + and the binding constant of the bond of gd 3 + and silsesquioxane a were calculated . further , the coordination number and the binding constant during titration using mn 2 + , cu 2 + , zn 2 + and ca 2 + instead of gd 3 + were also measured in the same manner . table 1 shows that the silsesquioxane a obtained in example 1 is firmly bonded with gd 3 + , and that this bond is 1 , 000 to 10 , 000 times stronger than that of ca 2 + , which antagonizes gd 3 + in a living body . accordingly , table 1 shows that , when using the contrast agent of the present invention , gd 3 + does not easily dissociate in a living body , which indicates a high possibility that the contrast agent of the present invention has low toxicity . mtt ( 3 -[ 4 , 5 - dimethylthiazol - 2 - yl ]- 2 , 5 - diphenyl tetrazolium bromide ) assay was performed using healthy liver cells of a mouse . the cell culture was performed in a dme culture medium of 37 ° c . in the presence of 5 % carbon dioxide . more specifically , the cells were prepared by a collagenase perfusion method ( seglen p . o ., methods in cell biology 1976 , 13 , 29 - 83 ), and the prepared cells were seeded at a 15 , 000 cells / 100 μl / well in 96 well microtiter plates . one day after the cell incubation , 10 μl of “ an aqueous solution of a gd complex with which a silsesquioxane a is coordinated ” or “ an aqueous solution of gd complex with which dota ( wako pure chemical ind . ltd .) is coordinated ” was added to each well , and the culture was continued . these aqueous solutions were prepared by mixing a chelator ( silsesquioxane a or dota ) and gadolinium chloride in water . their concentrations are adjusted to be ten times greater than the evaluation concentration ( concentration of a horizontal axis in fig3 ) of the gd complex . after three more days , 10 μl of mtt ( mtt concentration : 5 mg / ml ) dissolved in a phosphate buffered saline ( pbs ) was added to each well , and a four - hour incubation was performed . after removing and washing the supernatant ( the culture medium in which the mtt is dissolved ), 100 μl each of 10 % sodium dodecyl sulfate ( sds ) and 0 . 01 m of ammonium chloride solution was added . after overnight incubation , the cell survival rate was evaluated from the mtt decomposition amount . the mtt decomposition amount was calculated from absorbency at 600 nm of the solution ( 37 ° c .) obtained from the overnight incubation . fig3 shows the results . in fig3 , ▴ represents an average cell survival rate (%) when adding a complex of silsesquioxane a and gd , ▪ represents an average cell survival rate (%) when adding a complex of dota and gd , and the vertical bar represents the standard deviation of each cell survival rate . fig3 shows that the complex of silsesquioxane a and gd of the present invention containing two gd atoms has a high cell survival rate compared with a complex of gd and dota containing only one gd atom . the complex of the present invention has low toxicity . a contrast agent was prepared using silsesquioxanes a - c obtained in examples 1 to 3 , dota ( product of wako pure chemical ind . ltd . ), or dtpa ( product of aldrich ), as the ligand of a metal complex . more specifically , each ligand was dissolved in water , and a metal ion was added thereto to prepare an aqueous solution ( contrast agent ) containing a metal complex . table 2 shows , for each aqueous solution , the combination of the ligand and metal ion , the concentration ( μm ) of the ligand , and the addition amount ( μm ) of the metal ion . each aqueous solution shown in table 2 was sealed in a glass tube . a t1 weighted image of a proton was taken at 298k , 7t ( tesla ). the repetition time ( tr ) was 1 , 000 ms , and the echo time ( te ) was 12 ms . each glass tube containing one of the aqueous solutions shown in table 3 was held still in a coil , and an image of the glass tube was taken using a 7t unity inova mr scanner ( product of varian inc .) as a magnetic resonance imager ( mri ). for comparison , fig4 also shows a t1 weighted image of a glass tube that contains pure water instead of the aqueous solution . fig4 shows that , for example , in a comparison of two contrast media containing a metal complex having gd 3 + as a metal ion , the contrast agent having ligands of silsesquioxane a ( example 1 ) has a sensitivity ten times greater than the contrast agent having ligands of dota or dtpa . further , the contrast agent having ligands of silsesquioxane b ( example 2 ) and the contrast agent having ligands of silsesquioxane c ( example 3 ) have sensitivities 50 to 100 times greater than the contrast agent having ligands of dota or dtpa . accordingly , these contrast media of examples of the present invention have superior contrast properties . the t1 values measured upon the above image - taking using the aqueous solutions in test example 3 and the metal ion concentrations for each aqueous solution were applied to the following formula ( 1 ), thereby plotting a graph . a relaxation degree r 1 was calculated based on the inclination of the linear curve . the relaxation degree r 1 represents the proton relaxation performance per mol of the metal ion ( gd 3 + , mn 2 + ). the relaxation time t1 is an index showing the proton relaxation performance per mol of the contrast agent . the constant “ a ” represents an inverse of the t1 value of pure water . for comparison , an aqueous solution was prepared according to the same method as the example using dota in table 2 , except that pamam ( aldrich ) was used as a ligand . with this aqueous solution , the relaxation degree r 1 was calculated by the above method . the smaller the t1 value , the greater the contrast performance . therefore , in the following table 3 , the gd 3 + - silsesquioxane c complex has the greatest contrast performance . a greater r 1 value indicates a superior contrast performance in a t1 weighted image . in a comparison of the gd 3 + - silsesquioxane a complex and the gd 3 + - silsesquioxane c complex , the gd 3 + - silsesquioxane a complex has a greater r 1 value , and the gd 3 + - silsesquioxane c complex has a greater t1 value . this is because the number of gd + in the complex influences the contrast performance ( t1 value ). more specifically , the gd 3 + - silsesquioxane c complex having eight gd ( s ) 3 + coordinate bonds has a greater contrast performance than the gd 3 + - silsesquioxane a complex having two gd ( s ) 3 + coordinate bonds . table 3 shows that the contrast agents containing metal complexes having silsesquioxanes a - c as chelate ligands have significantly high contrast properties , compared with contrast media containing other metal complexes . fig2 is a view showing a state of silsesquioxane a coordinated to a metal ion . fig3 is a view showing the results of mtt assay according to experiment example 2 . fig4 is an mri image in relation to experiment example 3 . the horizontal axis denotes the ligand concentrations ( μm ) of the aqueous solutions , and the vertical axis denotes the metal complexes contained in the aqueous solutions . | US-73346408-A |
methods and apparatus for performing arthoplasty utilizes a plurality of apertures created in a bone , each aperture having a cross section defined perpendicular to an axis of the aperture that intersects a plane of a resected surface to be created in the bone and also intersects a peripheral rim border that externally delineates the resected surface . a pin feature is inserted into each of the plurality of apertures and the resected surface is created by guiding a cutting tool along at least a line of contact of the pin features . an implant can then be attached to the resected surface . | fig1 and 2 show a conventional oscillating saw blade system in action . the basic components are the oscillating saw , the cutting guide , and fixation features of the cutting guide , which in this case are 0 . 125 inch drill pins . the cutting guide possesses at least one slot to which the saw is engaged during cutting . a drawback about this technology is shown in fig2 as the saw blade is in an extended cantilever as it finishes the side of the cut furthest from the guide generating sometimes significant error requiring recutting or tweaking of the cut by eye as shown in fig2 . fig3 - 49 show various depictions of the placement of pin members in accordance with one embodiment of the present invention . fig3 is a view from medial to lateral showing the intended location of the cuts and some of the possible pin locations . in this particular form of this concept , the ‘ guide ’ is merely a series of independent pins positioned through , at , above , or below the cut surfaces to be created . for conventional tka , the basic surfaces to be created are the anterior cut , anterior chamfer cut , distal cut , posterior chamfer cut , and posterior cut as is made clear in fig3 , 17 , 32 , and 41 . fig4 shows the chamfer cuts being made by different cutting tools . in later figures , application of this concept to the tibia will be explored . although the embodiment of the pins shown is , well , pins , one versed in the art will recognize that the pin members could be drill bits , roughened shafts ( for purchase / fixation to the bone ), threaded pins ( where the threads may be used to facilitate fixation of the pins to bone or to ancillary guide surfaces ), or other cylindrical or non cylindrical cross - sectioned components having a generally longitudinal axis and at least one surface designed to serve as a tangential surface for purposes of defining the points and / or portions of the lines of contact that will defined a plane of a resected surface to be created . preferably , pin guide members are made of materials that are more durable than bone material and also at least as durable , if not more durable , than the materials of the planar saw blade of the cutting tool . materials could be harder or softer than the material comprising the cutting tool , and in some cases the cutting tool and the pins could be the same material — this is especially viable for ceramics which have very nice bearing characteristics . certain surface treatments for metal may also be advantageous ( titanium nitride , ceramic or non - metallic coating ). preferably , the cutting tool is prevented from cutting or abrading the cutting guide to avoid debris generation . although pulsating lavage will normally clean any debris from the cut surfaces , the possibility of a foreign body , allergic , or other adverse reaction should be avoided . in certain situations , however , it may be desirable to construct the pin member guides of allograft or autograft bone tissue , such as when used in cortical bone tissue where it may be acceptable to cut the pin member guides . diamond , or other carbon - based materials , could also be utilized , cost permitting . also , the pin guides could be constructed of plastics , liquid metal , or some other form of injection moldable material thereby reducing cost levels to an extent enabling the pins to be offered on a disposable or semi - disposable basis . it should be understood that the pinplasty technique of the present invention can be combined with any other forms of alignment and cutting guide tools and techniques . an example of such a combination is to modify a standard cutting guide , as shown in fig1 , to include holes that are tangent to the cutting guide slot and to which the pins of this invention are attached . this could be especially useful in the case of “ 4 in 1 ” cutting blocks wherein the blocks could be positioned against the cut distal surface and the pins passed through the block and into the bone and across , along , or about the cut surface to be created . “ 5 in 1 ” cutting blocks or other blocks could be augmented by this technology in a similar manner . alignment guides are not shown specifically in the drawings of this application . many different kinds of devices or alignment systems could be used to position the pins or cutting guides of this invention or to create bone aperture features or holes to which these guides are attached . outstanding examples include alignment or drill guides disclosed in u . s . pat . nos . 5 , 514 , 139 , 5 , 597 , 379 , 5 , 643 , 272 , 5 , 810 , 827 , and u . s . publ . no . u . s . 2002 - 0029038 a1 . it will be seen that the location and orientation of the pin members or pin cutting guides of the present invention are critical in obtaining desirable results . accordingly , an alignment system used to directly or indirectly dictate the position of these guides / pins must be both precise and accurate in positioning the guides / pins or in creating the bores within the bone tissue to which they are engaged . modification of prior art devices to accomplish this are fairly straight - forward . for instance , the ligament balancing alignment guide of u . s . pat . no . 5 , 597 , 379 could be modified to include a plurality of drill guide portals ( 58 ) and a plurality of apertures ( 44 ), corresponding to the 8 drill holes shown in fig1 of this patent . additional drill guide portals could be included and marked on the guide of u . s . pat . no . 5 , 597 , 379 to accommodate different sized femurs and thereby different sizes of prostheses and / or cutting guides . the immediately aforementioned was but one example of alignment systems that could be utilized to facilitate use of this new invention . in one embodiment for use in tka procedures , the pin guide members shown in many of the figures herein range in diameter between 0 . 125 inches and 0 . 158 inches . pin guide members could be larger or smaller depending upon the requirements of the bone resection procedure . the preferred diameters of the pin guide members for tka procedures represent a significant decrease in the overall material volume of any cutting guides for tka procedures . the material volume of a cutting guide can have a direct effect on the cost of producing the device , and , in general , the less the material volume , the lower the cost . thus , the guides disclosed may have a total material volume of somewhere between 0 . 0092 cubic inches and 0 . 118 cubic inches . in comparison , the conventional guide shown in fig1 probably has a volume somewhere in the area of 5 . 0 cubic inches or more , which is 40 to 500 times more massive than some of the guides or pins of the present invention . fig3 through 49 concentrate on mediolaterally , or ‘ side to side ’ oriented pins . although any kind of cutting tool or milling handle could be engaged to these pins , a sagittal saw ( fig1 - 14 ) and an oscillating saw ( fig2 through 32 ) are shown . a wire or gigli saw could also be used in conjunction with the pins or guides disclosed herein as the cutting profile of such a saw affects the same linear cutting profile as a planar saw blade . similarly , any of the following cutting tools effecting a linear cutting profile could also be used : rotating or oscillating or reciprocating cutters , linear milling tools , garrotes ( thin , highly tensioned wire cutter ), powered rasps or broaches , manual rasps or broaches , jack hammers , chisels , chain saws , osteotomes , abrasive wire cutters , oscillating / reciprocating / chain / gigli / coping / scroll / band / circular / hack / jig / sagittal saws , belt cutters , or cutting tools that combine elements of the aforementioned cutting tools . in one embodiment , cutting tools may be plunged across , along , or through the pin guides of the present invention in any direction desirable . the directions of tool movement with respect to the pins include those generally oblique , normal , or parallel to the long axis of any pin , guide , or guide surface of this invention . furthermore , the cutting tools may move linearly with respect to the bone and / or guide , or may be manipulated to move in circular , nonlinear , or ‘ sweeping motions ’ ( shown in fig1 through 15 ). furthermore , although the pins shown in fig1 show the upper surface of the guide pins having been used to guide the cutting tool to create the cut surface , the pins could easily be located in a more anterior location allowing their ‘ underside ’ to act as the guide surface ( see fig8 through 94 for an example of this principal of operation applied to the distal femoral cut ). this concept could be referred to as ‘ undercutting .’ this may be desirable if the ‘ artifacts ’ described with respect to fig4 and 44 are undesirable . the technique of cutting while engaged to the ‘ upper side ’ of the pins could be referred to as ‘ overcutting ’ ( a term not to be confused with removing too much bone ). fig4 through 49 show an alternative or adjunct / modular guide for use with the pins . this modular guide could be integrally formed with the pins or seperably attached thereto . the modular guide surfaces could help the surgeon initially align the cutting tool with respect to the pins and / or the cut to be created and / or / also to maintain that relationship during a portion of or the entirety of the cutting process used to create the cut . undercutting is also beneficial in this form of the present invention , as is the split pin , hollow pin , and hollow split pin embodiments of the present invention . referring again to fig4 and 44 , the placement of pins used in the overcutting form of the present invention leaves behind it the holes shown in fig4 which will be referred to as ‘ artifacts ,’ a normally undesirable thing . a major issue confronting surgeons and industry alike in the pursuit of minimally invasive arthroplasty , especially knees , is the control of polymethylmethacrylate ( otherwise known as pmma or bone cement ). it may be highly beneficial to first attach the implant to the bone , then inject bone cement through these artifacts or portals . the cement recesses formed in the fixation surfaces of the implant will readily accept the cement that ‘ oozes ’ up from these artifacts / pin holes and act to facilitate interdigitation of the bone cement with both the implant and the bone while controlling or helping to limit extravasion of the bone cement out from under the implant and into the joint space . this could be key in avoiding the presence of bone cement debris floating about the joint after surgery thus leading to premature failure of the bearing surfaces of the implants ( otherwise known as 3 rd body wear , a potential problem in cemented minimally invasive arthroplasty ). any one , all , or any combination of the artifacts could be used in this manner . it should be noted that , in many of the figures , the cut surface created by the cutting tool in accordance with the pinplasty technique of the present invention are shown as having already been completed for the sake of clarity . similarly , the bones may be shown as being transparent or translucent for the sake of clarity . the guides / pins , cutting tool , bones , and other items disclosed may be similarly represented for the sake of clarity or brevity . fig5 through 107 disclose a series of internal guides or pin members for use in conjunction with different cutting tools in different ways . fig5 through 56 show the pins / guide being inserted into preformed holes in the bone , while fig5 and 56 are intended to make clear that the pins and the guide surface that interconnects them are at least in some manner tangent and / or coplanar with the surface to be created in this form of the pinplasty technique of the present invention . fig5 to 71 show that a cutting tool ( in the instance shown , an oscillating saw blade ) could be located , oriented , and / or moved / manipulated along , across , and / or through the pins / guides of the present invention in any manner desired . in the embodiment shown in fig5 , the drill holes are oriented at approximately a 15 degree angle relative to a vertical line running from the top to the bottom . it will be recognized that it is intended that the pins / guides used in accordance with the pinplasty technique of the present invention may be inserted at any angle with respect to the orientations shown . the alignment systems used to dictate the location and orientations of the pin guide members of the present invention may therefore need to be ‘ infinitely adjustable ’ or , perhaps more properly , ‘ infinitesimally adjustable ’ in all 6 degrees of freedom , or any combination of degrees of freedom to facilitate proper pin / guide placement . this may be especially important in computer assisted surgery where initial placement is often estimated , and additional fine tuning of the location and / or orientation of alignment system or cutting guide systems is required . incremental adjustment , especially in well - designed manual alignment systems , may also work well . specifically , the pins of the present invention could also be oriented at up to a 90 degree angle relative to the vertical line that represents the tangential line formed on the surface to be resected . in the embodiment shown in fig5 , the longitudinal axis of the pin guide members are located parallel to each other and approximately 1 . 50 ″ apart from each other . although greater distance between pins may facilitate greater accuracy in final cut / pin location and orientation , the pins could be located more closely together to allow for decreasing or alternative surgical exposure of the bone . fig7 shows the distal end of a sagittal saw with its distal most teeth smoothly rounded to minimize any damage induced by contact between the cutting tool and the soft tissues surrounding the joint . given that a bruise is generally more desirable than a laceration ( especially in terms of arteries or nervous tissue ), this feature is particularly beneficial in connection with the present invention and in conjunction with other techniques or inventions . alternatively , the smoothing of the distal most teeth or distal end of the sagittal saw could be created by slipping a cover over the distal end area , or formed as an integral part of it , to form a non - cutting distal most area configured to minimize harm to tissues whose integrity it is desirable to maintain . in one embodiment , the distal most end could be fitted with teflon ® tip that would serve as this distal - most bumper of the sagittal saw blade . fig7 through 78 show a cutting tool ( in this example a sagittal saw ) traversing the pins / guide of the current invention in undercutting mode . fig7 through 84 are intended to make clear that even in overcutting mode , the use of the pins / guides of the present invention need not leave artifacts if it is so desired . fig7 shows an overcutting guide prior to its use with the distal cut it will participate in creating already made . fig8 shows the guide with respect to the femur prior to any cuts . similarly , no cuts have yet been made in fig8 ( except the holes ), but the bone is shown as being transparent . fig8 further clarifies this aspect of the present invention via a frontal view of the distal cut surface . fig8 shows the distal femur prior to cutting . in this form of the present invention , the pins will be engaged to the cutting tool over a lesser length than the hereinbefore disclosed forms , but may still act to guide the cutting tool effectively without creating artifacts . undercutting could also be implemented in conjunction with this form of the present invention . fig8 shows a saw capture on the overcutting guide with the cut shown . fig8 and 86 show the pins / guide without the bone . it should be noted that the cutting tool capture noted in fig8 could be modular and / seperable from the pins , or it could form a one piece construct with them , or there could be a second capture opposite the first such that the guide could be applied to left or right knees or other joints / bones ( this concept could be described as a ‘ bilateral design ’). it should be noted that any of the forms of the present invention disclosed herein could be adapted to bilateral design to facilitate ease of use and / economics by the surgeon , hospital , or staff , cleaning staff , and / or oem &# 39 ; s or contract manufacturers . fig8 through 94 disclose one form of an undercutting guide . as noted earlier , the potential advantage of an undercutting guide is that it is attached to holes formed in bone tissue that is to be removed by completion of the cuts thus avoiding the creation of artifacts . comparing fig8 and 89 also makes clear that the lower most portion of the cutting guide pins will still be fixed to bone overlying the posterior chamfer cut when the distal cut has been completed . thus , the distal cut will be accurate even if the last bit of bone to be cut beyond the distal cut shown in fig9 and 93 becomes less accurate as the bone to which the guide is attached is consumed . in other words , fig9 shows the distal cut completed and the remainder of the bone to be cut is simply to allow for the placement of subsequent alignment guides , cutting guides , sensors , or other instrumentation . in another embodiment , the pins of the present invention could be ‘ split ’ as shown in fig8 . additional guide surfaces could be incorporated into this embodiment as shown in fig8 where a modular or non - modular cutting tool ‘ capture ’ is disclosed for integral or modular attachment to the pins . fig9 shows the guide surface spanning the two pins as being biased to the medial side of the femur . this feature is intended to allow for greater ease of use in minimally or less invasive procedures without compromise of reproducibility . also , this guide surface is somewhat wavy shaped in order to conform to the contours of the femur thus allowing placement of the guide surface as close to the cut surface as possible to increase reproducibility by reducing the cantilevering effect demonstrated in fig1 and 2 , and to minimize the distraction or displacement of any soft tissue ( this makes the guide both easier to insert and use while minimizing the size of the incision necessary for use ). it should also be noted that the guide surface interconnecting the pins could be shaped like the symbol pi ( π ) where the guide surfaces extend beyond their intersection with the pins about the border of the cut ( s ) to be created . interestingly , fig9 shows that the pieces of bone to which the undercutting form of the present invention are attached may be removed from the incision after the cut is complete . this looks a bit like an olive stuck on the end of a toothpick and may reduce what is commonly referred to as ‘ fiddle factor .’ fig9 through 107 disclose various aspects of the “ split pin ” form of the present invention . this form provides for continuous or semi - continuous capture of the cutting tool in a slotted feature throughout the cutting process . fig9 shows the slotted feature as extending to the point allowing for the completion of the distal cut , but not beyond . it is easily enough modified to extend the slotted feature and / or the pins to extend beyond the bone to be cut to allow for the removal of remaining bone , or the design could be as shown for situations where it is desirable to prevent movement of the cutting tool beyond a certain point to protect soft tissues ( see fig1 and 170 for an example of this , and note that there are many applications where this may be desirable including endplate preparation in the spine where protecting anatomic structures such as the spinal cord , aorta , and vena cava is of paramount importance ). fig9 through 100 show a cutting tool , in this example a sagittal saw , with its long axis extending in a generally side to side direction while cutting . fig1 and 102 show a cutting tool , in this example an oscillating saw , whose long axis is extending in a generally top to bottom orientation . fig1 to 107 clearly demonstrate that the artifacts created by the use of this form of the present invention are significantly less pronounced than overcutting forms of the present invention . fig1 and 109 show the distal femur having been prepared to receive the cutting guide forms of the present invention that could be used to complete the remainder of the cuts . beneficially , a single guide could be used to complete all the cuts by being incrementally attached to the bone at the appropriate locations as shown in fig1 through 121 . alternatively , a modified ‘ 4 in 1 ’ cutting block designed to engage the pins of the present invention could be used . the modified ‘ 4 in 1 ’ block could further be modified by being vertically cut in half and having the pins extending laterally of the block to provide guidance of the cutting tool laterally beyond the location of the conventional guide surfaces . fig1 through 121 show a capture feature added to the guides previously shown in fig1 . note that fig1 demonstrates that despite the abbreviation of the laterally located guide surfaces ( to facilitate medial incision based procedure ), the cutting tool remains robustly guided by the guide of the present invention when both the medial and lateral side of a bone is cut . note that this design is shown to facilitate a medial approach and thus the guide has been ‘ medialized ’ to minimize necessary incision size — if a lateral approach were implemented , a ‘ lateralized ’ form of the present invention could be made available . fig1 through 127 show some of the combinations of the forms of the present invention in use to complete the posterior cut . as shown in fig1 , 125 , and 127 , two pins are located in overcutting mode , while two other pins are shown in undercutting mode . the combination of these pins acts to constrain motion of the cutting tool from traveling beyond the plane to be cut . for the sake of clarity , any combination of the forms of the present invention disclosed herein may be modified or combined to form constructs not specifically disclosed herein , but still within the scope of the present invention . tibial resection in tka can be somewhat frustrating to a certain percentage of orthopedic surgeons . this frustration appears to stem from the high demands upon the surgeon &# 39 ; s manual skills or craftsmanship . the forms of the present invention may help alleviate this issue by providing positive guidance of the cutting tool throughout all or most of the cutting process . also , it should be noted that these concepts allow for implementation with very small incisions . fig1 through 148 disclose a number of different forms of overcutting type pins / guides . cutting tool captures are not shown , but could be seperably attached or formed integrally with the guide or pins . it is important to note in fig1 the extent to which this and other forms of the present invention allow for contact with and guidance of the cutting tool . the solid lines ( shown in yellow ) show approximately where an oscillating saw would contact the pins , while the dashed lines ( shown in yellow ) outline the contact area between the saw and the guide surface bridging the pins . this creates a very stable surface for guiding the cutting tool . it should be noted that undercutting forms of the present invention could be used with guides or pins of similar configurations . fig1 through 148 show a pin or pins which are not physically interconnected with a guide surface . fig1 shows a pin embedded in the tibia that is in no way attached to the other components of the pin guide . it should be noted that it could easily be engaged to some form of mating feature in the guide surface bridging the other two pins shown , if desired . fig1 very importantly shows that a plurality of pins which are not interconnected could be positioned entirely within bone , or with very little of their material extending beyond the surface of the bone . this embodiment allows for extremely small incisions to be utilized while maintaining excellent cutting tool guidance . fig1 through 148 show two independently fixed pins extending beyond the surface of the bone enabling contact between the pins and the cutting tool prior to penetration of the cutting tool into the bone . movement of the cutting tool along the pins can be generally parallel to the long axis of the pins ( as shown in fig1 to 144 ) or transverse to the long axis of the pins ( as shown in fig1 to 148 ), but it will likely be desirable to implement both forms of tool manipulation to complete the cutting process . fig1 through 156 show a split pin form of the present invention for tibial resection . although an oscillating saw is disclosed in these figures , a multitude of cutting tools could be implemented for use with this and other forms of the present invention . a sagittal saw is one obvious choice , but perhaps a side cutting milling tool would yield even more superior results while avoiding damage to the soft tissue structures surrounding the joint . once again , the split pin form enables a less significant artifact . fig1 through 170 show a split pin with bridging guide surfaces . importantly , one potentially problematic issue with the split pin forms of the present invention may be the tendency of the slots to collapse or partially close preventing easy passage of the cutting tool along the pins . to avoid this , and the debris generation it would likely create , one embodiment of the guide possesses spacing features ( see fig1 and 158 ) to prevent collapse of the surfaces that guide the cutting tool . comparing fig1 and 167 shows that the pins can be extended partially across the surface to be cut , or entirely across the surface to be cut . this principal of operation could be critical in protecting the vascular and nervous structures posterior of the posterior capsule of the knee joint from accidental damage through contact with the cutting tool . this is more clearly shown in fig1 and 170 where the spacing features act to prevent the cutting tool from extending beyond the cut surface and into anatomic structures that must be preserved and protected from harm . this cost of damaging these anatomic structures could be the ability of the patient to walk or could require amputation due to nervous or vascular compromise . fig1 through 193 describe another embodiment of the present invention . the device overcomes the drawbacks of the inability to easily and accurately secure existing alignment or guide systems to a desired location or position , a problem often referred to as the fiddle factor problem . the fiddle factor problem extends intraoperative time , creates surgeon frustration and can lead to implant mal - alignment due to inaccurate alignment guide or cutting guide positionings . an example of the fiddle factor problem in existing alignment and guide systems is shown , for example , in the device by grimm described in u . s . patent publ . no . 2004 / 0122436 ( herein incorporated by reference ). as shown in fig1 of this application , it will be observed that the actuation of the locking mechanism generally indicated as 34 to fix the carriage 40 with respect to the sphere 22 will actually cause the carriage 40 to rotate with respect to sphere 22 . thus in use , the surgeon would attain the correct location and orientation of the cutting tool guide of grimm , as indicated on the computer display , and then attempt to lock varus valgus , flexion extension , and internal / external rotational alignment by way of the actuation of locking mechanism 34 , but in doing so , the carriage , and thereby the cutting tool guide would shift from the desired orientation . this dynamic will force the surgeon to iteratively tighten the lock , adjust the carriage , tighten the lock a little more , adjust the carriage a little more , tighten the lock even more , adjust the carriage a little more , etc ., until intraoperative time constraints would compel the surgeon to move forward with the procedure with alignment that is suboptimal . these problems can be compounded by several additional adjustment and locking mechanisms to similarly fiddle that need to be made prior to making the first cut . simply put , the major problem with the majority of surgically navigated “ anchor - cutting guide linkage ” type devices ( such as those applications identified in fig1 which are herein incorporated by reference ) is that the act of locking the orientation and location of the cutting guide in place with respect to the anchor and / or the desired implant location and orientation actually causes the location and orientation of the cutting guides to change , in some cases radically . as the ultimate objectives of surgical navigation are to improve accuracy and promote and facilitate minimally invasive implantation , the fiddle factor problem clearly runs counter to these objectives . one can clearly see this problem in effect by reviewing those devices described in patent or patent application numbers shown in fig1 , which are herein included by reference . this embodiment of the present invention solves the fiddle factor problem by providing for an elegant locking mechanism that secures a plurality of translation and rotational degrees of freedom in a manner which fails to shift the location and orientation of the cutting tool guide while it is being secured . more precisely , the sum of the force moment couples acting about the center of mass of the cutting tool guide ( s ) by the actuation of the locking mechanism are governed by the following equation : the primary components of this embodiment of the present invention are shown in fig1 . these include the anchor ( see also fig1 ), the locking sleeve ( see also fig1 through 180 ), the split sphere ( see also fig1 ), the cutting tool guide ( see also fig1 , 193 , and 214 through 219 ), and the surgical navigation sensor ( not shown for the sake of clarity and will herein be referred to simply as a “ sensor ”). the anchor possesses four primary features , either alone or in combination with the primary components of this embodiment of the present invention . those features include a bone penetrating and anchor stabilizing feature ( indicated as the anchor thread in fig1 and the drill tip in fig1 ), a locking feature ( indicated as the conical lock in fig1 ), a linkage engagement feature ( indicated as the locking channel in fig1 ), and a quick release feature ( indicated as the release tabs in fig1 ). in use , the anchor may be drilled into and fixed to a face of the bone in one continuous or semi - continuous step , or an aperture may be predrilled to which the anchor is subsequently fixed ( as shown in fig1 and 183 ). if pre - drilling is used , a simple template ( not shown ) including a faux guide surface , drill guide aperture , and handle may be used for the purpose of facilitating the surgeon &# 39 ; s “ eyeball ” placement of the pre - drilled aperture ; in other words , the faux guide surface acts as a general indication of where the surgeon thinks the cut is to be located simply based on how it looks relative to the bone based on the surgeon &# 39 ; s judgment / experience to facilitate pre - drilled aperture placement for the anchor enabling minimal adjustment of the cutting tool guide with respect to the anchor . the locking sleeve possesses three primary features alone or in combination with the primary components of the embodiment of the present invention including a drag feature ( indicated as the o - ring in fig1 ), a locking feature ( indicated as the cone contacting edge in fig1 ), and a surgeon grasping surface ( indicated in fig1 ). these features coact to enable rapid and effective locking and quick release of the cutting tool guide with respect to the anchor . the drag feature coacts with the anchor , split sphere , and cutting tool guide to affect frictionally resisted movement of the cutting tool guide with respect to the anchor about 3 , 4 , 5 , 6 , 7 , or 8 degrees of freedom . the split sphere , in this embodiment of the invention , possesses three primary features alone or in combination with the primary components of the embodiment of the present invention including an articulation aperture feature ( indicated in fig1 ), a spherical articulation feature ( indicated in fig1 ), and a relief feature ( indicated in fig1 ). as may be seen in fig1 , and by comparing fig1 & amp ; 191 , the articulation aperture feature of the split sphere coacts with the articular post of the cutting tool guide to enable frictionally resisted movement and frictionally affected locking of the cutting guide with respect to the split sphere . when enabling frictionally resisted movement ( herein described as “ drag mode ”), the amount of force against which this mechanism must resist movement of the cutting tool guide with respect to the anchor is at least equivalent to the force affected by way of gravity , and in preferred embodiments , is at least equivalent to the combination of force affected by gravity and the force affected by soft tissue contacting the device . when enabling frictionally affected locking ( herein described as “ locking mode ”), the amount of force against which this mechanism must resist movement of the cutting tool guide with respect to the anchor , in a preferred embodiment , is at least equivalent to the force moment couples the applied to the device by the combination of gravitational , soft tissue , and cutting tool contacting forces . to further facilitate the effectiveness of these modes , the internal and external surfaces of the split sphere , and optionally the features of the present invention that come into contact with them , are textured to facilitate robust fixation . such textures include , but are in no way limited to , # 7 to # 20 grit blast , tecotex ™, knurling , and other means known in the art for effectively increasing the surface area of a smooth surface . the spherical articulation feature of the split sphere enables both tri - axial rotational and single axial translational manipulation of the split sphere with respect to the anchor and along its long axis , as well as simultaneous locking of those degrees of freedom , and an additional axial translational degree of freedom of the articulation post of the cutting tool guide with respect to the articulation aperture feature of the split sphere . locking is attained by compression of the locking channel feature ( see fig1 ) of the anchor against the spherical articulation feature and , by way of the relief feature of the split sphere , the articulation post feature of the cutting tool guide . the relief feature of the split sphere enables two distinct functions . the relief feature enables elastic compression of the split sphere against the articulation post of the cutting tool in response to force applied to the split sphere by the locking channel feature in response to actuation of the conical lock feature . in the context of tibial resection for the embodiment of the present invention shown in fig1 and 191 , the sphere articulates with respect to the anchor in 4 degrees of freedom ( anterior to posterior , varus - valgus , internal external rotation , and flexion - extension ) while the articulation post , and thereby the cutting tool guide , articulate with respect to the split sphere , and thereby the anchor and bone , in at least one additional degree of freedom ( proximal - distal ). the second function of the relief feature is to optionally allow the articulation post of the cutting tool guide to be rotationally keyed to the split sphere to enable the split sphere and cutting tool guide to be rotated in tandem with respect to the locking channel of the anchor . in another embodiment of the present invention ( not shown ), the articulation post of the cutting tool guide could be split along its long axis and coact with an articulation feature on the cutting tool guide to enable mediolateral translation and locking of the cutting tool guide with respect to the bone wherein effective locking of the mediolateral degree of freedom would also be affected by actuation of the cone lock feature in addition to the aforementioned 5 degrees of freedom . in yet another embodiment of the present invention as shown in fig2 through 259 , a second spherical articulation feature could be formed integrally with the underside of the cutting tool guide shown in fig1 which would be ‘ grasped ’ by a mating spherical locking aperture on the top of the split articulation post which would subsequently allow for continuous , non - incremental manipulation of the cutting tool guide in six , seven , or eight degrees of freedom all a which would be locked by the actuation of a single locking mechanism ( see fig2 through 259 for an exemplary embodiment ). critically , in one embodiment of the present invention , all of these degrees of freedom are smoothly adjustable ( as that term is defined in u . s . pat . no . 6 , 685 , 711 by axelson , et al which is herein incorporated by reference ) to any desired location and orientation and are rigidly and quickly locked by the single actuation of a single locking mechanism that does not cause the cutting tool guide to move with respect to its desired location and orientation . the cutting tool guide ( see also fig1 , 176 , 193 , and 214 through 219 ), in this embodiment of the invention possesses three primary features alone or in combination with the primary components of the present invention including a cutting tool guide surface ( s ) feature ( fig1 , 176 , 193 , and 214 through 219 ), the articulation post feature ( fig1 , 176 , 193 , and 214 through 219 ), and the sensor ( not shown ). the cutting tool guide surface ( s ) takes many forms in different embodiments of the present invention . fig1 shows a fairly conventional oscillating saw blade guide with a saw blade capture feature , which could optionally be a non - integral modularly attachable feature . fig1 clearly shows optional guide gripping and soft tissue accommodating surfaces which enable the surgeon to grasp and manipulate the cutting tool guide to perfectly position the guide in the incision and with respect to the intended implant location and orientation as well as to provide significant surface area for saw blade guidance and contact while minimizing the displacement of soft tissue by the cutting tool guide and thereby minimizing the size of the incision necessary to perform resection . as may be seen in fig1 , the soft tissue accommodating feature is intended to contact both the medial and lateral edges of the incision for an anterior approach , or , optionally , in a quad - sparing type approach to contact more posteriomedial and anteriomedial edges of the incision ( it should be obvious to one of ordinary skill in the art that soft tissue contact occurs with this embodiment at any incision location and orientation about the knee , spine , or other joint without limitation ). additional optional features are beneficially added to the embodiments shown . in one embodiment of the present invention , a modularly attachable handle provided to attach to the cutting tool guide could be used to manipulate the cutting tool guide with respect to the desired implant location and beneficially includes extramedullary alignment rod ( s ) ( one extending along the anterior aspect of the tibia from proximal to distal locations and one extending along the medial or lateral aspects of the tibia from proximal to distal enable complete visual alignment as per conventional techniques for varus - valgus and flexion extension alignment ) and a depth or sizing stylus , as is known in the art , for contacting the bone and determining cut depth or location and / or implant size . as has been noted in the prior art , the computers facilitating surgical navigation techniques still have a tendency to “ crash ” and the availability of these features is crucial in avoiding leaving a surgeon “ stranded ” with a live patient on the table under anesthesia in the event of such a “ crash .” in yet another embodiment of the present invention , the cutting tool guide ( as shown in fig1 through 201 , and fig2 through 220 ) acts to guide a standard drill , pin , or coring drill to either position implements to which a cutting guide is attached , or to create apertures in bone to which the cutting guide is attached . in facilitating techniques more similar to prior art practices , the pins , drills , etc ., could be merely fixation means to provide additional stability to the cutting guide &# 39 ; s ( such as in the embodiment shown in fig1 ) fixation to the bone . it is of significant utility to utilize the drills , pins , etc ., as extensions of the cutting guide surface through the border of the cuts to be made and across the plane of the cut to be made to simultaneously fix the guide and implement the positioning of pinplasty style cutting guide embodiments of the present invention as shown in fig2 through 220 . the articulation post feature coacts with the split sphere feature as previously noted , and , optionally , with the second spherical articulation feature of the previously noted embodiment of the present invention . although the sensor feature of this embodiment of the present invention is central to surgically navigated surgery , it will be understood that there are multiple and numerous variations of sensor technologies ; features for modularly attaching sensors to cutting tool guides or other components of arthroplasty instrumentation or implants , features for forming the sensors as integral components of instrumentation and implants , that can be combined with this embodiment of the present invention . it will be appreciated that there are various ways in which electromagnetic phenomenon based sensors can be utilized to facilitate and determine bone cutting and / or implant placement . it will also be appreciated that multiple and numerous mechanical fiducial techniques and apparatus can be used in cooperation with the align and cutting guide systems . the following patents and patent applications describing various surgical navigation system and alignment and cutting guide systems that are beneficially utilized in whole or in part with the embodiments of the present invention are herein incorporated by reference : u . s . 2004 / 0122436 , u . s . 2003 / 0069591 , u . s . 2004 / 0039396 , u . s . 2004 / 0153083 , u . s . pat . no . 5 , 810 , 827 , u . s . pat . no . 6 , 595 , 997 , u . s . 2003 / 0069585 , u . s . 2003 / 0028196 , jp74214 - 2002 , u . s . 2003 / 0208122 , u . s . pat . no . 6 , 725 , 080 , u . s . 2004 / 0122305 , u . s . pat . no . 6 , 685 , 711 , u . s . 2004 / 0153085 , u . s . 2004 / 0152970 , u . s . pat . no . 6 , 694 , 168 , wo04100758 , wo04070580 , wo04069036 , u . s . pat . no . 5 , 799 , 055 , u . s . pat . no . 6 , 236 , 875 , u . s . pat . no . 6 , 285 , 902 , u . s . pat . no . 6 , 340 , 363 , u . s . pat . no . 6 , 348 , 058 , u . s . pat . no . 6 , 430 , 434 , u . s . pat . no . 6 , 470 , 207 , u . s . pat . no . 6 , 477 , 400 , u . s . pat . no . 6 , 491 , 699 , u . s . pat . no . 6 , 697 , 664 , u . s . pat . no . 6 , 701 , 174 , u . s . pat . no . 6 , 711 , 432 , u . s . pat . no . 6 , 725 , 080 , u . s . pat . no . 6 , 796 , 988 , and u . s . pat . no . 6 , 827 , 723 . another feature of the embodiments of the present invention is an elegant quick release mechanism enabling extremely rapid unlocking and removal to the cutting tool guides from the anchor before or after completion of bone resection . as noted in fig1 , the act of releasing the cutting tool guide from the anchor is as simple as the surgeon squeezing the release tabs together , manipulating the locking sleeve from lock mode to drag mode , and simply removing the cutting tool guide . this level of simplicity truly facilitates the easy instruction and operation of this embodiment of the present invention , even permitting surgeons to be able to pick up the surgical instrument and intuitively understand the proper use of the instrument without instruction . fig1 and 193 represent another embodiment of the present invention wherein the same cutting tool guide utilized to cut a first bone ( in the example shown , it &# 39 ; s the tibia ) is located and oriented to cut a bone that opposes the first ( in the example shown , it &# 39 ; s the femur ). as an especially useful ability for tka or unicondylar knee arthroplasty , the femur may be manipulated into positions of different degrees of flexion or extension to enable the cutting tool guide to be aligned with the desired location of different resected surfaces . fig1 shows the device positioned properly to create a distal resection , while fig1 shows the femur oriented to allow the cutting tool guide to be manipulated to cut the posterior cut , the anterior cut , and / or the chamfer cuts with respect to which the implant ( s ) are fixed . this embodiment of the present invention and the associated techniques that are facilitated by use of this embodiment of the present invention are easily and beneficially applied to the other embodiments of the present invention described herein . the methods of using the embodiments of the present invention are quite simple . attach the anchor to the bone , attach the split sphere and the cutting tool guide to the anchor , align the cutting tool guide with respect to the desired implant location and orientation as indicated and / or tracked by non - surgically navigated or surgically navigated system ( s ) and / or indicia , lock the cutting tool guide in said location and orientation , remove boney material to create a resected surface with respect to which an implant will be fixed to bone , remove the anchor from the bone , and attach the implant with respect to the bone ; wherein the step of aligning the cutting tool guide further includes the step of manipulating the cutting tool guide location and orientation in four , five , six , seven , or eight degrees of freedom all of which are locked by the actuation of a single locking mechanism . fig1 through 206 show yet another embodiment of the present invention . in this embodiment , the cutting tool guide is configured to guide the placement of drills , pins , punches , coring drills , etc ., to create apertures in bone which dictate implant location and orientation and to which cutting guides are subsequently attached ( this shall be referred to as a “ drill guide ”). fig1 shows the drill guide that is located and oriented with respect to the desired implant location and orientation in the same manner described for the embodiments of present invention described above for fig1 through 205 . in yet another embodiment of the present invention , fig1 and fig2 through 206 show the cannulated style pinplasty cutting guide for use in conjunction with the coring drill ( see fig1 , 197 and 202 ). it should be noted that fig1 , 200 , and 201 show the tibia as being semi - transparent for the sake of clarity . one of the principal benefits of utilizing a cannulated or coring drill is that the volume of living tissue that is disrupted by the surgical procedure is minimized thereby minimizing the amount of damage that must heal postoperatively for overcutting , or split pin style pinplasty . as minimizing postoperative recovery time and return to function are the core objectives of mis arthroplasty , every opportunity to minimize the damage to soft and osseous tissue is beneficially taken advantage of by these embodiments of the present invention . in use , the drill guide is manipulated into the desired location and orientation as hereinbefore described and locked or pinned in place . the coring drill ( shown in fig1 through 201 ), twist drill , punch , pin , nail , screw , or other bone penetrating feature is used create the apertures in the bone ( shown in fig2 ) to which the cutting guide is subsequently attached . the cutting guide then coacts with the cutting tool to partially or completely create the desired resection ( s ). fig2 through 212 show another embodiment of the present invention wherein the anchor is attached to a face of a bone to be subsequently removed prior to fixation of the prosthesis with respect to the resected surface ( s ). in comparing fig2 and 208 , it is clear that the anchor is fixed to bone to be replaced by the implant . fig2 through 212 show the modes ( undercutting , overcutting , conventional , and split pin , respectively ) of cutting guide embodiments of the present invention . fig2 makes it clear that the axis of the anchor may vary significantly with respect to the axis ( es ) of the drill guide or other cutting tool guide embodiments of the present invention ( fig2 makes it clear that the axis may vary by an included angle of greater than 180 degrees ). one advantage of the embodiments of the present invention is the low profile nature of the embodiments enabling the anchor feature and the cutting tool guide feature to both be positioned adjacent to bone within the same incision thereby avoiding the additional trauma and cosmesis compromise inherit in having to create a separate incision for the anchor feature as necessitated by the work of axelson , et al in u . s . pat . no . 6 , 685 , 711 by axelson , et al which is herein incorporated by reference . fig2 describes the cutting tool guide as being capable of being located immediately above , immediately below , or in fact straddling the anchor location to facilitate this optional use of the present invention . fig2 through 220 show yet another embodiment of the present invention wherein the cutting tool guide is both a saw blade guide and a drill or pin guide . this embodiment of the present invention could also be described as a hybrid pinplasty and conventional cutting guide as the placement of the pins in essence extend the cutting tool guiding surfaces of the cutting guide into the bone from a first position located outside the border of the cut to be created to a second location within the border of the cut to be created along an axis ( es ) that are parallel to the cut to be created . this embodiment of the present invention also makes clear that the pinplasty guide surfaces need not extend along parallel axes , but may instead be divergent or convergent with respect to each other . a feature of the present invention which differs from some of the other embodiments of the present invention is that the pin or drill of the present invention possesses a flat surface to be aligned in a coplanar fashion with the conventional cutting guide surface ( s ). also included within the scope of the present invention would be a cutting guide where the drill or pin guide apertures in the cutting tool guide are not interrupted by the cutting tool guide surface of the cutting tool guide , but posses a minimal wall thickness or a minimal interruption enabling the use of cylindrical pins or drills with guide surfaces for contact with the cutting tool that are only a few thousandths of an inch offset from the cutting tool guide surface . in other words , the centerline of the drill or pin guide apertures are parallel to but offset from the guide surfaces ( as indicated in fig2 ) by an amount generally less than 20 % of the diameter of the apertures . fig2 through 236 show yet another embodiment of the cutting guides of the present invention . this embodiment could be described as a hollow , divergent , split pin configuration cutting guide . in this embodiment of the present invention , the divergent angle of the pin axes are set to approximately 20 degrees , but divergent angles of up to 130 degrees are considered to be within the scope of the present invention as are pins that coact to form axes that intersect within the border of the resected surface ( s ) to be created as viewed from a direction normal to the resected surface to be created . one feature of critical benefit to mis procedures with respect to this embodiment of the present invention is the ability of the split pin to incorporate a stop feature ( as shown in fig2 ) where critical structures such as ligaments , tendons , capsule , veins , arteries , or nerves may be prevented from direct contact with the cutting tool &# 39 ; s cutting surfaces by limiting the depth to which the cutting tool may be extended in the direction of those critical structures prior to contacting the stop feature . another important feature of this embodiment of the present invention is the flexibility of the divergent guide that enables the cutting guide to be squeezed by the surgeon to initially line up and insert the tips of the pin features into the divergent apertures and then push the pins into the location desired ( as shown in fig2 and 224 ). it should also be noted that the two divergent pins could be constructed as independent constructs as opposed to the unitary structure shown in fig2 and optionally provide features for attachment of a bridging feature fig2 through 247 show an embodiment of the present invention that in essence provides for the apertures formed in the bone to act as the cutting guide in coacting with a carriage linked to a saw blade or other cutting tool . beneficially , the saw blade and carriage ( hereinafter referred to as the “ cutting tool / pin guide ”) may be packaged together as an assembly intended for single use only , or a limited number of uses , and / or as sterile or non - sterile . in essence , the retention feature of the cutting tool / pin guide enables the cutting tool and carriage components to coact to continuous guide the cutting tool as it traverses the surfaces within , along , and about the apertures formed in the bone to create the resected surfaces with respect to which the implant is to be fixed . this embodiment also possesses an effective stop feature preventing the cutting teeth from inducing catastrophic damage to soft tissue structures . fig2 through 253 show another embodiment of the present invention wherein the aperture guidance feature of the cutting tool is formed as component of the cutting tool . the independent or linked sphere or bullet features shown in fig2 ( and described therein as captured aperture engagement features ). a track , as indicated in fig2 , is formed in the end of the blade such that the aperture guidance feature may articulate therein to an extent greater than the arc or line through which the saw blade is oscillated by the saw . in use , the sphere or bullet features of the cutting tool are inserted into the apertures formed in the bone and manipulated by the surgeon to traverse the axis ( es ) of the apertures to cut the bone as shown in comparing fig2 , 247 , and 248 or fig2 , 252 , and 253 . fig2 through 259 show an embodiment of the present invention enabling as many as eight degrees of freedom to be rigidly locked by the actuation of a single locking mechanism . the second spherical articulation feature is critical to this embodiment of the present invention as it enables smooth adjustment and robust locking of three rotational degrees of freedom of the cutting tool guide ( shown in a generic form in fig2 ) with respect to the articulation post as shown in fig2 . fig2 shows a close up of the second spherical articulation feature with the mating collet of the articulation post of this embodiment of the present invention . fig2 shows a close up of the relief and multiple petal split sphere . in comparing fig2 , 258 , and 250 , it can be seen that although the surgeons will likely place the anchor in a location and orientation enabling the cutting tool guide to be located and oriented with little manipulation , this embodiment of the present invention enables radical realignment to be performed as the angle between the articulation post and the cutting tool guide may reside anywhere within a 150 degree included conical section swept about the center of the second spherical articulation feature &# 39 ; s center point ( compare fig2 and 259 ). the surgical application of the above described embodiments of the present invention for anchor - cutting tool guide - linkage type devices have been predominantly demonstrated in the context of tibial resection in tka or unicondylar knee arthroplasty . it should be noted that the scope of the present invention is in no way limited to this field of use and therefore several examples of additional fields of use shall be herein provided to demonstrate the significant utility of this invention . for years , spinal surgeons have struggled with the demands of polyaxial screw based pedicle screw technologies in that having the sphere formed as an integral part of the anchoring screw prohibits axial adjustment of the rods with respect to the screw spheres . the design of the anchor of this embodiment of the present invention is beneficially modified by shortening the relative length of the locking channel and providing split spheres positionable along the rod . the external surfaces of the anchor opposing the interior surfaces of the locking channel would be threaded , beneficially with a conical thread , to which a mating threaded cap is threadably attached . in use , the pedicle screws of the present invention would be attached to the vertebral bodies by way of the pedicles as per standard techniques , including placement by way of the present invention for screw placement under surgical navigation guidance . next , transversely oriented rods with split spheres along their lengths would be interconnected with the locking channel by contacting the spherical articulation feature of the split sphere with the interior surfaces of the locking channel . in the clinical application of scoliosis reduction and / or fusion , the spine would then be reduced ( or straightened , stretched , and generally realigned to a desirable configuration ) and the threaded cap would be actuated to move distally ( toward the tip of the screw that first penetrates the bone ) lock the spheres and thereby the rods in the desired location and orientation within the locking channel of the pedicle screw of the present invention . a second threaded cap could beneficially be implement with this technique to additionally lock the split sphere feature of the present invention in place by advancing it along the pedicle screw along external threads in a proximal direction . the proximal end of the anchor would beneficially include frangible ends that could be trimmed after complete locking to reduce the profile ( the extent to which the device displaces or traumatizes soft tissue and / or bone ) of the assembled device and therefore enhance its minimally invasive nature . it should further be noted that the locking channel could be partially countersunk or counterbored into the bone to further reduce the extent to which the anchors extend beyond the naturally occurring bone surfaces further enabling the rods to be positioned in close proximity to the bone ( thus reducing intraoperative invasion requirements for implantation of the system ). of specific interest in implantable embodiments of the present invention , the use of a biocompatible adhesive to permenantly lock the respective members of the assembly in position could be used to further facilitate permanent , robust locking . additionally , the surfaces of the coacting features could be textured or even porous to affect improved fixation with or without the use of adhesive compounds . commercially available materials and / or processes to provide textured or porous surfaces and / or materials include the publicly available material on tecotex ™ and trabeculite ™ from tecomet , inc . of connecticut and trabecular metal ™ distributed by zimmer , inc . of warsaw , ind . furthermore , the adhesive could be used to coat the assembly and thereby provide smooth external soft tissue contacting surfaces to avoid the well understood soft tissue reaction to stiff , sharp implant geometries coming into contact with soft tissue and thereby eliciting some level of foreign body response by living soft tissue manifest , for instance , by encapsulation of the offending implant by fibrous tissue . although specific examples of applying the embodiments of the present invention to femoral resection in knee surgery were given in fig1 and 193 , clearly this embodiment of the invention has significant utility where the anchor is attached to the femur for femoral resection , as opposed to being attached to the tibia for femoral resection . this embodiment of the present invention will beneficially implement the principals of operation utilized in any of the other embodiments of the present invention described herein including , but not limited to , the following : ( a ) attachment of the anchor feature to bone to subsequently be removed ; ( b ) embodiments of the cutting tool guide as a drill guide , saw blade cutting guide , punch guide , pin guide , hybrid drill guide / saw blade cutting guide , drill guide for screw or other fixation mechanism placement guide ; ( c ) four , five , six , seven , or eight degrees of freedom locked by the actuation of a single locking mechanism ; ( d ) attachment of the anchor to bone along an axis “ above ” or “ below ” the cuts to subsequently be made with respect to which the implant will be attached ; ( e ) attachment of the anchor to the femur wherein the cutting tool guide is manipulated to be located and oriented with respect to the tibia to facilitate tibial resection to create cuts with respect to which an implant will be attached . the requirements for effective femoral resection are quite different from tibial resection given the geometry of the implant surfaces to be fixed with respect to the femur in knee surgery and the soft tissue anatomy in and about the knee joint adjacent the femur . this creates opportunities to implement the present invention to even greater benefit . for instance , in a quad - sparing approach ( such as the technique popularized by zimmer , inc . ), a more medialized incision is utilized thus exposing femoral anatomic structures located more medially than a more standard medial para - patellar incision which facilitates insertion of cutting tools from a more generally mediolateral direction than the “ head on ” approaches favored in the standard approaches . thus , the cutting tool guide positioned by the embodiment of the present invention could be similar to those taught by u . s . pat . no . 5 , 514 , 139 , and u . s . pat . no . 5 , 810 , 827 ( which are both incorporated herein by reference ) wherein at least one continuous or discrete multi - planar guide surface ( s ) possessing cutting guides are positioned along the medial or lateral sides of the femur and are secondarily fixed in position by first locking and then pinning or screwing the cutting tool guide in place . a cutting tool of any kind known in the art may then be traversed along the guide surface ( s ) while cutting the bone to receive the femoral implant . further , cutting tool guides possessing both guide surfaces located to the medial or lateral sides of the femur and further “ wrapping around ” the more distal border of the femoral surface to be cut ( as may be seen in u . s . publ . application no . 2004 / 0153066 in fig2 through 32 by coon , et al . which application is herein incorporated by reference ) are also included in the scope of the present invention . the coon et al . work could be further modified to implement the overcutting , undercutting , hollow pin , split pin , or hollow split pin embodiments of the present invention wherein the cutting guides are attached to the bone subsequent to creation of the apertures or wherein the hybrid methodology described above is used in conjunction with the cutting tool guide shown in fig2 through 220 or with the other embodiments of the present invention . furthermore , benefit is obtained by limiting the number of cutting guide surfaces per guide to those corresponding to resected surfaces accessible through the incision with the knee positioned at different locations within its range of motion ( such as one guide to perform the more anterior cuts with the leg somewhere between − 10 and 45 degrees of flexion and one guide to perform the more posterior cuts with the leg somewhere between 60 and 145 degrees of flexion ) thus facilitating minimally invasive resection and implantation incision such as the modular or unitary guide rail shown in fig4 of this application optionally including the “ wrapping around ” guide surfaces of coon , et al . benefit will also be found in an embodiment of the present invention where a bracket is positioned and fixed to the side of the femur wherein the bracket is configured to receive cutting guide surfaces as illustrated in u . s . pat . no . 6 , 695 , 848 ( which is herein incorporated by reference ) fig1 a through 15c by haines , the applicant for the present invention . another embodiment of the present invention would be the implementation of the cutting tool guide shown in fig5 through 56 of u . s . pat . no . 6 , 702 , 821 ( which is herein included by reference ) by bonutti and / or utilizing the anchor feature of the present invention as a substitute for the anchor number 1338 in fig9 of u . s . publ . application no . 2003 / 0028196 ( herein incorporated by reference ) also by bonutti . in yet another embodiment of the present invention , the cutting tool guide could be implemented to create apertures in bone to be removed , such as the bone removed by the anterior chamfer cut and the posterior chamfer cut , wherein the long axis of the apertures extends in a generally mediolateral direction such as the apertures to which the pin shown in fig3 of this application which is imbedded in bone to be removed by the creation of the anterior chamfer cut ( since the anterior cut , posterior cut , and distal cut coact to define both the implant location , orientation , and size , the chamfers may be completed by conventional means without loss of the benefits of the present invention when applied to conventional total condylar femoral implants most commonly used with flat planar fixation surfaces for apposition and fixation with respect to complementary resected bone surfaces ). for curvilinear fixation , adaptation of these concepts to determine the location and orientation curvilinear or “ cortical ” prostheses , bmo prostheses , and or porous prostheses ( as shown and described in the co - pending applications by the inventor of the present invention ) is readily apparent . benefit will also be derived from adapting the present invention to act as what could be described as an abbreviate intramedullary rod type anchor of generally cruciform punch configuration as described in u . s . publ . application no . 2003 / 0069591 ( herein incorporated by reference ) for fig4 b by carson et al . benefit will also be derived from adapting the present invention as a substitute for the anchor feature of fig1 , and 5 through 8 of u . s . publ . application no . 2004 / 0153083 ( herein incorporated by reference ) by nemec et al . wherein the anchor is fixed to the bone through an incision other than the incision in which the cutting tool guide and / or cutting tool is positioned adjacent the bone to facilitate resection . another embodiment of the present invention may be illustrated by the use of the present invention in conjunction with the instrumentation and prostheses of u . s . publ . application no . 2003 / 0212403 ( herein incorporated by reference ) by swanson , which describes devices for use in a what is essentially a pure medial or pure lateral surgical exposure approach to tibial , femoral , and patellar resection and implantation . another embodiment of the present invention may be illustrated by way of combining the apparatus and methods of copending provisional applications ( previously incorporated by reference ) to facilitate both the improved longevity of the prosthesis and improved rate of patient recovery post operatively . another embodiment of the present invention may be illustrated by the use of the present invention in conjunction with the instrumentation and prostheses of u . s . patent application no . 2003 / 0130665 ( herein incorporated by reference ) by pinczewski , et al , which describes devices for use in a what is essentially a form of kinematic resection . it is clear the present invention has significant utility as a means for locating and orienting the cutting tools , cutting guides , and other surgical implements of pinczewski , et al both in kinematic resection and non - kinematic resection based techniques . very similarly , another embodiment of the present invention may be illustrated by use of the present invention in conjunction with the instrumentation and prostheses of u . s . pat . no . 6 , 482 , 409 by engh , et al , ( herein incorporated by reference ) which describes devices for use in what is in essence anothe form of kinematic resection . another embodiment of the present invention may be illustrated by the use of the present invention in conjunction with the instrumentation and prostheses of u . s . patent application no . 2003 / 0208122 ( herein incorporated by reference ) by melkent , et al , which describes devices for use in a what is essentially a freehand surgically navigated method for pin , screw , drill , or other bone displacing implements . as shown in fig8 - 11 of copending u . s . provisional patent application no . 60 / 551 , 080 , a similar method is demonstrated that in use in conjunction with the melkent , et al patent provide significant benefit in terms of ease of use and reduced intraoperative time . the copending application demonstrates that once the surgically navigated drill guide of fig8 - 11 of that application are properly located and oriented with respect to the desired prosthesis location and orientation while being tracked by indicia in as many as 6 degrees of freedom , the sharp leading tip of the cannulated drill guide is impacted into the bone such that the tip of the drill which is subsequently inserted through the cannulae first contacts bone inside the tip of the cannulated drill guide . this embodiment of the present invention mitigates opportunity for the drill tip to “ walk ” prior to penetrating the bone thus avoiding implant malalignment due to one of the greatest short comings of prior art joint and spinal arthroplasty systems . the implementation of coring drills , twist drills , punches , nails , screws , cannulated screws , pedicle screws , and other bone displacing tools is considered to be within the scope of the invention . another embodiment of the present invention may be illustrated by the use of the present invention in conjunction with the instrumentation and prostheses of as shown in the same copending u . s . provisional patent application no . 60 / 551 , 080 , which describes devices for pivotable guide surfaces . the embodiments of the present invention are beneficially applied to the creation of the bone aperture features shown therein and could further be implemented to guide the forstner style drill to facilitate the “ guideless cutting ” technique described by fig4 through 44 and the written description associated therewith . another embodiment of the present invention may be involves the use of a cutting tool guide in conjunction with the hybrid drill / pin guide of fig2 through 220 for femoral resection . in this embodiment , the anchor - cuttin tool guide - linkage device would be positioned adjacent the border of a resected surface to be created wherein the cutting tool guide possesses the “ wrap around ” feature herein described and the drill or pin guide features of fig2 through 220 . in this embodiment of the present invention , the cutting tool guide would be positioned as herein described and the pin - like cutting guide features extended or driven into the bone through , along , across , over , or under the cut surface to be created . of particular interest , positioning the cutting guide surfaces both medially and distally ( or optionally laterally and distally ) across less than ½ of the mediolateral width of the resection to be made and extending the pin - like cutting guide features a distance of at least ⅓ rd of the width of the resection to be made provides for excellent guidance of the cutting tool while enabling minimal incisions . yet another embodiment of the present invention includes alternative locking mechanisms to affect fixation of the split sphere feature of the present invention with respect to the anchor . any mechanism which adheres to the requirement that the sum of the force moment couples acting about the center of mass of the cutting tool guide is considered to be within the scope of the present invention including , but not limited to the following : a ) forceps type mechanisms applying force to the locking channel feature , b ) vice grips type mechanisms applying force to the locking channel feature , c ) surgical towel clamp type mechanisms applying force to the locking channel feature , d ) lockable pliers type mechanisms applying force to the locking channel feature , e ) cam locking type mechanisms applying force to the locking channel feature , f ) latchig type mechanisms applying force to the locking channel feature , g ) bolting type mechanisms applying force to the locking channel feature , h ) conical thread type mechanisms applying force to the locking channel feature , i ) wedge type mechanisms applying force to the locking channel feature , j ) pivot type mechanisms applying force to the locking channel feature , k ) and radially actuated type mechanisms and / or mechanisms where rotational motion , about or substantially about or in predefined relation to the locking channel feature ( such as a locking channel the extends along a first axis parallel to the central axis of the anchor feature and then bends in a second direction to form a “ divergent section ” wherein the locking mechanism acts on the diverging section to facilitate ease of use ) applies force to the locking channel feature . it should be noted that although the locking channel feature is shown as being substantially “ female ” in nature to its interaction with the split sphere as being substantially “ male ”, these roles could beneficially be reversed wherein the split sphere feature would be provided as the “ female ” component with locking affected by the expansion of the “ leaves ” of the “ male ” version of the locking channel . another embodiment of the present invention further facilitating ease of use and accuracy of implant location and orientation entails referencing the bone apertures described herein with a surgically navigated probe to verify the alignment of the bone apertures with respect to a desired location and orientation of the implant prior to creation of the resected surface . if an error is detected in the alignment of a single aperture , where a second aperture is properly aligned , a surgically navigated drill guide with a probe for referencing the properly aligned second aperture may be used to create a corrected aperture . if an unacceptable error is detected in both apertures , a plurality of pins may be provided wherein there are a plurality of lines of contact constituting a corrected plane of resection by providing cutting tool guide surface that are non - parallel to the axis of the apertures into which the pins are inserted . in this way , the malaligned apertures may be used as to hold or support the cutting guide that can correct for the malalignment of the apertures . another embodiment of the present invention of particular utility involves modification of the drill tip feature of the anchor of the present invention shown in fig1 . in a first embodiment , the drill tip takes the form of a cannulated or coring drill wherein the cannulation extends from the leading tip of the drill cutting teeth with the tip back through some or all of the anchor thread to minimize trauma to living bone . in second embodiment , minimized trauma and improved ease of use are facilitate by offering a truncated version of the anchor feature wherein the cannulated coring drill type anchor would be made to be “ self tapping ” by shortening the anchor feature so that its distal most tip possess threads that are interrupted by the coring drill cutting teeth or where the teeth interrupt the leading edge of a smooth shaft leading the the threads . this second embodiment would minimize trauma by limiting the penetration of the anchor feature into bone to perhaps 25 mm or less , and preferably 5 mm to 10 mm , minimizing the displacement of living bone , and facilitating quick , free hand or semi - free hand attachment of the anchor feature to the bone in a robust manner . the complete disclosures of the patents , patent applications and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated . various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention . it should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein . | US-3658405-A |
the present invention relates to the use of esculoside alone or in combination with adenylate cyclase stimulators , such as forskolin or salvia miltiorrhiza diterpenes and / or with phosphodiesterase inhibitors , such as apigenine - skeleton dimeric flavones , in topical formulations for the treatment of peripheral vasculopathies related to an impaired peripheral microcirculation , cellulitis or unesthetisms connected with a deposit of superfluous fat . for the reduction of the deposits of superfluous fat of any origin , the above mentioned products are advantageously also combined with caffeine , theophylline and derivatives thereof . | esculoside is a glucosidated coumarin extracted from the fruit pericarp and from the bark of aesculus hippocastanum . such a product has been used for a long time in the treatment of pathological conditions connected with an impaired permeability and capillary fragility , and it is still used for the topical or systemic administration in the treatment of venous stasis vasculopathies , hemorrhoids and as a decongestionant in ophthalmology . now it has surprisingly been found that esculoside , alone or in combination with the above cited products , when topically administered increases both arterial blood flow ( activity on myocytes of arteries and precapillary arterioles increasing the sphygmicity thereof ) in the administration area , and the number of perfused capillaries , thus improving the superficial and deep circulations . this phenomenon was measured by means of non - invasive techniques , such as infrared photopulsoplethysmography , laser doppler flowmetry and computerized videocapillaroscopy . the first two techniques provide evidence of the vasomotility of the arteries and precapillary arterioles , whereas the latter provides an evaluation of the changes in the capillary bed and the district angiotectonic . after recording the basal data , a placebo formulation or the formulation containing the active ingredient or the active principals are applied on the body area treated . usually two symmetric body parts are used , randomizing the test . immediately after the treatment , the treated areas are checked with a videocapillaroscope ( scopeman - moritex video imaging system , alfa strumenti , milan ) fitted with a halogen - light optical probe with 50 to 400 × magnifications , measuring the capillary density ( number of blood - perfused capillaries per surface unit ) and evaluating the space orientation of the capillaries and the morphology thereof . the instrumentation was fitted with a videocamera for continuously recording the biomicroscopical images to allow the quantification of any changes during the elaboration phase . twenty minutes after the treatment with esculoside alone or in combination with the products mentioned above , such as ginkgo biloba dimeric flavones or amentoflavone , to cite the most important compounds , an increase in capillary density up to 200 - 300 % took place , compared with the basal and placebo - treated control . the action of esculoside in concentrations ranging from 0 . 5 to 3 %, evaluated as described above , lasts from one to three hours . videocapillaroscopy , as mentioned above , allows an evaluation of skin microangiotectonic , providing evidence of the number of perfused capillaries as well as the orientation in space and stratification thereof . it has surprisingly been found , and it is a part of the present invention , that , when formulations containing esculoside alone or in combination with a co - agent of a compound having adenylate cyclase stimulating activity or antiphosphodiesterase activity , and optionally also other lipolytic agents such as caffeine , theophylline , pentoxifylline , are administered to the area affected with disorders due to chronic venous deficiency , such as cellulitis , or on deposits of superfluous fat such as the unesthetisms following a forced diet , a marked decrease in the pathology occurs thanks to the improvement of district microcirculation due to esculoside and to the lipolytic effect of the other components . the administrations are performed for times ranging from a few days to some months , usually three months , depending on the severity of the pathology or the unesthetism . as far as the vascular system is concerned , esculoside alone or in combination with antiphosphodiesterase agents or adenylate cyclase stimulating agents can be used in chronic venous insufficiency , in raynaud &# 39 ; s disease and in acrocyanosis , as well as against cold - induced vasospasm , particularly for microcirculation in the fingers and toes . the higher blood flow to the areas treated with the active ingredients also improve skin early ageing , particularly face and neck skin , cellulitis - like derm - hypoderm panniculopathies and stretch marks ( striae distensae ) moreover , the higher blood supply also acts favorably on non - glabrous skin , such as scalp , and is useful in the treatment of the primitive and secondary alopecias . in the cosmetic fields , the main uses of the products object of invention relate the ageing of the skin and cellulitis , which affects a high percentage of the population in the industrialized countries . by way of example of the above described uses , 20 patients suffering from chronic venous insufficiency ( stage i ) were subdivided into two groups and treated with a formulation containing 1 . 5 % esculoside or with placebo for 3 months , twice a day , administering the product from the trocanterian area to the ankle . the patients , before the long - term treatment , were checked to evaluate their response capability by an acute test by means of videocapillaroscopic measurement of the increase in cutaneous microcirculation . the capillary density in the group treated with placebo , measured 20 minutes after the treatment , was 8 . 6 ± 2 . 2 %, whereas in the group treated with esculoside it was 18 . 6 ± 3 . 1 %, with p & lt ; 0 . 01 calculated by student test . the observed symptoms and their intensity , evaluated according to a severity score ranging from 0 to 4 , are reported in the following tables : table i__________________________________________________________________________evaluation of the symptoms in patients affected with venousinsufficiencyof the leg , before and after a 3 months - treatment with 1 . 5 % esculoside . patient nobefore : 1 2 3 4 5 6 7 8 9 10after : 1 2 3 4 5 6 7 8 9 10__________________________________________________________________________leg heaviness 0 0 3 2 2 1 3 1 2 0 3 1 2 1 3 2 0 0 3 1oedema 0 0 2 1 3 1 2 0 1 0 3 2 1 0 2 1 1 0 3 1paresthesia 1 0 2 0 0 0 1 0 3 1 2 0 0 0 2 1 1 0 1 0diurnal cramps 0 0 4 2 2 0 3 1 0 0 2 0 3 1 2 0 0 0 0 0nocturnal cramps 0 0 3 1 1 0 3 1 0 0 1 0 2 0 1 1 0 0 0 0venous telangiectasia 1 1 1 1 2 2 1 1 2 2 3 3 1 1 3 3 1 1 0 0varices 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0nervous legs 0 0 4 1 3 0 4 2 3 1 4 2 2 0 3 0 1 0 3 1cold feet 3 2 4 1 4 2 4 1 4 2 3 1 4 2 4 2 4 2 3 1__________________________________________________________________________ ______________________________________symptoms before after p & lt ; ______________________________________leg heaviness 2 . 1 ± 0 . 38 0 . 9 ± 0 . 23 p & lt ; 0 . 01oedema 1 . 8 ± 0 . 33 0 . 6 ± 0 . 22 p & lt ; 0 . 01paresthesia 1 . 5 ± 0 . 34 0 . 3 ± 0 . 15 p & lt ; 0 . 01diurnal cramps 1 . 6 ± 0 . 48 0 . 4 ± 0 . 22 p & lt ; 0 . 01nocturnal cramps 1 . 1 ± 0 . 38 0 . 3 ± 0 . 15 p & lt ; 0 . 05venous 1 . 5 ± 0 . 31 1 . 5 ± 0 . 31 n . s . telangiectasiavarices 0 . 2 ± 0 . 13 0 . 2 ± 0 . 13 n . s . nervous legs 2 . 7 ± 0 . 42 0 . 7 ± 0 . 26 p & lt ; 0 . 01cold feet 3 . 7 ± 0 . 15 1 . 6 ± 0 . 16 p & lt ; 0 . 01______________________________________ in thigh cellulitis due to chronic venous insufficiency , a group of 20 subjects was treated from the trocanterian area to the ankle for three months with a formulation containing 1 . 5 % esculoside , 0 . 3 % of salvia miltiorrhiza extract ( this extract containing 15 % tanshinone a2 ), 0 . 4 % ginkgo biloba dimeric flavones ( prepared according to indena patent ep 0360556 ) and 0 . 2 % theophylline . in these subjects , the observed parameters dramatically changed , as shown by the data reported in fig1 . in another test , a group of 20 subjects affected with fibrosclerotic panniculopathy of the trochanterian area with a deposit of superfluous fat was treated for 2 months with a formulation containing 1 . 5 % esculoside , 0 . 3 % salvia miltiorrhiza extracts of and 1 % pentoxifylline . the main control parameter was the reduction of the deposit of superfluous fat , therefore the diameter of the trochanterian area was measured , and was surprisingly decreased by 2 . 6 ± 0 . 2 cm . a number of other tests were carried out changing the composition and the components ratios or the nature of the components , for the treatment of the above cited pathologies and unesthetisms . the formulations according to the invention contain , besides the above mentioned active principles , the conventional carriers , additives , preservatives and the like known in pharmaceutical technique , such as those reported in the following non - limiting examples . gel containing esculoside , salvia miltiorrhiza extract and ginkgo biloba dimeric flavones . ______________________________________salvia miltiorrhiza extract 0 . 30 gesculoside 1 . 50 gginkgo biloba dimeric flavones 0 . 50 ghydrogenated castor oil 40 ( oe ) 1 . 00 g ( cremophor rh40 - basf ) propylene glycol 1 . 50 gpreservatives 0 . 10 ghydroxyethyl cellulose 3 . 00 g ( natrosol 250 hhx - aqualon ) purified water q . s . to 100 g______________________________________ ______________________________________salvia miltiorrhiza extract 0 . 25 gesculoside 1 . 50 gcaffeine 0 . 50 ghydrogenated castor oil 40 ( oe ) 5 . 00 g ( cremophor rh40 - basf ) propylene glycol 3 . 00 gcarbomer 940 1 . 00 g ( carbopol 980 - goodrich ) ethanol 45 . 00 gphosphatidylcholine ( phospholipon 90 - 0 . 70 gnatterman ) gliceryl 6 ( oe ) caprilate / caprinate 15 . 00 g ( softigen 767 ) preservatives 0 . 40 gbutylhydroxytoluene 0 . 05 gα - tocopherol 0 . 20 gascorbic acid 0 . 30 gdimethicone copolyol 2 . 00 g ( sf 1188 - general electric ) 10 % triethanolamine sol . 5 . 00 gdepurated water q . s . to . 100 g______________________________________ cream containing esculoside , salvia miltiorrhiza extract and extract of cola nut titrated in caffeine - like alkaloids . ______________________________________salvia miltiorrhiza extract 0 . 25 gesculoside 1 . 50 gcola nut dry extract ( 14 % total alkaloids ) 0 . 50 ghydrogenated castor oil 40 ( oe ) 2 . 00 g ( cremophor rh40 - basf ) propylene glycol 2 . 00 gcarbomer 934 0 . 50 g ( carbopol 934 p - goodrich ) acrylates / alkyl c . sub . 10 - 30 - acrylate crosspolymer 0 . 50 g ( carbopol 1382 - goodrich ) ethanol 15 . 0 gpreservatives 0 . 40 gcetyl palmitate ( cutina cp - henkel ) 8 . 00 gpolyisoprene ( syntesqual - vevy ) 5 . 00 gpolysorbate 80 ( tween 80 - ici americans ) 2 . 00 gα - tocopherol 0 . 20 gascorbyl palmitate 0 . 10 ghydrogenated lanolin ( lanocerina - esperis ) 5 . 00 gdimethicone 350 cps ( tegiloxan 350 - tego ) 0 . 50 g10 % naoh sol . 2 . 40 gdepurated water q . s to . 100 g______________________________________ ______________________________________esculoside 1 . 00 gtheophylline 0 . 50 gbutylhydroxytoluene 0 . 10 gethyl alcohol 50 ° q . s . to 100 ml______________________________________ ______________________________________esculoside 1 . 00 gisopropyl myristate 5 . 00 gpreservatives 0 . 40 gperfume 0 . 10 gpolyacrylamide , c . sub . 13 - 14 3 . 00 gisoparaffin and lauric alcohol 7 ( oe )( sepigel 305 - seppic ) depurated water q . s . to 100 g______________________________________ | US-49886895-A |
the present invention relates to a novel liquid seasoning and a method for producing the liquid seasoning . according to the present invention , it is possible to provide a novel liquid seasoning that retains the function of salted rice malt , has a good balance among umami , sweetness and saltiness , has a less koji smell and is highly convenient , and to provide a method for producing the liquid seasoning . | the liquid seasoning of the present invention is obtained by performing fermentation and maturation at a low temperature of the preparation liquid prepared by mixing malted rice , salt and water , and subsequently carrying out a solid - liquid separation . in other words , the method for producing the liquid seasoning of the present invention comprises performing fermentation and maturation at a low temperature of a preparation liquid prepared by mixing malted rice , salt and water , and subsequently carrying out a solid - liquid separation . the malted rice used in the present invention may be prepared in accordance with a usual koji production method for producing malted rice . specifically , the malted rice is obtained by spraying koji - mold ( also referred to as seed malt ) on steamed rice prepared by steaming rice , and then breeding the koji - mold under the condition optimal to the koji - mold . for breeding the koji - mold , an automatic fermentation machine ( for example , hk - 60 , produced by yaegaki food & amp ; system , inc .) may be used to perform cultivation for 2 to 4 days at 25 ° c . to 40 ° c . the malted rice used in the present invention may be a commercial product . rice , such as nonglutinous rice , glutinous rice and brewer &# 39 ; s rice , preferably polished rice ( white rice ), may be washed as necessary , soaked in water and drained as necessary . the koji - mold is not limited in particular insofar as it is used for a normal production of koji . a preferable example is genus aspergillus ( asperugillus ), such as aspergillus oryzae and asperugillus sojae . the koji - mold used in the present invention may be a commercial product sold as seed malt or may be a cultured mold . in addition , the koji - mold may be granular or powdery . the koji - mold used in the present invention preferably has high saccharification power or high productibility of protease . specifically , the koji - mold used in the present invention may be koji - mold used for miso , koji - mold used for malted rice , or koji - mold used for soy sauce . more preferably , it is the koji - mold used for malted rice or the koji - mold used for miso . it is further more preferably the koji - mold used for miso . one kind of koji - mold among these koji - molds may be used singly , or two or more kinds of koji - molds may be used in combination . the preparation liquid of the present invention is obtained by mixing malted rice , salt and water . these may be simultaneously put in and mixed , or may be successively put in and mixed . the malted rice is mixed desirably to have 30 to 70 weight % relative to the preparation liquid , preferably 35 to 60 weight %, more preferably 40 to 55 weight %, and further more preferably 45 to 50 weight %. the salt is mixed to desirably have 8 to 20 weight % relative to the preparation liquid , preferably 10 to 16 weight %, more preferably 12 to 15 weight %, and further more preferably 13 to 14 weight %. this salt can inhibit or reduce growth of microorganisms in the preparation liquid . the phrase “ preforming fermentation and maturation at a low temperature of a preparation liquid ” in the present invention means that the preparation liquid is subjected to the fermentation and maturation at a temperature at which enzymes derived from koji - mold and contained in the preparation liquid are not inactivated ( deactivated ). here , the enzymes derived from the koji - mold refer to enzymes produced by the koji - mold , and includes , for example , amylase , protease , lipase and cellulase . these enzymes are weak against heat . in particular , protease is inactivated when the fermentation and maturation are performed at 60 ° c . or more ( see example 5 in the embodiment ). according to a preferable embodiment of the present invention , it is desirable that the low temperature is 4 ° c . to 40 ° c ., preferably 20 ° c . to 38 ° c ., more preferably 25 ° c . to 35 ° c ., and further more preferably 28 ° c . to 32 ° c . the enzymes derived from the koji - mold are not inactivated at these temperature . in the present invention , the “ fermentation and maturation ” means not only that fermentation is performed by the koji - mold but also that starch , proteins and lipids contained in rice are decomposed by the enzymes derived from the koji - mold . this may be mainly referred to as saccharification . it is noted that the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) may be referred to as “ salted rice malt ( shio - koji , shiokoji , shio koji )”. according to a preferable embodiment of the present invention , it is desirable to perform fermentation and maturation to an extent until the brix value ( value of brix ) of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) is increased by 4 % or more relative to the brix value in the first day of the fermentation and maturation , preferably until by 6 % or more , and further more preferably until by 9 % or more . here , the brix value in the first day of the fermentation and maturation means a brix value of the preparation liquid before onset of fermentation and maturation . that is , it is a brix value of the preparation liquid itself obtained by mixing malted rice , salt and water . in addition , the brix means a value measured using a refractometer . the value of brix varies in accordance with the increase and decrease of sucrose , salt , various amino acids , glucose , maltose , and other components . thus , the brix value varies in accordance with the composition of raw materials of the preparation liquid . for example , when the preparation liquid is obtained by mixing 50 weight % of malted rice , 13 weight % of salt and 37 weight % of water , it is desirable to perform the fermentation and maturation to an extent until the brix value of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) becomes 37 % or more , preferably until 39 % or more , and further more preferably until 41 % or more . the brix can be measured by one of ordinary skill in the art using a known method . for example , the brix can be measured using a commercial hand - held refractometer or a commercial digital refractometer . generally , measuring the brix is simpler than measuring the concentration of direct sugar . in addition , according to a preferable embodiment of the present invention , it is desirable to perform the fermentation and maturation to an extent until the concentration of direct sugar of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) is increased by 8 % or more relative to the concentration of direct sugar in the first day of the fermentation and maturation , preferably until by 12 % or more , and further more preferably until by 18 % or more . here , the direct sugar means direct reducing sugar , and the concentration of direct sugar varies in accordance with the composition of raw materials of the preparation liquid . for example , when the preparation liquid is obtained by mixing 50 weight % of malted rice , 13 weight % of salt and 37 weight % of water , it is desirable to perform the fermentation and maturation to an extent until the concentration of direct sugar of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) becomes 16 % or more , preferably until 20 % or more , and further more preferably until 26 % or more . the concentration of direct sugar can be measured by one of ordinary skill in the art using a known method . for example , the concentration of direct sugar can be measured using somogyi modification method ( nippon nogeikagaku kaishi 28 ( 3 ) 171 - 174 ( 1954 )) or a method shown by japan agricultural standards for soy - source . according to a more preferable embodiment of the present invention , it is desirable to perform the fermentation and maturation to an extent until the brix of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) is increased by 4 % or more relative to the brix in the first day of the fermentation and maturation and the concentration of direct sugar is increased by 8 % or more relative to the concentration of direct sugar in the first day of the fermentation and maturation , preferably until the brix is increased by 6 % or more and the concentration of direct sugar is increased by 12 % or more , and further more preferably until the brix is increased by 9 % or more and the concentration of direct sugar is increased by 18 % or more . when the brix of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) is increased by 4 % or more and the concentration of direct sugar of the preparation liquid after performing the fermentation and maturation ( matured product ) is increased by 8 % or more relative to the respective values in the first day of the fermentation and maturation , the balance among umami , sweetness , and saltiness becomes superior . according to an embodiment of the present invention , when the preparation liquid is obtained by mixing 50 weight % of malted rice , 13 weight % of salt and 37 weight % of water , it is preferable to perform the fermentation and maturation to an extent until the brix of the preparation liquid after performing the fermentation and maturation ( matured product ) becomes 37 % or more and the concentration of direct sugar of the preparation liquid after performing the fermentation and maturation ( matured product ) becomes 16 % or more , further preferably until the brix becomes 39 % or more and the concentration of direct sugar becomes 20 % or more , and further more preferably until brix becomes 41 % or more and the concentration of direct sugar becomes 26 % or more . according to a preferable embodiment of the present invention , it is desirable to perform the fermentation and maturation at a low temperature for 1 to 60 days , preferably for 2 to 30 days , further preferably for 3 to 21 days , further more preferably for 4 to 14 days , highly preferably for 6 to 13 days , particularly preferably for 8 to 12 days , and especially preferably for 10 days . as the temperature is lower , the activity of enzymes derived from koji - mold becomes lower and thus the period of the fermentation and maturation becomes longer . thus , according to a further preferable embodiment of the present invention , when the temperature of fermentation and maturation is in the range of 20 ° c . to 38 ° c ., it is desirable to perform the fermentation and maturation for 3 to 21 days , preferably for 4 to 14 days , further preferably for 6 to 13 days , furthermore preferably for 8 to 12 days , and most preferably for 10 days . according to a further preferable embodiment of the present invention , the fermentation and maturation is performed at 20 ° c . to 38 ° c . for 3 to 21 days to an extent until the brix of the preparation liquid after performing the fermentation and maturation ( i . e ., matured product ) is increased by 4 % or more and the concentration of direct sugar is increased by 8 % or more , relative to the respective values in the first day of the fermentation and maturation . thus , according to an embodiment of the present invention , the liquid seasoning of the present invention is obtained by carrying out the solid - liquid separation from the preparation liquid after performing the fermentation and maturation at a low temperature ( i . e ., matured product ) wherein the fermentation and maturation are performed until the brix and / or the concentration of direct sugar respectively become predetermined values , and / or wherein the fermentation and maturation are performed for a predetermined period . in the present invention , the “ solid - liquid separation ” means a method for separating solid matter from liquid . the solid - liquid separation method is not particularly limited , and may be a method normally used for sweet sake or soy sauce . for example , compression filtration using a compression filtration apparatus , compression using a filter cloth , solid - liquid separation using a centrifugal separation apparatus may be used . the compression filtration is preferable . the filtrate obtained by the solid - liquid separation can be directly used as the liquid seasoning of the present invention . the thus - obtained liquid seasoning has activity of enzymes derived from koji - mold , and the activity is equal to or higher than that of enzymes of the matured product before carrying out the solid - liquid separation . thus , according to an embodiment of the present invention , the liquid seasoning of the present invention has the enzyme activity , and preferably has the protease activity . in addition , the thus - obtained liquid seasoning has koji smell less than the koji smell of the matured product before carrying out the solid - liquid separation ( see examples 1 and 2 in the embodiment described below ), and has sweet smell associated with honey . further , the concentration of direct sugar of the thus - obtained liquid seasoning is similar to the concentration of the matured product before carrying out the solid - liquid separation . thus , it is preferable that the concentration of direct sugar of the liquid seasoning of the present invention is 16 % or more , further preferably 20 % or more , and further more preferably 26 % or more . a product prepared by further diluting the filtrate obtained by carrying out the solid - liquid separation may be used as the liquid seasoning of the present invention . here , it is preferable to perform the dilution so as to obtain a desired salt concentration . a product prepared by further sterilizing the filtrate obtained by carrying out the solid - liquid separation may be used as the liquid seasoning of the present invention . the sterilization method is not particularly limited insofar as the method is used usually for sterilizing liquid . for example , heat sterilization , sterilization by ethanol ( spirit ) addition , filter sterilization , or the like may be used . the sterilization by ethanol addition or the filter sterilization is preferable as the sterilization method because neither of them inactivate the enzymes of the liquid seasoning obtained . in the sterilization by ethanol addition , the amount of added ethanol is not particularly limited insofar as the amount leads to sterilization of the liquid seasoning . relative to the liquid seasoning , ethanol is added preferably to reach 0 . 5 to 10 weight %, more preferably 1 to 6 weight %, and further more preferably 2 to 5 weight %. when the concentration of added ethanol reaches 10 weight % or more , alcohol smell and alcohol taste become conspicuous . the sterilization by the filter sterilization can be performed , for example , by filtration using diatomaceous earth or by filtration using a microporous membrane . this filtration can reduce or eliminate microorganisms from liquid . the filtrate obtained by the solid - liquid separation may be further subjected to concentration or decolorization using filtration membrane , resin or the like to obtain the liquid seasoning of the present invention . in addition , the liquid seasoning of the present invention may contain other components , such as preservative , antioxidant and spice . here , in order to avoid inactivation of the enzymes , it is preferable that ph of other components in the aqueous solution is in a neutral range . according to an embodiment of the present invention , a food and drink is provided in which the liquid seasoning of the present invention is added . here , the food and drink is not particularly limited insofar as the food and drink is normally subjected to addition of salted rice malt , sweet sake , and soy sauce . it is noted that the liquid seasoning of the present invention infiltrates into foods faster than the salted rice malt . thus , it is possible in a short time to soften meats , to increase the taste of foods , or to impart the good balance among umami , sweetness , and saltiness of the liquid seasoning . traditionally , the salted rice malt has a rice - gruel - like form or a pasty form in which rice grains are battered and thickened . thus , when the salted rice malt is used for foods , it is necessary to apply or rub the salted rice malt to the foods by hands or a spatula . in contrast , the liquid seasoning of the present invention is in a liquid form , and thus has a good usability and great convenience . further , the liquid seasoning of the present invention can be used even to some kinds of foods for which use of the salted rice malt has been avoided because grains of koji contained in the salted rice malt have spoiled the appearance ( see example 3 in the embodiment described later ). the food and drink includes , for example , other seasonings such as miso , soy sauce , sweet sake , mayonnaise , dressing , and ponzu vinegar ; tsuyu such as soup of noodle , soup of oden , and soup of hot pot ; tare sauce such as sauce for broiled ( grilled , barbecued ) meat ; soaking solution for meat , fish and vegetable ; sauce such as meat sauce , and white sauce ; soup ; soup stock ; confection and bread ; and the like . in addition , the food and drink includes cooked foods such as broiled meat and fish in which meat of livestock and fish treated with the seasoning of the present invention are used , boiled dish , curry , stew , miso soup , spaghetti , hamburg steak , and dumpling ; and processed foods such as kimchi , pickles , kamaboko , sausage , frozen food , ready - made food , and chilled food . the amount of the liquid seasoning of the present invention added to the food and drink , to the meat of livestock , and to the fish is individually and appropriately selected in accordance with the target food and drink . although the present invention will be described in detail by referring to examples described below , the present invention is not limited to these examples . the liquid seasoning was produced in accordance with steps illustrated in fig1 . rice was soaked for 12 hours in water having the amount 1 . 2 times the amount of the rice , and was drained for 2 hours . then , the drained rice was steamed for 45 minutes using a steamer ( produced by hanyuda co . ltd .) and the steamed rice was obtained . after the steamed rice was cooled to the temperature of 30 ° c ., seed malt ( seed malt to be used for miso , obtained from higuchi matsunosuke shoten co . ltd .) was scattered and mixed several times ( tanekiri ) so that the seed malt relative to 1 kg of the steamed rice was 0 . 3 g ( steamed rice : seed malt = 1000 : 0 . 3 ). while being stirred occasionally , the rice mixed with the seed malt was cultivated for 42 hours at 35 ° c . by an automatic fermentation machine ( hk - 60 , produced by yaegaki food & amp ; system , inc .) and thus malted rice was obtained . a preparation liquid was obtained by mixing 50 kg of malted rice obtained , 13 kg of salt ( crude salt ) and 37 l of water . the preparation liquid was subjected to fermentation and maturation for 10 days at 30 ° c . and a matured product was obtained ( comparison block 1 ). the matured product obtained was subjected to compression filtration using a compression filtration apparatus ( pressure - filtration compression apparatus used for laboratory , produced by nsk engineering co ., ltd . ), and the filtrate was obtained as a liquid seasoning ( test block 1 ). sensory evaluation was carried out for the matured product obtained ( comparison block 1 ) and the liquid seasoning ( test block 1 ) by measuring ph , direct sugar , salt , and enzyme activity . the ph measurement was performed using a ph meter ( f - 72 , produced by horiba , ltd ). the direct sugar measurement was performed by somogyi modification ( nippon nogeikagaku kaishi 28 ( 3 ) 171 - 174 ( 1954 )). the salt measurement was performed using a potential - difference titration device ( at - 500n , produced by kyoto electronics manufacturing co ., ltd .). the enzyme activity measurement was performed in terms of the protease activity at ph 6 . 0 , which was measured by kageyama modification of phenol reagent method of folin - ciocalteu ( hakkokogaku zasshi 33 ( 1 ) 28 - 32 ( 1955 )). specifically , the following method was used . each of 5 g samples ( matured product , liquid seasoning ) was subjected to 10 fold dilution using 0 . 5 % nacl solution and filtration . then , 1 ml of the filtrate ( sample solution ) was further diluted using 4 ml of phosphate buffer at ph 6 . 0 . a 2 - ml aliquot of a solution prepared by adding phosphate buffer at ph 6 . 0 to milk casein to make a concentration of 1 . 5 % was added as a substrate to 1 ml of the diluted solution obtained ( test liquid ), and the resultant mixture was reacted for 1 hour at 37 ° c . then , 4 ml of 0 . 4 mol / l trichloroacetic acid was added to stop the reaction . the solution obtained was filtered . to 1 ml of the filtrate , 5 ml of 0 . 4 mol / l sodium carbonate was added , and 1 ml of a phenol reagent was further added . then , the resultant mixture was allowed to develop color for 20 minutes at 37 ° c . the colored solution was used as a test sample . note that a control ( blank sample ) was prepared in the following way . first , 4 ml of 0 . 4 mol / l trichloroacetic acid was added to 2 ml of the substrate in advance , 1 ml of the test liquid was added thereto , and the resultant mixture was reacted for 1 hour at 37 ° c . then , the reaction mixture was filtered and the firtrate was used for color development . the absorbance of the test sample and the blank sample at the wavelength of 660 nm was measured using a spectrophotometer ( uv - 1200 , shimadzu corporation ). the absorbance of the blank sample was subtracted from the absorbance of the test sample , and the result was multiplied by the dilution ratio and the factor ( coefficient ) of the phenol reagent to obtain the protease activity ( unit / g ) for 1 g of the sample ( specifically , protease activity ( unit / g )=[ absorbance of the test sample − absorbance of the blank sample ]× 350 ( the dilution ratio )× factor of the phenol reagent ). here , the factor of the phenol reagent was calculated using a tyrosine solution . specifically , the absorbance was measured under the same conditions as above except that 1 ml of 50 μg / ml tyrosine solution was used instead of the above - described solution . the factor of the phenol reagent was obtained by dividing the standard absorbance of the tyrosine solution of 0 . 350 by the measured absorbance . ( specifically , the factor of phenol reagent = 0 . 350 / absorbance of 50 μg / ml tyrosine solution for each preparation of the phenol reagent ). the sensory evaluation was carried out by 5 trained , specialized panelists . items of “ odor ” and “ taste ” of the matured product ( comparison block 1 ) and the liquid seasoning ( test block 1 ) were evaluated as described below and the average values are shown . in addition , sensory findings are also shown . 5 : good . no offensive smell ( koji - specific smell ( that is , koji smell ), smell produced by heating , stuffy smell ) is felt . sweet smell is strongly felt . 5 : good . no foreign taste ( unpleasant taste ) is felt . the balance among umami , sweetness and saltiness is very good . 4 : slightly good . no foreign taste is felt . the balance among umami , sweetness and saltiness is slightly good . 3 : normal . no foreign taste is felt . the balance among umami , sweetness and saltiness is good . 2 : slightly bad . a little foreign taste is felt . a little bitter taste is felt in umami , sweetness and saltiness . 1 : bad . foreign taste is felt . bitter taste is felt in umami , sweetness and saltiness . a preparation liquid was obtained by mixing 50 kg of malted rice obtained in the above - described example 1 ( 1 ), 13 kg of salt ( crude salt ), and 37 l of water . the preparation liquid was subjected to fermentation and maturation for 10 days at 30 ° c ., and the matured product was obtained . the matured product obtained was filled and packed in a heat resistant bag and was kept in warm water at 85 ° c . for 15 minutes , and a heated matured product was obtained ( comparison block 2 ). the heated matured product obtained was subjected to compression filtration using a compression filtration apparatus ( pressure - filtration compression apparatus used for laboratory , produced by nsk engineering co ., ltd . ), and the filtrate was obtained as a liquid seasoning ( test block 2 ). measurements of ph , direct sugar , salt and enzyme activity were performed by a method similar to the method used in example 1 ( 3 ), and a sensory evaluation was carried out for the heated matured product obtained ( comparison block 2 ) and the liquid seasoning ( test block 2 ). food material ( breast meat of chicken ) was cooked using the liquid seasonings ( respectively served as test block 1 : enzyme activity 55 ( unit / g ), and test block 2 : enzyme activity 0 ( unit / g )) obtained in the above - described example 1 and example 2 and the matured product obtained in example 1 ( comparison block 1 : enzyme activity 52 ( unit / g )) before the compression filtration treatment , and then the evaluation with respect to the seasonings was carried out . specifically , 100 g of breast meat of chicken was immersed in 8 ml ( corresponding to 10 g weight ) of the liquid seasoning ( test block 1 or test block 2 ) or 10 g of matured product at 5 ° c . for 12 hours , and the resultant meat was grilled . then , the sensory evaluation was carried out with respect to the cooked food . the sensory evaluation was carried out by 5 trained , specialized panelists . items of “ taste ” and “ softness ” of the meats were evaluated as described below and the average values are shown . the “ taste ” of meat was represented by a degree of strength , and was evaluated using the following evaluation criteria . the “ softness ” of meat was represented by a degree of strength , and was evaluated using the following evaluation criteria . food materials ( leg meat of chicken and pork loin ) were cooked by using the liquid seasoning ( test block 1 ) obtained in the above - described example 1 and using salted rice malt ( siokouji , obtained from hanamaruki foods inc . ), and the evaluation with respect to the seasonings was carried out . specifically , 10 weight % each of the liquid seasoning and the salted rice malt relative to the weight of the meat were applied to the leg meat of chicken and pork loin , the resultant materials were kept in this way at 5 ° c . for 24 hours , and then grilled . the sensory findings are shown for the cooked foods . the results showed that both the leg meat of chicken and pork loin cooked using the liquid seasonings were softer than those cooked using the salted rice malt . in addition , the pork loin cooked using the liquid seasonings had less smell of uncooked meat than that of the pork loin cooked using the salted rice malt . food material ( slice of fresh salmon ) was cooked by using the liquid seasoning ( test block 1 ) obtained in the above - described example 1 and using the salted rice malt ( siokouji , obtained from hanamaruki foods inc . ), and then an evaluation with respect to the seasonings was carried out . specifically , 10 weight % each of the liquid seasoning and the salted rice malt relative to the weight of the slice were applied to the surface of slice of fresh salmon , the resultant material was kept in this way at 5 ° c . for 24 hours , and then grilled . the , sensory findings are shown for the cooked food . the results showed that the taste was infiltrated only to the surface , in the slice cooked using the salted rice malt . in contrast , the taste was infiltrated into the center , in the slice cooked using the liquid seasoning and good gloss was also obtained for the grilled food . food material ( green soybeans ) was cooked by using the liquid seasoning ( test block 1 ) obtained in the above - described example 1 and using the salted rice malt ( shiokouji , obtained from hanamaruki foods inc . ), and then an evaluation with respect to the seasonings was carried out . specifically , 6 weight % each of the liquid seasoning and the salted rice malt relative to the boiling water for the green soybeans , were stirred in the water , and the raw green soybeans were boiled for 5 minutes . the sensory findings are shown for the cooked foods . the results showed that the green soybeans cooked using the salted rice malt had unsatisfactory taste and had pods on which koji grains were attached so as to spoil the appearance . in contrast , in the green soybeans cooked using the liquid seasoning , the taste was infiltrated into the center , and sweetness of the food material was brought out for a rich taste . a marinade was prepared by using the liquid seasoning ( test block 1 ) obtained in the above - described example 1 and using the salted rice malt ( shiokouji , obtained from hanamaruki foods inc . ), and then an evaluation with respect to the seasonings was carried out . specifically , the liquid seasoning or the salted rice malt and olive oil were mixed to prepare the marinade using the ratio ( liquid seasoning or salted rice malt : olive oil = 1 : 3 ). thin slices of white flesh ( red sea bream ) were soaked in the prepared marinade at 5 ° c . for 1 hour and the two kinds of carpaccio were prepared . then , sensory findings are shown for respective carpaccio . the results showed that the slice of white flesh prepared using the liquid seasoning was softer than the slice prepared using the salted rice malt , and the smell specific to fish was eliminated . bread was baked by using the liquid seasoning ( test block 1 ) obtained in the above - described example 1 and using the salted rice malt ( shiokouji , obtained from hanamaruki foods inc .). specifically , 40 ml of the liquid seasoning or 38 g of the salted rice malt was added to 280 g of strong flour , 20 g of sugar , 150 ml of water , 20 g of olive oil , 6 g of skimmed milk and 3 g of dry yeast , and loaves of bread were baked by a usual method . the sensory findings are shown for each of the loaves . the results showed that the bread baked using the liquid seasoning was moist and very tasty . comparison between the liquid seasoning and other seasonings ( sweet sake ( mirin ), and soy source made from rice ( kome - shoyu )) a comparison was performed between the liquid seasoning ( test block 1 ) obtained in the above - described example 1 and other seasonings ( mirin and kome - shoyu ) whose main raw material was rice , in terms of components of seasonings . specifically , raw material , salt , direct sugar , alcoholic content , and enzyme activity were measured as the components . the salt measurement , the direct sugar measurement , and the enzyme activity measurement were performed by methods similar to those used in example 1 ( 3 ). alcohol measurement was performed by a gas chromatography method . specifically , the measurement was performed by gc - 8a equipped with an fid detector ( produced by shimadzu corporation ) using a stainless - steel column ( 1 . 0 m length × 3 mm inner diameter ) filled with filler ( porapak ™ qs , produced by nihon waters k . k .). here , hon - mirin ( obtained from kikkoman corporation ) was used as the sweet sake . kome - shoyu ( obtained from ohtaka shoyu co ., ltd .) was used as the soy source made from rice . a preparation liquid was obtained by mixing 50 kg of malted rice obtained in the above - described example 1 ( 1 ), 13 kg of salt ( crude salt ) and 37 l of water . the preparation liquid was subjected to fermentation and maturation for 21 days at 30 ° c . and a matured product was obtained . on the 1st day , 2nd day , 3rd day , 4th day , 7th day , 10th day , 16th day , and 21st day of the fermentation and maturation , aliquots of the matured product were sampled and the brix and ph of each of the aliquots were measured . in addition , the direct sugar was measured on the 1st day and 10th day . further , the sugar composition was analyzed on the 10th day . the ph measurement and the direct sugar measurement were performed by the methods similar to those of example 1 ( 3 ). the brix measurement was performed by the following method . the matured product weighing 10 g and 10 ml of distilled water were mixed sufficiently , the mixture was left to stand for 5 minutes , and then filtered using a filter paper ( advantec 5b ). a handy refractometer ( hsr - 500 , produced by atago ) was used to measure the brix of the filtrate . adjustment was made on the dilution ratio ( a factor of 2 ) and the value of brix (%) of the matured product was obtained . the analysis of sugar composition was performed by a high performance liquid chromatography ( hplc ) method . results are shown in fig2 and 3 , and table 7 . a preparation liquid was obtained by mixing 50 kg of malted rice obtained in the above - described example 1 ( 1 ), 13 kg of salt ( crude salt ) and 37 l of water . the preparation liquid was subjected to fermentation and maturation at a high temperature ( 55 ° c .) for 10 days and a matured product was obtained ( comparison block 3 ). when the temperature of the fermentation and maturation is high , saccharification proceeds rapidly , which makes it possible to shorten the period of fermentation and maturation . hence , a matured product ( comparison block 4 ) was obtained by changing the period of fermentation and maturation to 1 day while maintaining the other conditions similar to those of the comparison block 3 . the enzyme activity of the matured product obtained was measured by a method similar to the method of example 1 ( 3 ). the results showed that the enzyme activity of comparison block 3 and the enzyme activity of comparison block 4 each were 0 ( unit / g ). | US-201314425911-A |
a strap fastener comprising a pair of engageable magnetic fasteners of opposite polarity to each other engageable on a common axis , a strap engagement portion connected to each magnetic fastener and extending transverse to said common axis of engagement of said magnetic fasteners ; and at least one protrusion to reside against a perimeter of an opposed magnetic fastener to resist movement of one magnetic fastener with respect to the other transverse to said common axis on which they engage . | referring firstly to fig1 to 3 , there are shown a magnetic member ( 10 ) and a housing ( 20 ) which , when assembled together , form a first preferred embodiment of the present invention of a magnetic buckle . the magnetic member ( 10 ) is the source of the magnetic coupling force for engaging with a counterpart magnetic buckle . preferably , this magnetic member includes a permanent magnet in the form of a magnetic slab made of a strong magnetic substance or alloy in order to provide a large magnetic force - to - volume ratio essential for a compact buckle design . with the current magnetic technology , a pair of complementary magnetic slabs having a diameter of 1 cm and a thickness of about 1 mm and with an appropriate design as mentioned herein can produce a magnetic coupling force of up to 20 - 30 n . in the present preferred example , the magnetic slab is substantially circular or cylindrical with a diameter of about 12 mm and a thickness of less than 1 mm . to provide a maximum magnetic coupling area , the two opposite magnetic poles are preferably disposed on the two opposing planes ( 11 , 12 ) of the magnetic slab so that the north pole is on one of the planar surfaces while the south pole is on the other . to increase the magnetic flux intensity on the coupling surface , the magnet member is preferable embedded within a casing made of a magnetic material , such as an iron , steel or other ferro - magnetic casing , with the magnetic coupling surface exposed . with such an embedment of a strong magnet on a ferro - magnetic casing , the magnetic strength of the exposed coupling surface is considerably strengthened by concentration . of course , magnetic members of other shapes and thickness can equally be used without loss of generality . for example , the magnetic member can be made into a rectangular , polygonal , trapezoidal or even irregular or non - geometric cross - section . in addition , a ring - or toroidal shaped magnetic member can also be utilized . the housing includes a holder portion ( 21 ) or receptacle for receiving the magnetic member and a strap receiving portion ( 25 ) for anchoring a flexible end of a strap for releasable engagement with a counter - part magnetic buckle . the magnetic member holder portion includes a base portion ( 22 ) which preferably conforms closely to the base dimensions of the magnetic member and an upstanding fencing wall ( 23 ) which extends upwardly along the perimeter of the base portion . the combined structure of the base portion together and the peripheral fencing wall provides a cavity casing within which the magnetic member is received with the magnetic coupling surface ( 11 ) exposed and unobstructed . the cavity casing , which includes the base portion ( 22 ) and the upwardly extending parametric peripheral wall ( 23 ), is preferably made of a magnetic material , for example , a ferro - magnetic substance such as chromium or nickel plated steel . the magnetic member can be glued to the cavity housing or retained by other means , including mechanical retention or embedment . when the magnetic member is enclosed by a magnetic material in this manner , the magnetic strength of the exposed magnetic surface will be reinforced and the magnetic coupling forces , when coupled with the opposite magnetic surface ( 10 ) of a similarly designed counterpart magnetic buckle , will be greatly enhanced when compared to magnetic members not so encased . with such a design , a more compact buckle with a strong magnetic strength can be provided . the strap receiving portion ( 25 ) includes a means ( 24 ) for receiving or otherwise connecting to the flexible end of a flexible strap . to enhance secured retention of the strap , the receiving portion may include a serrated slot or notch . the strap receiving portion ( 25 ) includes a means ( 24 ) for receiving the flexible end of a flexible strap in order to form a strap with a buckled end . to improve better retention of the strap end , the receiving portion may include a serrated slot or notch . in order to provide a low - profile buckle design , the strap receiving portion is relatively thin with a thickness which is preferably equal to or less than that of the peripheral wall of magnetic member . in addition , the strap receiving portion is preferably formed by placing it adjacent to the peripheral edge joining the magnetic polar surfaces rather than extending from either polar surfaces so that an over - all low - profile structure can be obtained . in the present embodiment , the strap receiving portion contains a rigid bridging portion which extends away from the cavity casing in a lateral or radial manner . in this arrangement , the strap receiving portion is substantially equi - distant from both polar surfaces and is joined to the cavity casing by the rigid bridging portion ( 27 ). the bridging portion ( 27 ) preferably includes a ribbon - shaped plate member with its wide surfaces substantially parallel to the magnetic coupling surfaces ( 11 , 12 ). of course , instead of ribbon shaped member , a thin shaft member may be used to join the strap receiving portion and the cavity casing . in any event , the portion of the housing which extends away from the cavity casing should be of a slim design so that an overall low - profile design can be achieved . for example and as shown in the figures , a substantial portion of that extension is preferably flat and the whole portion should be kept within the height of the peripheral wall of the magnetic member ( 10 ). alternatively , the strap - receiving means may be formed proximate and adjacent to the peripheral wall joining the polar surfaces ( 11 , 12 ) so that it is substantially equidistant from both polar surfaces ( 11 , 12 ). forming the strap - receiving means sidewise of the polar surfaces will always provide a desirable low - profile structure . referring now to fig4 in which there are shown a pair of complementary counterpart magnetic buckles in magnetic engagement , it can be seen that the magnetic coupling surfaces of the counterpart buckles a and b with magnetic coupling surfaces ( 11 ) of the opposite magnetic polarities are in physical contact . it should be noted that while it is preferable that both of the complementary buckles are of the same structural design as mentioned herein , a buckle of a different design but of a complementary nature can be used as a counterpart buckle or fastener . as can be seen from this figure , the laterally or radially extending strap receiving portions help to reduce the overall thickness of the engaged buckle pair , making the assembly particularly suitable for use in circumstances , for example in lingerie and brassiere applications , where a thin assembly is desirable . furthermore , in order to alleviate the risks of undesirable or accidental disengagement of the magnetically coupled buckle pairs , the portion of the peripheral wall at the end of the cavity casing directly opposing the strap receiving portion is made with a small projection or with an elevated teeth ( 26 ) resembling portion . the protruding portion ( 26 ) of the buckle is formed on the cavity wall ( 23 ) and extends beyond the surface of its magnetic coupling surface ( 11 ). this projection ( 26 ) will become a barrier member to the magnetic member ( 10 ) of the counterpart buckle by extending also beyond the magnetic coupling surface ( 11 ) of the counterpart buckle . with the elevated portion engaging with the edge of the magnetic member of the corresponding counterpart buckle , undesirable lateral slippage in both the left and right directions , i . e ., directions along both strap receiving portions can be greatly alleviated . when the buckles are to be un - coupled , a user only needs to slightly lift one of the buckles , for example , by pivoting against the counterpart buckle and then separating the buckles . to ensure sufficient space for accommodating the protruding member ( 26 ) without having to press against the bridging portion , a slight indentation corresponding to the location of the protruding portion is preferably provided so that the teeth ( 26 ) can rest above and away from the bridging portion . this slight indentation may also be accompanied by a discontinuation of the perimetric wall at the corresponding position to allow engagement of the teeth member . as shown in the figures , the indentation is formed at the intersection or junction between the bridging portion and the cavity housing . in the present specific example , the housing is integrally formed of a magnetic material so that one of the magnetic surfaces is in contact with the base portion while the peripheral wall of the magnetic member is enclosed within the cavity housing , leaving the magnetic coupling surface exposed . where a ring - or toroidal - shaped magnet member is used , the cavity housing may have a hollow base portion . to provide a decoration or an aesthetic design , the buckle may be enclosed within a thin magnetic permeable enclosure made , for example of , pvc , synthetic resins , rubber , nylon or the like material . furthermore , while the permanent magnet ( 10 ) is held by a holder portion which is made preferably of a magnetic material in order to strength the magnetic force on the exposed polar surface of the permanent magnet , it should be appreciated that the present invention can be made by having a magnetic enclosed within a housing which does not have the effect of concentrating the magnetic strength on a particular polar surface as long as there is provided a strap receiving means transverse or side - wise to the magnetic axis of the permanent magnet . while the present invention has been explained by reference to the preferred embodiments above , it should be appreciated that the embodiments are provided for illustration and assisting understanding only and do not intend to limit or restrict the scope of the present invention . | US-92001501-A |
a novel recreational game includes in combination a shield and a dart both including one - half of a structure for retaining the dart on the shield when the dart is thrown towards the shield . the dart is provided with an enlarged front head with an impact surface . the enlarged front head is weighted relative to the rest of the dart so that regardless of how it is thrown , the impact surface is in position to contact the shield when thrown towards the shield . | fig1 shows use of the recreational game of the present invention by two participants . the game includes shields 10 held by the players and darts 12 thrown and caught by the players . the darts 12 are uniquely designed so that the dart can be gripped in any manner and thrown from any position with any trajectory towards the shield ( see fig1 - 3 ) and still be captured by a fastening system 50 more fully described herein . referring to fig4 the shield 10 is preferably formed from any appropriate rigid lightweight plastic , or other material . the shield 10 has a front wall 20 and a rear wall 40 . the front wall 20 includes a retainer section 32 and a plurality of inwardly - tapering walls 28 which lead to and circumscribe an inset fastening surface 58 comprising a first part 52 of the two - part fastening system 50 . the tapered walls 28 form a perimeter 26 around the inset fastening surface 58 . as a result , a dart 12 which strikes a wall 28 tends to slide inwardly along the tapered walls 28 and be captured on the shield 10 instead of merely bouncing off the wall 28 . the retainer section 32 and tapered walls 28 are formed integrally with each other and together form the front wall 20 . the retainer section 32 of the front wall 20 forms two circular notches 34 with a section of the circumference removed to allow darts 12 to be placed therein , as shown in fig1 . the notches 34 are designed with a diameter smaller than that of the shaft of the dart 12 so that the darts 12 can be removably retained therein . the darts 12 are made from a foam material which allows the shaft to alternately deform and expand when placed in the notches 34 and removed therefrom , respectively , so that the darts 12 are securely retained in the notches 34 when placed therein . this construction allows the players to more easily store and access the darts 12 while playing . fig5 shows a rear view of the shield 10 . the shield 10 has a rear wall 40 formed from a plurality of interconnected planes 42 . the planes 42 define a vaulted surface 44 . more specifically , the planes 42 can include several inclined planes 42a rearwardly extending from the front wall 20 to join a plane 42b that is rearwardly offset from and parallel to the retainer section 32 of the front wall 20 . the rear wall 40 , and more specifically , the rearwardly - extending inclined planes 42a are connected to the front wall 20 near the perimeter 26 formed by the tapered walls 24 , and preferably to the tapered walls 28 . thus , the rear wall 40 forming the vaulted surface 44 connected to the front wall 20 defines a chamber 36 , as seen in fig6 . the chamber 36 has a foam material 38 therein . generally , means 45 for holding the shield 10 are provided on the rear wall 40 to allow the players to control the shields 10 . more specifically , the means 45 for holding the shield 10 include a pair of spaced flanges 46 provided preferably integral with the rear wall 40 , and more preferably to the plane 42b of the rear wall 40 parallel to the retainer section 32 . the spaced flanges 46 are each raised from the surface 44 of the rear wall 40 and form openings 47 between the vaulted surface 44 of the rear wall 40 and the flanges 46 . an adjustable strap 48 is fitted through the openings 47 . the strap 48 can have a velcro ® attachment thereon allowing the strap 48 to be looped through the openings 47 and adjustably connected to itself . fig1 shows a player &# 39 ; s hand in the strap 48 . likewise , the player can insert his arm through the strap 48 if desired , since the strap 48 is adjustable . when the player &# 39 ; s hand is in the strap 48 , the vaulted surface 44 formed by the planes 42 allow the players to more easily control and maneuver the shield 10 . the players can accordingly support the rear wall 40 of the shield 10 with their fingers on various planes 42 forming the rear wall 40 while the strap 48 evenly supports the shield 10 on the hand &# 39 ; s volar surface when the hand is in a relaxed state . just before a player catches a dart 12 , the natural reaction is for the player to tense that hand and , in particular , flex their fingers . the planes 42 forming the vaulted surface 44 in conjunction with the strap 48 allow for this flexure without any slippage of the fingers on the rear wall 40 with consequent loss in control of the shield 10 . the finger tips stay in secure contact with the flat , inclined planes 42a while the back of the hand contacts the strap 48 . both the strap 48 and the planes 42 act to effectively bias the back of the hand and the finger tips towards one another so that when catching darts 12 the players maintain a secure grip on the shield 10 . the rear wall 40 of shield 10 can be provided with a textured surface for an even more effective finger grip . while it is preferred to provide the rear wall 40 as a separate piece , it is also possible to provide all of the parts of the shield 10 , with the exception of the inset fastening surface 58 of the fastening system 50 , as an integral piece . the darts 12 , as illustrated in fig7 include an elongate shaft 60 having a forward end 62 and a rearward end 64 . a front head 70 extends longitudinally from the forward end 62 of the shaft 60 and wings 76 extend generally longitudinally along the rearward end 64 of the shaft 60 . the front head 70 is shown in a front view in fig8 . the front head 70 is generally frusto - conical in shape having a plurality of longitudinally - extending helical - shaped grooves 74 along the surface thereof . the front head 70 includes an impact surface 72 with part of the fastening system 50 secured thereto , the fastening system 50 being more fully described herein . the entire dart 12 is preferably made from a lightweight foam material which provides the game with an element of safety , particularly important for young children , and also allows the game to be employed indoors . the head 70 is solid and made from a denser foam material than the rest of the dart 12 , thereby being weighted relative to the rest of the dart 12 so no matter how the dart 12 is thrown or where it is gripped ( see fig1 - 3 ), the impact surface 72 of the head 70 will lead the rearward end 64 of the shaft 60 during flight so that the impact surface 72 can contact the inset fastening surface 58 of the shield 10 held by another player when thrown towards that player . this gives the players an opportunity to removably capture the darts 12 on the inset fastening surface 58 of their shield 10 and to then remove them therefrom and either store them in the notches 34 provided in the extension part 32 or to throw them at another player providing all ages a more exciting and enjoyable game for players than previously available games involving targets and projectiles . the elongate shaft 60 can be of a tubular construction having a hollow passageway 66 therethrough . the shaft 60 can be solid 68 at the forward end 62 of the shaft 60 near the head 70 or alternatively a plug can be inserted therein to be securely placed near the head 70 at the forward end 62 of the shaft 60 . this further insures that the dart &# 39 ; s center of gravity is sufficiently towards the forward end 62 of the shaft 60 so that the previously described flight of the dart 12 occurs when it is thrown towards another player . the grooves 74 provided in the head 70 assist the dart 12 in its flight by creating aerodynamic forces which tend to assist the dart 12 to fly in a stable , substantially straight and accurate course from one player towards another , indoors or outdoors . such assistance is further provided by the wings 76 which flare radially outward from the shaft 60 to provide aerodynamic stability and lift to the flight of the dart 12 . a two - part fastening system 50 includes two parts used for fastening the dart 12 to the shield 10 , and more particularly , the impact surface 72 of the dart 12 to the inset fastening surface 58 of the shield 10 . preferably , the fastening system 50 is velcro ® hook and loop textile material . the first part 52 of the fastening system 50 is the inset fastening surface 58 of the shield 10 which comprises a textile piece 59a which is further comprised of a plurality of elongated strips of material sewn together to form a continuous surface , as seen in fig4 . the textile piece 59a is flexible and has a surface of pile fabric forming upstanding loops . the textile piece 59a is stretched across the rear wall 40 and connected thereto forming the chamber 36 therebetween . the second part 54 is a textile covering 59b having outwardly - extending stiff hooks and spines formed of broken loops of filaments and is attached to the impact surface 72 of the dart 12 . the broken loops of filaments are designed to hookingly engage the upstanding loops of the textile piece 59a secured to the rear wall 40 of the shield 10 . the flexible textile piece 59a is drawn across the rear wall 40 spanning the area circumscribed by the perimeter 26 formed by the walls 28 so as to be slightly offset inwardly from the retainer section 34 of the shield 10 . due to provision of chamber 36 , the textile piece 59a may be deflected inwardly towards the rear wall 40 when a dart 12 strikes the same thereby yielding sufficiently to permit the upstanding loops of the textile piece 59a to engage and retain the broken loops of filament of the textile covering 59b secured to the impact surface 72 of the front head 70 of the dart 12 . this reduces the problem of having the dart 12 bounce off the shield 10 when the textile covering 59b of the impact surface 72 of the dart 12 strikes the textile piece 59a of the shield 10 . the foam material 38 provided within the chamber 36 prevents the textile piece 59a from contacting the rear wall 40 , and more particularly , the plane 42b of the rear wall 40 parallel to the retainer section 32 , when the dart 12 strikes the shield 10 . the foam material 38 substantially absorbs the impact of the dart 12 against the textile piece 59a preventing disengagement between the two . the provision of foam material 38 in the chamber 36 further insures that the dart 12 will not bounce off the shield 10 when the textile covering 59b of the impact surface 72 strikes the textile piece 59a of the shield 10 . the foregoing disclosure of specific embodiments is illustrative of the broad inventive concept comprehended by the invention . various changes in the size , shape and materials , as well as in the details of the illustrated constructions , may be made within the scope of the appended claims without departing from the spirit of the invention . | US-10206093-A |
a humidity altering device includes an impermeable housing confining a liquid absorbent element having a large capacity for holding a humectant liquid . the device is provided with at least one evaporation barrier which controls the rate of humectant liquid evaporation so as to maintain a predetermined level of relative humidity within a humidor for storage of various products , such as perishable foods and tobacco products , so as to maintain their freshness and desirability for extended periods of time . | referring now to the drawings wherein like reference numbers represent like elements , there is illustrated in fig1 a humidor generally designated by reference number 100 . the humidor 100 may be of any particular style , shape , size , configuration and the like , as is well known in the construction of humidors in general . by way of illustration only , the humidor is constructed from a container 102 of rectangular shape having four sidewalls 104 , 106 , 108 , 110 providing an open top which is closed by a hinged cover 112 opposing a bottom wall 113 . the humidor 100 can be constructed from a variety of materials , such as metal , plastic , wood , as well as composites of the aforementioned materials . the interior of the humidor 100 is sized to accommodate a plurality of products 114 and at least one humidity altering device 116 which is constructed in accordance with the present invention . as previously noted , the products 114 may include perishable foods , tobacco products such as cigarettes and cigars as illustrated , as well as other humidity sensitive products such as rare books , manuscripts , various clothing items ; and the like . although the humidor 100 has been disclosed in fig1 as illustrating storage of cigars , it is to be understood that the humidity altering device 116 may be used for any number of other products . in addition , the humidity altering device 116 is suitable for use in any particular style , construction or size of humidor 100 as to be explained hereinafter . turning now to fig2 through 5 , one embodiment of at humidity altering device 116 will now be described . the humidity altering device 116 is generally constructed to include a housing 118 , a liquid absorbent element 120 and at least one evaporation barrier 122 . optionally , the humidity altering device 116 may include an assembly 124 for releasably attaching the humidity altering device to an interior surface of the humidor 100 . the housing 118 is sized to accommodate the liquid absorbent element 120 having sufficient humectant liquid storage capacity for humidifying the humidor 100 of given size . the housing 118 is constructed from non - porous , impermeable materials such as plastic , ferrous metals , extruded aluminum which may be black anodized to enhance appearance , stainless steel , galvanized steel and the like . the interior and exterior surfaces of the housing 118 may also be coated with an electrodeposited polyurethane coating which additionally protects the housing when constructed of aluminum from corrosion , as well as providing a low - cost , decorative finish . the housing 118 is generally constructed from a continuous imperforated wall 126 formed by extrusion which defines a hollow interior 128 . however , the wall 126 may be formed from separate elements attached together in any suitable manner to define the interior 128 . the housing 118 , as illustrated , is provided with two open ends 130 having a shape conforming to the shape of the housing . as illustrated in the disclosed embodiment , the open ends 130 have an oval shape which , however , may also be square , circular , rectangular and the like . the open ends 130 provide openings 132 which are in communication with the interior 128 of the housing 118 . although the openings 132 have been described as provided at the ends of the housing 118 , the housing ends may be closed and the openings 132 provided within the wall 126 of the housing . any number of openings 132 may be provided within the housing 118 . in this regard , the housing 118 as illustrated may be provided with only one open end 130 , the other end being enclosed . each of the openings 132 are enclosed by the evaporation barrier 122 . the evaporation barrier 122 is constructed from a body 134 of non - porous , impermeable material such as plastic , for example , rigid polystyrene , aluminum and the like . the body 134 is provided with at least one opening 136 . although the opening 136 has been illustrated as an elongated slot , it is to be understood that the opening may be in any form , for example , oval , circular , square and the like , as well as being multiple openings within each of the evaporation barriers 122 . the openings 136 are suitably sized for controlling the evaporation rate of the humectant liquid absorbed in the liquid absorbent element 120 within the housing 118 . in this regard , the larger the openings 136 , the faster the evaporation rate of the humectant liquid , and accordingly , the ability to maintain a higher humidity level within the humidor 100 . generally , a relative humidity of about 60 - 70 % is found suitable for use in humidors 100 for storing tobacco products such as cigars . as should now be understood , the evaporation barrier 122 is sized to permit a controlled flow of humectant vapor into the humidified space within the humidor 100 , as well as allowing quick recharge of the liquid absorbent element 120 with the humectant liquid with no spillage , thereby requiring less maintenance and significantly prolonged humidity within the humidor . the evaporation barrier 122 is secured within each of the openings 132 within the housing 118 by any suitable means . for example , it is contemplated that a suitable moisture resistant adhesive may be employed . preferably , it is desirable that the evaporation barrier 122 be removable so as to facilitate replacement of the liquid absorbent element 120 if required , as well as eliminating the use of adhesives which are costly and add to the manufacturing process . in this regard , the evaporation barrier 122 is constructed to include a continuous shoulder 138 extending from the body 134 having a shape corresponding to the shape of the openings 132 . the shoulder 138 is provided with an outwardly facing planar surface 140 which frictionally engages the interior surface of the housing 118 so as to provide a friction fit therebetween . by virtue of the friction fit , the evaporation barrier 122 is releasably retained within each of the opened ends 130 of the housing 118 , while at the same time , providing a generally fluid tight seal thereat . accordingly , it should be appreciated that the shoulder 138 functions as a seal member for generally sealing the evaporation barrier 122 within the open ends 130 of the housing 118 without the use of adhesives and the like . in an alternative embodiment as shown in fig6 the evaporation barrier 122 is provided with an o - ring 142 surrounding the exterior surface of the shoulder 138 . in this regard , the shoulder 138 is spaced inwardly of the interior surface of the housing 118 to accommodate the o - ring 142 . the o - ring 142 provides a fluid tight seal by being compressed between the outer surface 140 of the shoulder 138 and the interior surface of the housing 118 within the opened ends 130 . the liquid absorbent element 120 can be constructed from a variety of liquid absorbent materials which can be shaped so as to substantially fill the entire interior 128 of the housing 118 . preferably , the liquid absorbent element 120 will release the humectant liquid as a vapor at a constant rate over time by not drying out from the exterior surfaces inwardly . in addition , the liquid absorbent element 120 should resist the growth of odor causing mold and bacteria , while limiting the need for conditioning fluids . in the preferred embodiment , the liquid absorbent element 120 will be capable of retaining close to 100 % of its available volume with the humectant liquid without oversaturation and drippage . although a number of synthetic foam materials are suitable for the liquid absorbent element 120 , the element in accordance with the preferred embodiment is constructed from urethane foam material which has germicidal properties . generally , the absorbent element 120 will have an average pore size of about 130 microns and an average porosity of about 92 %. the aforementioned material for use as the liquid absorbent element 120 may be obtained from hibco plastics , inc . of yadkinville , n . c . (# 151 foam rev . ns ). another material suitable for use as the liquid absorbent element 120 comprises a highly acetylized polyvinyl alcohol sponge material , like the urethane foam material , having an average pore size of about 130 microns and an average porosity of about 92 %. this material may be obtained from shima america corporation of elmhurst , ill . it is contemplated that other foam materials which have the capacity of absorbing a high weight percent of a liquid humectant , for example , water , and releasing same in the nature of a vapor are also suitable for use in the humidifying altering device 116 in accordance with the present invention . in use , the humidity altering device 116 is assembled as shown in fig2 with the liquid absorbent element 120 filling the interior 128 of the housing 118 . the liquid absorbent element 120 is saturated with water , and preferably deionized water to preclude mineral buildup , by immersing the device into a container of deionized water . alternatively , one of the evaporation barriers 122 may be removed and the deionized water poured into the housing 118 so as to saturate the liquid absorbent element 120 . in addition , it is also possible to pour the deionized water through one of the openings 136 within an evaporation barrier 122 . the humidity altering device 116 is operative to provide and maintain humidity necessary for storing and protecting perishables such as tobacco products , food products and other items such as fabrics and wood products . after a period of stabilization , the relative humidity within the humidor 100 will be controlled at a level of about 60 - 65 %, and preferably about 70 %. because the liquid absorbent element 120 provides an extremely high capacity for humectant liquid , the device allows repeated opening of the humidor 100 and still provides the necessary level of relative humidity for an extended period of time , which is typically beyond the conventional refilling intervals of existing humidifying devices . the humidity altering device 116 may be sized to provide the requisite relative humidity for a humidor 100 of given size . in this regard , the larger the volume of air space to be humidified , the larger the size of the humidity altering device 116 required . in this regard , by increasing the size of the humidity altering device 116 , there is a corresponding increase in the size of the liquid absorbent element 120 which will enable a greater storage capacity for the liquid humectant . in addition , the size of the openings 136 within the evaporation barriers 122 may also be varied depending upon the size of the humidor 100 . a particularly effective way of increasing the size of the humidity altering device 116 is to increase the length of the housing 118 , along with a corresponding increase in length of the liquid absorbent element 120 , and hence , its humectant liquid storage capacity . the humidity altering device 116 may be removably attached to the interior surface of one of the sidewalls 104 , 106 , 108 , 110 of the humidor 100 as shown in fig1 . any suitable fastening assembly may be used for this purpose . by way of illustration , one such fastening assembly includes the combination of a disk magnet 144 and a ferrous plate 146 . either the magnet 144 or plate 146 may be attached such as using an adhesive to the outer surface of the housing 118 . the other of the magnet 144 or plate 146 may be attached in a similar manner to the inner surface of one of the sidewalls 104 , 106 , 108 , 110 of the humidor 100 . in this manner , the humidity altering device 116 may be easily secured in removable fixed position to the interior of the humidor 100 . alternatively , the fastener assembly 124 may be constructed from cooperating velcro material , as well as other suitable means for securing the humidity altering device 116 to the interior of the humidor 100 . although the invention herein has been described with reference to particular embodiments , it is to be understood that the embodiments are merely illustrative of the principles and application of the present invention . it is therefore to be understood that numerous modifications may be made to the embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the claims . | US-3608098-A |
belt buckle for releasable connection of a belt to another belt or object . the belt buckle has a male buckle part with a plug - in extension and a female buckle part with a receptacle , and a locking device . the plug - in extension of the male buckle part is insertable into the receptacle of the female buckle part and the buckle parts are lockable to each other in a locking state by the locking device . in the locking state , the buckle parts are arrangeable relative to each other in a neutral position , in which the locking device can be brought into an unlocking position to separate the buckle parts . the buckle parts are additionally arrangeable relative to each other in a blocking position , pivoted in relation to the neutral position , in which the locking device is blocked in a locking position to prevent the buckle parts from being separated from each other . | fig1 and 2 show two top views of the belt buckle 1 in the plugged together and locked state , i . e . in the locking state , in which the plug - in extension 5 of the male buckle part 4 has been pushed completely into the plug - in - extension receptacle 7 of the female buckle part 6 . the locking devices 8 here are in the locking position thereof . fig1 to 4 show the neutral position in which the locking devices 8 can be brought or pivoted into the unlocking position thereof by pressure being exerted on the actuating regions 19 , and therefore the male buckle part 4 can be pulled with its plug - in extension 5 out of the plug - in - extension receptacle 7 of the female buckle part 6 in order to separate the buckle parts 4 and 6 from each other . the belts 2 and 3 which are connected releasably to each other by means of the belt buckle 1 are illustrated with dashed lines . in order to be able to fasten the belts 2 and 3 to the respective buckle parts 4 and 6 , the buckle parts 4 and 6 have corresponding belt receptacles 15 and 16 . the latter can be in any form known from the prior art . in the first exemplary embodiment , the male buckle part 4 has an adjustable belt receptacle 15 with a displaceably mounted clamping web 17 . the female buckle part 6 of said first exemplary embodiment is equipped with a fixing web 18 and is therefore not provided for adjusting the belt . of course , exemplary embodiments according to the invention in which the adjustability of the belt receptacles 15 and 16 is swapped , the two belt receptacles 15 and 16 are adjustable or the two belt receptacles 15 and 16 are formed with corresponding fixing webs 18 are possible . as can be seen particularly readily in the two top views according to fig1 and 2 , the plug - in extension 5 of the male buckle part 4 has , on both sides , shaped parts 20 and 21 which , in the locking state illustrated , project in the corresponding shaped - part receptacles 22 and 23 of the female buckle part 6 . in the neutral position illustrated in the first four figures , corresponding clearances 27 and 28 are located between the shaped parts 20 and 21 , on the one hand , and the shaped - part receptacles 22 and 23 , on the other hand , as a result of which the two buckle parts 5 and 6 can be pivoted relative to each other into the blocking position , which is also explained in detail further below . all this takes place in the locking state in which the locking device 8 , in the locking position thereof , locks the two buckle parts 4 and 6 to each other . fig3 shows a side view of the buckle 1 in the neutral position and also the section line aa . fig4 shows the section through the buckle 1 along the section line aa from fig3 . the belts 2 and 3 are not illustrated in fig3 and 4 . it can be seen particularly readily in the horizontal section according to fig4 that the locking devices 8 of this exemplary embodiment are designed as levers which are each formed so as to be pivotable about the pivot axis 10 . the actuating region 19 on which pressure can be exerted with the finger in order to bring the respective locking device 8 from the locking position illustrated in fig4 into the unlocking position is located in each case on one side with respect to the pivot axis 10 . opposite the respective actuating region 19 with respect to the pivot axis 10 , the locking devices 8 each have a retention region 26 with which , in the locking position illustrated , said locking devices engage in undercuts 9 of the male plug - in extension 5 in order thereby to lock the male buckle part 5 in the female buckle part 6 . the pre - tensioning springs 24 which pretension the locking device 8 in each case in the direction toward the locking position thereof can also be readily seen in this exemplary embodiment . in the exemplary embodiments shown , the plug - in extension 5 of the male buckle part 4 has a t - shaped head 25 . the undercuts 9 mentioned are located in the intersecting region of said t - shaped head 25 . in the neutral position shown in fig1 to 4 , the locking devices 8 can be pivoted about the respective pivot axis 10 into the unlocking position thereof ( not illustrated here ) by pressure being exerted on the respective actuating region 19 , in order thereby to be guided or pivoted out of the undercuts 9 . if this is the case , the unlocking position is reached and the plug - in extension 5 can be pulled out of the plug - in - extension receptacle 7 in order to separate the male buckle part 4 from the female buckle part 6 . for this purpose , in the neutral position , the male buckle part 4 can be pushed with the plug - in extension 5 thereof deeper by a certain distance into the plug - in - extension receptacle 7 so that the retention regions 26 of the locking devices 8 can be guided past the retaining lugs 11 which outwardly bound the undercuts 9 . fig5 to 10 now show a blocking position in which the locking devices 8 are likewise located in the respective locking position but can no longer be brought into the unlocking position by pressure being exerted on the actuating regions 19 . as seen from the neutral position according to the fig1 to 4 , the male buckle part 4 and the female buckle part 6 are pivoted relative to each other about a certain pivot angle x ( see fig8 ). in the exemplary embodiment shown , said pivoting takes place exclusively in a plane which , with respect to fig1 , 4 , 5 , 6 , 8 , 9 and 10 , lies parallel to the respective drawing page plane . in practice , the pivoting of the buckle parts 4 and 6 relative to each other out of the neutral position into the blocking position takes place virtually automatically by means of the belts 2 and 3 attached to the buckle parts 4 and 6 , and therefore a blocking position is virtually always taken up if the belt buckle 1 is not first of all brought into the neutral position for the intended unlocking and separating of the buckle parts 4 and 6 from each other . by this means , an unintentional opening or unlocking of the locking devices 8 is permanently avoided in practice without additional components . in the blocking position , the male buckle part 4 and the female buckle part 6 of the exemplary embodiment shown bear against each other by the respective stop regions 13 and 14 thereof in such a manner that deeper penetration of the plug - in extension 5 of the male buckle part 4 into the plug - in - extension receptacle 7 of the female buckle part 6 is prevented . as stated , the stop regions 13 and 14 can be formed at different locations of the male buckle part 4 and of the female buckle part 6 . these stop regions have to correspond in each case only in a manner corresponding to each other , in order , in the blocking position , to prevent further or deeper penetrating of the plug - in extension 5 into the plug - in - extension receptacle 7 . in the alternative shown , the stop regions 13 and 14 are formed on the shaped parts 20 and 21 and shaped - part receptacles 22 and 23 of the male and female buckle parts 4 and 6 . furthermore , as can be seen in fig8 , corresponding stop regions 13 and 14 can also be provided on the locking devices 8 themselves . fig8 shows the section bb according to fig7 . as stated , the buckle parts 4 and 6 are also in the blocking position in fig8 . it can be seen particularly readily here how the retaining lugs 11 secure the retention regions 26 of the locking devices 8 in the respective undercuts 9 in an interlocking manner . by this means , the locking devices 8 , even if pressure is inadvertently exerted on the actuating regions 19 , cannot be unlocked , i . e . cannot be pivoted from the locking position shown into the unlocking position ( not illustrated ). the retention regions 26 do not go past the retaining lugs 11 , since the plug - in extension 5 , as stated , cannot be pushed even deeper into the plug - in - extension receptacle 7 because of the stop regions 13 and 14 striking against each other . unlocking of the locking device 8 is therefore possible only if the male buckle part 4 and the female buckle part 6 are pivoted back relative to each other into the neutral position shown in fig1 to 4 . in the exemplary embodiment shown here of the belt buckle 1 , the male and female buckle parts 4 and 6 are formed in a correspondingly symmetrical manner with respect to an axis of symmetry 31 and 32 , drawn in in each case in fig2 and 6 . the axes of symmetry 31 and 32 rest on each other in the neutral position . in the blocking positions , said axes of symmetry are arranged at an angle , i . e . are not parallel to each other . the same situation as in fig6 is illustrated in fig9 , but the female buckle part 6 is shown in the region c partially in a sectional illustration corresponding to fig8 . fig1 shows the region d from fig9 on an enlarged scale . it can be seen here how the retention region 26 , and therefore the locking device 8 , is held in an interlocking manner in the undercut 9 by means of the retaining lug 11 such that opening , i . e . pivoting of the locking device 8 into the unlocking position , is not possible even when the actuating region 19 is acted upon . for this purpose , in the blocking position shown , the retaining lug 11 is closer to the pivot axis 10 than the radius 30 of the lowest bulge 12 of the undercut 9 . the radius 30 is the distance between the pivot axis 10 and the mentioned lowest bulge 12 . the tangent 29 to the radius 30 is also drawn in . fig1 shows a slightly modified exemplary embodiment of the male buckle part 4 . this exemplary embodiment differs from the previously shown exemplary embodiments only in that a fixing web 18 rather than a movable clamping web 17 is formed in the belt - receiving region 15 of said male buckle part 4 . otherwise , the form of the male buckle part 4 , in particular in the region and in the shaping of the plug - in extension 5 , corresponds to the first exemplary embodiment . fig1 once again shows a side view of the male buckle component 4 . the two shaped parts 20 and 21 can be seen particularly readily here . | US-201414173062-A |
a bather &# 39 ; s cap includes a cap body provided on its outer side with at least one hollow mounting plug integral with the cap body and having an enlarged end . at least one ornamental component is mounted on the hollow mounting plug . the ornamental component is securely held in place between the enlarged end of the hollow mounting plug and the adjoining portion of the outer side of the cap body . | the embodiments of fig1 - 4 will be discussed first . reference numberal 2 generally designates the cap body of a bather &# 39 ; s cap . mounted on the outer side 1 of the cap body 2 are a plurality of ornamental components 3 . these ornamental components may for example be comprised of two rubber parts 4 , 5 and a synthetic plastic part 6 which when assembled together have the general appearance of a flower . the cap body 2 is advantageously made of latex and is provided on its outer side 1 with projections 7 configurated as hollow mounting plugs 8 having enlarged ends , so that each mounting plug 8 has a neck 9 and a head 10 . whereas the cap body 2 in general has a thickness of 0 . 6 mm , the head 10 in comparison with the neck 9 is enlarged not only with respect to its external diameter , but additionally has a wall thickness of about 1 to 2 mm , so that the head 10 will have considerable stiffness and rigidity . surrounding each projection 7 there are arranged elevated portions 11 forming a closed wall 12 in the middle of which the hollow mounting plug 8 is located . to produce such a cap body 2 , use is advantageously made of a negative form 13 ( fig3 ) into which the latex material is poured . on the wall 14 of the form 13 there forms a layer which remains in the form 13 when after a certain time interval the still fluid portion of the latex material is shaken out of the form 13 . upon elapse of a short setting or curing time interval , the layer can be removed from the form 13 and will constitute the cap body 2 . the portion of the form 13 which surrounds the head 10 of the hollow mounting plug 8 has a higher temperature than the other portions of the form , resulting in an increased wall thickness for the head 10 . to this end , half shells 16 , 17 can be inserted into a carrier member 15 , with the half shells 16 , 17 being maintained at a higher temperature than the form layer 18 arranged on the inner side 21 of the carrier 15 . the form layer 18 is provided with cavities 19 for the formation of the walls 12 ( fig1 ), and is further provided with openings 20 for the necks 9 of the hollow mounting plugs 8 . the openings 20 , the elasticity of the material employed and the wall thickness of the head 10 are so matched to each other that the cap body 2 can be readily removed from the form 13 by simply exerting a slight pull . to mount the ornamental components 3 on the cap body 2 , in the embodiment of fig1 - 4 , use is made of a device 22 ( fig4 ) comprised of a bar - shaped support body 23 which from the inner side 24 of the cap body 2 is inserted into the opening 25 in the hollow mounting plug 8 . the cap body 2 is pulled downwardly , and likewise the hollow mounting plug 8 , causing the diameter of the head 10 to decrease , so that the rubber parts 4 , 5 and the synthetic plastic part 6 with their openings 26 can now be readily pushed down past the head 10 onto the neck 9 of the hollow mounting plug 8 , after a lubricating substance , particularly a soap solution , has been applied . when the snythetic plastic member 6 is correctly positioned , then the support body 23 is pulled out from the interior of the hollow mounting plug 8 . the head 10 reassumes its original configuration , so as to establish a secure mounting of the parts 4 , 5 and 6 by blocking the path of removal of the parts 4 , 5 and 6 . by means of the wall 12 and the configuration of the synthetic plastic member 6 , the petal - like portions of the rubber parts 4 , 5 are caused to a certain extent to bend up and away from the surface of the cap body 2 , thereby increasing the three - dimensionality of the appearance of the ornamental component 3 . the rubber parts 4 and 5 could alternatively be made of textile , synthetic plastic or another type of material . in the embodiments of fig5 - 10 , the enlargement of the end of the hollow mounting plug 8 is achieved by means of a specially provided anchoring member 27 . the member 27 is pushed from the inner side 24 of the cap body 2 through the opening 25 into the interior of the hollow mounting plug 8 . when the member 27 is pushed all the way into the interior of plug 8 , it imparts to the surrounding portion of the plug its diameter , which is greater than the diameter of the neck 9 of the plug 8 . in the embodiment of fig5 the hollow mounting plug 8 is formed from an initially smooth cap body 2 , by pushing the anchoring member 27 , from the inner side 24 of the cap body 2 , against the adjoining portion of the material of the cap body 2 , through the opening 26 of the ornamental component 3 located adjacent the outer side of the cap body 2 . in this event , the member 27 and the opening 26 in the ornamental component 3 are both advantageously of oblong shape , so that the member 27 can be pushed through the opening 26 , by reason of being oriented parallel to the opening 26 , and then twisted to lie transverse to the opening 26 , thereby establishing secure locking action . in the embodiments of fig3 - 6 the hollow mounting plugs 8 are again molded into the material of the cap body 2 . use is made in this case of a positive form 28 having prongs 29 . the form 28 is dipped into a bath of liquefied material , in particular latex . after a short time , a layer forms on the surface of the form . after the form is withdrawn from the bath , and upon elapse of a certain curing or setting time interval , this layer can be pulled off the form 28 and constitutes the cap body 2 . the ornamental components 3 , which in these embodiments are for example unitary members made of synthetic plastic material , can without any great effort be pushed onto the thusly configurated hollow mounting plugs 8 . thereafter , an anchoring member 27 , for example a spherical member 30 is pushed from the inner side 24 of the cap body 2 through the opening 26 of the ornamental component 3 into the interior of the hollow mounting plug 8 . as the spherical member 30 is pushed into the interior of the hollow mounting plug 8 , the material of the cap body 2 which surrounds the entrance of the hollow mounting plug 8 is stretched . however , as the spherical member 30 is pushed all the way into the end of the mounting plug 8 , the material of the cap body 2 contracts to its original shape and size , thereby establishing a secure anchoring of the ornamental component 3 on the cap body 2 . in order that the opening 25 at the inner side 24 of the cap body 2 not present an unaesthetic appearance , the configuration of the hollow mounting plug 8 is advantageously designed in the manner depicted in fig9 . the diameter 31 of the opening 25 is kept especially small , in every case smaller than the inner diameter 32 of the hollow mounting plug 8 . as a further possibility , the anchoring member 27 can have the form of a press fastener , as depicted for example in fig1 . the head 33 of the press fastener then serves for the secure anchoring of the ornamental component 3 , whereas the foot 34 of the press fastener completely covers the opening 25 . it will be understood that each of the elements described above , or two or more together , may also find a useful application in other types of constructions and methods differing from the types described above . while the invention has been illustrated and described as embodied in bathing caps and methods for their manufacture , 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 . 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 . | US-50200974-A |
therapeutic devices , especially vaso - occlusive devices or embolic coils , are delivered by an apparatus that includes a pullwire having a tine or tines that have an offset orientation that engages a therapeutic device . the pullwire passes through an opening of a headpiece . when the pullwire moves in a relative proximal direction , the tine moves toward a straight - line orientation , and the therapeutic device is liberated from the tine and from the pullwire . at this state , the therapeutic device is ready for deployment at a desired intraluminal location . | as required , detailed embodiments of the present invention are disclosed herein ; however , it is to be understood that the disclosed embodiments are merely exemplary of the invention , which may be embodied in various forms . therefore , specific details disclosed herein are not to be interpreted as limiting , but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriate manner . as shown in fig1 - 3 , the present disclosure provides for delivery and release of therapeutic devices , such as the illustrated embolic coil , which is generally designated at 11 . this is embodied in devices , systems and methods that are illustrated herein as preferred embodiments . according to one embodiment , the invention consists of a pullwire , generally designated at 12 , that has one or more tines 13 , 14 at the distal end of the pullwire 12 . each tine can assume a configuration where it is at an offset , non - straight - line or expanded state . as shown in fig1 , one or more tine will engage with the therapeutic device 11 in this offset configuration so as to grasp the therapeutic device in order to maneuver the device to a desired location within the vasculature . for example , as shown in fig1 , each tine may engage an embolic coil by intertwining with or interleaving between and pushing against one or more turns 15 of the embolic coil . when two tines 13 , 14 are provided , they together may assume a v - shape when engaged with the therapeutic device . consequently , the engaged therapeutic device 11 such as the illustrated embolic coil can be manipulated by moving the pullwire 12 . as shown in fig1 , the pullwire 12 and therapeutic device 11 may be enclosed in a guide tube 21 such as a catheter to guide and position the therapeutic device and pullwire . a pusher 22 is provided which is slidably positioned within the guide tube 21 . at the desired location in the body of the patient , the guide tube 21 and the pullwire 12 ( with engaged therapeutic device ) move relative to each other . either the guide tube is moved retrograde or the therapeutic device 11 is pushed out of the tube such that the therapeutic device is placed at the desired location within the patient , such as in or at an aneurysm . to release the therapeutic device from the pullwire , relative movement between the pullwire 12 and the pusher 22 is effected . according to one approach , a proximal portion ( not shown ) of the pullwire that is external to the patient is pulled proximally , typically beyond the proximal end of the guide tube 21 , which also is external of the patient . this continues until the pullwire is fully disengaged from the therapeutic device . according to another approach , the pullwire remains relatively stationary and the pusher 22 is moved distally , thereby moving the therapeutic device distally to slide it off of the pullwire . by either approach , each tine disengages from the therapeutic device and slides through and out of an opening 23 in a headpiece 24 to a position similar to that shown in fig2 . as relative pullwire movement continues in this proximal direction , each tine 13 is forced into a generally straight - line orientation at which the straightening effect being illustrated in fig2 continues until virtually all of the tine is straightened so as to have a longitudinal axis along or parallel to the axis of the pullwire 12 , which can be referred to as an unexpanded or collapsed configuration , when passing through the opening . in the embodiment shown in fig1 , the headpiece 24 is a component of the embolic device 11 and is attached to the coil at the proximal end 25 of the coil 15 . in the embodiment shown in fig2 , a headpiece 34 is secured to a body 32 of the pusher of that embodiment . the illustrated embolic device 31 has no headpiece type of component , and can be essentially a coil . another proximal end component ( not shown ) could be part of embolic device 31 , which component would be deployed together with the coil of such an embolic device . in either approach , each tine 13 slides through opening 23 in a proximal direction until it disengages the headpiece 24 or 34 . in fig3 , each tine 13 is shown completely disengaged from the embolic device 11 . the pullwire 12 and guide tube 21 are withdrawn , leaving the coil in the desired location . as shown in fig3 , when disengaged from the therapeutic device and the headpiece , the tines may reassume an expanded configuration offset from the straight - line configuration that exists when the tine passes through the opening 23 . with further reference to the alternative embodiment illustrated in fig2 , the headpiece 34 with opening 23 is attached to the distal end of the pusher 22 a by suitable means known in the art . alternatively , the headpiece 34 and pusher body 32 are integrally formed . each tine engages with the therapeutic device as shown in the fig1 embodiment . also , as in the fig1 embodiment , each tine is disengaged from the therapeutic device by relative movement between the pullwire 12 and the headpiece , such as by pulling the pullwire in a proximal direction through the pusher and / or guide tube . the pullwire and pusher body 32 with headpiece 34 are withdrawn from the body of the patient , leaving the embolic device 31 at the desired location . in one embodiment , each tine is formed from the same piece of material used to manufacture the pullwire by , for example , splitting the distal end of the rod or the like from which the pullwire is made . this type of unitary construction is preferred due to its relative simplicity . it also is preferred because the unitary approach avoids a possibility of failure of an attachment of a tine to a pullwire should an alternative embodiment be followed , such as one where the tine is manufactured from a separate piece of material and securely attached to the pullwire by means known in the art . as noted previously , one or more tine 13 , 14 can be provided at the distal end portion of the pullwire 12 . in the preferred embodiment that is illustrated , two tines are provided that are of approximately the same length and at approximately the same degree of offset from the longitudinal axis of the pullwire when in their offset configuration such as shown in fig1 . according to different embodiments , it is possible that only a single tine be provided so long as it securely engages and holds the embolic device . also , multiple tines may have different sizes or lengths , and they may be offset from the longitudinal axis of the pullwire to different extents . furthermore , there may be greater than two tines of the same size and orientation or having variations as noted . the material of each tine needs to have adequate shape properties so the tine will be in the offset , non - straight - line configuration when in use and will remain in that condition to provide adequate holding power when engaging the therapeutic device . the tine must also be flexible enough to readily move to the straight - line orientation in response to transverse forces applied to the tine as it moves through the opening 24 . while it is not essential that the tine also be resilient so as to “ spring back ” to the offset orientation ( as illustrated in fig3 ), this can be a property of the tine . when this latter feature is desired , each tine may be formed from a resilient material or a material having shape memory properties , typically tied to variations in temperature . examples of a resilient material include a spring stainless steel or other resilient material suitable for use within the body . each tine can be manufactured from a material that has shape memory , typically metals or metal alloys or polymers with the desired properties . a nitinol alloy has excellent shape memory attributes and is a preferred metal or alloy . when an alloy such as a nitinol is at a low temperature , which in this instance would be lower than human body temperature , the pullwire is made such that each tine is at the generally straight - line or unexpanded configuration . at a higher temperature approximating body temperature , each tine is at the offset orientation . with this configuration , the pullwire typically is assembled through the opening in the headpiece when at room temperature or below , which facilitates manufacture of the apparatus by allowing the tines to be easily fed through the opening . when the tines are exposed to a temperature greater than the transition temperature , each tine assumes the expanded state and engages with the coil . this expanded state is maintained when at body temperature when the device is placed in the patient . a preferred range for a transition temperature between the martensite state and the austenite state for a shape memory material such as a nitinol is 10 - 35 ° c . in the event the pullwire and the tine are not formed integrally , they can be formed from different materials . in that instance , the pullwire length that is proximal of the tine or tines need not have the same properties as described herein for the tine or tines . it is preferred that all or part of the pullwire , tine or tines will have radio - opaque properties . it will be understood that the embodiments of the present invention which have been described are illustrative of some of the applications of the principles of the present invention . numerous modifications may be made by those skilled in the art without departing from the true spirit and scope of the invention . various features which are described herein can be used in any combination and are not limited to procure combinations that are specifically outlined herein . | US-34498906-A |
a toothbrush with a handle having a base , a body , and a head . the body having a first section and a second section forming an oblique angle . a projector of sound or music located within the handle . the toothbrush having at least one bristle attached to the head . the toothbrush having a handle cover attached to the base . a method of using a toothbrush including the step of gripping the toothbrush . the method further including the step of engaging the projector of sound or music . the method still further including the step of utilizing the toothbrush while the projector of sound or music is activated . | fig1 illustrates a prior art illuminated toothbrush 10 , which comprises a handle 12 , an illumination circuit 14 , a brush 16 , and a grip 18 . as shown in fig1 , the handle 12 comprises a base 20 , a body 21 , and a head 26 . the body 21 has a first section 22 and a second section 24 . the handle 12 can be formed of hard , clear plastic . in one arrangement , the handle 12 can be a colored plastic . in another arrangement , the handle 12 can be a translucent plastic . the toothbrush handle 12 can be formed through an injection molding process . in such an embodiment , plastic in a liquid form can be injected into a mold having two sections . liquid plastic can be injected into the mold where it is then allowed to solidify . when the mold is opened it creates a handle having a brush side 28 and a non - brush side 30 . at the intersection of these two sides 28 , 30 can be a ridge 32 . the ridge 32 can be a surface characteristic resulting from the injection molding process . in the illustrated arrangement , the ridge 32 does not extend inside the handle 12 but exists on the surface . the injection molding process in constructing of the toothbrush handle 12 is conventional and does not form a part of the present invention . the brush 16 can have a bristle 80 . the bristle 80 can have a first end 82 and a second end 84 . the bristle second end 84 can be embedded in the head 26 of the handle 20 . the handle base 20 has an opening 38 and a cavity 50 , see fig2 . the illumination circuit 14 fits partially inside the cavity 50 and partially within grip 18 which is essentially hollow . the chamber 50 can extend within the section 22 . the chamber 50 can be generally cylindrical in shape . continuing to look at fig1 and 2 , the first section chamber 50 can be also positioned in off - center alignment with the base 20 because in the first section 22 is ergonomically designed to accommodate a user &# 39 ; s grip . in the ergonomic design , the brush side 28 of the first section 22 is contoured and the non brush side 30 of the first section 22 is flat . in addition , the brush side 28 of the first section 22 arrives at a point of the second section 24 at a greater angle than the non brush side 30 . in other words , the illumination circuit 14 extends within the first section 22 substantially parallel to the center line of the base member 20 but the first section 22 brush side 28 angles toward the inner point where the first section 22 meets the second section 24 and the non brush side 30 portion of the first section 22 also angles toward the point where the first section 22 meets the second section 24 . thus , for the first section chamber 50 to extend the furthest into the first section 22 of the handle 12 , the first section chamber 50 is preferably positioned closer to the non - brush side 30 of the first section 22 . fig3 - 14 illustrate embodiments of a toothbrush with a sound projection circuit that advantageously addresses the aforementioned problem . numerical reference to components is the same as in the previously described arrangement , except that a prime symbol (′) has been added to the reference . where such references occur , it is to be understood that the components are the same or substantially similar to previously - described components . fig3 shows a toothbrush 10 ′ with the non - brush side 30 ′ on the top . the handle 12 ′ has a base 20 ′ which has been formed on the non - brush side 30 ′ to receive the parts of the sound projection circuit 40 and activation means for activating the circuit 40 . a waterproof wall 44 is used to cover a switch 42 which is placed in the switch holder 62 . fig6 - 7 show the waterproof wall 44 and switch 42 respectively in more detail . fig4 shows a configuration of a sound projection circuit . a contact member 46 with a hole 70 is placed on post 72 . the batteries 48 fit in the battery holders 64 . the batteries 48 , switch 42 , waterproof wall 44 and contact member 46 are held in place by a printed circuit board ( pcb ) 50 and a screw 74 . the screw 74 is screwed into the post 72 . a microchip , not shown , is attached to the pcb . a loudspeaker 52 is also placed into the handle 12 ′. fig5 shows the sound projection circuit 40 installed into the handle , the handle cover 54 and bristle 80 ′. fig8 shows a more detailed view of the toothbrush handle 12 ′. fig9 shows a more detailed view of the toothbrush handle cover 54 . the sound project circuit 40 , as shown in fig1 , can have a loudspeaker 52 , a resistor 62 , a timing circuit 64 , and a power source 66 . the timing circuit 64 can include the microchip . the microchip is programmed with a unique sound or music . the unique sound or music is projected by the loudspeaker 52 after the switch 42 is pressed , completing the sound projection circuit 40 . the pcb 50 and microchip are preferably positioned on the outside of the handle 12 ′ preferably immediately below the handle cover 54 such that it can be easily installed by attaching the screw 74 described above . in this manner , during mass production , toothbrushes 10 ′ can be made with different microchips having different musical compositions or sound patterns . that is , a large number toothbrushes can be created with each toothbrush can have substantially the same or identical parts . to make toothbrushes with different musical or sound patterns , a different pcb board or microchip with a different musical program or sound pattern is added to the toothbrush . in this matter , product lines of toothbrushes with multiple musical or sound patterns can be cost effectively created . the timing circuit 64 preferably can function to activate the loudspeaker 52 for approximately 60 seconds . the timing circuit 64 also preferably can serve to control the loudspeaker 60 to project a sound intermittently for the time period in which it is engaged . in some embodiments , the loudspeaker 52 may stay on continuously and / or sound for a longer or shorter period of time . in the illustrated embodiment , the circuit is activated by closing an electrical switch 42 to complete a circuit . the switch 42 can be made of a flexible material . alternatively , the switch 42 may be of a hard material but have a flexible portion that may be used to engage the pcb 50 to connect the sound projection circuit 40 . in operation , the musical toothbrush 10 ′ is used by a user to indicate the duration of an amount of time . the user grips the toothbrush handle 12 ′ in their hand with the bristle 80 ′ surface with the bristle 80 ′ against their teeth and engages the switch 42 . the loudspeaker 52 begins to project sound intermittently in an on / off fashion . the loudspeaker 52 continues to sound for a period of approximately 60 seconds . the handle is designed to direct sound to the user in multiple ways so that the user may be accurately apprised of brushing time . the frequency of sound can remain constant , or vary in frequency . in some embodiments , the frequency can increase as the time approaches 60 seconds . in some embodiments , the frequency can remain constant through a first period of time , and increase in frequency in a second period of time . in one example , the frequency can remain constant for approximately 45 seconds ; then increase for the remaining 15 seconds . in other embodiments , different time intervals can be used , such as , for example , two even periods of thirty seconds each . as can be seen in fig1 , the toothbrush can be configured to have an illumination circuit 14 installed within the handle 12 ′. though not shown the toothbrush can have a loudspeaker and microchip installed so that the toothbrush can play music or sound and illuminate . the illumination circuit 14 can include a light emitted diode ( led ) 90 , batteries 48 , a first battery contact 94 , a second battery contact 96 and a connector 92 . the connector can be a simple electrical connector , a pcb or a timing circuit . fig1 - 14 illustrate alternative embodiments of the toothbrush having a front - mounted activation mechanism for activating a sound projection circuit 40 . the mechanism can comprise a variety of devices , some examples of which are illustrated and described below . fig1 illustrates an embodiment of a toothbrush 410 having an sound projection 40 and an activation mechanism 468 . the mechanism 468 can comprise a contact port 470 and a button 472 . the button 472 can comprise a metallic mesh 474 that surround the contact post 470 , and activates the sound projection circuit 40 , activating the loudspeaker , as described above . the mesh 474 can case the sound projection circuit 40 to activate through contact with a electrically - conducting inner surface , or support an electrically - conducting surface which activates the circuit 40 . the mesh 474 can be replaced by a spring , flexible rods , or any other suitable device , as described above . fig1 illustrates another embodiment of a toothbrush 510 having a front - mounted activation mechanism . the mechanism can comprise a push - button device 568 having a button 572 and a switch device 574 , as are well - known in the art . the push - button device 568 can cause the sound projection circuit 40 to activate the loudspeaker . the switch device 574 can be activated by manipulation of the button 572 , whether the button 572 is flexible or a rigid connection to the switch device 574 . the push - button device 568 can activate the circuit 40 once manipulated and future manipulations can be ignored by the circuit 40 until the timer has completed a cycle . this operation can occur in any embodiment described herein . fig1 illustrates another embodiment of a toothbrush 610 , wherein a loudspeaker projects sound or music by a sound projection circuit 40 . the circuit 40 can start a timed cycle upon receiving a signal from an activation device 668 . in the illustrated embodiment , the activation device 668 comprises a base 670 and two contact terminals 672 . the contact terminals 672 can activate the circuit 40 when electrical conduction occurs between the terminals 672 . in one embodiment , the circuit 40 and terminals 672 can be constructed to allow contact with human skin to both terminals 672 to cause conduction to occur , thereby activating the circuit 40 . in non - limiting examples , the palm of a human hand gripping the toothbrush can activate the circuit or , a finger or thumb pressed to touch both terminals 672 can activate the circuit 40 . water disposed in continuous contact with both terminals 672 can also activate the circuit 40 . although certain embodiments , features , and examples have been described herein , it will be understood by those skilled in the art that many aspects of the methods and devices shown and described in the present disclosure may be differently combined and / or modified to form still further embodiments . for example , any one component of the toothbrushes shown and described above can be used alone or with other components without departing from the spirit of the present invention . additionally , it will be recognized that the methods described herein may be practiced in different sequences , and / or with additional devices as desired . such alternative embodiments and / or uses of the methods and devices described above and obvious modifications and equivalents thereof are intended to be included within the scope of the present invention . thus , it is intended that the scope of the present invention should not be limited by the particular embodiments described above , but should be determined only by a fair reading of the claims that follow . | US-26785308-A |
the present invention relates to beverage supply systems for beverages comprising a flavor composition which comprises an oil phase and an aqueous phase . the flavor composition is concentrated such that it can separate into aqueous and oil phase under usual transport conditions and is provided in a unitized quantity corresponding to a batch supply for dilution to the desired beverage or an integer fraction of such a single batch supply . | as used herein the term “ beverage ” refers to a beverage composition which is in a single - strength , ready - to - serve , drinkable form . beverages of the present invention can comprise at least 50 % ( preferably at least 80 %) added water to dilute a bulk fruit juice concentrate and flavour composition . beverages contemplated within the scope of the present invention include both carbonated and noncarbonated forms . as used herein the term “ single strength ” refers to the recommended beverage strength , i . e . the ready - to - serve concentration of beverage compounds . as used herein the term “ fruit juice ” refers to citrus juices , noncitrus juices such as apple juice , grape juice , pear juice , cherry juice , berry juice , pineapple juice , kiwi juice , cashew juice , peach juice , apricot juice , plum juice , prune juice , mango juice , passion fruit juice , banana juice , and mixtures of these juices . as used herein , the term “ citrus juice ” refers to fruit juices selected from orange juice , lemon juice , lime juice , grapefruit juice , tangerine juice and mixtures thereof . all amounts of fruit juices referred to herein are on the basis of 100 % fruit juice in its single strength concentration . as used herein percentages are given as percent by weight of the beverage in its single strength dilution . percentages of water include the amount of water inherent in the beverage unless noted otherwise . optionally the beverages according to the present invention can comprise edible acids which include phosphoric acid , fumaric acid , adipic acid , lactic acid , tartaric acid , gluconic acid , succinic acid , malic acid , citric acid or their respective sour salts . also optionally the beverages according to the present invention can comprise supplemented solubilized minerals which include iron , calcium , magnesium , potassium , sodium , as well as supplemented vitamins . beverages of the present invention comprise a flavour composition which comprises a flavour selected from fruit flavours , botanical flavours and mixtures thereof . as used herein , the term “ fruit flavour ” refers to those flavour derived from the reproductive part of a seed plant , especially one having a sweet pulp associated with the seed . also included but less preferred within the term “ fruit flavour ” are synthetically prepared flavours made to simulate fruit flavours derived from natural sources . particularly preferred fruit flavours are the citrus flavours including orange flavours , lemon flavours , a variety of other fruit flavours can be used such as apple flavours , grape flavours , cherry flavours , pineapple flavours and the like . these fruit flavours can be derived from natural sources such as fruit juices and flavour oils , or else synthetically prepared . as used herein , the term “ botanical flavour ” refers to flavours derived from parts of a plant or other than the fruit . as such , botanical flavours can include those flavours from nuts , bark , roots and leaves , including tea leaves . also included within the term “ botanical flavour ” are synthetically prepared flavours made to simulate botanical flavours derived from natural sources . examples of such flavours include cola flavours , tea flavours and the like . these botanical flavours can be derived from natural sources such as essential oils and extracts , or else can be synthetically prepared . the flavour component can comprise a blend of various flavours e . g . lemon and lime flavours , cola flavours with citrus flavours to form cola flavours etc . if desired , fruit juices or their concentrates such as orange juice , lemon juice , lime juice , apple juice , grape juice and the like can be used in the flavour composition . the flavour in the flavour composition is sometimes formed into emulsion droplets which are then dispersed in the final beverage . because these droplets usually have a specific gravity less than that of water and would therefore form a separate phase in the final beverage , weighting agents ( which can also act as clouding agents ) are typically used to keep the emulsion droplets dispersed in the beverage . examples of such weighting agents are brominated vegetable oils ( bvo ) and resin esters , in particular the ester gums . see l . f . green , developments in soft drinks technology . vol . 1 ( applied science publishers ltd . 1978 ) pp . 87 - 93 for a further description of the use of weighting and clouding agents in liquid beverages . besides weighting agents , emulsifiers and emulsion stabilisers can be used to stabilise the emulsion droplets . examples of such emulsifiers and emulsion stabilisers include the gums , pectins , celluloses , polysorbates , sorbitan esters and propylene glycol alginates . see l . f . green , supra at p . 92 . the particular amount of the flavour composition effective for imparting flavour characteristics to the beverage of the present invention can depend upon the flavour ( s ) selected , the flavour impression desired , and the form of the flavour composition . for flavour compositions which are substantially free of fruit juice ( i . e . on a single strength basis comprising no more than about 1 % fruit juice by weight of the beverage ) the flavour composition can be comprised in the beverage at an amount of at least 0 . 01 % by weight of the beverage and typically from 0 . 05 % to 1 % by weight of the beverage . if fruit juice or concentrates thereof are part of the flavour composition up to twice these amounts can be used . beverages provided according to the present invention may also be carbonated . usually a beverage will be considered to be carbonated if it comprises more than 30 %, preferably more than 100 % by volume of the beverage of solubilized carbon dioxide . carbonated beverages comprise typically form 100 % to 450 %, preferably from 200 % to 350 % carbondioxide by volume of the beverage . the carbonated beverage can be placed in a container such as a bottle or a can and then sealed . see l . f . green , developments in soft drinks technology , vol . 1 ( applied science publishers ltd . 1978 ), pp . 102 - 107 , for a further description of beverage making in particular the process for carbonation . the flavour composition according to the present invention comprises two phases which separate out under typical storage conditions . this separation happens regardless of the amount of flavour composition . however , if the flavour composition amount is too large for using the whole flavour composition for a single batch dilution it must be metered to the required quantity prior to dilution ( not according to the present invention ). this however , requires a homogenisation of the flavour composition prior to metering or else substantially unequal quality between dilution batches would result . therefore , the beverage supply system according to the present invention requires the flavour composition to be provided in unitised quantities which by themselves or as integer multiples of the unitised quantity can be used for batch dilution to provide the beverage . the flavour composition is combined with a dilution composition in order to provide the beverage . the dilution composition provides the bulk quantity of the beverage typically the beverage comprises more than 99 % of the dilution composition . the dilution composition itself comprises essentially water . according to the present invention it should be understood that the dilution composition does not need to be a single liquid . it may for example be provided as a water source , a fruit juice concentrate or puree source , a sweetener source and an additive source which are combined in a batch mixture with the flavour composition when preparing the beverage . the dilution composition may also be itself prepared by combining various compounds or sub compositions such as a fruit juice concentrate or puree source , water , sweetener and other additive compositions . therefore , when referring hereinafter to the term dilution composition it includes all those compounds found in the beverage which are not part of the flavour composition or in other words the beverage without the flavour composition is the dilution composition . the beverage supply system according to the present invention is based on the widely availability of dilution compositions at even remote locations while flavour compositions in particular those supplied at high consistency of composition accuracy and quality of ingredients are typically not easily available and have to be transported to the place of mixing the dilution composition with the flavour composition . next to water the key compounds in the dilution composition are the fruit juice compounds or its concentrate or puree and the sweetener compounds . depending on the quantity desired for the final single strength beverage the fruit juice concentrate or puree , water and sweetener composition , are combined prior to combination with the flavouring composition or simultaneous therewith . beverage additives can be the mineral additives or vitamin additives mentioned above . the fruit juice composition usually will be capable of providing a full fruit juice with the exception of certain desirable flavour compounds . typically bulk fruit juice concentrate is separated from some of its flavour compounds when concentrating the raw fruit juice . the separated flavour compounds are typically supplied as part of the flavour composition . the fruit juice concentrate in the dilution composition will provide a certain sweetener effect due to its sugar content . this can be supplemented by additional sugar and / or other sweeteners . other sweeteners are in particular those nonnutritive sweeteners which can be either natural or synthetic and usually have a much greater sweetness intensity than sugar but without its caloric value . examples of such non - nutritive sweeteners are saccharin , cyclamate and aspartame also known as nutra - sweet as well as other non - caloric sweeteners known in the art . the sweetener composition provides together with the sweeteners already present in the flavour composition a maximum amount of solubilized sugar in the single strength beverage of 14 %, preferably a maximum 12 % by weight . it is , however , more typical to have substantially lower amounts of sugar and supplement the sweetness by the abovementioned non - nutritive sweeteners to provide sweetness comparable to about 5 %- 15 % by weight of sugar . in the following example a beverage supply system for making an orange flavoured juice drink comprising 10 % by weight juice on a single strength basis is described . the flavour composition is prepared to a concentration factor allowing a dilution with 250 times its weight . the flavour composition consists of orange aroma citronova , redd dist oil , redd aroma , tetrarome , aspartame , acesulfame k , lemon concentrate , and demineralised water . the ingredients can be obtained from any usual source but have been obtained in this case from the firmenich company , geneva , switzerland ( with the exception of demineralised water , lemon concentrate and the sweeteners aspartame and acesulfame k which are generally available to the public ). this flavour composition is packed into 20 kilo containers and shipped to the reconstitution plant for mixing and filling of the final beverage . the flavour composition separates into an oil phase and an aqueous phase within less than 2 hours after being packed standing at 20 ° c . a locally available dilution composition consist of two sub compositions , one being demineralised water in a quantity of 4177 . 35 kg , the other being an orange juice concenrtrate composition comprising 400 kg demineralised water , 2 . 25 kg ascorbic acid , 21 . 795 kg lemon concentrate , 112 . 605 kg citrus pulp and 266 kilo orange juice concentrate . the demineralised water together with the orange juice concentrate composition and one 20 kilo batch of the flavour composition are poured into a agitated premix tank of 5000 liter . they are then pumped through a single homogenisation system typical in the art and pasteurised at ultra high temperature before being placed in a sterile tank . from the sterile tank the finished beverage composition is distributed to a filling station for final packaging of the beverage . this process saves the complexity involved in providing the flavour composition from a bulk storage where constant homogenisation would be necessary . | US-81727797-A |
a motion sensitive device for causing an electronic signal to be sent to one or more output devices , comprising a printed circuit board , a battery connected to the printed circuit board , electrical circuitry connected to the printed circuit board , a motion sensitive switch connected to the printed circuit board , electrical output devices such as light emitting diodes connected to the printed circuit board and electrical circuits all providing means whereby the motion sensitive switch causes a signal to be transmitted to the output device when movement is sensed by the switch . the device is small enough to be used in wearing apparel and can provide safety vis - à - vis increased visibility for the user . | a novel motion sensitive switch and electrical circuitry are described . in the following description , for the purposes of explanation , specific component arrangements and constructions and other details are set forth in order to provide a more thorough understanding of the present invention . it will be apparent to those skilled in the art , however , that the present invention may be practiced without these specific details . in other instances , well known manufacturing methods and structures have not been described in detail so as to refrain from obscuring the present invention unnecessarily . referring first to fig1 the invention comprises several basic components including a motion sensor switch housing 10 , a power source 30 , electrical circuitry generally printed on a circuit board 36 and output device ( s ) 50 that generally comprise one or more illumination devices such as light emitting diodes . additionally , the motion sensor switch housing 10 , power source 30 and electrical circuitry generally printed on a circuit board 36 are positioned such that they are hidden from view , such as within the sole of a shoe , while the output device 50 is located such that the output is observable on the outside surface of the shoe . referring next to fig2 which illustrates in cut - away elevation a preferred embodiment of a motion sensitive switch in accordance with the present invention shown generally by the reference number 10 . in fig2 the circuit is in a closed position , with a moveable object having an electrically conductive surface and a magnetically attractable portion , generically referred to herein as an electrically conductive ball 20 , resting against two electrically conductive members ( pins ) supported in said housing 16 , 18 . referring also to fig4 an exploded view of the motion sensor switch 10 is shown . the motion sensor switch 10 is contained within an electrically non - conductive housing unit 12 . the switch 10 includes a positively charged electrically conductive pin 16 , a negatively charged electrically conductive pin 18 , an electrically conductive ball 20 and a magnet 24 . the pins 16 , 18 are connected to the circuit in such a manner that contact by the ball 20 concurrently with both pins 16 , 18 forms a closed circuit . the magnet is positioned within the chamber so that it attracts the ball 20 towards and in contact with the pins 16 , 18 when the device is inactive . in one embodiment of the invention , the housing 12 is essentially cylindrical in shape , having a top surface 26 and an opposing bottom surface 28 . when assembled , the magnet 24 is positioned within the housing 12 against the top surface 26 . two electrically conductive pins 16 , 18 are positioned adjacent to the magnet 24 and between the magnet 24 and the bottom surface 28 . pins 16 , 18 are positioned close enough together such that the ball 20 is not allowed to pass between the pins 16 , 18 and is therefore not allowed to directly contact the magnet 24 . the ball 20 is moveably positioned between the two pins 16 , 18 and the bottom surface 28 . the height of the housing 12 is roughly equivalent to , but slightly greater than , the combined heights of the ball 20 , the pins 16 , 18 and the magnet 24 . thus , there is sufficient space between the pins 16 , 18 and the magnet 24 such that the pins 16 , 18 and the magnet 24 are not in contact with each other . additionally , there is sufficient additional space between the pins 16 , 18 and the bottom surface 28 such that when the ball 20 is in contact with the bottom surface 28 , the ball 20 is not in contact with the pins 16 , 18 . when the device 10 is at rest , the ball 20 is biased towards the magnet 24 and rests against the pins 16 , 18 . when the ball is in this position , the circuit is closed . when the device 10 moves , the motion produces sufficient force to break the magnetic bond between the ball 20 and the magnet 24 , allowing the ball 20 to momentarily move freely within the housing unit 12 . while the ball 20 is not in contact with the pins 16 , 18 , the circuit is open . referring next to fig3 the two pins 16 , 18 extend beyond the wall of the motion sensor housing 12 and are connected to the remaining electronic circuitry . to prevent movement , the pins 16 , 18 rest in notches in the housing 12 when the switch 10 is fully assembled . referring next to fig5 another embodiment of the motion sensitive switch 10 is shown . in this embodiment , the electrically conductive ball 20 is magnetized and is therefore attracted to the ferro - magnetic , electrically conductive pins 16 and 18 . in its biased position , the ball 20 is at rest against the pins , 16 and 18 . on motion , the magnetic attraction of the ball 20 and the circuit are temporarily broken . on returning to the biased position , the circuit is re - established and the change of state , as described above , triggers the output device . this alternative embodiment is capable of carrying out its intended function of breaking and re - making the circuit in the absence of a separate magnet 24 . another major component of the invention is the electrical circuitry , generally placed on a printed circuit board . referring also back to fig1 the sensor switch housing is coupled to a printed circuit board 30 . also coupled to the printed circuit board 30 are a small battery 30 , a microprocessor 46 , memory , circuits 32 and connectors 34 for wiring to lights and / or other electrical devices . the change from closed to open causes a state change within the electrical circuitry . a second state change occurs when the ball 20 re - establishes contact with the pins 16 , 18 . the second state change causes a trigger signal to be sent to an output device 50 . in the preferred embodiment , the output device 50 produces lights and / or sounds . in the case where the output device 50 comprises a series of lights , the trigger signal consisting of the two state changes closely timed together , causes the lights connected to the circuitry to illuminate . the illumination pattern used in the preferred embodiment is an initial illumination pattern sequence followed by a second illumination pattern sequence . starting from the end of the initial trigger cycle and within the defined “ delay ” period of two seconds , if any additional trigger signal is detected , the led 50 will continue it &# 39 ; s flashing sequence . when no additional trigger signals are present after the two second “ delay ” period , the microprocessor selects a random “ end - cycle ” pattern of either 1 or 2 additional flashing sequences ( end - cycles ) and return to stand - by mode until a new trigger occurs . this end cycle consists of two different flash duration &# 39 ; s for the purpose of extending battery life : ( i ) one complete cycle ( 80 % probability ) or ( ii ) two complete cycles ( 20 % probability ). in the preferred embodiment , the microprocessor 46 begins lighting the first led 50 in response to a triggering event . the leds 50 illuminate in sequence , in a “ lighting cycle ,” beginning with the led 50 at one end of the strip and ending with the led 50 at the opposite end . each led 50 turns off in sequence before the next led 50 turns on . when the last led 50 is turned off it creates the “ end of the lighting cycle .” if the triggering event still exists at the end of the cycle , the microprocessor 46 causes the beginning of another lighting cycle . if no triggering event exists at the end of the cycle , the microprocessor 46 selects and performs an “ end cycle .” the number of end cycles is selected according to a random process ( done by the microprocessor 46 ) from the number { 1 , 2 , or 3 }, so that one , two , or three complete end cycles follow . lighting stops at the end of the final end cycle . in the preferred embodiment , several different flashing sequences are programmed into the electronic circuitry . the table below , identifies the flashing sequence of the preferred embodiment . the illumination pattern used in the preferred embodiment is a pre - defined initial signal sequence followed by a pre - defined sequential signal sequence followed by a randomly selected closing signal sequence . only the last “ randomly selected closing signal ” was incorporated into the circuit design . however , it should be noted that the invention is not limited to these specific lighting sequences . as noted above , the end cycle is randomly chosen from one of two different selections . the end cycle consists of two different flash duration &# 39 ; s of either one or two complete cycles . in an embodiment where the output device ( s ) 50 consist of audio devices , the trigger signal causes a series of sounds to be emitted instead of illuminated led output . now referring also to fig1 and 2 , in the biased position , the metallic ball 20 will remain contacted against the pins 16 and 18 . a trigger event occurs when the ball 20 moves away from and then re - contacts pins 16 and 18 . the momentary break in continuity and the re - contact of the pins 16 and 18 forms the trigger cycle that the microprocessor 46 accepts in order to start the led 50 flashing sequence . each trigger cycle is considered to be “ one - shot ” or non - re - occurring . when the trigger cycle is completed and output is sent from the microprocessor 46 , the led &# 39 ; s 50 will then begin to flash . to prevent the microprocessor 46 from processing multiple trigger inputs , any trigger input received between the “ start ” and “ end ” of a flash sequence is disregarded . after the end of a flash sequence , a “ delay ” period ( defined in one embodiment to be between 0 . 02 and 2 . 0 seconds ) will occur before the device will accept any new trigger inputs to start another flash sequence . if no trigger is received , microprocessor 46 will select a random end cycle to flash . during the end cycle , any trigger inputs are disregarded until the cycle is completed . upon triggering , the leds 50 will flash for a single cycle sequence . starting from the end of the initial trigger cycle and within the defined “ delay ” period of two seconds , if any additional trigger signal is detected , the led 50 will continue its flashing sequence . when no additional trigger signals are present after the “ delay ” period , the microprocessor 46 will then select a random “ end - cycle ” pattern of 1 or 2 additional flashing sequences and return to stand - by mode until a new trigger occurs . the type of power source used in the preferred embodiment is a small battery . the exact type of battery is not significant to the invention except that it should be small enough to conveniently fit into the item to which the invention is attached . the type of electrical circuitry capable of functioning in the manner described is readily available and familiar to those in the industry . while the foregoing detailed description has described several embodiments of a motion sensitive switch in accordance with the present invention , the above description is illustrative only and not limiting of the disclosed invention . indeed , it will be appreciated that the embodiments discussed above and the virtually infinite embodiments that are not mentioned could easily be within the scope and spirit of the present invention . thus , the present invention is limited only by the claims set forth below . | US-28867402-A |
a measuring device for measuring harvested crop throughput is provided with a dosing device that adds additional grain to the flow of harvested crop material being processed to better calibrate the measuring device . the dosing device adds a defined amount of grain that can be detected by the measuring device . | fig1 shows the threshing device of a combine harvester . it comprises a rotatabe threshing cylinder 10 . threshing concave 12 is arranged on a part of the circumference of threshing cylinder 10 . threshing cylinder 10 is supplied by feeder house 14 with a crop flow from a harvesting assembly . threshing cylinder 10 is provided with rasp bars that in conjunction with the concave 12 threshes the crop and loosens grain , so that the grain falls down through openings in threshing concave 12 . three sensors 16 , 18 and 20 , which can be known impact plate sensors , are arranged in series below the threshing concave . beater 22 is located downstream from the threshing cylinder 10 and directs the threshed crop to a separating device illustrated in fig2 . dosing device 24 is filled with grain supplied to it , e . g ., by an appropriate line from the grain tank or the clean grain elevator of the combine harvester . dosing device 24 is provided on the bottom with flap 26 that can be folded open . when flap 26 is opened , a defined amount of additional grain passes into the crop flow supplied to threshing cylinder 10 . sensors 16 , 18 and 20 then furnish the signals shown in the lower part of fig1 . when grain is added from dosing device 24 a signal rise is obtained . a corrected throughput of grain in threshing cylinder 10 is calculated by an evaluation device 50 from the original signal and from the signal changed by the defined addition of grain . fig2 shows the separating device of a combine harvester 10 . it consists of a known straw walker 30 . three sensors 32 , 34 and 36 with a known construction , e . g ., impact plate sensors , are arranged below straw walker 30 . they detect the amount of grain falling down from straw walker 30 . a second dosing device 38 is filled with grain supplied to it , e . g ., by an appropriate line from the grain tank or the clean grain elevator . dosing device 38 is provided on the bottom with flap 40 that can be opened . when flap 40 is opened , a defined amount of additional grain passes into the crop flow supplied to straw shaker 30 . sensors 32 , 34 and 36 then furnish the signals shown in the lower part of fig2 . when grain is added from dosing device 38 , a signal rise is obtained . a corrected throughput of grain in straw walker 30 is calculated by the evaluation device 50 using the original signal and the signals changed by the defined addition of grain . such a dosing device can also be arranged at the inlet of a sieve with one or several sensors being located below the sieve for detecting the separated grain . similar t the illustrated devices the sensor is / are connected to an evaluation device 50 designed in the manner described above . in all embodiments described the evaluation device 50 connected to the sensors can be connected to a display device that displays the grain throughput and / or the grain losses to the operator . the signals made available by the evaluation device 50 can also be used for automatically adjusting work parameters of the harvesting machine ( e . g ., travel speed , adjustment of the threshing cylinder , sieve apparatus opening and air - blast velocity in the sieve ) and / or for geo - referenced yield mapping . having described the illustrated embodiment , it will become apparent that various modifications can be made without departing from the scope of the invention as defined in the accompanying claims . | US-63032403-A |
a device used while cooking to retain utensils and protect a user &# 39 ; s hand and forearm from grease splatters is herein described . the device comprises a glove body made of a flexible fire - resistant material with individual finger and thumb appendages for increased dexterity . the device extends from the hand portion toward a wearer &# 39 ; s elbow where an elastic strap provides a seal which prevents heated grease from splattering inside of the glove . a pair of straps is located within the palm area to help retain spatulas , spoons , tongs , whisks , or other similar food preparation utensils . the straps are secured together with fasteners thereby allowing the straps to adjust to any size utensil handle . | the best mode for carrying out the invention is presented in terms of its preferred embodiment , herein depicted within fig1 and 2a , and alternately within fig2 b . however , the invention is not limited to the described embodiment and a person skilled in the art will appreciate that many other embodiments of the invention are possible without deviating from the basic concept of the invention , and that any such work around will also fall under scope of this invention . it is envisioned that other styles and configurations of the present invention can be easily incorporated into the teachings of the present invention , and only one particular configuration shall be shown and described for purposes of clarity and disclosure and not by way of limitation of scope . the terms “ a ” and “ an ” herein do not denote a limitation of quantity , but rather denote the presence of at least one of the referenced items . the present invention describes a cooking utensil gripping glove ( herein described as the “ device ”) 10 , which provides a means for protecting a user from injuries inflicted by splashes from heated cooking oil or frying grease . referring now to fig1 , an environmental view of the device 10 , according to the preferred embodiment of the present invention , is disclosed . the device 10 is depicted in as state of being worn on the forearm 60 of a user while gripping a utensil 50 within the glove 11 . the handle portion of the utensil 50 is stabilized by the encircling action of a first strap 14 being closed onto a second strap 15 by means of a hook - and - loop - type fastening means . it is envisioned that the device 10 is designed to be worn on a right hand , whereas a left - handed user would wear an alternate utensil gripping glove 20 in a similar manner on a left hand . it is further envisioned that a user could wear both the device 10 and the alternate device 20 simultaneously whenever additional protection for both the right and the left hand and forearm 60 is desired . referring now to fig2 a , a palm - side view of the device 10 , according to the preferred embodiment of the present invention , is disclosed . the device 10 comprises a glove 11 wherein the palm - side of each fingertip comprises a gripping pad 13 intended to facilitate picking up and retaining the handle portion of the utensil 50 or other cooking implements . the bottom end portion of the device 10 comprises an elastic closure 12 designed to prevent the intrusion of splashed heated oil or grease by providing a seal around a user &# 39 ; s forearm . the glove 11 further comprises a first strap 14 and a second strap 15 intended to stabilize the utensil within the palm of the glove 11 . the glove 11 is envisioned to be made of a fire - resistant material , such as : modecrylic fiber ( protex ®), aramid fiber ( nomex ®, kevlar ®), or mineral fiber ( kaowool ®), wherein appropriate fabric shapes are cutout and sewn , stitched , bonded , or laser welded together , or said materials in fiber form are knitted into the configuration of the glove 11 . the straps 14 and 15 are envisioned to be made of similar fire - resistant material as the glove 11 and to be provided with a hook - and - loop - type closure means . this type of closure is preferred in order to provide greater versatility depending on differing sizes handles of utensils 50 . the gripping pads 13 are made of the similar fire - resistant materials , whereby their gripping face portion is provided with a rough no - slip texture . the plurality of the pads 13 along with the straps 14 and 15 are envisioned to be bonded , sewn , or stitched onto the palm - side of each fingertip and within the palm of the glove 11 . referring now to fig2 b , a palm - side view of the device 20 , according to the alternate embodiment of the present invention , is disclosed . the alternate device 20 comprises an alternate glove 21 wherein the palm - side of each fingertip comprises the gripping pad 13 as well as a palm gripping pad 30 in a configuration generally similar to the glove 11 . the bottom end portion of the alternate glove 21 also comprises the elastic closure 12 and the palm portion of the glove 21 comprises a third strap 24 and a fourth strap 25 . the glove 21 and the straps 24 and 25 are made of the similar fire - resistant material and are manufactured by similar processes as the device 10 . it is envisioned that other styles and configurations of the present invention can be easily incorporated into the teachings of the present invention , and only one particular configuration shall be shown and described for purposes of clarity and disclosure and not by way of limitation of scope . the preferred embodiment of the present invention can be utilized by the common user in a simple and effortless manner with little or no training . after initial purchase or acquisition of the device 10 , it would be worn as indicated in fig1 . the method of utilizing the device 10 may be achieved by performing the following steps : removing the device 10 from a storage drawer ; grasping the elastic closure 12 between the thumb and index finger of the left hand ; moving the fingers of the right hand into a close proximity with each other ; inserting the fingers into the elastic closure 12 ; using the left hand thumb and index finger to pull the device 10 over the user &# 39 ; s forearm ; pulling the glove 11 toward the user &# 39 ; s elbow until the entire length of the forearm 60 is enclosed and each of the user &# 39 ; s fingers abut the inside finger tip portion of the glove 11 ; placing the handle of the utensil 50 hereinto the palm of the glove 11 and under the first strap 14 , whereby the bottom end portion of the handle of the utensil 50 rests against the base of the thumb ; holding the handle of the utensil 50 between the thumb and index finger of the gloved right hand ; using the thumb and index finger of the left hand to stabilize the handle portion of the utensil 50 by closing the first strap 14 tightly onto the second strap 15 ; proceeding with the desired cooking processes ; grasping and pulling one of the fingers of the glove 11 between the thumb and index finger of the left hand to initiate the removal of the glove 11 ; totally removing the glove 11 by using the thumb and index finger of the left hand to sequentially pull the fingers of the glove 11 ; and , washing , laundering or cleaning and storing the glove 11 . the method of utilizing the alternate device 20 may be achieved by performing steps similar to those described in the foregoing but with the assistance of the right hand instead of the left hand . the method of simultaneously utilizing the preferred device 10 and the alternate device 20 may be achieved by performing similar steps as those described in the foregoing , except that the assistance of the hand wearing the device 10 or of a helper will be needed to install the device 20 . the foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description . they are not intended to be exhaustive or to limit the invention and method of use to the precise forms disclosed . obviously many modifications and variations are possible in light of the above teaching . the embodiment was chosen and described in order to best explain the principles of the invention and its practical application , and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated . it is understood that various omissions or substitutions of equivalents are contemplated as circumstance may suggest or render expedient , but is intended to cover the application or implementation without departing from the spirit or scope of the claims of the present invention . | US-77586010-A |
the invention relates to an inlet for a tank which is intended for a liquid food product . the inlet is placed in the side wall of the tank and at the upper end of the tank . the inlet is further designed so that the inflowing product is distributed in fan - shape along the inside of the tank . the application also includes a method of supplying liquid food product to a tank . | in fig1 , untreated product enters through a conduit 1 , passes a balance tank 2 and continues via a conduit 3 to a heat treatment equipment unit 4 . the heat treatment equipment unit 4 may be a pasteurizer , an uht unit ( ultra high temperature ) or some other form of process equipment which requires circulation over a balance tank 2 . when the correct temperature has been reached in the heat treatment equipment 4 , the treated product passes out through a conduit 5 . if the correct temperature has not been reached , a valve 6 closes and another valve 7 opens so that the product enters into the balance tank 2 . in fig1 , which illustrates the prior art , the inlet 8 of the balance tank 2 is disposed in the lower region of the tank 2 , below the liquid surface 9 . until the correct temperature has been reached in the heat treatment equipment 4 , the product will be circulated over the balance tank 2 . the drawback inherent in the above - outlined circulation and the low positioning of the inlet 8 in the balance tank 2 is that there is a slight risk that untreated product may be mixed together with treated product . fig2 illustrates a circulation over a balance tank 2 where the tank 2 has an inlet 8 according to the present invention . in fig2 , untreated product enters through a conduit 1 and continues to a heat treatment equipment unit 4 . the heat treatment equipment unit 4 may be a pasteurizer , an uht - treatment equipment unit ( ultra high temperature ) or some other form of process equipment which requires circulation over a balance tank 2 . when the correct temperature has been reached in the heat treatment equipment 4 , the treated product passes out through a conduit 5 . if the correct temperature has not been reached , a valve 6 closes and another valve 7 opens so that the product enters into the balance tank 2 . the inlet 8 is positioned in the side wall 11 of the tank 2 and at the upper end of the tank 2 . until the correct temperature has been reached in the heat treatment equipment 4 , the product will be circulated over the balance tank 2 . the inlet 8 according to the present invention is shown in detail in fig4 and fig5 . the balance tank 2 , which is normally covered with an upper section 10 , is here illustrated without said upper section 10 . the inlet 8 passes through the side wall 11 of the tank 2 at the upper end of the tank 2 . the inlet 8 discharges in a pipe socket 12 which is thus fixedly secured against the inside of the tank 2 . the socket 12 has a downwardly directed opening with a span of 90 - 130 °, preferably 100 - 120 ° and in the preferred embodiment 110 °. the span is illustrated in fig4 as the angle α . in direct connection with the socket 12 and its opening , there is disposed a fan - shaped disk 13 . the disk 13 has a span which corresponds to the span of the opening of the socket 12 , i . e . 90 - 130 °, preferably 100 - 120 ° and in the preferred embodiment 110 °. the disk 13 also has side portions 14 which entail that the opening of the socket 12 is completely enclosed by means of the disk 13 and the side portions 14 . the disk 13 is further arched so that it follows the rounded inside of the side wall 11 of the tank 2 . moreover , the disk 13 is bulged downwards , so that the gap 15 which occurs between the disk 13 and the side wall 11 of the tank 2 is approx . 2 cm at a point 16 , located at the outer definition of the disk 13 , and the gap 15 is further approx . 1 cm at a point 17 , at the central region of the disk 11 as a result of the design of the gap 15 , so that it will be wider out towards the outer definition 16 of the disk 13 , an inlet 8 according to the present invention is capable of handling capacities of 5 , 000 - 20 , 000 l / h . when the flow rate of product is low ( 5 , 000 l / h ) the flow distributes in fan - shape from the central region 17 of the disk 13 halfway out towards the outer definition 16 of the disk 13 . when the product flow rate is high ( 20 , 000 l / h ) the flow distributes in fan - shape from the central region 17 of the disk 13 all the way out to the outer definition 16 of the disk 13 . the socket 12 of the inlet 8 has a length a which is 5 - 10 cm , preferably the length a is 7 - 8 cm . the disk 13 has a length b which corresponds to 1 - 1 . 5 times the diameter d of the inlet . the diameter d of the inlet is illustrated in fig3 . the inlet 8 is wholly manufactured of stainless steel so as to meet the extremely stringent hygiene requirements of the food industry . other materials may also occur , such as food - approved plastics . the design of the inlet 8 makes it easy to clean using the cip - equipment ( cleaning in place ) of the plant . trials have demonstrated that an inlet 8 in , for example , a balance tank 2 which enters straight into the tank 2 above the liquid surface 9 of the tank 2 gives an admixture of air of approx . 3 %. the longer time the product must be circulated over the balance tank 2 , the more air will be admixed into the product . corresponding trials with an inlet 8 according to the present invention demonstrate a possible admixture of air which is no longer capable of being measured . an air admixture of a few percent would also affect the product and there is , among other things , an increased risk of fouling of the product in the heat treatment equipment 4 . standardization of milk products is also affected by air admixture in that there will be a lower level of accuracy of the mixing ratios in the standardization . other measurement equipment also suffers from a lower level of accuracy if the product contains air . homogenization of milk products similarly suffers from poorer results if the milk product contains air . an inlet 8 according to the invention and according to the foregoing description may be employed for all types of tanks 2 where the intention is to obtain a controlled inflow of product . the inlet 8 may further by employed in a plurality of processes and for different types of products , which are negatively affected by an admixture of air . as will have been apparent from the foregoing description , the present invention realises a tank inlet which minimizes the admixture of air in the inflowing product . the inlet makes it possible for the product to be fed to the tank above the existing liquid surface , which may be a mandatory requirement in some countries . | US-86772008-A |
a two - photon imaging system capable of imaging of an image region in real time is presented . the imaging system comprises a source of excitation light that provides the excitation light as a plurality of laser beamlets . the plurality of laser beamlets is collectively scanned by a single - axis scanner along a first direction in the focal plane of the image region and oriented such that neither the rows nor columns are aligned with the first direction . as a result , each laser beamlet scans a different sub - region of the image region and the plurality of sub - regions are simultaneously scanned . as a result , the entirety of the image region is scanned in the same amount of time required to scan one image sub - region . | fig1 depicts a schematic drawing of a portion of an imaging system in accordance with an illustrative embodiment of the present invention . imaging system 100 is a two - photon laser - scanning microscopy system that comprises source 102 , lenslet array 104 , scanner 106 , optics system 108 , objective 110 , imager 112 , and processor 128 . in some embodiments , imaging system 100 is a single - photon microscopy system . in some embodiments , imaging system 100 is a multi - photon microscopy system that requires more than two photons to excite a fluorophore . fig2 depicts operations of a method suitable for imaging an image region in accordance with the illustrative embodiment of the present invention . method 200 begins with operation 201 , wherein light beam 116 is provided to lenslet array 104 . source 102 includes an ultrashort - pulsed regenerative fiber laser amplifier ( hereinafter referred to as a “ fiber laser ”) that emits light at approximately 1030 nm ( e . g ., a regenerative ultrafast yb 3 + laser amplifier , etc .). the fiber laser has an average power of 20 watts and a tunable repetition rate that is within the range of approximately 200 khz to approximately 2 mhz . as a result , the fiber laser provides pulses of optical energy that have higher energy than the typical output power of a conventional ti - sapphire laser . this enables an enhancement of the two - photon excitation effect for multiple laser foci in each of excitation signals 118 ; however , it keeps the average optical power delivered to image region 122 within a tolerable range . at operation 202 , lenslet array 104 distributes the optical energy in light beam 116 into excitation signals 118 ( i . e ., beamlets 118 ) and provides them to optics system 108 . lenslet array 104 is an array of microlenses operative for receiving light beam 116 and distributing it into a two - dimensional array of equal - intensity beamlets ( i . e ., excitation signals 118 ). in order to convert the output of the fiber laser into a plurality of substantially equal - intensity beamlets , prior to being received by lenslet array 104 , the output of the fiber laser is first expanded and then shaped at a beam shaper , which corrects the beam profile from gaussian to flat . once corrected , the now homogeneous - intensity laser beam is reduced again and provided to lenslet array 104 . the lenslet array splits the laser beam into a plurality of beamlets . in the illustrative embodiment , excitation signals 118 includes 25 beamlets ; however , the number of beamlets can have any practical value . excitation signals 118 typically includes hundreds of beamlets . optics system 108 is an arrangement of optical components for providing excitation signals 118 as a two - dimensional array of foci at focal plane 118 . optics system 108 includes numerous optical components , including aspheric lenses , meniscus compound lenses for mitigating field curvature at focal plane 118 , dichroic mirror 124 for removing light at the excitation wavelength from the light received at imager 112 , a tube lens , and scanner 106 . it should be noted that the design and arrangement of optics system 108 depicted in fig1 is merely exemplary and that myriad alternative designs and arrangements suitable for use in the present invention would be readily realizable for one of ordinary skill in the art . fig3 a depicts a portion of foci array 300 at focal plane 116 . foci array 300 is a two - dimensional array of foci 302 , which are arranged in equally spaced columns 304 and rows 306 . the x - and y - spacing , d , between adjacent foci 302 at focal plane 114 is equal and has a value of approximately 25 microns ; however , one skilled in the art will recognize that the spacing can have any suitable value . in some embodiments , the x - and y - spacing between foci 302 is different . each of rows 306 is parallel with array axis 308 . scanner 106 is a single - axis laser scanning mirror . in some embodiments , scanner 106 is a different scanning element , such as a rotatable prism , dual - axis scanning mirror configured to scan in only one dimension , and the like . the positions of scanner 106 and the aspheric lenses within optics system 108 are selected such that each of excitation signals 118 is incident on the center of scanner 106 as well as the back aperture of objective 110 . it is an aspect of the present invention that the use of a single - axis scanning element affords advantages over multi - photon imaging systems of the prior art , which include dual - axis scanners that raster scan a light beam over an image region . a single - axis scanning element can operate at a modest rate ( e . g ., the same as the frame rate of the system ) and requires a relatively simple controller . in contrast , a conventional raster - scanning mechanism requires that the fast - scanning axis operates at a much higher rate than the imaging frame rate . this need for high - speed scanning makes it extremely difficult , if not impossible , for such a scanner to work properly . for example , a typical prior - art high - speed mechanical scanner capable of khz ( or higher ) operation operates in resonance mode . as a result , such prior - art scanners are normally characterized by relatively poor angular position control , which gives rise to poor image resolution for their corresponding microscope systems . at operation 203 , scanner 106 scans excitation signals 118 along scan direction 310 ( i . e ., along the x - direction as shown in fig3 a - b ). in some embodiments , the scanner scans the excitation signals through the desired range of motion in approximately 1 millisecond . scanner 106 and optics system 108 are arranged such that foci array 300 is rotated relative to the array of beamlets in excitation signals 118 so that the scanner scans the beamlets along a direction that is at a non - zero angle with respect to the direction defined by the rows of beamlets . fig3 b depicts a portion of foci array 300 at focal plane 114 where the array is rotated by angle , θ , relative to the scanning direction 310 of scanner 106 . foci array 300 is tilted relative to the scan direction of scanner 106 to enable foci 306 to collectively scan the entirety of image region 122 . the value of θ is based on the spacing between foci 302 as well as the number of foci in each row 306 , n . in some embodiments , θ is equal to arctan ( 1 / n ). the values of angle , θ , and spacing , d , are selected so that the spacing between adjacent scanning lines is small enough to enable a desired spatial resolution ( e . g ., micron - level resolution ). in some embodiments , these values are selected to mitigate cross - talk as well . in some embodiments , the values of angle , θ , and spacing , d , are selected so that , along the direction orthogonal to scanning direction 310 ( i . e ., along the y - direction as shown in fig3 a - b ), the separation , s 1 , between adjacent foci within each row 306 is an even fraction of the separation , s 2 , between adjacent rows 306 . at operation 204 , fluorescence signals 120 are detected at imager 112 , which generates output signal 128 based on the fluorescence signals . fluorescence signals 120 are generated at fluorophores located in image region 122 . as fluorescence signals 120 are emitted from image region 122 , they are incident on dichroic mirror 124 , which passes reflected light at the excitation wavelength but reflects light at fluorescence wavelengths toward imager 112 . imager 112 is a multi - pixel photon collecting device characterized by noise that is nearly shot - noise - limited . imager 112 enables simultaneous capture of fluorescence signals from substantially all excited fluorophores in image region 122 . in the illustrative embodiment , exemplary imager 112 comprises an image intensifier and high - speed camera operative for directly forming multi - pixel images of image region 122 . in some embodiments , the high - speed camera includes a camera system having a frame rate of 25 khz and resolution of 768 × 768 pixels . such a camera is sufficiently fast to acquire 25 rounds of data acquisition in 1 millisecond . one skilled in the art will recognize , after reading this specification , that the combination of a high - speed camera and image intensifier represents only one of several imager systems suitable for use with the present invention . other suitable imagers include , without limitation , ultra - low - read - noise cameras ( e . g ., a single scientific cmos camera , etc . ), and the like . as discussed below and with respect to method 500 , it is advantageous that the camera of imager 112 include a frame trigger input such that accurate foci travel info can be developed for a plurality of sub - frames by synchronizing scanner 106 and the frame trigger . fig4 a - b depict schematic drawings of top and front views , respectively , of imaging system 100 , as well as the excitation paths through it . fig4 c depicts a top view of the optomechanics of system 100 , as well as excitation and emission paths through it . as shown in fig4 a - c , a slider mechanism is provided to enable swapping of optical components for either the multi - foci path or conventional single - focus two - photon path . it should be noted that , in some embodiments , imaging system 100 enables one - photon imaging capability , which affords more versatile operation using a single imaging system . it should further be noted that tissue scattering can lead to photons being emitted from different positions and overlapping into the same pixels at the camera of imager 112 . this can lead to a blurred image . this phenomenon is particularly problematic when imaging in tissue to depths greater than a few hundred microns . at operation 205 , imager 112 passes output signal 126 to processor 128 . at operation 206 , processor 128 reconstructs a fluorescence image of image region 122 from output signal 126 using a deconvolution algorithm . by using such an algorithm , a complete image frame can be reconstructed from multiple sub - frames while correcting for optical crosstalk between nearby foci . in some embodiments , the algorithm also provides spatial registration . it is an aspect of the present invention that the post - processing routine included in operation 206 enables extraction of latent image information from a blurred image by utilizing both the photon excitation / emission position information and optical system information ( i . e ., the point - spread function of system 100 ). fig5 depicts sub - operations suitable for use in operation 206 . operation 206 begins with sub - operation 501 , wherein a plurality of sub - frame images are taken for each full frame image , where each sub - frame image captures a fraction of the foci travels . the number of sub - frame images taken can be any practical number , based on the capability of imager 112 ; however , the number of sub - frame images taken with present technology is typically within the range of approximately 10 to approximately 20 . it should be noted that , as the number of sub - frame images taken increases , so does the amount of accurate foci position information that can be utilized for further deconvolution steps . unfortunately , increasing the number of sub - frame images also decreases the photon signal obtained from each sub - frame image . it should be further noted that a practical limit on the number of sub - frame images normally arises from the upper limit on camera throughput / frame rate . at sub - operation 502 , a point - spread function ( psf ) is estimated for image degradation induced by system 100 . deconvolution algorithms suitable for estimating the psf are described by biggs , et al ., in “ acceleration of iterative image restoration algorithms ,” applied optics , vol . 36 , pp . 1766 - 1776 ( 1997 ), which is incorporated herein by reference . estimation of the psf is performed with the assistance of some prior knowledge on foci - position information and the processes by which the image of image region 122 is degraded . exemplary degradation mechanisms include movement of image region 122 during imaging , misalignment within optical system 108 ( e . g ., out - of - focus lenses , optical element translation , etc . ), signal - dependent noise , electronic noise , quantization noise , and the like . image degradation can be modeled as : where f is the original undistorted image , g is the distorted noisy image , h is the psf of system 100 , { circle around ( x )} is the convolution operator , and n is the corrupting noise . at sub - operation 503 , the psf developed in sub - operation 502 is used in an iterative reconstruction algorithm that is applied to the rest of the sub - images . reconstruction algorithms suitable for use with the present invention include , without limitation , richardson - lucy deconvolution , maximum - entropy deconvolution , gerchberg - saxton magnitude and phase retrieval algorithms , and the like . in the illustrative embodiment , a specialized richardson - lucy deconvolution algorithm is applied to the rest of the sub - images in sub - operation 503 . in accordance with the present invention , an iterative reconstruction algorithm is expressed as : where { circumflex over ( ƒ )} k is the estimate of f after k iterations , * is the correlation operator , and m i is a foci - position mask for sub - frame i . it should be noted that accurate foci travel info can be developed for each sub - frame i synchronizing scanner 106 and a frame trigger applied to the camera of imager 112 . as a result , each iteration step of the estimation excludes any non - zero results for any pixel outside the foci position mask . typically , the foci - position mask , m i , for each sub - frame i is obtained during an offline calibration routine . a non - limiting example of a suitable calibration routine includes imaging the surface of a known , uniform fluorescence source , such as uranium compound glass , using system 100 where the system has a synchronized triggering signal , and acquiring the foci - position mask for each sub - frame directly at imager 112 . at sub - operation 504 , processor 128 sums the sub - images that have been through sub - operation 503 to form a complete fluorescence image of image region 122 . fig6 a - c depict images of a test specimen before deconvolution , after computation assembly of raw sub - images , and after application of the complete deconvolution routine , respectively . images 600 - 602 are obtained after light propagation through 250 microns of brain tissue . careful examination of images 600 - 602 reveals that many of the finer features of test image 600 are restored in image 602 . one skilled in the art will recognize that the proposed deconvolution routine requires heave data - transfer and computation workload . conventional state - of - the - art cameras are limited to recording only a few seconds of video under typical operating conditions of imaging system 100 . it is to be understood that the disclosure teaches just one example of the illustrative embodiment and that many variations of the invention can easily be devised by those skilled in the art after reading this disclosure and that the scope of the present invention is to be determined by the following claims . | US-201414562885-A |
a topical treatment for skin disorders and diseases comprising a combination of at least one antifungal agent and at least one hydroxy acid agent formulated into shampoos , creams , lotions , gels , sprays , foams , pads , films , patches , and solutions for treatment of skin disorders and diseases in both humans and animals . | before explaining the preferred embodiment of the present invention in detail , it is to be understood that the present invention is not limited in its application to the details of formulations and arrangements of the components set forth in the following description . the present invention is capable of other embodiments and of being practiced and carried out in various ways . also , it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting . it is also to be understood that where ranges are provided for the various agents and drug examples , they are approximate ranges and are not to be limiting except where noted otherwise . the present invention contemplates a combination of two different types and classes of drug into topical dosage forms for the treatment of human and animal skin disorders and diseases . according to the invention , an antifungal agent and a hydroxy acid are combined to create a stable compound effective for the treatment of topical fungal infections , especially those associated with hyperkeratotic lesions as well as other infections such as yeast infections . antifungal agents comprise a broad range of therapeutic agents . non - limiting examples of synthetic antifungal agents are used both topically and systemically include : pyridone and its derivatives ( e . g . ciclopirox and ciclopirox olamine ); azole antifungals , including imidazoles and its derivatives ( e . g . clotrimazole , miconazole , ketoconazole , econazole , terconazole , tioconazole , sertaconazole , butoconazole , oxiconazole , sulconazole , metronidazole , and posoconazole ) and triazoles and its derivatives ( e . g . terconazole , itraconazole , fluconazole , etc . ); allylamines and its derivatives ( e . g . terbinafine , neftifine , butenafine , etc . ); tetraene macrolide ( e . g . nystatin ); polyene macrolide ( e . g . amphotericin b ); halogenated phenolic ether ( e . g . haloprogin ); and , benzoxaborole and its derivatives . the penicillum spp . based antifungal griseofulvin is also an important and suitable antifungal for use in the invention . alpha hydroxy acids and beta hydroxy acids are useful in several skin diseases and disorders and many have hyperkeratolic properties as well . non - limiting examples of alpha hydroxy acids useful in the treatment of skin disorders include lactic acid , mandelic acid , citric acid , glycolic acid , glucuronic acid , and pyruvic acid . non - limiting examples of beta hydroxy acids useful in the treatment of skin disorders include salicylic acid , papain , chymopapain , and urea . in each case , the combination includes beta hydroxy acid , when used in a range of about 2 % to about 10 %, alpha hydroxy acid , when used in a range of about 5 % to about 15 % and antifungal agent in the range in about 0 . 05 % to about 10 %. it should be noted that beta hydroxy acid and alpha hydroxy acid can be used alone or in conjunction or combination with one another . additionally , more than one antifungal may be used . in the preferred embodiment , ciclopirox and salicylic acid are agents of choice . while having different chemical and physical properties from one another , they contain structures that , using the inventive formula and combining process , enable their combination in a stable and effective compound . though ciclopirox and salicylic acid are used in the preferred embodiment , this is in no way to be considered limiting in considering the scope of the inventions and the appended claims . other combinations of antifungals and hydroxy acid agents may also be used in a similar fashion . once the antifungal and hydroxy acid are combined according to the description above , they can be further combined with additional components , depending on the intended final use of the product . in a typical formulation , in addition to the antifungal and hydroxy acid combination , any or all of the following may be added without negatively impacting the drugs : a . surfactants b . viscosity adjusting agents c . ph - adjusters d . stabilizers e . preservatives f . moisturizers / humectants g . fragrance / color suitable surfactants can be found in almost any class , including anionic , amphoteric , cationic , non - ionic surfactants . anionic surfactants have excellent foaming properties , moderate to low irritation potential , and good viscosity building ability . anionic surfactants include the alkylsulfates , alkylether sulfates , sulfonates , taurates , sulfosuccinates , sacosinates , glutamates , and isothionates . anionic synthetic detergents include water - soluble salts , particularly the alkali metal salts , of organic sulfuric reaction products having in their molecular structure an alkyl group containing from about 8 to about 22 carbon atoms and a moiety selected from the group comprising of sulfonic acid and sulfuric acid ester moieties . ( included in the term alkyl is the alkyl portion of higher acyl moieties .) examples of this group of synthetic detergents are the sodium and potassium alkyl sulfates , especially those obtained by sulfating the higher alcohols ( c . sub . 8 - c . sub . 18 carbon atoms ) produced by reducing the glycerides of tallow or coconut oil ; sodium and potassium alkyl benzene sulfonates , in which the alkyl group contains from about 9 to about 20 carbon atoms in straight - chain or branched - chain configuration ; sodium alkyl glyceryl ether sulfonates , especially those ethers of higher alcohols derived from tallow and coconut oil ; sodium coconut oil fatty acid monoglyceride sulfonates and sulfates . anionic phosphate surfactants are surface active materials having substantial detergent capability in which the anionic solubilizing group connecting hydrophobic moieties is an oxy acid of phosphorus . the more common solubilizing groups , of course , are — so . sub . 4 h and — so . sub . 3 h . alkyl phosphate esters such as ( r — o ). sub . 2 po . sub . 2 h and ropo . sub . 3 h . sub . 2 in which r represents an alkyl chain containing from about 8 to about 20 carbon atoms are useful herein . these phosphate esters can be modified by including in the molecule from one to about 40 alkylene oxide units , e . g ., ethylene oxide units . formulae for these modified phosphate anionic detergents are ## equ24 ## or ## equ25 ## in which r represents an alkyl group containing from about 8 to 20 carbon atoms , or an alkylphenyl group in which the alkyl group contains from about 8 to 20 carbon atoms , and m represents a soluble cation such as hydrogen , sodium , potassium , ammonium or substituted ammonium ; and in which n is an integer from 1 to about 40 . another class of suitable anionic organic detergents includes salts of 2 - acyloxyalkane - 1 - sulfonic acids exemplified by the reaction product of fatty acids esterified with isethionic acid and neutralized with sodium hydroxide where , for example , the fatty acids are derived from coconut oil . these salts have the formula ## equ26 ## where r . sub . 1 is alkyl of about 9 to about 23 carbon atoms ( forming with the two carbon atoms an alkane group ); r . sub . 2 is alkyl of 1 to about 8 carbon atoms ; and m is a water - soluble cation . the water - soluble cation , m , can be , for example , an alkali metal cation ( e . g ., sodium , potassium , lithium ), ammonium or substituted - ammonium cation . specific examples of substituted ammonium cations include methyl -, dimethyl -, and trimethyl - ammonium cations and quaternary ammonium cations such as tetramethyl - ammonium and dimethyl piperidinium cations and those derived from alkylamines such as ethylamine , diethylamine , triethylamine , mixtures thereof , and the like . specific examples of beta - acyloxy - alkane - 1 - sulfonates , or alternatively 2 - acyloxy - alkane - 1 - sulfonates , useful herein include the sodium salt of 2 - acetoxy - tridecane - 1 - sulfonic acid ; the potassium salt of 2 - propionyloxy - tetradecane - 1 - sulfonic acid ; the lithium salt of 2 - butanoyloxy - tetradecane - 1 - sulfonic acid ; the sodium salt of 2 - pentanoyloxy - pentadecane - 1 - sulfonic acid ; the sodium salt of 2 - acetoxy - hexadecane - 1 - sulfonic acid ; the potassium salt of 2 - octanoyloxy - tetradecane - 1 - sulfonic acid ; the sodium salt of 2 - acetoxy - heptadecane - 1 - sulfonic acid ; the lithium salt of 2 - acetoxy - octadecane - 1 - sulfonic acid ; the potassium salt of 2 - acetoxy - nonadecane - 1 - sulfonic acid ; the sodium salt of 2 - acetoxy - uncosane - 1 - sulfonic acid ; the sodium salt of 2 - propionyloxy - docosane - 1 - sulfonic acid ; the isomers thereof . useful beta - acyloxy - alkane - 1 - sulfonate salts are the alkali metal salts of beta - acetoxy - alkane - 1 - sulfonic acids corresponding to the above formula wherein r . sub . 1 is an alkyl of about 12 to about 16 carbon atoms , these salts being preferred from the standpoints of their excellent cleaning properties and ready availability . another preferred class of anionic detergent compounds herein , both by virtue of superior cleaning properties and low sensitivity to water hardness ( ca ++ and mg ++ ions ) are the alkylated . alpha .- sulfocarboxylates , containing about 10 to about 23 carbon atoms , and having the formula : ## equ27 ## wherein r is c . sub . 8 to c . sub . 20 alkyl , m is a water - soluble cation as hereinbefore disclosed , preferably sodium ion , and r ′ is either short chain length alkyl , e . g ., methyl , ethyl , propyl , and butyl or medium chain length alkyl , e . g ., hexyl , heptyl , octyl , and nonyl . in the latter case , i . e . the medium chain length esters , the total number of carbon atoms should ideally be in the range 18 - 20 for optimum performance . these compounds are prepared by the esterification of alpha .- sulfonated carboxylic acids , which are commercially available , using standard techniques . specific examples of the alkylated . alpha .- sulfocarboxylates preferred for use herein include , short chain length esters ( ammonium methyl -. alpha .- sulfopalmitate , triethanolammonium ethyl -. alpha .- sulfostearate , sodium methyl -. alpha .- sulfopalmitate , sodium ethyl -. alpha .- sulfopalmitate , sodium butyl -. alpha .- sulfostearate , potassium methyl -. alpha .- sulfolaurate , and lithium methyl -. alpha .- sulfolaurate , including mixtures ); and , medium chain length esters ( sodium hexyl -. alpha .- sulphomyristate , potassium octyl -. alpha .- sulpholaurate , ammonium methyl - hexyl -. alpha .- sulpholaurate , and mixtures thereof ). anionic organic detergents the beta .- alkyloxy alkane sulfonates group are also useful . these compounds have the following formula : ## equ28 ## where r . sub . 1 is a straight chain alkyl group having from 6 to 20 carbon atoms , r . sub . 2 is a lower alkyl group having from 1 ( preferred ) to 3 carbon atoms , and m is a water - soluble cation as hereinbefore described . non - limiting examples of beta .- alkyloxy alkane sulfonates , or alternatively 2 - alkyloxy - alkane - 1 - sulfonates , having low hardness ( calcium ion ) sensitivity useful herein to provide superior cleaning levels under household washing conditions include , potassium -. beta .- methoxydecanesulfonate , sodium 2 - methoxytridecanesulfonate , potassium 2 - ethoxytetradecylsulfonate , sodium 2 - isopropoxyhexadecylsulfonate , lithium 2 - t - butoxytetradecylsulfonate , sodium . beta .- methoxyoctadecylsulfonate , and ammonium . beta .- n - propoxydodecylsulfonate . another suitable class of anionic surfactants is the water - soluble salts of the organic , sulfuric acid reaction products of the general formula wherein r . sub . 1 is chosen from the group comprising of a straight or branched chain , saturated aliphatic hydrocarbon radical having from 8 to 24 , preferably 12 to 18 , carbon atoms ; and m is a cation . examples are the salts of an organic sulfuric acid reaction product of a hydrocarbon of the methane series , including iso -, neo -, meso - and n - paraffins , having 8 to 24 carbon atoms , preferably 12 to 18 carbon atoms and a sulfonating agent e . g . so . sub . 3 , h . sub . 2 so . sub . 4 , oleum , obtained according to known sulfonation methods , including bleaching and hydrolysis . preferred are alkali metal and ammonium sulfonated c . sub . 12 - 18 n - paraffins . other useful synthetic anionic detergents are alkyl ether sulfates . these surfactants have the formula ro ( c . sub . 2 h . sub . 4 o ). sub . x so . sub . 3 m wherein r is alkyl or alkenyl of about 10 to about 20 carbon atoms , x is 1 to 30 , and m is a water - soluble cation as defined hereinbefore . the alkyl ether sulfates useful in the present invention are condensation products of ethylene oxide and monohydric alcohols having about 10 to about 20 carbon atoms . preferably , r has 14 to 18 carbon atoms . the alcohols can be derived from fats , e . g ., coconut oil or tallow , or can be synthetic . lauryl alcohol and straight chain alcohols derived from tallow are preferred herein . such alcohols are reacted with 1 to 30 , and especially 6 , molar proportions of ethylene oxide and the resulting mixture of molecular species , having , for example , an average of 6 moles of ethylene oxide per mole of alcohol , is sulfated and neutralized . examples of alkyl ether sulfates of the present invention are sodium coconut alkyl triethylene glycol ether sulfate ; lithium tallow alkyl triethylene glycol ether sulfate ; and sodium tallow alky hexaoxyethylene sulfate . especially useful alkyl ether sulphates are those comprising a mixture of individual compounds , said mixture having an average alkyl chain length of from about 12 to 16 carbon atoms and an average degree of ethoxylation of from about 1 to 4 moles of ethylene oxide . such a mixture also comprises from about 0 to 20 % by weight c . sub . 12 - 13 compounds ; from 60 to 100 % by weight of c . sub . 14 - 15 - 16 compounds ; from about 0 to 20 % by weight of c . sub . 17 - 18 - 19 compounds ; from about 3 to 30 % by weight of compounds having a degree of ethoxylation of 0 ; from about 45 to 90 % by weight of compounds having a degree of ethoxylation of from 1 to 4 ; from about 10 to 25 % by weight of compounds having a degree of ethoxylation of from 4 to 8 ; and from about 0 . 1 to 15 % by weight of compounds having a degree of ethoxylation greater than 8 . additional examples of useful anionic synthetic detergents are those resulting from the reaction product of fatty acids esterified with isethionic acid and neutralized with sodium hydroxide where , for example , the fatty acids are derived from coconut oil ; sodium or potassium salts of fatty acid amides of methyl tauride in which the fatty acids , for example , are derived from coconut oil . di - anionic detergents compounds , those surfactants containing two anionic functional groups and including the disulfonates , disulfates , or mixtures thereof , where r is an acyclic aliphatic hydrocarbyl group having 15 to 20 carbon atoms and m is a water - solubilizing cation , for example , the c . sub . 15 to c . sub . 20 disodium 1 , 2 - alkyldisulfates , c . sub . 15 to c . sub . 20 dipotassium - 1 , 2 - alkyldisulfonates or disulfates , disodium 1 , 9 - hexadecyl disulfates , c . sub . 15 to c . sub . 20 disodium - 1 , 2 - alkyldisulfonates , disodium 1 , 9 - stearyldisulfates and 6 , 10 - octadecyldisulfates . the aliphatic portion of the disulfates or disulfonates is generally substantially linear , thereby imparting desirable biodegradable properties to the detergent compound . water - solubilizing cations include the customary cations known in the detergent art , i . e ., the alkali metals , and the ammonium cations , as well as other metals in group iia , iib , iiia , iva and ivb of the periodic table except for boron . preferred water - solubilizing cations are sodium or potassium . still other anionic synthetic detergents include the class designated as succinamates . this class includes such surface active agents as disodium n - octadecylsulfosuccinamate ; tetrasodium n -( 1 , 2 - dicarboxyethyl )- n - octadecylsulfo - succinamate ; diamyl ester of sodium sulfosuccinic acid ; dihexyl ester of sodium sulfosuccinic acid ; dioctyl esters of sodium sulfosuccinic acid . other suitable anionic detergents are olefin sulfonates having about 12 to about 24 carbon atoms . the term “ olefin sulfonates ” is used herein to mean compounds which can be produced by the sulfonation of alpha - olefins by means of uncomplexed sulfur trioxide , followed by neutralization of the acid reaction mixture in conditions such that any sultones which have been formed in the reaction are hydrolyzed to give the corresponding hydroxy - alkanesulfonates . the sulfur trioxide can be liquid or gaseous , and is usually , but not necessarily , diluted by inert diluents , for example by liquid so . sub . 2 , chlorinated hydrocarbons , etc ., when used in the liquid form , or by air , nitrogen , gaseous so . sub . 2 , etc ., when used in the gaseous form . when used in the invention , anionic surfactants should be in a concentration range of about 3 % to about 30 %. amphoteric surfactants are very mild , making them particularly suited for use in personal care and household cleaning products . these surfactants have excellent dermatological properties . they are frequently used in shampoos and other cosmetic products , and also in hand dishwashing liquids because of their high foaming properties . amphoteric surfactants can be anionic ( negatively charged ), cationic ( positively charged ) or non - ionic ( no charge ) in solution , depending on the acidity or ph of the water . they are compatible with all other classes of surfactants and are soluble and effective in the presence of high concentrations of electrolytes , acids and alkalis . these surfactants may contain two charged groups of different sign . whereas the positive charge is almost always ammonium , the source of the negative charge may vary ( carboxylate , sulphate , sulphonate ) and include ordinary alkali metal soaps ( e . g . sodium , potassium , ammonium and alkylolamminium salts of higher fatty acids containing from about eight to about 24 carbon atoms and preferably from about 10 to about 20 carbon atoms ). suitable fatty acids can be obtained from natural sources such as , for instance , from plant or animal esters ( e . g ., palm oil , coconut oil , babassu oil , soybean oil , caster oil , tallow , whale and fish oils , grease , lard , and mixtures thereof ). the fatty acids also can be synthetically prepared ( e . g ., by the oxidation of petroleum , or by hydrogenation of carbon monoxide by the fischer - tropsch process ). resin acids are suitable such as rosin and those resin acids in tall oil . napthenic acids are also suitable . sodium and potassium soaps can be made by direct saponification of the fats and oils or by the neutralization of the free fatty acids which are prepared in a separate manufacturing process . particularly useful are the sodium and potassium salts of the mixtures of fatty acids derived from coconut oil and tallow , i . e ., sodium or potassium tallow and coconut soap . betaines are classified generally as amphoteric surfactants . ( e . g . cocamidopropyl betaine , sodium cocoamphoacetate ) when used in the invention , amphoteric surfactants should be in a concentration range of about 2 % to about 15 %. cationic surfactants are quatermary ammonium compounds that acts as a hair conditioners . examples include cetyltrimethyl ammonium chloride , strearyl dimethyl benzyl ammonium chloride and polyquaterniums . when used in the invention , cationic surfactants should be in a concentration range of about 0 . 01 % to about 5 %. nonionic surfactants are modified linear alcohol ethoxylated compounds and , for example , include glycol fatty esters , sorbitans , tweens , and fatty acid derivatives . when used in the invention , nonionic surfactants should be in a concentration range of about 2 % to about 20 %. in addition to surfactants , viscosity adjusting agents may be added . these agents are used specifically to increase viscosity of product . polymeric and non - polymeric materials are useful . examples include acrylate polymers , natural gums - acacia , tregacanth , pectin , etc . when used in the invention , they should be in a concentration range of about 0 . 1 % to about 16 %. ph - adjusters are organic and inorganic acids and bases employed to adjust ph of products to improve physical and chemical stability . examples include citric acid , lactic acid , sodium hydroxide , ethanolamines , hydrochloric acid , etc . when used in the invention , ph - adjusters would be expected to be in a concentration range of about 0 . 5 % to about 10 %, although the final concentration will be in an amount as is necessary for the particular product produced under the invention , and may be outside of this range . stabilizers include chelating and anti - oxidant agents such as disodium edta , bht , and bha , among others . when used in the invention , they should be in a concentration range of about 0 . 01 % to about 2 %. preservatives serve to preserve products microbiologically during shelf - life of product . examples include parabens , sorbic acid , germalls , potassium sorbate , and sodium benzoate . when used in the invention , they should be in a concentration range of about 0 . 1 % to about 3 %. moisturizers , or humectants , may be added to certain formulations . examples include glycerin , sorbitol , and sodium pca . when used in the invention , they should be in a concentration range of about 0 . 5 % to about 5 %. fragrance and / or color may be added if desired . if included , they should be in a concentration range of about 0 . 01 % to about 2 %. finally , a vehicle is used . normally this will be water in a range of about 25 % to 65 %. it is to be understood that the above discussion represents non - limiting explanations and examples of suitable components . as those skilled in the arts will quickly understand , there are myriad other components , by category or type , that may be used within the scope and spirit of the invention . an example of the invention is seen below where the inventive formulation is used in a shampoo . the base for each example below contains one or more of the following comprises : a . vehicle b . surfactants c . viscosity adjusting agents d . ph - adjusters e . stabilizers f . preservatives g . moisturizers / humectants h . fragrance / color as can be seen , this shampoo example composition includes salicylic acid 6 % and ciclopirox 1 %. here a shampoo composition comprising salicylic acid at 6 % and ketoconazole 2 %. here a cream comprising econazole nitrate 2 % and salicylic acid 6 % here a foaming lotion comprising ciclopiroxolamine 1 % and salicylic acid 6 % the above examples are for illustrative purpose only . they are intended to provide examples of the versatility of the inventive combinations and should not be considered limiting . additional combinations for use in cream , lotion , gel , solution / serum , films , patches , foam , spray , and pad dosage forms is also contemplated using the disclosed formulation and preparation standards . for cream , lotion , gel , solution , foam , spray , film , patches , and pads , the concentration range for the hydroxy acid and antifungal will be : 1 . alpha hydroxy acid in the range of 5 % to 15 % ( alone or in combination with a beta hydroxy acid ) 2 . beta hydroxy acid in the range of 2 % to 10 % ( alone or in combination with a alpha hydroxy acid ) 3 . antifungal agent in the range of 0 . 1 % to 5 % ( alone or in combination ) vehicle — concentration range : about 25 % to about 75 % oil phase — fatty acids , alcohols , esters , etc .— concentration range : about 10 % to about 50 % surfactants — anionic , non - ionic , cationic , fatty acids and derivatives — concentration range : about 2 % to about 18 % solvent / solubilizers — organic alcohols , ethers , esters , salts of fatty acids , glycols , glycerols , etc .— concentration range : about 2 % to 3 about 0 % viscosity adjuster — synthetic polymers and natural gums — concentration range : about 1 % to about 15 % preservatives — concentration range : about 0 . 05 % to about 4 % ph adjusters — concentration range : about 0 . 5 % to about 15 % moisturizers — concentration range : about 3 % to about 10 % stabilizers — concentration range : about 0 . 02 % to about 3 % color and fragrance — concentration range : about 0 . 001 % to about 2 % — solvents — concentration range : about 5 % to about 80 % gelling agents — concentration range : about 0 . 1 % to about 15 % ph adjusters — concentration range : about 1 % to about 15 % surfactants — concentration range : about 1 % to about 10 % solubilizer — concentration range : about 0 . 1 % to about 10 % preservatives — concentration range : about 0 . 1 % to about 5 % stabilizers — concentration range : about 0 . 02 % to about 3 % moisturizers — concentration range : about 1 % to about 10 % the efficacy of the inventive formula is demonstrated by the following laboratory studies . in study number one , four preparations made having a base corresponding to the shampoo formula listed above ( all ingredients with the exception of an antifungal and a hydroxy acid ) were produced . the first preparation included ciclopirox 1 % but no hydroxy acid ( preparation 1 ). the second preparation included salicylic acid 6 % but . no antifungal agent ( preparation 2 ). the third preparation included no active ingredients ( preparation 3 ). the fourth preparation included ciclopirox 1 % and salicylic acid 6 % ( preparation 4 ). each of the preparations was exposed to t . mentagrophytes , var . 1 and t . mentagrophytes , var . 2 for one , three , and five minutes . inoculum level for var . 1 was 1 × 10 5 and for var . 2 was 3 . 51 × 10 5 . the results are presented below . as expected , preparation 3 , no actives , had very little effect on fugal kill rates . not unexpectedly , preparation 2 , salicylic acid 6 %, no antifungal agent , very little effect , and preparation 1 , ciclopirox 1 %, no hydroxy acid , had some effect on the kill rate , with preparation 1 ( containing an antifungal having significantly higher kill rates than either preparations 2 or 3 . however , preparation 4 , containing the inventive formula ciclopirox 1 % and salicylic acid 6 % had over twice the log reduction kill rate as preparation 1 which contained only the antifungal agent . preparation 4 showed no growth for var . 1 and 2 at 1 , 3 , and 5 minutes with 5 log reduction . preparations 1 , 2 and 3 showed growth with lower log reduction . in study number two , three preparations made having a base corresponding to the cream formula listed above ( all ingredients with the exception of an antifungal and a hydroxy acid ) were produced . the first preparation included no active ingredients ( preparation 1 ). the second preparation included ciclopirox olamine 1 % but no hydroxy acid ( preparation 2 ). the third preparation included ciclopirox 1 % and salicylic acid 6 % ( preparation 3 ). each of the preparations was exposed to c . albicans for five , fifteen , thirty minutes . inoculum level was 9 . 75 × 10 5 . the results are presented below . as expected , preparation 1 , no actives , had very little effect on fugal kill rates . not unexpectedly , preparation 2 , antifungal agent but no hydroxy acid had some effect on the kill rate . however , preparation 4 , containing the inventive formula ciclopirox 1 % and salicylic acid 6 % had over twice the log reduction kill rate as preparation 2 . preparation 3 showed no growth at 5 , 15 , and 30 minutes with 5 . 99 log reduction . preparations 1 and 2 showed growth with lower log reduction . it is to be understood , however , that even though numerous characteristics and advantages of the preferred and alternative embodiments have been set forth in the foregoing description , together with details of the structure and function of the embodiments , the disclosure is illustrative only , and changes may be made in detail within the principles of the invention to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed . | US-21448108-A |
a multi - leaf collimator for a radiotherapy apparatus comprises at least one array of laterally - spaced elongate leaves , each leaf being driven by an associated motor connected to the leaf via a drive means so as to extend or retract the leaf in its longitudinal direction , the drive means comprising a sub - frame on which at least a subset of the motors are mounted , the sub - frame being mounted at a location spaced from the leaf array in a direction transverse to the lateral and longitudinal directions , and including a plurality of threaded drives disposed longitudinally , each being driven by a motor and being operatively connected to a leaf thereby to drive that leaf . | the inherent limitation on the minimum length of the rack and pinion - type system is the number of motors mounted on the side of the module . for example , assuming that each module is designed to drive 40 leaves , that each motor is 10 mm in diameter and ( therefore ) spaced 14 mm apart in a double row , then the length of the module will have to be 14 ×( 40 / 2 ), i . e . 280 mm , plus the distance over which the leaves are expected to travel . if we take a rough figure of 70 mm for this distance , this makes an overall length for the system of 350 mm . the minimum overall height will be the motor diameter plus the height of the rack , i . e . about 32 mm . a rack and pinion module when mounted on the leafbank will therefore increase the treatment head diameter significantly . the mlc actuator described herein features a lead screw that runs parallel to the leaf , which means that the length of the drive modules are shorter overall , as the leadscrew only needs to be a slightly longer than the required leaf travel . the overall length of actuator including motors can therefore be about 200 mm , with a height of about 24 mm . this however faces the difficulty noted above , i . e . that the leadscrew needs a minimum diameter in order to be economic to produce and sufficiently rigid in operation . for mlc arrays in which the individual leaf thickness falls close to or below this diameter , this raises difficulties in accommodating both the leadscrews and the motors that drive them . the mlc actuator described herein incorporates a leadscrew drive assembly which actuates the leaf indirectly via a lug which projects out from the drive assembly and engages with a drive coupling for the leaf . the leadscrews and lugs run in machined guide slots in a bearing block which both houses the lugs ( etc ) and provides mounting for the drive assemblies . it still remains , of course , that the leadscrews may be wider than the leaves , and it will usually be the case that the motors are wider . accordingly , each leaf will ( generally ) only be a fraction of the width of its associated drive mechanism . an alternative way of viewing this is that laterally arrayed drive mechanisms will only be able to drive a fraction of the leaves . therefore , a number of such arrays can drive all of the leaves , if the drive from each array can be transmitted to the leaves satisfactorily . a specific pattern of drive mechanisms is therefore needed in order to mount the leadscrews drives into a compact removable module . we have chosen to divide the drive to the leaves in a number of ways so as to distribute the drive mechanism arrays . first , leaves can be driven from their upper edge or their lower edge . this is defined by the convention that mlc arrays are usually described as having a top that is closest to the radiation source and a bottom that is closest to the patient . such a convention is necessary since the mlc array is mounted in a radiation head that rotates around the patient , and therefore in use the array may take up any orientation . thus , an upper subframe can carry half of the drive mechanisms and drive every other leaf , and a lower subframe can carry the other half to drive the remaining leaves . next , each subframe can carry two rows of leadscrews , one above the other . the lugs associated with each leadscrew can be of a corresponding length . this spaces the motors and allows them to drive laterally adjacent leadscrews . finally , the leadscrews do of course have two ends and can be driven from either . accordingly , half the leadscrews in each subframe can be driven from the front ( which we define as the end most distant from the beam ) and half from the rear ( defined correspondingly ). these three binary divisions allow 2 3 combinations , i . e . each situationally identical drive means drives one in eight leaves . this division can be as follows : the precise pattern of the leadscrews , lugs , and guiding slots in the bearing block is derived from the angle and pitch of the leaf and the required space for the drive motor . such a pattern can also allow the drive motor axis to match the leaf centre line , ensuring an efficient transfer of linear motion . by mounting the drive motors on the front and rear surfaces of the drive modules ( upper and lower subframes ) the area required to mount the drive motors can be dispersed over 2 faces . this also has the advantage of only requiring 2 sizes of drive mechanism , thereby maintaining a low parts count . thus , the drive system is split into 2 modules ; 2 per side , upper and lower . each of these modules contains 40 motor / leadscrew drives , allowing for 80 leaves in total . each module has 20 motors mounted on the front face and 20 on the rear face . the method for mounting of the motor / leadscrew drives is designed specifically to fit the pattern of machined slots in the modules . this leadscrew design incorporates a precision machined leadscrew with an acme thread form . the leadscrew nut is injection moulded in a low friction plastic material , which allows the assembly to run quietly without lubrication . the leadscrew nut fits into the lug , and can be easily replaced by removing the motor assembly . the machined guide slots for the lugs can also be formed with non - parallel sides , and the lugs profiled correspondingly . thus , viewed along the guide slot , the profile can be akin to that of a key for a cylinder lock . this provides non - vertical surfaces which act as bearings , removing from the leadscrew nut the side and moment loads which will occur in moving the mass of the tungsten leaf . on previous designs , these loads adversely affected the life of the nut . the leadscrew is also supported in this way , reducing both whipping and buckling tendencies . the guide slot profile may also feature a “ v ” or fir tree shape in the leg of the slot , which will increase the bearing surface area of the key and reduce friction . a lower portion of the lugs are exposed below the drive module . these sections engage into the top or bottom of a drive coupling for the leaf via a mating cut - out in the drive coupling . referring to fig3 , this shows a single leaf and its associated drive . the tungsten attenuation portion 100 is relatively thin in a lateral direction in order to allow good resolution , is long in its longitudinal direction to allow a wide range of movement , and is deep in the beam direction to allow good attenuation of the beam . a front edge 102 of the attenuation portion 100 is curved in a generally known manner so as to provide a sharper penumbra . a rear edge of the attenuation portion 100 is vertical , and is joined to a drive coupling 104 . the drive coupling 104 has one edge , in this case the upper edge , which is co - linear with the corresponding edge of the attenuation portion 100 except for a recess 106 into which a lug 108 fits snugly . the opposing edge of the drive portion 104 is rebated back from the corresponding edge of the attenuation portion 100 in order to reduce the overall weight of the device and to avoid interference with the drive mechanism on the other side . it will be apparent that the relative orientations of the attenuation and drive portions can be reversed to allow the leaf to be driven from the top edge ( as shown ) or from the bottom edge . the lug 108 fits snugly in the recess 106 of the drive coupling 104 but is not fixed in place . the lug 108 is however attached to a pair of cylinders 110 , 112 through which a leadscrew 114 passes , and between which a leadscrew nut 116 is fixed . thus , as the leadscrew 114 is rotated , the nut 116 is forced in one direction or another and takes with it the cylinders 110 , 112 , the lug 108 , the drive coupling 104 and the attenuation portion 100 . the cylinders offer rigidity to the structure retaining the leadscrew nut 116 , and also offer lateral support to the leadscrew 144 to inhibit both whipping and buckling . finally , at one end of the leadscrew 114 , a motor 118 is provided in order to drive the leadscrew . thus , by simple reversal of the orientations of the drive coupling 104 and / or the motor 118 / leadscrew 114 , two of the above divisions can be achieved . the remaining third division is achieved by substitution of a longer lug 108 . accordingly , the spatial distribution of the various drive motors is achieved with an exceptionally low parts count . fig4 shows one leaf bank from one end . the side - by side ( i . e . laterally arrayed ) leaves 100 are supported at their top and bottom edges in a leaf guide ( not visible ). counting the leaves from the left hand side of fig4 , the odd - numbered leaves are driven from their lower edge and the even - numbered leaves are driven from their upper edge . thus , an upper subframe 120 carries leadscrews , lugs , motors etc for the even - numbered leaves and a lower subframe 122 carries leadscrews , lugs , motors etc for the odd - numbered leaves . apart from dimensional issues relating to the divergent nature of the leaves 100 , the two subframes are functionally and structurally identical . within each subframe , for example the upper subframe 120 , the first two leaves that are controlled ( i . e . leaves 2 and 4 ) are connected via lugs 108 of varying lengths to a leadscrew running in a guide machined in the otherwise solid block that forms the subframe . these two guides are placed at differing heights so as to separate the motors 118 . the next leaf ( i . e . leaf 6 ) is then connected to a leadscrew at the same upper level as leaf 2 . to provide sufficient space , the motor for leaf 6 is located at the other end of the subframe 120 and drives its associated leadscrew from its other end . the pattern then continues , so that the next leaf that is driven in a manner identical to leaf 2 is leaf 10 . fig5 shows one subframe , with the leaf bank and leaf guide removed . an array of motors 118 can be seen at one end , distant from the beam , and an opposing array of motors 124 can be seen at the other end , closest to the beam . the lugs 108 can be seen projecting from the guide slots 126 ; when this sub - assembly is replaced under ( or over ) the leaf array then these lugs will project into the recesses 106 of the drive portions 104 of the leaves 100 . in this way , the drive mechanism can be easily removed for service , repair or replacement . fig6 shows how the motors 118 are retained on the subframe 122 . each motor has a pair of flanges projecting outwardly in two opposed directions around a part ( but not all ) of the circumference of the motor 118 . fortuitously , there will be a pair of guide slots 126 a and 126 b either side of the motor 118 which contain a leadscrew that is driven from the other end of the subframe 122 . thus , the ends ( at least ) of these slots 126 a and 126 b will be empty , and thus a mushroom - head screw 128 a and 128 b respectively can be screwed into the end of these slots 126 a and 126 b by providing a suitable tapping in the ends of the slots . in this way , by rotating the motor 118 so that the flanges are located under the mushroom - headed screws , then tightening the screws , the motor 118 will be retained securely . to remove the motor 118 , both screws can be loosened , and the motor rotated in the direction of arrow 130 to move the flanges clear of the screw heads and allow the motor to be withdrawn in the direction of arrow 132 . in this arrangement , each screw will retain two motors , one on either side . this still permits individual motors to be removed , since the motors either side will still be retained by one screw , on their other side . this is generally preferable to providing each motor with a single flange and a single retaining screw ; whilst this could be done , and would mean that each screw only held one motor , it would weaken the retention of the motors generally . there could of course be further layers of leadscrews and motors beyond the two illustrated . although this will incur a cost in terms of a greater complexity , it will permit a still greater ratio of motor spacing to leaf thickness to be achieved . fig7 to 10 show alternative profiles for the lug and 108 and the guide slot 126 in which it slides . fig7 shows the simplest option , a parallel - sided guide slot 126 formed in the subframe 122 , with an enlarged root 134 . the leadscrew 114 sits in the enlarged root 134 and is surrounded by the leadscrew nut 116 . the lug 108 extends from the leadscrew nut 116 , along the guide slot 126 and out of the subframe 122 , to engage with the drive portion 104 of the leaf 100 . this arrangement is obviously easiest to manufacture . however , it then requires the lug 108 to support the leaf 100 despite the fact that the centre of mass of the leaf 100 is offset from the line along which the lug 108 is driven . this will create a rotational moment on the lug 108 which will seek to rotate the lug 108 within the plane of the guide slot 126 . this will create an uneven wear pattern on the lug 108 , the leadscrew nut 116 , and the leadscrew 114 and may be detrimental to the long - term performance of the drive mechanism . fig8 therefore shows an adjustment to this design to alleviate this . the lug 108 is no longer parallel - sided , but includes a step 136 to one side part way along its length . the thickness of the lug 108 remains the same through the step ; that is , the outward bulge 138 on one side is matched by a corresponding recess 140 on the other side . matching formations are provided in the guide slot 126 , to accommodate the outward bulge and to project into the recess . by providing a non - flat surface to the lug 108 and a corresponding shape to the guide slot 126 , rotation of the lug 108 in the guide slot 126 is inhibited . support for the lug 108 against rotation is provided by the interaction of the bulge 138 and the recess 140 with the corresponding formations in the guide slot 126 . some lubrication may be useful in these areas , and a coating of graphite is suitable . the arrangement shown in fig8 is a simple and straightforward one which illustrates the concept . in practice , the bulges and recesses could be located elsewhere along the height of the lug 108 / guide slot 126 , and / or they could be duplicated so that multiple such formations are present . where several such formations are provided , they could be oriented in the same direction , or in different orientations such as alternate directions or a mix of directions . fig9 shows a further variation . in this arrangement , the lug 108 has a pair of adjacent bulges 142 , 144 on one side , duplicated on the other side . corresponding recesses are formed in the guide slot 126 . this arrangement has the advantage of being symmetrical as compared to that of fig8 , and also avoids any narrowing of the lug 108 that might cause it to be weakened . fig1 shows a further alternative . a pattern of recesses 146 are formed in the sides of the lug 108 , in this case four on each side in two groups of two each . corresponding bulges are provided on the internal surfaces of the guide slot 126 . the shapes described above can be formed at the necessary scale by processes such as wire discharge machining . fig1 illustrates an alternative embodiment which may be simpler to manufacture in that the potentially complex shapes illustrated in fig7 to 10 are avoided . in the above embodiments , the leafbank comprises a set of leaves that run in a leafguide , driven via separately attached drive couplings in the form of ‘ tails ’ that can be made of a lighter and cheaper material . a separate drive module uses guided ‘ keys ’ running in accurately machined slots , which fit into slots in the drive couplings . this allows the drive module to be removed and replaced very quickly . in the alternative embodiment , the keys are made with slots that fit over the edges of the slots in the drive couplings . it is therefore no longer necessary to constrain the keys against movement in their roll axis ( around the axis of the leadscrew ). this allows the drive couplings to be fitted with a looser tolerance , reducing manufacturing time and cost . this also allows the key drive profile to be greatly simplified . with the key restrained in roll , it is possible to use the leadscrew to constrain the key in pitch and yaw , eliminating the need for the sliding contact and complicated machining of the drive module . the key can be simplified in material and form , reducing cost further . thus , referring to fig1 , a plurality of leaves 200 are provided in the usual side - by - side relationship . fig1 shows a single leaf for clarity purposes , but this will be supplemented by many other leaves on either side — typically making up a bank of 20 , 40 or 80 leaves in total on each bank . the leaves 200 are supported in a guide 202 which supports the upper edge 204 and the lower edge 206 of the leaves in slots 208 formed in the guide . the guide 202 can be fixed to one side of the radiotherapy beam so that the leaves 200 are extendable into the beam by sliding in the guide slots 208 , thereby limiting the lateral extent of beam on that side to a desired shape . alternatively , the guide 202 can be mounted on a moveable support , its position thereby being adjustable in rotation around the beam and / or longitudinally relative to the leaves so as to enable a wider range of adjustment of the leaf positions . a similar bank of leaves is usually provided on the opposite side of the beam in order to collimate the other lateral extent of the beam . the leaf 200 is illustrated in fig1 in a partially advanced position , shown in solid lines , and a withdrawn position shown in dotted lines . the withdrawn position illustrated is one that lies beyond the normal fully retracted position , in which the leaf has been fully retracted and then withdrawn further so that is no longer supported by the guide slots 208 . such a position would only be reached during assembly , maintenance , or disassembly , but allows us to illustrate the construction of the leaf . each leaf 210 is of a substantially radio - opaque material such as tungsten , and the drive couplings 212 can be of a lighter and less expensive material such as steel or aluminium . this allows the tungsten forward portion 210 to be projected into the beam , driven by a rearward drive coupling that never enters the beam and does not therefore need to be of a radiopaque material . the overall weight and cost of the unit is thereby minimised . the drive coupling 212 of each leaf 200 includes a rectangular cut - out section 214 , visible more clearly in the dotted outline version of the leaf 200 shown in the withdrawn position . this receives a corresponding drive lug 216 that is threaded onto a leadscrew 218 . the leadscrew 218 is , in turn , mounted in a subframe 220 and provided with a drive motor ( not shown ) in a pattern similar to that described above . in this embodiment , the leadscrew 218 is supported by the subframe 220 at either end . the drive lug 216 has an extent in the longitudinal direction ( i . e . parallel to the leadscrew 218 and the leaf 200 ) of ( for example ) 10 mm or more , generally at least 50 % of its extent transverse to the leadscrew 218 . it is therefore constrained against rotation about axes transverse to the leadscrew 218 . the drive lug 216 extends transversely away from the leadscrew 218 toward the cut - out 214 of the leaf tail 212 . the lug 216 ends with an interface region that keys with the cut - out 214 ; in this example it comprises a solid rectangular section 222 that matches the rectangular cut - out 214 and ( when assembled ) fits into the cut - out 214 . on either longitudinal side of the rectangular section 222 , there are laterally - spaced flanges 224 that fit snugly either side of the leaf tail 212 and prevent the lug 216 from rotating around the leadscrew 218 . thus , the drive lug 216 is prevented from movement in all axes other that longitudinal translation along the leadscrew 218 as the leadscrew 218 rotates . this movement of the drive lug 216 will then cause a corresponding movement of the leaf 200 . through the use of the above - described embodiments , it is possible to produce a reliable 160 - leaf multi - leaf collimator , that is a collimator with 80 leaves on each side of the beam . current commercially - available large - aperture mlcs have a total of 80 leaves , i . e . 40 leaves per side as illustrated in fig4 , but the increased space efficiency achieved by the present invention allows this to be doubled by appropriate thinning of the leaves . this means that instead of a projected width at the isocentre of 1 cm , each such leaf will have a resolution of 5 mm — with an attendant improvement in resolution and accuracy of delivery . an improvement of the resolution to 160 leaves instead of 80 will also require improvements in the treatment planning systems and software , and the associated control systems and software in order to take advantage of the additional degrees of freedom offered by doubling the number of leaves . in the longer term , this does not present a particular difficulty , but in the short term clinics may wish to replace hardware and other systems incrementally . accordingly , there may be advantages in an mlc that retains the ability to operate in a 160 - leaf mode but which is fully compatible with 80 - leaf control systems . this is indeed possible through the present invention . if the same leaves are inserted into the same leaf guide , but oriented so that they are organised in identical pairs , then these leaf pairs can be driven together , in unison , by providing suitable upper and lower subframes 120 as illustrated in fig3 et seq . adjacent leaf pairs will have co - located recesses 106 in their associated drive couplings , into both of which the same lug 108 can project . some care may need to be taken in designing the appropriate width for the lug 108 to ensure that an adequate drive is transmitted to both leaves . thus , the device will operate as an 80 - leaf collimator and can be controlled and driven in the same way . however , as and when the clinic is able to upgrade other aspects of their radiotherapy equipment , the upper and lower subframes can be replaced with items adapted for 160 - leaf operation and the leaves removed and re - inserted in the pattern appropriate to independent operation of each leaf . another use of the described collimator drive is for a variable - pitch collimator . such a collimator includes leaves having a plurality of different thicknesses , such as a group of narrow leaves in the central region flanked on either side by relatively thicker leaves . thus , a fine resolution is available in the central area of the aperture where it is usually needed , but the full aperture of the mlc is available when needed . such collimators are limited by ( inter alia ) difficulty in driving the various leaves accurately and the present invention can assist with this . it will of course be understood that many variations may be made to the above - described embodiment without departing from the scope of the present invention . 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 . | US-201414565873-A |
a sports racket , especially a tennis racket , having reduced tendancy to transmit vibrational energy to the arm of the user , having a bow portion , and a hollow space within or surrounding said bow portion fully packed with spherical plastic beads such as low density polystyrene beads . | the racket of the present invention includes a composite frame having a hollow section in or surrounding the bow , filled with spherical plastic beads . the hollow section can be a continuous channel , multiple sections , or a plastic bag or tube within a hollow section of the bow . the hollow section filled with spherical plastic beads can also be within the throat and handle portions of the racket . the bow can be aluminum , but is preferably composite such as graphite , ceramic , boron fibers , fiberglass , or even composites with wood . generally in the case of wood rackets , especially in the case of rackets which have previously been manufactured , the embodiment wherein a bead - containing channel is secured to the outside of the bow portion , is employed . this channel , 16 in fig3 and 4 , can be added as a retrofit device , and adhered either by glue or by a squeeze fit due to the shape and resilience of the plastic of the channel . in the case of normally hollow rackets such as aluminum , graphite or other composites , and the like , the channel filled with beads preferably also includes the throat and handle portions , i . e ., the beads preferably fill the bow , throat , and handle ( sometimes referred to as the grip ). the spherical plastic beads are the key to the invention . they are near perfect shock absorbers . the fact that they are near uniform spheres causes them to always occupy about 60 % by volume of the hollow space , as is the case for any near uniform spheres within a cylinder - like space . about 40 % of the space within the hollow portion , therefore , remains unfilled space , thus the beads never become so tightly packed as to behave as a solid . mesh sizes between about 1 and 2 millimeters are expecially preferred . sufficient packing so as to prevent any unrestrained movement of the beads within the space is a requirement of the invention to prevent vibration . the beads can be any suitable plastic , the lighter the weight types being the most preferred , for example , polystyrene , polybutadiene , acrylic , pvc , butadiene , and the like . glass beads or lead shot would not be suitable because they would be too heavy and would not absorb sufficient shock for their weight . the racket of the invention is stiff and light like a graphite racket , but is far more vibration and shock absorbent due to the creation of hundreds of tiny billiard - ball like impacts within the racket frame when a ball is struck by the strings of the racket , which dissipate the shock due to the impact of the ball . referring to the exemplary embodiment shown in fig1 the sports racket 11 can be a tennis racket having a bow portion 12 and strings 17 . the cross section illustrated in fig2 shows a hollow space 13 within the bow portion fuly packed with spherical plastic beads 14 ( strings deleted in fig2 and 4 for clarity ). the beads in the preferred example are low density polystyrene , but can also be pvc , acrylic , butadiene , or any low density plastic spheres . the beads , as will any uniform sized spheres packed in a space , occupy about 60 % of the space . in this example , a very thin , light weight plastic tube of polyethylene 15 is used to contain the beads to prevent them from leaking out through the grommet holes used for stringing . the racket is made lighter than ususual to compensate for the weight of the beads filling the channel , and so the overall weight of the tennis racket is about 11 . 5 to 13 . 5 ounces , typical for tennis rackets , preferably about 12 to 13 ounces . in the embodiment shown in fig3 a bead - containing channel 16 , formed from a rubber - like plastic such as polysiloxane rubber or polysulfone , surrounds the racket bow 12 . this embodiment is prefered with wooden rackets 10 which are difficult to hollow out , or as a modification to existing composite rackets . the channel 16 would be sold as an accessory which can be added to a racket and either glued in place or held in place by the resilient effect of the plastic and a snug fitting design . fig4 shows a section through 4 -- 4 of fig3 wherein the channel 16 is shown snugly fit on the outside of the bow 12 ( strings are deleted for clarity ). the channel 16 is filled with spherical plastic beads 14 . while a few embodiments of the invention are described in detail herein , various alternatives , modifications , and improvements should become readily apparent to those skilled in the art without departing from the spirit and scope of the invention . | US-21617788-A |
angiogenesis , the formation of new blood vessels , is an integral part of normal physiological and developmental processes as well as several pathologies , ranging from tumor growth and metastasis to inflammation and ocular disease . methods and compositions are provided for controlling normal angiogenesis and for treating angiogenesis associated or mediated diseases . | polypeptides which are members of the psp94 family include ; wild type psp94 as defined in seq id no . : 1 , a recombinant psp94 as defined in seq id no . : 2 and psp94 derivatives , fragments and analogues as defined , for example in the amino acid sequence defined in seq id no . : 3 , seq id no . : 4 , seq id no . : 5 , seq id no . : 6 and seq id no . : 7 . pck3145 ( seq id no . : 5 ) was chosen as a representative of the psp94 family based on previous encouraging results of tumor growth inhibition observed in animals . test compound . the wild type amino acid sequence of pck3145 has been disclosed , for example , in international application no . : pct / ca01 / 01463 and is defined herein in seq id no . : 5 . a pck3145 derivative has been generated by attaching an acetylaminomethyl group to the sulfur atom of each of the three cysteines of pck3145 . these groups stabilize the compound by preventing formation of peptide dimers or polymer by blocking the sulfhydryl group of cysteines . this pck3145 derivative is defined in seq id no . : 7 . the drug was manufactured by multiple peptide systems ( 3550 ) ( general atomics court , san diego , calif .) using standard solid - phase peptide chemistry and lyophilized into a powder . other type of synthesis or manufacture method may however be performed to make a peptide or polypeptide of the invention . other pck3145 derivatives , analogs and fragments ( e . g ., seq ids no : 88 , 98 , etc .) may be generated similarly . the reconstituted drug used in the present example is made from a solution containing a 20 mg / ml of pck3145 derivative ( seq id no . : 5 derivative ); seq id no . : 7 , in a phosphate buffer at ph 7 . 4 for dilution in sterile saline ( 0 . 9 % nacl , bp ) prior to intravenous administration . the solutions is filled into type 1 glass vials , stoppered with teflon ®- faced butyl stoppers , and sealed with flip - off seals . the drug was administered to patients characterized as having metastatic adenocarcinoma of the prostate , stage 1v prostatic cancer and as having a metastatic hormone resistant prostatic cancer . biological samples were drawn during different time points . plasma samples were placed on dry ice and stored frozen ( approximately − 70 ° c .) and subsequently analyzed for total mm p - 9 levels . mmp - 9 assay methodology . an elisa assay measuring total mmp - 9 , i . e ., human active and pro - mmp - 9 , ( quantikine ®, cat . no . : dmp900 , r & amp ; d systems inc .) was performed on plasma - heparin samples . plasma samples have been collected from individuals at day 1 ( before treatment ) and at day 27 of each treatment cycle . the quantikine ® mmp - 9 immunoassay is a solid phase elisa designed to measure total mmp - 9 ( 92 kda pro - and 82 kda active forms ) in serum , plasma , saliva , urine and cell culture supernatants . it is calibrated with cho - cells expressed recombinant human pro - mmp - 9 and the antibodies were raised against the recombinant factor . both antibodies also recognize recombinant human active mmp - 9 . natural human mmp - 9 showed dose - response curves that were parallel to the standard curves obtained using the recombinant quantikine ®) kit standards , indicating that the quantikine ® kit may be used to determine relative mass values of natural human mmp - 9 . the assay employs the quantitative sandwich enzyme immunoassay technique . a monoclonal antibody specific for mmp - 9 has been pre - coated onto a microplate . standards and samples are added into the wells , and mmp - 9 is thus bound by the immobilized antibody . after washing away unbound substances , an enzyme - linked polyclonal antibody specific for mmp - 9 is added to the wells . following a wash to remove unbound antibody - enzyme reagent , a substrate solution is added to the wells and color develops in proportion to the amount of total mmp - 9 ( pro and / or active ) bound in the initial step . the color development is stopped and the intensity of the color is measured . zymography . zymography is a technique generally used to analyze the activity of matrix metalloproteinases ( mmps ) in biological samples . it involves the electrophoretic separation of proteins under denaturing ( sodium dodecyl sulfate ( sds )) but non - reducing conditions through a polyacrylamide gel containing gelatin ( for example , 10 % gel containing 1 mg / ml gelatin for mmp - 9 and mmp - 2 assays ). the resolved proteins are re - natured by exchanging sds with a non - ionic detergent such as triton x - 100 and the gel is incubated in an incubation buffer for activation of mmp - 2 and mmp - 9 ( for example at 37 ° c . for 18 hrs ). the gel is stained with coomassie blue and the mmp - 2 and mmp - 9 bands may be visualized as clear bands against a blue background ( i . e ., the mmps degrade the gelatin and are visualized as clear bands ; pro mmp - 2 is 68 kda and pro - mmp - 9 is 92 kda ). these bands can be quantified using densitometry . materials . cell culture media were obtained from life technologies ( burlington , ontario , canada ) and serum was purchased from hyclone laboratories ( logan , utah ). electrophoresis reagents were purchased from bio - rad ( mississauga , ontario , canada ). the polyclonal ( c - 1158 ) and monoclonal ( a3 ) antibodies , used for precipitation and detection , respectively , of vegfr - 2 , and the anti - pdgfr pab ( 958 ) were obtained from santa cruz biotechnologies ( santa cruz , calif .). antiphosphotyrosine mab py99 was also purchased from santa cruz biotechnologies . anti - phospho - erk polyclonal antibodies were from cell signaling technology ( beverly , mass .). anti - mouse and anti - rabbit horseradish peroxidase - linked secondary antibodies were purchased from jackson immunoresearch laboratories ( west grove , pa .) and enhanced chemiluminescence ( ecl ) reagents were from amersham pharmacia biotech ( baie d &# 39 ; urfé , québec , canada ). human recombinant pdgf was obtained from r & amp ; d systems ( minneapolis , minn .). micro bicinchoninic acid protein assay reagents were from pierce ( rockford , ill .). all other reagents were from sigma - aldrich canada . vegf production . vascular endothelial growth factor ( isoform 165 ) was pcramplified from a pblast / vegf plasmid ( invivogen , san diego , calif .) and cloned into the ptt vector ( 14 ). vegf was produced following large - scale transient transfection of human 293sfe cells in serum - free medium . the recombinant protein was expressed by the transiently transfected cells and secreted into the medium . the culture was harvested five days after transfection , the medium was clarified by centrifugation at 3 , 500 g for 10 minutes and filtered through a 0 . 22 μm membrane . clarified culture medium was loaded onto a heparin - sepharose column and the bound vegf was then eluted using a nacl gradient in pbs . a buffer exchange for pbs was performed by gel filtration and the final purified material was sterile - filtered , and stored in aliquots at − 80 ° c . cell culture . human umbilical vein endothelial cells ( huvec ) and pulmonary aortic smooth muscle cells ( pasmc ) were obtained from clonetics and maintained in endothelial cell basal medium - 2 , ( ebm - 2 ; clonetics ) and smooth muscle medium - 2 ( smgm - 2 ; clonetics ), respectively . cells were cultured at 37 ° c . under a humidified atmosphere containing 5 % co 2 . for experimental purposes , cells were plated in 8 100 - mm plastic dishes at 5 , 000 cells / cm 2 and were grown to confluence before overnight serum starvation . cells were treated with vehicle or with a pck3145 derivative diluted in 0 . 1 n naoh , and stimulated with 50 ng / ml vegf , pdgf or with 1 μm s1p . immunoprecipitation and immunoblotting procedures . after treatment , cells were washed once with phosphate - buffered saline ( pbs ) containing 1 mm sodium orthovanadate and were incubated in the same medium for 1 h at 4 ° c . the cells were solubilized on ice in lysis buffer ( 150 mm nacl , 10 mm tris - hcl , ph 7 . 4 , 1 mm edta , 1 mm egta , 0 . 5 % nonidet p - 40 , 1 % triton x - 100 ) containing 1 mm sodium orthovanadate . the cells were then scraped from the culture dishes and the resulting lysates were clarified by centrifugation at 10 , 000 g for 10 min . protein concentrations were determined using the micro bicinchoninic acid method . for immunoprecipitation studies , lysates were clarified by a 1 h incubation at 4 ° c . with a mixture of protein a / protein g sepharose beads . after removal of the sepharose beads by low - speed centrifugation , identical amounts of protein ( 200 μg ) from each sample were transferred to fresh tubes and incubated in lysis buffer overnight at 4 ° c . in the presence of 2 μg / ml of specific antibodies . immunocomplexes were collected by incubating the mixture with 25 μl ( 50 % suspension ) of protein a —( rabbit primary antibody ) or protein g —( mouse primary antibody ) sepharose beads , for 2 h . nonspecifically - bound material was removed by washing the beads three times in 1 ml of lysis buffer containing 1 mm sodium orthovanadate , and bound material was solubilized in 25 μl of two - fold concentrated laemmli sample buffer , boiled 5 min , and resolved by sds - page . the proteins were transferred onto polyvinylidene difluoride ( pvdf ) membranes , blocked 1 h at room temperature with tris - buffered saline / tween 20 ( 147 mm nacl , 20 mm tris / hcl , ph 7 . 5 , and 0 . 1 % tween 20 ) containing 2 % bovine serum albumin and incubated overnight at 4 ° c . with primary antibody . immunoreactive bands were revealed after a 1 h incubation with horseradish peroxidase - conjugated anti - mouse or anti - rabbit antibodies , and the signals were visualized by enhanced chemiluminescence ( amersham biosciences , baie d &# 39 ; urfée , qc ). rat aortic ring assay : the isolated rat aorta is cut into segments that are placed in culture , in a matrix - containing environment such as matrigel . over the next 7 - 14 days , the explants are monitored for the outgrowth of endothelial ( and other ) cells as this is affected by the addition of test substances . quantification is achieved by measurement of the length and abundance of vessel - like extensions from the explant . use of endothelium - selective reagents such as fluorescein - labeled bsl - 1 allows quantification by pixel counts . chick aortic arch assay : aortic arches are dissected from day 12 - 14 chick embryos and cut into rings similar to those of the rat aorta . when the rings are placed on matrigel , substantial outgrowth of cells occurs within 48 h , with the formation of vessel - like structures readily apparent . test substance is added to the medium and quantification of endothelial cell outgrowth is achieved by the use of fluorescein - labeled lectins such as bsl - 1 and bsl - b4 or by staining of the cultures with labeled antibodies to cd31 . standard imaging techniques are used for the enumeration of endothelial cells and for delineating the total outgrowth area . cornea angiogenesis assay : a pocket is made in the cornea of a rabbit &# 39 ; s eye or mice &# 39 ; s eye and angiogenesis is stimulated by an angiogenesis inducer ( e . g . vegf ) introduced into this pocket . the inducer elicits ingrowth of new vessels from the peripheral limbal vasculature . slow - release materials such as elvax ( ethylene vinyl copolymer ), hydron or sponge may be used to introduce test substances into the corneal pocket . inhibition of angiogenesis is monitored by the effect of the inhibitor on the locally induced ( e . g ., sponge implant ) angiogenic reaction in the cornea ( e . g ., vegf ). the test inhibitor may be administered by several administration mode including , orally , systemically , the latter either by bolus injection or , for example , by use of a sustained - release method such as implantation of osmotic pumps loaded with the test inhibitor . the vascular response is monitored by direct observation throughout the course of the experiment . this may be done by using a slit lamp for the rabbit but needs only a simple stereomicroscope in mice . visualization of the mouse corneal vasculature may be achieved by injecting india ink or fluorochrome - labeled high - molecular weight dextran . methods for quantification include measuring the area of vessel penetration , the progress of vessels toward the angiogenic stimulus overtime , or in the case of fluorescence , histogram analysis or pixel counts above a specific ( background ) threshold . cam assay : the cam of day 7 - 9 chick embryos is exposed by making a window in the egg shell , and tissue or organ grafts are then placed directly on the cam . the window is sealed , eggs are reincubated , and the grafts are recovered after an appropriate length of incubation time . the grafts are then scored for growth and vascularization . the angiogenic reaction may be evaluated by ranking the vascularization on a 0 to 4 basis but also using imaging techniques such as the measurement of bifurcation points in a designated area around the test material . alternatively , an entire egg contents may be used . test substances are administered by placing them on membranes or on the underside of coverslips and applied to a desired area . test compounds are assessed by their effect either on the normal development of the cam vasculature itself or on induced angiogenesis . alternatively , fertilized chick embryos are removed from their shell on day 3 or 4 , and a methylcellulose disc containing the test compound is implanted on the chorioallantoic membrane . the embryos are examined 48 hours later , if a clear avascular zone appears around the methylcellulose disc , the diameter of that zone is measured . such avascular zone indicates a compound having an anti - angiogenic activity ( u . s . pat . no . 5 , 001 , 116 ( col . 7 , incorporated herein by reference ). matrigel endothelial cell tube formation assay : matrigel ( 12 . 5 mg / ml ) was thawed at 4 ° c ., and 50 μl were quickly added to each well of a 96 - well plate and allowed to solidify for 10 min at 37 ° c . the wells were then incubated for 18 h at 37 ° c . with huvec ( 25 , 000 cells / well ). the formation of capillary - like structures was examined microscopically and pictures ( 50 ×) were taken using a retiga 1300 camera and a zeiss axiovert s100 microscope . the extent to which capillary - like structures formed in the gel was quantified by analysis of digitized images to determine the thread length of the capillary - like network , using a commercially available image analysis program ( northern eclipse ). matrigel plug assay : matrigel containing test cells or substances is injected subcutaneously , where it solidifies to form a plug . this plug is recovered after 7 - 21 days in the animal and examined histologically to determine the extent to which blood vessels have entered it . fluorescence measurement of plasma volume is achieved using fluorescein isothiocyanate ( fitc )- labeled dextran 150 . quantification may alternatively be achieved by measuring the amount of hemoglobin contained in the plug . in another alternative assay ( the sponge / matrigel assay ) matrigel alone is first introduced into the mouse . a sponge or tissue fragment is then inserted into the plug . new vessels are measured by injection of fitc . other angiogenesis assays are described , for example , in staton , c . a . et al ., ( int . j . exp . path . ( 2004 ), 85 , 233 - 248 ) the entire content of which is incorporated herein by reference . biologically active psp94 family member ; fragments , derivatives and analogues may be prepared by techniques known in the art ( recombinant technology , solid phase synthesis , etc .). the biological activity of derivatives , fragments and analogues may be determined by any of the techniques described herein or known in the field to be relevant for any of the biological activity described above . for example , serum - starved quiescent endothelial cells ( huvec ) may be incubated with different doses of a putative pck3145 derivative , analog or fragment ( e . g ., any of seq id nos . : 9 to 98 , combinations ) for 24 h and then stimulated with vegf . cells may be washed with pbs containing naf / na 3 vo 4 and incubated in the same medium buffer for 1 h at 4 ° c . the cells may be scraped from the culture dishes and the resulting lysates clarified by centrifugation . sds - page ( sodium dodecyl sulfate polyacrylamide gel electrophoresis ) may be performed to separate the proteins . western blotting and immunodetection may be performed by using anti - phosphoerk and anti - erk antibodies . the bands may be quantified to determine the level of inhibition of erk phosphorylation by the putative pck3145 derivative . an inhibitory effect of vegf - induced erk phosphorylation by the putative pck3145 derivative , analog or fragment means that the derivative is biologically active . in another example , a matrigel containing a putative pck3145 derivative , fragment or analog with an angiogenesis - inducer is injected subcutaneously , to an animal . this plug is recovered after 7 - 21 days from the animal and examined histologically to determine the extent to which blood vessels have entered it . quantification is performed as described above . a biologically active pck3145 derivative , fragment or analog is identified by the reduction in the number of blood vessels which have entered the matrigel plug or the extent to which blood vessels have entered it . a derivative , fragment or analog causing a diminution in the formation or propagation of blood vessel ( tubes , capillary - like structures ) in an agiogenesis assay described herein is considered to be a biologically active derivative , fragment or analog . each putative derivative , fragment or analogue may be tested using this technique or any other techniques described herein or known in the art . results of mmp - 9 levels in patient &# 39 ; s plasma , before and after one or more treatment cycle with pck3145 derivative ; seq id no . : 7 are illustrated in table 2 . normal values of healthy volunteers were not determined in this study but lizasa et al ., has determined that the normal range of plasma mmp - 9 concentrations is about 11 . 4 to 59 . 4 ng / ml . based on theses values , patients were sub - divided into two categories ; those having normal value of mmp - 9 ( below 100 μg / l ) and those having an elevated level of mmp - 9 ( higher than 100 μg / l ) at baseline ( see column identified as d1c1 in table2 ). in the normal value mmp - 9 category ( patients identified as e , f , g , h and i ), there was no significant decrease in mmp - 9 levels after one cycle of treatment ( column identified d27c1 ) compared to baseline levels . for patients e and g , no decrease in mmp - 9 levels was observed compared to baseline values even after 2 cycles of treatment ( column identified d27c2 ). there was still no mmp - 9 decrease even after 3 cycles of treatment for patient e ( d27c3 ). in the elevated mmp - 9 category ( patients identified as a , b , c and d ), a significant decrease was observed for each patient after only one cycle of treatment ( see column identified as d27c1 ). for example a decrease of up to 89 % in mmp - 9 levels was observed for patient a compared to baseline levels . for patient b , the decrease in mmp - 9 was 41 % after cycle 1 . for patients c and d the decrease at cycle 1 was 90 % and 34 % respectively . this decrease was maintained for patients b and c who have received more treatment cycles ( see columns identified as d27c2 , d27c3 and d27c4 ). for example , at treatment cycle 2 , patient b showed a reduction of 64 % of its baseline level of mmp - 9 . a similar reduction was also measured for patient b at treatment cycle 3 ; i . e ., a 65 % reduction , and at treatment cycle 4 ; a 75 % reduction . in the case of patient c , a reduction of 76 % in mmp - 9 levels was measured at cycle 2 . in order to support in vivo results described in example 1 , zymography assays and western blots were performed on cell lines incubated with a pck3145 derivative ( seq id no . : 7 ). in the experiment presented in fig1 , 2 . 5 × 10 5 matlylu tumor cells ( american type culture collection no . : jhu - 5 )) were seeded in t - 25 flasks containing rpmi with 10 % fetal bovine serum ( fbs ). after overnight incubation , the cells were washed once with serum free medium and treated with various concentrations of the pck3145 derivative ( 500 ug / ml and 1 mg / ml ) in the presence of 50 ug / ml collagen type - i in serum free rpmi for 72 hrs . control cells received 50 ug / ml collagen or only serum free medium . the media were collected after 72 hours of exposure to the pck3145 derivative and subjected to gelatin zymography . zymography for mmp - 2 and mmp - 9 was performed in sds - polyacrylamide gel electrophoresis ( sds - page ) ( 10 %) containing 0 . 1 % gelatin ( invitrogen ). twenty - four microliters of culture media was mixed with non - reducing sample buffer and subjected to electrophoresis without boiling . after electrophoresis , gels were soaked for 30 minutes in 2 . 5 % triton x - 100 solution with 2 - 3 washing steps . the gels were then incubated for 18 hours at 37 ° c . in buffer containing 50 mm tris / hcl , ph 7 . 6 , 50 mm nacl , 10 mm cacl 2 and 0 . 05 % brij - 35 . after incubation , the gels were stained with 0 . 2 % coomassie blue and de - stained until clear proteolytic bands appeared . gels were scanned with microtek flatbed scanner ( scanmaker 5 software ; microtek lab , redondo beach , calif .). the band intensities were determined using the image quant software ( version 5 . 0 ) from molecular dynamics . the mmp - 9 and mmp - 2 gelatinase zymography standard were purchased from chemicon ( catalogue no . cc073 ). one nanogram of purified human pro - mmp - 2 and pro - mmp - 9 standards were used in every gel run . results of this experiment are illustrated in fig1 and indicate that pck3145 derivative treatment of matlylu cells resulted in a dose - dependent reduction of mmp - 9 secreted in the cell culture media , as detected by zymography . a separate western blot experiment was performed in which matlylu cells were treated with 100 ug / ml , 500 ug / ml and 1 mg / ml of the pck3145 derivative for 72 hrs . at the end of the experiment , the media were collected and concentrated 5 times using amicon centrifugal filter devices ( 3500 molecular weight cut - off ). twenty five microliters samples were separated on sds - page gel under reducing conditions using pre - cast gels of 4 - 12 % bis - tris ( invitrogen ). following electrophoresis , the proteins were transferred on nitrocellulose membrane . non - specific binding sites were blocked using 5 % skimmed milk in 10 mm phosphate buffer saline ( pbs ) containing 0 . 05 % tween - 20 for 1 hour at room temperature . the membrane was later incubated with a primary antibody ( monoclonal , rdi - mmp - 9abm - 2a5 ) at a concentration of 1 ug / ml ( in 10 mm pbs , containing 0 . 5 % bovine serum albumin ( bsa ) and 0 . 05 % tween - 20 ) for 3 hours at room temperature . the membranes were washed three times in pbs ( 5 minutes each wash ) to remove non - specific binding and they were incubated with the secondary antibody ( rabbit anti - mouse igg horseradish peroxidase - conjugated ( dako no . 0260 )) at a dilution of 1 : 5000 for one hour . detection of specific mmp - 9 protein was made by incubating the membrane in ecl ™ reagent ( electro - chemoluminescence , roche ) and exposing to the x - ray film . results of this experiment are illustrated in fig2 and again indicate that treatment of matlylu cells pck3145 derivative resulted in a dose - dependent reduction of mmp - 9 levels . the effect of the pck3145 derivative ( seq id no . : 7 ) on mmp extracellular levels was assessed by gelatin - zymography in the conditioned media of serum - starved huvec . after 16 hours of starvation , huvec were stimulated with vegf in the presence or not of the pck3145 derivative . a further 24 hours treatment shows that pck3145 derivative effectively downregulated by approximately 35 % the basal prommp - 2 levels in the extracellular media ( fig3 ). most importantly , the effect of pck3145 derivative ( 300 μg / ml ) was also observed on vegf - induced prommp - 2 secretion as the inhibition was of approximately 50 %. when these experiments were performed in serum - free media , but in the presence of the mapk inhibitor pd98059 , vegf - induced prommp - 2 extracellular levels were also significantly decreased . these results suggest that the effect of pck3145 derivative towards mmp secretion is indeed regulated through a mapk pathway in endothelial cells . vegf is a strong activator of erks ( extracellular - signal - regulated protein kinases ) 1 and 2 via vegf receptor 2 . in order to test the ability of the pck3145 derivative in potentially antagonizing vegf - mediated erk phosphorylation , serum - starved quiescent endothelial cells ( huvec ) were incubated with vehicle ( phosphate - buffered saline ( pbs ) ph 7 . 4 ) or pck3145 derivative ( 300 μg / ml ) for 24 h and then stimulated with vegf , bfgf ( basic fibroblast growth factor ) or s1p ( sphingosine - 1 - phosphate ). cells were washed with pbs containing naf / na 3 vo 4 and incubated in the same medium buffer for 1 h at 4 ° c . the cells were scraped from the culture dishes and the resulting lysates clarified by centrifugation . western blotting and immunodetection using anti - phosphoerk and anti - erk antibodies was then performed . the results show a specific inhibitory effect of the pck3145 derivative on erk phosphorylation induced by vegf ( fig4 a ) but not that induced by bfgf or s1p ( fig4 a ). this inhibitory effect was confirmed for two endothelial cells , huvec and baec ( not shown ). the total amount of erk in each sample of cells was unaffected by the pck3145 derivative ( fig4 a ). although , pck3145 derivative also seemed to stimulate erk phosphorylation induced by s1p in huvec ( fig4 a ), that result was found not statistically significant . moreover , a dose - response to pck3145 derivative was found to gradually inhibit the extent of erk phosphorylation by vegf ( fig4 b ). the effect of pck3145 derivative was found comparable to that of pd98059 , a documented pharmacological inhibitor of erk phosphorylation . the lack of effect of a scrambled peptide ( seq id no . : 99 ) is demonstrated as a negative control ( fig4 c ). finally , a time - course of pck3145 derivative effect is shown at 3 and 24 hrs demonstrating the necessity of a long term action of pck3145 derivative ( fig4 d ). this three dimensional ecm model assay provides physiologically relevant environment for studies of cell morphology , biochemical function , and gene expression in endothelial cells ( ec ) that can be modulated for instance by tumor growth factors or hypoxic culture conditions . moreover , proteomic - based approaches to monitor levels of protein expression can also be achieved . when plated on matrigel , ec have the ability to form capillary - like structures . the extent of capillary - like structures formation ( density and size of structures ) can be quantified by analysis of digitized images to determine the relative size and area covered by the tube - like network , using an image analysis software ( un - scan - it , empix imaging ). huvec were trypsinised , counted and seeded on matrigel . adhesion to matrigel was left to proceed for 30 minutes . treatment with increasing concentrations of the pck3145 derivative ( 0 - 300 μg / ml ) was then performed in serum - free media for 24 hours . the extent of capillary - like structure formation was then assessed afterwards . the results show that the pck3145 derivative negatively affects tubulogenesis ( fig5 ). the multifunctionality of vegf at the cellular level results from its ability to initiate a diverse , complex and integrated network of signaling pathways via its major receptor , vegfr - 2 . thus , the inhibitory effect of the pck3145 derivative on erk phosphorylation induced by vegf was examined to verify whether it was a consequence of an inhibition of the phosphorylation of vegfr - 2 . huvec were grown , serum - starved , pretreated with the pck3145 derivative ( 300 μg / ml ; 24 h ), and stimulated with vegf as described in gingras et al . [ biochem j 348 : 273 - 280 , ( 2000 )]. after each treatment , equal amounts of protein were immunoprecipitated with anti - vegfr - 2 polyclonal antibodies and analysed by western blotting . results of this experiment show that the pck3145 derivative inhibited the phosphorylation of vegfr - 2 induced by vegf in huvec ( fig6 a ). this inhibitory effect of the pck3145 derivative is also shown to be dose - dependent ( fig6 b ), and could be to a certain extent compared to the action of ptk787 , a known pharmacological inhibitor of the tyrosine kinase activity associated to the vegfr - 2 . finally , the lack of effect of a scrambled peptide is shown ( fig6 c ) and suggests the specificity of action of the pck3145 derivative . the potential inhibitory action of the pck3145 derivative towards the tyrosine kinase activity associated to the vegfr - 2 was also tested on the kinase activity associated to another receptor the pdgf receptor ( pdgfr ) in pasmc ( pulmonary aortic smooth muscle cells ). similar treatment of the pck3145 derivative as for huvec was performed . interestingly , pck3145 derivative leads to the inhibition of pdgfr phosphorylation induced by pdgf ( fig7 a ), as well as of the pdgf - induced erk phosphorylation ( fig7 b ). in order to investigate the potential intracellular pathways triggered by the pck3145 derivative , a gene - reporter assay using the seap ( secreted alkaline phosphatase ) mercury profiling kit ( clontech ) was performed in glioma cells ( u - 87 ). this assay enables the monitoring of transcription factors that are triggered by a particular experimental condition by assaying the alkaline phosphatase activity in the extracellular media . the pck3145 derivative triggers significantly two pathways : the mapk / jnk pathway ( sre ) and the nfkb pathway ( fig8 a ). the mapk pathway induction is extremely strong as compared to that of the nfkb pathway . the latter however potentially suggests the involvement of pro - apoptotic pathways that would be triggered by the pck3145 derivative . intriguingly , the secretion of the constitutively expressed seap was found to be inhibited suggesting a potential effect of the pck3145 derivative on a more general constitutive secretion pathway . the induction of the mapk pathway by the pck3145 derivative is further confirmed by the rapid and transient induction of erk phosphorylation between 5 - 10 minutes ( fig8 b ) and is shown to be dose - dependent ( fig8 c ). finally , the effects of the pck3145 derivative were also compared to those of a scrambled peptide . these results show that the scrambled peptide was unable to induce erk phosphorylation comparable to that of the pck3145 derivative ( fig8 d ). finally , these results also indicate that the mapk inhibitor pd98059 antagonized the induction of erk phosphorylation by the pck3145 derivative . matrigel containing the pck3145 or its derivative ( seq id no . : 5 or seq id no . : 7 ) is injected subcutaneously to a rat . this solidified plug is recovered after 7 - 21 days in the animal and examined histologically to determine the extent to which blood vessels have entered the plugs . in another assay , fertilized chick embryos are removed from their shell on day 3 or 4 , and a methylcellulose disc containing pck3145 ( seq id no . : 5 or seq id no . : 7 ) is implanted on the chorioallantoic membrane . the embryos are examined 48 hours later and the diameter of the avascular zone is measured . the overall effects of psp94 family members described herein make them useful for treatment of several diseases in addition to the previously disclosed utility ( inhibition of tumor cell growth and skeletal metastasis ). the content of each publication , patent and patent application mentioned in the present application is incorporated herein by reference . although the present invention has been described in details herein and illustrated in the accompanying drawings , it is to be understood that the invention is not limited to the embodiments described herein and that various changes and modifications may be effected without departing from the scope or spirit of the present invention . sequence description : seq id no : 1 : ser cys tyr phe ile pro asn glu gly val pro gly asp ser thr arg 1 5 10 15 lys cys met asp leu lys gly asn lys his pro ile asn ser glu trp 20 25 30 gln thr asp asn cys glu thr cys thr cys tyr glu thr glu ile ser 35 40 45 cys cys thr leu val ser thr pro val gly tyr asp lys asp asn cys 50 55 60 gln arg ile phe lys lys glu asp cys lys tyr ile val val glu lys 65 70 75 80 lys asp pro lys lys thr cys ser val ser glu trp ile ile 85 90 sequence description : seq id no : 2 : glu ala glu ala tyr val glu phe ser cys tyr phe ile pro asn glu 1 5 10 15 gly val pro gly asp ser thr arg lys cys met asp leu lys gly asn 20 25 30 lys his pro ile asn ser glu trp gln thr asp asn cys glu thr cys 35 40 45 thr cys tyr glu thr glu ile ser cys cys thr leu val ser thr pro 50 55 60 val gly tyr asp lys asp asn cys gln arg ile phe lys lys glu asp 65 70 75 80 cys lys tyr ile val val glu lys lys asp pro lys lys thr cys ser 85 90 95 val ser glu trp ile ile 100 sequence description : seq id no : 3 : tyr thr cys ser val ser glu pro gly ile 1 5 10 sequence description : seq id no : 4 : asn glu gly val pro gly asp ser thr arg lys cys met asp leu 1 5 10 15 sequence description : seq id no : 5 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 15 sequence description : seq id no : 6 : ile val val glu lys lys asp pro lys lys thr cys ser val ser glu 1 5 10 15 trp ile ile sequence description : seq id no : 7 ( an acetylaminomethyl group may be attached to the sulfur atom of cysteine 7 , of cysteine 10 and / or of cysteine 12 ) glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 15 sequence description : seq id no : 8 : tcatgctatt tcatacctaa tgagggagtt ccaggagatt caaccaggaa atgcatggat 60 ctcaaaggaa acaaacaccc aataaactcg gagtggcaga ctgacaactg tgagacatgc 120 acttgctacg aaacagaaat ttcatgttgc acccttgttt ctacacctgt gggttatgac 180 aaagacaact gccaaagaat cttcaagaag gaggactgca agtatatcgt ggtggagaag 240 aaggacccaa aaaagacctg ttctgtcagt gaatggataa tctaa 285 sequence description : seq id no : 9 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 sequence description : seq id no : 10 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile sequence description : seq id no : 11 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser sequence description : seq id no : 12 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys sequence description : seq id no : 13 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys 20 sequence description : seq id no : 14 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr 20 sequence description : seq id no : 15 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu 20 sequence description : seq id no : 16 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val 20 sequence description : seq id no : 17 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser 20 sequence description : seq id no : 18 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr 20 25 sequence description : seq id no : 19 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro 20 25 sequence description : seq id no : 20 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val 20 25 sequence description : seq id no : 21 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly 20 25 sequence description : seq id no : 22 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr 20 25 sequence description : seq id no : 23 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp 20 25 30 sequence description : seq id no : 24 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys 20 25 30 sequence description : seq id no : 25 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 sequence description : seq id no : 26 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn sequence description : seq id no : 27 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys sequence description : seq id no : 28 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln 35 sequence description : seq id no : 29 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg 35 sequence description : seq id no : 30 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile 35 sequence description : seq id no : 31 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe 35 sequence description : seq id no : 32 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys 35 sequence description : seq id no : 33 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys 35 40 sequence description : seq id no : 34 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu 35 40 sequence description : seq id no : 35 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp 35 40 sequence description : seq id no : 36 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys 35 40 sequence description : seq id no : 37 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys 35 40 sequence description : seq id no : 38 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr 35 40 45 sequence description : seq id no : 39 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile 35 40 45 sequence description : seq id no : 40 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val 35 40 45 sequence description : seq id no : 41 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 sequence description : seq id no : 42 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu sequence description : seq id no : 43 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys 50 sequence description : seq id no : 44 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys 50 sequence description : seq id no : 45 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp 50 sequence description : seq id no : 46 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro 50 sequence description : seq id no : 47 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys 50 sequence description : seq id no : 48 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys 50 55 sequence description : seq id no : 49 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr 50 55 sequence description : seq id no : 50 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys 50 55 sequence description : seq id no : 51 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser 50 55 sequence description : seq id no : 52 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser val 50 55 sequence description : seq id no : 53 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser val ser 50 55 60 sequence description : seq id no : 54 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser val ser glu 50 55 60 sequence description : seq id no : 55 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser val ser glu trp 50 55 60 sequence description : seq id no : 56 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser val ser glu trp ile 50 55 60 sequence description : seq id no : 57 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 ile ser cys cys thr leu val ser thr pro val gly tyr asp lys asp 20 25 30 asn cys gln arg ile phe lys lys glu asp cys lys tyr ile val val 35 40 45 glu lys lys asp pro lys lys thr cys ser val ser glu trp ile ile 50 55 60 sequence description : seq id no : 58 : ser glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 15 sequence description : seq id no : 59 : asn ser glu trp gln thr asp asn cys glu thr cys thr cys tyr glu 1 5 10 15 thr sequence description : seq id no : 60 : ile asn ser glu trp gln thr asp asn cys glu thr cys thr cys tyr 1 5 10 15 glu thr sequence description : seq id no : 61 : pro ile asn ser glu trp gln thr asp asn cys glu thr cys thr cys 1 5 10 15 tyr glu thr sequence description : seq id no : 62 : his pro ile asn ser glu trp gln thr asp asn cys glu thr cys thr 1 5 10 15 cys tyr glu thr 20 sequence description : seq id no : 63 : lys his pro ile asn ser glu trp gln thr asp asn cys glu thr cys 1 5 10 15 thr cys tyr glu thr 20 sequence description : seq id no : 64 : asn lys his pro ile asn ser glu trp gln thr asp asn cys glu thr 1 5 10 15 cys thr cys tyr glu thr 20 sequence description : seq id no : 65 : gly asn lys his pro ile asn ser glu trp gln thr asp asn cys glu 1 5 10 15 thr cys thr cys tyr glu thr 20 sequence description : seq id no : 66 : lys gly asn lys his pro ile asn ser glu trp gln thr asp asn cys 1 5 10 15 glu thr cys thr cys tyr glu thr 20 sequence description : seq id no : 67 : leu lys gly asn lys his pro ile asn ser glu trp gln thr asp asn 1 5 10 15 cys glu thr cys thr cys tyr glu thr 20 25 sequence description : seq id no : 68 : asp leu lys gly asn lys his pro ile asn ser glu trp gln thr asp 1 5 10 15 asn cys glu thr cys thr cys tyr glu thr 20 25 sequence description : seq id no : 69 : met asp leu lys gly asn lys his pro ile asn ser glu trp gln thr 1 5 10 15 asp asn cys glu thr cys thr cys tyr glu thr 20 25 sequence description : seq id no : 70 : cys met asp leu lys gly asn lys his pro ile asn ser glu trp gln 1 5 10 15 thr asp asn cys glu thr cys thr cys tyr glu thr 20 25 sequence description : seq id no : 71 : lys cys met asp leu lys gly asn lys his pro ile asn ser glu trp 1 5 10 15 gln thr asp asn cys glu thr cys thr cys tyr glu thr 20 25 sequence description : seq id no : 72 : arg lys cys met asp leu lys gly asn lys his pro ile asn ser glu 1 5 10 15 trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 20 25 30 sequence description : seq id no : 73 : thr arg lys cys met asp leu lys gly asn lys his pro ile asn ser 1 5 10 15 glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 20 25 30 sequence description : seq id no : 74 : ser thr arg lys cys met asp leu lys gly asn lys his pro ile asn 1 5 10 15 ser glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 20 25 30 sequence description : seq id no : 75 : asp ser thr arg lys cys met asp leu lys gly asn lys his pro ile 1 5 10 15 asn ser glu trp gln thr asp asn cys glu thr cys thr cys tyr glu 20 25 30 thr sequence description : seq id no : 76 : gly asp ser thr arg lys cys met asp leu lys gly asn lys his pro 1 5 10 15 ile asn ser glu trp gln thr asp asn cys glu thr cys thr cys tyr 20 25 30 glu thr sequence description : seq id no : 77 : pro gly asp ser thr arg lys cys met asp leu lys gly asn lys his 1 5 10 15 pro ile asn ser glu trp gln thr asp asn cys glu thr cys thr cys 20 25 30 tyr glu thr 35 sequence description : seq id no : 78 : val pro gly asp ser thr arg lys cys met asp leu lys gly asn lys 1 5 10 15 his pro ile asn ser glu trp gln thr asp asn cys glu thr cys thr 20 25 30 cys tyr glu thr 35 sequence description : seq id no : 79 : gly val pro gly asp ser thr arg lys cys met asp leu lys gly asn 1 5 10 15 lys his pro ile asn ser glu trp gln thr asp asn cys glu thr cys 20 25 30 thr cys tyr glu thr 35 sequence description : seq id no : 80 : glu gly val pro gly asp ser thr arg lys cys met asp leu lys gly 1 5 10 15 asn lys his pro ile asn ser glu trp gln thr asp asn cys glu thr 20 25 30 cys thr cys tyr glu thr 35 sequence description : seq id no : 81 : asn glu gly val pro gly asp ser thr arg lys cys met asp leu lys 1 5 10 15 gly asn lys his pro ile asn ser glu trp gln thr asp asn cys glu 20 25 30 thr cys thr cys tyr glu thr 35 sequence description : seq id no : 82 : pro asn glu gly val pro gly asp ser thr arg lys cys met asp leu 1 5 10 15 lys gly asn lys his pro ile asn ser glu trp gln thr asp asn cys 20 25 30 glu thr cys thr cys tyr glu thr 35 40 sequence description : seq id no : 83 : ile pro asn glu gly val pro gly asp ser thr arg lys cys met asp 1 5 10 15 leu lys gly asn lys his pro ile asn ser glu trp gln thr asp asn 20 25 30 cys glu thr cys thr cys tyr glu thr 35 40 sequence description : seq id no : 84 : phe ile pro asn glu gly val pro gly asp ser thr arg lys cys met 1 5 10 15 asp leu lys gly asn lys his pro ile asn ser glu trp gln thr asp 20 25 30 asn cys glu thr cys thr cys tyr glu thr 35 40 sequence description : seq id no : 85 : tyr phe ile pro asn glu gly val pro gly asp ser thr arg lys cys 1 5 10 15 met asp leu lys gly asn lys his pro ile asn ser glu trp gln thr 20 25 30 asp asn cys glu thr cys thr cys tyr glu thr 35 40 sequence description : seq id no : 86 : cys tyr phe ile pro asn glu gly val pro gly asp ser thr arg lys 1 5 10 15 cys met asp leu lys gly asn lys his pro ile asn ser glu trp gln 20 25 30 thr asp asn cys glu thr cys thr cys tyr glu thr 35 40 sequence description : seq id no : 87 : ser cys tyr phe ile pro asn glu gly val pro gly asp ser thr arg 1 5 10 15 lys cys met asp leu lys gly asn lys his pro ile asn ser glu trp 20 25 30 gln thr asp asn cys glu thr cys thr cys tyr glu thr 35 40 45 2 ) information for seq id no : 88 : ( i ) sequence characteristics : ( a ) length : 15 ( b ) type : amino acid ( c ) strandedness : single ( d ) topology : linear ( ii ) molecule type : ( ix ) feature : name / key : modified site location : 1 other information : the residue in this position is either glutamic acid , asparagine , or aspartic acid . ( ix ) feature : name / key : modified site location : 4 ( d ) other information : the residue in this position is either threonine , or serine . ( ix ) feature : name / key : modified site location : 6 ( d ) other information : the residue in this position is either glutamic acid , asparagine , or aspartic acid . ( ix ) feature : name / key : modified site location : 8 ( d ) other information : the residue in this position is either glutamic acid , asparagine , or aspartic acid . ( ix ) feature : name / key : modified site location : 9 ( d ) other information : the residue in this position is either threonine , or serine . ( ix ) feature : name / key : modified site ( b ) location : 11 ( d ) other information : the residue in this position is either threonine , or serine . ( ix ) feature : ( a ) name / key : modified site ( b ) location : 13 ( d ) other information : the residue in this position is either tyrosine , or phenylalanine . ( ix ) feature : name / key : modified site ( b ) location : 14 ( d ) other information : the residue in this position is either glutamic acid , asparagine , or aspartic acid . ( ix ) feature : ( a ) name / key : modified site ( b ) location : 15 ( d ) other information : the residue in this position is either threonine , or serine . ( vi ) original source : ( a ) organism : ( xi ) sequence description : seq id no : 88 : xaa trp gln xaa asp xaa cys xaa xaa cys xaa cys xaa xaa xaa 1 5 10 15 sequence description : seq id no : 89 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 20 25 30 sequence description : seq id no : 90 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu trp 20 25 30 gln thr asp asn cys glu thr cys thr cys tyr glu thr 35 40 45 sequence description : seq id no : 91 : glu trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu 1 5 10 15 trp gln thr asp asn cys glu thr cys thr cys tyr glu thr glu trp 20 25 30 gln thr asp asn cys glu thr cys thr cys tyr glu thr glu trp gln 35 40 45 thr asp asn cys glu thr cys thr cys tyr glu thr 50 55 60 sequence description : seq id no : 92 : glu tyr gln thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 15 sequence description : seq id no : 93 : glu trp asn thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 15 sequence description : seq id no : 94 : glu trp gln thr asp gln ser glu thr cys thr cys tyr asp thr 1 5 10 15 sequence description : seq id no : 95 : trp gln thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 sequence description : seq id no : 96 : gln thr asp asn cys glu thr cys thr cys tyr glu thr 1 5 10 sequence description : seq id no : 97 : glu trp gln thr asp asn cys glu thr cys thr cys 1 5 10 sequence description : seq id no : 98 : glu trp gln thr asp asn cys glu thr cys thr cys d - tyr glu thr 1 5 10 15 sequence description : seq id no : 99 : thr - cys ( acm )- glu - asn - cys ( acm )- thr - glu - thr - gln - trp - cys ( acm )- glu - thr - asp - tyr | US-427304-A |
optimized hearing aid parameter settings are automatically determined from a multiplicity of data obtained by applying different test methods for testing the auditory perception of a person . data pertaining to the auditory perception of the user are first obtained by different test methods . the data from the individual tests can be incomplete , inconsistent or untypical , or even erroneous . however , the subsequent combination of where possible all available data in a computational unit affords the possibility of automatically obtaining hearing aid parameter settings by way of which a hearing aid operated thereby compensates the present loss of hearing of the relevant user in an optimized fashion . | referring now to the figures of the drawing in detail and first , particularly , to fig1 thereof , there is shown an exemplary flowchart . there , at least one hearing test is first of all performed in a first method step s 1 using an objective test method ( objective hearing test ), e . g . an impedance measurement , a measurement of otoacoustic emissions , bera or cera measurements , speech audiometry , etc . in a second method step s 2 there subsequently is a transformation of the data obtained from the objective hearing test into equivalent data from standard audiometry . depending on the type of the underlying measurement , the algorithm for the data processing advantageously utilized uses different transformation curves . it can be assumed that it is not always a precise tone audiogram value , but more likely an estimation interval , that can be determined for a given frequency . furthermore , at least one hearing test using a subjective test method ( subjective hearing test ), e . g . tone audiometry or loudness scaling , is performed in a method step s 3 . subsequently , in a further method step s 4 , the data obtained in method step s 2 and the data obtained in method step s 3 are combined in a preferably weighted combination . in the ideal case , this can be carried out by simple averaging of the preferably transformed measurement values . neural networks or fuzzy logic can advantageously be used in the case of conflicting data or missing values . these neural networks should run through a learning phase before they are used , during which learning phase they are trained in respect of typical losses of hearing and their associated objective and subjective measurement results in order to make the audiological pattern recognition simpler in the respectively present data record at a later stage . further learning based on new measurements can be possible , but it is not required . alternatively , an assignment of the various measurement values to a loss of hearing category can be carried out by means of data clustering analysis . here , there is also the essential prerequisite of collecting different types of loss of hearing in advance together with their associated measurement data . in the subsequent method step s 5 , an amplification curve is calculated from the combined data obtained in method step s 4 . optionally , in a further method step s 6 , there is at least one hearing test for determining the resolving capabilities of the hearing , for localizing or for speech intelligibility taking into account cera and / or bera data for determining feature parameters of a hearing aid to be set , e . g . in respect of the noise suppression , speech - sensitive processing or directional microphone setting . finally , hearing aid parameter settings are determined in a method step s 7 ( likewise optional ) as a function of the data determined in method step s 6 . referring now to fig2 , there are shown the results from four different test methods , by means of which data relating to the auditory perception ( audiological data ) of a user was obtained . in the illustrated sequence in the left column of the figure these are , from top to bottom : the result of a hearing test with a hearing test instrument , in which the hearing threshold was determined at four different frequencies , the result of a speech intelligibility test , the result of a measurement of otoacoustic emissions ( oae ), and the result of a measurement of brainstem potentials . the results of the hearing tests when applying the four different test methods are illustrated graphically in each case in the left column in fig2 . what is illustrated in each case is the loss of hearing at the respective signal frequency determined by the test . the result of each test method is preferably subsequently transferred automatically to a standard audiogram by means of the utilized algorithm . the individual underlying test methods accordingly only supply data for a portion of the frequency range ( part - frequency range ) that can be transmitted by the hearing aid , from which data the loss of hearing of the relevant person emerges at different frequencies in a fragment - like fashion . accordingly , required amplification values for an input signal for compensating the individual loss of hearing in the test person obtained can be determined from the results obtained by the individual test methods , see the graphs in the second column of fig2 . the graphs show that the amplification values are in each case only determined , more particularly calculated or established by means of lookup tables , for that frequency range for which data is also available from the respective test method . accordingly , it is only a part - transmission function of the hearing aid that is determined in each case . in the graph in the third column , the upper diagram now illustrates the results of all graphs of the second column unified in a single diagram . this shows that the test methods lead to inconsistent results . more particularly , a number of different amplification values result for individual frequencies . therefore , according to the invention , the fragment - like amplification characteristics resulting from the different test methods are subsequently combined to a unified amplification characteristic that is continuous over the entire required frequency range . in the process , a multiplicity of different mathematical methods can be used , either individually or in combination . examples of this include : averaging , forming data clusters , factor analysis , extrapolation , etc . furthermore , a continuous amplification characteristic for the relevant frequency range can also be determined by applying neural networks and / or fuzzy logic . it is also possible for the most suitable amplification characteristic to be selected from a number of predetermined amplification characteristics . the result of this calculation is illustrated in the exemplary embodiment in the lower diagram in the right ( third ) column . a preferred embodiment of the invention provides for different weighting of the audiological data obtained by different test methods . in the process , the different weighting can be effected automatically , for example by virtue of the fact that the data obtained by a speech test are included in determining the hearing aid parameter settings with a higher weighting than data from a simple hearing test ( measurement of the hearing threshold ). different weightings can moreover be fixed by manual user inputs on an individual basis . moreover , automatic evaluation of the present data is also possible . thus , a data record with very many measurement points can be afforded a higher weighting than a data record with only a few measurement points . a plausibility check can also lead to different weightings . thus , a data record with many implausible measurement points can be downgraded in respect of its weighting . the invention provides for the implementation of an algorithm in a hearing aid adjustment instrument , which implements the above - described procedure . in the process , this is preferably a hand - held instrument . the audiological data obtained by applying different test methods are entered into the hearing aid adjustment instrument . additionally , or alternatively , the hearing aid adjustment instrument can itself also generate audiological data , for example by carrying out a simple hearing test . the hearing aid adjustment instrument automatically generates hearing aid parameter settings from the audiological data in the described fashion and transmits said hearing aid parameter settings to a hearing aid to be adjusted , and so the hearing aid brings about a transmission function in respect of an input signal entering the hearing aid , by means of which the individual loss of hearing of the user is compensated . it will be understood by those of skill in the pertinent art that the invention is not subject to any limitations in respect of the type and number of test methods that can be used for determining audiological data . in the simplest case only one hearing test method is used and the amplification characteristic with the best match to the test result is selected from a collection of predetermined transmission characteristics . | US-87096210-A |
grease - like compositions are provided for repelling rodents . the compositions utilize nontoxic mineral , synthetic , or vegetable oil based gels containing silica , clay , urea , polytetrafluoroethylene , or metallic soap thickeners and capsaicin . | the following description and examples illustrate a preferred embodiment of the present invention in detail . those of skill in the art will recognize that there are numerous variations and modifications of this invention that are encompassed by its scope . accordingly , the description of a preferred embodiment should not be deemed to limit the scope of the present invention . a rodent repellent composition based on a grease - like gel composition for use on exterior and interior surfaces of a structure , such as homes , restaurants , and office buildings is provided . the repellent composition is particularly preferred for use on rodents ( e . g ., mice , rats , moles , voles , squirrels , and chipmunks ); however , the repellent is also suitable for use on other mammals , e . g ., raccoons and opossums . the repellent composition is suitable for use on any organism which possesses taste receptor cells sensitive to capsaicin or similar substances . insects can also be repelled by the repellent compositions of preferred embodiments ; however , birds do not have the receptor to which capsaicin binds , so it does not function as an irritant for them . unlike conventional rodent repellents that rely on odiferous components such as menthol , the repellents of preferred embodiments rely on a different mechanism of action and thus can be odor - free . the repellents of preferred embodiments work by the rodent making contact with the composition , which contains capsaicin , white pepper , or other components that produce a strong burning sensation in the mouth upon ingestion , but which are odorless or relatively odor - free . use of menthol and other odiferous components conventionally employed in repellents is avoided , as such components can reduce the effectiveness of a gel repellent composition because it discourages rodents from making physical contact with the composition . the repellent ingredient of the compositions of preferred embodiments is preferably capsaicin ( 8 - methyl - n - vanillyl - 6 - nonenamide ). it is the active component of chili peppers , which are plants belonging to the genus capsicum . it is an irritant for mammals , including humans , and produces a sensation of burning in any tissue with which it comes into contact . birds do not have the receptor to which capsaicin binds , so it does not function as an irritant for them . capsaicin and several related compounds are called capsaicinoids and are produced as a secondary metabolite by chili peppers . pure capsaicin is a hydrophobic , colorless , odorless , crystalline to waxy compound . capsaicin is the main capsaicinoid in chili peppers , followed by dihydrocapsaicin . these two compounds are also about twice as potent to the taste and nerves as the minor capsaicinoids nordihydrocapsaicin , homodihydrocapsaicin , and homocapsaicin . besides the six natural capsaicinoids , one synthetic member of the capsaicinoid family exists , the vanillylamide of n - nonanoic acid . table 1 provides a listing of several capsaicinoids . other components exhibiting similar properties can also be used as the repellent ingredient of the compositions of preferred embodiments . one such preferred component is piperine , the active piquant chemical in white and black pepper . allyl isothiocyanate , the active piquant chemical in mustard , radishes , horseradish , and wasabi can also be employed , as can allicin , the active piquant flavor chemical in uncooked garlic and onions . a particularly preferred repellent additive is capsaicin , due to its lack of odor in purified form . piperine also exhibits minimal odor in purified form . in applications where odor is not a concern , allyl isothiocyanate and allicin can advantageously be employed . while one repellent additive can advantageously be employed , combinations of two or more additives , e . g ., capsaicin and piperine , are also suitable for use . the repellent additive ( s ) typically comprise from about 0 . 005 wt . % or less to 0 . 5 wt . % or more of the repellent formulation , preferably from about 0 . 025 wt . % to about 0 . 1 wt . % of the repellent formulation . repellent additives are preferably employed in purified form ; however , in certain embodiments it can be acceptable to provide at least a portion of the repellent additive in a form of powdered vegetable product ( e . g ., chili powder ). the repellent additive can be mixed into to the grease base in powder or other solid form , or in a solubilized form . to improve the solubility of the repellent additive or other additives in the grease formulation , in certain embodiments it can be preferred to add an activator agent or other solubility improver to the grease base ( the term “ solubility improving additive ” as employed herein is used to collectively refer to both activator agents and solubility improvers ). esters , such as polyol esters can optionally be employed as solubility improving additives . alternatively , if the repellent additive is provided in a purified form , the additive can be dissolved or dispersed in a suitable solvent , which is then mixed into the grease base . suitable solvents for capsaicin include , e . g ., hexane , chloroform , ethylacetate , ethyl ether , acetonitrile , acetone , and ethanol . ethanol , petroleum ether , and dichloromethane are solvents for piperine . allyl isothiocyanate and allicin are soluble in most organic solvents and are slightly soluble in water . while any suitable solvent for the repellent additive can be employed , if desired , ethanol , e . g ., denatured ethanol , is generally preferred as the most environmentally acceptable activator agent . when ethanol is provided in denatured form , it can contain ethanol in combination with other additives . for example , the denatured ethanol may contain about 1 - 99 % ethanol and about 1 - 99 % additives , about 95 % ethanol and about 5 % additives , about 90 % ethanol and about 10 % additives , about 75 % ethanol and about 25 % additives , about 50 % ethanol and about 50 % additives . additives employed in denatured alcohol include , for example , methanol , isopropyl alcohol , acetone , methyl ethyl ketone , methyl isobutyl ketone , and denatonium . in a preferred embodiment , the denatured ethanol contains 95 % ethanol and 5 % additives . the solubility improving additive ( s ) typically comprise from about 0 . 25 wt . % or less to 5 wt . % or more of the repellent formulation , preferably from about 0 . 5 wt . % to about 3 wt . % of the repellent formulation , and more preferably from about 1 wt % to about 2 wt % of the repellent formulation . the capsaicin or other rodent repelling ingredient is provided in a grease - like base . preferred grease - like bases include one or more base oil or fluid components as a carrier . the oil or base fluid may include any number of materials , which are typically divided into two groups : petroleum derived oils ; and synthetic fluids , which are generally chemical reaction products . petroleum derived oils include paraffinic oils , naphthenic oils , and aromatic oils . synthetic fluids including polyalphaolefins , glycols , alkylated naphthalenes , alkylated benzenes , and esters have been used in compounding oil - based products . it is generally preferred to employ base oils that are both low cost and exhibit low toxicity . accordingly , light or heavy grade white oil ( a transparent , colorless mineral oil composed mainly of c15 - c40 alkanes and cyclic paraffins ), preferably of a purity suitable for use in food or cosmetics , is preferably employed as a base oil . alternatively , or in addition to mineral oil , vegetable oils can be utilized . vegetable oils are lipids ( esters ) derived from plants . suitable vegetable oils include , but are not limited to , coconut oil , corn oil , cottonseed oil , olive oil , palm oil , peanut oil , rapeseed oil , safflower oil , soybean oil , sunflower oil , almond oil , casher oil , hazelnut oil , macadamia oil , mongongo nut oil , pecan oil , pine nut oil , pistachio oil , walnut oil , bottle gourd oil , buffalo gourd oil , pumpkin seed oil , watermelon seed oil , acai oil , blackcurrant seed oil , borage seed oil , evening primrose oil , amaranth oil , apricot oil , apple seed oil , argan oil , artichoke oil , avocado oil , babassu oil , ben oil , borneo tallow nut oil , cape chestnut oil , carob pod oil , cassia oil , cocoa butter oil , cocklebur oil , cohune oil , coriander seed oil , dika oil , false flax oil , flax seed oil , grape seed oil , hemp oil , kapok seed oil , kenaf seed oil , lallemantia oil , manila oil , meadowfoam seed oil , mustard oil , nutmeg butter , okra seed oil , papaya seed oil , perilla seed oil , pequi oil , pine nut oil , poppyseed oil , prune kernel oil , quinoa oil , ramtil oil , rice bran oil , royle oil , sacha inchi oil , tea seed oil , thistle oil , tigernut oil , tomato seed oil , wheat germ oil , algae oil , copaiba , honge oil , jatropha oil , jojoba oil , milk bush , and petroleum nut oil . polyalphaolefins can be employed as base oil . such polyalphaolefins include high viscosity polyalphaolefins as described in u . s . pat . no . 4 , 827 , 064 . for example , high viscosity polyalphaolefins possess a higher viscosity index than conventional polyalphaolefins of similar molecular weight . high viscosity polyalphaolefins generally exhibit higher film strengths than conventional viscosity polyalphaolefins are generally of higher viscosity than conventional polyalphaolefins of similar molecular weight , but exhibit lower pour points than the corresponding conventional polyalphaolefins . the lower pour point of high viscosity polyalphaolefins makes them suitable for use at lower temperatures than conventional polyalphaolefins . high viscosity polyalphaolefins also exhibit superior oxidative stability than conventional polyalphaolefins . high viscosity polyalphaolefins are characterized by a uniform molecular structure with low branch ratios . the branch ratio is the ratio of methyl (— ch 3 ) to methylene (— ch 2 —) moieties in the molecular structure ). high viscosity polyalphaolefins typically possess a branch ratio of less than about 0 . 19 , while conventional polyalphaolefins branch possess a branch ratio greater than 0 . 2 . the polymerization reaction by which high viscosity polyalphaolefins are formed is generally highly specific , resulting in a low number of isomers formed . the resulting high viscosity polyalphaolefin product oligomers have an atactic molecular structure of mostly head - to - tail attachments , with some head - to - head connections . high viscosity polyalphaolefins generally possess an average molecular weight of from about 300 to about 45 , 000 , a carbon number of from about 30 to 1000 , and a viscosity at 100 ° c . of about 3 to about 5000 cst . the viscosity is typically in the range of about 150 to about 3000 cst at 100 ° c . the branch ratio is typically less than 0 . 19 . a high viscosity polyalphaolefin is marketed under the trade name supersyn ™ by exxon mobil corporation of houston , tex . polyalphaolefin base oils suitable for use in formulations of preferred embodiments include exxon mobil corporation &# 39 ; s spectrasyn ™ line of polyalphaolefin fluid . examples of spectrasyn ™ polyalphaolefin fluid include spectrasyn ™ 100 , spectrasyn ™ 40 , spectrasyn ™ 10 , spectrasyn ™ 8 , spectrasyn ™ 6 , spectrasyn ™ 5 , spectrasyn ™ 4 , spectrasyn ™ 2c , and spectrasyn ™ 2 . the viscosities of the spectrasyn ™ polyalphaolefin fluid vary . for example , spectrasyn ™ 100 and spectrasyn ™ 40 have relatively high viscosities . spectrasyn ™ 100 has a viscosity of 1240 cst at 104 ° f ., and spectrasyn ™ 40 has a viscosity of 396 cst at 104 ° f . spectrasyn ™ 10 , spectrasyn ™ 8 , spectrasyn ™ 6 , spectrasyn ™ 5 , spectrasyn ™ 4 , spectrasyn ™ 2c , and spectrasyn ™ 2 have relatively low viscosities . for example , spectrasyn ™ 10 has a viscosity of 66 cst at 104 ° f ., spectrasyn ™ 2 has a viscosity of 5 cst at 104 ° f ., spectrasyn ™ 2c has a viscosity of 6 . 4 cst at 104 ° f ., spectrasyn ™ 4 has a viscosity of 19 cst at 104 ° f ., spectrasyn ™ 5 has a viscosity of 25 cst at 104 ° f ., spectrasyn ™ 6 has a viscosity of 31 cst at 104 ° f ., and spectrasyn ™ 8 has a viscosity of 48 cst at 104 ° f . the viscosity of the polyalphaolefin can be selected in order to achieve a formulation with desired characteristics . generally , it is preferred to employ a high viscosity polyalphaolefin so as to provide greater structural integrity , weather resistance and stickiness to the repellant formulation . alkylated naphthalene is generally employed as additional base fluid to impart increased thermal and oxidative stability to a grease composition . see , e . g ., u . s . pat . no . 5 , 177 , 284 and u . s . pat . no . 5 , 457 , 254 . mono or poly substituted alkylated naphthalenes can be employed . similar to the alkylated naphthalenes are the polymers of alkyl benzenes , such as dodecylbenzenes , tetradecylbenzenes , dinonylbenzenes , di -( 2 - ethyl - hexyl )- benzenes , and the like . alkylated aromatics are formed by the reaction of olefins or alkyl halides with aromatic compounds , such as benzene . suitable alkylated naphthalenes can be obtained from exxon mobil corporation . alkylated naphthalene fluids suitable for use in formulations of preferred embodiments include exxon mobil corporation &# 39 ; s synesstic ™ line of alkylated naphthalene . examples of synesstic ™ alkylated naphthalene fluids include synesstic ™ 5 and synesstic ™ 12 . synesstic ™ 12 alkylated naphthalene has a viscosity of 109 cst at 104 ° f ., and synesstic ™ 5 alkylated naphthalene has a viscosity of 29 cst at 104 ° f . one preferred class of synthetic fluid bases is that of synthetic polyolefins , particularly hydrogenated polyalphaolefins , although other synthetic polyolefins may be utilized as well . examples of the synthetic hydrocarbon oils which may be utilized as additional synthetic fluid base oils for the formulations of preferred embodiments are preferably saturated . such oils may be prepared by polymerizing unsaturated monomers ( e . g ., ethylene ) and hydrogenating the resulting polymer prior to use to remove any residual unsaturation from the oil . examples of the saturated hydrocarbon and halo - substituted hydrocarbon oils include polyethylenes , polypropylenes , polybutylenes , propylene - isobutylene copolymers , chlorinated polybutylenes , poly ( 1 - hexenes ), poly ( 1 - octenes ), poly ( 1 - decenes ); polyphenyls such as biphenyls , terphenyls , alkylated polyphenyls , and the like ; alkylated diphenyl ethers and alkylated diphenyl sulfides and derivatives , including deuterated and hydrogenated derivatives . the hydrogenated polyolefins derived from alphaolefins such as ethylene , propylene , 1 - butene , and the like are especially preferred for use as additional synthetic base oils . in certain embodiments , however , it may be preferred to use a polyolefin derived from a branched chain monomer , for example , isobutylene . dibasic acid esters can be employed as base oils . polyol esters include molecules containing two or more alcohol moieties , such as trimethylolpropane , neopentylglycol , and pentaerythritol esters . synthetic polyol esters are the reaction product of a fatty acid derived from either animal or plant sources and a synthetic polyol . polyol esters have excellent thermal stability and generally resist hydrolysis and oxidation better than other base stocks . naturally occurring triglycerides and vegetable oils , as discussed above , are in the same chemical family as polyol esters . trimethylolpropane esters may include mono , di , and tri esters . neopentyl glycol esters may include mono and di esters . pentaerythritol esters include mono , di , tri , and tetra esters . dipentaerythritol esters may include up to six ester moieties . preferred esters are typically of those of long chain monobasic fatty acids . esters of c20 or higher acids can be employed , e . g ., gondoic acid , eicosadienoic acid , eicosatrienoic acid , eicosatetraenoic acid , eicosapentanoic acid , arachidic acid , arachidonic acid , behenic acid , erucic acid , docosapentanoic acid , docosahexanoic acid , or ligniceric acid , or esters of c18 or lower acids , e . g ., butyric acid , caproic acid , caprylic acid , capric acid , lauric acid , myristoleic acid , myristic acid , pentadecanoic acid , palmitic acid , palmitoleic acid , hexadecadienoic acid , hexadecatienoic acid , hexadecatetraenoic acid , margaric acid , margroleic acid , stearic acid , linoleic acid , octadecatetraenoic acid , vaccenic acid , or linolenic acid . in certain embodiments , it may be preferred to esterify pentaerythritol with a mixture of different acids . particularly preferred synthetic ester oils are the esters of trimethylol propane , trimethylol butane , trimethylol ethane , pentaerythritol and / or dipentaerythritol with one or more monocarboxylic acids containing from about 5 to 10 carbon atoms . polyol polyesters may be obtained by reacting various polyhydroxy compounds with carboxylic acids . when the carboxylic acids are dicarboxylic acids , monohydroxy compounds can be substituted for the polyols . for example , synthetic esters include the esters of dicarboxylic acids such as phthalic acid , succinic acid , alkyl succinic acid , alkenyl succinic acid , maleic acid , azelaic acid , suberic acid , sebacic acid , fumaric acid , adipic acid , linoleic acid dimer , malonic acid , alkyl malonic acid , alkenyl malonic acid , and the like . these dicarboxylic acids may be reacted with alcohols such as , for example , butanol , hexanol , dodecyl alcohol , 2 - ethylhexyl alcohol , and the like . specific examples of such esters include dibutyl adipate , di ( 2 - ethylhexyl ) sebacate , di - n - hexyl fumarate , dioctyl sebacate , diisooctyl azelate , diisodecyl azelate , dioctyl phthalate , didecyl phthalate , and the like . silicon - based oils including siloxanes , such as polyalkylsiloxane , polyarylsiloxane , polyalkoxysiloxane , and polyaryloxysiloxane oils and silicone oils may also be suitable for use as additional base oils . specific examples of some suitable polysiloxanes include methyl phenyl silicone , methyl tolyl silicone , methyl ethylphenyl silicone , ethyl phenyl silicone , propyl phenyl silicone , butyl phenyl silicone , and hexyl propylphenyl silicone . preferred silicon - based oils also include silicones such as alkyl phenyl silicones . preferred alkyl groups for alkyl phenyl silicones include aliphatic groups , e . g ., methyl , propyl , pentyl , hexyl , decyl , and the like ; alicyclic groups , e . g ., cyclohexyl , cyclopentyl , and the like ; aryl groups , e . g ., phenyl , naphthyl , and the like ; aralkyl groups ; and alkaryl groups , e . g ., tolyl , xylyl , and the like ; and halogenated , oxygen - containing , and nitrogen - containing organyl groups such as halogenated aryl groups , alkyl and aryl ether groups , aliphatic ester groups , organic acid groups , cyanoalkyl groups , and the like . the alkyl groups preferably contain from 1 to about 30 carbon atoms . alkyl phenyl silicones are particularly preferred . alkyl phenyl silicones are particularly preferred , especially those having a viscosity of from about 20 , 25 , 50 , 75 , 100 , 125 , or 150 cst to about 200 , 250 , 500 , 750 , 1000 , 1250 , 1500 , 1750 , or 2000 cst at 25 ° c . particularly preferred base oils for use in formulations of preferred embodiments include dow corning ® brand silicone fluids . silicone fluids from dow corning are high - performance , liquid lubricating materials that demonstrate excellent performance over a wide temperature range . dow corning ® 200 fluid , a dimethyl silicone fluid , is available in a range of viscosities ( 10 cst or lower to 1 , 000 cst or higher ). dow corning ® 510 fluid , a phenyl methyl silicone fluid , is available in 50 cst or lower to 30 , 000 cst or higher viscosities . it functions over a wide range of ambient temperatures ( from − 51 ° c . to 204 ° c .). dow corning ® 550 fluid is a 125 cs phenyl methyl silicone fluid . it resists oxidation and has a wide service temperature range ( from − 40 ° c . to 232 ° c .). dow corning ® 710 fluid is a 500 cs phenyl methyl silicone fluid with excellent heat stability and resistance to evaporation and oxidation , and functions over a wide temperature range ( from − 18 ° c . to 260 ° c .). dow corning ® fs - 1265 fluid is a fluorosilicon fluid with a viscosity of from 300 cst or less to 10 , 000 cst or more . it resists oxidation , harsh chemicals , fuels , and high temperatures , and functions over a temperature range of from − 40 ° c . to 204 ° c .). particularly preferred white , off - white , and translucent white base oils for use in formulations of preferred embodiments include dow corning ® brand silicone fluids . dow corning ® brand silicone fluids are available in light to heavy consistencies . for example , dow corning ® 7 release compound is a white - translucent light consistency dimethyl silicone compound with a service temperature range of − 40 ° c . to 204 ° c . and a specific gravity at 25 ° c . of 1 . 0 . dow corning ® 4 electrical insulating compound is a white - translucent medium consistency dimethyl silicone compound with a service temperature range of − 57 ° c . to 204 ° c . and a specific gravity at 25 ° c . of 1 . 0 . dow corning ® 111 valve lubricant and sealant is a white - translucent heavy consistency dimethyl silicone compound with a service temperature range of − 40 ° c . to 204 ° c . and a specific gravity at 25 ° c . of 1 . 0 . the fda has permitted dow corning ® 4 and 7 electrical insulating compounds and dow corning ® 111 valve lubricant and sealant for food contact and they are listed under nsf standard 51 for food processing , and nsf 51 for potable water applications . another white , off - white , or translucent white base oil for use in formulations of preferred embodiments is dow corning ® 112 high performance lube / sealant . dow corning ® 112 sealant is a white - translucent stiff grease - like silicone compound containing an inert amorphous silica filler in combination with selected polydimethyl silicone fluids . dow corning ® 112 has a specific gravity at 25 ° c . of 1 . 1 . serviceability from − 40 ° c . to 232 ° c ., excellent water and oil resistance , good resistance to most chemicals , and low volatility . instead of or in addition to a base oil , a grease can be employed in formulations of preferred embodiment . such greases typically comprise a base oil and a thickener . particularly preferred greases are designated as suitable for food contact or processing , or potable water applications . dow corning &# 39 ; s ® molycote ® bg 20 high performance synthetic grease is an example of a grease that can be used instead of or in addition to a base oil in formulations of preferred embodiments . molycote ® bg 20 high performance synthetic grease is a beige synthetic polyolester grease with lithium complex thickener . molycote ® bg 20 &# 39 ; s properties include a wide temperature range if − 45 ° c . to 182 ° c . polyethers suitable for use as base oils may include polyphenyl ether fluids , preferably those containing from 3 to 7 benzene rings and from 2 to 6 oxygen atoms , wherein the oxygen atoms link the benzene rings , which may be hydrocarbyl - substituted . the hydrocarbyl substituents are preferably free of unsaturated hydrocarbon groups . the preferred aliphatic substituents include saturated hydrocarbon groups containing from 1 to 6 carbon atoms , such as ethyl , propyl , butyl , and t - butyl groups . preferred aromatic substituents include aryl groups such as phenyl , tolyl , t - butyl phenyl , and alphacumyl . polyphenyl ethers consisting exclusively of chains of from 3 to 7 benzene rings with at least two oxygen atom joining the benzene rings exhibit superior thermal stability , for example , the polyphenyl ethers such as 1 -( p - methylphenoxy )- 4 - phenoxy benzene and 2 , 4 - diphenoxy - 1 - methyl benzene ; 4 - ring polyphenyl ethers such as bis [ p -( p - methylphenoxy ) phenyl ] ether and bis [ p -( p - t - butylphenoxy ) phenyl ] ether , and the like . polyalkylene glycols ( also referred to as polyalkylene oxides ) are polymers of alkylene oxides . polyalkylene oxides and derivatives thereof wherein the terminal hydroxyl groups have been modified by esterification , etherification , and the like , also constitute a class of synthetic lubricating oils that can be utilized as a component of the base oil . these oils include those prepared through polymerization of ethylene oxide and propylene oxide , the alkyl and aryl ethers of these polyoxyalkylene polymers such as methyl polyisopropylene glycol ether having an average molecular weight of about 1000 , diphenyl ether of polyethylene glycol having a molecular weight of about 500 to 1000 , and diethyl ether of polypropylene glycol having a molecular weight of about 1000 to about 1500 . polyalkylene glycols suitable for use in formulations of preferred embodiments include plurasafe ® brand silicone fluids from basf . the base fluid may contain as its sole component a single base oil or a mixture of two or more base oils ( e . g ., of different chemical compositions or same category but different characteristics , e . g ., different viscosities , viscosity indexes , molecular weights , produced by different manufacturing processes , and the like ). in certain embodiments , however , it may be preferred to combine one or more high viscosity polyalphaolefins with one or more other mineral or synthetic base fluids . the base oil ( s ) and / or base fluid ( s ) typically comprise from about 70 wt . % or less to about 95 wt . % or more of the repellent formulation , preferably from about 75 wt . % to about 90 wt . % of the repellent formulation . the base oil is thickened into a grease base by addition of a thickener . thickener systems that can be advantageously employed include fumed silica , hydrophobic fumed silica , modified clay , dye and pigment thickeners , thickeners such as carbon black , graphite , polytetrafluoroethylene ( ptfe ), polyurea , and the like . the thickener can be added to the base oil using methods conventionally employed for preparing greases . generally , a base oil is provided , or a blend of base oils is prepared , and then the thickener is added to the base oil with mixing . silica gel is advantageously employed as it can increase the adhesiveness of the composition , thereby increasing the time of contact between the composition and the target rodent . silica gel is a granular , vitreous , highly porous form of silica . silica gel is commonly employed as a food grade desiccant . fumed silica , also known as pyrogenic silica , is a non - crystalline , fine - grain , low density and high surface area silica . fumed silica has a very strong thickening effect . primary particle size is 5 - 50 nm . the particles are non - porous and have a surface of 50 - 600 m 2 / g . density 2 . 2 g / cm 3 . fumed silica is made from flame pyrolysis of silicon tetrachloride or from quartz sand vaporized in a 3000 ° c . electric arc . fumed silica serves as a universal thickening agent , a thickener in milkshakes , and an anticaking agent in powdered foods . like silica gel , it serves as a desiccant . hydrophobic silica is a silica that has hydrophobic groups chemically bonded to the surface . hydrophobic silica can be made both from fumed and precipitated silica . the hydrophobic groups are normally alkyl or polydimethylsiloxane chains . the toxicological properties of silicas make them desirable thickening agents for the grease bases of preferred embodiments . fumed silicas suitable for use in formulations of preferred embodiments include aerosil 972 ™ manufactured by degussa corporation of orange , calif . or cabosil ts720 ™ manufactured by cabot corporation of boston , mass . aerosil 972 ™ is a hydrophobic fumed silica after treated with dimethyldichlorosilane . aerosil 972 ™ has a specific surface area of about 110 ± 20 m 2 / g , an approximate tamped density of about 50 g / l , and an average primary particle size of about 16 nm . it is preferable that when using aerosil 972 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. cabosil ts720 ™ is an insoluble white powder having a density of 2 . 2 g / cm 3 at 20 ° c . it is preferable that when using cabosil ts720 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. soap thickeners prepared by combining one or more fatty acids with one or more metal metal - containing components , e . g ., alkali or alkaline earth metal hydroxides , oxide and / or isopropoxides can also be advantageously employed as low cost , low toxicity additives . when a soap thickener is employed , the soap itself can be added to the base oil , or the reactants yielding the soap can be added separately to the base oil and allowed to react . in certain embodiments it can be desirable to alter the mixing process and / or parameters , or the sequence of addition of components , as is appreciated by one skilled in the art . for example , the reactants yielding the soap may be added separately to different base oil components , or different portions of the base oil blend , then the partially additized blend components may be mixed . when reactants yielding soap are employed , the reactants are typically added to the base oil blend , and the mixture is heated to saponify the grease . after the saponification reaction reaches a sufficient degree of completion , the grease is allowed to cool and the remaining additives are incorporated into the grease . preferred metal containing components include alkaline earth metal hydroxides , such as calcium hydroxide , which exhibits good water resistance . preferred fatty acids generally include those obtained from vegetable sources which contain from 10 to 22 carbon atoms . a single fatty acid or two or more fatty acids can be employed . fatty acids containing 18 carbon atoms are particularly preferred , especially stearic acid or 12 - hydroxy stearic acid ; however , other fatty acids can advantageously be employed , including but not limited to gondoic acid , eicosadienoic acid , eicosatrienoic acid , eicosatetraenoic acid , eicosapentanoic acid , arachidic acid , arachidonic acid , behenic acid , erucic acid , docosapentanoic acid , docosahexanoic acid , ligniceric acid , butyric acid , caproic acid , caprylic acid , capric acid , lauric acid , myristoleic acid , myristic acid , pentadecanoic acid , palmitic acid , palmitoleic acid , hexadecadienoic acid , hexadecatienoic acid , hexadecatetraenoic acid , margaric acid , margroleic acid , stearic acid , linoleic acid , octadecatetraenoic acid , vaccenic acid , and linolenic acid . one or more or more additional fatty acids may be employed to provide a more complex structure to the grease with increased cross - linking . although , higher molecular weight acids can provide additional lubricity to the grease , they are generally inferior as additional complexing acids . accordingly , one or more lower molecular weight fatty acids are used , preferably fatty acids containing from 2 to 10 carbon atoms , so as to provide greater cross - linking . especially preferred is acetic acid . to form the grease , the preferred alkaline earth ( e . g ., calcium ) oxide or hydroxide is added to the base oil blend . then , the fatty acids are added . the saponification reaction occurs upon heating the metal and fatty acids to a suitable temperature , typically about 175 ° c . the elevated temperature is then maintained , e . g ., for about 20 minutes or until the reaction proceeds to a satisfactory degree of completion . the mixture is preferably stirred , either continuously or intermittently , during heating . after the resulting soap - containing mixture is cooled , the remaining additives are added . the preferred metal complex soap thickener is a calcium complex in which the fatty acid complex is formed by the reaction of calcium hydroxide with several organic acids including acetic acid and 12 - hydroxystearic acid . the thickener ( s ) typically comprise from about 3 wt . % or less to 20 wt . % or more of the repellent formulation , preferably from about 4 wt . % to about 15 wt . % of the repellent formulation . the base greases of preferred embodiments may contain various polymers which function as tackifying agents . the addition of polymers may add to the viscosity and also to the adhesive qualities of the composition so that the composition can be applied to both horizontal and vertical surfaces . the ability to apply the composition to vertical surfaces enhances its utility because this increases the potential number of surfaces on which the composition may be used . useful tackifying agents include polymers like polybutene , polybutylene ( e . g ., polyisobutylene ), olefin copolymers , methacrylates , polyalphaolefins , and ethylene / propylene copolymers . food grade tackifiers are particularly preferred . tackifiers are generally provided in a suitable carrier , e . g ., paraffinic oil , naphthenic oil , while oil , or polyalphaolefin , and can include polyisobutylene in white mineral oil and have a viscosity of , e . g ., 2500 cst @ 100 ° c . or more ( e . g ., 3000 or 4000 cst @ 100 ° c .). the tackifier ( s ) typically comprise from about 2 . 0 wt . % or less to 20 wt . % or more of the repellent formulation , preferably from about 3 wt . % to about 15 wt . % of the repellent formulation . other additives as are known in the lubricating arts may also be employed in the base greases of preferred embodiments . these include metal deactivators such as benzotriazole , substituted benzotriazole and 2 , 5 - di - mercapto - 1 , 3 , 4 - thiodiazole , which protect ferrous and nonferrous metal surfaces from corrosion . the base grease can also include conventional fillers , thickeners , thixotropic agents , antioxidants , corrosion prevention materials , and the like , depending upon the surface to which the repellent formulation is to be applied . solid lubricant components can be added at any suitable step in the grease manufacturing process , for example , when the thickener is added if the thickener is not a metal soap type which is formed by a chemical reaction in the oil . solid additives are preferably added to the grease with sufficient mixing , working , homogenizing , or the like , to ensure a complete , uniform , and thorough dispersion of solid particles . preferably , solid lubricants are added to the grease after the thickener is formed or added . various compounds known for use as oxidation inhibitors can be utilized in grease formulations of various embodiments . these include phenolic antioxidants , amine antioxidants , sulfurized phenolic compounds , and organic phosphites , among others . is it especially preferred that the antioxidant includes predominately or entirely either a hindered phenol antioxidant such as 2 , 6 - di - tert - butylphenol , 4 - methyl - 2 , 6 - di - tert - butylphenol , 2 , 4 - dimethyl - 6 - tert - butylphenol , 4 , 4 ′- methylenebis ( 2 , 6 - di - tert - butylphenol ), and mixed methylene bridged polyalkyl phenols , or an aromatic amine antioxidant such as the cycloalkyl - di - lower alkyl amines ( n , n ′- di - lower - alkyl phenylenediamines , such as n , n ′- di - sec - butyl - p - phenylenediamine , and its analogs ), and phenylenediamines , or a combination of one or more such phenolic antioxidants with one or more such amine antioxidants . a variety of corrosion inhibitors are also available for use in the grease formulations of various embodiments , including dimer and trimer acids , such as are produced from tall oil fatty acids , oleic acid , linoleic acid , and the like . other useful types of corrosion inhibitors are the alkenyl succinic acid and alkenyl succinic anhydride corrosion inhibitors such as , for example , tetrapropenylsuccinic acid , tetrapropenylsuccinic anhydride , tetradecenylsuccinic acid , tetradecenylsuccinic anhydride , hexadecenylsuccinic acid , hexadecenylsuccinic anhydride , and the like . also useful are the half esters of alkenyl succinic acids having 8 to 24 carbon atoms in the alkenyl group with alcohols such as the polyglycols . also useful are the aminosuccinic acids or derivatives . preferably a dialkyl ester of an aminosuccinic acid is used containing an alkyl group containing 15 - 20 carbon atoms or an acyl group which is derived from a saturated or unsaturated carboxylic acid containing 2 - 10 carbon atoms . most preferred is a dialkylester of an aminosuccinic acid . the various additives that can be included in the base greases of preferred embodiments are used in conventional amounts as are known in the grease industry . the amounts used in any particular case are preferably sufficient to provide the desired functional property to the grease composition , and such amounts are well known to those skilled in the art . the repellent formulations of preferred embodiments typically include a carrier agent , an activator agent , a repellent , a thickener , and a tackifying agent , as described above . in some embodiments , the activator agent , the carrier agent , and / or the tackifying agent may be omitted from the composition . preferably , the repellent formulation utilizes a white oil . white oils include any of various highly refined , colorless mineral or hydrocarbon oils of low volatility and a wide range of viscosities . they are typically used for lubrication of food and textile machinery and as medicinal and mineral oils . white oils include technical white oils such as usp or technical grade white oil , and can be used as a carrier agent / base oil in formulations of preferred embodiments . in such embodiments , the white oil is typically present at from about 78 . 0 to 88 . 0 wt . % in the formulation , and more desirably at about 83 . 9 wt . %. in other embodiments , white oil is desirably present at about 82 . 9 wt . % in the formulation . the repellent formulation preferably utilizes fumed silica , such as aerosil 972 ™ manufactured by degussa corporation of orange , calif . or cabosil ts720 ™ manufactured by cabot corporation of boston , mass . when using aerosil 972 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. when using cabosil ts720 ™, it is preferably present in the repellent formulation at from about 5 . 0 to 12 . 0 wt . %, and more desirably at about 10 . 0 wt . %. the repellent composition preferably includes one or more tackifying polymers , preferably an olefin copolymer , polybutene , polyalphaolefin , or polymethacrylate of suitable viscosity . the tackifying agent is preferably present in the formulation in total at from 5 . 0 to 10 . 0 wt . %, and more desirably at about 5 . 0 wt . %. the repellent composition preferably includes an activator agent such as denatured ethanol . when using denatured ethanol , it is preferably present in the formulation in total at from 1 . 0 to 2 . 0 wt . %, and more desirably at about 1 . 0 part by weight . the repellent additive in the repellent composition is preferably natural capsaicin . when using natural capsaicin , it is preferably present in the formulation in total at from 0 . 025 to 1 . 00 wt . %, and more desirably at about 0 . 075 wt . %. preferably , the repellent compositions of preferred embodiments contain no menthol , peppermint oil , citronella , or other components that repel rodents by emitting an odor that rodents find offensive . the repellent composition may preferably include one or more tackifying polymers , preferably an olefin copolymer , polybutene , polyalphaolefin , or polymethacrylate of suitable viscosity . in some embodiments , the repellent formulation utilizes two different tackifiers , preferably polyalphaolefin and an olefin copolymer . in such a preferred embodiment , the tackifiers are preferably present in the formulation in total at from about 0 . 05 wt . % to about 10 . 0 wt . %. more preferably polyalphaolefin is present in the formulation at about 5 . 0 wt . % and an olefin copolymer is present in the formulation at about 1 . 0 wt . %. in preferred embodiments where polyalphaolefin is present in the formulation at about 5 . 0 wt . % and an olefin copolymer is present in the formulation at about 1 . 0 wt . %, the white oil is preferably present at about 82 . 9 wt . %. although the repellent compositions of preferred embodiments can be made by various methods as will be appreciated by one of skill in the art , the following is an exemplary method for use in preparing a repellent composition of a preferred embodiment comprising technical grade white oil , denatured ethanol , fumed silica , tackifying polymer , and capsaicin . in a first step , the full amount of technical grade white oil is added to a mixer . in a next step , denatured ethanol and fumed silica are sequentially or concurrently added to the white oil while mixing . next , the mixture is heated up to about 120 ° f . ( 49 ° c .). the mixture is maintained at this temperature while mixing until the fumed silica is completely or nearly completely dispersed and the mixture clear . thereafter , the polymer tackifier is added while mixing and maintaining the mixture at about 120 ° f . ( 49 ° c .). mixing at about 120 ° f . ( 49 ° c .) is continued until the polymer is completely or nearly completely dissolved and the mixed product is clear . then , the capsaicin is completely mixed in , and the product is cooled down to about 120 ° f . ( 27 ° c .). the repellent composition thus prepared is stable at ambient temperatures in environments supporting rodents . the examples below list different exemplary formulations for the rodent deterrent composition of preferred embodiments . in the examples below , the column “ component ” lists exemplary ingredients for the composition , the column “ mass %” lists desirable parts by weight of the ingredients in the composition and the column “ range mass %” lists exemplary parts by weight of the ingredients . the asterisk “*” indicates that the base oil component is added to bring the total mass % up to 100 %, after the other ingredients are accounted for . the repellent compositions of preferred compositions can be applied to surfaces using similar techniques to application of caulk . a line , bead , or strip of the repellent composition is applied to a surface in an area where rodents are to be repelled . when a rodent contacts the repellent composition , e . g ., by stepping on it , the repellent composition is transferred to the rodent &# 39 ; s paw . when the rodent attempts to remove the repellent composition , e . g ., by eating it off , the repellent additive in the repellent composition produces an unpleasant taste , thereby discouraging the rodent from contacting the repellent composition again ( e . g ., attempting to cross a strip of the repellent composition ). the repellent compositions of preferred embodiments can offer numerous advantages over conventional repellent compositions . the repellent compositions of preferred embodiments can be odor free or low odor , enabling them to be employed in areas such as restaurants , stores , and homes where odors would otherwise be offensive or unacceptable . the repellent compositions of preferred embodiments are non - toxic and environmentally friendly , making them acceptable for use near soil or water sources ( rivers , streams , canals , water features , ground water , etc . ), or areas inhabited by children , pets ( e . g ., dogs , cats ) or non - pest native species ( e . g ., native birds , mammals , reptiles , amphibians , fish ). the repellent compositions of preferred embodiments are tacky , enabling them to remain in place when applied to non - horizontal surfaces ( e . g ., slanting , vertical , or inverted ), and to persist on rodents &# 39 ; paws when contacted , which increases the repellent effect when the rodents groom themselves to remove the repellent composition . the repellent compositions of preferred embodiments are also water resistant , such that they can remain in place and retain their repellency when exposed to the elements ( rain , snow ). the repellent compositions of preferred embodiments are stable and maintain good viscosity / tackiness when exposed to hot or cold ambient conditions . all references cited herein are incorporated herein by reference in their entirety . to the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification , the specification is intended to supersede and / or take precedence over any such contradictory material . unless otherwise defined , all terms ( including technical and scientific terms ) are to be given their ordinary and customary meaning to a person of ordinary skill in the art , and are not to be limited to a special or customized meaning unless expressly so defined herein . terms and phrases used in this application , and variations thereof , especially in the appended claims , unless otherwise expressly stated , should be construed as open ended as opposed to limiting . as examples of the foregoing , the term ‘ including ’ should be read to mean ‘ including , without limitation ,’ ‘ including but not limited to ,’ or the like ; the term ‘ comprising ’ as used herein is synonymous with ‘ including ,’ ‘ containing ,’ or ‘ characterized by ,’ and is inclusive or open - ended and does not exclude additional , unrecited elements or method steps ; the term ‘ having ’ should be interpreted as ‘ having at least ;’ the term ‘ includes ’ should be interpreted as ‘ includes but is not limited to ;’ the term ‘ example ’ is used to provide exemplary instances of the item in discussion , not an exhaustive or limiting list thereof ; adjectives such as ‘ known ’, ‘ normal ’, ‘ standard ’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time , but instead should be read to encompass known , normal , or standard technologies that may be available or known now or at any time in the future ; and use of terms like ‘ preferably ,’ ‘ preferred ,’ ‘ desired ,’ or ‘ desirable ,’ and words of similar meaning should not be understood as implying that certain features are critical , essential , or even important to the structure or function of the invention , but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention . likewise , a group of items linked with the conjunction ‘ and ’ should not be read as requiring that each and every one of those items be present in the grouping , but rather should be read as ‘ and / or ’ unless expressly stated otherwise . similarly , a group of items linked with the conjunction ‘ or ’ should not be read as requiring mutual exclusivity among that group , but rather should be read as ‘ and / or ’ unless expressly stated otherwise . with respect to the use of substantially any plural and / or singular terms herein , those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application . the various singular / plural permutations may be expressly set forth herein for sake of clarity . it will be further understood by those within the art that if a specific number of an introduced claim recitation is intended , such an intent will be explicitly recited in the claim , and in the absence of such recitation no such intent is present . for example , as an aid to understanding , the following appended claims may contain usage of the introductory phrases “ at least one ” and “ one or more ” to introduce claim recitations . however , the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “ a ” or “ an ” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation , even when the same claim includes the introductory phrases “ one or more ” or “ at least one ” and indefinite articles such as “ a ” or “ an ” ( e . g ., “ a ” and / or “ an ” should typically be interpreted to mean “ at least one ” or “ one or more ”); the same holds true for the use of definite articles used to introduce claim recitations . in addition , even if a specific number of an introduced claim recitation is explicitly recited , those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number ( e . g ., the bare recitation of “ two recitations ,” without other modifiers , typically means at least two recitations , or two or more recitations ). furthermore , in those instances where a convention analogous to “ at least one of a , b , and c , etc .” is used , in general such a construction is intended in the sense one having skill in the art would understand the convention ( e . g ., “ a system having at least one of a , b , and c ” would include but not be limited to systems that have a alone , b alone , c alone , a and b together , a and c together , b and c together , and / or a , b , and c together , etc .). in those instances where a convention analogous to “ at least one of a , b , or c , etc .” is used , in general such a construction is intended in the sense one having skill in the art would understand the convention ( e . g ., “ a system having at least one of a , b , or c ” would include but not be limited to systems that have a alone , b alone , c alone , a and b together , a and c together , b and c together , and / or a , b , and c together , etc .). it will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms , whether in the description , claims , or drawings , should be understood to contemplate the possibilities of including one of the terms , either of the terms , or both terms . for example , the phrase “ a or b ” will be understood to include the possibilities of “ a ” or “ b ” or “ a and b .” all numbers expressing quantities of ingredients , reaction conditions , and so forth used in the specification are to be understood as being modified in all instances by the term ‘ about .’ accordingly , unless indicated to the contrary , the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained . at the very least , and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application , each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches . furthermore , although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding , it is apparent to those skilled in the art that certain changes and modifications may be practiced . therefore , the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein , but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention . | US-201414567223-A |
a portable hand - held spirometer capable of being accommodated in a pocket or handbag , comprising a chassis , an enclosed curved passageway in communication with the chassis including an inlet , for receiving the forced expiration of the user , and an outlet , through which the expiration may be exhausted , a vane pivotally mounted in the passageway , between the inlet and the outlet , for moving under the influence of the user &# 39 ; s forced expiration from a first position closing off the passageway to a succession of other open positions forming an ever widening gap between the vane and part of the passageway as the vane moves therethrough , a bottom cover for incrementally measuring various positions of the vane , throughout its travel as a function of time , a device to convert the measurements to various diagnostic parameters applicable to the user &# 39 ; s lung condition , and a device to report the values . | turning now to the drawings wherein like elements are identified with like numerals throughout the six figures , fig1 and 3 show the spirometer 1 of this invention to have a chassis 3 comprising a broad top plate 5 defined by a straight front edge 7 and a u - shaped edge 9 extending rearward from the terminal ends thereof . a front surface 11 depends from front edge 7 a short distance to form the front wall of the spirometer . a closable battery box 13 is nested behind front wall 11 and under top plate 5 which will hereinafter be more fully explained . an aperture 15 is formed in front wall 11 preferably to one side thereof forming the opening to a bore 17 that extends rearward therefrom and interior said spirometer . a short tube 19 either of disposable cardboard or reusable plastic is provided for insertion in bore 17 to facilitate blowing into the spirometer . a small door 21 is slidably received in front wall 11 and arranged to be moved by a handle or projection 23 back and forth to facilitate covering and uncovering aperture 15 as desired as a guard to keep foreign matter out of the interior of the spirometer when it is not in use . a bottom cover 25 is provided for attachment about chassis edge 9 , the spaced - apart sides 27a and 27b and bottom edge 29 of front wall 11 . cover 25 extends rearward from bottom edge 29 to an upwardly extending u - shaped rear wall 31 then upwardly to join with u - shaped chassis rear edge 9 . bottom cover 25 thus forms along with chassis plate 5 a curved passageway 33 , of general rectangular cross - section , interior of the spirometer . a series of apertures 35 are formed in bottom cover 25 and closely spaced together , preferably on the opposite side of cover 25 from where aperture 15 is located in front wall 11 to provide an outlet as will be more fully explained . a vane 37 is pivotally mounted in passageway 33 , preferably on the inside radius of the curvature thereof . vane 37 is defined by a flat plate 39 , reinforced with cross - ribs 41 , extending outward from a pivotal edge 43 to an outer edge 45 and joined together through spaced - apart top and bottom edges 47a and 47b , respectively . vane 37 is arranged to swing from a first position 49 at the inner end 51 of bore 17 and across passageway 33 through a succession of other positions further into curved passageway 33 , urged therethrough by the forced expiration of the user &# 39 ; s breath into bore 17 . top and bottom vane edges 47a and 47b are arranged to swing in the arch in close proximity with the under surface of top plate 5 and the top surface of bottom cover 25 that formed the top and bottom of passageway 33 . the term &# 34 ; close proximity &# 34 ; is meant to indicate a gap therebetween of a few thousandths of an inch . the outer edge 45 of vane 37 is made straight and aligned such that it too moves into close contact , i . e . a few thousandths of an inch , with the inside surface of cover rear wall 31 when vane 37 is in its first position at the inner end 51 of bore 17 . preferably , curved passageway 33 is of a fixed radius and vane 37 is mounted off - center from the center of curvature thereof by a shaft 53 built into or made a part of vane pivotal edge 43 . van shaft 53 extends upward through an aperture 55 formed in chassis plate 5 and extends downward into a short cylinder 57 formed on chassis 3 . as vane 37 pivots about pivotal edge 43 away from inner bore end 51 or first position 49 , there is created an ever - increasing gap 59 , shown in dotted line in fig3 between vane outer edge 45 and the inside surface of rear wall 31 thereby allowing more and more forced air to pass through passageway 33 and out exhaust apertures 35 . this construction allows spirometer 1 to sense flows of air from a minimum of about 2 liters per minute to a maximum of about 800 liters per minute and therefore covers a far wider range of air flows than is currently possible with existing portable units . this renders spirometer 1 usable by a wide range of individuals whose lung size may vary such as from a small child through large adults to the elderly . a first means 61 is provided for rapidly and accurately measuring the incremental change of positions of vane 37 as it rotates through its arch in air passage 33 under the positive pressure of the forced expiration of air by the user blown into aperture 15 and out exhaust apertures 35 . it is through these rapid incremental measurements over time of the different positions of vane 37 , that fvc , pef , fev , and other particular lung function parameters are calculated . as shown more particularly in fig1 and 6 , first means 61 includes a cam lobe 63 attached to vane shaft 53 and preferably mounted such that the plane of the cam lobe is perpendicular or normal to the axis of pivotal edge 43 . cam lobe 63 is attached to vane pivotal edge 43 by shaft 53 so that it is rotated by the pivotal movement of vane 37 . a sensor arm 65 is pivotally mounted at one end 67 and extends toward cam lobe 63 . a cam following surface 69 is formed on sensor arm 65 and adapted to contact cam lobe 63 for movement there against . a small permanent magnet 71 is attached to sensor arm 65 . a hall effect device 73 is mounted independently of permanent magnet 71 , preferably on a circuit board 75 that is mounted atop and parallel to chassis plate 5 and is positioned near magnet 71 so as to measure the magnetic flux variations generated by the movement of magnet 71 . as shown in fig1 and 6 , as vane 37 is rotated by the forced expiration of air traveling through passageway 33 , cam lobe 63 is caused to rotate and shifts the position of sensor arm 65 so as to move magnet 71 closer to or further away from hall effect device 73 . such movement causes a change in the magnetic lines of flux entering hall effect device 73 and generates analog data through a position detector 76 as to the position of vane 37 and any particular point in air passageway 33 . a second means 77 is provided to convert the analog data generated by detector 7 through relative movement between hall effect device 73 and magnet 71 into digital data for determining the various diagnostic parameters applicable to the user &# 39 ; s lung condition as determined by the forced expiration into spirometer 1 to move vane 37 . as shown in fig6 second means 77 includes a microprocessor 79 connected as is already known in the art and including an analog - to - digital converter 81 and a clock 83 to provide a plurality of time segments over which the analog measurements may be made to create the digital information . it is preferred that clock 83 be arranged to provide a multiplicity of time units , such as 150 separate time frames per second , in which vane 37 would be measured as to its position in passageway 33 throughout the forced expiration by the user . such information , gathered in light of the ever - widening gap 59 created during the forced expiration by the user , may be readily converted to digital information that can be computed , based upon known parameters already inputted to a memory unit 85 of microprocessor 79 to compute the forced vital capacity ( fvc ), the forced expired volume during the first second ( fev 1 ), the peak expiratory flow ( pef ), fev 1 as a fraction of fvc expressed as a percentage , and fev 25 - 75 . a third means , such as a display drive 87 , for displaying the data , such as a liquid crystal display 89 is provided and preferably mounted on circuit board 75 . a fourth means 91 , shown in fig3 is provided along with vane 37 to render an adjustable bias to vane 37 in either direction . one embodiment of fourth means 91 is shown in fig2 to include a coil spring 93 , positioned near vane pivotal edge 43 wherein one end of coil spring 93 is attached to vane shaft 53 and the other end attached to a cap 97 that fits tightly by friction down into cylinder 57 . a small slot 99 is formed in cap 97 to receive the blade of a standard screwdriver to twist or reposition cap 97 and spring 93 one way or the other to increase or decrease the bias on vane 37 . this is useful in calibrating the spirometer . a fifth means 101 , shown in fig4 is also provided , preferably in the form of a spring 103 bearing against sensor arm 65 near its pivotal mounting 67 to bias sensor arm 65 against cam lobe 63 to effect more accurate movement of permanent magnet 71 through the rotation of cam lobe 63 . a top cover 105 is provided for positioning over circuit board 75 , fastened thereto with screws 106 , and , along with front wall 11 and bottom cover 25 , enclosing spirometer 1 . a window 107 is formed in top cover 105 over liquid crystal display 89 through which one may observe the readouts as they occur . a tactile button start and sequence switch 109 is provided to be pressed to start a testing sequence . various user friendly directions are programmed to appear in display 89 such as &# 34 ; please blow &# 34 ;, &# 34 ; ready &# 34 ;, &# 34 ; blow again &# 34 ; or a symbol denoting low battery or other such information . the results of the test are preferably programmed to appear on liquid crystal display 89 in a sequence of readings that each remain on the display for approximately five seconds . advancing the readout of the aforesaid calculations can be accomplished more rapidly by pressing switch 109 . holding the switch down for longer than five seconds will re - set the device for another blow . as the readouts are made to appear in display 89 , they are also recorded in memory unit 85 for later viewing or transfer via a modem to the physician &# 39 ; s office for analysis . as shown in fig3 and 6 , a dip switch ( dual in - line package switch ) 111 is preferably located under bottom cover 25 for use by the physician or other monitoring person to select specific lung parameters that are to be viewed . chassis 3 , top plate 5 , front wall 11 , bottom cover 25 , top cover 105 and many of the various components therein are most conveniently made from plastics , both for light weight and for ease of manufacturing . battery box 13 holds one or a plurality of batteries to power the computer and other electronic hardware . bottom cover 25 is preferably made removable from chassis 3 for ease in changing the batteries , cleaning the air passageways , and selecting various positions in dip switch 111 to isolate certain parameters apart from one another . the spirometer is prepared for use by using tactile button 109 , inserting air tube 19 in bore 17 , and blowing in one continuous blow into tube 19 . the forced air will move vane 37 from its first position across passageway 33 , near the inner end of bore 17 , through an arch about its pivot shaft 53 and through a succession of other open positions while forming ever - widening gap 59 . the air is exhausted through exhaust apertures 85 while second means 77 measures the changing positions of vane 37 . third means 87 converts the analog data to digital data that is displayed on liquid crystal display 89 . while the invention has been described with reference to a particular embodiment thereof , those skilled in the art will be able to make various modifications to the described embodiment of the invention without departing from the true spirit and scope thereof . it is intended that all combinations of elements and steps which perform substantially the same function in substantially the way to achieve substantially the same result are within the scope of this invention . | US-82971792-A |
an intra - oral cavity device for preventing contact between upper and lower teeth of an anesthetized patient . the device includes an elongate pillow that when gripped between the teeth of a patient , prevents contact between the teeth and / or gums and thereby prevents damage to the teeth and / or gums . the pillow may be made of a fibrous , porous and / or absorbent material . the device is adapted for single use and thus disposal after use by a patient . a method of the use of performing surgery using such a device is also provided . | as illustrated in fig1 and 2 , a surgical patient , such as a human , has an oral cavity 5 in which is placed one or more cushion devices . during surgical procedures , a tube 7 , e . g ., an endotracheal tube or lma , may be inserted into the oral cavity to provide gas for the surgical patient or for other purposes . gas is supplied from a source 8 of gas such as a pressurized tank or a pump . the oral cavity 5 includes teeth projecting from gums 10 with the teeth including front teeth designated generally 11 and molars designated generally 12 . the teeth 11 and 12 are in both the upper ( maxilla ) and lower ( mandible ) jaws 14 and 15 respectively . it is to be noted that some patients may not have teeth or only a few teeth or false teeth and therefore , as used herein and in the claims , between the gums means between the upper and lower teeth , where and if present , and / or gums unless otherwise indicated . even though a portion of the device 3 may be between teeth , it is also between the gums . false teeth are usually removed from a patient prior to being anesthetized . as best seen in fig1 and 2 , an intra - oral device 3 that includes a pillow 21 that is shown in detail in fig3 , is positioned between the upper and lower - jaws 14 and 15 on at least one side of the mouth or one on each side of the mouth , to be retained between the upper and lower gums along the side gums and if the patient has teeth , between the upper and lower rear teeth 12 . as seen in fig3 , an intra - oral cavity cushion device 3 is provided . the device 3 includes a pillow 21 , a finger tab 24 and means designated generally 26 for maintaining the pillow as a monolithic structure during storage , use and removal . in the form of the invention shown in fig3 , the pillow 21 is comprised of a fibrous and / or porous ( formed by interstitial spaces between the fibers and threads ) material such as absorbent cotton . the fibrous material may be woven , knit or felt which is absorbent and porous and may be of natural fiber or synthetic fiber or a combination thereof . in a preferred embodiment , the material can be a cotton gauze 22 ( a woven material ) rolled into an elongate roll . the tightness of the roll will determine the firmness and compressibility of the pillow 21 . it is preferred that under the anticipated force of biting by the patient , that when compressed , the pillow have a transverse dimension of at least about ¼ inch and preferably between the gums in the range of between about ¼ inch and about ½ inch to provide adequate space between the front teeth and / or gums 11 for the tube 7 to prevent its being occluded . preferably , the gauze is a woven gauze as is well known in the art and can be clean and / or sterile as delivered to the surgeon for use . it has been found that a pillow 21 having a transverse dimension , which for example , in a round cross section execution is the diameter of the pillow 21 with a diameter being at least about ⅜ inch and preferably in the range of between about ⅜ inch and about 1 inch ( in a relaxed or unloaded condition ) to provide sufficient support to hold the teeth spaced adequately for positioning the tube 7 between the front teeth . the pillow 21 has two portions which will vary in length depending on the patient &# 39 ; s teeth and / or gum size . an intra - oral portion is designated by the bracket 29 and an extra - oral portion is designated by the bracket 30 . in a preferred embodiment , the length of the pillow 21 designated l in fig3 is in the range of between about 1½ inches and about 3½ inches . typically , the intra - oral portion 29 has a length in the range of between about 1½ inches and 2½ inches with the remainder , if any , of the length of the pillow 21 being the extra - oral portion , i . e ., that portion that may project from the patient &# 39 ; s mouth during use . the size of the oral cavity , gums and / or teeth of the patient and / or how far in the pillow needs to be inserted will determine how much of the pillow is intra - oral and how much is extra - oral . in some cases , the entire length of the pillow may be intra - oral . in the form of invention shown in fig3 , the pillow 21 comprises a fibrous woven gauze . the pillow can be advantageously produced by forming the gauze 22 into a roll . this can be accomplished by rolling five three by three inch squares of gauze , each having four layers of material . the exterior layer can be an unfolded layer of gauze 32 having two layers wrapped tightly around the inner layers of gauze . such an execution is particularly advantageous when making the pillow 21 by hand . in mass production , other forms and arrangements of fibrous material may be used . for example , the inner layers of material may be random fibers or random pieces of woven , knit or felt like material wrapped inside an outer layer which forms a continuous sheet of material enclosing the inner material . a finger tab 24 is provided to assist in handling of the pillow 21 by the surgeon or other personnel working in the operating room , for example , the anesthesiologist . the finger tab 24 is preferably flexible to help prevent injury to the patient and to provide a means of securing the intra - oral device to the patient . a preferred finger tab 24 is an elongate ribbon of adhesive backed fabric having one end projecting from an end of the pillow 21 and a portion of the length thereof positioned between contacting surfaces of the material forming the pillow 21 . the tab 24 , for example , can be a synthetic or natural fiber material , can have a width in the range of between about ¼ inch and about ½ inch , and is clean and / or sterile when used by medical personnel . the tab may also be polymeric . the tab 24 in a preferred embodiment has the exposed end thereof folded over where two adhesive backed face portions 31 engage one another such that the tab is substantially free of adhesive on at least two exterior surfaces , i . e ., the adhesive is not generally exposed . the other end 34 has exposed adhesive that adheres the tab 24 to the pillow 21 , for example , by adhesively being secured to a layer of a sheet of the fabric comprising the pillow 21 , either one of the interior sheets or the exterior sheet . means 26 is provided to retain the pillow 21 as a monolithic structure with a sheet exterior . in the case of the structure illustrated in fig3 , the means 26 includes a retainer 33 that prevents the exterior sheet and interior material from unrolling or separating . the retainer 33 includes an adhesive tape such as tegaderm which can encircle the pillow 21 around a substantial part thereof and is secured to the exterior fabric sheet or encircle the entirety of the pillow &# 39 ; s outer periphery and be secured to itself and the exterior fabric sheet . it also may extend along substantially the entire length of the pillow . the retainer 33 preferably bridges the exposed end 35 of the exterior fabric sheet of the pillow 21 and is adhesively secured to the pillow material on both sides of the end 35 to prevent unrolling . the tape comprising the illustrated retainer preferably has an adhesive coating that is water resistant to prevent the adhesive from becoming unattached from the pillow 21 or itself when moisture from the oral cavity is exposed thereto or from the pillow if wetted prior to use . the tape should be flexible and be cut and tear resistant and may be polymeric . adhesive tape is particularly advantageous because it will not cause any physical damage to the patient and is readily flexible to conform to the shape of the pillow when it is either stored or deformed during use . a shrinkable polymeric tube or elastic band can be used as an alternate to or in combination with an adhesive tape retainer 33 . fig4 shows a first alternative embodiment of the present invention and comprises a pillow designated generally 51 . in this alternate form of invention , the pillow 51 is comprised of a tubular covering or sock 53 which can be made of a sheet of woven , knit or felt fabric made of fibrous material such as natural , synthetic or a combination of fibers like cotton , polyester or the like . the cover 53 may be formed with a seam or seamless in its elongate or longitudinal dimension and has normally closed ends 55 , only one being shown in fig5 . the cover 53 has an interior 57 that can be filled with fibrous , porous and / or absorbent material 58 such as natural or synthetic fibers like cotton or polyester , a sponge - like material such as cellulosic or elastomeric sponge . the fibrous material may be random fibers compressed in the covering 53 or rolled sheet material . as shown , one end 55 has a selectively sealable opening 59 that can be expanded or contracted by use of a drawstring 61 . the material 58 may be inserted through the opening 59 and then by pulling of the drawstring 61 , the opening 59 can be closed to prevent loss of the material 58 . the drawstring 61 can also serve as a finger tab like the tab 24 . the dimensions and compressibility of the device 51 can be the same as the dimensions and compressibility of the device 21 . further , the drawstring 61 serves the same function as the tape 33 providing means for preventing the material 58 from separating from the pillow and retaining the pillow as a monolithic structure . fig5 shows a second alternative embodiment of the present invention . in this embodiment , the pillow designated generally 71 is made of a foam or sponge - like material either cellulosic or elastomeric with interstitial voids . the pillow 71 has the same dimensions and characteristics as those described for the pillows 21 and 51 . the pillow 71 may include a tube such as the tube 53 shown in fig4 or may have the exterior of the foam material exposed for contact with the patient . the pillow 71 may be made by rolling the foam or sponge material 72 in a spiral or other suitable pattern like the pillow 21 . also , the pillow 71 is a monolithic structure and may be made by forming the pillow such as by cutting or molding , not requiring any additional rolling or the like . a tab 24 may be provided by adhesively securing it to the pillow 71 . alternatively , a slot or opening 75 may be cut or otherwise formed in the pillow 71 with the tab 24 having a portion thereof inserted into the slot 75 and being adhesively secured to the pillow 71 . if the pillow 71 is made by rolling foam or sponge material in a spiral pattern or other pattern ( as shown ), then the tab 24 may extend through the opening 75 and be secured between surfaces of the foam comprising the pillow 71 as the tab 24 is secured in the pillow 21 . in the event the pillow is made by rolling foam material , means 26 such as that used for the pillow 21 may be utilized to retain the pillow 71 as a monolithic structure during storage and use . in use , any of the three disclosed embodiments or other embodiments of the present invention are used during a surgical procedure where the patient is anesthetized by having a sheet of fabric such that the exterior and interior material will remain as part of the intra - oral device and the device will remain as an integral structure . further , the use of a retainer as described also helps prevent the dislodging of fibers from either the interior or exterior of the device as well as reducing the shearing of any material from the device if it is of a foam or sponge - like structure . prior to being anesthetized , the size of the oral cavity will be estimated to determine the appropriate size of device and pillow . prior to inserting the device into the oral cavity and between the gums , the pillow may be wetted with water , but is preferred that the pillow be able to absorb water in an amount of at least about ¼ of its relaxed volume . the mouth of the patient is opened and the device is installed . only one may be used or alternatively , one between each side of the mouth leaving , if desired , an extra - oral portion and the tab positioned extra - orally . by wetting the device , the device can be conformed to a shape with the wetness helping the device retain that shape to facilitate insertion of the device in the appropriate location in the mouth . further , wetting can help reduce mouth dryness during the surgical procedure . if desired , the finger tab 24 may be secured to the patient , for example , by taping it to the cheek which will help prevent dislodgment of a pillow 21 from the mouth and to help retain it in place . alternately , the tab 24 may be provided with an adhesive surface allowing the tab to be directly secured to the patient . in such an execution , the adhesive surface may be covered with a removable member such as those used on bandages to allow for convenient storage and handling . after insertion of one or two devices 3 into the oral cavity , the surgical procedure is performed once the patient is adequately anesthetized . after being anesthetized , an lma or an endotracheal tube may be inserted into the oral cavity as is known in the art and preferably is inserted prior to insertion of the device 3 . after the surgical procedure is completed , the patient is allowed to wake up while retaining the device ( s ) 3 in place between the gums . two of the devices may be secured together with their respective tabs or with a common tab . after the patient has adequately awakened , the device may be removed from the oral cavity . in the event the tab is secured to the patient , it is separated from the patient prior to removal of the device . the device 3 may then be disposed of in an appropriate manner . fig5 shows an additional embodiment of the present invention . this embodiment may be utilized in any of the embodiments of the invention . one or more sensors 81 are carried by the pillow 71 and are operable to sense a condition or change in condition in the oral cavity such as the patient &# 39 ; s temperature . also , on occasion , a patient will expectorate bile or stomach contents which can eventually get into the lungs causing damage due to acidity thereof . the sensor 81 can be connected to an apparatus such as a monitor 83 which would sound an alarm or provide some other visual or audio signal indicative of the fluid coming into the mouth . the presence of such fluid can be indicated by a change in ph , a change in the moisture content of the pillow or by sensing for certain gases in the oral cavity . in a preferred embodiment , the sensor 81 would sense for a change in acidity and a signal from the monitor 83 would be provided to surgical personnel to indicate the presence of such fluid allowing the personnel to remove or otherwise handle the expectorated fluid . the sensor 81 may also be operable to sense for moisture , e . g ., by a change in conductance . the sensor 81 may also be operable to sense a patient &# 39 ; s temperature . such a temperature sensor can be a thermocouple , which can be shielded for safety . the sensor 81 could also sense a plurality of such conditions . the shielding of the sensor 81 can be a resilient cover , such as a soft plastic , to protect the teeth and oral cavity tissue from damage and the shield can be positioned to contact tissue in the oral cavity . the sensor 81 can also be shielded by being imbedded inside the pillow . the sensor 81 can extend through the pillow 71 from end - to - end extending from the ends if desired . if shielding is not desired , the sensor 81 may be affixed to the exterior of the pillow as desired . shielding may be partial or total . the use of the described pillow permits easy temporary mounting of the sensor to the pillow as well as easy adjustment of the position of the sensor . as is evident from the foregoing description , certain aspects of the present invention are not limited by the particular details of the examples illustrated herein and it is therefore contemplated that other modifications and applications , or equivalents thereof , will occur to those skilled in the art . it is accordingly intended that the claims shall cover all such modifications and applications that do not depart from the spirit and scope of the present invention . other aspects , objects and advantages of the present invention can be obtained from a study of the drawings , the disclosure and the appended claims . | US-68394002-A |
an implantable medical lead comprises an insulating lead body housing having an outer surface . a thin , flexible membrane surrounds the insulating housing , the membrane having an inner surface confronting the outer surface of the housing . a lubricious interface between the inner surface of the membrane and the outer surface of the housing facilitates movement of the insulating housing relative to the membrane in response to frictional engagement of the membrane with adjacent structure . also disclosed is a method of fabricating such a lead . | the following description is of a best mode presently contemplated for practicing 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 whose scope is defined by the appended claims . although the invention will be described in the context of implantable cardiac stimulation and sensing leads , it will be evident to those skilled in the art that the invention described herein has broader utility , being applicable to a wide variety of implantable medical leads for stimulating selected body tissue and sensing the electrical activity of such tissue . by way of example and not limitation , fig1 – 3 show an endocardial pacing , sensing and defibrillation system 10 comprising a lead 12 and an implantable medical device ( imd ) 14 that may comprise a pacemaker / icd . the lead 12 includes a lead body 16 having a proximal end 18 and a distal end 20 . the lead 12 is illustrated to be of a quadripolar design , but is not intended to be limiting of the invention . the proximal end 18 of the lead 12 incorporates a connector assembly 22 compatible with a standard such as the is - 4 standard for connecting the lead body to the imd 14 . the connector assembly 22 includes a tubular pin terminal contact 24 and ring terminal contacts 26 – 28 electrically coupled to electrodes along the distal end 20 of the lead body . the connector assembly 22 of the lead is received within a receptacle ( not shown ) in the imd 14 containing electrical terminals positioned to engage the contacts 24 and 26 – 28 on the connector assembly 22 . as is well known in the art , to prevent ingress of body fluids into the receptacle , the connector assembly 22 is provided with spaced sets of seals 30 . in accordance with standard implantation techniques , a stylet or guide wire ( not shown ) for delivering and steering the distal end of the lead body during implantation is inserted into a lumen of the lead body through the tubular connector terminal pin 24 . the lead body 16 extends along a central , longitudinal axis 32 and preferably comprises a tubular sheath or housing 34 made of an insulating , biocompatible , biostable polymer , for example , silicone rubber or polyurethane . although various insulating housing materials are intended to be encompassed by the invention , silicone rubber is often preferred because of its flexibility and long term biostability . the distal end 20 of the lead body may carry one or more electrodes whose configurations , functions and placement along the length of the distal end will be dictated by the indicated stimulation therapy , the peculiarities of the patient &# 39 ; s anatomy , and so forth . the lead body 16 illustrates but one example of the various combinations of stimulating and / or sensing electrodes that may be utilized . more particularly , the distal end 20 of the lead body terminates at a distal extremity 36 incorporating an electrical stimulating and / or sensing tip electrode 38 . as is well known in the art , the distal end of the lead body is placed so as to position the surface of the tip electrode 38 in electrical communication with the body tissue to be stimulated and / or sensed . in conventional fashion , the distal end 20 of the lead body may include passive fixation means ( not shown ) that may take the form of conventional projecting tines for anchoring the lead body within the right atrium or right ventricle of the heart . alternatively , the passive fixation or anchoring means may comprise one or more preformed humps , spirals , s - shaped bends , or other configurations manufactured into the distal end 20 of the lead body 16 where the lead is intended for left heart placement within a vessel of the coronary sinus region . the fixation means may also comprise an active fixation mechanism such as a helix . it will be evident to those skilled in the art that any combination of the foregoing fixation or anchoring means may be employed . the distal end 20 of the lead body may also carry one or more ring electrodes as well as one or more cardioverting / defibrillating coils . in the example under consideration , two ring electrodes 40 and 42 and a single cardioverting / defibrillating coil 44 are included . the ring electrodes 40 and 42 may serve as both tissue - stimulating and sensing electrodes . other electrode configurations may , of course , be employed pursuant to lead constructions well known in the art . for example , an alternative electrode arrangement may include additional ring stimulation and / or sensing electrodes as well as additional cardioverting and / or defibrillating coils spaced apart along the distal end of the lead body . thus , as emphasized , fig1 – 3 are illustrative only ; the distal end of the lead body may carry only pacing and sensing electrodes , only cardioverting / defibrillating electrodes or a combination of pacing , sensing and cardioverting / defibrillating electrodes . where defibrillating electrodes are included these may be of conventional coil design or , for greater flexibility , they may comprise spaced apart , relatively short metallic rings or they may be made of an electrically conductive polymer or coating . the kind of electrode configuration used will depend upon the particular application and accordingly any electrode configuration known in the art or developed in the future may be utilized . the ring and cardioverting / defibrillating electrodes 40 , 42 and 44 shown in the example are electrically connected to the ring terminal contacts 26 – 28 on the connector assembly 22 . in accordance with one form of the invention , the lead body 16 may be isodiametric , that is , the outside diameter of the lead body may be the same throughout its entire length . by way of example and not limitation , the outside diameter of the lead body 16 may range from about 0 . 026 inch ( 2f ) to about 0 . 130 inch ( 10f ). also , in accordance with well known techniques , the outer surface of the lead body 16 may have a lubricious coating along its length to facilitate its movement through a lead delivery introducer and the patient &# 39 ; s vascular system . the insulating housing 34 may have various cross - sectional configurations . in the example shown , the housing 34 comprises a tubular , multilumen structure having an outer , generally cylindrical surface 50 ( fig2 and 3 ). more specifically , the lead body housing 34 is a quadrilumen structure defining four axially or longitudinally extending , parallel passages or lumens comprising a central lumen 52 and three outer lumens 54 – 56 disposed about the central lumen 52 . the central lumen 52 may enclose a low friction liner of ptfe , for example ( not shown ), through which a stylet , guide wire , or inner coil may be passed for delivering and steering the distal of the lead body during implantation thereof . in the example shown , the central lumen 52 contains an electrical coil conductor 58 connecting the tip electrode 38 to the pin terminal contact 24 on the connector assembly 22 . the lumens 54 – 56 contain insulated electrical conductors 60 – 62 , respectively , that may each be in the form of a multifilar , braided cable typically of mp35n or mp35n / ag alloy . alternatively , one or more of the conductors 60 – 62 may comprise monofilament , non - coiled wires of , for example , nitinol , mp35n , or the like . the cable or wire conductors 60 – 62 connect the various ring and cardioverting / defibrillating electrodes 40 , 42 and 44 on the distal end of the lead body with the associated terminal contacts 26 – 28 on the proximal connector assembly . in accordance with one specific , exemplary embodiment of the invention , the lead body housing 34 between the connector assembly 22 and the proximal end of the cardioverting / defibrillating electrode 44 is enclosed within a thin , flexible , stretchable , sleeve - like or tubular , polymer membrane 66 . the tubular membrane 66 has a distal end 68 adjacent to the proximal end of the cardioverting / defibrillating electrode 44 , a proximal end 70 adjacent to the distal end of the connector assembly 22 , and an inner surface 72 confronting the outer surface 50 of the housing 34 . the distal end 68 of the tubular membrane is attached to the outer surface 50 of the housing by means of a continuous , fluid - tight , circumferential seal 74 of medical adhesive or a comparable bonding agent . a similar circumferential seal 76 of medical adhesive or comparable bond attaches the proximal end 70 of the membrane to the outer surface of the housing . the confronting inner surface 72 of the membrane and the outer surface 50 of the housing thus define a thin , annular , fluid - tight interface space 78 sealed at its opposite ends . in the embodiment of fig1 – 3 , the space 78 contains a lubricious interface in the form of a lubricious medium 80 . a . the membrane 66 may be made of any thin , flexible ( that is , stretchable ), biocompatible , biostable material such as , without limitation , any of the following : 1 . medical grade elastomeric silicone rubber ; 2 . medical grade elastic polyurethane ; 3 . medical grade elastic polyester ; 4 . woven , knitted , or composite fabrics with controlled stretch ; 5 . flexible plastic memory shaped polymers ; and 6 . silicone - urethane copolymers . b . the thickness of the membrane 66 in its relaxed state may range from about 0 . 0005 inch to about 0 . 005 inch . c . the lubricious medium 80 contained within the interface space 78 may comprise , without limitation : 1 . a medical grade silicone oil , gel , foam or grease ; 2 . a medical grade ptfe powder ; or 3 . a hydrocarbon agent such as mineral oil , paste or powder . d . by way of example only , the volume of the lubricious medium 80 injected into the space 78 may comprise approximately 0 . 01 cc per linear centimeter of the length of the space 78 . the tubular membrane 66 is slid into place over the housing preferably in an interference fit so that the membrane is stretched longitudinally and circumferentially over the outer surface of the housing 34 when it is installed . for example , the housing may have an outer diameter of 0 . 060 inch while the membrane may have an inner diameter of 0 . 058 inch in its unstretched state . using a medical adhesive or comparable bonding agent , one end 68 or 70 of the tubular membrane 66 is then attached to the outer surface 50 of the housing 34 about the entire circumference of the housing to seal the one end of the membrane at 74 or 76 . the lubricious medium 80 is then injected into the interface space 78 ; the medium will form a thin film within the space 78 . the other end 68 or 70 of the membrane is then similarly attached to the outer surface 50 of the housing to completely seal the filled interface space 78 . alternatively , both ends of the membrane 66 may be sealed followed by injection of the medium 80 through the wall of the membrane using a hypodermic needle or comparable expedient . if necessary , the puncture through the membrane may be sealed with medical adhesive . alternatively , instead of an interference fit between the housing and the membrane , these elements may be dimensioned for a clearance fit or an even fit . by way of example , an appropriate interference fit may be obtained when , prior to assembly of the housing 34 and the membrane 66 , the diameter of the outer surface 50 of the housing 34 is greater , for example , by 0 . 001 inch , than the diameter of the inner surface 72 of the membrane 66 in its unstretched state . a clearance fit may be obtained when prior to assembly the diameter of the housing surface 50 is less , for example , by 0 . 001 inch than the diameter of the membrane surface 72 . an even fit may be obtained when the aforementioned diameters are the same prior to assembly . turning now to fig4 , there is shown an implantable cardiac pacing , sensing and cardioverting / defibrillating system 100 that includes a lead 102 in accordance with an alternative embodiment of the invention . generally , the description of the lead shown in fig1 is applicable to the alternative embodiment of fig4 . thus , the lead 102 includes a lead body 104 having a connector assembly 106 at a proximal end 108 of the lead body . the connector assembly 106 is adapted to be received by an imd such as a pacemaker / icd 110 . a plurality of spaced - apart electrodes 112 – 115 including a cardioverting / defibrillating electrode 115 are disposed along a distal end 116 of the lead body . the cardioverting / defibrillating electrode 115 may be positioned along the distal end of the lead body so as to provide electrical stimulation to , for example , the right ventricle of the heart . in addition to the cardioverting / defibrillating electrode 115 , the embodiment of fig4 includes a second cardioverting / defibrillating electrode 118 disposed along the distal end 116 proximally of the first cardioverting / defibrillating electrode 115 and positioned to stimulate , by way of example , the tissue of the superior vena cava ( svc ). the lead body 104 includes a polymer , tubular housing 120 of silicone rubber or the like having an outer surface 122 . in accordance with the alternative embodiment of fig4 , the portion of the lead body housing 120 between the cardioverting / defibrillating electrodes 115 and 118 is enclosed within a first membrane 124 having the properties already described in connection with the first embodiment . the membrane 124 has a distal end 126 adjacent to the proximal end of the first cardioverting / defibrillating electrode 115 and a proximal end 128 adjacent to the distal end of the second cardioverting / defibrillating electrode 118 . the membrane ends 126 and 128 are attached to the outer surface 122 of the lead body housing 120 by means of continuous , fluid tight , circumferential seals of medical adhesive or a comparable bonding agent in the manner already described . the portion of the lead body housing 120 between the proximal end of the second cardioverting / defibrillating electrode 118 and the distal end of the connector assembly 106 is enclosed within a second membrane 130 having the properties already described . the membrane 130 is attached to the outer surface 122 of the lead body housing 120 by means of continuous , fluid tight , circumferential seals at opposed , distal and proximal ends 132 and 134 , respectively , of the membrane . as before , the annular , thin , fluid - tight interface spaces between the membranes 124 and 130 , on the one hand , and the outer surface 122 of the housing 120 , on the other , each contains a lubricious interface in the form of a lubricious medium , all as previously described . in accordance with another specific embodiment of the invention , the lubricious interface between the membrane ( s ) and the associated lead body housing may comprise , instead of an injectable medium , various surface treatments or surface modifications such as lubricious thin films or coatings . thus , with reference to fig5 , there is shown in axial cross - section a portion of a lead body 150 including , as before , a lead body housing 152 having an outer surface 154 . the outer surface 154 of the lead body housing along at least a portion of the length thereof is enclosed within a membrane 156 of the kind previously described . the membrane 156 has an inner surface 158 confronting the outer surface 154 of the lead body housing 152 . disposed between the confronting inner surface 158 of the membrane 156 and the outer surface 154 of the housing 152 is a lubricious interface that , in accordance with the specific , exemplary embodiment of fig5 , comprises a lubricious film or coating 160 on the inner surface 158 of the membrane 156 and a lubricious film or coating 162 on the outer surface 154 of the lead body housing . it will be evident that instead of providing a lubricious film or coating on each of the two surfaces 154 and 158 , such a film or coating may be provided on only one of the two surfaces . the lubricious film or coating 160 , 162 may take the form of any of the well known lubricious films or coatings that are presently applied to the outer surface of implantable leads , for example , the molecular coatings on cardiac leads sold by st . jude medical , inc ., under the registered trademark , “ fast - pass ”. it will be evident that the embodiment of fig5 is applicable to the single membrane lead body structure of fig1 – 3 as well as to the multiple membrane structure of fig4 . the flexibility of the membrane ( s ) and the properties of the lubricious interface of the various embodiments disclosed herein are such that the membrane ( s ) will slide over the lead body housing and stretch , wrinkle , twist or wind as the lead body housing moves relative to the patient &# 39 ; s body tissue such as the wall of a vein . the relative motion between the membrane ( s ) and the housing greatly reduces abrasive wear of the lead body . further , the invention preserves the small outer diameter of the lead , as well as lead flexibility and isodiametric features . moreover , it will be apparent that the invention is applicable to all implantable medical leads , including both endocardial and epicardial cardiac leads . while several illustrative embodiments of the invention have been shown and described , numerous variations and alternative embodiments will occur to those skilled in the art . such variations and alternative embodiments are contemplated , and can be made without departing from the spirit and scope of the invention as defined in the appended claims . | US-67631603-A |
the present invention relates to processes for the manufacture of suspensions comprising one or more water soluble or water insoluble pharmaceutical or nutraceutical active ingredients with a particle size in the range of from 0 . 01 to 10 micron . more specifically , suspensions prepared by this process can be used to formulate pharmaceutical compositions , especially in liquid fill capsules . | the suspensions are preferably prepared by mixing the crystals and the non - aqueous medium in a high shear mixer prior to milling . milling may be carried out using any of the commercially available equipment capable of reducing particle size to the dimensions required for the present invention . nanocrystal suspensions can further be mixed with pharmaceutical excipients and formulated for administration . for example , the suspension may be filled into hard or soft capsules for administration to humans or animals by the oral , rectal or vaginal route . the formulations of the present invention are stable , involve less manufacturing steps and have improved dissolution properties . it is also unexpected that the formulation of the invention can be used for both water soluble and water insoluble apis . by formulating such compositions using lower particle size ( micron or sub - micron ) crystals this has a beneficial effect on the release of water soluble and insoluble drugs . suspensions of all the examples cited above in the historical literature have been suspensions of poorly water soluble apis for parenteral or oral administration . the current invention may also be used for water soluble actives . water soluble actives can be incorporated into lipophilic or hydrophilic non - aqueous liquids as suspended particles and then filled into capsules for oral administration . water soluble actives in hydrophilic non - aqueous liquids will generally provide quite rapid release of the water soluble active in the gastrointestinal tract . incorporation of the drug as a lower particle size ( micron or sub - micron ) should lead to an enhanced absorption in vivo . similarly , water soluble apis incorporated into lipophilic non - aqueous solvents such as oils will again release the drug in the gastrointestinal tract following digestion of the oil by the surfactants and bile salts in the gi tract . nanocrystals can be formed using two methods , controlled crystallisation or physical ablation . physical ablation is conveniently performed using milling , for example , using a ball mill , a jet mill , a colloidal mill or a rotor stator . using a ball mill creates particles of the desired species which are presented in a slurry and the slurry is exposed to plural rotating balls which ablate the particles . the ultimate size of the particles depends on several factors which include the number of milling balls , the size of the milling balls , the size of the grinding chamber , rotational speed of the chamber and the milling time . the balls are typically rotated at high speed and the particle size of the species reduces until the desired size distribution , e . g . nanocrystals , is achieved . in this specification , the term “ nanocrystals ” is intended to mean particles which have a size of from 0 . 01 to 10 microns , preferably 0 . 01 to 2 microns , more preferably 60 to 800 nm and particularly 100 nm to 400 nm . for the purpose of determining the range of particle sizes in a nanocrystal suspension , when the mean particle size is in the range of 0 . 01 to 800 nm it is preferred that all the nanocrystals in the suspension have a particle size of up to and including 1 micron . when the mean particle size is in the range of 0 . 01 to 250 nm , it is preferred that all the nanocrystals in the suspension have a particle size of up to and including 500 nm . in the present invention , the non - aqueous medium is always a single component and it may be a liquid , a solid or a semi - solid at human body temperature or room temperature . the non - aqueous medium could be a lipid , for example , a phospholipid or a non - lipid . the suspension of nanocrystals of active substance in the non - aqueous medium may be solid or semi - solid or liquid at human body temperature and or room temperature . particularly important benefits of the invention are derived from formulating pharmaceutical or nutraceutical substances in liquid and semi - solid ( hot melt ) formulations according to the present invention and filling the resultant suspension directly into hard two piece capsules ( gelatine or hpmc ) or softgels . if required , pharmaceutical excipients may be added to the suspension immediately prior to the filling process . however , it is preferred to direct fill the suspension which is obtained from the milling process of the present invention directly into capsules . liquid filled capsules can be characterised by the chemical properties of the non - aqueous medium ( i . e ., hydrophobic or hydrophilic based fill materials ) or the physical properties of the composition ( i . e . suspension ). the present invention is directed in particular to hydrophobic suspensions using active substances suspended in oils or oil / wax mixtures often referred to as semi - solids , and hydrophilic suspensions using active substances suspended in hydrophilic vehicles such as poloxamer and polyethylene glycols . the suspended active substances may be highly water soluble to practically water insoluble ( solubility less than 0 . 1 mg / ml ). in the present invention , the suspensions for filling into capsules are liquid , ideally with viscosity in the range 0 . 1 - 1 . 0 pa · s at the filling temperature . some suspensions will be liquids with a viscosity in this range at room temperature ( 21 - 25 ° c .) while other suspensions may need to be heated to above the melting point of the non - aqueous medium . in some cases this will require nano - milling at a temperature above the melting point of the non - aqueous medium . the maximum temperature suitable for filling is about 80 ° c . in general , for unmilled active substance the loading in suspensions for liquid fill suspensions is usually in the range 1 % to 30 % w / w . in certain active substance / non aqueous medium combinations a higher loading can be achieved , for example , up to 50 % w / w . hydrophobic non - aqueous media include refined specialty oils such as arachis oil , castor oil , cottonseed oil , maize ( corn ) oil , olive oil , sesame oil , soybean oil and sunflower oil ; medium - chain triglycerides and related esters such as caprylic / capric triglycerides ( akomed e , akomed r , miglyol 810 , and captex 355 ), medium - chain triglyceride ( labrafac cc ), propylene glycol diester of caprylic / capric acid ( labrafac pg ), propylene glycol monolaurate ( lauroglycol fcc ), fractionated coconut oil ( miglyol 812 ), caprylic / capric / diglyceryl succinate ( miglyol 829 ), medium - chain diesters of propylene glycols ( miglyol 840 ), partial ester of diglycerides with natural fatty acids ( softisan 645 ), medium - chain mono - and diglycerides ( akoline mcm and capmul mcm ). hydrophilic non aqueous medium include solubilizing agents , surfactants , emulsifying agents , and adsorption enhancers compatible with hard gelatine capsules such as propylene glycol monocaprylate ( capryol 90 ), polyglycolized glycerides ( gelucire 44 / 14 and 50 / 13 ), polyoxyl - 40 hydrogenated castor oil ( cremophor rh 40 ), glycerol monostearate / di - triglycerides + glycerine ( imwitor 191 ), glyceryl monocaprylate ( imwitor 308 *), glyceryl cocoate / citrate / lactate ( imwitor 380 ), glyceryl mono - di - caprylate / caprate ( imwitor 742 ), isosteryl diglyceryl succinate ( imwitor 780 k ), glyceryl cocoate ( imwitor 928 ), glyceryl caprylate ( imwitor 988 ), oleoyl macrogol - 8 glycerides ( labrafil m 1944 cs ), linoleoyl macrogolglycerides ( labrafil m 2125 cs ), peg - 8 caprylic / capric glycerides ( labrasol ), lauric acid , propylene glycol laurate ( lauroglycol 90 ), oleic acid , peg mw & gt ; 4000 , polyglycerol dioleate ( plurol oleique cc 497 ), polyoxyethylene - polyoxypropylene copolymer ( poloxamer 124 and 188 ), partial glycerides of hydroxylated unsaturated fatty acids ( softigen 701 ), peg - 6 caprylic / apric glycerides ( softigen 767 ), polyoxyethylene glyceryl trioleate ( tagat to ), polyoxyethylene ( 20 ) sorbitan monooleate ( tween 80 ), vitamin e tpgs , hydrogenated polyoxyl castor oil ( cremophor el ), glycerin ( with a content & gt ; 5 %), glycofurol 75 , peg mw & lt ; 4000 , n - methyl - 2 - pyrrollidone ( pharmasolve ), propylene glycol , sorbitan monooleate ( span 80 ), diethylene glycol monoethylether ( transcutol p ). other suitable non - aqueous media include for example , waxes such as carnauba wax , bees wax which are liquids at & gt ; 85 ° c . and 65 ° c . respectively . semi - solid lipids include , for example , vitamin e tpgs ( a water soluble natural - source vitamin e d - α - tocophyeryl polyethyleneglycol succinate ) which has a melting point of about 38 ° c . or gellucire ® 44 / 14 ( a saturated polyglycolized glyceride consisting of mono -, di - and triglycerides and of mono - and di - fatty acids of polyethylene glycol ( peg ), which has a melting point of about 44 ° c ., which can be obtained by reacting hydrogenated palm kernel oil with peg 1500 ). other lipids which may be used include gellucire ® 90 / 10 , phosal 50pg , labrasol , miglyol 812 , cremophor rh40 , cremophor el , labrafil or combinations thereof . the pharmaceutical composition may comprise one or more pharmaceutical and / or nutraceutical active substance . suitable active substances include antispasmodics such as propantheline bromide and hyoscine butylbromide ; antisecretory drugs such as h2 receptor antagonists and proton pump inhibitors ; aminosalicylates ; corticosteroids such as budesonide and prednisolone ; azathioprine ; methotrexate ; laxatives such as peripheral opioid receptor antagonists ( methyl naltrexone bromide ), 5ht receptor agonists such as prucalopride and bisacodyl ; inotropic drugs such as digoxin , milrinone , and enoximone ; diuretics such as thiazides , bumetanide , furosemide , triamterene and amiloride ; anti - arrhythmics such as adenosine , dronedarone and amiodarone hydrochloride ; beta - adrenoceptor blocking drugs such as propranolol , atenolol and bisoprolol ; anti - hypertensives such as methyldopa , clonidine hydrochloride , prazosin , captopril , lisinopril , irbesartin and eprosartan ; anticoagulants such as warfarin , apixaban and phenindione , lipid regulating drugs such as atorvastatin and simvastatin ; antihistamines such as acrivastine , cetirizine hydrochloride and loratadine ; hypnotics and anxiolytics such as flurazepam , zolpidem tartrate , zaleplon , clormethiazole and benzodiazepines ; antipsychotic drugs such as flupentixol , levomepromazine , sulpride and trifluoperazine ; antimanic drugs such as valproic acid and lithium carbonate ; antidepressants such as tricyclics , maois and serotonin re - uptake inhibitors ; cns stimulants such as atomoxetine and methylphenidate hydrochloride ; appetite suppressants such as phenteramine and diethylpropion ; anti - nausea drugs such as cinnarizine , cyclizine , phenothiazines and ondansetron ; analgesics such as aspirin and paracetamol ; antiepileptics such carbamazepine , phenytoin , valproate and ethosuximide ; dopaminergics such as apomorphine hydrochloride , bromocriptine and pramipexole ; antimuscarinics such as orphenadrine hydrochloride and procyclidine hydrochloride ; antibacterials such as penicillins , cephalosporins , clindamycin and metronidazole ; antidiabetic drugs such as sulfonylureas , biguanides and pioglitazone ; sex hormones such as testosterone ; calcitonin ; bisphosphonates such as alendronic acid and risedronate sodium ; antithyroid drugs such as carbimazole and propylthiouracil ; cytotoxic drugs such as alkylating drugs , anthracyclines , antimetabolites , vinca alkaloids and etoposide ; minerals and vitamins ; nsaids such as diclofenac potassium , dexketoprofen , ibuprofen , and etodolac ; itraconazole ; nifedipine ; alfaxalone ; ursadiol ; acyclovir ; fenofibrate . examples of active substances with high solubility are metoprolol , diltiazem , verapamil , propranolol , cimetidine , acyclovir , captopril and neomycin b . examples of active substances with low solubility are danazol , ketoconazole , glibenclamide , nifedipine , mefenamic acid , itraconazole , hydrochlorothiazide and taxol . preferably , the pharmaceutical composition comprises the nanocrystal suspension obtained directly from the milling process and optionally a pharmaceutical excipient . the pharmaceutical composition may further comprise a degradable encapsulant . optionally , the encapsulant is a capsule material . preferably , the capsule material is hard or soft gelatine . other suitable capsule materials include starch , starch derivatives , hydroxypropylmethylcellulose ( hpmc ), pululan , alginates and gelatine / polyethylene glycol ( peg ). thermosetting non - aqueous media which are solid at room temperature may also be used . in this case , the drug crystals are milled at a temperature where the milling can be conducted in a liquid state before optionally being mixed with one or more excipients and then filled into capsules . e . g . for examples reported above using vitamin e tpgs and gellucire ® 44 / 14 it should be possible to conduct milling to produce nanocrystals of active substance in these liquids by milling at a temperature of 50 - 60 ° c . the pharmaceutical compositions of the present invention may further comprise an excipient which may be added to the non - aqueous nanocrystal suspension before being filled into capsules . suitable excipients include binders , emollients , fillers , lubricants , dyes , flavourings , anti - oxidants , ph modifiers , particle stabilisers / adsorbents , viscosity modifiers and preservatives . in order to test dissolution rate , a number of compositions were formulated , as set out in the following examples and dissolution experiments were performed . in each case itraconazole was used as the drug . this is a poorly soluble drug which is an orally active triazole antimycotic agent with broad spectrum activity . accordingly , it is desired to improve the bioavailability of this drug . in the following examples , there is an example of a hydrophilic non aqueous medium and a hydrophobic non - aqueous medium . in both examples , dissolution was tested in 0 . 1m hcl . as the dissolution data for the hydrophobic miglyol suspension illustrate , dissolution is generally poor despite there being an improved dissolution for milled drug particles compared to unmilled drug particles . it will be entirely clear to the skilled person that if these dissolution experiments had been conducted in dissolution media containing surfactant ( thus more closely mimicking the expected dissolution from the gi tract ) then a greater difference between dissolution of nano - milled and non - milled would be observed . the invention will now be illustrated with particular reference to the following examples : preparation and evaluation of nanocrystal itraconazole in a single component non - aqueous medium a ) an itraconazole suspension ( 1 . 6 %) in poloxamer 124 was prepared using a dm100 lena nano - milling system . the itraconazole suspension was prepared using a dm100 lena nanoceutics processing machine with zirconium grinding media ( 150 ml of 0 . 2 mm zirconium beads ( 22974 )). to ensure the circulation of the poloxamer , the dm100 was connected with a peristaltic pump which allowed poloxamer to re - circulate through the milling system . the circulation loop was not connected to the cooling system of the lena dm100 . zirconium beads ( 150 ml ) were added gradually to the hopper of the mill whilst poloxamer ( 250 mls ) was circulating . approximately 5 ml of poloxamer was poured out through the sampling nozzle into a small beaker containing 4 g of itraconazole and the resultant itraconazole suspension was returned slowly to the mill for processing for the required time . samples were collected and analyzed using malvern zetasizer to monitor the particle size distribution ( psd ) for the itraconazole suspension . the particle size of itraconazole prior to milling was measured to be in the range 10 - 50 micron . the particle size range of three samples of milled itraconazole was determined using a malvern zetasizer nano s ® model no . : zen3600 ( wavelength 633 nm ) and the average particle size range calculated . b ) the suspension was isolated and stored at ambient conditions and analysed after 2 , 3 and 18 days to measure the particle size stability of the nanocrystals in suspension . the particle size of the samples is provided in table 1 . surprisingly it is possible to mill itraconazole in a single component media ( poloxamer 124 ) without other stabilisers to produce nanocrystals of an extremely low particle size . the psd of itraconazole reached as low 58 nm , although some psd growth was observed after 2 days at room temperature ( 25 ° c .). however , during the longest storage period ( 18 days ), the psd of the suspension remained stable at around 200 nm . samples of the nanomilled itraconazole suspension in poloxamer 124 were filled directly into gelatine capsules ( 710 mg of suspension containing a nominal drug loading of 1 . 6 % itraconazole i . e . 11 . 36 mg of drug ). suspensions of unmilled itraconazole were also prepared at 1 . 6 % itraconazole in poloxamer 124 and filled into gelatine capsules ( 710 mg ). dissolution was conducted in 0 . 1n hcl and the data recorded and provided in table 2 . the study was conducted using a dm100 lena nanoceutics processing machine with zirconium grinding media ( 150 ml of 0 . 2 mm zirconium beads ( 22974 )). the particle size of the unmilled itraconazole was in the range 10 - 50 micron and the particle size of milled samples were determined using a zetasizer nano s ® model no . : zen3600 ( malvern ). samples were collected and analyzed using malvern zetasizer to monitor the particle size distribution ( psd ) for the api suspension . the suspension was isolated and stored at ambient conditions and analysed after 3 and 20 days to measure the stability of the suspension . the average particle size of the samples is provided in table 3 . samples of the nanomilled itraconazole suspension in miglyol 814n were filled directly into gelatine capsules ( 630 mg of suspension containing a nominal drug loading of 2 . 0 % itraconazole i . e . 12 . 6 mg of drug ). suspensions of unmilled itraconazole were prepared at 2 . 0 % itraconazole and filled into gelatine capsules ( 630 mg ). dissolution was conducted in 0 . 1n hcl and the data recorded and provided in table 4 . | US-201214353019-A |
a very small diameter intravascular stent device which may be used to occlude or partially occlude an aneurysm in the human brain which is comprised of a thin - walled skeletal cylindrical tube formed of undulating or sinusoidal elements which , when compressed , nest tightly with each other . | [ 0024 ] fig1 illustrates a self - expanding stent device 10 which is laser cut to form a thin - walled , skeletal tubular member 11 comprised of nickel - titanium alloy . once cut , the wall 12 of the tubular member 11 includes several openings , or cells 14 . when the skeletal tubular member 11 is placed over an aneurysm , a physician is able to deliver embolic coils or other such devices through the cells 14 and into the aneurysm . the tubular member 11 also functions to cover the mouth of the aneurysm thus obstructing , or partially obstructing , the flow of blood into the aneurysm . also , the tubular member 11 prevents medical devices such as embolic coils from escaping the aneurysm . the preferred length of the skeletal tubular member 11 may range from 0 . 0795 inches to 3 . 15 inches . the diameter of the tubular member 11 varies depending on its deployment configuration . in a non - deployed or expanded state , the diameter of the tubular member 11 may extend up to about 0 . 4 inches . when the skeletal tubular member 11 is compressed to fit within the lumen of a deployment catheter , the diameter may be reduce to about 0 . 014 inches . attached to the proximal end 16 of the skeletal tubular member 11 are three proximal legs 18 , 18 a , and 18 b that extend longitudinally from the tubular member 11 . the proximal legs 18 , 18 a , and 18 b are preferably biased outwardly from the longitudinal axis of the tubular member 11 . this outwardly biased configuration aids in the deployment system as subsequently described . t - shaped or i - shaped attachment flanges 20 , 20 a , and 20 b are attached to the tips of each proximal leg 18 , 18 a , and 18 b . fig1 a describes the t - shaped or i - shaped flanges 20 , 20 a , and 20 b in more detail . attached to the distal end 21 of the skeletal tubular member 11 are two distal legs 22 and 22 a that extend longitudinally away from the tubular member 11 . [ 0028 ] fig1 a illustrates in detail one of the t - shaped or i - shaped attachment flanges 20 which is also laser cut from the skeletal tubular member 11 at the proximal end of one of the proximal legs 18 . the t - shaped or i - shaped attachment flange 20 is slightly arched and oriented on the proximal leg 18 such that the arch coincides with the wall 12 of the tubular member 11 . [ 0029 ] fig2 illustrates the repetitive cell pattern of the skeletal tubular member 11 . the cell pattern may be formed by interconnected undulating members 24 and struts 26 . each strut 26 has a proximal end 28 and a distal end 30 . each undulating member 24 has a proximal end 32 , a plurality of peaks 34 , and a distal end 36 . the proximal end 32 is the left tip of an undulating member 24 . the peaks 34 are the highest and lowest points of an undulating member 24 . the distal end 36 is the right tip of an undulating member 24 . the undulating members 24 and struts 26 are interconnected in a way to maximize “ nesting ” of the undulating members 24 to thereby minimize the compressed diameter of the skeletal tubular member 11 during deployment . the proximal end 28 of each strut 26 is attached to a peak 34 of an undulating member 24 and the distal end 30 of the same strut 26 is attached to a peak 34 of an adjacent undulating member 24 . this interconnection of undulating members 24 and struts 26 permits the cells 14 of the skeletal tubular member 11 to collapse and allows the tubular member 11 to attain a compressed diameter . the repetitive cell pattern of the skeletal tubular member 11 may also be formed by interconnected sinusoidal members 38 and struts 26 . each sinusoidal member 38 has a proximal end 40 , a plurality of positive peaks 42 , a plurality of negative peaks 44 , and a distal end 45 . the proximal end 40 is the left tip of a sinusoidal member 38 . the positive peaks 42 are the highest points of a sinusoidal member 38 . the negative peaks 44 are the lowest points of a sinusoidal member 38 . the distal end 45 is the right tip of a sinusoidal member 38 . the sinusoidal members 38 and struts 26 are interconnected in a way to maximize “ nesting ” of the sinusoidal members 38 thereby minimizing the compressed diameter of the skeletal tubular member 11 during deployment . each strut 26 connects a positive peak 42 of a sinusoidal member 38 with a negative peak 44 of an adjacent sinusoidal member 38 . this interconnection of sinusoidal members 38 and struts 26 permits the cells 14 of the skeletal tubular member 11 to collapse and allows the tubular member 11 to attain a compressed diameter . also illustrated in fig2 are the proximal legs 18 , 18 a , and 18 b and the distal legs 22 and 22 a . in the repetitive cell pattern formed by undulating members 24 and struts 26 , the proximal legs 18 , 18 a , and 18 b are connected to the proximal ends 32 of undulating members 24 , and the distal legs 22 and 22 a are connected to the distal ends 36 of undulating members 24 . in the repetitive cell pattern formed by sinusoidal members 38 and struts 26 , the proximal legs 18 , 18 a , and 18 b are connected to the proximal ends 40 of sinusoidal members 38 , and the distal legs 22 and 22 a are connected to the distal ends 45 of sinusoidal members 38 . it should be understood that the stent device of the present invention may alternatively be coated with an agent , such as heparin or rapamycing , to prevent stenosis or restenosis of the vessel . examples of such coatings are disclosed in u . s . pat . nos . 5 , 288 , 711 ; 5 , 516 , 781 ; 5 , 563 , 146 and 5 , 646 , 160 . the disclosures in these patents are incorporated herein by reference . [ 0035 ] fig3 illustrates the deployment system 46 for the stent device 10 . the deployment system 46 includes an outer sheath 48 which is essentially an elongated tubular member , similar to ordinary guiding catheters which are well known to those of ordinary skill in the art . the deployment system 46 also includes an inner shaft 50 located coaxially within the outer sheath 48 prior to deployment . the inner shaft 50 has a distal end 52 and a proximal end ( not shown ). the distal end 52 of the shaft 50 has three grooves 54 , 54 a , and 54 b disposed thereon . when the deployment system 46 is not fully deployed , the stent device 10 is located within the outer sheath 48 . the t - shaped or i - shaped attachment flanges 20 , 20 a , and 20 b on the proximal legs 18 , 18 a , and 18 b of the tubular member 11 are set within the grooves 54 , 54 a , and 54 b of the inner shaft 50 , thereby releasably attaching the stent device 10 to the inner shaft 50 . this deployment system is described in more detail in u . s . pat . no . 6 , 267 , 783 assigned to the same assignee as the present patent application . the disclosure in this patent is incorporated herein by reference and made a part of the present patent application . a novel system has been disclosed in which a self - expanding stent device comprises a laser cut , skeletal tubular member having a plurality of cells . 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 claims which follow . | US-16324802-A |
an improved composition for alleviating and treating the condition of scarring is provided . the system is directed to a product or composition which includes a silicone compound as a delivery medium , to which an oil compound such as sea buckthorn oil as an antioxidant is added . the product is prepared by mixing the two ingredients . | the inventive dermatological product includes one or more silicone compounds as the delivery medium . the one or more silicone compounds may be present in an amount between about 40 . 0 and 99 . 9 weight percent of the overall composition . preferably , the silicone compounds are present in an amount between about 80 and 99 weight percent . the preferred silicone compounds are selected from cyclopentasiloxane , cyclotetrasiloxane and dimethicone . other silicone compounds that are suitable include cyclomethicone , dimethicone copolyol , polysiloxane , silicone dioxide and polydimethylsiloxane . the inventive product also includes an oil . the oil may be present in an in an amount between about 0 . 01 and 50 weight percent , with between about 0 . 1 and 5 weight percent being preferred . the preferred oil is sea buckthorn oil , although other medical oils such helichrysum oil , tea tree oil , neroli oil and rosehip seed oil can be used . sea buckthorn oil is an oil that is extracted from the seeds , fruit and / or leaves of the plant species hippophae rhamnoides , which is found mainly in eastern europe and central asia , sea buckthorn oil is known to have significant anti - oxidant , anti - inflammatory effects . it is obtained from the company liberty natural , inc . located in 20949 s harris rd , oregon city , oreg . 97045 . sea buckthorn oil contains essential fatty acids , vitamins and other nutrients which are ideal for skin nutrition and scar improvement . the purpose of the oil in the inventive product is to enhance healing . in preparing the inventive composition , the oil is mixed with the silicone compound until the composition is uniform . the inventive product may also include a sunscreen compound . the sun screen compound may be present in the overall composition in an amount no greater than about 50 % weight percent and should be present in an amount between about 5 % and 25 % weight percent . the sun screen compound is added to the inventive composition in order to provide sun - blocking properties . suitable sun screen compounds include titanium dioxide , zinc oxide , octyl salicylate , avobenzone , homosalate , octylcrylene , oxybenzene and octyl methoxycinnamate . this ingredient is added to the inventive composition by mixing together until the composition is uniform . optionally , the inventive product includes an anti - inflammatory compound . the anti - inflammatory compound may be present in the overall composition in an amount no greater than 5 % weight percent and should be in an amount between about ) 0 . 1 % and 5 % weight percent . the preferred anti - inflammatory compound is hydrocortisone . the anti - inflammatory compound is added to the inventive composition by mixing until uniform composition . optionally , the inventive product includes an antibiotic compound . the antibiotic compound should be added to the composition in either powder or solution found by determining its strength , as well known in the medical art , and as authorized under fda guidelines . the preferred antibiotic compound is bacitracin ( usp 400 u in 1 gm — preferred ) or neomycin ( usp 3 . 5 mg in 1 gm — preferred ). other suitable antibiotic compounds include polymyxin b ( usp 5 , 000 u in 1 gm — preferred ). the antibiotic compound is added to the inventive composition by mixing until the composition is uniform . optionally , the inventive product includes a bruise treatment compound . the bruise treatment compound may be present in the overall composition in an amount up to 50 % weight percent , and is preferably present in the overall composition in an amount between about 5 % and 25 % weight percent . the preferred bruise treatment compound is arnica montana which is homeopathic oil made from the arnica montana plant . others include chamomile , lavender , st . john &# 39 ; s wort , calendula and preparations made from the spongilla lacustris sponge species . the bruise treatment compound is added to the inventive composition by mixing together until the composition is uniform . the dermatological product of the invention is generally applied to a patient &# 39 ; s skin in a sufficient quantity to cover the affected area . in a preferred embodiment , the dermatological product is a liquid gel product , although it may also be provided in a spray form . a clinical test of thirty ( 30 ) patients receiving the dermatological product to treat scarring was performed . all thirty patients self - reported that the appearance of their scar improved after a completed course of topically applying the dermatological product to existing scars ; and all thirty patients reported that they were satisfied with the results . additionally , twenty - nine ( 96 %) of the patients said they would recommend the product to a friend and only one patient ( 3 . 4 %) reported minor side effects . patients involved in the test were also asked to rate the improvement of the appearance of their scars as a result of the treatment . patients were asked to rate the improvement as one of : 0 %; 25 %; 50 %; 75 %; or 100 %. seventeen patients were treating surgical incisions and the average of these patients improvement ratings was 54 %. fourteen patients were treating keloid / old scars and the average of these patients &# 39 ; improvement ratings was 46 %. five patients were treating pigmented scars / burns and the average of these patients &# 39 ; improvement ratings was 75 %. the test data demonstrate that treatment in accordance with the invention significantly reduces the effects of scarring . this disclosure only illustrates several embodiments of a dermatological product , however , other types and variations are possible , and the disclosure is not intended to be limiting in that regard . thus , although the description above contains much specificity , the details provided should not be construed as limiting the scope of the embodiments but merely as providing illustrations of some of the presently preferred embodiments . the description is not to be taken as restrictive on the scope of the embodiments and is understood as a broad and general teaching in accordance with the present invention . while the present embodiments of the invention have been described using specific terms , such description is for present illustrative purposes only , and it is to be understood that modifications and variations to such embodiments , including but not limited to the substitutions of equivalent features , compounds , or substances , and the reversal of various features thereof , may be practiced by those of ordinary skill in the art without departing from the spirit and scope of the invention . the scope of the invention will now be defined in the following claims . | US-201414456464-A |
a tool with a telescopic extensible handle for removing a hanging basket of plants from a high hook , the tool including a pivotable ring mounted in a bifurcated support attached to the end of the handle , a hook attached to one end of the support for hanging the tool when not in use , and an upwardly pointing fork for removing baskets hanging from a flexible chain . a method of removing and replacing hanging baskets employing a gimbaled support ring is also disclosed . | the features of the tool of this invention may be seen in the accompanying drawing . an elongated handle 10 has a basket supporting structure attached to its distal end 18 . handle 10 preferably is made of telescopically extensible and retractable sections so it may be used for any of a wide variety of heights , or alternatively , it may be made in several separate sections attachable to each other to make the handle longer or shorter . handle 10 is attached , as by welding or bolting , to the midpoint 17 of a bifurcated yoke support 11 having its two ends 14 pointing upward away from the handle . preferably , yoke support 11 is generally semicircular in shape . ring 12 is mounted pivotally to yoke support ends 14 by means of pivot pins 13 so that ring 12 is freely pivotable through 360 ° inside of yoke support 11 . ring 12 is of the appropriate size to encircle a flower pot under its top ledge as may be seen in fig2 wherein a typical flower pot 19 is shown in dotted lines . the shape of yoke support 11 may be varied to fit different shapes of flower pots . for example , if the pot is deep it will be necessary to shape yoke support 11 to be longer in the direction of the handle . on the two ends 14 of yoke support 11 are placed two types of hook members . the first hook member 15 is positioned with its open side facing downward toward handle 10 . hook member 15 is intended to be used in hanging the tool on a hook or a rod when the tool is not is use . preferably , hook member 15 is generally semicircular in shape . the second hook member 16 is positioned with its open side facing upward away from handle 10 . this hook member is used on hanging baskets which are hung by flexible cords or chains , perhaps connected to a ring which is hung from a hook . the cord , chain , or ring is caught between the arms of hook member 16 and the entire basket and its cords or chains are lifted from the supporting hook . hook member 16 preferably is v - shaped or in the form of a fork . because of the various sizes and shapes of hanging baskets , it may be necessary to have more than one tool to handle the different size baskets in a single location . it also is feasible to employ one tool with a large diameter ring 12 to which can be detachably attached reduced size rings to handle smaller baskets . it is also feasible to employ rings of different shapes , e . g ., rectangles , ellipses , triangles , etc ., to handle baskets of different shapes . it is , of course , preferred that the tool of this invention be light in weight and yet strong . the tool may be made of solid or tubular components although the latter are preferred for strength and lightness . preferably , the tool is made of metal , such as steel or aluminum , or plastic such as vinyl , polyethylene , fiber - glass reinforced polyester , or the like . with ring 12 pivotable through 360 ° it functions as gimbals in that the flower pot will remain upright in ring 12 regardless of the position of handle 10 . this permits a pot to be lifted from a high hook moving handle 10 from a vertical position when the pot is seated in ring 12 to a horizontal position when the pot is brought to the ground with the pot remaining upright during the entire movement of handle 10 . this is very convenient , particularly if , at the same time , handle 10 can be retracted telescopically , or shortened by detaching separable sections , while retrieving a basket from a high place . a preferred arrangement is to have ring 12 suspended below pivot pins 13 in order to provide more stability for the basket being supported in ring 12 . if too much of the weight of the plant and the basket is above the level of pivot pins 13 there is a possibility that the basket and plant may tip and not remain upright during the handling of the tool of this invention . if ring 12 is suspended downwardly by tabs 20 from pins 13 there is little or no chance that the basket and plant will tip over during manipulation of the tool and basket supported thereon so long as the center of gravity of the basket and its contents is below the level of pivot pins 13 . in using the tool of this invention one would stand generally under the hanging basket to be retrieved , extend the handle upwardly until the ring support 12 encircled the basket and contacted it in a supporting manner , perhaps under the collar of the basket or alternatively tightly gripping the side of the basket . the handle would be extended upwardly still farther until the basket was able to be removed from the overhead hook or nail supporting it . the handle is then rotated or swung in an arc from its generally vertical position to a generally horizontal position where the basket can be rested on a supporting surface , e . g ., the ground , the floor of a building , a table or the like . during its movement from the handle in a vertical position to a horizontal position , ring support 12 pivots automatically to maintain the basket in the same upright position relative to the earth at all positions of the handle , as in gimbals . the plant can then be treated , watered , fertilized , pruned , or the like . the entire procedure is then reversed to place the hanging basket on its overhead hook . during the rotation or swinging of the handle through an arc , the handle may be extended or retracted if the handle is made of telescopically connected sections ; or alternatively , if the handle is made of attachable / detachable separate sections , the handle can be made longer or shorter to accommodate the needs of the operator and the surrounding space . while the invention has been described with respect to certain specific embodiments , it will be appreciated that many modifications and changes may be made by those skilled in the art without departing from the spirit of the invention . it is intended , therefore , by the appended claims to cover all such modifications and changes as fall within the true spirit and scope of the invention . | US-69868485-A |
the invention relates to indole - derived compounds and to the use of said compounds for the preparation of a medicament that can be used to treat diseases related to the process of splicing pre - messenger rnas in the cell , such as frasier syndrome , frontotemporal dementia linked to chromosome 17 , leigh syndrome , atypical cystic fibrosis , certain neuropathologies including alzheimer &# 39 ; s disease linked to a mutation in the tau protein , muscle atorphy which affects the smn gene , depression linked to a serotonin splicing impairment , and certain cancers in which the global splicing process is affected , as well as viral diseases such as aids . | by “ diseases related to pre - messenger rna splicing processes within the cell ” is meant all the diseases related to the splicing process , which is to say , diseases caused by splicing - process modifications and diseases whose appearance requires that cellular splicing processes are activated . meant in particular are genetic diseases resulting from splicing - process modification such as for example frasier syndrome , frontotemporal dementia related to chromosome 17 ( a form of parkinson &# 39 ; s ), leigh syndrome ( a type of encephalopathy ), atypical cystic fibrosis , certain neuropathologies , such as in particular alzheimer &# 39 ; s , related to tau protein mutation , amyotrophy that influences the smn ( survival of motor neuron ) gene , depression related to disturbances in serotonin splicing and certain cancers in which the overall splicing process is affected ( notably breast cancer , colon cancer and certain lymphomas ). equally meant are diseases of viral origin or due to the intrusion of a virus into a human or animal , termed viral diseases , for which ese sequences are identified . aids , whose ese sequences are identified in the splicing of certain pre - messenger rna of key genes implicated in the replication of the virus responsible for aids , can be cited in particular . by “ atom of halogen ” is meant the group f , cl , br and i , and more particularly cl . by “ anhydro base ” is meant a compound resulting from acid - base neutralization ( with loss of water ) of iminium hydroxides containing an acid site conjugated with the iminium function ( see iupac ). in the case of the present invention , hydroxide is replaced by amino in the anhydro base . the first advantage related to the use of indole derivatives such as benzo - indole or pyrido - indole according to the invention to treat diseases related to the splicing process is of a financial nature . indeed , the cost of production of these molecules is much lower than that of antisense oligonucleotides or of pna hybrid molecules . the second advantage of indole derivatives according to the invention is related to their ease of administration and the fact that this treatment strategy does not require the use of expression vectors . penetration of the molecules according to the invention into the cells and their targeting towards specific tissues can be carried out either by using polymers ( uekama , k . et al ., cyclodextrins in drug carrier systems . crit . rev . ther . drug carrier . syst . 1987 . 3 , 1 - 40 ), by using vectors such as peptides and lipids ( prochiantz , a ., getting hydrophilic compounds into cells : lessons from homeopeptides . curr . opin . neurobiol . 1996 . 6 , 629 - 634 et vives , e . et al ., a truncated hiv - 1 tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus . j . biol . chem . 1997 . 272 , 16010 - 16017 ) or by using particles such as nanoparticles and liposomes ( douglas , s . j . et al ., nanoparticles in drug delivery . crit . rev . ther . drug carrier . syst . 1987 . 3 , 233 - 261 and gregoriadis , g . et al ., liposomes in drug delivery . clinical , diagnostic and ophthalmic potential . drugs 1993 . 45 , 15 - 28 ). in a preferred embodiment , the benzo - indole derivatives are pyrido - carbazole derivatives , and in formula i , when x represents cr4 , ring a represents r1 represents a — n — r6r7 or — nh — r8 group , a hydrogen atom , a — c ═ n — oh or — o — c (═ o )( ch 3 ) or — c ≡ n group , r4 represents a hydroxy group or a methoxy group possibly substituted by a phenyl group , r2 , r5 , r6 , r7 , r8 , r9 , r10 , r11 and r12 are such as defined previously . in another preferred embodiment , the pyrido - indole derivatives are derivatives of pyrido - pyrrolo - isoquinoline ( or quinoline ) and in formula i , when x represents n or n + r4 anhydro base , ring a represents r1 represents a halogen atom , an amino group , — n — r 6 r 7 or — nh — r8 , n and r5 is absent when x represents n + r4 anhydro base , r6 , r7 , r8 , r9 , r10 , r12 and r13 are such as previously defined . in still another preferred embodiment , the pyrido - indole derivatives are derivatives of benzo - pyrido - indole and in formula i , when x represents n , ring a represents r3 represents a halogen atom , an amino group , a — n — r6r7 or — nh — r8 group , r5 represents a hydrogen atom or a methyl group , r2 and r11 represent a hydrogen atom or a methyl group , or are respectively absent when ring a is in position a and c , r13 represents a hydrogen atom , and z , r6 , r7 , r8 , r9 , r10 and r12 are such as previously defined . n ′-( 9 - methoxy - 5 , 6 , 11 - trimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 9 - methoxy - 6 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 10 - chloro - 2 , 6 - dimethyl - 2h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline , 9 - hydroxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl acetic acid ester , 1 -( 3 - dimethylamino - propylamino ) 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - carbaldehyde oxime , n ′( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n ′-( 6 , 11 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , allyl -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , n , n - diethyl - n4 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- pentane - 1 , 4 - diamine , n , n - dimethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- propane - 1 , 3 - diamine , 9 - methoxy - 1 -[ 6 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- hexylamino ]- 2 , 5 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 2 - ium iodide , { 3 -[ 4 ( 3 - amino - propyl )- piperazin - 1 - yl ]- propyl }- 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , ( 3 - imidazol - 1 - yl - propyl )- 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , ( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 , 2 , 6 , 6 - tetramethyl - piperidin - 4 - yl )- amine , n - ethyl - n -[ 3 -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propyl ]- succinamic acid , n - ethyl - n -[ 3 -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - ylamino )- propyl ]- succinamic acid , 5 , 11 - dimethyl - 1 -( 3 - methyl - butylamino )- 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , 2 -{( 2 - hydroxy - ethyl )-[ 3 -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - ylamino } propyl ]- amino - ethanol , n , n - diethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- ethane - 1 , 2 - diamine , n ′-( 9 - benzyloxy - 6 - methoxymethyl - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - diethyl - propane - 1 , 3 - diamine , 1 -( 3 - diethylamino - propylamino )- 6 - methoxymethyl - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , 9 - methoxy - 5 - methyl - 4 , 6 - dihydro - 3h - pyrido [ 4 , 3 - b ] carbazol , n -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- propane - 1 , 3 - diamine , 1 -( 3 - diethylamino - propylamino )- 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n - 3 -( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - 1 - diethyl - butane - 1 , 3 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 , 6 , 11 - trimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- ethane - 1 , 2 - diamine , n -( 6 , 11 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , n -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n ′-( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′ 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n -( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - carbonitrile , 1 -( 3 - diethylamino - propylamino )- 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , ( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 3 - morpholin - 4 - yl - propyl )- amine , n - ethyl - n ′-( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- pentane - 1 , 5 - diamine , n -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- hexane - 1 , 6 - diamine , n ′-( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - ethane - 1 , 2 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , ( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 - pyrrolidin - 1 - yl - ethyl )- amine , 3 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propane - 1 , 2 - diol , 1 - diethylamino - 3 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propan - 2 - ol , ( 3 - imidazol - 1 - yl - propyl )-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- amine , decyl -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , n -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- butane - 1 , 4 - diamine , 8 - methyl - 11 -( 3 - methylamino - propylammo )- 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , 1 - diethylamino - 3 -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propan - 2 - ol , n , n - diethyl - n ′-( 9 - methoxy - 5 , 6 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- ethane - 1 , 2 - diamine , n - n , diethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- propane - 1 , 3 - diamine , n - 1 , n - 10 - bis -( 3 - diethylamino - propyl )- 3 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline - 1 , 10 - diamine , n - ethyl - n ′-( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n -( 5 , 6 - dimethyl - 5h - benzo [ f ] pyrido [ 4 , 3 ] indol - 1 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , n ′-( 9 - methoxy - 5 , 6 - dimethyl - 5h - benzo [ f ] pyrido [ 4 , 3 - b ] indol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 1 -( 3 - dimethylamino - propylamino )- 5 , 6 - dimethyl - 5h - benzo [ f ] pyrido [ 4 , 3 - b ] indol - 9 - ol , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n ′- methyl - propane - 1 , 3 - diamine , 5 -( 7 - chloro - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 3 - yloxy )- pentanoic acid ethyl ester , n , n - dimethyl - n ′-( 10 , 11 - dimethyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline ) 4 - yl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 10 , 11 - dimethyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 -] quinoline )- 4 - yl - propane - 1 , 3 - diamine , n ′-( 7 - methoxy - 10 , 11 - dimethyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 7 - methoxy - 10 , 11 - dimethyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4 - yl )- propane - 1 , 3 - diamine , 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl - amine , n , n - diethyl - n ′-( 7 - methoxy - 11 - methyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4 - yl )- propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 11 - methyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline )- 4 - yl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 7 - methoxy - 5 , 11 - dimethyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4yl )- propane - 1 , 3 - diamine , n , n - dimethyl - n ′-( 11 - methyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline )- 4 - yl - propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - propylamino )- 8 - ethyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , 7 -( 3 - diethylamino - propylamino ) 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 4 - ol , 11 -( 3 - dimethylamino - propylamine )- 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n ′-( 3 - methoxy - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′- 8 - ethyl - 3 - methoxy - 7 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - propylamino )- 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 2 - ol , n , n - diethyl - n ′-( 3 - methoxy - 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - propylamino )- 7 , 8 - dimethyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , 7 -( 3 - dimethylamino - propylamino )- 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 4 - ol , n ′-( 2 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- n , n - diethyl - propane - 1 , 3 - diamine , n ′-( 7 , 8 - dimethyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - dimethyl - n ′-( 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , 7 -( 3 - diethylamino - propylamino )- 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n , n - diethyl - n ′-( 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , 4 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamine , n , n - diethyl - n ′-( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , n ′-( 4 - methoxy - 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 7 -( 3 -( dimethylamino - propylamino )- 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 4 - ol , n , n - dimethyl - n ′-( 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - 2 - methyl - propylamino )- 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- propane - 1 , 3 - diamine , 11 -( 3 - amino - propylamino )- 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , n ′-( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 4 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n -( 3 - amino - propyl ) n ′-[ 3 -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - ylamino )- propyl ] butane - 1 , 4 - diamine , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- hexane - 1 , 6 - diamine , n -[ 3 -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamino )- propyl ]- propane - 1 , 3 - diamine , n -[ 3 -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamino )- propyl ]- n - methyl - propane - 1 , 3 - diamine , n -[ 3 -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - ylamino )- propyl ]- propane - 1 , 3 - diamine , n -( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl - amine . in a highly preferred embodiment , the pyrido - carbazole derivatives are selected from the group comprised of : n ′-( 9 - methoxy - 5 , 6 , 11 - trimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 9 - methoxy - 6 , 11 - dimethyl - 5h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 9 - hydroxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl acetic acid ester , 1 -( 3 - dimethylamino - propylamino ) 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - carbaldehyde oxime , n ′( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , allyl -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , n , n - diethyl - n4 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- pentane - 1 , 4 - diamine , 9 - methoxy - 1 -[ 6 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- hexylamino ]- 2 , 5 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 2 - ium iodide , { 3 -[ 4 ( 3 - amino - propyl )- piperazin - 1 - yl ]- propyl }- 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , ( 3 - imidazol - 1 - yl - propyl )- 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , ( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 , 2 , 6 , 6 - tetramethyl - piperidin - 4 - yl )- amine , n - ethyl - n -[ 3 -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propyl ]- succinamic acid , 5 , 11 - dimethyl - 1 -( 3 - methyl - butylamino )- 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n ′-( 9 - benzyloxy - 6 - methoxymethyl - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - diethyl - propane - 1 , 3 - diamine , 1 -( 3 - diethylamino - propylamino )- 6 - methoxymethyl - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , 9 - methoxy - 5 - methyl - 4 , 6 - dihydro - 3h - pyrido [ 453 - b ] carbazol , 1 -( 3 - diethylamino - propylamino )- 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 , 6 , 11 - trimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- ethane - 1 , 2 - diamine , n -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - carbonitrile , 1 -( 3 - diethylamino - propylamino )- 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , ( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 3 - morpholin - 4 - yl - propyl )- amine , n - ethyl - n ′-( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- pentane - 1 , 5 - diamine n -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- hexane - 1 , 6 - diamine , n ′-( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - ethane - 1 , 2 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , ( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 - pyrrolidin - 1 - yl - ethyl )- amine , 3 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propane - 1 , 2 - diol , 1 - diethylamino - 3 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propan - 2 - ol , decyl -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , 1 - diethylamino - 3 -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propan - 2 - ol , n , n - diethyl - n ′-( 9 - methoxy - 5 , 6 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- ethane - 1 , 2 - diamine , n - ethyl - n ′-( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , n ′-( 7 - methoxy - 10 , 11 - dimethyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 7 - methoxy - 10 , 11 - dimethyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4 - yl )- propane - 1 , 3 - diamine , 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl - amine , n , n - diethyl - n ′-( 7 - methoxy - 11 - methyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4 - yl )- propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 7 - methoxy - 5 , 11 - dimethyl - 10h - pyrido [ 2 , 3 - b ] carbazol - 4yl )- propane - 1 , 3 - diamine . in another highly preferred embodiment , the pyrido - pyrrolo - isoquinoline derivatives are selected from the group comprised of : 10 - chloro - 2 , 6 - dimethyl - 2h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline , n ′-( 6 , 11 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - dimethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- propane - 1 , 3 - diamine , n - ethyl - n -[ 3 -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - ylamino )- propyl ]- succinamic acid , 2 -{( 2 - hydroxy - ethyl )-[ 3 -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - ylamino } propyl ]- amino - ethanol , n , n - diethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- ethane - 1 , 2 - diamine , n -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- propane - 1 , 3 - diamine , n - 3 -( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - 1 - diethyl - butane - 1 , 3 - diamine , n -( 6 , 11 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , n ′-( 5 ) 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n -( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , ( 3 - imidazol - 1 - yl - propyl )-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- amine , n - n - diethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- propane - 1 , 3 - diamine , n - 1 , n - 10 - bis -( 3 - diethylamino - propyl )- 3 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline - 1 , 10 - diamine , n , n - dimethyl - n ′-( 10 , 11 - dimethyl - 10h - pyrido [ 3 ′ 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline ) 4 - yl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 10 , 11 - dimethyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline )- 4 - yl - propane - 1 , 3 - diamine , n , n - diethyl - n ′-( 11 - methyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline )- 4 - yl - propane - 1 , 3 - diamine , n , n - dimethyl - n ′-( 11 - methyl - 10h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 3 , 2 - g ] quinoline )- 4 - yl - propane - 1 , 3 - diamine , n -( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl - amine . in another highly preferred embodiment , the benzo - pyrido - indole derivatives are selected from the group comprised of : n -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- butane - 1 , 4 - diamine , 8 - methyl - 11 -( 3 - methylamino - propylamino )- 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n -( 5 , 6 - dimethyl - 5h - benzo [ f ] pyrido [ 4 , 3 ] indol - 1 - yl )- n ′- ethyl - propane - 1 , 3 - diamine , n ′-( 9 - methoxy - 5 , 6 - dimethyl - 5h - benzo [ f ] pyrido [ 4 , 3 - b ] indol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 1 -( 3 - dimethylamino - propylamino )- 5 , 6 - dimethyl - 5h - benzo [ f ] pyrido [ 4 , 3 - b ] indol - 9 - ol , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n ′- methyl - propane - 1 , 3 - diamine , 5 -( 7 - chloro - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 3 - yloxy )- pentanoic acid ethyl ester , 11 -( 3 - dimethylamino - propylamino )- 8 - ethyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , 7 -( 3 - diethylamino - propylamino ) 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 4 - ol , 11 -( 3 - dimethylamino - propylamine )- 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n ′-( 3 - methoxy - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′- 8 - ethyl - 3 - methoxy - 7 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - propylamino )- 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 2 - ol , n , n - diethyl - n ′-( 3 - methoxy - 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - propylamino )- 7 , 8 - dimethyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , 7 -( 3 - dimethylamino - propylamino )- 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 4 - ol , n ′-( 2 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- n , n - diethyl - propane - 1 , 3 - diamine , n ′-( 7 , 8 - dimethyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n , n - dimethyl - n ′-( 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , 7 -( 3 - diethylamino - propylamino )- 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n , n - diethyl - n ′-( 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , 4 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamine , n , n - diethyl - n ′-( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , n ′-( 4 - methoxy - 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 7 -( 3 -( dimethylamino - propylamino )- 10 , 11 - dimethyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 4 - ol , n , n - dimethyl - n ′-( 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- propane - 1 , 3 - diamine , 11 -( 3 - dimethylamino - 2 - methyl - propylammo )- 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- propane - 1 , 3 - diamine , 11 -( 3 - amino - propylamino )- 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 3 - ol , n -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , n ′-( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 4 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n -( 3 - amino - propyl ) n ′-[ 3 -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - ylamino )- propyl ] butane - 1 , 4 - diamine , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- hexane - 1 , 6 - diamine , n -[ 3 -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamino )- propyl ]- propane - 1 , 3 - diamine , n -[ 3 -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamino )- propyl ]- n - methyl - propane - 1 , 3 - diamine , n -[ 3 -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - ylamino )- propyl ]- propane - 1 , 3 - diamine . in an embodiment even more preferred , the indole derivatives are selected from the group comprised of : n ′-( 9 - methoxy - 5 , 6 , 11 - trimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n ′-( 9 - methoxy - 6 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 10 - chloro - 2 , 6 - dimethyl - 2h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline , 1 -( 3 - dimethylamino - propylamino ) 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n ′( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , allyl -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , n , n - diethyl - n4 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- pentane - 1 , 4 - diamine , 9 - methoxy - 1 -[ 6 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- hexylamino ]- 2 , 5 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 2 - ium iodide , ( 3 - imidazol - 1 - yl - propyl )- 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- amine , ( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 , 2 , 6 , 6 - tetramethyl - piperidin - 4 - yl )- amine , n - ethyl - n -[ 3 -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propyl ]- succinamic acid , n - ethyl - n -[ 3 -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - ylamino )- propyl ]- succinamic acid , 5 , 11 - dimethyl - 1 -( 3 - methyl - butylamino )- 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n , n - diethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- ethane - 1 , 2 - diamine , 1 -( 3 - diethylamino - propylamino )- 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n , n - diethyl - n ′-( 9 - methoxy - 5 , 6 , 11 - trimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- ethane - 1 , 2 - diamine , n ′-( 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , 1 -( 3 - diethylamino - propylamino )- 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 9 - ol , n , n - diethyl - n ′-( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine , 1 - diethylamino - 3 -( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propan - 2 - ol , n -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- butane - 1 , 4 - diamine , n , n - diethyl - n ′-( 9 - methoxy - 5 , 6 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- ethane - 1 , 2 - diamine , n , n - diethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline - 10 - yl )- propane - 1 , 3 - diamine , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n ′- methyl - propane - 1 , 3 - diamine , 4 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamine , n -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - yl )- propane - 1 , 3 - diamine , n ′-( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- n , n - dimethyl - propane - 1 , 3 - diamine , n -[ 3 -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamino )- propyl ]- n - methyl - propane - 1 , 3 - diamine , 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl - amine . 10 - chloro - 2 , 6 - dimethyl - 2h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline , ( 9 - methoxy - 6 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 , 2 , 6 , 6 - tetramethyl - piperidin - 4 - yl )- amine , n - ethyl - n -[ 3 -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - ylamino )- propyl ]- succinamic acid , n - ethyl - n -[ 3 -( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - ylamino )- propyl ]- succinamic acid , 9 - methoxy - 5 - methyl - 4 , 6 - dihydro - 3h - pyrido [ 4 , 3 - b ] carbazole , n -( 3 - amino - propyl ) n ′-[ 3 -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - ylamino )- propyl ] butane - 1 , 4 - diamine , n -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - yl )- hexane - 1 , 6 - diamine , n -[ 3 -( 3 - methoxy - 10 - methyl - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indol - 7 - ylamino )- propyl ]- propane - 1 , 3 - diamine , n -[ 3 -( 3 - methoxy - 8 - methyl - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indol - 11 - ylamino )- propyl ]- propane - 1 , 3 - diamine . another object of the invention is the compounds such as previously described for use as medicines . in a preferred embodiment , the compounds according to the invention have the capacity to inhibit pre - messenger rna splicing processes that are either constitutive , or , more specifically ., dependent on regulatory sequences termed eses ( exonic splicing enhancers ), ises ( intronic splicing enhancers ), esss ( exonic splicing silencers ) and isss ( intronic splicing silencers ). in a still more preferred embodiment , the splicing processes are either constitutive and / or dependent on ese regulatory sequences . in another preferred embodiment according to the invention , the diseases related to the splicing process are the genetic diseases resulting from splicing - process modification such as for example frasier syndrome , frontotemporal dementia related to chromosome 17 ( a form of parkinson &# 39 ; s ), leigh syndrome ( a type of encephalopathy ), atypical cystic fibrosis , certain neuropathologies , such as in particular alzheimer &# 39 ; s , related to tau protein mutation , amyotrophy that influences the smn ( survival motor neuron ) gene , depression related to disturbances in serotonin splicing and certain cancers in which the overall splicing process is affected ( notably breast cancer , colon cancer and certain lymphomas ). in another preferred embodiment , the diseases related to the splicing process are diseases of viral origin for which ese sequences are identified . in an embodiment according to the invention , the aforementioned medicine also includes an excipient that makes it possible to formulate the compounds according to formula i and the aforementioned medicine is presented in solid or liquid form to be prepared and to be administered by intravenous route . the compounds according to the invention will be administered preferably by intravenous route at a concentration of 80 - 100 mg / m 2 ( cf . paoletti c . et al ., antitumor activity , pharmacology , and toxicity of ellipticine , ellipticinium , and 9 - hydroxy derivatives : preliminary clinical trials of 2 - methyl - 9 - hydroxy ellipticinium ( nsc 264 - 137 ) in recent results in cancer research , vol 74 , pp . 108 - 123 , 1980 , g . mathé and f . m . muggia , eds ( springer - verlag pbl ). the concentration will be chosen by those skilled in the art according to the organ or tissue to be treated , the state of advancement of the disease and the targeting method used . the compounds presented in tables 1 and 2 below were tested in a concentration range of 1 μm , 10 μm and 100 μm , and were selected initially on the basis of their capacity to inhibit , in vitro , the splicing of two types of model pre - mrnas . table 1 represents the compounds according to the invention and table 2 represents compounds tested having a chemical structure different from the compounds according to the invention . the first type of pre - messenger corresponds to minx derived from an adenovirus transcript for which splicing is constitutive ( zillmann , m . et al . ( 1988 ), gel electrophoretic isolation of splicing complexes containing u1 small nuclear ribonucleoprotein particles . mol . cell biol . 8 , 814 - 821 ). this pre - messenger is obtained in radioactive form by transcription in vitro according to a protocol provided by promega using 1 μg of linearized plasmid , 20 units of sp6 polymerase and 5 μm [ α - 32p ] utp in a reaction volume of 25 μl . 50 fmol of this transcript were used for standard splicing reactions containing in 20 μl : 10 mm triethanolamine ph 7 . 9 ; 50 mm kcl , 0 . 1 mm edta ; 10 % glycerol ; 0 . 5 mm dtt ; 20 mm creatine phosphate ; 2 . 5 mm atp ; 2 . 5 nm mgcl 2 and 6 % polyvinylalcohol . the reactions were left to incubate for 1 h at 30 ° c . to test the effect of the compounds according to the invention , 1 μl of the suitable dilution of each compound was added at the beginning of the reaction in the form of a soluble solution in 10 % dmso . the rnas produced during the splicing reaction were extracted , analyzed on a 7 % polyacrylamide denaturing gel then revealed by autoradiography . an example of inhibition of minx transcript splicing obtained with 10 μm of compound c 2 ( lane 4 ) is presented in fig1 . the second type of m3s1 pre - messenger is derived from the human beta - globulin gene ( labourier , e . et al . ( 1999 ), antagonism between rsf1 and sr proteins for both splice - site recognition in vitro and drosophila development . genes dev . 13 , 740 - 753 ) and its splicing is strictly dependent on an auxiliary ese sequence recognized specifically by the sr asf / sf2 protein . conditions for the transcription , splicing and analysis of this pre - messenger &# 39 ; s products are identical to those used for the minx pre - messenger . an example of the m3s1 splicing inhibition obtained with 10 μm of compounds c 2 , c 3 and c 14 ( lanes 4 , 5 and 12 ) is presented in fig2 . the activity of the products has also been tested in splicing - complex formation reactions in vitro ( fig3 ) as described in pilch b . et al . ( specific inhibition of serine - and arginine - rich splicing factors , phosphorylation , spliceosome assembly , and splicing by the antitumor drug nb - 506 . cancer res . 2001 . 61 , 6876 - 6884 ). m3s1 transcript splicing reactions in the presence of various compounds according to the invention performed under the same conditions as those described for fig1 are stopped after 30 minutes of incubation by the addition of heparin and glycerol at a final concentration of 1 mg / ml and 15 %, respectively . the splicing complexes are separated on a non - denaturing 5 % acrylamide gel and are revealed by autoradiography . fig3 shows an example of inhibition of the formation of splicing complexes a and b to the detriment of the appearance of abortive complexes for compounds c 2 , c 3 and c 14 ( lanes 3 , 4 and 9 ), used at a concentration of 50 μm . all of the compounds represented in table 1 are capable of inhibiting the formation of m3s1 transcript splicing complexes at concentrations ranging between 10 μm and 50 μm . in vivo inhibition of the ese - dependent splicing of gfp ( green fluorescent protein ) mrna in order to test the efficiency of indole derivatives ex vivo , fibroblast hela cell lines were established stably expressing a transgene corresponding to gfp whose sequence was interrupted by an ese sequence flanked by two identical introns of the human beta - globulin gene described in example 1 ( see fig5 a ). to detect the messenger rnas arising from the splicing of this gene , the rt - pcr technique was used with primers in the gfp sequence on each side of the ese and the pcr products were analyzed on agarose gel . in almost all the lines established , a single fragment of 250 base pairs ( bp ) was amplified by pcr ( fig5 a , lanes 2 and 3 ) and it corresponds to an rna messenger which included the ese between the two gfp sequences . the result indicates that the ese has a dominant effect and that the rna messenger produced after splicing contains the two parts of the gfp interrupted by the ese ( fig5 a , gfp - ese - gfp ). conversely , the treatment of cells by indole derivatives c 28 ( lane 4 ) and c 14 ( lane 5 ) revealed a fragment of 194 bp , to the detriment of the 250 bp fragment , which no longer contained an ese sequence between the gfp sequences , thus demonstrating that certain indole derivatives according to the invention can suppress the effect of eses in cells . certain compounds represented in table 1 were tested with a concentration at least equal to 1 μm and proved to be ineffective in this test at this concentration as they did not induce a change in the splicing profile of the gfp - ese transgene . nevertheless , it should be noted that the ese of the gfp - ese transgene used in the experiments described above is specific to the protein sr sf2 / asf and it is quite probable that the other compounds according to the invention represented in table 1 are capable of influencing the splicing controlled by other types of eses specific to other sr proteins ( sc35 , 9g8 , srp55 , srp40 or srp75 ). this hypothesis is supported by the in vitro splicing results represented in table 3 below which indicate that compounds c16 , c19 , c42 , c50 , c57 , c76 , c77 , c78 , c79 , c80 , c82 , c85 , c87 , c88 , c93 and c95 inhibit the activity of the srp55 protein specifically . the present invention thus encompasses the use of indole - derived compounds for the treatment of genetic diseases resulting from modification of the splicing processes , either consecutive or dependent on ese , ise , ess or iss regulatory sequences . in order to demonstrate the selectivity of the action on ese sequences by the compounds according to the invention , it was decided to use another model substrate containing two introns whose splicing depends on two different ese sequences . in this substrate the sequences corresponding to exon 7 - intron 7 - exon 8 of the gene coding for the pyruvate dehydrogenase e1α subunit ( pdh e1α ) are inserted downstream from the m3s1 sequence ( m3s1 - pdh , see fig4 a ). intron 7 of this transcript contains a point mutation which creates a high affinity sr hsc35 protein binding site . this mutation , which causes the loss of pdh e1α expression in patients suffering from leigh syndrome ( an encephalopathy in children ), leads to the appearance of a cryptic site 46 nucleotides downstream from the authentic 5 ′ splicing site ( fig4 a ). this substrate , likely to give rise to two products , one with and one without the 46 nucleotides of pdh intron 7 , is ideal for determining the specificity of the compounds with respect to the various ese sequences present within the same transcript . compound c 2 , which inhibits m3s1 , abolishes m3s1 - pdh splicing completely ( fig4 b , compare lanes 1 and 2 ). inhibition of m3s1 - pdh is also observed with compound c 8 ( fig4 b , lane 5 ), indicating that the ese sequence contained in m3s1 is required to initiate the first splicing event serving to eliminate intron 1 . conversely , compound c 4 , inactive on m3s1 , has no effect ( fig4 b , lane 3 ). however , the screening of other compounds that do not modify m3s1 splicing revealed in a surprising way that compound c 7 blocks the formation of rna species arising from pdh splicing that include the 46 nucleotides of intron 7 , but has no effect on those derivatives from normal pdh splicing ( fig4 b , lane 4 ). compound c 7 is thus an excellent inhibitor of defective splicing that is dependent on hsc35 ese , but not on authentic splicing . this compound can thus be envisaged for treating patients suffering from this encephalopathy . the aids virus , like practically all retroviruses , has recourse to alternative splicing to express the genes essential to its replication . indeed , the version of the virus that integrates itself into the genome of human cells is transcribed in the form of a single precursor which , by alternative splicing , generates 40 different rna messengers coding for viral proteins essential to its replication ( furtado et al ., 1991 . analysis of alternatively spliced human immunodeficiency virus type - 1 mrna species , one of which encodes a novel tat - env fusion protein . virology , 185 : 258 - 270 ; purcell and martin , 1993 . alternative splicing of human immunodeficiency virus type 1 mrna modulates viral protein expression , replication , and infectivity . j . virol ., 67 : 6365 - 78 ). these splicing events are controlled by several ese regulatory sequences , some of which are localized downstream from the splicing sites responsible for the expression of key viral replication proteins such as tat , rev , vpu , env and nef ( caputi et al ., 2004 . a bidirectional sf2 / asf - and srp40 - dependent splicing enhancer regulates human immunodeficiency virus type 1 rev , env , vpu , and nef gene expression . j . virol . 78 : 6517 - 26 ; pongoski et al ., 2002 . positive and negative modulation of human immunodeficiency virus type 1 rev function by cis and trans regulators of viral rna splicing . j . virol . 76 : 5108 - 20 ). since the compounds according to the invention inhibit the use of ese - sequence - dependent splicing sites , their effectiveness to block viral replication was tested . to this end , human lymphocyte cell line u1 , which is chronically infected by hiv ( folks et al ., 1988 . characterization of a promonocyte clone chronically infected with hiv and inducible by 13 - phorbol - 12 - myristate acetate . j . immunol ., 140 : 1117 - 1122 ) and which produces large quantities of virus after stimulation by pma ( phorbol myristate acetate ), was used . as a result , this cell line constitutes an excellent model to mimic the transition between the latency phase and the viral production phase observed in patients infected by hiv . the results of this experiment are presented in fig6 in which u1 cells ( 5 × 10 5 ) were treated with 50 nm of pma in the absence ( fig6 , lane 1 ) or in the presence of 2 . 5 μm of compounds c 47 , c 97 , c 58 , c 57 , c 92 , c 91 , c 90 , c 83 , c 73 , c 34 , c 51 , c 45 , c 13 , c 10 , c 44 , c 6 , c 7 , c 41 , c 50 , c 32 , c 2 , c 1 , c 29 , c 35 and c 99 ( fig6 , lanes 3 - 27 , respectively ). after 24 h of treatment , the virus &# 39 ; s transcripts were amplified by rt - pcr using specific vih , bss and sj4 . 7a primers ( jacquenet et al ., 2001 , a second exon splicing silencer within human immunodeficiency virus type 1 tat exon 2 represses splicing of tat mrna and binds protein hnrnp . h . j . biol . chem . 276 : 40464 - 75 ) and a radioactive tracer ( α - 32p ) ctp . the amplification products were analyzed on a 7 % polyacrylamide denaturing gel and then revealed by autoradiography . among the 29 compounds tested , compounds c 47 , c 97 , c 57 , c 92 , c 91 , c 83 , c 51 , c 13 , c 10 , c 44 , c 41 , c 50 , c 32 , c 2 , c 1 , c 29 , c 35 and c 99 ( lanes 3 , 4 , 6 - 8 , 10 , 13 , 15 - 17 , 20 - 27 , respectively ) were shown to be excellent inhibitors of hiv multiplication because no amplification of the virus was detected in the cells treated by these compounds . 50 % nah ( 90 mg ) is added to the solution of 10 - chloro - 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline ( 400 mg ; product known , already published ) in n , n - dimethylacetamide ( 20 ml ) cooled to − 10 ° c . the mixture is stirred for 30 min then ch 3 i ( 0 . 11 ml ) is introduced and the mixture is stirred again at − 10 ° c . for 2 . 5 h . water and ch 2 cl 2 are added and the organic phase is separated , dried ( mgso 4 ) and dry evaporated . the residue obtained is chromatographed on a silica column by eluting successively with ch 2 cl 2 - etoh ( 9 : 1 v / v ) then etoh - net 3 ( 95 : 5 v / v ) to yield respectively 10 - chloro - 5 , 6 - dimethyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline ( 66 mg , 16 % yield ) and the expected 10 - chloro - 2 , 6 - dimethyl - 2h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinoline ( 138 mg , 32 % yield ) in the form of yellow microcrystals ( point melting & gt ; 260 ° c .). nmr in agreement . the mixture of 1 - chloro - 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazole ( 1 . 0 g ; product known , already published ) and 4 - amino - 2 , 2 , 6 , 6 - tetramethylpiperidin ( 1 . 0 g ) is heated at 150 ° c . for 21 h . excess amino is eliminated by evaporation under reduced pressure . water is added to the residue obtained to form a solid . this solid is filtered , washed with water , then recrystallized from xylene to yield the expected ( 9 - methoxy - 5 - methyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )-( 2 , 2 , 6 , 6 - tetramethyl - piperidin - 4 - yl )- amine ( 1 . 0 g , 71 % yield ) in the form of yellow microcrystals ( melting point : 223 - 225 ° c .). nmr in agreement . a solution of 100 mg of succinic anhydride ( 1 mm ) and 376 mg ( 1 mm ) of n - ethyl -( 9 - methoxy - 5 , 11 - dimethyl - 6h - pyrido [ 4 , 3 - b ] carbazol - 1 - yl )- propane - 1 , 3 - diamine in 100 ml of dry toluene was brought to reflux for 5 h . the precipitate obtained after cooling was dried and recrystallized in acetone . 270 mg ( 54 . 6 %) of the desired product were obtained in the form of a solid ( f ˜ 150 °). centesimal analysis for c 27 h 32 n 4 o 4 + h 2 o ; calc . : c , 65 . 57 ; h , 6 . 93 ; n , 11 . 33 exp . : c , 65 . 18 ; h , 6 . 88 ; n , 10 . 95 . nmr and ms in agreement . a solution of 75 mg of succinic anhydride ( 0 . 75 mm ) and 250 mg ( 0 . 75 mm ) of n - ethyl - n ′-( 6 - methyl - 5h - pyrido [ 3 ′, 4 ′: 4 , 5 ] pyrrolo [ 2 , 3 - g ] isoquinolin - 10 - yl ) propane - 1 , 3 - diamine in 80 ml of dry toluene was brought to reflux for 4 h . the precipitate obtained after cooling was dried and recrystallized with acetone . 240 mg ( 65 . 6 %) was obtained in the form of solid ( f ˜ 150 °). centesimal analysis for c 24 h 27 n 5 o 3 + 3h 2 o ; calc . : c , 59 . 12 ; h , 6 . 82 ; n , 14 . 37 ; exp . ; c , 59 . 14 ; h , 6 . 88 ; n , 14 . 17 . nmr and ms in agreement . a suspension of 1 . 5 g of 2 -(- 6 - methoxy - 1 - methyl - 9h - carbazol - 2yl )- ethylamine in 15 ml of ethyl formate is brought to reflux for 20 h . the solution obtained is concentrated under a vacuum and the paste obtained is taken up in dichloromethane . after complete evaporation under reduced pressure , the solid obtained is ground then washed with pentane to yield 1 . 6 g ( 98 %) of n - formyl intermediate derivative . 1 . 6 g of this intermediate are dissolved in 120 ml of dry toluene and the mixture is brought to reflux in a tricol flask equipped with a dean stark . 12 ml of pocl 3 are added dropwise over 10 min and reflux is maintained for 24 h . after cooling and evaporation of the toluene and the pocl 3 , under reduced pressure , the solid is taken up in 500 ml 2 n hcl and brought to boil . a light insoluble is filtered and , from the cooled solution , the hydrochloride is dried . the aforementioned is taken up in 2 n nh 4 oh ( up to ph 12 ). after drying , the dry yellow precipitate yields 1 . 4 g ( 92 %) of the desired product . nmr in agreement . the mixture of 11 - chloro - 8 - methyl - 3 - methoxy - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indole ( 210 mg ; product known , already published ) and spermine ( 1 . 0 g ) is heated at 170 ° c . for 18 h . excess amino is eliminated by evaporation under reduced pressure and the residue obtained is taken up in ch 2 cl 2 then washed with water . the organic phase is dried ( mgso 4 ) and dry evaporated . the free base obtained is dissolved in boiling absolute ethanol ( 15 ml ) and then poured into a solution containing maleic acid ( 410 mg ) and ethanol ( 10 ml ). the precipitate obtained is filtered at 20 ° c ., washed with ethanol and dried away from moisture to yield 270 mg ( 39 %) of the expected product &# 39 ; s tetramaleate salt . centesimal analysis for c 43 h 54 n 6 o 17 + 2h 2 o ; calc . : c , 53 . 64 ; h , 6 . 03 ; n , 8 . 73 ; exp . : c , 53 . 83 ; h , 6 . 01 ; n , 8 . 79 . nmr in agreement . the mixture of 11 - chloro - 8 - methyl - 3 - methoxy - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indole ( 360 mg ; product known , already published ) and hexane - 1 , 6 - diamine ( 5 ml ) is heated at 170 ° c . for 18 h . excess amino is eliminated by evaporation under reduced pressure and the residue obtained is taken up in ch 2 cl 2 then washed with water . the organic phase is dried ( mgso 4 ) and dry evaporated . the free base obtained is dissolved in boiling absolute ethanol ( 15 ml ) and then poured into a solution containing maleic acid ( 648 mg ) and ethanol ( 10 ml ). the precipitate obtained is filtered at 20 ° c ., washed with ethanol and dried away from moisture to yield 700 mg ( 89 %) of the expected product &# 39 ; s bimaleate salt . centesimal analysis for c 31 h 36 n 4 o 9 + 2h 2 o ; calc . : c , 57 . 76 ; h , 6 . 21 ; n , 8 . 69 ; exp . : c , 58 . 22 ; h , 9 . 91 ; n , 8 . 47 . nmr in agreement . the mixture of 7 - chloro - 10 - methyl - 3 - methoxy - 11h - benzo [ g ] pyrido [ 4 , 3 - b ] indole ( 335 mg ; product known , already published ) and n -( 3 - aminopropyl )- 1 , 3 - propanediamine ( 8 ml ) is heated at 170 ° c . for 18 h . excess amino is eliminated by evaporation under reduced pressure and the residue obtained is taken up in ch 2 cl 2 then washed with water . the organic phase is dried ( mgso 4 ) and dry evaporated . the free base obtained is dissolved in boiling absolute ethanol ( 15 ml ) and then poured into a solution containing maleic acid ( 620 mg ) and ethanol ( 10 ml ). the precipitate obtained is filtered at 20 ° c ., washed with ethanol and dried away from moisture to yield 460 mg ( 53 %) of the expected product &# 39 ; s trimaleate salt . centesimal analysis for c 35 h 41 n 5 o 13 + h 2 o ; calc . : c , 55 . 48 ; h , 5 . 68 ; n , 9 . 25 exp . : c , 55 . 01 ; h , 5 . 68 ; n , 9 . 14 . nmr in agreement . the mixture of 11 - chloro - 8 - methyl - 3 - methoxy - 7h - benzo [ e ] pyrido [ 4 , 3 - b ] indole ( 290 mg ; product known , already published ) and n -( 3 - aminopropyl )- 1 , 3 - propanediamine ( 5 ml ) is heated at 170 ° c . for 30 h . excess amino is eliminated by evaporation under reduced pressure and the residue obtained is taken up in ch 2 cl 2 then washed with water . the organic phase is dried ( mgso 4 ) and dry evaporated . the free base obtained is dissolved in boiling absolute ethanol ( 15 ml ) and then poured into a solution containing maleic acid ( 620 mg ) and ethanol ( 10 ml ). the precipitate obtained is filtered at 20 ° c ., washed with ethanol and dried away from moisture to yield 360 mg ( 48 %) of the expected product &# 39 ; s trimaleate salt . centesimal analysis for c 35 h 41 n 5 o 13 + 1 . 5 h 2 o ; calc . : c , 54 . 83 ; h . 5 . 74 ; n , 9 . 14 exp . : c , 54 . 98 ; h , 5 . 91 ; n , 8 . 76 . nmr in agreement . | US-57084904-A |
the invention relates to an improved design of wire tensioner for use in electric wire fences . as well as attaching a wire to a fence post , and tensioning the wire , the device also insulates the wire from the metal post . the device comprises an insulating means or body which has an engagement face for engaging with internal surface of a fence post and a spring for applying a tensioning force to the wire . any changes in the length of the wire due to ambient temperature variation can be absorbed by the spring , thus minimising maintenance adjustments of the wire tension . the spring may also be used to press the engagement face against the surface of the fence post , and therefore hold the device in position . the present invention also provides for installing the devices inside a fence post and which contains the high voltage and earth wire connections . | fig1 shows a cross - section of a device ( 1 ) according to one embodiment of the present invention . the preferred embodiment of the device ( 1 ) is rotationally symmetric about the centreline shown in fig1 , and contains a passage ( 6 ) in a ( wire ) insulating means , insulating body ( 2 ). according to this embodiment , the passage ( 6 ) is part of an opening in the device ( 1 ) which is used to hold a wire attachment means , or gripper unit ( 10 ). the “ ribbed ” section ( 3 ) is a compressible spring which experiences compression as tension in a wire , being held and tensioned by the device ( 1 ), increases . in this way , the “ ribbed ” section ( 3 ) acts as a wire tensioning means , or spring , such that tension is applied to the wire by compression of the spring ( 3 ). in alternative embodiments , any other suitable type of compression spring ( 3 , 4 ) could be used to act as a wire tensioning means . in the preferred embodiment , the tension force in the wire is proportional to ( and in some embodiments equal to ) the compression force in the spring ( 3 ). typically , the wire ( or other elongate element ) is held in tension by using one of the devices ( 1 ) according to the present invention at one , or both , ends of the wire . any changes in the wire length , for example , from ambient temperature variation , can then be absorbed by the spring ( 3 ) of the device ( 1 ) at either or both ends of the wire , thus minimising maintenance adjustments of the wire tension . thus , the device ( 1 ) allows the tension in the wire to be controlled ( for example it allows the wire tension to be maintained substantially constant , or to be maintained above a pre - determined threshold ) as the length of the wire changes , for example through a normal range of ambient temperatures , without requiring manual adjustment . typically , such a range of ambient temperatures might be 0 degrees celsius to 50 degrees celsius . more typically , the range might be 5 degrees celsius to 30 degrees celsius . the temperature range could also include values above or below those given above . in the embodiment shown in fig1 , the body ( 2 ) and the spring ( 3 ) are formed from a single elastomeric moulding , and are made from an insulating material . also shown in this embodiment are a first shield portion ( 7 ) for surrounding and insulating a portion of a wire , and a second shield portion ( 8 ) for at least partially insulating a wire , a spring , and / or a wire gripper . both the first ( 7 ) and second ( 8 ) shield portions may be formed from the same ( elastomeric ) moulding as the insulating body and the spring . the first ( 7 ) and second ( 8 ) insulating portions may be formed by any insulating medium , such as an elastomer , polythene , or propylene . in some embodiments , the body ( 2 ), spring ( 3 ), first shield portion ( 7 ) and second shield portion ( 8 ) may be formed separately , and may not necessarily be formed of the same material . for example , in the embodiment shown in fig2 , the spring ( 4 ) is a more conventional helical type metal spring , which may or may not be formed integrally with the body ( 2 ). one or more of the body ( 2 ), the spring ( 3 ), the first shield portion ( 7 ) and / or the second shield portion ( 8 ) may be made from a material which is resistant to degradation from ( solar ) ultra violet ( uv ) radiation . in one embodiment of the invention , the passage ( 6 ) formed in the body ( 2 ) may be blocked when the device ( 1 ) is not in use . the passage ( 6 ) may therefore require breaking through in order to allow a wire and / or a wire gripper to pass through it . the embodiments shown in fig1 and 2 both comprise a frustro conical internal space ( 9 ) which is used to hold a wire gripper ( 10 ) for gripping a wire . the wire gripper ( 10 ) may be a conventional wire gripper , such as that shown in fig3 a and 3 b . in an embodiment of the invention which uses a wire gripper of the type shown in fig3 a and 3 b , in use the wire gripper ( 10 ) is inserted into the passage ( 6 ) of the device ( 1 ), as shown in fig4 a and 4 b . the conventional wire gripper ( 10 ) shown in cross - section in fig3 a comprises an internal split cone section which can be made of hardened steel and serrated to provide a tight grip on a wire which is inserted into the split cone sections when that wire is put under tension . the wire gripper ( 10 ) shown in fig3 a and 3 b is further adapted so as to comprise a spade tab ( 11 ) for making the electrical connections between the relevant wires so that an electrical circuit can be created in an electric fence . the plan view of the wire gripper ( 10 ) shown in fig3 shows a metal washer with a spade tab ( 11 ). two or more such tabs ( 11 ) may be provided , if necessary , for example one for each ( electrical ) connector or connecting wire . while the hv circuit is usually continuous ( so that a cut wire anywhere can generate an alarm ), the same requirement does not apply to the earth wire . thus two tabs may be needed for connection to the earth wire ( usually , inside the fence post ). other embodiments of the invention can use or comprise different styles of wire gripper . these different styles of wire gripper can be conventional , non - conventional or adapted from a conventional wire gripper . fig4 a shows a device ( 1 ) according to an embodiment of the invention similar to that shown in fig1 assembled with a wire gripper ( 10 ) similar to that shown in fig3 a and 3 b . fig4 a shows a case where the spring ( 3 ) is uncompressed . this would occur , for example , if the wire being held by the wire gripper ( 10 ) were to be under very low tension or no tension at all . fig4 b shows a state where the spring ( 3 ) in the device ( 1 ) is fully compressed . this could occur , for example , when the wire being held by the wire gripper ( 10 ) is shorter than , or has contracted from the length of , the wire being held by the wire gripper ( 10 ) shown in fig4 a . the change from the spring ( 3 ) being uncompressed in fig4 a to compressed in fig4 b could occur , for example , due to a change in the length of the wire caused by a change in ambient conditions , such as a temperature variation . as shown in fig4 a and 4 b , the device ( 1 ) is arranged such that the compression force in the spring ( 3 , 4 ) is directly applied , or transferred , to the wire as a tension force in the wire . as such , the compression force in the spring ( 3 , 4 ) can directly affect the tension force in the wire i . e . a change in the compression force in the spring can lead to a ( calculable ) change in tension force in the wire , and vice versa . for example , as the tension force in the wire increases , or tries to increase , ( for example due to a temperature variation ), the spring ( 3 , 4 ) compresses , and thus the compression force in the spring ( 3 , 4 ) increases . thus , the increase in tension in the wire can be controlled through the increase in compression force in the spring ( 3 , 4 ). the spring constant of the spring ( 3 , 4 ) can be chosen as appropriate to control the tension in the wire within a desired range , for example by considering the likely temperature variation that the wire will experience . a portion of a member , here a fence post ( 13 ), is also shown in fig4 a and 4 b . the first shield portion ( 7 ) of the device ( 1 ) is shown as being inserted into a hole ( 14 ) in the fence post ( 13 ), such that the engagement face ( 5 ) of the device ( 1 ) is engaged with an inside face ( 15 ) of the fence post ( 13 ). thus , the engagement face ( 5 ) ensures that the device ( 1 ) as a whole cannot move in the direction of the force applied to the device ( 1 ) due to tension force in the wire , thereby ensuring that the compression force in the spring ( 3 , 4 ) is transferred to the wire . as the conditions are varied such that the wire gripper ( 10 ) moves from the position shown in fig4 a to the position shown in fig4 b , the wire gripper ( 10 ) moves through the passage ( 6 ) in the device ( 1 ) so that in the fully compressed state shown in fig4 b , the outer face of the conical section of the wire gripper ( 10 ) is in contact with the inner face of the conical section ( 9 ) of the device ( 1 ). in other embodiments , the conical sections need not be in contact in the fully compressed state . other embodiments may not require a conical section in either the wire gripper ( 10 ) or the device ( 1 ). typically , the spring ( 3 ) would be fully compressed when a force of about 20 kg is applied . in operation , this applied force could come from tension in a wire being held by the wire gripper ( 10 ). typical movement experienced by the wire gripper ( 10 ) when the spring ( 3 ) moves from the uncompressed state shown in fig4 a to the compressed state shown in fig4 b would be approximately 1 cm . in other embodiments , the spring ( 3 ) could be designed or selected so as to be fully compressed with an applied force of either more than 20 kg or less than 20 kg , and the movement of the wire gripper ( 10 ) experienced when the spring ( 3 ) moves from the uncompressed state to the fully compressed state could be more than one 1 cm or less than 1 cm . fig5 shows a portion of an electric fence ( 12 ) according to an embodiment of the present invention . the electric fence ( 12 ) comprises a post ( 13 ), which may be a galvanised steel channel section post , fitted with at least one device ( 1 ), also according to the present invention , wires ( 16 ) and electrical wiring connections ( 17 ). in the embodiment shown , the first shield portion ( 7 ) of the device ( 1 ) is inserted into a hole ( 14 ) in the fence post ( 13 ), such that an engagement face ( 5 ) of the device ( 1 ) is engaged with an inside face ( 15 ) of the fence post ( 13 ). the device ( 1 ) may fit snugly in the hole ( 14 ) or can be held in engagement with the fence post ( 13 ) by tension in the wire ( 16 ). the posts ( 13 ) can be constructed as either end strain posts or as double end strain posts . they may be fitted with a cover so as to create a hollow , enclosed interior space . in the embodiments shown in fig5 the wiring ( 17 ) to create high voltage and earth circuits is inside the post ( 13 ). thus , by arranging the device ( 1 ) such that it can be located into a ( hollow ) fence post ( 13 ), the complete electrical fence wiring circuits can be located inside the fence posts , leading to a reduction in installation time , greater operating security , and a reduction in the potential for damage caused by weathering . the wiring can be more complex than shown in fig5 provided that the hv and earth circuits are completed . preferably , the hv and earth wires alternate . the spade connection ( 11 ) on the wire gripper ( 10 ) may enable rapid wiring of the electrical circuit , thereby reducing the time taken to complete the wiring connections for a conventional system . the second shield portion ( 8 ) in the embodiment of the device ( 1 ) shown in fig1 provides the necessary electrical insulation to prevent hv pulses in the wires ( 16 ) tracking through the device ( 1 ), for example along its surface to the metal of the post ( 13 ), which is earthed . the first shield portion ( 7 ), which may also be ribbed , is also designed to exceed the maximum tracking length so that earthing of the hv wire to the metal of the post ( 13 ) is prevented . preferably , the first and second shield portions ( 7 , 8 ) are arranged to insulate the post ( 13 ) from high voltages in the wires of up to about 6000 - 8000 volts or more . the first shield portion ( 7 ) and the second shield portion ( 8 ) may either be integral to the device ( 1 ), or they could be made in separate parts . this option allows optimisation of both the compression and solar uv resistant properties of the different sections . for example , in one embodiment , only those parts of the device ( 1 ) that are located outside the post ( 13 ) in operation ( for example , the first shield portion ( 7 )) use a material that is resistant to degradation through exposure to uv radiation , whereas in other embodiments , all of the device ( 1 ) is made from a material that is resistant to degradation through exposure to uv radiation . according to the embodiment of the invention shown in fig5 , which uses the device ( 1 ) according to an embodiment of the invention shown in fig1 or 2 , if any wire is cut , say by an intruder , the spring ( 3 ) returns to the uncompressed state and allows the wires ( 16 ) being held by the wire gripper ( 10 ) to earth on the post ( 13 ). the movement from the compressed to loss or uncompressed states could be used as a signal or indicator of a wire being cut or damaged , for example to assist detection of an intruder . | US-83295307-A |
an expandable container comprising two or more slidably engaged sections which are adapted to telescope into a compact unit for storage , but for use the sections are extended to provide two to four times the volume capacity of the closed or unextended container . the fluid and vacuum integrity of the system is obtained by a closure means at each juncture of telescoping sections such as flexible film which is sealed over junctures of the sections , thus leaving the sections free to slide in and out . the expandable container has found particular utility in vacuum liquid collection systems employed by hospitals . | referring to fig2 the collection system or container of the present invention can be seen in the &# 34 ; open &# 34 ; or extended configuration . in this embodiment the collection system is comprised of two sections , upper section 1 and lower section 2 , slidably engaged . the lower section 2 is adapted to slide inside of section 1 . the upper section 1 consists of a vertical wall 11 having a particular cross section or shape which , as shown by reference to fig3 is rectangular . the wall 11 is hermetically attached to top member 12 and is open at the lower end . seated inside of the lower end of wall 11 is the vertical wall 9 of lower section 2 which has the same cross section as upper wall 11 , but with outside dimensions approximately the same as the inside dimension of wall 11 of upper section 1 . reference to fig1 will show the collection system of fig2 in the closed or collapsed configuration . referring again to fig2 wall 9 is hermetically sealed to bottom member 10 which has a peripheral shoulder 7 which seats against the lower edge of wall 11 when the lower section 2 is fully seated in upper section 1 in the closed position . the shoulder 7 serves to prevent lower section 2 from going too far into the upper section 1 , making it difficult to grasp and pull out for use in the extended configuration as shown in fig2 . the shoulder 7 also provides a convenient point to grasp when the lower section 2 is slid out to the extended position . attached inside of the lower section 2 on wall 9 and near the upper edge thereof are the latches 5 . the upper ends 6 of the latches 5 are aligned with slots 24 in wall 9 . each latch 5 is a resilient material biased so as to force the end 6 through slot 24 when there is no force holding it back . thus when the lower section 2 is seated inside the upper section 1 in a closed configuration the wall 11 holds end 6 back ; however when the lower section 2 is slid down to the extended position with the slot 24 below wall 11 , the end 6 is biased out . when the latch 5 is in this position the end 6 is seated against the lower edge of wall 11 , and lower section 2 can not be inadvertently pushed or drawn back into the closed position shown in fig1 . this is a particularly important feature when the collection system is employed with a vacuum , for the lower section 2 will tend to be pushed back into the upper section 1 by the vacuum in the container space formed by the two sections . hermetically attached to upper section 1 , about wall 11 in an air and liquid impervious flexible film 3 , which in this embodiment is an air tight plastic bag . the bag 3 provides in this embodiment not only the air tight seal for the juncture of the two sections but also serves to hold the lower section 2 in the engaged position shown . in an alternate embodiment ( not shown ) the two sections are held in the extended position by means of a slot in wall 11 , which slot will align with the slot 24 in wall 9 thus allowing the end 6 of latch 5 to engage the wall 11 , thereby locking the two sections in place . in order to return the lower section 2 to the closed position in either embodiment described above , the latch 5 is depressed until end 6 is within the slot 24 while a slight upward pressure is applied to the lower section 2 while the upper section 1 is maintained in a fixed position . in addition to the latch 5 , there may be positioned in the lower section 2 , support members or walls 4 which also provide some support to the upper section 1 because of the engagement of the two sections . in order to provide communication throughout the entire lower section 2 , the support members 4 have opening 8 as can be seen by reference to fig4 . the support members 4 are not essential but do provide an additional degree of reliability of the collection system with vacuums and structurally , they allow lighter walls 9 and 11 . other known techniques can be used such as ribs or vanes in the walls 9 and 11 to reduce wall thickness and weight . again in fig2 the upper section 1 has located on the top member 12 an inlet 13 and an outlet 14 , both adapted to have tubes attached thereto . the inlet 13 comprises an elongated tubular member which extends almost to the lower edge of the wall 11 . the elongated tube 13 is a preferred refinement and insures that fluids flowing in through inlet 13 are not drawn inadvertently into the outlet 14 by the force of the suction . the inlet 13 , however , need only provide an ingress into the container . in the embodiment shown in fig2 a further improvement is the safety valve juxtaposed below the outlet 14 . the safety valve is comprised of arm 18 pivotally mounted by means of nibs 19 in corresponding indentions in projections 17 attached to top member 12 . located at the opposite end of the arm 18 from the pivot is a flotation ball 20 , which is operably aligned to seat into outlet 14 when the fluid rises toward the top member 12 and block the outlet so that the fluid will not pass into the vacuum source . in some applications , however , as when the collection system is one of several units in series the safety valve is not desirable and would be omitted in all but the last collection system in the series . a further feature which increases the versatility of the present collection system is the provision of one or more auxiliary openings in the top member 12 . in the embodiment of fig2 there are provided two threaded necks 15 with screw cap closures 16 , which provide an air tight seal . these removable closures 16 allow removal of the collected specimen without disruption of the system , by pouring the speciment out through the opened neck 15 . a strap 21 is attached to the upper section 1 by rivets 22 . the strap 21 provides a convenient means to carry one or more of the collection systems by hand . a particular utility for the strap 21 is seen by reference to fig1 wherein the strap as mounted on prongs 38 is depicted by phantom strap 21 &# 39 ;. prongs similar to those illustrated are found on some hospital pumps such as those previously mentioned . the strap 21 may be hung on any convenient prong , handle or the like . the purpose being to remove the collection system from the floor and to put it out of the way . this procedure can also put the collection system into a better position for observation of the fluids collected . the strap can be made of flexible or semi - flexible material such as cloth , leather or nylon , polypropylene or the like . adjacent to the top member 12 is an extension of wall 11 which forms a protective enclosing wall 23 around the top member 12 . the purpose of this protective wall 23 is to provide a degree of protection to the elements projecting from the top member 12 , particularly during shipment and storage . referring now to fig5 there is shown an embodiment wherein in addition to upper section 25 and lower section 28 there are two intermediate sections 26 and 27 . each of the lower sections is slidably engaged in the preceding section . the upper section 25 has a top member 34 and a protective wall 33 is provided . the lower section 28 is enclosed with a bottom member 32 which has a shoulder 33 serving the same purposes as shoulder 7 , previously described in fig2 . each adjacent section in fig5 is hermetically sealed to the next section by means of a continuous flexible film , 29 , 30 and 31 circumventing the collection system . in fig5 the four section collection system is only partially extended . the remainder of system may be substantially the same as previously described . fig6 shows the same collection system as depicted in fig1 - 5 , but in a cylindrical configuration as indicated by the circular cross section of wall 36 . referring to fig7 another configuration is depicted having a configuration similar to that of fig1 with bowed out sides 37 . the cross section of the top view can be characterized as elliptoid , i . e ., being an ellipse with the ends cut off . these or practically any other shape can be used , limited only by fabrication cost and reason . each of the sections will have cooperating configuration with the other sections of the collection system . similarly each of the collection systems may have the various modifications described above . in order to provide a clearer understanding of the invention as used in a collection system , a brief description of the setup of the device of fig1 will be given . in fig1 a preferred embodiment in use is depicted . for example if the present container is to be used with a portable vacuum pump , such as the gomco thermotic 765 a *, there are projections , such as prongs 38 , located thereon . the strap 21 is stretched over the projections ( prongs ) 38 , as shown by phantom strap 21 &# 39 ;. thus positioned it is a simple matter to extend the container to its full capacity by grasping shoulder 7 and pulling it downward to the position indicated by phantom section 2 &# 39 ;. the container will now preferably be in the configuration shown in fig2 . referring again to fig1 the inlet 13 is connected by means of tube 39 to the patient and the outlet 14 is connected by means of tube 40 to the suction of the pump . the system is now ready for operation . as noted above in use as a collection system , the present container must have transparency or at least translucency ; however , when used in other applications , translucency may be unimportant and opaque materials may be used in the construction thereof . fig8 shows an embodiment wherein the sealing of the sections in extended position is achieved by a circumferential gasket . in the figure , upper section 101 and lower section 102 are shown in the fully extended position . the inwardly projecting flange 107 seats against the outwardly projecting shoulder 108 . the circumference of the upper section 101 is smaller at the end of the section which is adjacent the gaskets 103 and 104 in the extended position shown . the gaskets 103 and 104 are a resilient material such as closed cell neoprene now available on the market . the small diameter can be seen by reference to line α , which is the projection of the shoulder 108 of the lower section . it can be seen that the portion of upper section 101 above that in contact in the extended position has a circumference greater than shoulder 108 , thus allowing the sections to move easily into the extended configuration . however as the end portion of upper section 101 comes into juxtaposition to shoulder 108 its smaller circumference , which is substantially the same as line α , compresses the resilient gaskets and forms an air tight seal . one gasket would operate , and two are merely a safeguard . the gasket 103 and 104 are set in annular grooves 105 and 106 respectively in shoulder 108 and are annular about the circumference of lower section 102 , however they project outward when the larger portion of upper section 101 is juxtaposed thereto . they are shown in their compressed state in fig8 . this mode of sealing the sections together will operate best when there are no sharp angles to be sealed . for example , the circular configuration shown in fig6 would be well adapted to this sealing mode or the configuration of fig7 with the corners rounded off . the other features previously described are also adapted to this sealing embodiment . | US-59337275-A |
a nonsteroidal anti - inflammatory drug which is phenylacetic acid derivative and methods of using the same in topically controlling eye inflammations . | the compounds which are effective for use in this invention have the formula : ## str1 ## wherein r = hydrogen or c 1 to c 5 alkyl , x = mono -, di -, tri - and tetrahydroxy substituted c 2 to c 10 alkyls , and y = hydrogen , c 1 to c 5 straight or branched chain alkyl , particularly pivalyl . included also are ophthalmically acceptable salt forms of each compound . these compounds may exist in several steroisomeric forms . all of the steroisomeric forms are therapeutically active . thus , they are all intended to be within the scope of this invention , both ( r , s ) and racemic modifications thereof . it is preferred that r = hydrogen or methyl and that x = monohydroxy substituted c 2 and that y = hydrogen or pivalyl . it is believed that the active compound is where &# 34 ; y &# 34 ; equals hydrogen , but prodrugs may be metabolized to this form and be active . thus , prodrugs which are designed to cross the cornea rapidly may be desirable , such as the pivalyl . the ophthalmically active compounds may be incorporated into various ophthalmic formulations for delivery to the eye . for example , the compounds may be combined with ophthalmologically acceptable preservatives , surfactants , viscosity enhancers , buffers , sodium chloride and water to form an aqueous ophthalmic suspension . in order to form sterile ophthalmic ointment formulations , the active ingredient is combined with a preservative in an appropriate vehicle , such as mineral oil , liquid lanolin , or white petrolatum . sterile ophthalmic gel formulations may be prepared by suspending the active nonsteroidal drugs of this invention in a hydrophilic base prepared from a combination of carbopol - 940 ( a ) carobxy vinyl polymer available from the b . f . goodrich company ) according to published formulations for analogous ophthalmic preparations . preservatives and tonicity agents can also be incorporated . the specific type of formulation selected will depend on various factors , such as the type of ophthalmic inflammation being treated and dosage frequency . ophthalmic solutions or suspensions suitable for easy eye drop administration , ointments and gels are the preferred dosage forms . the active , nonsteroidal compounds of this invention will normally be contained in these formulations in an amount of from about 0 . 05 % by weight to about 5 . 0 % by weight , preferably from about 0 . 5 % by weight to about 3 . 0 % by weight . thus , for topical presentation these formulations may be delivered in modest excess to the surface of the eye from 1 - 6times per day depending upon the discretion of the clinician . as heretofore mentioned , the compounds per se of the invention may be used or ophthalmically acceptable salt forms thereof . the ophthalmologically acceptable salts of the compounds of this invention include those formed from inorganic bases such as group i hydroxides , like sodium hydroxide , and those formed from organic bases such as amines , etc . suitable ophthalmically acceptable carriers are generally known and of course must be non - eye - irritating , non - toxic , and allow for safe , easy eye administration topically . generally for this invention aqueous - base systems wherein the carrier includes a buffer system to provide eye safe ph , a viscolyzer to provide suitable viscosity for eye comfort , an antibacterial agent , and a chemical preservative are adequate . the ophthalmically acceptable buffer should provide a composition having a ph within the range of about 5 . 5 to about 7 . 8 , preferably from about 6 . 8 to about 7 . 4 . suitable ophthalmically acceptable buffers can be selected from the water soluble salt forms of citrate , borate , phosphate , corbonate , and acetate . the viscolyzer suitable for use in this invention should provide the composition with a viscosity within the range of from about 4 centipoises to about 100 centipoises , preferably from about 5 centipoises to about 35 centipoises . suitable viscolyzers can be selected from the group consisting of hydroxyethylcellulose , hydroxypropyl methylcellulose , methylcellulose and a polyacrylamide sold under the trade name gelamide 250 by american cyanamide . in addition , the ophthalmic composition ideally will include antibacterials to provide safety and efficacy for storage stability . the amount of antibacterial can be within the range of from about 0 . 004 % to about 0 . 5 % by weight / volume of the composition . a suitable antibacterial would include , for example , from about 0 . 004 % to about 0 . 02 % by weight / volume of benzalkonium chloride , from about 0 . 25 % to about 0 . 5 % of chlorobutanol , about 0 . 1 % of thimerosal , about 0 . 05 % methylparaben , about 0 . 01 % propylparaben , and sodium chloride in an amount sufficient to make an isotonic solution . finally , chemical preservatives may also be used , for example sodium thiosulfate at about a 0 . 3 % level and ethylenediaminetetraacetic acid at about 0 . 05 %. it goes without saying that the precise ophthalmic carrier must be selected to provide pharmaceutical elegance , to provide eye comfort and to allow for effective topical administration . formulation of such is well within the skill of the ordinary artisan who prepares ophthalmic carrier compositions . the compounds used as the anti - inflammatories of this invention have features which enhance the aqueous solubility of the anti - inflammatory drug while retaining sufficient lipid solubility to promote intraocular penetration . they also will maintain the pharmacophore necessary to exhibit anti - inflammatory activity . the compounds thus take into account both solubility for sufficient ocular penetration and anti - inflammatory activity , and balance these in unique compounds duly suited for the unique penetration and distribution processes for drugs in the eye . the following examples serve to further illustrate but not limit the compounds , compositions and method of the present invention . a rabbit cornea model was used in the tests shown in the examples because , as those of ordinary skill in the art know , rabbit cornea testing has been mostly correlated with test results for the human eye , r . d . schoenwald et al , biopharm . drug dispos ., 3 , 231 ( 1982 ). excised rabbit corneas were carefully mounted between two halves of a plastic cylinder . various concentrations of ibuprofen as a comparative model : ## str2 ## or the compound of the present invention wherein r and y = hydrogen and x = hydroxyethoxy were placed on the epithelial side initially and drug appearing on the endothelial side was measured over time . the slope from the quantity of drug crossing the excised cornea over time was used to calculate the corneal permeability coefficient ( cm / sec ): table i______________________________________ permeability coefficientinitial cell conc . (× 10 . sup .- 6 cm / sec )( mcg / ml ) ibuprofen invention______________________________________500 21 . 6 -- 250 23 . 9 6 . 42150 21 . 2 6 . 65 60 22 . 8 6 . 53 mean = 22 . 4 mean = 6 . 53______________________________________ ph = 7 . 6 , temp . = 37 , 95 % o . sub . 2 5 % co . sub . 2 the solubilities of the two were compared and found to be as follows : when the maximum penetration rate ( mpr ) is calculated : mpr = ( sol ) ( perm . coeff . ), ibuprofen equals 1 . 68 mg / cm 2 / sec and the invention is 32 . 7 mg / cm 2 / sec . thus , the invention has a 19 . 5 fold greater corneal penetration rate . corneal anti - inflammatory activity was compared . the leibowitz anti - inflammatory model was used , h . m . leibowitz and a . kupferman , &# 34 ; anti - inflammatory effectiveness in cornea of topically administered prednisolone ,&# 34 ; invest . ophthalmol ., 13 , 757 ( 1974 ) and h . m . leibowitz and a . kupferman , &# 34 ; bioavailability and therapeutic effectiveness of topically administered corticosteroids ,&# 34 ; trans . am . acad . ophthalmol . otolaryngol ., 79 , 78 ( 1975 ). this method consists of first injecting tritiated thymidine intravenously into white rabbits . in approximately 2 days , the radioactive , thymidine is incorporated into polymorphonuclear leucocytes ( pmn ) which upon injection of clover oil into the stroma of the cornea will migrate to the site of injection . topical treatment of nonsteroidal anti - inflammatory drugs , if effective , will suppress the migration of polymorphonuclear cells to the injection site . the reduction of radioactivity in the cornea becomes a measure of drug effectiveness to suppress the inflammation process . the results are summarized below as a percent reduction of radioactivity occurring from no drug treatment . table ii______________________________________ % decrease ( compareddrug treatment * dpm ** to control ) ______________________________________invention 1 % solution 6720 ( sd = 3368 ) 19prednisolone acetate 4288 ( sd = 2846 ) 481 % suspensionno treatment 8255 ( sd = 5956 ) 0______________________________________ * drug treatment started at the time of clove oil injection ( n = 6 / treatment group ); all treatment groups received 8 - 9 doses / day of invention . ** disintegrations per minute prednisolone acetate was used as a comparative , highly effective steroidal anti - inflammatory , which like many of the other effective ones is known to produce certain undesirable side effects . the initial results for the topical instillation of 1 % of the invention show a 19 % decrease in corneal inflammation following clove oil chemotaxis . these results for the invention are significantly less potent than the results observed for 1 % prednisolone acetate suspension . this is not surprising in light of the superior potency of steroids , particularly prednisolone acetate , and the generally lower potency of nonsteroidal anti - inflammatory drugs . the values obtained for 1 % prednisolone acetate agree with published results by leibowitz . ibuprofen itself is reported to be effective for post - operative corneal inflammation in patients taking 1200 gm / day , but no reports are published to indicate its topical efficacy on corneal inflammation . the superior permeability characteristics of the compound of the present invention over ibuprofen indicates much higher effective activity without systemic side effects . | US-14797488-A |
a method of using photodynamic therapy to perform selective targeted therapy of biological tissue . the method includes intravenously injecting a porphyrin - based photosensitizing drug followed by irradiating the tissue with light while the drug is being injected . the duration of the irradiation and other parameters are controlled so that the selected biological tissue is treated and non - selected tissue is not damaged . by controlling the flow rate of the injection and other parameters , so that irradiation of the effected tissue overlaps with injection of drug , the target tissue is effectively treated without damage to non - target tissue . | the inventors have studied pharmacokinetics of porphyrin - based photosensitizing drugs in test animals and in humans and studied photo damage to selected tissues and non - selected tissues at various times after administration of these drugs in order to find a safe and effective treating period . in particular , the inventors have discovered therapeutic parameters , e . g ., the dosage of photosensitizing drugs , the administration route , the light dose , the start - time and the end - time of the irradiation that provide an improved treatment for the reduction of port wine stains . it has been surprisingly discovered that by performing irradiation for a period of time overlapping intravenous injection of the photosensitizing drug , improved therapeutic results are obtained . pdt treatment according to the invention involves three key components : a photosensitizing drug , light , and tissue oxygen . the photosensitizing drug used in the inventive method is a poryphin based drug that can be administrated systematically and can aggregate at the pws lesions and be excited by light of a specific wavelength . the photosensitizing drug used in the inventive method may be excited from a ground singlet state to an excited singlet state . after excitation , the photosynthesizing drug undergoes a reaction with other compounds in the tissue to form singlet oxygen and / or other radicals . ultimately , these destructive reactions kill lesion cells through direct cytotoxicity and vascular closure . a possible mechanism of pdt for pws is summarized as follows : while shining the light at the pws lesion during or shortly after intravenous injection of the photosensitizing drug , i . e ., while the drug is still highly concentrated inside the circulation ( including within the pws vessels ), the drug distributes mainly to endothelial cells and diffuses little to the surrounding epithelium tissue . as such , the photochemically induced reactive oxygen species ( ros ) may be located within the vessels and , therefore , selectively effectively treat the endothelial cells without harming the normal epidermis , which is free of photosensitizing drugs . the normal dermal tissue beneath the lesion is protected from the laser damage because of the shallow penetration of the laser that is used . pdt destruction of pws vessels leads to color blanching of the pws lesion . since the amount of photosensitizing drug outside the vessels is low , the vascular acting pdt - induced skin lesion is negligible or reversible . in general , pdt procedures involve the combination of photosensitizing drugs and light sources . the pdt procedures according to some embodiments of the invention minimize scarring associated with the treatment of port wine stains in a patient . the varied parameters of photosensitizing drugs may include dosage and means of delivery , and the parameters of the light source may include light flux ( light dosage , light energy density ), light intensity and light duration . each parameter in effective and selective pdt is interrelated so an optimal combination is controlled for selective treatment of the lesions . the present invention provides a specific set of such parameters providing for an enhanced selected treatment of pws lesions . since edema is the most common side effect occurring in pdt for pws , it is reduced by treatment with antihydropic agents such as prednisone . the lesions may form a scar or crust 1 week after pdt and may last for 2 - 4 weeks . as used herein , the term scar means a mark left on the skin by the healing of injured tissue and the term crust means dried serum , pus or blood mixed with epithelial and / or bacterial debris . any resulting infection is treated after pdt by the administration of anti - infective drugs , such as antibiotics . therapeutic effect of treatment is assessed by examining the color of lesions following treatment , as set forth in table 3 , below . the effectiveness of pws treatment with pct is categorized as being excellent ( i ), good ( ii ), effective ( iii ) or ineffective ( iv ). as shown in table 3 , an excellent grade means that the color of the pws completely fades ( i . e ., & gt ; 90 %). in some embodiments of the present invention , the porphyrin - based photosensitizing drugs may comprise a hematoporphyrin derivative ( hpd ), photosynthesizing drug ( psd - 007 ), hematoporphyrin monomethyl ether ( hmme ), e . g ., ( hemoporfin ) or porfimer sodium , e . g ., ( photofrin ). in certain embodiments , the porphyrin - based photosensitizing drug is hemoporfin . in some embodiments , the treatment method includes irradiation of the lesion 0 - 10 minutes after the start of injection of the porphyrin based drug . the irradiating light has a wavelength in the range of between about 200 and about 700 nm and a power density in the range of 10 - 500 mw / cm 2 . in certain embodiments the irradiation wavelength is in the range between about 400 and about 580 nm and the power density is about 60 - 100 mw / cm 2 . the irradiating light source used in the treatment methods of the invention maybe a continuous laser or quasi - continuous laser . as used herein , a continuous laser is a laser which transmits light continuously and a quasi - continuous laser is a laser which is switched on for certain time intervals during treatment . in certain embodiments , the irradiating light source is selected from an ar - ion laser ( 514 . 5 nm and 488 . 0 nm ), a kyp laser ( pulsed nd : yag laser , 532 nm ), and copper vapor laser ( 510 . 6 nm and 578 . 2 nm ) and light emitting diode ( led ). in certain embodiments , the laser is a kyp laser ( pulsed nd : yag laser , 532 nm ). in some embodiments , particularly for treating adults , the power density applied to the lesion may be about 80 to about 100 mw / cm 2 , while in children it may be about 60 to about 80 mw / cm 2 . as used herein an adult is a person who is fully grown or developed past the stage of puberty and a child is a person between the stages of birth and puberty . depending on the size of the patient being treated , it may be preferable to adapt the treatment for a child or adult accordingly . the skilled practitioner will be able to make such adjustments in treatment . in some embodiments , particularly for patients having a large lesion , multiple laser spots ( e . g ., double laser spots ) may be applied so that by combining multiple laser spots , the entire portion of the large lesion is covered with irradiating light . in certain embodiments of the invention , treatment of pws over multiple treatment applications is used , the interval of each two adjacent treatments depending on the t 1 / 2 of the photosensitizing drugs used . if the same portion of the lesion requires more than one treatment , the interval of time between two adjacent treatments may be at least 2 months to 4 months . if a different portion of the lesion needs treatment after the first treatment , the interval of time between two adjacent treatments may be at least 2 weeks to 4 weeks . there is no maximum amount of time between treatments , but the interval between treatments is governed by whether the same portion of a lesion is being treated multiple times . the pws in the dermis is irradiated through the epidermis for a time period sufficient to selectively destroy cutaneous blood vessels within the pws . as a result , the port wine stain is destroyed without substantial biological damage to the epidermis . the photosensitizing drugs used in the present methods are porphyrin - based photosensitizing drugs which can be produced by any method , such as the methods described by daming qin ( journal of biology , 1991 , 42 ( 4 ): 4 - 6 ), deyu xu ( chinese journal of pharmaceuticals , 1989 , 20 ( 10 ): 440 - 446 ), wenhui chen ( chinese j laser med surg , 1993 , 12 ( 1 ): 3 - 7 ) or the method in cn01131939 , and porfimer ( photofrin ) provided by quadra logic technologies phototherapeutics inc . the contents of which are incorporated by reference . the following examples illustrate methods and effects of pdt for pws . the examples are in no way intended to limit the scope of the invention . the test conditions not described here are common conditions to skilled persons , or they are the conditions advised by the manufacturers . the concentrations of hpd and psd - 007 in a test animal &# 39 ; s ( i . e ., chicken ) blood was monitored by injecting the drug into the neck vein at a dose of 10 mg / kg of body weight , and taking blood samples approximately every 10 minutes . the results are shown in table 4 and fig1 . hpd and hmme in chicken blood were monitored at various times after injection . hpd or hmme was injected in chicken neck veins at a dose of 10 mg / kg , taking a blood sample every 10 minutes following injection . the results shown in table 5 and fig2 show that serum concentrations of both drugs reach a peak 10 minutes after injection and then drop . the two curves shown in fig2 have generally the same pattern . porphyrin - based photosensitizing drugs were injected intravenously at a dose of 2 . 5 and 5 . 0 mg / kg body weight for 20 minutes with a constant flow rate , and the pharmokinetics measured . blood samples were taken at 5 , 10 , 20 , 25 , 30 , 40 , 50 , 80 , 110 , 140 , 200 , 260 and 380 minutes separately to measure the serum concentrations of porphyrin - based photosensitizing drugs . the pharmacokinetic results shown in fig3 show that the c max values of each dose is 17 . 491 ± 7 . 045 and 35 . 724 ± 4 . 539 μg · ml − 1 respectively , the auc 0 ˜ n value is 6 . 342 ± 2 . 824 and 17 . 531 ± 3 . 467 μg · ml − 1 · h , respectively , and the t 1 / 2 values are 1 . 26 ± 0 . 33 and 1 . 31 ± 0 . 33 h , respectively . a solution of 1 ml saline was injected in the superficial vein ( e . g . median cubital vein ) of patients to ensure no liquid leaked into tissues adjacent to the blood vessels into which the injection was made . at the same site , hmme was injected intravenously for 20 minutes with a constant flow rate by using an infusion pump . the doses applied were 2 . 5 mg / kg body weight or 5 . 0 mg / kg body weight . next , 2 - 4 ml of saline solution was again injected to prevent the drugs from aggregating locally . irradiation with ktp532 laser was then applied to the patient &# 39 ; s lesion site 0 - 10 minutes after the start of injection , for a total duration of irradiation of either 20 minutes ( denoted as the 20 min group ), or 30 minutes ( denoted as the 30 minute group ). the laser had a wavelength in the range of between about 532 nm and a power density of about 80 - 100 mw / cm 2 . when irradiation was started immediately after the start of injection , the overlap between the injection and irradiation was about 20 minutes , when irradiation started 5 minutes after the start of injection , the overlap between drug injection and light irradiation was approximately 15 minutes , and when irradiation was started 10 minutes after the start of injection , the overlap was about 10 minutes . the therapeutic results were measured 8 weeks after the treatment . a dose of 5 . 0 mg / kg body weight of the poryphin based drug was injected , total irradiation durations were 20 min and 30 min respectively , and the effects and adverse effects were assessed . the results as shown in table 6 show that in the 20 min group , the excellence rate was 10 . 0 %, significant response rate was 55 . 0 % and response rate was 80 . 0 %. in the 30 min group , the excellence rate was 36 . 8 %, significant response rate was 78 . 9 % and response rate was 94 . 7 %. the effect on different types of pws , was also assessed as shown in table 7 , which shows that the excellence rate and significant response rate on red type lesions was higher than purple type lesions for both the 20 min group and the 30 min group . the most common adverse temporary effects included swelling , burning , redness , pain , blister and crust formation in pdt for pws and these symptoms occurred in almost every case . scar or crust thickness was measured as thickening of crusts . the crust levels served as an assessment index for scars . the adverse effects in the subjects in the present method were mild or moderate ; the subjects in the present study reported feeling “ nothing at all .” however the 30 min treatment group showed worse adverse effects compared to the 20 min treatment group as shown in table 8 . no serious - thick crusts occurred and no scars were present in any patient treated for 20 min . ( table 9 ), which indicates that the present invention unexpectedly reduces and in some cases , eliminates scar formation after treatment . in this example doses of 2 . 5 and 5 . 0 mg / kg body weight respectively , were applied , the patient was irradiated for 20 min , and the therapeutic effects and the adverse effects were assessed . the results in table 10 show that in the 5 . 0 mg / kg group , excellent rate was 5 . 0 %, significant response rate was 40 . 0 % and response rate was 75 . 0 %; while in 2 . 5 mg / kg group , the excellent rate was 0 %, significant response rate was 2 . 5 % and response rate was 40 %. the effect on different types of pws was also assessed , as shown in table 11 : the excellent rate and significant response rate for red type lesions was higher than purple lesions for both the 5 . 0 mg / kg group and 2 . 5 mg / kg group . the 5 . 0 mg / kg group responded better than the 2 . 5 mg / kg group . no serious - thick crusts occurred and no scars were formed in any treated patients as shown in table 12 . this result demonstrates that the present invention reduces and in some cases , eliminates this discomfort and scarring . although specific embodiments of the invention have been described and illustrated , it is to be understood that modifications can be made without departing from the invention &# 39 ; s sprit and scope . the scope of the invention as defined in the appended claims is intended to cover these and other variation . | US-84875510-A |
method for non - invasively determining glucose level in fluid of subject , typically blood glucose level . a particular device is mounted on the skin of the patient for a fixed period of time . the device is mounted on the skin such that a substrate such as paper or gel or an aqueous glucose solution carried by the device are in contact with the patient &# 39 ; s skin . water and / or glucose migrates between the substrate or the aqueous glucose solution of the device . the degree of migration of the substance in question is monitored , for example the amount of glucose remaining in an aqueous solution of the device is measured at the end of the fixed period . this can be done by a conventional or other spectrophotometric method , for example . the glucose level is determined based on the degree of migration of the migrating substance . that is , the degree of migration is correlated with previously determined fluid glucose levels based on directly measured fluid glucose levels . in another approach , impedance alone is measured at the skin surface over a relatively short time period , even less than one second and the impedance is correlated with previously determined glucose levels . it is thus possible , through such a correlation , to routinely non - invasively determine fluid glucose levels . | turning to fig1 of the drawings , patch device 10 includes absorbent paper strip 12 , occlusive barrier 14 , soft contour cushion 16 , and adhesive top plastic bandage 18 . paper strip 12 , can be , for example , a 2 cm × 4 cm piece of chromatography paper ( whatman no . 1 chr ) folded over on itself to form a square . occlusive barrier 14 is of an impermeable flexible plastic material bonded to soft contour cushion 16 . contour cushion 16 is bonded to plastic bandage material 18 . device 10 is placed over a skin site , typically the wrist , and held in place by ends of bandage 18 bearing a skin adhesive . the absorbent paper strip is then inserted between the skin and occlusive barrier 14 to permit transport of biochemicals of interest between the skin and the paper substrate . such biochemicals of interest include glucose and water involved in monitoring the diabetic condition of skin . alternatively , the absorbent paper strip may be positioned beneath a metal electrode 20 which is inserted between device 10 and the skin , as illustrated in fig1 a . in use , device 10 is placed over the skin site and fixed by attaching adhesive ends of bandage 18 to the skin . the absorbent paper substrate is inserted between the skin and occluded surface 14 of the device . in experiments described further below , a stock aqueous solution of glucose was made to the concentration required to provide a desired amount of glucose to be deposited by micropipette to the paper strip which was allowed to dry at room temperature prior to use . the amount of glucose remaining with the absorbent paper substrate after skin contact was determined by inserting the paper strip into a screw cap test tube . test reagent ( toluidine kit , # 635 - 6 , sigma , st . louis ) was admitted , the cap attached and the mixture heated at 100 ° c . for 10 minutes . the color which developed was measured at a wavelength of 635 nm in 1 cm transmission spectral cells and the concentration of glucose present determined from the amount of spectral absorption . absorbance as a function of known amounts of glucose added to paper strips is plotted in fig2 to establish that observed absorbance is in proportion to the amount of glucose present . in one set of experiments , the chromatographic paper was loaded with 0 . 1 ml of a solution ( glucose , 300 mgs percent and cholate sodium salt , 2 gms percent ) and dried in room air . cholates have been found to enhance penetration of glucose into an external hydrogel as described in u . s . pat . no . 5 , 139 , 023 ( issued to carey et al . t on may 24 , 1988 ), the specification of which is incorporated herein by reference . the amount of glucose remaining with the substrate after 30 minutes was plotted as a function of blood glucose determined directly from a blood sample using a lancet prick and measuring the blood glucose concentration using an elite glucometer ( miles canada , diagnostics division , division of bayer ). typical results are shown in fig3 and 4 . u . s . pat . no . 4 , 746 , 508 , the specification of which is incorporated herein by reference , describes bile salt analogs that have penetration enhancement properties . another set of similar experiments was carried out in which the chromatography paper was loaded with 0 . 10 ml of a solution ( glucose , 300 mgs percent and urea , 10 gms percent ) and dried in room air . the results are plotted in fig5 . another embodiment of a device of the invention is patch device 22 shown in fig6 . device 22 includes a substrate well 24 ( methocel gel 0 . 5 %, isotonic ( sodium chloride ) gel , and buffered isotonic gel and gel with penetration enhancers such as urea , substituted ureas , cholates , lecithins , aliphatic alcohols , aliphatic acids , substituted aliphatic acids and emulsifiers ), lower membrane material 26 ( biofill -- biological skin substitute , microcrystalline cellulose , productos biotecnologicos s . a ., bom retiro , curitiba , parana , brazil ), insert rubber ring 28 and upper impermeable transparent plate 30 . the transparent plate could be replaced by a second membrane . intermediate collar 32a , having adhesive on both its upper and lower surfaces , secures the lower membrane to the rubber ring . upper collar 32b , having adhesive on both its upper and lower surfaces , secures transparent plate 30 to the rubber ring . lowermost collar 32c , having adhesive on both its upper and lower surfaces , secures protective impermeable tape 34 to the underside of the device so that the tape covers lower membrane 26 . for use , the well is filled with a glucose solution and the device is closed by the upper impermeable plate and the bottom membrane . a skin site is prepared by wiping with a preparatory pad and allowed to dry . the lower protective paper is removed from the lower adhesive collar and the device is placed in contact with the skin . the inner diameter of ring would typically be between about 0 . 25 inches ( 0 . 64 cm ) and about 0 . 5 inches ( 1 . 3 cm ) and it could typically have a depth of between about 0 . 04 inches ( 0 . 1 cm ) and about 0 . 16 inches ( 0 . 4 cm ). these dimensions of course can be optimized in terms of the overall gel volume needed or desired and the surface area provided for exposure to person &# 39 ; s skin in use . the lower collar typically has an outer diameter of about 11 / 4 inches ( 3 . 2 cm ) and again the collar dimensions and adhesive used can be varied to obtain suitable adhesion of the device to a person &# 39 ; s skin for the length of time it is to be adhered thereto . other possible materials that might be used as a membrane include membranous tissue material used to make kling tite ™, naturalamb ™ natural skin condoms , trojan ™ premium product , carter wallace , cranbury , n . j ., usa , cyclopore membranes , hydrophylic and hydrophobic , ( whatman inc . ), and gelman membranes . any semi - permeable membrane that permits the solute ( s ) of interest to diffuse therethrough reproducibly would be suitable . carbopol is a polymer of acrylic acid crosslinked with a polyfunctional agent ( b . f . goodrich ). another possible gel would be methocel ( dow chemical , midland , mich . ), which is a water miscible polymer of hydroxypropyl methylcellulose . other gelling agents include collagen , gelatin , silica gel and other hydrophilic materials which provide gel strength , dissolve the solute ( s ) of interest and permit diffusion of the solute ( s ). gel solutions used may contain sufficient sodium chloride and sodium bicarbonate to establish isotonic conditions compatible with that of interstitial fluid . isotonic gel , ph and other agents may be adjusted to facilitate penetration of glucose through stratum corneum . the membrane and gel must be compatible with each other in the sense that the membrane must retain the gel while permitting diffusion of the solute ( s ) of interest . as with the paper substrate described above , the gel is usually loaded with glucose and the glucose concentration is chosen to be great enough to diffuse through the lower membrane and into the skin . it might be found preferable to manufacture more than one standard or pre - selected gel , say three gels , having low , medium and high glucose concentrations that each provide satisfactory performance under particular circumstances . for example , it might be found that a gel having a relatively high glucose concentration works particularly well for use following a heavy meal . the optimum value would be determined by the need to exceed the peak load while at the same time avoiding saturating the skin site , but at the same time the necessity of having a measurable difference between the initial and final levels of glucose in the substrate gel . it might be necessary to select based upon individual glucose tolerance curves . optimization of sampling time might vary depending upon site glucose levels and the rate of transfer possible to achieve between the gel and site . after a given length of time , device 22 is removed from the subject &# 39 ; s skin . the glucose concentration in the gel is determined by inserting the electrometric probe of an elite glucometer into the gel and drawing a small amount of the solution , about 3 μl , into the probe . the glucometer yields a reading in about a minute . results obtained using device 22 are shown in fig7 and 9 . in one set of experiments ( fig7 ), a gel substrate ( loaded with glucose , 400 mgs percent ) was placed in the reservoir well and calibrated by measuring the concentration of glucose which had effused across the semipermeable membrane into a 100 μl drop of water placed on top of the semipermeable membrane ( the device being in a position inverted to that shown in fig6 ). fig7 shows the concentration of glucose measured in the water droplet as a function of time . conversion of concentration data to logarithmic form shows that the glucose effuses from the reservoir well into the water drop according to first - order kinetics for mass transfer , that is , that the transfer of glucose into the external volume of water is consistent with a diffusion - limited process . in another set of experiments , the device was placed on the wrist of human subjects with the semipermeable membrane against the skin to permit glucose to diffuse from the reservoir well across the semipermeable membrane into the skin for thirty minutes . thereafter , the calibration procedure was repeated to determine the remaining concentration of glucose . fig8 shows the calibration procedure pre - ( upper plot ) and post - application ( lower plot ) of the device to skin of human subjects . the slower rate of effusion of glucose ( post vs pre ) from the reservoir chamber into a 100 μl water drop indicates that post glucose concentration is less than that of the pre condition . the difference in glucose concentration reflects the amount of glucose which diffused from the gel into the skin . similar experiments were carried out with a similar gel containing 5 % urea , the results being shown in fig9 . in another series of experiments , effusion of water from the skin was measured . water taken up from the skin using an occlusive patch device similar to that shown in fig1 was determined . in these experiments , however , no glucose was added to the paper prior to positioning the device on a person &# 39 ; s skin . in a first set of experiments , the device was left in place for 30 minutes and then the paper was weighed . the person &# 39 ; s blood glucose level was also determined directly using an elite glucometer as described above . representative data are plotted in fig1 . as can be seen , there is an increase in water absorbed by the paper from the skin with increasing blood glucose concentration . these experiments were extended by measuring the amount of glucose taken up by the paper substrate of the device as determined using a trinder enzymatic assay . the amount of glucose ( absorbance at 505 nm ) plotted as a function of the amount of water taken up from the skin water ( mgs ) is shown in fig1 . a similar experiment was carried out in which occluded paper strips were analyzed for water absorbed and retained in situ using ekg type metal electrodes for occlusion , fig1 a . dc ohmmeter type instruments showed that retention of water under a metal electrode occlusion decreased dc resistance . see fig1 and 13 . in fig1 , electrical resistance ( mω ) is plotted as a function of time . in fig1 , log r is plotted as function of time , showing that the decrease in resistance is , at least approximately , a first order process . blood glucose levels were also determined directly , as before , over time . the time taken for resistance to decrease a standardized amount ( 150 × 10 3 ω ) was plotted against the directly measured glucose level . see fig1 . as can be seen , the time for the resistance to decrease the standardized amount decreased with the directly measured blood glucose level . a modification of the fig6 device was used to obtain the results shown in fig1 . in the modified device , upper plate 30 and collar 32b were replaced with an adhesive film . lower membrane 26 and intermediate collar 32a were omitted , collar 32c remaining for adherence of the device to the skin . well 24 was filled with a 0 . 4 ml of solution having a glucose concentration of about 475 mgs / dl and about 5 gms percent of propylene glycol . propylene glycol is a wetting agent used to enhance diffusive contact of the aqueous solution of glucose with the skin . the device , oriented in a position inverted to that illustrated , was fixed to the skin by lifting the filled horizontal device to bring it into contact with the forearm of a subject held horizontally above the device . the arm with the device affixed thereto can be moved freely , without particular restraint , although care must be taken to avoid disturbing the device and to preclude detachment from the arm . after about thirty minutes , the arm was oriented with the device oriented upwardly with the outer film on top . the film was punctured and the electrode tip of an elite glucometer was inserted directly into the solution in the well of the device to measure the glucose concentration . blood glucose levels were determined as above and glucose level of the solution ( mgs / dl ) was plotted as a function of the blood glucose level . see fig1 . as can be seen , the glucose remaining in the device after 30 minutes decreases with increasing blood glucose level . another embodiment of the invention involves measurement of impedence at the skin surface . experiments were carried out with measurements being taken with a dermal phase meter ( dpm ) available from nova ™ technology corporation of gloucester , mass . measurements were taken at two skin sites , the forearm and the middle finger . the scale of the meter is from 90 to 999 . blood glucose measurements were also measured directly ( mgs / dl ) using an elite glucometer , as described above . measurements were taken at various times to track changes in skin hydration from that present while fasting overnight , attending ingestion of a typical meal for breakfast or lunch and following a peak of blood glucose and decline to about 100 mgs / dl . in these experiment , a probe sensor was placed against the skin surface and held lightly until the instrument indicated completion of data acquisition . time interval ( latch time ) for data acquisition was selected at zero seconds ( instantaneous ). other suitable time periods can be anywhere 0 and 30 seconds , or between 0 . 5 and about 10 seconds , or between about 1 and 5 seconds or about 5 seconds . the results obtained using the dermal phase meter are plotted as function of blood glucose concentration in fig1 and 17 , respectively . each plotted point represents the average of 10 measurements using the dermal phase meter . the data of fig1 , 12 and 14 show that water absorbed by a paper substrate ( for a fixed period of time ) increases with increasing blood glucose concentration . the data of fig1 show that the amount of glucose which migrates to a paper substrate ( over a fixed time period ) increases with increasing blood glucose concentration . it is thus clear that both water and glucose are capable of migrating through the corneum stratum of the skin . the data of fig1 show that migration of glucose from water ( of a device containing 0 . 4 ml of a 475 mgs / dl glucose in water solution ) into the skin increases with increasing blood glucose . fig1 and 17 indicate that the degree of hydration of the skin increases with increasing blood glucose concentration . a possible explanation for the foregoing observations is now given , although the inventor does not wish to be limited by any theory . the approach used to obtain the results shown herein , and in particular in fig1 to 17 , can be used to non - invasively determine the blood glucose level of a subject and this benefit of the invention is not diminished by the presence or absence of the following explanation . it is assumed that the pathway by which water travels into the skin is by means of interstitial spaces or channels . from the results of fig1 it is inferred that the water contained in such interstitial spaces increases with increasing blood glucose concentration . as the glucose concentration of such interstitial fluid is reflective of blood glucose level , the glucose concentration in the interstitial fluid also increases with increasing blood glucose concentration . as an explanation for the downward slope of the data plotted in fig1 , a two - step process is proposed . firstly , water from the device &# 34 ; hydrates &# 34 ; the skin . water diffuses more rapidly than glucose from the device into the interstitial spaces to which it has access through the stratum corneum . there is a limit to the amount of water which can be contained in such spaces . in a second , slower step , but one which is promoted by increased hydration of the skin , glucose diffuses from the device into the interstitial channels . it would be expected that the rate of the second step would be in some proportion to the difference between the concentrations of glucose in the device and the interstitial spaces . in any event , since the degree of skin hydration increases with the blood glucose of the subject , &# 34 ; full &# 34 ; hydration of the skin through the first step of the process occurs more rapidly with increasing blood glucose concentration . this in turn means that the second step occurs more readily when the blood glucose of the subject is higher . it is thus observed that the amount of glucose which diffuses from the device into the skin increases with increasing glucose concentration . it is likely that the two steps of the process occur simultaneously to some extent ( although at different rates ), but the results of fig1 indicate that the first step of the process predominates and hence the degree of glucose depletion from the device depends more on the initial degree of hydration of the skin than on the concentration of glucose in the interstitial spaces . the data plotted in fig1 and 17 indicate that the degree of skin hydration , measured over a relatively short period of time , increases with blood glucose concentration . returning to the data plotted in fig3 and 5 , in which the substrate bearing glucose was paper , the substrate bears insufficient water for the hydration process to occur appreciably , the second step of the process predominates and hence the degree of glucose depletion from the paper substrate is inversely related to the concentration of glucose in the interstitial spaces and hence also to blood glucose concentration . a substrate of the present invention , for use in connection with an aspect of this invention in which glucose is loaded to the substrate prior to use has the property that a suitable amount of glucose can be loaded to the substrate and retained by the substrate , subject to proper storage , until the substrate is brought into contact with skin a substrate for use in connection with an aspect of this invention in which glucose transfers to an unloaded substrate has the property that transfer , i . e ., diffusion of the glucose into the substrate occurs readily . the test subjects of the experiments described above were non - diabetic and free of any apparent endocrinological abnormality that would compromise the observed results . studies were performed in the morning on fasting subjects . after baseline measurements on fasting , food was ingested to raise blood glucose levels . studies continued until blood glucose levels declined to baseline levels . in accordance with the theory proffered above for the results shown in fig1 , it is contemplated that a migratory substance other than glucose could be monitored in order to determine the blood glucose level of a subject . in one contemplated approach , an aqueous solution of a substance which , like water , migrates readily into interstitial spaces could be used . in a second alternative contemplated approach , an aqueous solution of a substance which , like glucose , migrates slowly into the interstitial spaces could be used . in either case , a substance that provides advantageous light - absorbance characteristics for convenient monitoring could be chosen . further , since it might well be possible to use a substance which is not present in the interstitial spaces of skin ( or occurs at a constant concentration therein ) the rate of the second step of the process would be uncomplicated by the presence of the substance in the interstitial space , as could potentially cause problems with glucose . the use of such a substance would thus provide the added advantage that the diffusion thereof would be independent of glucose concentration and has the potential of providing even more reliable results than those obtainable through the monitoring of glucose . the invention now having been described , including the best mode currently known to the inventor , the claims which define the scope of the protection sought for the invention follow . | US-68865096-A |
modular display rack systems , which are easily configurable , have interchangeable components , and are capable of being packaged and shipped in small containers , are described . preferred methods for using modular display rack systems are also disclosed . in some of the embodiments disclosed , one or more ladder racks are used to erect a single tower modular display rack , a two tower modular display rack and so forth . each ladder rack used to construct the modular display rack system may include a support base pivotally attached via a pivot pin to a lower portion of the ladder rack . the support base supports the load of the ladder rack and the modular display rack system and also pivots to a folded position if desired . | the detailed description set forth below in connection with the appended drawings is intended as a description of the presently preferred embodiments of the modular display rack in accordance with the present invention and is not intended to represent the only forms in which the present invention may be constructed or utilized . the description sets forth the features and the steps for constructing and using the modular display rack of the present invention in connection with the illustrated embodiments . it is to be understood , however , that the same or equivalent functions and structures may be accomplished by different embodiments that are also intended to be encompassed within the spirit and scope of the invention . also , as denoted elsewhere herein , like element numbers are intended to indicate like or similar elements or features . referring now to fig2 there is shown an embodiment of a triple tower or a three - ladder modular display rack ( hereinafter “ display rack ”), generally designated 10 . according to one embodiment , the modular display rack 10 may be disassembled into smaller components , allowing it to be portable and modular than prior art systems . the modular architecture of the display rack 10 allows it to be boxed up in small packages , assembled into a single ladder rack or multiple ladder racks , and inventoried by components instead of rack configurations since the single , double , and triple ladder racks do not have to be kept separately . the display rack 10 according to the embodiment illustrated in fig2 includes an upper rack portion 12 and a lower base portion 14 . for a three - ladder rack system 10 , the upper rack portion 12 includes two end ladders 16 and a center ladder 18 . assuming the vertical direction is the lengthwise direction and the horizontal direction is the direction of width of the ladder , the end and center ladders 16 , 18 are interconnected by a plurality of removable lateral support bars 20 along the horizontal direction and to the base in the vertical direction , by a plurality of fasteners 21 . in an exemplary embodiment , there is an upper pair of lateral support bars 22 and a lower pair of lateral support bars 24 . these lateral support bars 22 , 24 are removeably connected to the ladders by a detent - like arrangement . each individual pairs of lateral support bars permit hangrail brackets 11 and shelf brackets ( not shown ) to be hung on either a first side 26 and / or a second side 28 . the lower base portion 14 includes two end stabilizer bars 30 , a center stabilizer bar 32 , and two removable cross - bars 34 used to removeably connect the two end stabilizer bars 30 with the center stabilizer bar 32 . each stabilizer bar 30 , 32 is also equipped with casters 36 , which may be fixed or rail type casters . however , other casters may be used such as swivel stem style casters with breaks and locks . if used , these swivel stem style casters prevent the display rack 10 from moving when pushed accidentally . the stem style casters may screw or thread directly into the stabilizer bars 30 , 32 , or , alternatively , thread into corresponding nuts ( not shown ) welded to the base of the stabilizer bars . other casters and methods for installing the same are conventional in the art and may also be used as will be apparent to one skilled in the art . referring now to fig3 there is shown a double tower or a two - ladder modular display rack 31 . like the display rack of fig2 the modular display rack 31 comprises an upper rack portion 12 and a lower base portion 14 . the upper rack portion 12 includes two end ladders 16 removeably secured to the base in the vertical direction by several fasteners 21 . the two removable end ladders 16 are attached to each other by an upper and a lower pair of lateral support bars 22 , 24 . the lower base portion 14 includes two end stabilizer bars 30 removeably secured to each other by a single cross - bar 34 . the lower base portion 14 also includes a plurality of casters 36 , which may be fixed or rail type casters . however , as discussed above , other casters may be used such as swivel stem style casters with breaks and locks . as readily apparent to a person of ordinary skill in the art , the double tower display rack 31 is a subcombination of the triple tower display rack shown in fig2 . to create the double tower display rack 31 from the triple tower display rack 10 , the center ladder 18 , the two pair of lateral support bars 22 , 24 , the center stabilizer bar 32 , and one of the removable cross - bars 34 are removed from the triple tower rack 10 . conversely , to assemble a multiple tower rack , such as a four tower rack or higher , additional center ladders 18 , cross - bars 34 , and lateral support bars 20 , collectively referred to as rack components , are added . this eliminates the need for the advance production and storage of pre - welded multiple tower racks . racks of different configurations may now be created via the addition or the removal of the rack components . referring now to fig4 there is shown and described a single tower or a single ladder display rack 38 in accordance with practice of the present invention . the single ladder display rack 38 comprises an upper rack portion 12 and a lower base portion 14 . the upper rack portion 12 includes a slightly modified single unit ladder 40 . it is slightly modified with respect to the end ladder 16 and the center ladder 18 of fig2 and 3 . as further discussed below , the single unit ladder 40 may be similar to the end and center ladders 16 , 18 except for the lack of side mounted u - shape brackets . however , for ease of inventory or the minimization of components , an end ladder 16 or a center ladder 18 may be used in place of the single unit ladder 40 to provide the same overall functionality . the lower base portion 14 of the single ladder display rack 38 includes a single cross - style base 42 . to minimize the number of different components , the cross - style base 42 may be assembled by removeably securing two half - bars 44 onto the center stabilizer bar 32 . accordingly , one component used for the single tower that may not be present in the double tower and the triple tower rack is the half - bars 44 used in the single cross - style base 42 . the cross - style base 42 also utilizes a plurality of casters 36 . as discussed above , these casters may be a fixed type , a flanged type , a swivel type and the like . accordingly , minor changes between caster types are contemplated to fall within the spirit and scope of the present invention . fig5 - 19 are now referred for a detailed description of the various components embodied in the display racks of fig2 - 4 . specifically , fig5 is a semi - schematic diagram of the end ladder 16 of fig2 and 3 . according to one embodiment of the invention , the end ladder 16 includes a pair of u - shape brackets 46 . the end ladder 16 also includes a pair of vertical braces 48 taking the form of rectangular tubing pieces . the upper end 50 of each vertical brace 48 may be machined , rolled , or extruded ( collectively “ machined ”) with a smooth finish for aesthetic appeal and for eliminating sharp edges . this upper end 50 may be shaped in a half - dome , half arrow , or any other shapes helping to eliminate sharp edges and providing a minimum aesthetic appeal . the lower end 52 , because it braces onto a stabilizer bar , is machined with a flat finish . the pair of vertical braces 48 is fixedly secured together by a plurality of cross - braces 54 . the number of cross - braces in the ladder 16 depends on the length of the ladder . the vertical braces 48 and the cross braces 54 have the following configuration : l × w × d , where l is the length , w is the width , and d is the depth of the rectangular tubing ( fig5 a ). in an embodiment where each vertical brace 48 has a width x , each of the cross - braces 54 , which may also be made from rectangular tubing pieces , have a depth that is less than half x . this provides , at each cross - brace to vertical brace welded location , space for accommodating a pair of cross - braces 54 . in other words , at the top cross - brace location 56 , two cross - braces 54 , one superimposed over the other but separated by a small gap , are welded to the pair of vertical braces 48 . thus , two times the depth of the cross - brace plus the small gap should be the same as or slightly less than the width of the vertical brace 48 . exemplary dimensions are further discussed below . referring now to fig6 there is shown and described a center ladder 18 in accordance with practice of the present invention . the center ladder 18 may be similar to the end ladder 16 except that the center ladder includes two sets of u - shape brackets 46 on each side of the vertical brace 48 . this allows the center brace 18 to be used in the center of any multiple ladder arrangements and be used to join adjacent ladders together by way of removeably securing lateral support bars to the u - shape brackets 46 . referring now to fig7 a single unit ladder 40 is shown and described . the single unit ladder 40 may be similar to the end ladder except for the lack of u - shape brackets welded to the vertical braces 48 . the u - shape brackets are not included in the single unit ladder 40 since it is used as a stand - alone tower rack , and not contemplated to be expanded into other configurations . although the end , center , and single unit ladders of fig5 , and 7 are shown having a particular dimension with a particular number of cross - braces , a person skilled in the art should recognize that alternative dimensions and alternative number of cross - braces may also be used . the dimensions and number of cross - braces may also be customizable based on needs and requests of merchants and customers . similarly , instead of welding a pair of cross - braces at each of the cross - brace to vertical brace location or using a u - shape bracket ( for allowing hangrail brackets 11 and shelf brackets ( not shown ) to be mounted on either a first side 26 and / or a second side 28 of the rack ), a single cross - brace and / or a single u - shape bracket may be used . if so , for a particular attachment location , only a single hangrail , a single shelf bracket , or a single removable lateral support bar may be used . referring now to fig8 there is shown and described a base bracket 58 , which is a blown up view of detail a indicated in fig5 . according to one embodiment , the base bracket 58 is a flat steel plate having two through holes 60 machined therein . the base bracket 58 is fixedly secured to the vertical braces 48 by any number of known welding methods , including arc welding , brazing , and resistance welding . the two through holes 60 allow a pair of fasteners 21 to be inserted therethrough and to tighten the ladder against a stabilizer bar such as , stabilizer 30 or 32 . it is understood that any number of welding methods apply whenever the term “ weld ”, “ welded ”, or “ welding ” is used . referring to fig9 and 10 , there is shown and described an exemplary lateral support bar 20 , which can be the upper 22 or the lower lateral support bar 24 . the lateral support bar can be made from a rectangular tubing piece and is welded on each end by a flange 62 . the flange 62 includes an engagement tip 64 configured to engage a u - shape bracket 46 in a detent - like fashion . the flange 62 may be made from a flat steel plate . referring now to fig1 and 12 , there is shown and described an exemplary u - shape bracket 46 , which is a blown up view of detail b indicated in fig6 . according to one embodiment , the u - shape bracket 46 is a steel channel having two sides 66 and a base 68 . each of the two sides 66 comprises a square finish 70 or a rounded finish , a first open face 72 , and a rear attachment face 74 . the open face 72 allows a lateral support bar 20 , when set in position , to slide in - between the two sides 66 and rest on top of the base 68 . conversely , the rear attachment face 74 is configured to be welded to a main vertical brace 48 by its two end surfaces 76 ( fig1 ). as indicated , the base 68 terminates short of the rear attachment face 74 to form a receiving channel 78 . accordingly , when a lateral support bar 20 is set in position inside the u - shape bracket 46 , the receiving channel 78 provides an opening or a gap for the engagement tip 64 located on the flange 62 , which , as discussed , is located on each of the ends of the lateral support bar 20 ( fig9 ). accordingly , the engagement tip 64 and the receiving channel 78 interact to removeably secure one ladder with another ladder ( such as securing one end ladder 16 to a center ladder 18 ). in an exemplary embodiment , two u - shape brackets 46 are welded , side - by - side , to the main vertical brace 48 . in this fashion , the two u - shape brackets 48 may accommodate two lateral support bars 20 in a side - by - side fashion to provide two hanging surfaces for hangrails 11 and the like . in order to allow sufficient space for the engagement end of the hangrail to engage the lateral support bar 20 , the two u - shape brackets 46 may be welded with a flat plate ( not shown ) disposed therebetween . according to one embodiment , this plate serves to not only add structural rigidity to the two u - shape brackets , but also fix or define a gap in - between the u - shape brackets to enable the engagement end of the hangrail 11 to grab onto . referring now to fig1 and 14 , there is shown and described an end stabilizer bar 30 , also referred to as a base bar , in accordance with practice of the present invention . the end stabilizer bar 30 includes two leg extension pieces 82 welded to a center load - bearing piece 80 . again , all three pieces , the two leg extension pieces 82 and the center load - bearing piece 80 , may be made from rectangular tubing . in an exemplary embodiment , at the end 84 of each leg extension 82 , a tapered or slanted finish 84 is provided . this serves to both beautify the ends of the stabilizer bar 30 and eliminate sharp edges . in the illustrated embodiment , the center load - bearing piece 80 includes two through holes 86 . these through holes 86 , which extend the entire width of the center load bearing piece , are positioned so that when an end ladder 16 is mounted to the end stabilizer bar 30 by , for example , positioning the base bracket 58 directly over the center load bearing piece 80 , the through holes 86 align with the through holes 60 on the base bracket 58 . after the through holes 60 , 86 are aligned , a pair of fasteners 21 , such as a pair of bolt and nut combination , may be inserted therethrough and tightened . a person skilled in the art should recognize that any other number of through holes may be used depending on the width of the center load bearing piece and the dimension of the holes . a joining bracket 88 is provided which is welded to one of the axial ends of the center load - bearing piece 80 . a pair of nuts 90 are also provided and welded onto the joining bracket 88 to serve as gripping points for a pair of bolts ( not shown ). thus , to join two end stabilizer bars 30 ( or one end stabilizer bar 30 and one center stabilizer bar 32 ) together , a removable cross - bar 34 is placed over the joining bracket 88 in a telescoping fashion . a pair of bolts ( not shown ) are then inserted and tightened against the pair of nuts 90 to thereby removeably secure the cross - bar 34 to the end stabilizer bar 30 . as discussed above , the lower base portion 14 may be practiced with swivel type casters . when that is the case , the two leg extensions 82 are fitted or welded with a pair of swivel nuts 92 . the swivel type casters can then thread or screw directly into the swivel nuts 92 to be removeably secured the casters thereto . referring now to fig1 and 16 , there is shown and described the joining bracket 88 discussed in reference with fig1 and 14 , which are blown up drawings of detail c in fig1 . in the illustrated embodiment , the joining bracket 88 is an extended l - shape bracket that includes a first tall side 94 and a second short side 96 . the second short side 96 allows access to the central portion where the nuts 90 can be welded to the bracket . in addition , because the joining bracket 88 is designed to fit into one of the ends of a removable cross - bar 34 in a telescoping fashion , the second shorter side 96 has the effect of reducing drag or friction as the removable cross - bar 34 engages the joining bracket 88 . thus , because of the telescoping style arrangement , it is understood that the joining bracket 88 has a smaller cross - sectional area than the cross - sectional area of the cross - bar . a person skilled in the art should recognize , however , that instead of a tall side and a short side , two tall sides may be used to render a u - shape bracket . referring now to fig1 , there shown and described a top plan view of the center stabilizer bar 32 of fig2 . the center stabilizer bar 32 may be similar to the end stabilizer bar 30 except that the center stabilizer bar includes two joining brackets 88 instead of one . this enables the center stabilizer bar 32 to be used in - between two end stabilizer bars 30 and be connected on each side by a removable cross - bar 34 . referring now to fig1 , there is shown and described a removable cross - bar 34 taken along reference line x - x of fig2 . according to one embodiment , the removable cross - bar 34 is made from rectangular tubing and is drilled on both ends with a pair of holes 98 . the holes are configured so that they align with the pair of nuts 90 welded to the joining bracket 88 ( fig1 ). accordingly , when the removable cross - bar 34 is slid over the joining bracket 88 in a telescoping fashion , the holes 98 align with the nuts 90 on the joining bracket 88 . in this fashion , a pair of bolts may then be inserted to removeably secure the cross - bar 34 with one of the end stabilizer bars 30 or one of the center stabilizer bars 32 . referring now to fig1 , there is shown and described a top plan view of the cross - style base 42 of fig4 . the cross - style base 42 may be a center stabilizer bar 32 with two half - bars 44 mounted in a telescoping fashion with the two joining brackets 88 . alternatively , the joining brackets 88 may be eliminated altogether by welding two half - bars 44 directly onto the center stabilizer bar 32 . this alternative method will produce a cross - style base 42 that is permanently fixed . in general terms , a multi - tower rack may be assembled in the following fashion with reference to fig2 - 4 . in assembling the lower base portion 14 , two end stabilizer bars 30 are fastened with one center stabilizer bar 32 for creating a three - tower rack . a cross - bar 34 is slid over the joining bracket 88 of the end stabilizer bar 30 and tightened with a pair of bolts at the cross - bar holes 98 . the other end of the cross - bar 34 is then slid over the joining bracket 88 of the center stabilizer bar 30 and then tightened with another pair of bolts . this is then repeated on the other side with another end stabilizer bar 30 and another cross - bar 34 to form the base . after the lower base portion 14 is assembled , it may be disassembled by reversing the steps . in assembling the upper rack portion 12 , two end ladders 16 are fastened on the two end stabilizer bars 30 by inserting a pair of bolts at the base bracket 58 through the through holes 86 of each end ladder 16 . the u - shape brackets 46 on each of the end ladders 16 are turned so that they face inward , toward the center stabilizer bar 32 . in the same fashion , a center ladder 18 is mounted over the center stabilizer bar 32 . eight lateral support bars 20 are then used to removeably secure the two end ladders 16 with the center ladder 18 . this is done by lowering the flange ends 62 of the lateral support bars into corresponding pair of u - shape brackets 46 . the engagement tips 64 of the various flanges 62 should slide into their respective receiving channels 78 . once the upper rack portion 12 is assembled , it may be disassembled by reversing the steps . a modular display rack system 100 provided in accordance with other aspects of the present is shown in fig2 , which includes a lower base portion 14 having a quick connect / disconnect mechanism 102 , and an upper base portion 12 having an attachment mechanism 104 . the display rack system 100 is similar to the display rack system shown in fig2 - 4 in that it also includes end ladders 106 removeably secured to one another by a plurality of lateral support bars 20 . the end ladders 106 are each formed by connecting a plurality of cross - braces 54 to two vertical braces 48 . as before , peripheral connecting devices 105 , 108 for hanging and displaying merchandise items may be attached to the display rack system 100 along a first side 26 , a second side 28 , or even a third side 110 , which is perpendicular to the first and the second sides . referring now to fig2 a , a semi - schematic partial exploded view of the modular display rack system 100 of fig2 is shown . the lower end section 112 of one of the end ladder racks 106 include a joining bracket 114 for joining one end of a cross bar 34 , which then joins to another joining bracket of another end ladder rack 106 ( or a center ladder rack ) to form a display rack system ( fig2 ). in one exemplary embodiment , the joining bracket 114 is sized to be received in the opening 115 of the cross - bar 34 , which telescopically mounts over the joining bracket 114 to engage therewith . the joining bracket 114 may comprise a rectangular tubing welded to a lower exterior surface 116 of the vertical brace 48 , or to both vertical braces 48 for a center ladder rack , as further discussed below . alternatively , a c - channel , an angle or l - channel , or other equivalent brackets may be used instead of the rectangular tubing for implementing the joining bracket 114 . referring to fig2 b in addition to fig2 a , a fastener 118 is threadedly engaged to a first surface 120 of the joining bracket 114 . more preferably , the fastener 118 projects through an opening on the first surface 120 of the joining bracket 114 and fastens to a nut ( not shown ). the nut may be welded subjacent the opening on an underside surface of the first surface 120 . the cross - bar 34 may be joined to the joining bracket 114 by sliding the opening 115 of the cross - brace over the joining bracket and aligning a slot 122 positioned proximate the opening 115 around the fastener 118 . the fastener 118 may then be fastened against the to suface of the cross bar 34 to secure the cross - bar with the joining bracket 114 . for reference purposes , the lateral support bars 20 may be referred to herein as upper horizontal bars and the cross - bars 34 may be referred to herein as lower horizontal bars . referring now to fig2 c in addition to fig2 a , a quick connect / disconnect mechanism 102 is shown for securing a stabilizer bar 124 to an end ladder rack 106 ( or to a center ladder rack ). the quick connect / disconnect mechanism 102 comprises a locking pin 126 , a locking flange 128 , and a resilient member 130 . in one exemplary embodiment , the locking pin 126 includes a longitudinal planar surface 132 extending the entire length of the locking pin and an optional pair of spaced part position locators or notches 134 a , 134 b . a pair of spring clips , c - clips , or hairpin clips 135 a , 135 b may be utilized to engage the notches 134 a , 134 b if incorporated , or directly to the locking pin to frictionally grip the surface of the locking pin , if not incorporated . the locking flange 128 includes a chamfered opening 136 sized to receive the locking pin 126 and may incorporate any number of shapes , including a rectangle , a rhombus , a square , etc . the chamfered opening 136 includes a planar section 138 sized to abut the longitudinal planar surface 132 of the locking pin 126 to eliminate relative rotation between the locking pin and the flange 128 . the locking flange 128 further includes a pair of male detents or tabs 140 for engaging a pair of locking apertures 142 of the stabilizer bar or base bar 124 . the locking apertures 142 are positioned adjacent a central opening 144 of the stabilizer bar , which is adapted to receive the locking pin 126 . the locking apertures 142 and the central opening 144 may extend the width of the stabilizer bar , i . e ., are present on both surfaces of the stabilizer bar . the stabilizer bar 124 may include a pair of stationary or rotatable casters 36 for facilitating moving the modular display rack . as previously discussed , the vertical braces 48 of the end ladder rack 106 ( and of the center ladder rack , as further discussed below ) may generally be made from rectangular tubing . the vertical braces 48 each comprises an inwardly facing surface 146 and an outwardly facing surface 148 . for reference purposes , inwardly facing surfaces of a pair of adjacent vertical braces 48 ( of either a center ladder rack or an end ladder rack ) face one another . a retaining aperture 150 may be located at or near the lower end section 112 of each inwardly facing surface 146 of each vertical brace 48 , but not on the outwardly facing surface 148 of the same vertical brace . the retaining aperture 150 comprises a chamfered opening and includes a planar section 152 sized to abut with the longitudinal planar surface 132 of the locking pin 126 to eliminate rotation of the locking pin relative to the vertical brace 48 . however , it is envisioned that alternative quick connect / disconnect mechanisms may be made to operate with retaining apertures 150 positioned on the outwardly facing surfaces instead of or in addition to the inwardly facing surfaces of the vertical braces . for example , such retaining apertures may be incorporated to enable the locking pins to extend through the vertical braces . the quick connect / disconnect mechanism 102 is mounted to the stabilizer bar 124 and the end ladder rack 106 by first inserting the locking pin 126 through the central opening 144 of the stabilizer bar 124 . the locking pin 126 should be inserted so that the notches 134 a , 134 b on the locking pin 126 straddle either side ( on the outside surface ) of the stabilizer bar 124 . the clips 135 a , 135 b are then engaged with the notches 134 a , 134 b on the locking pin 126 to confine the stabilizer bar 124 to an area between the two notches 134 a , 134 b , i . e ., the stabilizer bar should be fixed axially along the locking pin between the notches . the opening 136 on the flange 128 is then mounted over the locking pin 126 , on either end of the locking pin until the male detents 140 on the flange engage the locking apertures 142 of the stabilizer bar 124 . the resilient member 130 is now assembled over the end of the locking pin 126 on the end where the flange 128 is positioned . the quick connect / disconnect mechanism 102 and the stabilizer bar 124 are now assembled to the end ladder rack 106 by forcing the two ends of the locking pin into the retaining apertures 150 of the inwardly facing surfaces 146 of the vertical braces 48 . the vertical braces 48 will momentarily and reversibly deflect or bend to enable the pin of the quick connect / disconnect mechanism 102 to be received by the retaining apertures 150 of the inwardly facing surfaces 146 . alternatively , a spring bias telescopic rod may be used for the locking pin 126 , two or more resilient members 130 may be used instead of one , and a tongue and groove arrangement instead of a chamfered surface for rotational control of the components of the quick connect / disconnect mechanism may be used . other variations for implementing a quick connect / disconnect mechanism are also contemplated and are deemed to fall within the scope of the present invention . another modular display rack system 101 provided in accordance with aspects of the present invention is shown in fig2 , which incorporates the quick connect / disconnect mechanism 102 of fig2 a - 21 c . the display rack system 101 comprises an end ladder rack 106 joined to a center ladder rack 154 by a plurality of lateral support bars 20 and a cross bar 34 . the center ladder rack 154 is then connected to either an end ladder rack or another center ladder rack ( not shown ) via another set of lateral support bars 20 ( partially shown ) and cross bar 34 ( partially shown ). an end stabilizer bar 124 is connected to the lower end section 112 of the end ladder rack 106 and to the center ladder rack 154 using the quick connect / disconnect mechanism 102 of the present invention . the center ladder rack 154 differs from the end ladder rack 106 in that it has joining brackets 114 and u - shaped brackets 46 on the exterior surfaces 116 of both of its vertical braces 48 . as previously discussed , there may be one or two u - shaped brackets 46 at each u - shaped bracket location . in one embodiment , the end stabilizer bar 124 may be rotated from a first normal support position ( fig2 ) to a second folded upright position ( fig2 ). the rotation of the end stabilizer bar 124 from the first normal support position to the second folded upright position may be accomplished by moving the flange 128 to compress the resilient member 130 . a finger gripping portion may be incorporated on the flange to facilitate manipulating the flange to compress the resilient member . the compression action causes the tabs 140 of the flange 128 to disengage from the locking apertures 142 of the stabilizer bar 124 . the stabilizer bar 124 is then free to rotate about the locking pin , which acts as a pivot pin , until a bar end 156 is positioned in the folded space 158 of the end ladder rack 106 ( or center ladder rack 154 ). the folded space 158 is defined by the lower most cross brace 54 and portions of the two vertical braces 48 near the lower end section 112 of either the end ladder rack or center ladder rack . the flange 128 may then be released and when released is urged by the resilient member 30 against the end stabilizer bar 124 . the two tabs 140 of the flange now engage with the edges of end stabilizer bar 124 to maintain the end stabilizer bar in the second folded upright position . alternatively , if the stabilizer bar 124 is in a first normal support position ( fig2 ), it may be moved to a second folded upright position ( fig2 ) in a reversed manner as discussed above . the end stabilizer bar 124 may be attached to either the end ladder rack 106 and / or the center ladder rack 154 at the manufacturing plant and shipped to a retailer , a department store , or an end user in the folded upright position . alternatively , the end stabilizer bar 124 and the quick connect / disconnect mechanism 102 may be shipped separately and assembled on site to use in the manner and fashion described in the foregoing paragraphs . to form the modular display rack system 101 of fig2 , a cross bar 34 may be mounted over a joining bracket 114 ( fig2 a and 21 b ) of the end ladder rack 106 and to one or more center ladder racks 154 to form a three or more modular tower display rack system . lateral support bars 20 are then attached to adjacent u - shaped brackets 46 of adjacent ladder racks to provide lateral support to two adjacent ladder racks ( i . e ., to either two end ladder racks , two center ladder racks , or one end ladder and one center ladder rack ). [ 0082 ] fig2 shows a semi - schematic exploded perspective view of a three tower modular display rack system 160 provided in accordance with aspects of the present invention . the modular display rack system 160 comprises two end ladder racks 106 and one center ladder rack 154 . the two end ladder racks 106 may be removably joined to the center ladder rack 154 using two cross bars 34 to connect with the joining brackets 114 located near the lower end 112 of each of the ladder racks . four sets of lateral support bars 20 are used to engage with 8 sets of u - shape brackets to support the ladder racks laterally , i . e ., perpendicular to the height of the ladder racks . each set of lateral support bars and u - shape brackets may comprise two lateral support bars and two u - shaped brackets or just one of each . end stabilizer bars 124 may be mounted to the lower end of the ladder racks 106 , 154 to support the modular display rack system 160 . the ladder racks 106 , 154 may be supplied with the end stabilizer bars 124 mounted at the factory or separately installed on site , as previously discussed . in either scenario , the end stabilizer bars 124 must be rotated to the normal support position ( fig2 ) before the modular display rack may be used to display merchandise items . a semi - schematic perspective view of another modular display rack system 162 provided in accordance with aspects of the present invention is shown in fig2 . the display rack system 162 is similar to the display rack system 160 of fig2 except that three additional center ladder racks 154 and corresponding number of cross bars 34 , lateral support bars 20 , and end stabilizer bars 124 are added to form the six ladder rack modular display rack system 162 . alternatively , fewer or more center ladder racks 154 may be added to decrease or increase the size of the modular display rack system . the display rack system 160 of fig2 is again shown in fig2 along with several peripheral devices 105 , 108 , 164 . one peripheral device can be a straight arm hangrail 105 having an engagement bracket 166 for engaging a vertical brace 48 , a lateral support bar 20 , or a cross brace 54 . the straight arm hangrail 105 comprises a beam surface for hangers , hooks , and the like to hang on . another peripheral device is a u - shaped hanging bracket 108 . the u - shape hanging bracket 108 comprises two outwardly extending arms 168 connected to one another by a connecting arm 170 to form a u - shaped surface for hangers and the like to hang from . the ends of the outwardly extending arms 168 each comprises an engagement bracket 166 for engaging with a vertical brace 48 , a lateral support bar 20 , or a cross brace 54 . the engaging brackets 166 may comprise c - channels and c - channels with notches and slots cut out in the walls of the channels to engage with the vertical brace 48 , the lateral support bar 20 , or the cross brace 54 , or any combination thereof . a peripheral device comprising a shelf 164 may also be used with the modular display rack system 160 of the present invention . the shelf 164 may comprise two or more engaging brackets 166 formed on the underside of the top shelf surface 170 to engage with either the vertical brace 48 , the lateral support bar 20 , or the cross brace 54 . once mounted , the shelf 164 may function as display surface for merchandise items , such as clothes , toys , food , etc . the shelf 164 may be made from steel , wood , thermoplastic , fiberglass , or other materials having sufficient hardness and rigidity to provide support for merchandise items . a semi - schematic perspective view of the modular display rack 160 of fig2 is again shown in fig2 with alternative peripheral devices . in one embodiment , the modular display rack system 160 may include one or more t - hangrails 172 , one or more rising hangrails 178 , one or more sloping arm hangrails 180 , and one or more display boxes 182 . the t - hangrail 172 shown comprises a first arm section 174 having an engaging bracket 166 attached to one end thereof and a second arm section 176 attached to the end opposite the engaging bracket . the ends of the second arm section 176 may include flanges 62 ( see , e . g ., fig9 and 10 ) to shield sharp edges of the second arm section and to provide a stop ledge for clothe hangers and hooks , i . e ., to prevent the same from sliding off of the second arm section . the rising hang rails 178 shown include a first arm section 174 having an axis attached to an engagement bracket 184 having a different axis . the axis of the first arm section 174 is offset from the axis of the engagement bracket 184 to enable the rising hangrail 178 to be hung from the second set of cross brace 54 a , third set of cross brace 54 b , and so forth . this offset configuration allows the rising hangrail 178 to be hung without the first arm section 174 or the second arm section 178 of the rising hangrail hitting or abutting any part of the tower rack or any part of the display tower , i . e ., the offset provides clearance for the rising hangrail to be hung on any of the cross braces along the height of a particular ladder rack . a sloping arm hangrail 180 may also be used with the modular display rack system 160 of the present invention . the sloping arm hangrail 180 comprises an arm section 186 attached to an engagement bracket 166 , and more particularly to a side of the c - channel of the engagement bracket at an angle . the arm section 186 comprises a plurality of spaced apart bumps 188 , which act to distribute hangers or hooks that are hung on the sloping arm hangrail 180 to prevent them from collecting together . display boxes 182 having a width w , a height h , and a depth d may also be used with the modular display rack system 160 of the present invention . the display boxes 182 may be made from wood , thermoplastic , thin sheet metal , and the like and attached to one or more stabilizer bars 124 to provide shelf space for merchandise items . the width d , height h , and depth d of the display boxes 182 may vary depending on needs and aesthetic appeal of the end user . a semi - schematic perspective view of the modular display rack 162 of fig2 is shown in fig2 with a plurality of peripheral devices mounted thereto for providing surfaces for displaying merchandise items . although the plurality of peripheral devices are shown concentrated on the first three ladder racks , they may be mounted anywhere on the modular display rack system 162 in any fashion a user desires . for example , the peripheral devices may be spaced apart along the first side 26 , the second side 28 , or the third side 110 of the modular display rack and along all six tower racks 106 , 154 . as shown , a u - shaped hanging bracket 108 is hung on a first side 26 of the modular display rack 162 . the u - shaped hanging bracket 108 may also include a wire meshed basket hung on the frame of the u - shaped bracket to provide a pocket , such as a drawer , for displaying items , such as socks , packaged food , etc . another peripheral device shown is a shelf hangrail 190 comprising a shelf surface 192 hung to either the cross braces 54 or lateral support bars 20 of the modular display rack system 162 . an angled shelf hangrail 194 comprising a shelf surface 196 positioned at an angle to two or more engagement brackets ( not shown ) is also shown . as readily apparent , the particular peripheral devices shown are exemplary only and variations in the structures and the manner and fashion in which peripheral devices are used with the modular display racks of the present invention to display merchandise items are contemplated . listed below are exemplary rectangular tubing and bracket dimensions . however , it is understood that these are exemplary only and that other dimensions , thickness , etc . may be altered without changing the scope of the invention . accordingly , a mere change in size or dimension is contemplated within the present invention . flange 62 — 47 . 6 mm l — 12 . 7 mm w ×{ fraction ( 1 / 16 )}″ to ⅛ ″ thick extended l - shape bracket 88 — 50 . 8 mm l × 54 . 5 mm w ( tall side )× 36 . 6 mm d × 19 mm w ( short side )×{ fraction ( 1 / 16 )}″ to ⅛ ″ thick center load bearing piece 80 — 127 mm l × 60 . 2 mm w × 406 mm d tubing can have a range of 11 — 20 gauge , and where necessary { fraction ( 3 / 16 )}″ or even ¼ ″ although the preferred embodiments of the invention have been described with some specificity , the description and drawings set forth herein are not intended to be delimiting , and persons of ordinary skill in the art will understand that various modifications may be made to the embodiments discussed herein without departing from the scope of the invention , and all such changes and modifications are intended to be encompassed within the appended claims . various changes to the modular display rack may be made including manufacturing the entire rack out of square tubing , changing the dimension of the tubing pieces , adding more or fewer cross - braces and u - shape brackets , changing the metallurgy , changing the finish ( from nickel to grinded steel finish or brush steel finish ), using posts instead of casters , and changing the type of casters . other changes may also include using different means to practice the quick connect / disconnect mechanism disclosed herein , including using a spring loaded telescopic pivot pin , using two resilient members , using fewer or more clamps , etc . accordingly , many alterations and modifications may be made by those having ordinary skill in the art without deviating from the spirit and scope of the invention . | US-42152403-A |
this invention provides a method of treatment of infectious disease organisms comprising introducing minute particles into the interior of infectious cells . these particles possess ferromagnetic , paramagnetic or diamagnetic properties . after being localized intracellularly , these particles are inductively heated by application of an alternating electromagnetic field . the inductive heating is continued for a period of time sufficient to bring about an intracellular temperature rise to a minimum necessary to kill the infectious organism . | the present invention achieves a precise increment of heat rise within the cells of the infectious organism . on the basis of the cell resting temperature and the thermal sensitivity of the individual infectious organism , the internal temperature of the invading cell is raised to the minimum necessary to cause cell death . in accordance with the present invention , there are found to be a number of approaches which can achieve the end result of destroying the infectious organism &# 39 ; s cells without causing damage to the host &# 39 ; s cells . in its broadest aspect , the invention proposes the introduction into the infectious cells of minute particles of a ferromagnetic , paramagnetic or diamagnetic material . particularly useful particles include both inorganic elements and compounds as well as metal containing organic compounds . inorganic elements and compounds particularly well - suited , owing to their favorable magnetic parameters , comprise elements such as dysprosium , erbium , europium , gallium , holmium , samarium , terbium , thulium , ytterbium or yttrium and compounds thereof , such as dysprosium sulfate , erbium sulfate , europium oxide , europium sulfate , holmium oxide , samarium sulfate , terbium oxide , terbium sulfate , thulium oxide , ytterbium sulfide , yttrium oxide , yttrium sulfate , yttrium ferrioxide ( y 3 fe 5 o 12 ) and yttrium aluminum oxide ( y 3 al 5 o 12 ). metal containing organic molecules useful for the application discussed above comprise particles of iron - dextrans such as feooh - dextran complexes and other dextran complexes and other dextran metal complexes wherein the metal is selected from the group comprising cobalt , zinc , chromium , nickel , platinum , manganese and rare earth metals such as dysprosium , erbium , europium , gallium , holmium , samarium , terbium , thulium , ytterbium and yttrium , ferric ammonium citrate , enterochelin , hydroxamates , phenolates , ferrichromes , ferritin , ferric mycobactins , and iron - sulfur proteins such as ferredoxin and rubredoxin . particularly appropriate metal containing organic structures for use with the present invention are the porphyrins such etioporphyrins , mesoporphyrins , uroporphyrins , coproporphyrins , protoporphyrins , and dicarboxylic acid containing porphyrins and substituted porphyrins such as tetraphenylporphyrin sulfonate ( ttps ). especially advantageous protoporphyrins comprise hematoporphyrins , chlorophylls , and cytochromes . in addition to the naturally occurring protoporphyrins which possess iron or magnesium containing moieties , mixed metal hybrid porphyrins may also be prepared . for example , by substituting an alternative metal for the iron in hematoporphyrin , the advantages of the porphyrin moiety ( e . g ., in terms of specificity of localization ) is retained while the unique magnetic properties of the new metal enhance the sensitivity of the substituted molecule . suitable metals for purposes of substitution comprise cobalt , manganese , zinc , chromium , nickel , platinum and rare earth series of metals dysprosium , erbium , europium , gallium , holmium , samarium , terbium , thulium , ytterbium and ytterium . suitable porphyrin acceptors comprise any dicarboxylic acid containing porphyrin , such as protoporphyrins ( e . g ., hematoporphyrins ) and the like . the principle upon which the present invention is based is grounded in the discovery that infectious organisms may transport , metabolize and sequester many elements or compounds in quite a different manner from that of the cells of the more advanced host organisms it usually infects . in one aspect of this invention , this specificity is used to selectively concentrate the above - mentioned minute particles within the cells of the infectious organisms , with little or no uptake of said particles by the host cells . the particles introduced into the infectious cells will generally be infectious organism - specific , i . e ., an element or compound peculiar to the metabolism of the organism being treated . compounds which are particularly useful in this regard are any of the above - mentioned metal - chelating transport substances specific to the various groups of microorganisms . also potentially of value in this process are such metal - containing organic structures as the porphyrins , including hematoporphyrins , cytochromes and chlorophylls . in addition to the naturally occurring porphyrins , mixed metal hybrid porphyrins may be prepared , substituting manganese , zinc , cobalt , chromium , nickel , platinum and rare earth series of metals such as dysprosium , erbium , europium , gallium , holmium , samarium , terbium , thulium , ytterbium and yttrium . the minute particles described are to be administered to the patient either orally or parenterally , i . e ., intravenously , intramuscularly , intraperitoneally , subcutaneously , topically or in suppository form , depending upon the nature and localization of the infection . dosage and frequency of administration may also vary depending upon the nature of the infectious organism . the next stage of the present invention is to differentially kill the infectious cells by causing inductive heating within the cytoplasm of said cells using a high - frequency alternating electromagnetic field , bringing about a precise rise in temperature of the cell . the principle of inductive heating through the use of hysteresis is a known principle . similarly , the monitoring of the temperatures of the living cells is a presently available technique well known to medical science . inductive heating of the minute particles is achieved through use of an electric oscillator operating in the high frequency range which heats the particles by subjecting them to an intense high - frequency field within a large but otherwise conventional helical coil , field energy being converted to heat through hysteresis losses and the resistor dissipation of eddy currents . the helical induction coil is of sufficient internal diameter to permit the patient to pass within and of such length to encompass the length of the patient . preferably the internal diameter would be greater than 3 - 6 feet in diameter , since diameters of inductive coils of greater than 6 feet have a preferential effect on the overall process by providing a minor uniform flux gradient to the patient . the frequency of the electromagnetic alternating high - frequency field will range from 1 kilohertz to 100 megahertz , and the power input of the oscillator - generator will range from 0 kilowatts to 30 kilowatts per kg . of patient body weight 1 kilowatts of power per 1 . 0 kilograms of body weight . in this power and frequency range , the colis selected to produce from 0 to 5 × 10 4 oersteds , preferably from 10 to 10 , 000 oersteds . the time necessary to inductively heat the minute particles held within the infectious cells depends substantially upon the frequency and the power production of the alternating electromagnetic field and ultimately the strength of the field produced . it should be noted , however , that it is only necessary to raise the temperature of the infectious cell to the minimum required to cause cell death , concentration of particles in the vehicles and the and that the variables with respect to the type and electromagnetic treatment are not critical provided that the necessary temperature is attained . in a further embodiment of the invention , treatment may be accomplished by inductive heating of magnetic particles endogenous to the invading cells . as noted above , many types of microorganisms possess metal - containing compounds routinely in the cell ; among these are storage proteins or metabolically essential porphyrins such a hematoporphyrin , chlorophylls , or cytochromes . for example , a large number of organisms produce ferredoxins or rubredoxins , iron - sulfur storage proteins which differ from genus to genus in their structure and the amount of bound iron . these are not found in the cells of most higher organisms . also other compounds , such as certain cytochromes or ferritin , while they may also occur in host cells , have been shown to generally be different in structure from those of the host organism . the difference in structure between microbial metal - containing compounds and host cell metal - containing compounds implies a difference in magnetic characteristics , such as magnetic susceptibility , between the pathogen &# 39 ; s compounds and those of the host cells . magnetic susceptibility is known to be temperature dependent , and may be routinely measured by magnetometer devices . by measuring the magnetic susceptibilities of particles at certain temperatures , it is possible to calibrate the magnetometer equipment so that measurement of magnetic susceptibility indicates the exact temperature of the particle in question . this capability may be used to selectively monitor the internal temperature of the invading cell ( as described by gordon in u . s . pat . no . 4 , 106 , 488 , and copending u . s . patent application ser . no . 464 , 870 for the treatment of cancer cells ) by focusing on the magnetic susceptibility of a particle unique to the pathogen , and bringing about a precise rise in temperature sufficient to kill the pathogenic cells without harming the host cells . as noted above , there are a number of naturally occurring compounds which would be eminently suitable for employing this method of treatment . a partial list of compounds specific to a particular organism or organisms , which have magnetic characteristics that may prove particularly useful in this regard , is represented in the following table : ______________________________________ compound______________________________________fungiphycomyces . sup . 1 ferritinsaccharomyces . sup . 2 yeast cytochrome acandida . sup . 2bacteriae . coli . sup . 3 bacterio - ferritinclostridium . sup . 4 clostridial ferredoxinpseudomonas . sup . 4 pseudomonad ferredoxin putidaredoxinpeptostreptococcus . sup . 4 rubredoxinnumerous protozoan . sup . 2 and cytochrome obacterial species______________________________________ . sup . 1 ( david , c ., microb . iron metab ., j . b . nielands , ed ., p . 149 , 1974 ) . sup . 2 ( yamanaka , t . and okunuki , k ., microb . iron metab ., j . b . nielands , ed ., p . 349 , 1974 ). . sup . 3 ( rosenberg , h . and young , j . g ., microb . iron metab ., j . b . nielands ed ., p . 67 , 1974 ). . sup . 4 ( lovenberg , w ., microb . iron metab ., j . b . nielands , ed ., p . 349 , 1974 ). this list is intended only to be exemplary , and is not limiting as to possible other applications of the treatment . the above - described treatment method is particularly well - suited to the treatment of organisms for which the metabolic pathways are poorly known , and for which there is no known chemotherapeutic agent . all that would be necessary is the identification of a specific metal - containing compound endogenous to the infectious organism , and said treatment would then be applicable . a further embodiment of the invention is the surface sterilization of objects using ferromagnetic , paramagnetic or diamagnetic particles . in this application of the invention , unsterile objects may be immersed in a solution containing said particles , which may be in the form of any of the compounds or elements mentioned in the previous embodiments . the concentration of the particles in solution would not be critical . the contaminating organisms would , over a period of time , take up the particles and concentrate them within their cytoplasm . a high - frequency alternating magnetic field could then be applied to the objects raising the internal temperature of the contaminating organism by inductive heating , and eventually killing them . because of the nature of this application of the invention , precise control of the temperature rise below a certain level would not be necessary , since no host cells are involved . this method provides a unique way of ridding objects , such as surgical instruments , of potentially dangerous microorganisms . | US-52484483-A |
the systems and methods provide effective neuromuscular stimulation to meet a host of different prosthetic or therapeutic objections . the systems and methods also provide convenience of operation , flexibility to meet different user - selected requirements , and transportability and ease of manipulation , that enhance the quality of life of the individual that requires chronic neuromuscular stimulation . | the various aspects of the invention will be described in connection with providing functional neuromuscular stimulation for prosthetic or therapeutic purposes . that is because the features and advantages that arise due to the invention are well suited to this purpose . still , it should be appreciated that the various aspects of the invention can be applied to achieve other objectives as well . i . system for providing functional neuromuscular stimulation using a universal external controller [ 0039 ] fig1 shows a system 10 that makes possible the restoration of function to muscles in the body that are otherwise paralyzed due to lack of neuromuscular stimulation , e . g ., due to spinal cord injury or stroke . spinal cord injury or stroke can break or otherwise disrupt the path or paths by which electrical signals generated by the brain normally travel to neuromuscular groups , to stimulate coordinated muscle contraction patterns . as a result , even through the nerves and muscles are intact , no electrical stimulation is received from the spinal cord , and the associated muscles do not function . in use , the system 10 generates and distributes electrical current patterns to one or more targeted neuromuscular regions . the resulting patterns of neuromuscular stimulation restore desired muscle function in the targeted region or regions . the stimulatation can be achieved by direct application of electrical current to a nerve ( e . g ., using a nerve cuff electrode ), or by indirect distribution of electrical current to a nerve through adjacent muscle tissue ( e . g ., using epimysial or intramuscular electrodes ). as will be described in greater detail later , the system 10 can restore function to a single , targeted neuromuscular region , for example , to upper extremity muscles in the arm , e . g ., to restore hand - grasp functions ; or to lower extremity muscles in the leg , to restore standing or ambulatory functions ; or to bladder and bowel muscles , to restore micturition ; or to muscles controlling ( in males ) erection and ejaculation , or ( in females ) lubrication , to restore sexual or reproductive function . the system 10 can also be selectively operated to restore function to more than one targeted neuromuscular region , making it possible for an otherwise paralyzed individual to use the system 10 to selectively perform not only hand - grasp functions , but also to selectively perform standing / ambulatory and / or bladder and bowel control functions and / or other stimulation functions , as well . the system 10 comprises basic functional components that can be assembled and arranged to achieve single or several neuromuscular stimulation functions . generally speaking , as shown in fig1 the basic functional components for a prosthetic neuromuscular stimulation function include ( i ) a control signal source 12 ; ( ii ) a pulse controller 14 ; ( iii ) a pulse transmitter 16 ; ( iv ) a receiver / stimulator 18 ; ( v ) one or more electrical leads 20 ; and ( vi ) one or more electrodes 22 . as assembled and arranged in fig1 the control signal source 12 functions to generate an output , typically in response to some volitional action by a patient , or a trained partner , or another care giver . in response to the output , the pulse controller 14 functions according to preprogrammed rules or algorithms , to generate one or more prescribed stimulus timing and command signals . the pulse transmitter 18 functions to transmit these prescribed stimulus timing and command signals , as well an electrical operating potential , to the receiver / stimulator 18 . the receiver / stimulator 18 functions to distribute electrical current patterns according to the prescribed stimulus timing and command signals , through the leads 20 to the one or more electrodes 22 . the one or more electrodes 22 store electrical energy from the electrical operating potential and function to apply electrical current patterns to the targeted neuromuscular region , causing the desired muscle function . the basic functional components can be constructed and arranged in various ways . in a representative implementation , some of the components , e . g ., the control signal source 12 , the pulse controller 14 , and the pulse transmitter 16 comprise external units manipulated outside the body . in this implementation , the other components , e . g ., the receiver / stimulator 18 , the leads 20 , and the electrodes 22 comprise implanted units placed under the skin within the body . other arrangements of external and implanted components can occur , as will be described later . in the representative implementation shown in fig2 a system 24 supports multiple prosthetic or therapeutic objectives . for purpose of illustration , in fig2 the system 24 is capable of achieving ( i ) a hand - grasp function in upper extremity arm muscles ; ( ii ) a standing function in lower extremity leg muscles ; and ( iii ) a bladder and bowel control function . to accomplish the different hand - grasp , standing , and bladder and bowel control functions , the system 24 dedicates , for each function , a function - specific external control signal source 12 ( 1 )( 2 )( 3 ), a function - specific external pulse transmitter 16 ( 1 )( 2 )( 3 ), a function - specific implanted receiver / stimulator 18 ( 1 )( 2 )( 3 ), function - specific implanted leads 20 ( 1 )( 2 )( 3 ), and function - specific implanted electrodes 22 ( 1 ) ( 2 ) ( 3 ). to control all three function - specific receiver / stimulators , the system 24 employs a single , external pulse controller 26 , which , for this reason , will also be called the “ universal external controller .” in concert with the other function - specific components , the universal external controller 26 selectively achieves all three hand - grasp , standing , and bladder and bowel control functions . for the hand - grasp function , epimysial and intramuscular electrodes 22 ( 1 ) are appropriately implanted by a surgeon in the patient &# 39 ; s arm . the function - specific implanted electrodes 22 ( 1 ) are positioned by the surgeon by conventional surgical techniques to affect desired neuromuscular stimulation of the muscles in the forearm and hand . desirably , the neuromuscular stimulation affected by the electrodes 22 ( 1 ) achieves one or more desired palmar grasp patterns ( finger tip - to - thumb pinching ) and / or one or more desired lateral grasp patterns ( thumb to flexed index finger pinching ). the palmar grasp patterns allow the individual to grasp large objects ( e . g ., a cup or book ), and the lateral grasp patterns allow the individual to grasp small or narrow objects ( e . g ., a pen or fork ). implanted leads 20 ( 1 ) connect the electrodes 22 ( 1 ) to the function - specific implanted receiver / stimulator 18 ( 1 ) in conventional ways . the receiver / stimulator 18 ( 1 ) is placed by a surgeon under the skin on the chest . the receiver / stimulator 18 ( 1 ) receives the stimulus timing and command signals and power from the universal external controller 26 through the function - specific external pulse transmitter 16 ( 1 ). in the illustrated embodiment , the pulse transmitter 16 ( 1 ) takes the form of a transmitting coil , which is secured to a skin surface over the receiver / stimulator 18 ( 1 ), e . g ., by tape . the pulse transmitter 16 ( 1 ) transmits the stimulus timing and command signals and power through the skin to the receiver / stimulator 18 ( 1 ) for the hand - grasp function in the form of radio frequency carrier waves . the electrodes store electrical energy from the carrier waves . the stimulus timing and command signals for the standing function are distributed as biphasic current pulses in discrete channels to individual implanted electrodes 22 ( 1 ). the biphasic pulses provide amplitude and duration electrical signals that achieve the desired coordinated muscular finger - grasp function . because the implanted receiver / stimulator 18 ( 1 ) receives power from universal external controller 26 through the external pulse transmitter 16 ( 1 ), the implanted receiver / stimulator 18 ( 1 ) requires no dedicated battery power source , and therefore has no finite lifetime . the external control source 12 ( 1 ) for the hand - grasp function is coupled to the universal external controller 26 . as will be described in greater detail later , the external controller 26 can support a variety of external control sources 12 ( 1 ), which can be coupled to the controller by cable or by wireless link , as will also be described in greater detail later . in the embodiment illustrated in fig1 the external controller 12 ( 1 ) comprises a mechanical joy stick - type control device , which senses movement of a body region , e . g ., the shoulder , which is therefore also called a shoulder position sensor . the shoulder position sensor can comprise , e . g ., a two axis angle transducer that measures motion of the shoulder relative to the chest . the shoulder position sensor can be secured to the skin of the shoulder in the region of the sternal notch and clavicle using tape . as will be described later , when the user manipulating the shoulder in predetermined ways , the shoulder position sensor generates functional or proportional signals that , when processed according to the pre - programmed rules of the controller 26 , select or deselect either palmar or lateral grasp patterns , proportionately control of the opening and closing of the hand , or lock the hand in a desired grasping position . as will be described in greater detail later , in an alternative implementation , manipulation of input buttons on the universal external controller 26 also can be used to perform these finger - grasp functions . further details of these function - specific components for the hand - grasp function can be found in peckham et al u . s . pat . no . 5 , 167 , 229 , which is incorporated herein by reference . commercial examples of such function - specific components can also be found in the freehand ™ system , sold by neurocontrol corporation ( cleveland , ohio ). for the standing function , epimysial and intramuscular electrodes 22 ( 2 ) are appropriately implanted by a surgeon in the patient &# 39 ; s upper leg . the function - specific implanted electrodes 22 ( 2 ) are positioned by the surgeon by conventional surgical techniques to affect desired neuromuscular stimulation of the muscles in the hip and thigh . desirably , the neuromuscular stimulation affected by the electrodes 22 ( 2 ) achieves a contraction of leg muscles in the hip and thigh to bring the individual to an upright and standing position . in this position , the individual can stand upright and move about , typically with the aid of a walker or arm crutches . implanted leads 20 ( 2 ) connect the electrodes 22 ( 2 ) to the function - specific implanted receiver / stimulator 18 ( 2 ) in conventional ways . the receiver / stimulator 18 ( 2 ) is placed by a surgeon under the skin in the abdomen or thigh . the receiver / stimulator 18 ( 2 ) receives the stimulus timing and command signals and power from the universal external controller 26 through the function - specific external pulse transmitter 16 ( 2 ). as in the finger - grasp function , in the illustrated embodiment , the pulse transmitter 16 ( 2 ) for the standing function takes the form of a transmitting coil , which is secured to a skin surface over the receiver / stimulator 18 ( 2 ), e . g ., by tape . the pulse transmitter 16 ( 2 ) transmits the stimulus timing and command signals and power through the skin to the receiver / stimulator 18 ( 2 ) for the standing function in the form of radio frequency waves . as in the finger - grasp function , the stimulus timing and command signals for the standing function are distributed by the receiver / stimulator 18 ( 2 ) in discrete channels to individual implanted electrodes 22 ( 2 ) and provide electrical amplitude , duration , and interval command signals that achieve the desired coordinated muscular standing function . the external control source 12 ( 2 ) for the standing function is coupled to the universal external controller 26 . as explained earlier in the context of the finger - grasp function , the universal external controller 26 can accommodate input from a variety of other external control sources , either by hard - wire or wireless links . in the illustrated implementation , the external control source 12 ( 2 ) comprises a remote control button accessible to the individual , by which the user ( or care giver ) can select or deselect the standing function . one or more input buttons on the universal external controller 26 itself can also be used to select and deselect the standing function . for the bladder control function , cuff electrodes 22 ( 3 ) are appropriately implanted by a surgeon about sacral nerves that lead to the bladder and bowel . the function - specific implanted electrodes are positioned by the surgeon by conventional surgical techniques to affect neuromuscular stimulation of muscles in the bladder , bowel and urethral sphincter . desirably , the neuromuscular stimulation affected by the electrodes 22 ( 3 ) achieves a contraction of the muscles of the bladder , urethral sphincter , and bowel . after the bladder has contracted in response to the neuromuscular stimulation , it is possible to relax the sphincter muscles , allowing the bladder to empty . implanted leads 20 ( 3 ) connect the electrodes 22 ( 3 ) to the implanted receiver / stimulator 18 ( 3 ) in conventional ways . the receiver / stimulator 18 ( 3 ) is placed by a surgeon under the skin in the abdomen . the receiver / stimulator 18 ( 3 ) receives the stimulus command signals from the universal external controller 26 through the external pulse transmitter 16 ( 3 ). as with the finger - grasp and standing functions , in the illustrated embodiment , the pulse transmitter 16 ( 3 ) takes the form of a transmitting coil , which is secured to a skin surface over the receiver / stimulator 18 ( 3 ), e . g ., by tape . the pulse transmitter transmits the stimulus command signals through the skin to the receiver / stimulator 18 ( 3 ) for the bladder and bowel control function in the form of radio frequency waves . as explained earlier in the context of the finger - grasp and standing functions , the universal external controller 26 can accommodate input from a variety of other external control sources 12 ( 3 ), either by hard - wire or wireless links , to also affect the bladder and bowel control function . in the illustrated implementation , the external control source 12 ( 3 ) for the bladder and bowel function comprises an external remote control device , that can select or deselect the bladder and bowel control function . one or more input buttons on the universal external controller 26 itself can also be used to select and deselect the bladder and bowel control function . further details of these function - specific components for the bladder and bowel control function can be found in brindley u . s . pat . no . 3 , 870 , 051 , which is incorporated herein by reference . commercial examples of such function - specific components can also be found in the vocare ™ system , sold by neurocontrol corporation ( cleveland , ohio ). as fig3 a , 3b , 3 c , and 4 show , the universal external controller 26 is desirably housed in a compact , lightweight , hand held housing 28 . in one implementation , the housing 28 measures about 9 . 5 cm by 5 . 6 cm × 2 . 7 cm , and weighs , e . g ., about 160 g . as such , the controller 26 readily fits into a pocket or can be clipped onto the belt of an individual . desirably , the controller 26 is battery powered . in the illustrated embodiment , the controller 26 includes a power input slot that receives an interchangeable , rechargeable , industry - standard battery 30 ( see fig4 ), e . g ., a lithium ion battery used in association with a motorola ™ star tech ™ cellular phone . the controller 26 desirably interchageably accommodates rechargeable batteries of various capacities , so that different power usage levels of the controller ( depending upon the number and type of prosthetic functions of the controller 26 ) can be readily supported . desirably , the battery 30 cannot be charged when connected to the universal external controller 26 , so that the controller 26 ( and , thus , the user ) cannot be connected to main power . instead , the battery 30 must be removed and coupled to an associated external battery charger ( not shown ). the controller 26 also desirably includes a display screen 32 and keypad 34 , which together form an interactive interface between the individual user and the controller 26 . the display 32 can comprise , e . g ., a liquid crystal display . the display 32 presents to the individual pertinent operational and status information , and also prompts the individual to select or modify operational settings using the keypad 34 . the keypad 34 can comprise , e . g ., a one - piece silicone - rubber molded unit . the controller 26 desirably houses a microprocessor 36 , which , in the illustrated embodiment ( see fig4 ), is implemented on a main , double - sided circuit board 38 . the main circuit board 38 carries the components of the microprocessor 36 , e . g ., high and low voltage supplies , a high voltage protector , input / output ports 112 ( shown in fig3 b ) and drivers for the external control signal sources and pulse transmitters , a microcontroller , keypad interface , the liquid crystal display 32 , and an audio device ( e . g ., a buzzer ). the microprocessor 36 also desirably includes a 900 mhz transceiver , to allow wireless linking between the controller 26 and a compatible external wireless control signal source 12 ( 1 ) ( 2 ) ( 3 ), as will be described in greater detail later . if desired , additional full size or half - size circuit boards 40 ( see fig4 ) can be optionally provided , to handle special input signal conditioning for one or more of the function - specific control signal sources ( e . g ., the joy stick - type shoulder position sensor ). the microprocessor 36 can be realized with , e . g ., a conventional mc68hc12 microcontroller . the microprocessor 36 also desirably includes a flash memory device on the main circuit board 38 , which can be realized with e . g ., a conventional eeprom memory chip . the flash memory device carries embedded , programmable code , which will also be call the “ firmware .” the firmware expresses the pre - programmed rules or algorithms under which the stimulation timing and command signals are generated in response to input from the various external control sources , as well as the pre - programmed rules or algorithms that govern operation of the display 32 and keypad 34 of the controller 26 to create the user interface , as well as the other input / output devices supported by the controller 26 . the microprocessor 36 of the controller also desirably includes an infrared transceiver . the transceiver allows the wireless transfer of information to and from the microprocessor through an optical lens 42 ( see fig3 c and 4 ). this makes possible wireless programming of the firmware by infrared link by an external computer , as will be described later . this also makes possible wireless linking between two or more controllers 26 , for exchange of information and for replacement and backup purposes . as will be described later , the microprocessor 36 also accepts programming input via the input keypad 34 , allowing the individual user or care giver to program operation of the controller 26 to the extent permitted by the firmware . in the illustrated embodiment , the housing 28 encloses the display 32 , keypad 34 , and circuit board ( s ) 38 and 40 between front ( keypad side ) and rear ( battery side ) housing shells 44 and 46 , which can be made , e . g ., from molded abs impact - resistant plastic . spash - proof gaskets 48 are desirably placed at appropriate places , e . g ., about the keypad , battery contacts , and housing shells , to seal the housing 28 against ingress of moisture . a lcd lens window 50 desirably covers the display 32 . pivots 52 for a conventional flip cover can also be provided on the housing 28 . [ 0079 ] fig5 shows a representative circuit block diagram for the microprocessor 36 of the universal external controller 26 . the specific circuitry shown in fig5 allows the selection of a desired neuromuscular stimulation objective and supports the generation of output signals to one neuromuscular stimulation assembly to achieve the objective . however , it should be appreciated that the circuitry can be modified to include multiple parallel output stages , so that concurrent outputs to different neuromuscular stimulation assemblies can be provided . as shown in fig5 the circuitry is built on two printed circuit boards : the main circuit board 38 and the auxiliary board 40 . fig5 a to 5 m show representative circuit schematics for the components carried on the two boards 38 and 40 . the main circuit board 38 consists of five circuit modules . these are ( see fig5 ) the power supply module 200 , the implant driver module 202 , the microcontroller module 204 , and the user interface module 206 . the representative implementation mounts these modules on a double - sided , 6 - layer fr4 printed wiring main circuit board 38 ( 88 mm × 49 mm ). in the illustrated embodiment , the functions supported by the main circuit board 38 include : ( i ) mounting of push buttons of the keypad 34 for user control ; ( ii ) mounting of the display 32 and audio device for user prompting and information display ; ( iii ) mounting of contacts for user serviceable battery 30 ; ( iv ) mounting of output plug contacts for the indicated function - specific pulse transmitters ; ( v ) an interface to auxiliary control boards 40 , e . g ., for specialized function - specific control signal sources 12 ( 1 ) ( 2 ) ( 3 ); ( vi ) control of processing functions via the microprocessor 36 and memory chip ; ( vii ) interface to the keypad 34 , display 32 , audio device , and other user interfaces to the microprocessor 36 ; ( viii ) drivers for the indicated function - specific pulse transmitters 16 ( 1 )( 2 )( 3 ); ( ix ) interface to the battery 30 , including detection of battery charge status ; ( x ) provision of an infrared communications link ; and ( xi ) provision of a 900 mhz communications link . various circuit components and configurations can be placed on the main board to realize these and other functions . a representative implementation will be generally described with reference to fig5 a to 5 m and associated tables . the representative implementation meets medical grade ipc standard design rules , using no wires and all standard components , except one custom made transformer . the representative implementation uses no adjustable components , except one trim capacitor ( to accommodate variations in the one custom made transformer ). the representative implementation is emc compatible . the power supply module 200 includes a low - voltage supply circuit 208 ( shown schematically in fig5 a ) and a high - voltage supply circuit 210 ( shown schematically in fig5 b ). the low - voltage supply circuit 208 converts the battery voltage of 2 . 7 to 4 . 2 v to the general circuit operation voltage of 5 . 0 v . the high - voltage supply circuit 212 converts the same battery voltage to the variable operating voltage for the implant drivers ( 5 . 0 to 8 . 5 v for the finger - grasp and standing functions , and 10 to 40 v for the bladder / bowel control function ). each voltage supply circuit 208 and 210 is a dc / dc converter built around a specific ic chip . the level of the high voltage is set by the microcontroller module 204 via a dac . a high - side current sensing ic provides output current value to the microcontroller module 204 . the implant driver module 202 includes the function - specific driver 212 for the bladder and bowel control function ( fig5 d ), the function - specific driver 214 for the hand - grasp function ( fig5 e ), and the function - specific driver 216 for the standing function ( fig5 f ), with an associated high voltage protector ( fig5 c ), to provide failsafe hardware protection . the hand - grasp and standing function drivers 214 and 216 generate amplitude - modulated carrier of 6 . 78 mhz for powering and communicating with the implanted function - specific receivers / stimulators , respectively 18 ( 1 ) and 18 ( 2 ). as will be described in greater detail later , the output rf for each of these drivers 214 and 216 can be set by the user at one of five levels between 0 . 5 to 1 . 0 w . this variable rf power setting ensures reliable coupling to the associated implanted function - specific receiver / stimulator 18 ( 1 ) or 18 ( 2 ) at the specific depth of implantation ( which can vary ), while minimizing battery consumption . the bladder and bowel control driver 212 generates high voltage ( 10 to 40 v ), high current ( up to 1 a ) pulses to excite the associated receiver / stimulator 18 ( 3 ). three identical output stages can be controlled by the microcontroller module 204 for interfacing with either a 3 - channel or a 2 - channel receiver / stimulator 18 ( 3 ). the function of the high - voltage protector 218 is to prevent accidental application of high voltage to the finger - grasp or standing drivers 214 to 216 in case of a firmware failure . the microcontroller module 204 ( schematically shown in fig5 g ) is built around a motorola hc12 chip . the hc12 chip has 1 - kbyte ram and 32 - kbyte flash eerom . the built - in flash memory is used for the system firmware . an external 8 - kbyte eeprom chip is used for user - specific data , such as for finger - grasp patterns ( as will be described later ). a 4 - mhz ceramic resonator is selected for obtaining a 2 - mhz clock frequency in the hc12 . the hc12 uses a synchronous serial peripheral interface ( spi ) to communicate with three peripheral chips : the lcd display driver ; the dac for high - voltage setting ; and the adc in the auxiliary board 40 ( as will be described later . the hc12 also uses an asynchronous serial communication interface ( sci ) to communicate with the infrared transceiver 220 ( shown schematically in fig5 k ) and the 900 - mhz transceiver 222 ( shown schematically in fig5 l ). the internal 8 - channel , 10 - bit adc of the hc12 is used to monitor the critical parameters such as battery voltage , output voltage to the low - voltage supply 208 , output voltage and output current of the high - voltage supply 210 , and the received signal strength of the 900 - mhz transceiver 222 . the user interface module 206 consists of the circuitry 224 for the keypad 34 ( shown schematically in fig5 h ), the circuitry 226 for the liquid crystal display ( lcd ) 32 ( shown schematically in fig5 i ), and the circuitry 222 for the 900 - mhz transceiver ( shown in fig5 l ). in the keypad circuit 224 , a pair of perpendicularly situated reed switches is connected in parallel to each of the regular pushbutton switches for the “ enter ” and “ exit ” functions , as will be described later . the reed switches allow the user to operate the device using a finger ring with a magnet , without having to physically touch the keypad 34 . the lcd circuit 226 has a 16 character × 4 roll screen 32 with led back lighting . the volume of the sound generated by the buzzer circuit 228 ( shown schematically in fig5 j ) is adjustable by changing the pulse width . the infrared transceiver 220 ( shown schematically in fig5 k ) is implemented with a transceiver ic and discreet transmitting led and receiving photo diode . the 900 mhz transceiver ( shown schematically in fig5 l ) is formed with a loop antenna , an amplitude - sequenced hybrid ( ash ) transceiver module , and a dedicated microcontroller chip for decoding the received commands . input and output level shifters are used for interfacing the 3 - v transceiver module 222 with the 5 - v hc12 microcontroller . in the representative implementation , the controller also includes a double - sided , 6 - layer fr 4 printed wiring board 40 ( 40 mm × 46 mm ) ( shown schematically in fig5 m ), which serves as an input signal conditioning card for a joy - stick type shoulder position sensor , which is used in the illustrated embodiment to carry out the finger - grasp function . the main board 38 and auxiliary board 40 are connected together through a 30 - contact interboard connector 240 . the auxiliary board 40 includes an input filter 230 having low - pass filters and surge suppressors for improving immunity to electromagnetic interference . the auxiliary board 40 also includes a differential amplifier 232 , which has two instrumentation amplifier ic chips set a gain of 10 for both x and y axis signals coming from the shoulder position sensor . the auxiliary board 40 also includes a an analog - to - digital converter 234 , which is a 2 - channel , 12 - bit serial adc chip . a power supply 236 on the board 40 uses a charge - pump ic to convert battery voltage to the 5 v excitation level for the shoulder position sensor . the 5 v output is pulsed at a duty cycle of { fraction ( 1 / 16 )} to conserve battery power . the board 40 also includes switch interface relays 238 , which relays the two external switches to the microcontroller module 204 , while also providing the signal about the connection of the sensor or the switches . the following tables describe for ready reference further details of the components and their functions as shown in fig5 and 5a to 5 m . [ 0091 ] table 2 the high voltage supply circuit 210 ( fig5 b ) component description circuit function c2101 capacitor filter hv converter noise fed back to battery voltage network m2102 power mos fet , hv converter battery p ch power switch m2101 power mos fet , gate drivers for m2102 n ch r2101 , resistors gate drivers networks for r2102 m2102 and m2102 u2101 pwm dc / dc provides control and power up drive for high voltage converter flyback power converter c2102 - c2104 capacitors filters switching noise within and to u2102 regulator r2103 resistor sets basic switching frequency for u2101 regulator r2104 , r - c network supply + 5 v , ( vdd ) to c2105 u2101 and decouple vmos gate drive noise from mpu supply b2101 , r - c network supply vbat to storage c2106 , − 7 inductor l2101 and decouple power switching noise battery voltage network l2101 inductor , dynamic energy storage power for power conversion m2103 power mos fet , power converter switch n ch r2105 resistor , low w current sense , pwm control , limit d2101 rectifier , switch mode communtating schottky 60 v , rectifier 1 . 0 a c2108 , capacitors switching output filter c2109 r2106 , resistors high voltage feedback r2107 , potentiometer , sense divider with cpu u2102 digital 32 pos control through setting linear or the digital pot r2108 , r - c network power up preset network c2110 for u2102 u2103 transconduct - translates current sense ance current voltage across pins 2 - 7 sense amp input to ground reference signal r2109 resistor current sense scaling resistor c2112 capacitor output noise filter r2111 - r2113 resistor divides hv level for cpu divider net hv monitor input and free hand hv upper limit [ 0092 ] table 3 the bladder and bowel control function driver 212 ( fig5 d ) component description circuit function d2201 - d2204 zener protects hv power and transient vocare switches from clamp diode transient discharge and loss of hv converter control c2201 , capacitors filter hv converter noise c2302 and provide energy reservoir for vocare pulse load m2202b power mos fet , hv converter switch for p ch free hand driver m2202a , power mos fet , hv converter switch for m2205a , b p ch vocare coils c , b , a m2201 , − 3 , − 4 , power mos fet , gate drivers for m2202 − 6 n ch and m2205 r2203 - r2214 resistor gate drivers networks for m2202 and m2205 u2201 comparator conditioned switch for hv to free hand driver r2201 , resistor divides logic level to r2202 divider match hv upper limit sense voltage above which free hand high voltage will not switch on [ 0093 ] table 4 the hand - grasp function driver 214 ( fig5 e ) and the standing function driver 216 ( fig5 f ) component description circuit function u2301 crystal controls power drive oscillator frequency module , 13 . 5600 mhz u2302 dual flip flop divide oscillator by 2 for 6 . 78 mhz ism frequency and bi - phase drive for class b output stage r2301 , resistors rf isolated logic input r2304 networks u2303 and gate output stage gate driver buffers r2306 - r2308 resistors gate drive hi - low through current limiters r2309 , resostors gate pull - downs r2310 m2301 , power mos fets class b power amplifier m2302 c2307 - c3211 passive filter harmonic and radiated l2301 - l2303 emission suppression c2305 , capacitors local rf bypass c2305 b2301 - b2305 ferrite beads radiated emission suppression r2302 resistor connection to dc continuity coil check c2312 capacitor rf filter [ 0094 ] table 5 the microcontroller module 204 ( fig5 g ) component description circuit function c1201 - c1205 capacitors microcontroller supply bypasses c1206 capacitors local bypass for power reset chip , u1202 u1201 microcontroller provides all system control and interface d1201 , r - diode network programming pulse r1202 interface d1202 diode prevents input drive when mpu is powered down y1201 , quartz crystal , mpu clock reference and r1201 4 . 0 mhz and associated bias resistor resistor r1203 , c1208 r - c networks a / d converter input thru r1210 , filter networks c1215 c1216 - c1222 capacitors spike filters on operator switch inputs u1202 ic , power monitors vdd and reset monitor reset on power drops below 4 . 4 volts for 20 msec u1203 ic , 2 . 50 volt provides 2 . 5 volt a / d ref reference c1207 capacitor noise filter for a / d ref r1211 - r1213 resistors serial buss pull - downs r1222 , r - c network pull - up for implant coil r1223 continuity check input r1224 , resistors daughter bd . tp1 , 2 pull - r1225 downs u1204 ic , serial alterable non - volatile eeprom memory for setup preferences r1214 resistor chip select pull - up ( inactive ) u1205 ic , ir and rs - provides serial ir send 232 interface receive functions d1203 led , ir ir link ir emitter r1216 resistor sets ir led operating current c1225 capacitor local bypass for ir transmit switching noise c1224 capacitor local bypass for ir / rs - 232 power d1203 diode , ir photo ir link ir detector r1215 , − 17 - resistors pull - downs for u2105 18 control and data lines u1208 ic , remote decodes encrypted button control application data encrypte / decode chip c1226 capacitor local bypass for remote control chip power r1220 , resistors pull - downs for u1208 r1221 control and data lines u1206 , ic , 2 - way mpx telemeter and ir u1207 switch communications to one set of mpu lines r1219 resistor pull - downs for tel - ir control line j1201 2 × 15 pos . option daughter board female jack [ 0095 ] table 6 the user interface module ( fig5 h ) component description circuit function u1301 ic , 3 . 0 v switches buzzer power regulator c1301 capacitor local bypass for buzzer regulator c1302 capacitor filters switching noise within buzzer regulator c1303 , capacitors regulator output c1309 filters r1301 , resistors mpu interface and pull - r1308 down d1301 diode inductive spike clamp ls1301 sound provides audible signal transducer u1302 lcd module provides visual user interface c1304 capacitor local bypass for lcd module r1302 resistor lcd ( chip sel ) pull - up ( inactive ) r1303 , resistors lcd and interface bias r1304 u1303 ic , 3 . 0 v switches buzzer power regulator c1305 capacitor local bypass for buzzer regulator c1306 capacitor filters switching noise within buzzer regulator c1307 , capacitors regulator output c1308 filters r1306 , resistors mpu interface and pull - r1307 down sw1301 - spst , mom push user interface buttons sw1312 sw1309 - spst , mom mag alternate control mode sw1312 reed u1202 ic , power monitors vdd and reset monitor reset on power drops below 4 . 4 volts for 20 msec j1301 zif jack , lcd jack ribbon [ 0096 ] table 7 the infrared transceiver 220 ( fig5 k ) component description circuit function c1401 capacitor filter noise fed back to vdd r1401 resistor pull - down ( disable ) tel , shd ( active & lt ; off & gt ; low ) u1401 linear low drop provides + 3 . 0 volts for regulator transceiver module , u1402 c1402 capacitor filters switching noise within u1401 c1403 , capacitors regular output filters c1409 r1403 resistor transmit , teltxd hi - z pull - down r1404 resistor transmit power set r1402 , r - c network agc bias supply and c1404 bypass c1405 capacitor peak detector attack - decay time constant r1403 resistor vbbo load isolation resistor r1405 resistor sets bandwidth of baud rate low pass filter r1406 , resistors pull - ups for ct0 and ct1 r1108 mode r1401 resistor rx ddata pull - down u1403 single 74 hct level translates rx data equivalent or to 5 volt logic gate c1406 , capacitors antenna tuning c1407 ant1401 , − 02 metal strips telemeter antenna elements c1408 capacitor antenna match [ 0097 ] table 8 the input filter 230 ( fig5 m ) component description circuit function j4101 jack , 14 pos , shoulder position female transducer module input b1401 ferrite bead , 1 × 10 common mode choke , 10 lines emi suppression ds4101 - zener , protects shoulder ds4109 transient position diff . amp . from clamp 9 v transient discharge l4101 , l - c networks filter dc power and l4103 , ground lines to external c4101 , c4110 shoulder position and l4102 , transducer module l4104 c4102 , c4111 r4109 , r4116 r - c networks filter differential x c4103 , c4112 and y signal and three thru r4115 , switch closure signal r4122 c4109 , lines from external c4118 shoulder position transducer module r4108 , r4123 zero ω jumpers em immunity test jumpers [ 0098 ] table 9 the differential amplifier 232 and a - d converter 234 ( fig5 m ) component description circuit function u4102 , ic , shoulder position u4104 instrumentation transducer amplifier differential amp f4205 , − 6 resistors input pull down load , r4208 , − 9 amplifier c4209 , capacitors differential low pass c4210 filter r4207 , resistors gain set , differential r4210 amplifier u4203 , ic , reference , pseudo ground for u4102 , u4205 2 . 5 v u4104 c4204 , capacitors pseudo ground noise c4205 filter u4201 ic , step up provide switchable low charge pump noise power to shoulder w / linear position transducer and regulator amplifier r4204 resistor shd input over drive protection c4201 capacitor local bypass of noise fed back to battery voltage c4202 capacitor charge pump c4203 capacitor regulator output bypass u4206 a / d converter , provides expanded 12 bit / 2 ch resolution of shoulder serial position amplifier output u4207 ic , ref ., full scale ref ., for 4 . 096 v u4106 a / d c4206 capacitor full scale ref ., noise filter c4207 capacitor local bypass for a / d conv . r4211 - r4213 resistors serial buss pull up and downs r4214 resistor board identification load j4201 2 × 15 pin , male daughter to main bd . bd . mt plug connector r4201 - r4203 resistors pull - downs switch closure lines d4201 - d4203 diodes , signal reverse drive protection for mpu the pre - programmed rules for the controller 26 ( comprising the firmware ) are contained in the eeprom memory chip . the rules govern , e . g ., the operation of the user interface , the generation of the stimulation timing and command signals by the supported function - specific utilities , the interface with the various function - specific control signal devices ( including wireless links ), the special modulation of pulse outputs , and communication with external programming sources . the control algorithms expressing the rules can be realized as a “ c ” language program implemented using the ms windows ™ application . the firmware , once embedded , can be reprogrammed or updated in various ways , including linkage ( by cable or wireless infrared ) of the controller 26 to an external computer with the appropriate software , or by the user using the keypad 34 on the controller 26 itself . further details of these representative implementations of these functional blocks of the controller firmware will now be described . in the illustrated implementation ( see fig3 a ), the front shell 44 of the controller 26 presents the display 32 on which the various screens generated by the user interface are displayed . the user interface also displays on the screen 32 various graphic icons , e . g ., a battery life icon 54 , a stimulation energy application icon 76 , and others ( not shown ), such an alarm or warning icon and a external computer connection icon . associated audible signals can also be used to provide information regarding the status of these indications , e . g ., low or discharged battery , errors , etc . the front shell 44 of the controller 26 also presents the keypad 34 , through which the user communicates with the interface . in the illustrated implementation ( see fig3 a ), six push buttons 56 to 66 are present . the push button 56 is used to turn the controller on . the button 56 also serves an enter key to progress from screen to screen of the interface . the push button 58 is used as to exit out of certain programming screens , as well as a control signal source in certain functions . the push buttons 60 and 62 are used to scroll up and scroll down the screens , to move through the menus generated by the user interface . the push bottons 64 and 66 are used to increment or decrement selections during certain functions . an audible signal or beep can be selectively generated upon pushing the buttons 56 to 66 . upon power up , the firmware displays an appropriate welcome screen ( not shown ) and executes a main loop , which continues to runs in the background at prescribed time intervals ( e . g ., every 16 msec ). the main loop self - tests the microprocessor 36 for defective hardware or corruption of the flash memory contents . errors noted by the main loop interrupt operation of the controller 26 and cause the user interface to display appropriate error icon and audible signal . absent an error during start up , the user interface function displays a task selection menu 68 ( see fig3 a ) on the display screen 32 . the task selection menu 68 lists the specific therapeutic or prosthetic functions supported by the controller 26 . in the illustrated implementation , the listed functions are ( i ) the finger - grasp function ; ( ii ) the standing function ; and ( iii ) the bladder and bowel control function , as already described . the user selects a function by scrolling ( operating the scroll buttons 60 and 62 ) and pushing the enter button 56 . upon selection , the firmware executes the function - specific processing utility dedicated to the selected function . by way of example , the details of the processing utility dedicated the finger - grasp function will be described . similar interface and control features can be executed to carry out the other functions . in the illustrated implementation ( see fig6 ), the opening screen 70 for the finger - grasp function list four operational choices : exercise ; function ; patterns ; and set up . by selecting exercise ( using the scroll bottons 60 and 62 and the enter button 56 ), the screen displays an exercise regime screen 72 ( see fig7 ), which also shows a time delay before an exercise regime is automatically initiated by the firmware . different exercise regimes ( designated exercise 1 , exercise 2 , exercise 3 , etc .) can be selected by the user by pressing the enter button 56 once within a predetermined short time interval ( e . g ., 3 seconds ) after a given exercise regime screen 72 is displayed . typically , the timing parameters and exercise grasp patterns for each exercise regime have been preprogrammed into the firmware by a clinician , as will be described later . with the desired exercise regime selected , the user presses the enter button 56 or waits for the time delay to expire . the display 32 shows an exercise underway screen 74 to indicates that stimulation is being applied to carry out the selected exercise regime . the exercise underway screen 74 displays a stimulation on icon 76 , as well as the time remaining for the exercise session . as soon as the selected exercise regime is completed , the display 32 shows an exercise completed screen 78 . after a prescribed time period of no further input ( e . g ., two minutes ), the firmware turns the controller 26 off to conserve battery life . this automatic time - out feature is executed throughout the interface . when patterns is selected on the opening screen 70 ( by use of the scroll buttons 60 and 62 and enter button 56 ) ( see fig8 ), the display 32 shows a grasp pattern selection menu 80 by which lateral and palmar grasp patterns can be selected . the menu 80 lists “ lateral ” and “ palmar ” followed by numbers . the user scrolls using the buttons 60 and 62 to select either pattern . the user then increments or decrements using the buttons 64 and 66 to select the specific pattern by number . for example , there can be several lateral patterns ( designated lateral 1 , lateral 2 , lateral 3 , and lateral off ) and several palmar patterns ( designated palmar 1 , palmar 2 , palmar 3 , and palmar off ), which typically have been pre - programmed into the firmware by a clinician , as will be described later . when done choosing , the user selects the enter button 56 , which returns to the opening screen 70 for the finger - grasp function . when a shoulder position sensor is coupled to the universal external controller 26 ( designated as sw 1 in fig9 ), selection of function on the opening screen 70 allows the user to control the finger - grasp function using the external shoulder position sensor . typically , the clinician will have previously preprogrammed the controller 26 so that either back and forth shoulder movements or up and down shoulder movements sensed by the shoulder position sensor will generate the appropriate proportional commands to open and close the grasp . the clinician may also have preprogrammed the controller so that quick movements of the shoulder position sensor will lock the grasp . alternatively , the clinician may have preprogrammed the controller to lock the grasp in response to input from a remote lock switch ( designated as sw 2 in fig9 ) coupled to universal external controller 26 . the remote lock switch toggles the existing grasp pattern between a locked and unlocked position , and can be used by individuals who have difficulty with or do not want to use the shoulder jerk motion . with the function selected , the user turns the shoulder position sensor on . the firmware responds to shoulder movement input in either elevation / depression or protraction / retraction to grade hand position and strength from opened to closed . thus , for example , by retracting the shoulder , the hand opens , and by protracting the shoulder , the hand closes . in response to shoulder movement , the firmware turns the stimulation on to undertake the last selected lateral grasp pattern . the firmware executes a proportional control algorithm that , in response to the prescribed shoulder movement ( e . g ., protracting the shoulder ), applies stimulation to progressively close the user &# 39 ; s hand in the desired grasp pattern . changing the prescribed shoulder movement ( e . g ., retracting the shoulder ) changes the execution of the proportional control algorithm to apply stimulation to progressively open the hand . the hand can be thereby progressively opened or closed in this manner . pressing a switch on the shoulder sensor will toggle between lateral and palmar grasp patterns as shown in fig9 a grasp - function status screen 82 is displayed as the control algorithm is being executed . a graphical depiction on the grasp - function status screen 82 ( which , in the illustrated embodiment , comprises a directional arrow and a bar chart ) proportionally tracks the grasp position of the hand from open to closed , and vice versa . the grasp - function status screen 82 also displays the current grasp pattern . the stimulation on icon 76 is also displayed . if so programmed , a small quick shoulder motion will lock the grasp in the then - existing position , and the grasp - function status screen will accordingly change to indicate the grasp is “ locked .” with the grasp locked , the user is able to move the shoulder without altering the then - existing grasp pattern . when the user wants to regain control of the hand , a subsequently small quick shoulder motion will unlock the grasp , and the grasp function resumes according to the prescribed shoulder movement from the then - existing position . the grasp - function status screen 82 changes to indicate that the grasp is “ unlocked ” and the proportional direction display resumes . alternatively , if so programmed , depressing a remote lock switch will cause the grasp to lock and unlock . desirably , according to preprogrammed rules in the firmware , when the unlock command has been given , the grasp command enters a realignment state , during which the existing position of the grasp will not change until the user moves the shoulder back to the position where the lock command occurred . this keeps the user &# 39 ; s hand from step - jumping opened or closed until the user is prepared to control it . alternatively , the realignment state can be automatically implemented , during which , upon receiving an unlock command , the firmware aligns the grasp command range with the user &# 39 ; s current shoulder position . the position of the command range can be automatically adjusted during proportional control , too . these options are selectable during programing of the firmware . appropriate audio signals can be also generated by the controller to mark changes in the stimulated grasp pattern from open to close , locked and unlocked , lateral and palmar . holding the enter button 56 for a predetermined time ( e . g . 2 seconds ) turns the controller 26 and the ongoing stimulation off . holding the switch on the shoulder position sensor for a prescribed period will also turn the ongoing stimulation off . if a shoulder position sensor is not coupled to the universal external controller 26 , the user can subsequently control a selected grasp pattern by using the keypad 34 on the controller 26 itself . in a representative implementation , with the opening screen 70 for the finger - grasp function displayed , depressing the enter button 56 for a prescribed time period ( e . g ., 2 seconds ) turns the stimulation on to undertake the last selected lateral grasp pattern . as fig1 shows , the grasp - function status screen 82 is displayed , as previously described . the firmware executes a gated ramp control algorithm that , in response to pressing or holding the control button 58 , applies stimulation to progressively close the user &# 39 ; s hand in the desired grasp pattern . pressing the enter button 56 changes the execution of the gated ramp algorithm to apply stimulation to progressively open the hand . the hand can be progressively opened or closed in this manner . the graphical depiction on the grasp - function display screen 82 ( i . e ., in the illustrated embodiment , the directional arrow and a bar chart ) proportionally tracks the grasp position of the hand from open to closed , and vice versa . pressing the enter button 56 twice while executing a grasp function toggles between a selected lateral or palmar grasp pattern . the grasp - function display screen likewise displays the current grasp pattern and the stimulation on icon 76 . by releasing the enter button 56 as the hand is opening or closing , the gated ramp algorithm locks the hand at the then - existing grasp position , and the grasp - function status screen 82 accordingly indicates that the grasp is “ locked .” when the user wants to regain control of the hand , a subsequently pressing the enter button 56 resumes the grasp function in the last selected direction from the last - existing position . upon receiving a lock command , the gated ramp control algorithm maintains the grasp as the last - existing command level until it receives a further command from the keypad 34 to unlock the grasp pattern or to turn the controller 26 off . holding the enter button 56 for a predetermined time ( e . g . 2 seconds ) turns the controller 26 and the stimulation off . the firmware can permit an individual user to program designated functions of the controller using the keypad 34 . the extent to which the firmware allows this will vary according to degree of freedom the manufacturer or clinician wants to provide an individual user . selection of setup in opening screen 70 ( using the scroll buttons 60 and 62 and control button 58 ) permits this function . in one representative implementation , the firmware allows the user to customize the controller 26 by ( i ) selecting the grasp lock control input source ; ( ii ) disabling sound that accompanies use of the keypad 34 or shoulder position sensor ; ( iii ) or changing the volume of audible feedback . selection of setup displays a selection menu screen 84 ( see fig1 ), where the permitted reprogramming selections are listed . by scrolling to the appropriate selection ( using buttons 60 and 62 ), incrementing or decrementing the associated status selections ( using buttons 64 and 66 ), and by selecting ( by pressing the enter button 56 ), the various reprogramming selections can be accomplished . for example , the user can choose to lock the grasp using an external switch or by shoulder motion itself ; or turn the keypad sound on or off ; or turn the audible feedback for shoulder sensor movement on or off ; or adjust audible feedback volume from medium or high . the universal external controller 26 can accommodate input from a variety of external control sources , such as myoelectric surface electrodes , remote control switching devices , reed switches , and push buttons on the user interface panel of the universal external controller 26 itself . external control sources can be coupled to the universal external controller 26 by direct ( i . e ., cable ) connection , or by wireless link ( e . g ., 900 mhz ). when the universal external controller 26 is not otherwise engaged in the execution of a functional task , the controller 26 can be linked to a remote computer 86 for programming by a clinician ( see fig1 ). the link can comprise a hardware interface , e . g ., an interface module and serial cable to route and translate data between the remote computer 26 and universal external controller 26 . alternatively , the firmware of the universal external controller 26 allows communication through an infrared link , thereby eliminating the need for an interface module , serial cable and any direct hardware connection . the infrared link simplifies communication and eliminates electrical safety concerns associated with direct electrical connection . the firmware establishes communication with the remote computer 86 , to identify and qualify incoming information received from the remote computer 86 . the interface desirably includes a clinician set up screen 88 ( see fig1 ), which is displayed upon pushing the control button 58 when in the opening menu 70 for a given selected function . the clinician set up screen 88 shows a computer link prompt , which can be selected by use of the buttons 64 and 66 and control button 58 to show a computer link status screen 90 . the computer link status screen 90 indicates “ waiting ” and then “ talking ” as the link between the universal external controller 26 and the remote computer 86 is established . in the illustrated implementation ( see fig1 ), the remote computer 86 desirably executes a programming system 92 , which can be used to control , monitor and program the universal external controller 26 in the selected function . the programming system 92 allows a clinician to customize the firmware residing in an individual universal external controller 26 according the specific needs of the user and the treatment goals of the clinician . the primary purpose of the programming system 92 is to adjust parameters and store the parameters affecting the selected function in the universal external controller 26 , which is used by the patient during daily operation . the system 92 also desirably provides an interface to display visual feedback to the clinician and user about the operation of the control algorithms and equipment associated with the controller 26 . in a representative implementation , when the finger - grasp function is selected , and the universal external controller 26 and remote computer 86 are linked , the programming system 92 can be run to assess the muscle recruitment patterns , set grasp stimulation patterns , adjust controller parameters , set exercise timing , and retrieve usage data resident in the firmware affecting the finger - grasp function . the programming system 92 enables inputs from the universal controller 26 to be monitored and stimulus outputs to be controlled in real time . the programming system 92 also allows operational parameters to be saved to an electronic patient file and downloaded to the universal external controller 26 . the universal external controller 26 can then be disconnected from the programming system , allowing portable operation , as already described . desirably , the programming system 92 can be installed on a personal computer ( e . g ., a 233 mhz pentium ii laptop with 800 × 600 resolution monitor ) running microsoft windows ™ 98 or higher . the programming system 92 desirably includes a clinician programming interface , which allows allows the clinician to observe , modify , and program the stimulus patterns , the shoulder position control characteristics , and the exercise sequences in an expeditious and user - friendly way . in a representative implementation , the clinician programming interface can be written in the visual basic 6 programming language for execution in the windows environment . in the illustrated implementation ( see fig1 ), the system is composed of a generic module 94 including generic patient information and as well as one or more specific modules 96 for each of the function - specific tasks supported by the controller 26 ( e . g ., the finger - grasp function , the standing function , and the bladder and bowel control function ). the generic patient information module 94 stores all general information about the patient using the particular universal external controller 26 . the information in this module 94 does not necessarily relate to any particular function - specific device , but includes , e . g ., fields for entering personal information that the patient may prefer to keep confidential . the number and nature of the specific modules 96 will vary according to the number and nature of the function - specific tasks that the controller 26 supports . by way of example ( see fig1 ), for the finger - grasp function , there can be a system device information module 98 , an electrode profiling module 100 , a lateral and palmar grasp patterns programming module 102 , a shoulder position sensor programming module 104 , and an exercise programming module 106 . appropriate counterpart modules can also provided for the other treatment functions supported by the controller 26 . for the finger - grasp function , the device information module 98 captures , stores , displays , and allows modification of information that relates to the components arranged to accomplish the finger - grasp function system , including surgical implantation procedures , device serial numbers , electrode mapping , and progress notes . for the finger - grasp function , the remaining modules 100 to 106 allow optimization and programming of functional features of the components . the electrode profiling module 100 aids the clinician in determining the stimulation thresholds and operational range of parameters for each electrode implanted on a muscle . this information determines system performance and configures electrodes for grasp programming . for example , for each electrode , the maximum force that can be obtained from the electrode during use can be determined , as can specific points of interest ( poi ) of the recruitment characteristics of each muscle . for each electrode / muscle , the threshold for recruitment and the maximum desired force is determined for each grasp pattern . additional poi &# 39 ; s can be denoted such as spillover to other muscles and other comments . the grasp programming module 102 provides a mechanism for the clinician to program , view , and modify grasp patterns . the grasp pattern coordinates the activity of the muscles implanted with electrodes to produce different functional grasp , e . g . lateral and palmar grasps . the main functions of the module 102 are to program , view , and modify the activation level of each electrode as a function of percent command . this module 102 provides templates and example grasps that the therapist can modify for the individual patient . the therapist can then test the pattern , compare to previous patterns , and modify the pattern before transferring them to the universal external controller 26 . the shoulder position sensor programming module 104 provides a mechanism for the therapist to program , view , and modify the shoulder position proportional control and lock parameters . the module 104 allows the therapist to determine the patient &# 39 ; s range of shoulder motion , select control and locking directions , select stationary or mobile command , display visual feedback to aid the patient in understanding the operation of the shoulder controller , set the parameters for locking the grasp , test the shoulder position sensor settings , both with and without an active grasp , and compare the new settings with previous settings . the exercise programming module 106 enables the therapist to program , view , and modifying patient exercise routines . the main functions of this module 106 include setting exercise duration , setting the delay in starting the exercise , selecting the exercise patterns , and selecting specific exercise timing parameter . it also allows the therapist and user test the exercise patterns prior to programming . in the illustrated implementation , the clinician set up screen 88 ( see fig1 ) also includes a coupling power prompt . when selected ( using the buttons 60 and 62 and the control button 58 ), a coupling power select screen 108 is displayed . the screen 108 allows the clinician ( using the increment / decrement keys 64 and 66 and control button 58 ) to select an appropriate couple power setting , from 1 ( lowest ) to 5 ( highest ). the clinician can thereby adjust the power output of the pulse transmitter 16 for the selected function . the controller 26 is thereby able to adjust to different different depths of implantation for the receiver / stimulator for a given function , which , in turn , dictate different radio frequency power levels to transcutaneously link the receiver / stimulator for that function to the associated pulse transmitter for that function . the clinician is thereby able to customize the controller 26 to optimize reliable coupling while maximizing battery life . in the illustrated implementation ( see fig1 ), the clinician set up screen 88 also includes a device status prompt . when selected ( using the buttons 60 and 62 and control button 58 ), a device status screen 110 is displayed . information on the device status screen 110 allows the clinician to assess the operating state of the controller 26 for monitoring and trouble shooting purposes . in addition to the allowing optimization of coupling power ( as just described ), the firmware also incorporates preprogrammed rules that promote other power conserving techniques aimed at prolonging battery life . in the illustrated embodiment , the power conserving techniques includes pulsed signal output ( to the receiver / stimulator ) and pulsed signal input ( from the control signal source ). as previously described , under the control of the pre - programmed rules in the firmware of the microprocessor 36 , the universal external controller 26 governs the hand - grasp function by generating prescribed stimulus timing , command , and power signals based upon input received from the shoulder position sensing control signal source . the prescribed stimulus timing , command , and power signals are formatted for transmission by the function - specific pulse transmitter in the form of modulated radio frequency carrier wave pulses . by pulsing the output command signal for the hand - grasp function , the universal controller conserves power , to thereby conserve battery life . as shown in fig1 a , the output command signals are transmitted during successive frame intervals 114 . each successive frame interval includes 114 an on period 116 , during which radio frequency energy is generated to transmit the command signals to the function - specific pulse transmitter , and an off period 118 , during which no radio frequency energy ( and thus no command signals ) are being transmitted . the duration of the frame interval 114 can vary . in a representative embodiment , the on periods 116 and off periods 118 begin on 1 msec boundaries , so that the frame interval 114 is an integer multiple of 1 msec . the frame rate is set to equal the stimulus frequency , which equals 1 / frame interval . in a representative embodiment , the stimulus frequency is 6 . 78 mhz ± 5 khz . within each on period 116 of a given frame interval 114 ( see fig1 b ), there is a power up phase 120 , followed by an output stimulus phase 122 , followed by a recharge phase 124 ( to allow for radio frequency magnetic field decay ). the command signals 126 are transmitted only during the output stimulus phase 122 . the command signals 126 are transmitted in channel groups 128 , with a channel 128 group dedicated to a given implanted electrode where stimulation is to be applied . each channel group 128 includes a set amplitude command 130 and an set duration command 132 . the length of the output stimulus phase 122 will , of course , depend upon the number of channels receiving stimulation and the nature of the stimulation . when a channel has no command output ( i . e ., there are no set amplitude or duration commands for that channel ), the next higher stimulation channel assumes its time slot . in the illustrated embodiment , all commands begin on 1 msec boundaries ( as previously stated ). representative time periods for the phases are , for the power up phase 120 : 16 msec in duration if the off period 118 is more than 52 msec in duration , otherwise , 6 msec ; for the output stimulus phase 122 : 2 times n msec in duration , where n is the number of channels being stimulated ; and for the recharge phase 124 , 10 msec in duration . as frame rates increase , the off period 118 will become shorter until there is no off period 118 . within each channel group 128 , the set amplitude command 130 and the set duration command 132 are arranged within a pulse window 134 ( see fig1 c and 14d ). the initial period of the pulse window includes a coding window 136 . the preprogrammed rules of the firmware generate successive radio frequency pulses during which radio frequency energy is applied ( rf on ) and during which radio frequency energy is not applied ( rf off ). in a representative embodiment , the total interval for a given rf on and rf off sequence is 10 μsec (± 1 μsec ), and the rf on interval within this period is 4 μsec (± 1 μsec ). gaps 140 are formed between the rf on and rf off periods , which in the representative embodiment last 6 μsec (± 1 μsec ). the pre - programmed rules of the firmware establish the set amplitude command and the set duration command depending upon the number and sequence of gaps 140 in the pulse window 134 . the coded correlation prescribed between the number and sequence of gaps 140 and the related commands can , of course , vary . in a representative implementation ( see fig1 c ), a succession of two to nine gaps 140 in the initial coding window 136 prescribe the channel for which a set duration command 132 is to be effective . two to nine gaps 140 identify channels 1 to 8 , respectively ( i . e ., two gaps means channel 1 , three gaps means channel 2 , and so on ). in fig1 c , seven gaps identify a set duration command for channel 6 . as further shown in fig1 c , the succession of channel gaps 140 in the coding window 136 is followed by a gap 142 having a length ( i . e ., duration ) which sets the actual duration of the stimulation pulse that is to be applied to the prescribed channel . the length of the gap 142 outside the coding window 136 can vary , e . g ., between 1 μsec to 200 μsec . in fig1 c , the gap 142 outside the coding window 136 is shown to be 65 μsec , which specifies a stimulus duration of 65 μsec . in the representative implementation ( see fig1 d ), a succession of eleven gaps 140 in a successive coding window 136 prescribes the amplitude of the pulse that is to be applied to the earlier prescribed channel . as fig1 d shows , following the eleven gaps 140 in the coding window 136 is another succession of gaps 144 outside the coding window 136 , the number of which set the pulse amplitude . for example , in the representative implementation , eleven gaps 140 in the coding window 136 followed by one gap 144 sets an amplitude of 14 ma ; eleven gaps 140 in the coding window 136 followed by two gaps 144 sets an amplitude of 8 ma ; eleven gaps 140 in the coding window 136 followed by three gaps 144 sets an amplitude of 2 ma , and eleven gaps 140 in the coding window 136 followed by four gaps 144 sets an amplitude of 20 ma . in fig1 d , a pulse amplitude of 2 ma is set . in a representative embodiment , each pulse window 134 is assigned a duration of at least 410 μsec . within the pulse window 134 , the initial coding window 136 is assigned a duration of 150 μsec (± 5 μsec ). the input from the shoulder position sensor can also be pulsed , to conserve power consumption . in the illustrated embodiment , as already explained , the power supply 236 on the auxiliary board 40 converts battery voltage to the 5 v excitation level for the shoulder position sensor . the 5 v output to the shoulder sensor is pulsed at a duty cycle of , e . g ., { fraction ( 1 / 16 )}. thus , the input from the shoulder position sensor to the controller 26 is received in pulses . the firmware of the universal external controller 26 can be programmed for use in association with other components to perform other neuromuscular stimulation functions . for example , the universal external controller 26 can be used to provide therapeutic exercise and pain relief for stroke rehabilitation and surgical speciality applications , including shoulder subluxation , gait training , dysphagia , tenolysis , orthopedic shoulder , and arthroplasty . details of the treatment of shoulder subluxation by neuromuscular stimulation are set forth in copending u . s . patent application ser . no . 09 / 089 , 994 , filed jun . 3 , 1998 and entitled “ percutaneous intramuscular stimulation system ” and copending u . s . patent application ser . no . ______ , filed jan . 6 , 2001 and entitled “ treatment of shoulder dysfunction using a percutaneous intramuscular stimulation system ,” both of which are incorporated herein by reference . the universal external controller 26 as described herein incorporates several fundamental features that address convenience , flexibility , and ease of use . ( i ) the controller 26 can be worn on the users body by virtue of it having a low weight and size . ( ii ) the user can be enabled to modify parameters , such as how to control the system , the type and degree of exercise they undertake , and the type and degree of stimulus parameters they use for their stimulation function . ( iii ) the utilization of cell phone battery technology makes the service , maintenance , and usage of the system more “ consumer - like ” and therefore easier to understand and use . ( iv ) the controller 26 isolates the user from ever having to connect the system directly to any source of power or communication link . the system uses the rechargeable battery as its sole power source and the infrared link as a communications port to a computer . ( v ) the controller 26 enables an extremely flexible control - input port that allows for , ( vi ) the controller 26 can support simultaneous control of two independent rf based implantable pulse generators ( e . g ., motor - control , and / or bladder / bowel control , and / or erection control function ). ( vii ) the controller 26 can communicate to any rf - based implantable pulse generators . thus , the controller 26 can be easily integrated into an existing rf - based stimulation system . ( viii ) the controller 26 can be programmed by a host computer , or be programmed directly by the user or a trained technician , without the need of an external host computer . the following examples are provided to exemplify the convenience , flexibility , and ease of use of a controller 26 that embodies features of the invention . different selectable neuromuscular functions it has already been explained how the controller 26 can enable individual selection of different . functional neuromuscular stimulation functions , e . g ., the finger - grasp function , or the standing function , or the bladder and bowel control function . the controller 26 can also be configured to provide these and other different neuromuscular functions concurrently . for example , using the menu - driven interface of the controller 26 , as previously described , the user can select to implement a standing function concurrently with a bladder and bowel control function . in this arrangement , e . g ., a user could affect concurrent neuromuscular stimulation to enable micturation while in a standing position . in the arrangement , the controller 26 receives control signals through one input to affect the operation of the standing function ( e . g ., a remote push - button control coupled to the input , or a push button programmed for this purpose on the user interface panel of the universal external controller 26 itself ) while receiving other control signals through another input to affect operation of the bladder and bowel control function ( e . g ., another remote push - button control coupled to the other input , or another push button on the controller 26 programmed to accomplish this purpose ). concurrently , the controller 26 generates one stimulation output to the receiver / stimulator 18 ( 2 ) for the standing function , while generating another , different stimulation output to the receiver / stimulator 18 ( 3 ) for the bladder and bowel control function . in this arrangement , the controller 26 concurrently supports different control signal inputs and different stimulation outputs to different stimulation assemblies . the controller 26 can be further configured to concurrently provide an additional finger - grasp function , based upon control signal input received by the controller 26 from e . g ., a shoulder position sensor , and a stimulation output generated by the controller 26 to the receiver / stimulator 18 ( 1 ) for the finger - grasp function . these concurrent , multiple stimulation functions make possible normal user control over the bladder and bowel function , while standing . selection of the bladder and bowel control function concurrent with the selection of the finger - grasp function can also be accomplished , without selection of the standing function , to provide normal control over the bladder and bowel function while in a seated position . as another example , concurrent selection of the finger - grasp function and the standing function would enable the user to grasp objects while in a standing position . concurrent selection of these two functions would also allow the user to ambulate while carrying an object grasped in the user &# 39 ; s fingers . again , normal control over these functions is thereby provided . as previously explained , the universal external controller 26 can accommodate input from a variety of external control sources , such as myoelectric surface electrodes , remote control switching devices , reed switches , and push buttons on the user interface panel of the universal external controller 26 itself . external control sources can be coupled to the universal external controller 26 by direct ( i . e ., cable ) connection , or by wireless link ( e . g ., 900 mhz ). these different control signal sources can be selected for operation concurrently to achieve different , concurrent stimulation functions ( as the preceding example 1 demonstrates ). these different control sources can also achieve the same stimulation function based upon different source inputs . for example , the user can choose to affect the standing function , e . g ., by operation of a remote push - button control , or a reed switch , or a push button programmed for this purpose on the universal external controller 26 itself . in addition , the user can also provide a designated care partner with a remote control switch to affect the standing function independently of the user , either by wireless transmission of a control signal or by a cable connection . thus , for example , while the user holds of an ambulation assistance device , such as a walker , the care partner can remotely affect the standing function for the user , so that the user can be lifted to a standing position while the assistance device lends ancillary support and stability . conversely , the care partner can remotely affect the termination of the standing function , so that the user can return to a seated position while the assistance device lends ancillary support and stability . various features of the invention are set forth in the following claims . | US-82277901-A |
a hydraulically actuated surgical instrument . the instrument may comprise a handle portion and a shaft . the shaft is mechanically coupled to the handle . the instrument may also include an end effector mechanically coupled to the shaft along its longitudinal axis . the end effector may comprise a surgical implement and a hydraulic device . at least a portion of the surgical implement may be translatable along a transverse axis , wherein the transverse axis is substantially perpendicular to the longitudinal axis of the shaft . also , the hydraulic device may be positioned to be expandable toward the surgical instrument in a direction substantially parallel to the transverse axis of the shaft . | the terms “ proximal ” and “ distal ” are used herein with reference to a clinician gripping a handle of an instrument . for example , referring to the surgical instrument 10 shown in fig1 , the end effector 12 is distal with respect to the more proximal handle portion 20 . it will be further appreciated that for convenience and clarity , spatial terms such as “ vertical ” and “ horizontal ” are used herein with respect to the drawings . however , surgical instruments are used in many orientations and positions , and these terms are not intended to be limiting and absolute . as used herein , the term “ surgical implement ” refers to a component or set of components configured to engage tissue to accomplish a surgical task . examples of surgical implements include , but are not limited to : endocutters , graspers , clamps , cutters , staplers , other surgical fasteners , clip appliers , probes or access devices , drug / gene therapy delivery devices , energy devices such as ultrasound , rf , or laser devices , etc . as used herein , the term “ surgical fastener ” refers to any kind of fastener used in surgical settings including , for example , a staple , a hernia tacker , etc . as used herein , the term “ surgical fastener ” may also refer to a device for deploying a staple , hernia tacker , etc . as used herein , the term “ fluidically coupled ” means that the elements are coupled together with an appropriate line or other means to permit the passage of pressurized fluid medium , air , etc . therebetween . as used herein , the term “ line ” as used in “ supply line ,” “ hydraulic line ” or “ return line ” refers to an appropriate fluid passage formed from conduit , pipe , tubing , etc . for transporting pressurized hydraulic fluid from one component to another . as used herein , the term , “ hydraulic fluid ” refers to any fluid suitable for use in a hydraulic system . non - limiting examples of hydraulic fluids include oil , air , etc . in one non - limiting embodiment , hydraulic fluids may be biocompatable fluids including , for example , glycerine oil , saline , etc . turning to the figures , the surgical instrument 10 of fig1 includes a handle portion 20 and an implement portion 22 . the implement portion 22 includes a shaft 23 and an end effector 12 . the end effector 12 shown in fig1 is configured to act as an endocutter including surgical implements for clamping , stapling and severing , however , it will be appreciated that the advantages of the present invention may be achieved with end effectors ( not shown ) including alternate and / or additional surgical implements . referring back to the non - limiting embodiment shown in fig1 , the handle portion 20 of the instrument 10 includes a pistol grip 24 toward which a closure trigger 26 is pivotally drawn by a clinician to cause clamping , or closing , of the anvil 18 toward the elongate channel 16 of the end effector 12 . a firing trigger 28 is farther outboard of the closure trigger 26 and is pivotally drawn by the clinician to cause the stapling and severing of clamped tissue in the end effector 12 . the force necessary to cause the closure , stapling , and severing of tissue may be provided by a plurality of hydraulic devices ( not shown in fig1 ) located in the end effector 12 such as , for example , bladders , cylinders , etc . in various embodiments , the hydraulic devices may be supplied with pressurized hydraulic fluid via hydraulic line bundle 306 extending from handle 20 of the instrument 10 to the end effector 12 , for example , through the elongate shaft 23 . fig2 - 5 show views of the end effector 12 configured to perform clamping , severing and stapling of tissue according to various embodiments the present invention . the end effector 12 may include anvil 18 and elongate channel 16 configured to receive a staple cartridge 37 . the anvil 18 may pivot towards the elongate channel 16 and staple cartridge 37 about anvil pivot 14 . fig2 shows the anvil 18 in an open position , while fig3 shows the anvil 18 in a pivoted or closed position . force necessary to pivot or drive the anvil 18 , in various embodiments , may be provided by closure sleeve 32 . for example , when the clinician actuates closure trigger 26 , the closure sleeve 32 may be translated distally toward the end effector driving the anvil 18 into the closed position shown in fig3 . when the closure trigger 26 is released , the closure sleeve 32 may be translated proximally away from the end effector 12 . the instrument 10 may include a spring or other energy storage device causing the anvil 18 to return to the open position shown in fig2 when the closure sleeve 32 is retracted . force may be transferred from the closure trigger 26 to the closure sleeve 32 by any mechanism known in the art including , for example , a gear system , an electric motor , a hydraulic device , etc . referring back to fig2 , the end effector 12 may include a transversely presented cutting edge 326 . the cutting edge 326 may be driven by a hydraulic cutting bladder 322 positioned below the cutting edge 326 . a cutting bar 324 may be positioned between the cutting bladder 322 and cutting edge 326 . in various embodiments , the cutting bladder 322 , bar 324 and edge 326 may be fastened to one another . it will be appreciated that the hydraulic cutting bladder 322 , in various non - limiting embodiments , may be replaced by any kind of hydraulic device including , for example , a hydraulic cylinder . in response to a clinician actuating the firing trigger 28 , the hydraulic cutting bladder 322 may expand in a transverse direction . this drives the cutting edge 326 , causing it to move through the elongate channel 16 and staple cartridge 37 in a transverse direction and sever any tissue ( not shown ) present between the anvil 18 , staple cartridge 37 and elongate channel 16 , for example , as described in more detail below with reference to fig2 - 26 . referring again to fig3 a cross sectional view of the end effector 12 is shown including staples 222 and staple drivers 220 according to various embodiments . a plurality of staples 222 and staple drivers 220 are shown positioned adjacent the cutting edge 326 . each staple driver 220 may be positioned below one , or a plurality of staples 222 included in the staple cartridge 37 . a staple hydraulic bladder 327 may be positioned below the staple drivers 220 . the staple hydraulic bladder 327 may be expandable in a transverse direction toward staple drivers 220 . the staple hydraulic bladder 327 may expand in response to the actuation of the firing trigger 28 by the clinician . expansion of the staple hydraulic bladder 327 forces the staple drivers 220 and staples 222 toward staple forming pockets ( not shown in fig3 ) present in the anvil 18 , thus driving the staples . fig4 shows a three dimensional view of the end effector 12 of the instrument 10 with a portion of the staple cartridge 37 removed to expose features of the elongate channel 16 , such as recesses 212 , 214 , and components of the staple cartridge 37 , such as staple drivers 220 , in their unfired position . the cutting edge 326 is shown at its unfired position , located in the center of staple drivers 220 . fig4 also shows tissue stops 244 located at the proximal end of the anvil 18 . tissue stops 244 may , in various embodiments , prevent tissue from coming into contact with components of the anvil pivot 14 , causing the end effector 12 to jam . fig5 depicts a three dimensional view of the end effector 12 in an open position with a staple cartridge 37 installed in the elongate channel 16 . on a lower surface 200 of the anvil 18 , a plurality of stapling forming pockets 202 are arrayed to correspond to a plurality of staple apertures 204 in an upper surface 206 of the staple cartridge 37 . each aperture 204 may correspond to an individual staple 222 located within the staple cartridge 37 immediately below the aperture 204 as shown in fig3 . slot 49 , positioned in the middle of the staple cartridge 37 , may enclose the cutting edge 326 ( not shown in fig5 ). the staple cartridge 37 may be snap - fit into the elongate channel 16 . for example , extension features 208 , 210 of the staple cartridge 37 engage recesses 212 , 214 ( shown in fig4 ) of the elongate channel 16 . in various embodiments , staples 222 included in the end effector 12 may be driven according to one or more staple zones , with each staple zone able to be fired or driven separately . fig6 - 8 show a non - limiting zoned embodiment including six staple zones , with each staple zone including one hydraulic device and one staple driver configured to drive a plurality of staples . for example , a right distal staple zone includes right distal staple bladder 332 ( shown in fig6 ), and right distal staple driver 370 ( shown in fig7 ). it will be appreciated that various non - limiting embodiments of the present invention may include more or fewer than six staple zones depending on the application , with each zone including as many or as few staples as desired . it will also be appreciated that that individual staple zones according to various embodiments of the present invention may include multiple staple bladders and / or staple drivers . referring back to fig6 , a top down view of the elongate channel 16 is shown including six hydraulic staple bladders 328 , 330 , 332 , 334 , 336 and 338 . each of the bladders may correspond to one of the six zones of staples . the bladders 328 , 330 , 332 , 334 , 336 , 338 as well as cutting bladder 322 ( positioned below cutting bar 324 in fig1 ) may be individually provided with pressurized hydraulic fluid through respective hydraulic lines 340 , 342 , 344 , 346 , 348 , 350 , 352 included in hydraulic line bundle 306 . accordingly , in various embodiments , each of bladders 328 , 330 , 334 , 336 , 338 and 322 may drive associated surgical implements individually or according to a firing pattern . fig7 shows a top down view of the elongate channel 16 and staple cartridge 37 with the upper surface 206 of the staple cartridge 37 removed to show staple drivers 370 , 372 , 374 , 376 , 378 , 380 . each staple driver may correspond to one of the six staple zones . also , each staple driver 370 , 372 , 374 , 376 , 378 , 380 is positioned above the staple bladder 328 , 330 , 332 , 334 , 336 , 338 ( shown in fig1 ) corresponding to the same staple zone . for example , right distal staple bladder 332 is positioned above the right distal staple driver 370 . it will be appreciated that it is not necessary to have only one staple driver corresponding to each staple bladder 328 , 330 , 332 , 334 , 336 , 338 . for example , in one non - limiting embodiment , a staple driver 220 may be provided for each individual staple 222 . fig8 shows an exploded three dimensional view of the elongate channel 16 with staple cartridge 37 implementing the staple zone scheme shown in fig6 and 7 . the staple cartridge 37 may include staple recesses 354 , 356 , 358 , 360 , 362 , 364 . each staple recess may house staples 222 ( not shown in fig8 ) and one of staple drivers 370 , 372 , 374 , 376 , 378 ( not shown in fig8 ). when the staple cartridge 37 is installed in the elongate channel 16 , each staple recess , including staples 222 and the staple drivers described above , may align with at least one staple bladder 328 , 330 , 332 , 334 , 336 , 338 . when the staple bladders 328 , 330 , 332 , 334 , 336 , 338 are inflated , they may extend into the staple recesses 354 , 356 , 358 , 360 , 362 , 364 , creating a transverse force against the staple drivers 370 , 372 , 374 , 376 , 378 , which in turn drive the staples 222 . fig8 also shows that the staple cartridge 37 may include channels 366 for receiving hydraulic lines 340 , 342 , 344 , 346 , 348 , 350 , 352 , shown in fig1 . the channels 366 prevent the various hydraulic lines from being pinched between the staple cartridge 37 and the elongate channel 16 . fig9 shows a cross - sectional view of the end effector 12 showing the configuration of bladders 328 , 334 , 322 , 338 and 334 according to various embodiments . bladder 328 is shown positioned below staple driver 370 . inflating bladder 328 causes a transverse force to be exerted on the driver 370 , which may drive the staple 222 . the other staple bladders 334 , 338 and 334 shown in fig9 may operate in a similar fashion . cutting bladder 322 may also create a transverse force when inflated . the transverse force may cause cutting bar 324 to rise transversely , pushing cutting edge 326 transversely through any tissue ( not shown ) present in the end effector 12 . fig1 shows the implement portion 22 of the surgical stapling and severing instrument 10 in disassembled form . the staple cartridge 37 is shown comprised of a cartridge body 216 , staple drivers 370 , 372 , 374 , 376 , 378 , 380 , cutting edge 326 and staples 222 . when assembled , the cartridge body 216 holds the staple drivers 370 , 372 , 374 , 376 , 378 , 380 and staples 222 . when the implement portion 22 is assembled , cutting bladder 322 , cutting bar 324 and cutting edge 326 may be positioned along the elongate channel 16 as shown . staple bladders 328 , 330 , 332 , 334 , 336 , 338 may also be positioned along the elongate channel 16 and may be used to drive staples 222 , for example , according to the zoned scheme described above . the staple cartridge 37 may be placed in the elongate channel 16 such that the cutting bladder 322 , cutting bar 324 and cutting edge 326 align with channel 49 and such that lines of staples 222 and drivers 370 , 372 , 374 , 376 , 378 , 380 align with bladders 328 , 330 , 332 , 334 , 336 , 338 . the embodiments described above show staples 222 resting on a staple bladder 327 , or staple bladders 328 , 330 , 332 , 334 , 336 , 338 , with various staple drivers 220 therebetween . it will be appreciated , however , that in various non - limiting embodiments , staples may be hydraulically driven utilizing other mechanisms . for example , fig1 - 12 show a staple 222 resting directly on a staple bladder 504 ( e . g ., without a staple driver ). a hydraulic line 506 may provide pressurized hydraulic fluid to the bladder 504 , for example , in response to the actuation of the firing trigger 28 by the clinician . when pressurized hydraulic fluid is provided to the staple bladder it may expand transversely , as shown in fig1 . the transverse motion of the staple bladder 504 may force the staple 222 against staple forming pocket 202 , thereby driving the staple 222 . the assembly shown in fig1 - 12 may be incorporated into the end effector 12 , for example , by placing a staple bladder or bladders 504 along the elongate channel 16 . it will be appreciated that in various embodiments , each bladder 504 may drive one or a plurality of staples 222 . fig1 shows another non - limiting embodiment showing an additional mechanism including a staple driving cylinder 510 . the cylinder 510 may include a piston 512 . the staple 222 may rest on the piston 512 . a staple driver ( not shown in fig1 ) may or may not be present between the piston 512 and the staple 222 . a hydraulic line 514 may provide pressurized hydraulic fluid , causing the piston 512 to extend . in response , the piston 512 may drive staple 222 into contact with staple pocket 202 as described above . in various embodiments , the cylinder 510 may drive one or a plurality of staples 222 . it will be appreciated that the assembly shown in fig1 may be incorporated into end effector 12 by placing one or more cylinders 510 along the elongate channel 16 . fig1 shows an exploded view of another non - limiting exemplary embodiment for hydraulically driving staples according to various embodiments of the present invention . staples 222 are shown resting on staple driver 517 which in turn rests on deployment plate 516 . guidance rails 518 are shown surrounding the deployment plate 516 . when provided with pressurized hydraulic fluid , bladder 522 may expand transversely . this may cause the deployment plate 516 to expand transversely along guidance rails 518 , driving staples 222 . the guidance rails 518 may insure that deployment plate 516 expands in a transverse direction . in one non - limiting embodiment , staples 222 may rest directly on the deployment plate 516 ( e . g ., without drivers 517 ). it will be appreciated that the assembly shown in fig1 may be incorporated into the end effector 12 by placing one or more bladders 522 , guidance rails 518 , and deployment plates 516 along the elongate channel 16 . fig1 - 17 show yet another non - limiting exemplary embodiment for hydraulically driving staples according to various embodiments . fig1 shows a hydraulic bladder 524 mated to a rigid deployment plate 526 . the deployment plate 526 may include a series of apertures 528 . each aperture may correspond to one or more staples . when pressurized hydraulic fluid is applied to the bladder 524 , it may expand transversely through the apertures 528 in the deployment plate 526 . the portions of the bladder 524 extending through apertures 528 may provide a transverse driving force to one or more staples 222 , as shown in fig1 . in various embodiments , the instrument 10 may include an articulating end effector 12 as shown in fig1 . the end effector 12 may pivot away from the axis of the elongate shaft 23 at articulation pivot 368 . it can be seen that the hydraulic line bundle 306 passes through articulation pivot 368 with ease . fig1 shows an embodiment of the instrument 10 equipped with a hydraulic system 321 according to various embodiments . a hydraulic pump 302 may generate pressurized hydraulic fluid when firing trigger 28 and / or the closure trigger 26 is actuated . the hydraulic pump 302 may be any kind of device suitable for pressurizing hydraulic fluid including , for example , a cylinder , a bladder , etc . in various embodiments , an additional pump ( not shown ) may be included , for example , to drive the anvil 18 in response to actuation of the closure trigger 26 . pressurized hydraulic fluid generated by the hydraulic pump 302 may be provided to valve unit 304 which may in turn provide the fluid to various bladders and / or cylinders ( not shown in fig1 ) located in the end effector 12 via hydraulic line bundle 306 . valve unit 304 may include any kind of valve or valves suitable for controlling and directing the flow of hydraulic fluid . in various non - limiting embodiments , the valve unit may include electrically actuated valves , such as , for example , piezo valves or electro active polymer ( eap ) valves which may be configured in response to an electrical signal . one embodiment of the hydraulic system 321 that may be employed to control the end effector 12 is depicted in schematic form in fig1 a . in this non - limiting embodiment , the pump 302 is embodied as a conventional hydraulic pump assembly that includes a fluid reservoir 432 . in one embodiment , the pump 302 is powered by a battery 434 supported within the handle . in another non - limiting embodiment , the pump 302 may be powered by the same battery 320 powering the control circuit 318 described below . it will be appreciated that the pump 302 could also be powered by other means , such as by alternating current . in one non - limiting embodiment , the pump 302 may be a hydraulic bladder or cylinder powered by mechanical force derived from one or more of the triggers 26 , 28 . the pump 302 may be fluidically coupled to the reservoir 432 by supply line 436 that may have a conventional check valve 438 therein . see fig1 a . in one embodiment , a discharge line 440 attached to the discharge port 431 of the pump 302 is piped to a manifold 442 that has designated supply lines for each bladder coupled thereto . for example , in the embodiment depicted in fig1 a , a supply line 444 is coupled to bladder 328 and has a control valve 460 therein for controlling the flow of pressurized fluid through the line 444 to bladder 328 . supply line 446 is coupled to bladder 330 and has a control valve 462 therein . supply line 448 is coupled to bladder 332 and has a control valve 464 therein . supply line 450 is coupled to bladder 334 and has a control valve 466 therein . supply line 452 is coupled to bladder 336 and has a control valve 468 therein . supply line 454 is coupled to bladder 338 and has a control valve 470 therein . supply line 456 is coupled to cutting bladder 322 and has control valve 472 therein . a return valve 478 is provided to permit the fluid to return from the bladders into the manifold line 442 and through a return line 459 that is attached to the manifold 442 and the reservoir 432 . as can be seen in fig1 a , the return line 459 may have a return valve 478 therein . valves 460 , 462 , 464 , 466 , 468 , 470 , 472 , 474 , 478 comprise a valve unit , generally designated as 304 and described above . the valve unit 304 may be configured by a control circuit 318 in response to input received from input buttons , such as buttons 308 , 310 , 312 , 314 , and / or 316 . a battery 320 may provide electrical power to the control circuit 318 and buttons 308 , 310 , 312 , 314 , 316 . the control circuit 318 may be any kind of circuit capable of generating signals for configuring valve unit 304 in response to input from buttons 308 , 310 , 312 , 314 , 316 . in one non - limiting embodiment , the control circuit 318 may include a microprocessor and other related components including random access memory ( ram ), read only memory ( rom ), etc . in other non - limiting embodiments , the control circuit 318 may include various logical circuit elements . the control circuit 318 may configure the valves in response to input buttons 308 , 310 , 312 , 314 , 316 . in one non - limiting embodiment , each input button 308 , 310 , 312 , 314 , 316 may correspond to a particular surgical implement , or portion of a surgical implement , included in the end effector 12 . for example , button 308 may correspond to a cutter while buttons 310 , 312 , 314 , 316 may each correspond to a zone of staples ( not shown in fig2 ). selecting the button 308 , 310 , 312 , 314 , 316 corresponding to a surgical implement may cause the control circuit 318 to configure the valve unit 304 such that a hydraulic device corresponding to the function is fired when firing trigger 28 is depressed , driving the corresponding surgical implements . multiple buttons may be selected to create firing patterns including more than one implement . in other non - limiting embodiments , each input button 308 , 310 , 312 , 314 , 316 may represent a pre - determined firing order and / or pattern . for example , selecting a button 308 , 310 , 312 , 314 , 316 may cause the control circuit 318 to configure the valve unit 304 such that hydraulic devices corresponding to particular surgical implements are fired when the firing trigger 28 is depressed . it will be appreciated that various embodiments may have more or fewer input buttons than are shown . in various non - limiting embodiments , control circuit 318 may configure the valve unit 304 to introduce a delay to the driving of one or more surgical implements included in the end effector 12 . for example , it may be desirable to drive a cutting implement and then delay for a predetermined time before driving one or more zones of a stapling implement . the delay may be accomplished according to any suitable method . in one non - limiting embodiment , the control circuit 318 may configure the valve unit 304 to open a path for hydraulic fluid between the hydraulic pump 302 and a first surgical implement included in the end effector 12 . when the firing trigger 28 is actuated , the pump 302 may generate pressurized hydraulic fluid , which drives the first surgical implement . the control circuit 318 may sense when the first surgical implement is driven ( e . g ., by sensing the position of the firing trigger 28 ), for example using sensor 405 shown in fig1 a . when the first surgical implement is driven , the control circuit 318 may begin a timer that counts off a predetermined delay time . at the expiration of the predetermined delay time , the control circuit 318 may configure the valve unit 304 to provide the pressurized hydraulic fluid to a second surgical implement . hydraulic pressure generated at the actuation of the firing trigger 28 may be sufficient to drive the second surgical implement , or in various embodiments , the hydraulic pump 302 may be utilized to generate additional hydraulic pressure . in use , the surgical stapling and severing instrument 10 is used as depicted in fig1 , and 20 - 26 . in fig1 - 2 , the instrument 10 is in its start position , having had an undriven , fully loaded staple cartridge 37 snap - fitted into the distal end of the elongate channel 16 . both triggers 26 , 28 are forward and the end effector 12 is open , such as would be typical after inserting the end effector 12 through a trocar or other opening into a body cavity . the instrument 10 is then manipulated by the clinician such that tissue 248 to be stapled and severed is positioned between the staple cartridge 37 and the anvil 18 , as depicted in fig2 . with reference to fig2 - 22 , next , the clinician moves the closure trigger 26 proximally until positioned directly adjacent to the pistol grip 24 , locking the handle portion 20 into the closed and clamped position . the retracted cutting edge 326 in the end effector 12 does not impede the selective opening and closing of the end effector 12 , but rather resides along the elongate channel 16 , positioned in the slot 49 of the staple cartridge 37 . in response to the actuation of the closure trigger 26 , the anvil 18 may be driven to pivot along anvil pivot 14 . with reference to fig2 - 24 , after tissue clamping has occurred , the clinician moves the firing trigger 28 proximally causing hydraulic fluid to be pressurized , for example , by hydraulic pump 302 . when the instrument is configured to cut , the hydraulic pressure may cause cutting bladder 322 to inflate , forcing cutting bar 324 through slot 49 and into contact with cutting edge 326 , which may sever the tissue 248 . when the instrument is configured to staple , the hydraulic pressure may cause one or more of the staple bladders 328 , 330 , 332 , 334 , 336 , 338 ( not shown in fig2 ) to inflate , exerting a vertical force on drivers 220 which in turn drive staples 222 . with reference to fig2 - 26 , the clinician continues moving the firing trigger 28 until brought proximal to the closure trigger 26 and pistol grip 24 . thereby , all of the ends of the staples 222 are bent over as a result of their engagement with the anvil 18 . the process is completed by releasing the firing trigger 28 and by then depressing the release button 30 while simultaneously squeezing the closure trigger 26 to open the end effector 12 . while the present invention has been illustrated by description of several embodiments and while the illustrative embodiments have been described in considerable detail , it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail . additional advantages and modifications may readily appear to those skilled in the art . for example , although the embodiments described above have advantages for an endoscopically employed surgical severing and stapling instrument 10 , a similar embodiments may be used in other clinical procedures . it is generally accepted that endoscopic procedures are more common than laparoscopic procedures . accordingly , the present invention has been discussed in terms of endoscopic procedures and apparatus . however , use herein of terms such as “ endoscopic ”, should not be construed to limit the present invention to a surgical instrument for use only in conjunction with an endoscopic tube ( i . e ., trocar ). on the contrary , it is believed that the present invention may find use in any procedure where access is limited to a small incision , including but not limited to laparoscopic procedures , as well as open procedures . for yet another example , although an illustrative handle portion 20 described herein is operated hydraulically in response to input from a clinician , it is consistent with aspects of the invention for some or all of the functions of a handle portion to be powered by other means ( e . g ., pneumatic , electromechanical , ultrasonic , mechanical , etc .). furthermore , controls of each of these functions may be manually presented on a handle portion or be remotely controlled ( e . g ., wireless remote , automated remote console , etc .). any patent , publication , or other disclosure material , in whole or in part , that is said to be incorporated by reference herein is incorporated herein only to the extent that the incorporated material does not conflict with existing definitions , statements , or other disclosure material set forth in this disclosure . as such , and to the extent necessary , the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference . any material , or portion thereof , that is said to be incorporated by reference herein , but which conflicts with existing definitions , statements , or other disclosure material set forth herein will only be incorporated to the extent that no conflict arises between that incorporated material and the existing disclosure material . | US-27021705-A |
a catheter that comprises a sheath that is connected at opposing ends to concentric tubes that move relative to each other in a manner that alternatively covers and exposes a medical device loaded onto the catheter . a portion of the sheath is arranged so as to invert upon itself so that axial movement of one tube relative to the other simultaneously moves the inversion point over or away from the device , alternatively covering or exposing the device . | referring to fig1 a - c , one exemplary embodiment of an improved delivery system 10 for a medical device 12 comprises a catheter 14 having a distal end 16 and a proximal end 18 . in the figures shown , and by way of example , the medical device 12 is a self - expanding frame . the catheter 14 further comprises a first inner tube 22 and an outer tube 24 . at the distal end of the outer tube 24 is a cap 26 affixed to the outer tube 24 . the cap 26 is preferably configured to have a smooth rounded surface at its distal most - end . by way of simplifying the description herein , fig1 a shows the system 10 such that the distal end of inner tube 22 is positioned proximal distal end of outer tube 24 , whereas fig1 b shows the inner tube 22 pulled in a proximal direction , with fig1 c showing it pulled further in the proximal direction . the catheter 14 further comprises a sheath 30 preferably made of resilient pliable material , such as those used in the industry , the sheath may comprise in whole or in part a braided , woven , or stitched structure , a polymer , or may comprise an inflatable balloon . a first end 32 of the sheath 30 is affixed to an outer surface of the cap 26 affixed to the distal end of the outer tube 24 . a second end 34 of the sheath 30 is affixed to the outer surface of the distal end of the inner tube 22 . as shown in fig1 a , the sheath 30 is configured to constrain the medical device 12 in a collapsed position for delivery to a target site . the sheath 30 is configured so that it overlaps itself on an external surface of the catheter 14 to form an inversion point 36 proximal of the distal end . the sheath 30 is further configured to conform to the smooth rounded distal surface of the cap 26 such that , as the inner tube is pulled in a proximal direction , the sheath smoothly slides over the cap causing the inversion point 36 to move distally . fig1 a through 1c show that progression . as the sheath 30 is pulled so that the inversion point 36 moves distally , the medical device 12 is progressively exposed , permitting it to expand as desired . with the embodiment shown in fig1 a - 1c , the inner tube 22 does hot need to advance distally beyond the distal cap 26 of the outer tube 24 . indeed , the catheter 14 need sot be placed much more distal than the target site of the medical device 12 . thus , deployment of a medical device using this embodiment may be made translumenally through the vasculature in one of many possible directions . for example , with respect to an aortic valve replacement , where the medical device 12 is an expandable valved frame , the catheter 14 may be directed transfemorally , transapically or through the sub - clavian artery conveniently . the device 12 may be delivered antegrade or retrograde through the arterial or venous system . once the medical device 12 is deployed , the entire catheter 14 may be withdrawn proximally from the target site . it should be appreciated that loading of the medical device 12 onto the outer tube 24 of catheter 14 would entail collapsing the medical device over the outside surface of the outer tube 24 and then moving the inner tube 22 distally relative to the outer 24 so as to cause the inversion point 36 to move proximally over the medical device 12 , when the inversion point has reach its proximal - most point , as shown in fig1 a , then catheter 14 may then be used to deliver the medical device 12 . for a self - expanding frame , collapse may be induced by , for example , reducing its temperature . for a balloon expandable frame , the device 12 can be crimped onto the outer tube 24 in one of many known ways . in that case , outer tube 24 would comprise a dilation balloon for in - situ deployment . a variation on the embodiment of fig1 a - 1c is shown in fig2 a through 2c , where the components are the same . with this embodiment of catheter 114 , the second end 34 of the sheath is attached to the inner tubs 22 so as to permit effective advancement of the inner tube 22 in the distal direction , rather than the proximal direction . as the inner tube 22 is directed distally , the inversion point 36 also advances distally , exposing the medical device 12 . while the embodiment of fig2 a - 2c may be used in a variety of delivery directions , as discussed above with the embodiment of fig1 a - 1c , it is preferred that the target site for the medical device 12 using this catheter embodiment 14 be such that there is sufficient room distal of the target site for effective advancement of the inner tube 22 . referring to fig3 a and 3b , a third exemplary embodiment is shown . there , a medical device 212 is shown sheathed within catheter 214 , which has similar components to catheters 14 and 114 discussed above , but with a somewhat different arrangement . catheter 214 has a proximal end 216 and a distal end 218 , and comprises an inner tube 222 and an outer tube 224 , where the outer tube and inner tube are movable relative to each other . a collar 226 is affixed to the outside of inner tube 222 . a sheath 230 , covering medical device 212 , has a first end 232 affixed to collar 226 and a second end 234 affixed to the outside distal end of outer tube 224 . the sheath 230 is arranged so as to create an inversion point 236 at a distal location . as the outer tube 224 is retracted proximally , the inversion point 236 likewise moves proximally , exposing the medical device 212 in the same way as explained with the other embodiments . it should be understood that with any of these exemplary embodiments , or any variation on these configurations , the clinician may manipulate the alternative of the inner or outer tubes to expose the medical device , although this would result in the medical device moving toward a target site during its deployment , rather than remaining stationary during deployment . for example , in the first embodiment , instead of pulling the inner tube 22 proximally , the medical device 12 may be exposed by advancing the outer tube 24 distally . the result is the same ; the inversion point 36 is advanced distally . likewise , the outer tube 24 of embodiment 2 a - 2 c could be pulled proximally rather than the other tube advanced distally and the inner tube 222 of embodiment 3 a - 3 b could be pulled distally , rather than the other tube being advanced proximally . one advantage of using an inverting sheath to load and deploy a medical device is that the sheath alternatively covers and exposes the medical device by predominantly a rolling motion rather than a sliding motion , which results is less friction between the medical device and the sheath . this reduces the force required to retract the sheath , which enables more control over the deployment position by , for example , reducing the compression and elongation of the delivery catheter . in addition , where the medical device comprises a prosthetic tissue - based heart valve sutured to a self - expandable frame , the pattern &# 39 ; s body heat can cause the frame to want to revert to its natural expanded configuration , thereby exerting an outward force against the sheath . during deployment , friction between the sheath and medical device can damage the tissue - based heart valve and sutures . accordingly , reducing the friction between the sheath and medical device by using a rolling motion rather than a sliding motion can help reduce damage to the medical device and help maintain the condition of the medical device . in other cases , the medical device may be coated with a drug or bioactive material , and the friction caused by sliding the coated stent out of the sheath can result in removal of some of the drug or bioactive material . in some embodiments , the surface of the sheath that contacts the medical device may be tacky , which enables the tacky surface to frictionally engage the medical device and reduce sliding between the medical device and sheath . the surface can be made tacky by , for example , application of a polymeric material such as polyurethane or another thermoplastic elastomer to the surface or by fabricating the surface from the tacky material . it is contemplated that the surface of the sheath that contacts itself when inverted may be provided with a lubricious coating or can be made of a lubricious material . the lubricious coating or material can be made of , tor example , ptfe , eptfe , a hydrophilic material , or any other substance that reduces the friction as the inverted sheath slides over itself . where desired , the sheath may be reinforced to minimize elongation of the sheath as tension is applied . for example , axially - oriented tension bands ( not shown ) having high tensile modulus material such as ultra high weight polyethylene , kevlar , carbon , steel , titanium , in the form of a monofilament or fiber may be incorporated within or on the sheath . in operation , the catheters described are particularly suited for delivery of a heart valve , where precise placement is important . other critical and less - critical target sites are also contemplated . in the case of a self - expanding aortic valve replacement , the catheter may be delivered transfemorally , transeptally , transapically or through the sub - clavian , among other possible entry ways . in one procedure , the catheter is deployed so that the valved frame is positioned entirely aligned with the target site ; e . g ., aortic annulus up to ascending aorta . the frame may then be exposed from one end to the other , depending upon the direction of delivery , by either advancing the inner tube relative to the outer tube ( for the embodiment of fig2 ) or vice versa ( for the embodiment of fig1 ), or retraction of the outer shaft ( for the embodiment of fig3 ). as the frame is exposed , it expands outwardly to engage the native intimal lining so placement accuracy is maximized . when , the sheath is fully removed and the frame fully expanded , the catheter may then be withdrawn though the functioning prosthetic valve and removed from the patient . although embodiments of this invention have been disclosed in the context of certain preferred embodiments and examples , it will be understood by those skilled in the art that the embodiments of the present invention extend beyond the specifically disclosed embodiments to other alternative embodiments and / or uses of the invention and obvious modifications and equivalents thereof . in particular , while the present loading system and method has been described in the context of particularly preferred embodiments , the skilled artisan will appreciate , in view of the disclosure , that certain advantages , features , and aspects of the system may be realized in a variety of other applications , many of which have been noted above . additionally , it is contemplated that various aspects and features of the invention described can be practiced separately , combined together , or substituted for one another , and that a variety of combination and subcombinations of the features and aspects can be made and still fall within the scope of the invention . thus , it is intended that the scope of the present invention herein disclosed should not be limited by the particular disclosed embodiments described above , but should be determined only by a fair reading of the claims . | US-201615361617-A |
the present invention relates to a tip assembly for a mobility device such as a cane or walking stick , for example . the tip assembly including a specially shaped extension for enhanced gripping of the surface upon which the associated mobility device is being used . the tip assembly also generally includes a dampening element to assist in dissipating the reverberations of contacting the tip assembly with hard surfaces over time . | example embodiments will now be described more fully with reference to the accompanying drawings . example embodiments are provided so that this disclosure will be thorough , and will fully convey the scope to those who are skilled in the art . numerous specific details are set forth such as examples of specific components , devices , and methods , to provide a thorough understanding of embodiments of the present disclosure . it will be apparent to those skilled in the art that specific details need not be employed , that example embodiments may be embodied in many different forms and that neither should be construed to limit the scope of the disclosure . in some example embodiments , well - known processes , well - known device structures , and well - known technologies are not described in detail . referring to fig1 - 3 in particular , there is shown a tip assembly for a mobility device in accordance with the teachings of the present invention . by the phrase “ mobility device ”, it is contemplated that the present invention can be used in association with a variety of ambulatory devices such as canes , walking sticks , crutches , walkers and other such devices . the assembly includes the following major components , a tip body 20 , a coupler 60 and a dampener 80 . optionally , depending on the intended use , the assembly may also include an anchor 100 integrated with the dampener . the body 20 which is formed from a rubber or rubber - like material includes a hollow sleeve 24 along one end 22 which fits over the shaft 4 of the ambulatory device 2 demonstrated herein in the form of a c - cane . extending from the sleeve is a substantially bulbous portion 26 . while the sleeve fits securely over the end of the cane , it is contemplated that it and the tip itself may move slightly along the shaft during use . by allowing some movement along the shaft , the tip can better allow the dampener to more effectively stifle the force transmission from the surface to the user . the bulbous portion 26 , which is ball - like along the exterior wall 28 , is provided with a plurality of spaced apart , outwardly extending protrusions 30 which serve to enhance gripping the surface upon which it is disposed . while the protrusions may have a variety of shapes and sizes , a currently preferred embodiment includes protrusions having sharp sidewalls 32 to give edges 34 . the end 36 opposite the sleeve end , as best shown in fig5 , is generally flat and may include a series of recesses 38 shown here in the form of rings . the end 36 also includes an aperture 40 . internally , the body includes an inner diameter wall 42 defining a receptacle 44 for receiving the cane shaft 4 , the coupler 60 and the dampener 80 . the inner diameter wall 42 may receive the cane shaft in a substantially press fit relationship . under at least one embodiment , the sleeve is intended to move slightly up and down the cane shaft as pressure is exerted upon the tip assembly and then released during use . if the tip assembly is intended to be permanently installed , an adhesive substance may be utilized between the inner wall and the cane shaft . the inner wall , as shown , has a first diameter 46 and a second reduced diameter portion 48 . this , in turn , provides a first shelf 50 and a second shelf 52 , respectively . the second major component is a coupler 60 . the coupler 60 is defined by a first substantially cylindrical portion 62 and a second , larger cylindrical portion 66 . the first portion may have a slightly reduced diameter along the leading edge to facilitate insertion within the cane shaft . the indented transition portion 64 , separating the two distinct cylindrical portions , serves to engage the inwardly projecting flange 6 occurring along the end wall 8 of the cane shaft . the first cylindrical portion plugs into the end of the cane shaft in a press fit relationship . the second cylindrical portion seats against the inner wall 42 of the tip body and the shelf 52 . occurring along the end of the coupler 60 , according to the embodiment of fig1 - 5 , is an internally threaded pocket 72 . while not depicted , the size of the mating fastener can be larger than the pocket to force radial expansion of the second cylindrical portion . this will further secure attachment of the coupler within the receptacle of the tip body . the coupler 60 is typically formed from a rubber or thermoplastic - like material . the third major component is referred to herein as a dampener 80 . the dampener 80 is generally intended to provide the assembly with a shock absorbing feature . the dampener body 82 is formed from a material having a durometer hardness of less than about 70 . by forming the dampener from a material which is generally softer than that of the tip body 20 , the force transmission can be lessened as there is a buffer between the hard cane tip and the tip body . the dampener 80 can be provided in differing durometers of hardness so that the overall assembly can be tailored to the surface conditions on which the ambulatory device is being used . in this regard , dampeners of differing durometers can be color coded to make it easier to select the appropriate dampener . these may be provided as a kit with different hardness depending on the weight of the user or the surface for ambulation . for instance , a lighter person may benefit more from a dampener with durometer 30 and a heavier person may benefit from a dampener of durometer 50 . under the embodiment depicted in fig1 - 5 , the dampener includes a threaded stem 84 extending from a first end 86 which mates with the threaded pocket 72 of the coupler . along the opposite end 88 , the dampener may include a tab 90 which extends into the aperture 40 . under an alternative embodiment as shown best in fig4 , the dampener may include an anchor 100 to enhance contact with the surface on which the cane is to be utilized . in this case , the anchor 100 is generally an extension of stem 84 and projects beyond the end 88 and through the aperture 40 of the tip body . the anchor can be in the form of a sharpened spike 102 which can better penetrate surfaces covered with ice , for example . other shapes , such as that shown in fig6 , depict the anchor in the form of a cylindrical stud 104 with or without a cut - out 106 shown . referring to fig7 , an embodiment is provided wherein the threaded stem 84 a is provided as part of the coupler 60 a and the threaded pocket 72 a is formed in the dampener 80 a . it should therefore be understood by those of ordinary skill in the art that the mechanical fastening between the coupler of the dampener can come in different forms . the foregoing description of the embodiments has been provided for purposes of illustration and description . it is not intended to be exhaustive or to limit the disclosure . individual elements or features of a particular embodiment are generally not limited to that particular embodiment , but , where applicable , are interchangeable and can be used in a selected embodiment , even if not specifically shown or described . the same may also be varied in many ways . such variations are not to be regarded as a departure from the disclosure , and all such modifications are intended to be included within the scope of the disclosure . | US-201414168384-A |
compounds having the structural formula i or a pharmaceutically acceptable salt thereof , wherein r is optionally substituted phenyl or heteroaryl , cycloalkenyl , — cch 3 , — c ≡ c — ch 3 , — ch ═ c 2 , x is alkylene , — cch 2 — or — cnch 2 —; y is — nch 2 ch 2 n —, — och 2 ch 2 n —, — o —, — s —, — ch 2 s —, — 2 — n —, or optionally substituted divalent heteroaryl , piperidinyl or piperazinyl ; and z is optionally substituted phenyl , phenylalkyl or heteroaryl , diphenylmethyl or r 6 — c —; or when y is z is also r 6 — so 2 —, r 7 — n — c —, r 7 — n — c — or r 6 oc —; or when y is 4 - piperidinyl , z can be phenylamino or pyridylamino ; or z and y together are substituted piperidinyl , substituted pyrrolidinyl or substituted phenyl ; r 14 is h , halogen or optionally substituted alkyl ; and q , q 1 , m , n , r 2 , r 3 , r 4 , r 6 , r 7 and r 8 are as defined in the specification are disclosed , their use in the treatment of parkinson &# 39 ; s disease , alone or in combination with other agents for treating parkinson &# 39 ; s disease , and pharmaceutical compositions comprising them . | referring to compounds of formula i above , preferred compounds of formula i are those wherein r is r 1 - furanyl , r 1 - thienyl , r 1 - pyrrolyl , r 1 - pyridyl or r 10 - phenyl , more preferably r 1 - furanyl or r 10 - phenyl . r 1 is preferably hydrogen or halogen . r 10 is preferably hydrogen , halogen , alkyl or — cf 3 . another group of preferred compounds is that wherein x is alkylene , preferably ethylene . y is preferably with q preferably being nitrogen . preferably , m and n are each 2 , and r 4 is h . a preferred definition for z is r 5 - phenyl or r 5 - heteroaryl . r 5 is preferably h , halogen , alkyl , alkoxy , hydroxyalkoxy or alkoxyalkoxy . r 6 is preferably r 5 - phenyl . r 14 is preferably hydrogen . when y and z together form a piperidinyl or pyrrolidinyl ring fused to a monocyclic or bicyclic aryl or heteroaryl ring , preferred fused ring structures are and a 2 and a 3 each are — c ( r 16 )( r 17 )—, or a 1 and a 3 each are — c ( r 16 )( r 17 )— and a 2 is a 1 and a 2 each are — c ( r 16 )( r 17 )—, and a 3 is j 1 , j 2 , j 3 and j 4 are selected from the group consisting of — n ═ and — c ( r 18 )—, provided that 0 - 2 of j 1 , j 2 , j 3 or j 4 are — n ═ and the remainder are — c ( r 18 )—; j 5 is — n ( r 17 )—, — o —, — s — or — c ( r 16 )( r 17 )—; each r 16 is independently selected from the group consisting of hydrogen , c 1 - c 6 - alkyl , c 1 - c 6 - alkoxy , — cf 3 , halogen , — oh and no 2 ; each r 17 is independently selected from the group consisting of hydrogen and c 1 - c 6 alkyl ; and each r 18 is independently selected from the group consisting of hydrogen , c 1 - c 6 - alkyl , cf 3 , halogen , no 2 , c 1 - c 6 - alkoxy , — o — c ( o )—( c 1 - c 6 - alkyl ), — nh 2 , — nh ( c 1 - c 6 - alkyl ), — n ( c 1 - c 6 - alkyl ) 2 , — nh — c ( o )—( c 1 - c 6 - alkyl ), — nh — so 2 —( c 1 - c 6 - alkyl ), — so 2 nh ( c 1 - c 6 - alkyl ), — so 2 n ( c 1 - c 6 - alkyl ) 2 , — so 2 nh 2 and — oh . in the above structures , when a 1 , a 2 or a 3 is two of the bonds are part of the ring and the third bond joins the ring to the variable x . in the definition of q and q 1 , “ at least one of q and q 1 is means that one of q and q 1 can be nitrogen and the other is selected from the remaining groups , both are nitrogen , both are ch , or one is ch and the other is selected from the remaining groups . as used herein , the term alkyl includes straight or branched chains . alkylene , referring to a divalent alkyl group , similarly refers to straight or branched chains . cycloalkylene refers to a divalent cycloalkyl group . cycloalkenyl refers to a c 4 - c 6 cycloalkyl ring comprising one double bond . heteroaryl means a single ring heteroaromatic group of 5 to 6 atoms comprised of 2 to 5 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of n , o and s , provided that the rings do not include adjacent oxygen and / or sulfur atoms . examples of single - ring heteroaryl groups are pyridyl , oxazolyl , isoxazolyl , oxadiazolyl , furanyl , pyrrolyl , thienyl , imidazolyl , pyrazolyl , thiazolyl , isothiazolyl , thiadiazolyl , pyrazinyl , pyrimidyl , pyridazinyl and triazolyl . bicyclic heteroaryl means a bicyclic heteroaromatic group of 5 to 10 atoms comprised of 1 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from the group consisting of n , o and s , provided that the rings do not include adjacent oxygen and / or sulfur atoms . examples of bicyclic heteroaryl groups are naphthyridyl ( e . g ., 1 , 5 or 1 , 7 ), imidazopyridyl , pyrido [ 2 , 3 ] imidazolyl , pyridopyrimidinyl and 7 - azaindolyl . benzofused heteroaryl bicyclic groups comprise a heteroaryl ring as defined above fused at adjacent carbon atoms to a phenyl ring . examples of benzofused heteroaryl groups are indolyl , quinolyl , isoquinolyl , phthalazinyl , benzothienyl ( i . e ., thionaphthenyl ), benzimidazolyl , benzofuranyl , benzoxazolyl and benzofurazanyl . all positional isomers are contemplated , e . g ., 2 - pyridyl , 3 - pyridyl and 4 - pyridyl . n - oxides of the ring nitrogens for all heteroaryl groups are also included . r 5 - substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above . divalent heteroaryl means a heteroaryl ring bonded to two different groups . in the context of this invention , when y is divalent r 5 - heteroaryl , one ring member is attached to the variable x , and another ring member is attached to variable z ; the r 5 substituents are attached to the remaining ring members . divalent heteroaryl groups are named by adding “ diyl ” to the name of the ring , for example , a pyridinediyl ring is shown : certain compounds of the invention may exist in different stereoisomeric forms ( e . g ., enantiomers , diastereoisomers and atropisomers ). the invention contemplates all such stereoisomers both in pure form and in mixture , including racemic mixtures . certain compounds will be acidic in nature , e . g . those compounds which possess a carboxyl or phenolic hydroxyl group . these compounds may form pharmaceutically acceptable salts . examples of such salts may include sodium , potassium , calcium , aluminum , gold and silver salts . also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia , alkyl amines , hydroxyalkylamines , n - methylglucamine and the like . certain basic compounds also form pharmaceutically acceptable salts , e . g ., acid addition salts . for example , pyrido - nitrogen atoms may form salts with strong acid , while compounds having basic substituents such as amino groups also form salts with weaker acids . examples of suitable acids for salt formation are hydrochloric , sulfuric , phosphoric , acetic , citric , oxalic , malonic , salicylic , malic , fumaric , succinic , ascorbic , maleic , methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art . the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner . the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous naoh , potassium carbonate , ammonia and sodium bicarbonate . the free base forms differ from their respective salt forms somewhat in certain physical properties , such as solubility in polar solvents , but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention . all such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention . compounds of formula i are prepared by methods known in the art . preferably , the compounds of formula i are prepared by the methods shown in the following reaction schemes . in the reaction schemes and the examples that follow , the following abbreviations are used : ts ( tosyl ); bn ( benzyl ); me ( methyl ); et ( ethyl ); and ac ( acetyl ). in scheme 1 , alkylation of a 5 - amino - imidazolo [ 4 , 3 - e ]-[ 1 , 2 , 4 ]- triazolo -[ 1 , 5 - c ] pyrimidine of formula ii is used to prepare compounds of formula i : starting materials of formula ii can be reacted with an alkyl diol ditosylate and a base such as nah in an inert solvent such as dimethylformamide ( dmf ), or with a chloro - bromo - or dibromo - alkyl compound under similar conditions , to obtain the 7 - and 9 - alkyl - substituted intermediates of formula iiia and iiib . the compound of formula iiia is then reacted with an amine of the formula z - y — h in an inert solvent such as dmf at an elevated temperature to obtain a compound of formula ia , i . e ., a compound of formula i wherein x is alkylene . alternatively , starting materials of formula ii can be reacted with a compound of formula z - y — x — cl and a base such as nah in an inert solvent such as dmf to obtain a mixture of a 7 - substituted compound of formula i and the corresponding 9 - substituted compound . compounds of formula ii can be prepared using the general procedure described in scheme 2 . commercially available 2 - amino - 6 - bromo purine or 2 - amino - 6 - choloro purine can be reacted with the corresponding hydrazide in butanol at elevated temperatures to produce the displacement product , which can be treated with n , o - bis ( trimethylsilyl ) acetamide to produce ii . to prepare compounds of formula i wherein y is piperazinyl and z is r 6 — c ( o )—, r 6 — so 2 —, r 6 — oc ( o )—, r 7 — n ( r 8 )— c ( o )— or r 7 — n ( r 8 )— c ( s )—, a compound of formula i wherein z - y is 4 - t - butoxycarbonyl - 1 - piperazinyl is deprotected , for example by reaction with an acid such as hcl . the resultant free piperazinyl compound , iv , is treated according to procedures well known in the art to obtain the desired compounds . the following scheme 3 summarizes such procedures : another method for preparing compounds of formula i is shown in scheme 4 : in this procedure , chloroimidazo - pyrimidine v , wherein r 20 is as defined above , is reacted with a compound of formula z - y — x — cl in a manner similar to the alkylation procedure of scheme 1 ; and the resultant intermediate is reacted with a hydrazide of formula h 2 n — nh — c ( o )— r ( or with hydrazine hydrate , followed by a compound of formula cl — c ( o )— r ). the resultant hydrazide undergoes dehydrative rearrangement , e . g ., by treatment with n , o - bis -( trimethylsilyl ) acetamide ( bsa ) or a combination of bsa and hexamethyldisilazane ( hmds ) and at elevated temperatures . starting materials are known or are prepared by processes known in the art . another method for preparing compounds of formula i is illustrated in the following scheme 5 : in analogy to scheme 1 , chloride v is converted into alkylated compound xii , and this is further reacted with xiv , where r ′ is preferably t - butyl or benzyl , to obtain derivative xiii . a solvent such as dmf may be employed at a temperature of 60 - 120 ° c . this is then reacted as in scheme 1 to furnish xv . the r ′ group is next removed , such as removal of a t - butyl group with hcl or trifluoroacetic acid ( tfa ), furnishing hydrazine xvi . acylation of xvi furnishes xvii , which is subjected to dehydrative cyclization as described above to provide desired la . alternatively , xii may be reacted with a hydrazide xviii to obtain xix , which can be converted to xvii analogously to preparation of xv . to prepare compounds of formula iia , wherein r 14 is other than hydrogen , the following procedure can be used : the amide of formula xix is prepared by reacting the pyrimidine of formula xviii and the acid chloride or anhydride in the presence of a base such as naoh , and the compound of formula xix is then cyclized using a reagent such as pocl 3 to obtain the chloroimidazolo - pyrimidine of formula va . the compound of formula va is reacted with the hydrazide as described in scheme 2 to obtain the intermediate iia , which can then be used to prepare a compound of formula i as described in scheme 1 . compound xviii , the acid chlorides and the hydrazines are known or can be prepared by processes known in the art . schemes 7 to 10 show procedures for preparing starting materials for compounds wherein y and z together form an aryl - or heteroaryl - fused piperidinyl or pyrrolidinyl group . the resultant y - z portions can be reacted with a compound of formula iiia as described in scheme 1 to obtain the desired compounds of formula 1 . the aromatic portions of the fused ring groups are substituted by independently selected r 18 groups , designated in the schemes as r 18 ′ , r 18 ″ and r 18 ″ . benzyl piperidinone is cyclized with an aminoacrylaldehyde of formula xx to form the benzyl protected tetrahydronaphthyridine of formula xxi , followed by hydrogenolysis to obtain the compound of formula xxii . quaternization of a naphthyridine of formula xxiii followed by reduction gives a benzyl protected tetrahydronaphthyridine of formula xxia . hydrogenolysis provides the desired product of formula xxiia . [ 2 + 2 + 2 ] cyclization of a diyne of formula xxiv with an acetylene of formula xxv provides the benzyl protected isoindoline of formula xxvi . hydrogenolysis provides the desired compound of formula xxvii . pictet - spengler cyclization of a phenethylamine of formula xxviii gives a substituted tetrahydroisoquinoline of formula xxix . step 1 : heat a mixture of 2 - amino - 6 - bromo purine ( 1 . 0 g , 4 . 7 mmol ) and 2 - furoic hydrazide ( 0 . 88 g , 7 . 0 mmol ) in butanol ( 10 ml ) at 120 ° c . overnight . collect the solid by filtration , wash with ch 3 oh and dry the solid in vacuum oven to produce a white solid . ms ( esi ): m + 1 = 260 . 1 . pmr ( dmso ) δ 6 . 71 ( d , j = 1 . 6 hz , 1h ), 7 . 32 ( s , 1h ), 7 . 41 ( bs , 2h ), 7 . 96 ( s , 1h ), 8 . 19 ( s , 1h ), 10 . 40 ( bs , 1h ), 10 . 86 ( s , 1h ). step 2 : heat the product of step 1 ( 1 . 3 g , 5 mmol ) in n , o - bis ( trimethylsilyl ) acetamide ( 6 . 10 g , 30 mmol ) at 100 ° c . overnight . cool the reaction mixture and pour it on ice water and stir for 4 h . collect the solid by filtration and wash with ch 3 oh , et 2 o and dry to produce a white solid . ms ( esi ): m + 1 = 242 . pmr ( dmso ) δ 6 . 71 ( dd , j = 1 . 7 & amp ; 3 . 4 hz , 1h ), 7 . 21 ( d , j = 2 . 9 hz , 1h ), 7 . 67 ( s , 1h ), 7 . 92 ( s , 1h ), 7 . 99 ( s , 1h ). step 3 : combine the product of step 2 ( 5 . 0 g , 20 . 7 mmol ) and ethylene glycol ditosylate ( 8 . 45 g , 22 . 8 mmol ) in dry dmf ( 30 ml ). cool the reaction mixture to 0 ° c . under n 2 . add nah ( 60 % in oil , 0 . 91 g , 22 . 8 mmol ) in portions , keeping internal temperature at 0 ° c . warm the reaction mixture to room temperature and stir overnight . pour the reaction mixture on ice / water and stir for 4 h . collect the solid by filtration and chromatograph it on silica gel to produce the title compound . ms ( esi ): m + 1 = 440 . 10 , pmr ( dmso ) δ 1 . 98 ( s , 3h ), 4 . 38 ( d , j = 4 . 3 hz , 2h ), 4 . 47 ( t , j = 4 . 4 hz , 2h ), 6 . 72 ( dd , j = 1 . 7 & amp ; 3 . 4 hz , 1h ), 6 . 96 ( d , j = 8 . 1 hz , 2h ), 7 . 25 ( m , 1h ), 7 . 32 ( d , j = 8 . 2 hz , 2h ), 7 . 73 ( s , 2h ), 7 . 93 ( s , 1h ), 7 . 94 ( d , j = 0 . 8 hz , 2h ). in a similar manner to preparation 1 , but employing the corresponding hydrazide , the following compounds were prepared : a ms ( esi ), m + 1 = 252 . 1 ms ( esi ) m + 1 = 450 . 1 pmr ( dmso ) δ 7 . 53 ( d , j = 7 . 5 hz , pmr ( dmso ) δ 1 . 96 ( s , 3h ), 4 . 38 ( d , 4h ), 7 . 65 ( s , 2h ), 8 . 01 ( s , 1h ), j = 4 . 5 hz , 2h ), 4 . 49 ( t , j = 4 . 6 hz , 2h ), 8 . 25 ( d , j = 6 . 7 hz , 2h ), 6 . 95 ( d , j = 8 . 5 hz , 1 h ), 7 . 32 ( d , j = 8 . 2 hz , 2h ), 7 . 55 ( m , 3h ), 7 . 72 ( s , 2h ), 7 . 94 ( s , 1h ), 8 . 27 ( dd , j = 1 . 4 & amp ; 8 . 0 hz , 2h b ms ( esi ), m + 1 = 270 ms ( esi ) m + 1 = 468 . 1 pmr ( dmso ) δ 7 . 38 ( m , 3h ), pmr ( dmso ) δ 1 . 97 ( s , 3h ), 4 . 39 ( t , 7 . 57 ( m , 1h ), 7 . 85 ( bs , 2h ), 8 . 17 2h ), 4 . 49 ( t , 2h ), 6 . 94 ( d , 2h ), 7 . 31 ( d , ( dt , 1h ), 8 . 50 ( s , 1h ), 2h ), 7 . 41 ( m , 2h ), 7 . 60 ( m , 1h ), 7 . 70 ( bs , 2h ), 7 . 96 ( s , 1h ), 8 . 21 ( dt , 2h ), c ms ( esi ), m + 1 = 320 . 1 ms ( esi ) m + 1 = 518 pmr ( dmso ) δ 7 . 63 ( s , 2h ), 7 . 80 pmr ( dmso ) δ 2 . 06 ( s , 3h ), 4 . 43 ( m , ( m , 3h ), 7 . 92 ( m , 2h ), 8 . 05 ( s , 1h ) 4h ), 6 . 97 ( d , j = 7 . 0 hz , 2h ), 7 . 33 ( d , j = 7 hz , 2h ), 7 . 74 - 7 . 97 ( m , 7h ), d ms ( esi ), m + 1 = 270 . 1 ms ( esi ) m + 1 = 468 . 1 pmr ( dmso ) δ 7 . 35 ( m , 1 h ), 7 . 60 pmr ( dmso ) δ 1 . 95 ( s , 3h ), 4 . 38 ( t , ( m , 1h ), 7 . 70 ( bs , 2h ), 7 . 97 ( d , 2h ), 4 . 49 ( t , 2h ), 6 . 94 ( d , 2h ), 7 . 31 ( d , 1h ), 8 . 01 ( s , 1h ), 8 . 1 ( d , 1h ), 2h ), 7 . 39 ( m , 2h ), 7 . 63 ( m , 1h ), 7 . 77 ( bs , 2h ), 7 . 95 ( s , 1h ), 8 . 99 ( d , 1h ), 8 . 11 ( d , 1h ) e ms ( esi ), m + 1 = 253 . 1 ms ( esi ), m + 1 = 315 . 1 pmr ( dmso ) δ 7 . 53 ( dd , j = 4 . 8 & amp ; pmr ( cdcl3 ) δ 3 . 94 ( t , j = 5 . 9 hz , 2h ), 7 . 7 hz , 1h ), 7 . 71 ( bs , 2h ), 8 . 00 ( t , 4 . 52 ( t , j = 5 . 9 hz , 2h ), 6 . 04 ( bs , 2h ), j = 7 . 7 hz , 2h ), 8 . 05 ( s , 1h ), 8 . 31 7 . 43 ( dd , j = 5 . 2 & amp ; 7 . 9 hz , 1h ), 7 . 87 ( s , ( d , j = 7 . 7 hz , 1h ), 8 . 73 ( d , j = 4 . 8 hz , 1h ), 7 . 91 ( t , j = 7 . 9 hz , 1h ), 8 . 56 ( d , 1h ), j = 7 . 9 hz , 1h ), 8 . 82 ( bs , j = 5 . 2 hz , 1h ) combine the product of preparation 1 ( 0 . 17 g , 0 . 39 mmol ) and 1 -( 4 methoxy ) phenyl piperazine ( 0 . 18 g , 0 . 77 mmol ) in dmf and heat at 90 ° c . for 20 h . concentrate and purify by flash column chromatography to obtain the title compound as a white solid , ms ( esi ), m + 1 = 430 . 1 in a similar fashion , using the appropriately substituted piperazine , the following compounds were prepared : z c 23 h 25 n 9 o 2 ; ms ( esi ), m + 1 = 460 . 1 c 25 h 29 n 9 o 3 ; ms ( esi ), m + 1 = 504 . 1 c 25 h 28 fn 9 o 3 ; ms ( esi ), m + 1 = 522 . 1 c 26 h 28 f 3 n 9 o 3 ; ms ( esi ), m + 1 = 572 . 1 c 22 h 21 f 2 n 9 o ; ms ( esi ), m + 1 = 466 . 1 c 22 h 21 clfn 9 o ; ms ( esi ), m + 2 = 484 . 1 , m + = 482 . 1 c 22 h 22 cln 9 o ; ms ( esi ), m + 2 = 466 . 1 , m + = 464 . 1 c 21 h 21 cln 10 o ; ms ( esi ), m + 2 = 467 . 1 , m + = 465 . 1 c 22 h 24 n 10 o ; ms ( esi ), m + 1 = 445 . 1 c 20 h 20 fn 11 o ; ms ( esi ), m + 1 = 450 . 1 c 19 h 20 n 10 os ; ms ( esi ), m + 1 = 437 . 1 combine the product of preparation 1a and 1 -( 2 , 4 - difluoro phenyl ) piperazine 5 in dmf and heat at 80 ° c . for 20 h . concentrate and purify by flash column chromatography to obtain the title compound as a white solid , mass spectrum ( esi ), m + 1 = 476 . 1 . z c 27 h 31 n 9 o 2 ; ms ( esi ), m + 1 = 514 . 1 c 27 h 30 fn 9 o 2 ; ms ( esi ), m + 1 = 532 . 1 c 24 h 23 f 2 n 9 ; ms ( esi ), m + 1 = 476 . 1 c 24 h 23 clfn 9 ; ms ( esi ), m + 2 = 494 . 1 , m + = 492 . 1 c 24 h 24 cln 9 ; ms ( esi ), m + 2 = 476 . 1 , m + = 474 . 1 c 22 h 22 fn 11 ; ms ( esi ), m + 1 = 460 . 1 c 21 h 22 fn 10 s ; ms ( esi ), m + 1 = 447 . 1 using 1 -( 4 - methoxy ) phenyl piperazine and the appropriate tosylate from preparation 1 in the procedure of example 1 , the following compounds were prepared : [ 0106 ] z c 28 h 30 f 3 n 9 o 2 ; ms ( esi ), m + 1 = 582 . 1 c 28 h 29 f 4 n 9 o 2 ; ms ( esi ), m + 1 = 600 . 1 c 25 h 22 f 5 n 9 ; ms ( esi ), m + 1 = 544 . 1 c 25 h 22 clf 4 n 9 ; ms ( esi ), m + 1 = 560 . 1 c 25 h 22 clf 3 n 9 ; ms ( esi ), m + 1 = 542 . 1 , 210 . 1 , 194 . 0 c 23 h 21 f 4 n 11 ; ms ( esi ), m + 1 = 528 . 1 , 210 c 22 h 21 f 3 n 10 s ; ms ( esi ), m + 1 = 515 . 1 [ 0107 ] z c 27 h 30 fn 9 o 2 ; ms ( esi ), m + 1 = 532 . 1 c 27 h 29 f 2 n 9 o 2 ; ms ( esi ), m + 1 = 550 . 1 c 24 h 22 f 3 n 9 ; ms ( esi ), m + 1 = 494 . 1 c 24 h 22 clf 2 n 9 ; ms ( esi ), m + 1 = 510 . 1 c 24 h 23 clfn 9 ; ms ( esi ), m + 1 = 492 . 1 c 21 h 21 f 2 n 11 ; ms ( esi ), m + 1 = 478 . 1 c 21 h 21 fn 10 s ; ms ( esi ), m + 1 = 465 . 1 [ 0108 ] z c 27 h 30 fn 9 o 2 ; ms ( esi ), m + 1 = 532 . 1 c 27 h 29 f 2 n 9 o 2 ; ms ( esi ), m + 1 = 550 . 1 c 24 h 22 f 3 n 9 ; ms ( esi ), m + 1 = 594 . 1 c 24 h 22 clf 2 n 9 ; ms ( esi ), m + 1 = 510 . 1 c 24 h 23 clfn 9 ; ms ( esi ), m + 1 = 492 . 1 c 21 h 21 f 2 n 11 ; ms ( esi ), m + 1 = 478 . 1 c 21 h 21 fn 10 s ; ms ( esi ), m + 1 = 465 . 1 [ 0109 ] z c 26 h 30 n 8 o 3 ; ms ( esi ), m + 1 = 503 . 1 c 23 h 23 fn 8 o ; ms ( esi ), m + 1 = 447 c 26 h 29 n 9 o ; ms ( esi ), m + 1 = 484 using the appropriate piperazine and the appropriate tosylate made by a procedure analogous to preparation 1 in the procedure of example 1 , the title compound was prepared . mass spectrum ( esi ) m + 1 = 547 . 1 ( c 28 h 33 fn 9 o 2 ). using the appropriate piperazine and the chloride of preparation 1 e in the procedure of example 1 , the title compound was prepared . mass spectrum ( esi ) m + 1 = 528 . 1 ( c 26 h 30 n 10 o 2 ). because of their adenosine a 2a receptor antagonist activity , compounds of the present invention are useful in the treatment of depression , cognitive function diseases and neurodegenerative diseases such as parkinson &# 39 ; s disease , senile dementia as in alzheimer &# 39 ; s disease , and psychoses of organic origin . in particular , the compounds of the present invention can improve motor - impairment due to neurodegenerative diseases such as parkinson &# 39 ; s disease . the other agents known to be useful in the treatment of parkinson &# 39 ; s disease that can be administered in combination with the compounds of formula i include : l - dopa ; dopaminergic agonists such as quinpirole , ropinirole , pramipexole , pergolide and bromocriptine ; mao - b inhibitors such as deprenyl and selegiline ; dopa decarboxylase inhibitors such as carbidopa and benserazide ; and comt inhibitors such as tolcapone and entacapone . one to three other agents can be used in combination with the compounds of formula i , preferably one . the pharmacological activity of the compounds of the invention was determined by the following in vitro and in vivo assays to measure a 2a receptor activity . human adenosine a 2a and a 1 receptor competition binding assay protocol a 2a : human a 2a adenosine receptor membranes , catalog # rb - ha2a , receptor biology , inc ., beltsville , md . dilute to 17 pg / 100 ul in membrane dilution buffer ( see below ). membrane dilution buffer : dulbecco &# 39 ; s phosphate buffered saline ( gibco / brl )+ 10 mm mgcl 2 . compound dilution buffer : dulbecco &# 39 ; s phosphate buffered saline ( gibco / brl )+ 10 mm mgcl 2 supplemented with 1 . 6 mg / ml methyl cellulose and 16 % dmso . prepared fresh daily . a 2a : [ 3h ]- sch 58261 , custom synthesis , amershampharmacia biotech , piscataway , n . j . stock is prepared at 1 nm in membrane dilution buffer . final assay concentration is 0 . 5 nm . a 1 : [ 3h ]- dpcpx , amershampharmacia biotech , piscataway , n . j . stock is prepared at 2 nm in membrane dilution buffer . final assay concentration is 1 nm . a 2a : to determine non - specific binding , add 100 nm cgs 15923 ( rbi , natick , mass .). working stock is prepared at 400 nm in compound dilution buffer . a 1 : to determine non - specific binding , add 100 μm neca ( rbi , natick , mass .). working stock is prepared at 400 μm in compound dilution buffer . prepare 1 mm stock solutions of compounds in 100 % dmso . dilute in compound dilution buffer . test at 10 concentrations ranging from 3 μm to 30 μm . prepare working solutions at 4 × final concentration in compound dilution buffer . perform assays in deep well 96 well plates . total assay volume is 200 μl . add 50 μl compound dilution buffer ( total ligand binding ) or 50 μl cgs 15923 working solution ( a 2a non - specific binding ) or 50 μl neca working solution ( a 1 non - specific binding ) or 50 μl of drug working solution . add 50 μl ligand stock ([ 3h ]- sch 58261 for a 2a , [ 3h ]- dpcpx for a 1 ). add 100 μl of diluted membranes containing the appropriate receptor . mix . incubate at room temperature for 90 minutes . harvest using a brandel cell harvester onto packard gf / b filter plates . add 45 μl microscint 20 ( packard ), and count using the packard topcount microscintillation counter . determine ic 50 values by fitting the displacement curves using an iterative curve fitting program ( excel ). determine ki values using the cheng - prusoff equation . male sprague - dawley rats ( charles river , calco , italy ) weighing 175 - 200 g are used . the cataleptic state is induced by the subcutaneous administration of the dopamine receptor antagonist haloperidol ( 1 mg / kg , sc ), 90 min before testing the animals on the vertical grid test . for this test , the rats are placed on the wire mesh cover of a 25 × 43 plexiglass cage placed at an angle of about 70 degrees with the bench table . the rat is placed on the grid with all four legs abducted and extended (“ frog posture ”). the use of such an unnatural posture is essential for the specificity of this test for catalepsy . the time span from placement of the paws until the first complete removal of one paw ( decent latency ) is measured maximally for 120 sec . the selective a 2a adenosine antagonists under evaluation are administered orally at doses ranging between 0 . 3 and 3 mg / kg , 1 and 4 h before scoring the animals . in separate experiments , the anticataleptic effects of the reference compound , l - dopa ( 25 , 50 and 100 mg / kg , ip ), were determined . adult male sprague - dowley rats ( charles river , calco , como , italy ), weighing 275 - 300 g , are used in all experiments . the rats are housed in groups of 4 per cage , with free access to food and water , under controlled temperature and 12 hour light / dark cycle . the day before the surgery the rats are fasted over night with water ad libitum . unilateral 6 - hydroxydopamine ( 6 - ohda ) lesion of the middle forebrain bundle is performed according to the method described in ungerstedt et al , brian research , 24 ( 1970 ), p . 485 - 493 , and ungerstedt , eur . j . pharmacol ., 5 ( 1968 ), p . 107 - 110 , with minor changes . briefly , the animals are anaesthetized with chloral hydrate ( 400 mg / kg , ip ) and treated with desipramine ( 10 mpk , ip ) 30 min prior to 6 - ohda injection in order to block the uptake of the toxin by the noradrenergic terminals . then , the animals are placed in a stereotaxic frame . the skin over the skull is reflected and the stereotaxic coordinates (— 2 . 2 posterior from bregma ( ap ), + 1 . 5 lateral from bregma ( ml ), 7 . 8 ventral from dura ( dv ) are taken , according to the atlas of pellegrino et al ( pellegrino l . j ., pellegrino a . s . and cushman a . j ., a stereotaxic atlas of the rat brain 1979 , new york : plenum press ). a burr hole is then placed in the skull over the lesion site and a needle , attached to a hamilton syringe , is lowered into the left mfb . then 8 μg 6 - ohda - hcl is dissolved in 4 μl of saline with 0 . 05 % ascorbic acid as antioxidant , and infused at the constant flow rate of 1 μl / 1 min using an infusion pump . the needle is withdrawn after additional 5 min and the surgical wound is closed and the animals left to recover for 2 weeks . two weeks after the lesion the rats are administered with l - dopa ( 50 mg / kg , ip ) plus benserazide ( 25 mg / kg , ip ) and selected on the basis of the number of full contralateral turns quantified in the 2 h testing period by automated rotameters ( priming test ). any rat not showing at least 200 complete turns / 2 h is not included in the study . selected rats receive the test drug 3 days after the priming test ( maximal dopamine receptor supersensitivity ). the new a 2a receptor antagonists are administered orally at dose levels ranging between 0 . 1 and 3 mg / kg at different time points ( i . e ., 1 , 6 , 12 h ) before the injection of a subthreshold dose of l - dopa ( 4 mpk , ip ) plus benserazide ( 4 mpk , ip ) and the evaluation of turning behavior . using the above test procedures , the following results were obtained for preferred and / or representative compounds of the invention . results of the binding assay on compounds of the invention showed a 2a ki vaules of 0 . 3 to 1000 nm , with preferred compounds showing ki values between 0 . 3 and 50 nm . selectivity is determined by dividing ki for a1 receptor by ki for a2a receptor . preferred compounds of the invention have a selectivity ranging from about 100 to about 2000 . preferred compounds showed about a 50 - 75 % decrease in descent latency when tested orally at 1 - 3 mg / kg for anti - cataleptic activity in rats . for preparing pharmaceutical compositions from the compounds described by this invention , inert , pharmaceutically acceptable carriers can be either solid or liquid . solid form preparations include powders , tablets , dispersible granules , capsules , cachets and suppositories . the powders and tablets may be comprised of from about 5 to about 70 percent active ingredient . suitable solid carriers are known in the art , e . g . magnesium carbonate , magnesium stearate , talc , sugar , lactose . tablets , powders , cachets and capsules can be used as solid dosage forms suitable for oral administration . for preparing suppositories , a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted , and the active ingredient is dispersed homogeneously therein as by stirring . the molten homogeneous mixture is then poured into convenient sized molds , allowed to cool and thereby solidify . liquid form preparations include solutions , suspensions and emulsions . as an example may be mentioned water or water - propylene glycol solutions for parenteral injection . aerosol preparations suitable for inhalation may include solutions and solids in powder form , which may be in combination with a pharmaceutically acceptable carrier , such as an inert compressed gas . also included are solid form preparations which are intended to be converted , shortly before use , to liquid form preparations for either oral or parenteral administration . such liquid forms include solutions , suspensions and emulsions . the compounds of the invention may also be deliverable transdermally . the transdermal compositions can take the form of creams , lotions , aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose . preferably , the pharmaceutical preparation is in unit dosage form . in such form , the preparation is subdivided into unit doses containing appropriate quantities of the active component , e . g ., an effective amount to achieve the desired purpose . the quantity of active compound of formula i in a unit dose of preparation may be varied or adjusted from about 0 . 1 mg to 1000 mg , more preferably from about 1 mg to 300 mg , according to the particular application . the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated . determination of the proper dosage for a particular situation is within the skill of the art . generally , treatment is initiated with smaller dosages which are less than the optimum dose of the compound . thereafter , the dosage is increased by small increments until the optimum effect under the circumstances is reached . for convenience , the total daily dosage may be divided and administered in portions during the day if desired . the amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age , condition and size of the patient as well as severity of the symptoms being treated . a typical recommended dosage regimen for compounds of formula i is oral administration of from 10 mg to 2000 mg / day preferably 10 to 1000 mg / day , in two to four divided doses to provide relief from central nervous system diseases such as parkinson &# 39 ; s disease . the compounds are non - toxic when administered within this dosage range . the doses and dosage regimen of the dopaminergic agents will be determined by the attending clinician in view of the approved doses and dosage regimen in the package insert , taking into consideration the age , sex and condition of the patient and the severity of the disease . it is expected that when the combination of a compound of formula i and a dopaminergic agent is administered , lower doses of the components will be effective compared to the doses of the components administered as monotherapy . the following are examples of pharmaceutical dosage forms which contain a compound of the invention . those skilled in the art will recognize that dosage forms can be modified to contain both a compound of formula i and a dopaminergic agent . the scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided . [ 0159 ] no . ingredients mg / tablet mg / tablet 1 . active compound 100 500 2 . lactose usp 122 113 3 . corn starch , food grade , as a 30 40 10 % paste in purified water 4 . corn starch , food grade 45 40 5 . magnesium stearate 3 7 total 300 700 mix item nos . 1 and 2 in a suitable mixer for 10 - 15 minutes . granulate the mixture with item no . 3 . mill the damp granules through a coarse screen ( e . g ., ¼ ″, 0 . 63 cm ) if necessary . dry the damp granules . screen the dried granules if necessary and mix with item no . 4 and mix for 10 - 15 minutes . add item no . 5 and mix for 1 - 3 minutes . compress the mixture to appropriate size and weigh on a suitable tablet machine . [ 0161 ] no . ingredient mg / capsule mg / capsule 1 . active compound 100 500 2 . lactose usp 106 123 3 . corn starch , food grade 40 70 4 . magnesium stearate nf 7 7 total 253 700 mix item nos . 1 , 2 and 3 in a suitable blender for 10 - 15 minutes . add item no . 4 and mix for 1 - 3 minutes . fill the mixture into suitable two - piece hard gelatin capsules on a suitable encapsulating machine . while the present invention has been described in conjunction with the specific embodiments set forth above , many alternatives , modifications and variations thereof will be apparent to those of ordinary skill in the art . all such alternatives , modifications and variations are intended to fall within the spirit and scope of the present invention . | US-26975402-A |
a transport device for receiving and securely holding an ossicular prosthesis for implantation in a middle ear to replace or bridge at least parts of a component of a human ossicular chain to an operating surgeon , has a substantially flat base plate of thin metal sheet having a thickness of substantially half a millimeter , a holding device integrated in the substantially flat base plate for holding the ossicular prosthesis , an outer packaging enclosing the base plate on all sides during transport , and the base plate has a device for ensuring safe transport provided with burr - shaped segments extending laterally outward from the base plate and clampable or braceable against inner walls of the outer packaging . | the embodiment of transport device 1 according to the invention — which is depicted schematically in the figures of the drawing and includes an ossicular prosthesis 2 for implantation in the middle ear , which comprises on one end thereof a first fastening element 2 a for mechanical connection to the tympanic membrane or a component of the ossicular chain , and , on the other end thereof , a second fastening element 2 b for mechanical connection to a further component of the ossicular chain or directly to the inner ear , and a connecting element 2 c which connects the two fastening elements 2 a , 2 b in a sound - conducting manner , and wherein at least parts of ossicular prosthesis 2 are made of a material having memory effect are subjected to shape - altering thermal treatment when ossicular prosthesis 2 is implanted in the middle ear — is characterized , according to the invention , in that transport device 1 comprises a flat base plate 5 which is typically formed of thin metal sheet having a small thickness . according to the preferred embodiment depicted , at least one suspension device 6 b for receiving and holding ossicular prosthesis 2 , and which is connected to base plate 5 and can be twisted by way of fine segments 6 b ′, is integrated therein , wherein suspension device 6 b aligns with the surface of base plate 5 during manufacture of transport device 1 and , for suspension of ossicular prosthesis 2 , can be rotated relative to this lying - flat production state by approximately 90 ° relative to base plate 5 by way of plastic deformation of segments 6 b ′, and then extends above the surface of base plate 5 . advantageously , transport device 1 is manufactured together with suspending device 6 b out of one integrated blank by machining base plate 5 using laser treatment and / or anodizing . furthermore , the embodiment depicted of transport device 1 according to the invention also contains a prosthesis mock - up 3 , which is designed to match ossicular prosthesis 2 and is part of a test device for determining an optimized power setting and / or energy application site for the preparation of parts of ossicular prosthesis 2 to be subjected intraoperatively to thermal treatment . prosthesis mock - up 3 is identical in design to ossicular prosthesis 2 in terms of material , geometric shape , and manufacturing method , at least in the regions in which associated prosthesis 2 will be subjected intraoperatively to thermal treatment . in the embodiment of transport device 1 according to the invention depicted in the drawing , ossicular prosthesis 2 and associated prosthesis mock - up 3 are made of a material having memory effect , at least in the region of first fastening element 2 a . the prosthesis can also comprise a device for varying the length thereof ; in that particular case , the prosthesis and the associated prosthesis mock - up are made of a material having memory effect , at least in the region of the device for varying the length . in many ossicular prosthesis and , optionally , the associated prosthesis mock - ups , a nickel - titanium alloy , nitinol in particular , is used as the preferred material having memory effect . in every representation of prosthesis mock - up 3 shown in the drawing , a detent device 4 is provided , which is used to secure prosthesis mock - up 3 in a processing position , which is preferably upright , as shown in fig4 a and 4 b . possible details of detent device 4 are shown in enlarged depictions in fig2 a and 2 b , e . g . a tab - shaped operating element 4 a or locking elements 4 b , 4 b ′ which , in the locked state , enclose a counter - holder , as shown clearly in fig4 b . a feature that is also common to all of the embodiments of transport device 1 according to the invention shown in the drawing is that a holding device which can swivellably accommodate prosthesis mock - up 3 is provided . fig1 and 3 a to 3 e show base plate 5 with installed ossicular prosthesis 2 and prosthesis mock - up 3 in the lying - fiat transport state ; fig4 a and 4 b show prosthesis mock - up 3 upright and locked into position after removal of prosthesis 2 ; prosthesis mock - up 3 and prosthesis 2 are not present in fig5 a to 5 d ; fig5 a and 5 b especially show the state of holding device 5 immediately after production thereof , and fig5 c and 5 d show the state shortly before installation of ossicular prosthesis 2 on holding device 5 . not shown are possible embodiments of the transport device according to the invention , in , which the holding device is designed such that it can accommodate only the prosthesis mock - up , but not the associated ossicular prosthesis ( or vice versa ). the figures of the drawing show the particularly preferred embodiment of the invention , in which the holding device for prosthesis mock - up 3 comprises a suspending device 6 a which is connected to base plate 5 and can be twisted by way of fine segments 6 a ′, and is used to suspend one end of prosthesis mock - up 3 . as mentioned above , fig5 c and 5 d illustrate , in particular , the state of transport device 1 shortly before installation of ossicular prosthesis 2 , wherein suspending devices 6 b for accommodating prosthesis 2 are rotated by way of segments 6 b ′ relative to the lying - flat state shown in fig5 a and 5 b by approximately 90 ° relative to base plate 5 . in contrast , prosthesis mock - up 3 is suspended in the unrotated state of suspending device 6 a for transporting the test device to the operating surgeon , and is swivelled by approximately 90 ° relative to the plate and locked into position — as shown clearly in fig4 a and 4 b — only when the optimal processing parameters of ossicular prosthesis 2 are to be determined . transport device 1 according to the invention includes an outer packaging which encloses base plate 5 on all sides during transport , and is in the form of a container in particular , such as a case , a can , or a box , which is not depicted separately in the drawing . moreover , according to the invention , transport device 1 comprises a device for ensuring safe transport , which comprises burr - shaped segments 7 extending laterally outwardly from base plate 5 in the base - plate plane , which can also extend out of the base - plate plane at an angle in non - depicted embodiments of the invention . segments 7 ensure that transport device 1 — comprising installed ossicular prosthesis 2 which is relatively sensitive to mechanical damage , and prosthesis mock - up 3 which may also installed — will not slip during transport to the operating surgeon , wherein segments 7 can be clamped or braced against inner walls of the outer packaging mentioned above . in the embodiment of the invention shown , base plate 5 is optically coded or labelled . the coding or labelling 8 contains technical information on ossicular prosthesis 2 and / or associated prosthesis mock - up 3 , and manufacturer &# 39 ; s information . the coding can also include simple color coding . as an alternative or in addition thereto — in embodiments which are not depicted in the drawing — the ossicular prosthesis and / or the associated prosthesis mock - up can also be optically coded and / or labelled , wherein the coding or labelling also contains technical information on the ossicular prosthesis and / or prosthesis mock - up . the technical information in the coding or labelling 8 contains , for example , a size classification of ossicular prosthesis 2 used , and a recommended starting value for the electrical power or luminous power which should be applied within the scope of a test handling of prosthesis mock - up 3 at the beginning of the determination of optimized processing parameters for the parts of ossicular prosthesis 2 to be subjected intraoperatively to thermal treatment . the coding and / or labelling 8 is created most simply using laser treatment and / or anodizing . likewise , base plate 5 itself is preferably manufactured and machined further by laser - cutting the plate out of a larger sheet . in particular , the miniscule structures of the above - described elements of base plate 5 , such as suspending devices 6 a and 6 b , associated twistable segments 6 a ′ and 6 b ′, and burr - shaped segments 7 for ensuring safe transport cannot be created in practically any other manner without expenditure becoming unreasonable . in the embodiment shown of transport device 1 according to the invention , place - holder pins 9 a , 9 b are provided in base plate 5 to hold open first fastening element 2 a of ossicular prosthesis 2 , as well as the corresponding section of associated prosthesis mock - up 3 , in a defined manner during transport to the operating surgeon ; said place - holder pins 9 a , 9 b lock the thermally pretreated parts of ossicular prosthesis 2 composed of a material having memory effect , and optionally prosthesis mock - up 3 , in the desired geometry , thereby ensuring that unwanted changes in shape are prevented even if warming occurs during transport . the embodiment of transport device 1 according to the invention shown in the figures of the drawing comprises a middle ear prosthesis 2 , in the case of which first fastening element 2 a is in the form of a clamp which can be clipped onto the limb of incus , for example , or onto another component of the ossicular chain . in this embodiment , second fastening element 2 b is designed , on the end opposite the clamp , as a piston for use to couple ossicular prosthesis 2 directly to the inner ear . in embodiments of the invention that are not depicted in the drawing , the transport device can be designed such that it can accommodate an ossicular prosthesis , the fastening elements of which are designed with different geometries , e . g . as a sleeve , loop , or hook . the first fastening element can be a top plate which rests on the tympanic membrane . in addition , the second fastening element , for example , can be designed not as a piston but rather in the form of a clamp or piston for placement against the base of the stapes , or as a slotted bell for fastening the ossicular prosthesis to the stapes . in further embodiments of the invention that are not depicted in the drawing , a ball joint can be integrated into connecting element 2 c in order to ensure a certain amount of post - operative flexibility of ossicular prosthesis 2 between the connection points thereof . this is taken into account accordingly in the geometric design of suspending devices 6 b . embodiments of the transport device according to the invention that are likewise not depicted in the drawing are those in which base plate 5 is designed as a working plate for the preparation of ossicular prosthesis 2 before implantation in the middle ear . in particular , the ossicular prosthesis can be designed to have a variable length , and the base plate can be designed as a working plate for setting a specific desired length of the ossicular prosthesis . explicit depictions are also not presented of further possible embodiments in which the ossicular prosthesis can be connected to an active vibration part of an active , partially implantable hearing aid . it will be understood that each of the elements described above , or two or more together , may also 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 transport device comprising device for ensuring safe transport of ossicular prosthesis , 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 . 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 . | US-201113103698-A |
in a laparoscopic surgery or the like , access is provided to an opening in a body cavity that contains insufflation gas at an insufflation pressure . the flow of insufflation gas from the body cavity through the opening is limited in response to the sensed insufflation pressure in the cavity . | as shown in fig1 an insufflation system 10 is used to insufflate a body cavity 11 in the area of an incision 13 in a patient 12 . the system 10 includes a valve assembly 14 , a valve pump 16 , a controller 18 , an insufflation pump 20 , and an insufflation needle 22 . the controller 18 controls the valve pump 16 to provide pressurized air to the valve assembly 14 , as described in detail below . the controller 18 also controls the insufflation pump 20 to regulate the insufflation pressure in the body cavity 11 . the insufflation pump 20 ( e . g ., a dyonic laparoscopic insufflator model no . 7205362 ) can supply pressures sufficient to insufflate the body cavity 11 . for example , the insufflation pump 20 can inflate the body cavity 11 to approximately 50 mm hg ( 2 in . hg ), while a typical insufflation pressure is 15 mm hg ( 0 . 6 in . hg ). a signal representing the insufflation pressure is provided by an insufflation pressure sensor 72 and sent to the controller 18 . the controller 18 can be any device capable of sending control signals to control the insufflation pump 20 and the valve pump 16 , e . g ., a personal computer or a dedicated microprocessor and associated circuitry . typically , the controller 18 is programmed using software , hardware , firmware , hardwiring , or a combination of any of these . a surgeon can access the body cavity 11 through the valve assembly 14 , e . g ., to insert an implement into the cavity . as shown in fig2 the valve assembly 14 includes a bladder 23 carried in a rigid tube 24 attached to a sleeve 38 . the sleeve 38 is flexible and sized to fit over the surgeon &# 39 ; s forearm . the proximal end 42 of the sleeve 38 includes , for example , a hook and loop fastener strap that can be secured around the surgeon &# 39 ; s arm to guard against loss of insufflation gas . the sleeve 38 connects to a sleeve coupling 40 that releasably connects to the tube 24 using a releasable coupling such as disclosed in u . s . pat . no . 5 , 653 , 705 ( issued aug . 5 , 1997 to de la torre ) incorporated by reference herein . a circular inside surface 26 of the tube 24 forms a seal , preferably air - tight , with an outer perimeter 25 of the bladder 23 . the bladder 23 fits snugly within , and is bonded to , the tube 24 . the bladder 23 can be sealed to the tube 24 by , e . g ., an adhesive , heat welding , or inflating the bladder 23 to expand and conform it to the inside surface 26 of the tube 24 with an interference fit . also , the bladder 23 can be carried by a rigid or semi - rigid member that is slid into the tube 24 and mounted at an appropriate location . the bladder - and - member assembly can be removed , e . g ., for replacement when it becomes worn or soiled . the tube 24 is sized to allow access to the body cavity 11 ( fig1 ) through an opening 28 defined by the bladder 23 along the direction indicated by arrows 30 . for example , the tube 24 can be sized to allow insertion of the surgeon &# 39 ; s hand and / or forearm through the opening 28 , in which case the inside surface 26 can have a diameter on the order of 100 mm ( 4 in .). for inserting smaller implements such as endoscopes or surgical instruments , the tube can be smaller , e . g ., with an inside diameter on the order of 5 - 10 mm ( 0 . 2 - 0 . 4 in .). the tube 24 has a distal section adapted to be mounted to the patient 12 . as shown , the distal section includes a flange 44 that can be mounted directly to the patient using an adhesive , by suturing , or by other appropriate means . the bladder 23 is inflatable , conical and annular . the bladder 23 is preferably flexible enough that an inner surface of the bladder 23 conforms to the periphery of the implement , yet is durable enough to resist puncture or rupture in normal use . for example , the bladder 23 can be made of a flexible polymer , such as polypropylene or latex . the maximum intended operating pressure of the bladder 23 depends on a variety of factors such as the bladder material , the amount that the surgeon needs to manipulate the implement inside the opening 28 , and the bladder &# 39 ; s shape . the conical shape of the bladder 23 allows it to conform , either actively under control of the controller 18 or passively due to , e . g ., the insufflation pressure , to the implement . the conical shape also facilitates insertion of implements through the opening 28 , while guarding against the bladder 23 turning upwards , and thus allowing insufflation gas in the body cavity 11 to escape , when the surgeon removes the implement . either or both the bladder 23 and the implement can be lubricated to facilitate insertion and removal of the implement . the valve pump 16 ( e . g ., an aci medical model no . 025 . 20 - 12 ) is connected to the bladder 23 by a valve pump gas line 52 . the bladder 23 conforms to the implement as the valve pump pressurizes the bladder 23 . the valve pump 16 can pressurize the bladder 23 , e . g ., up to 200 mm hg , and can release gas from the bladder 23 to reduce the pressure in the bladder 23 to as low as 0 mm hg . the pressure in the bladder 23 is monitored by a bladder pressure sensor 74 , in the valve pump 16 , that sends a signal representative of the bladder pressure to the controller 18 . if the bladder pressure exceeds the maximum desired pressure for the bladder 23 , then the valve pump 16 , either on its own or under direction of the controller , can shut off , reduce output , or provide either or both of a visual or audio warning . the valve pump 16 also has a manual shutoff switch 70 . the valve pump 16 can be a multichannel pump as shown in fig3 . as shown in fig3 if the valve pump 16 is a multichannel pump ( i . e ., it can provide multiple independent pressures to , and sense multiple independent pressures in , multiple valves ), then two valve assemblies 14a , 14b similar to valve assembly 14 can be used together in a surgical procedure . alternatively , separate valve pumps 16 , one for each valve , can be used . signals representing bladder pressures are provided by bladder pressure sensors 74a , 74b to the controller 18 . the valve 14a is sized for insertion of the surgeon &# 39 ; s hand ( not shown ) and the valve 14b is sized to receive an implement such as a surgical instrument or a visual aid device ( not shown ). in a surgical procedure , the valve assemblies 14a , 14b are attached to the patient 12 so that they are sealed in or around the incision 13 . for instance , the valve assembly 14a is attached around the incision 13 and the valve assembly 14b is inserted through a body wall 50 of the patient 12 directly into the body cavity 11 . the valve pump 16 is connected to the bladders 23a , 23b through respective valve pump gas lines 52a , 52b . the insufflation needle 22 is inserted through the body wall 50 , and an insufflation pump gas line 54 connects the insufflation needle 22 to the insufflation pump 20 . the valve pump gas lines 52a , 52b . and the insufflation pump gas line 54 are preferably flexible , and made of a material that can withstand the pressures encountered during use . electrical lines 56 and 58 connect the controller 18 to the valve pump 16 and the insufflation pump 20 , respectively , and provide bi - directional communication between the pumps and the controller 18 for the pressure and control signals . during the procedure , the controller 18 actively controls the insufflation pump 20 and the valve pump 16 to maintain sufficient insufflation pressure inside the body cavity 11 . insufflation pressure may drop due to , among other things , leaks in or around the insufflation needle 22 , the tubes 24a , 24b , or in the openings 28a , 28b . insufflation gas can also escape when the endoscope is removed , e . g ., to clean off condensation or body fluids . the controller 18 can control the valves to allow insufflation gas to escape from the body cavity 11 . referring to fig4 when the insufflation pressure is at or above a desired insufflation pressure ip 1 , the bladders in the valves are pressurized to bp 1 , typically 1 - 2 mm hg ( 0 . 04 - 0 . 08 in . hg ), with the valve pump 16 releasing gas from the bladder 23 as necessary . should the insufflation pressure drop below ip 1 , the controller 18 signals the valve pump 16 to pressurize the bladders and the insufflation pump 20 to pressurize the cavity . as the insufflation pressure drops below the desired pressure ip 1 , the valve pump 16 linearly increases the bladder pressures until the maximum bladder pressure bp max is reached . insufflation gas is supplied as necessary to the body cavity . the surgeon can also adjust the bladder pressure , e . g ., so that he can more easily manipulate the implement . for example , fig5 shows an alternative valve assembly 76 including a sectional bladder 78 that has several triangular - shaped bladder segments or wedges 34 . the bladder segments 34 may be fed by a single valve pump line 36 from the valve pump 16 . alternatively , the sectional bladder 78 may be a single piece with an undivided peripheral portion and a segmented central portion . other bladder segment shapes could instead be used , such as rectangles or wedges with flattened or concave ends , as opposed to pointed ends . also , the perimeter 79 of the sectional bladder 78 ( or the perimeter 25 of the bladder 23 ) may be elliptical , rectangular , or square , with the inside surface 26 of the tube 24 having a similar shape . the bladder 23 does not have to be annular . for example , the bladder can be a spherical balloon with no opening , carried on one side of the inner wall of the tube 24 . as the bladder inflates , it presses the surgical implement against the opposite wall , and forms a seal around it . regardless of shape or configuration , the bladder 23 can be inflated with , and the valve pump 16 can supply , any fluid capable of pressurizing the bladder , such as a liquid ( e . g ., saline ). the tube 24 and sleeve coupling 40 can take a variety of forms . the tube 24 can be flexible or semi - rigid . all or part of the tube 24 can be pleated , giving the tube an accordion shape . the distal section of the tube 24 can include a threaded end 46 to be screwed into a mating coupling or other device ( not shown ) that seals to the patient 12 in or around the incision 13 ( fig1 ). the sleeve coupling 40 can be adapted to have the sleeve 38 clipped , snapped , or tied to the sleeve coupling 40 . the relationship between insufflation pressure and bladder pressure does not have to be the linear relationship shown in fig4 . for example , the bladder pressure could be a step response as a function of the insufflation pressure , rising quickly from bp 1 to the maximum bladder pressure when the insufflation pressure drops below ip 1 . fig6 illustrates another embodiment of a valve assembly 80 that can be used at or near the incision 13 . a sealing device 60 retracts the incision 13 and supports a bladder 82 , which can be similar to the bladder 23 of fig2 or the sectional bladder 78 of fig5 . the sealing device 60 can be an inflatable annular bladder , or can be rigid . the tube 24 ( fig2 ) can be configured to include the sealing device 60 . fig7 illustrates another embodiment of a valve assembly 84 , in which an iris shutter 86 can be used to close off a tube 88 . a lower ring 66 is fixedly attached to the tube 88 . a motor 62 actuates an upper ring 64 of the iris shutter 86 , causing a flexible sheath 68 to twist and conform to the implement . while the iris shutter 86 is shown as being displaced a distance away from the patient 12 , the iris shutter 86 may also be used at the level of the incision 13 . | US-99057297-A |
an implant includes an elongate threaded portion defining a first central longitudinal axis and a groove . the groove defines a second longitudinal central axis that extends in the same direction as the first central longitudinal axis . a blade portion extends from the elongate threaded portion and has a taper terminating at a point . | this description of preferred embodiments is intended to be read in connection with the accompanying drawings , which are to be considered part of the entire written description . the drawing figures are not necessarily to scale and certain features of the invention may be shown exaggerated in scale or in somewhat schematic form in the interest of clarity and conciseness . in the description , relative terms such as “ horizontal ,” “ vertical ,” “ up ,” “ down ,” “ top ,” and “ bottom ” as well as derivatives thereof ( e . g ., “ horizontally ,” “ downwardly ,” “ upwardly ,” etc .) should be construed to refer to the orientation as then described or as shown in the drawing figure under discussion . these relative terms are for convenience of description and normally are not intended to require a particular orientation . terms including “ inwardly ” versus “ outwardly ,” “ longitudinal ” versus “ lateral ,” and the like are to be interpreted relative to one another or relative to an axis of elongation , or an axis or center of rotation , as appropriate . terms concerning attachments , coupling , and the like , such as “ connected ” and “ interconnected ,” refer to a relationship wherein structures are secured or attached to one another either directly or indirectly through intervening structures , as well as both movable or rigid attachments or relationships , unless expressly described otherwise . the term “ operatively connected ” is such an attachment , coupling or connection that allows the pertinent structures to operate as intended by virtue of that relationship . the disclosed implant , systems , and methods advantageously enable an implant to be installed through a small incision while stabilizing a joint , such as a metatarsophalangeal joint . additionally , the implant is capable of being completely disposed within a toe of a patient , which prevents the implant from being caught on bed sheets or other objects like the conventional pins when installed for treating a joint condition . fig1 - 8 illustrate one example of an improved implant 100 for treating hammer toe in accordance with some embodiments . as best seen in fig1 and 2 , implant 100 includes a threaded portion 102 and a blade portion 104 , which are connected together at an engagement portion 106 . implant 100 may have a substantially linear geometry , such that a longitudinal axis defined by blade portion 104 is aligned or collinear with a longitudinal axis defined by threaded portion 102 , and have an overall length of approximately 19 mm ( approximately 0 . 75 inches ). however , in some embodiments , blade portion 104 is disposed at angle with respect to a longitudinal axis defined by the threaded portion 102 such that a longitudinal axis defined by the blade portion 104 is not aligned nor collinear with a longitudinal axis defined by threaded portion 102 . for example , in some embodiments , the angle is between zero and 45 degrees , and more particularly between approximately five and fifteen degrees . commonly assigned u . s . patent application ser . no . 13 / 086 , 136 , filed apr . 13 , 2011 and which is incorporated by reference herein in its entirety , discloses one example of an implant having an angled ( e . g ., non - linear ) configuration . one of ordinary skill in the art will understand that implant 100 may have other dimensions and be provided in different sizes . for example , implant 100 may be provided in lengths of 16 mm and 22 mm , to identify only a few potential lengths . threaded portion 102 includes a plurality of threads 108 disposed along its entire length . in some embodiments , the length of threaded portion 102 is approximately 13 mm ( approximately 0 . 5 inches ). threaded portion 102 tapers to a pointed tip 110 to facilitate the advancement of threads 108 into bone . in some embodiments , threads 108 have a maximum outer diameter of approximately 2 mm ( approximately 0 . 08 inches ), although one skilled in the art will understand that thread portion 102 may have other dimensions and be configured to be received within a phalanx bone of a person . for example , in some embodiments , threads 108 have an outer diameter of between approximately 1 . 6 mm and 4 mm , such as , for example , 1 . 6 mm , 2 . 4 mm , 3 . 2 mm , and 4 . 0 mm , to identify only a few potential possibilities . threaded portion 102 includes a groove 109 sized and configured to receive a k - wire , pin , or other surgical device or instrument therein as described in greater detail below . groove 109 extend along the length of threaded portion 102 in a direction that is parallel to a longitudinal length defined by threaded portion 102 . in some embodiments , as best seen in fig1 and 2 , a central axis of groove 109 is disposed adjacent to a central longitudinal axis defined by threaded portion 102 . put another way , the central axis defined by groove 109 is not collinear with , and is parallel to , the central axis defined by threaded portion 102 , which extends through the center of threaded portion 102 and blade portion 104 . in some embodiments , groove 109 is disposed such that it is tangent to a minor diameter of threads 108 . although not shown , in some embodiments groove 109 is collinear with the central axis defined by threaded portion 102 ( and blade portion 104 ). fig6 and 7 show a k - wire 10 disposed within groove 109 . in some embodiments , such as the embodiment illustrated in fig7 , a gap g is provided between k - wire 10 and a side 128 of blade portion 104 , which is disposed opposite of side 130 of blade portion 104 as shown in fig4 and 8 . gap g enables bone to be received between surgical device 10 and blade portion 106 . as best seen in fig1 , blade portion 104 includes a plurality of serrated edges 112 on first side 114 and on a second side 116 . serrated edges 112 each have a thickness that is approximately equal to the thickness of blade portion 104 . put another way , in some embodiments , blade portion 104 does not taper along its thickness direction as best seen in fig3 . serrated edges are separated from one another by valleys or indentations 126 shown in fig1 and 3 . blade portion 104 may have a width that is greater than its thickness as best seen in fig1 and 2 . for example , blade portion 104 may have a width of approximately 0 . 4 centimeters ( approximately 0 . 16 inches ) and a thickness of approximately 0 . 1 centimeters ( approximately 0 . 04 inches ) each of which taper to point 118 at the distal - most end of blade portion 104 . in some embodiments , blade portion 104 has a substantially rectangular cross - sectional area as illustrated in fig4 , although one skilled in the art will understand that blade portion 104 may have other cross - sectional geometries . engagement portion 106 includes a pair of protrusions 120 extending from opposite sides of implant 100 and having rounded outer edges 122 as best seen in fig1 and 2 . the sides 124 of protrusions 120 may be substantially parallel with each other as shown in fig5 . protrusions extend away from one another in a direction that is perpendicular with respect to a longitudinal direction of implant 100 . a method of installing implant 100 in a joint between at least two bones is described with reference to fig9 - 15 . although the method is described as installing an implant in the bones of a proximal interphelangeal joint ( pip ) 200 , i . e ., the joint between proximal phalange 202 and middle phalange 304 , one of ordinary skill in the art will understand that the technique for installing the implant 100 may be applied to other joints , such as , for example , the distal interphelangeal ( dip ) joint , i . e ., joint 208 between middle phalange 304 and distal phalange 206 . as shown in fig9 , an incision is made to open the pip joint 200 . in some embodiments , a cutting tool 300 having a blade 302 is used to resect adjacent faces of proximal phalanx 202 and middle phalanx 204 as shown in fig1 . the resected surfaces of proximal phalanx 202 and middle phalanx 204 may be debrided as understood by one of ordinary skill in the art . a k - wire , pin , or other suitable surgical device 10 is inserted into the middle phalange 204 and driven through distal phalange 206 and out the end of the toe as shown in fig1 . in some embodiments , middle phalange 204 is broached or pre - drilled to create an opening 210 also shown in fig1 , and a pilot hole 212 is formed in proximal phalange 202 using a drill , broach , or other suitable surgical device ( not shown ). the hole 210 created by the broach is located at a distance from the k - wire 10 that corresponds to the distance of gap g . k - wire 10 is inserted such that trailing end 10 b ( not shown in fig1 ) is disposed within middle phalange 204 or otherwise positioned with respect to joint 200 such that implant 100 can be driven into proximal phalange 202 . in some embodiments , threaded portion 102 of implant 100 is driven into proximal phalange 202 using a driving tool . for example , fig1 illustrates implant 100 being driven into middle phalange 204 using a driving tool 400 , such as a driving tool disclosed in commonly assigned u . s . patent application ser . no . 13 / 086 , 136 , which is incorporated by reference herein in its entirety . one of ordinary skill in the art will understand that other driving tools can be used . shaft 402 of driving tool 400 can be engaged with a chuck of a drill ( not shown ) to advance threaded portion 102 of implant 100 into pilot hole 212 . implant 100 is driven into bone until engagement portion abuts bone . implant 100 is decoupled from driving tool 400 by axially pulling handle ( not shown ) away from implant 100 with sufficient force to flex o - ring 404 and separate driving tool 400 from implant 100 . fig1 illustrates threaded portion 102 of implant 100 disposed within a first bone , such as proximal phalange 202 , and end 10 b of surgical device 10 disposed within a second bone , such as middle phalange 204 . blade portion 104 is exposed as it extends from the distal end of middle phalange 202 . the middle phalange 204 is repositioned such that hole 210 formed by broaching the middle phalange 204 aligns with the blade portion 104 of implant 100 , which extends from the end of proximal phalange 202 . additionally , k - wire 10 disposed within middle phalange 204 aligns with the groove 109 defined by blade portion 104 of implant 100 , which is disposed within proximal phalange 202 . middle phalange 204 is pressed into engagement with the blade portion 104 as shown in fig1 . serrated edges 112 of blade portion 104 help to maintain the engagement between middle phalanx 204 and blade portion 104 of implant 100 . in some embodiments , k - wire 10 is advanced across joint 200 , into and through middle phalange 202 , and into metatarsal 214 through implant 100 as shown in fig1 . the k - wire 10 is received within groove 109 such that implant 100 engages surgical device 10 . what was initially leading end 10 a ( fig1 and 13 ), can be blunted or capped to provide an exposed blunt end 10 c shown in fig1 . the surgical device 10 can remain within a patient for a period of time , e . g ., minutes , hours , days , or months , and then be removed as shown in fig1 to leave behind implant 100 . thus , in some embodiments a surgical method includes forming an incision to gain access to a joint between the first bone and the second bone , resecting at least one of the first end of the first bone and the first and of the second bone , and flexing the first bone relative to the second bone to expose the first end of the first bone and the first end of the second bone . a first surgical device is inserted into the first bone until a trailing end of the first surgical device disposed adjacent to a first end of the first bone . the first end of the first bone is broached at a location that is adjacent to a location at which the first surgical device is disposed in the first bone . a pilot hole is formed in the first end of the second bone , and a threaded portion of an implant is advanced into the pilot hole formed in the second bone . the first bone is repositioned such that the hole formed in the first end of the first bone by the broach is aligned with a blade portion of the implant extending from the first end of the second bone . the first bone is forced into engagement with the blade portion of the implant . the first surgical device is advanced across the joint , into the second bone such that first surgical device is received within a groove defined by the threaded portion of the implant . the first surgical device is further advanced across a second joint into a third bone . after a period of time , the first surgical device is removed from its engagement with the implant and the first , second , and third bones while the implant remains disposed within the first and second bones . the implant described above may advantageously be installed through a small incision as described above . further , the inclusion of a groove in the implant that is sized and configured to receive a k - wire enables the implant to be installed while the joint is stabilized . although the disclosed implant , system , and method have been described in terms of exemplary embodiments , they are not limited thereto . rather , the appended claims should be construed broadly , to include other variants and embodiments of the system , implant , and method , which may be made by those skilled in the art without departing from the scope and range of equivalents of the implant , system , and method . | US-201314043105-A |
a method of making chunk tomato pieces from tomatoes . the tomatoes are introduced into a tomato preparation system where they are cleaned , de - stemmed , peeled and chopped . this creates a mixture of tomato chucks , seeds and juice . the tomato chunks are separated from the seeds and juice . the juice is separated from the seeds and subsequently added back to the chunks in proper proportions . | referring to fig1 through 4 , in one embodiment of the present invention , methods and systems are provided for making chunk tomato pieces from tomatoes . a processing system 10 includes a device 12 for receiving whole and / or partially crushed tomatoes , hereafter generally referred to as the “ received tomato ”. processing system 10 peels , de - stems and then sends the received tomatoes to a maceration processing unit 14 . maceration begins with the transport of the received tomatoes to various feed conveyors , generally denoted as 15 , including but not limited to surge bins . the received tomatoes are continuously feed into maceration processing unit 14 by the conveyors 15 . feeding of the received tomatoes can be achieved in a variety of different manners , including but not limited to dropping the received tomatoes into maceration processing unit 14 in feed , and the like . maceration occurs when the received tomatoes are exposed to a continuously moving cutting device . the cutting device reduces received tomato mass into chunks . cutting device can also slice and / or dice , e . g ., cube , the received tomatoes . generally , maceration processing unit 14 produces tomato chunks , seeds and tomato juice . this mixture is then strained at a separating device 16 that removes the seeds and recycles the juice , chunks and pulp . the recycled juice , chunks pulp are then received at a receiving unit 18 and a suitable separating device 16 is employed . in another embodiment , illustrated in fig2 , the seeds are removed in the straining process and the remaining material is received at a high speed centrifugation device 20 . at centrifugation device 20 puree is further processed in order to create tomato paste . the remaining tomato chunks are then received at receiving unit 18 . in one embodiment , a liquatex separator is utilized , which is commercially available from rotex inc ., cincinnati , ohio . in various embodiments , the flow of chunks is diluted with tomato juice in order to create a diluted mass of chunks . the tomato juice can be received from processing apparatus 10 . the diluted mass of chunks can be passed across a rotex . the diluted mass of chunks can be sprayed with tomato juice . the spray can be delivered in the form of a water fall of tomato juice that cascades over the chunks . in one embodiment , the seeds , chunks and tomato juice are separated into three flows . the tomato juice can flow in a closed - loop system . at least a portion of the tomato juice that is separated from the chunks flows in a return path to spray the chunk and seed mixture . the tomato juice flows in a closed - loop pumping circuit within processing apparatus 10 . the closed - loop pumping circuit 22 can include a tomato juice reservoir 24 which can be pre - charged . tomato juice can then flow from tomato juice reservoir 24 to a spray nozzle 26 that sprays the tomato chunks with tomato juice . tomato juice reservoir 24 is filled with tomato juice prior to chopping the tomatoes . an equilibrium is created between the spray and the tomato juice reservoir . a tomato juice and tomato chunk balance without seeds is created . in one embodiment , the balance is in the range of 85 % 60 % tomato juice and 15 %- 40 % tomato chunk . in another embodiment , the balance is about 75 % tomato juice 25 % tomato chunk . with certain embodiments of the present invention , methods and systems are provided for making deseeded chunks of tomatoes from tomatoes during a continuous process while maintaining a commercial rate of flow and with minimal impact on the size and shape of the tomato chunks . in one embodiment , the methods and systems of the present invention for a seed removal of at least 90 %, at least 95 % and at least 99 %.\ in this example , apparatus 10 was utilized to separate tomato chunks from seeds . a modified rotex unit , with liquid recirculation and a feed system was utilized . four tests were performed . tests were initiated with recovered and reconstituted juice . testing occurred for a total of 61 minutes . reject stream ( seeds , juice and residual juice ) was analyzed via placement on punch plate screen with 0 . 090 ″ openings . this allowed liquid ( as compared to seeds and pectin ) to drip free . visually acquired data indicated significant reduction of seeds in finished product , as evidenced by the pulp feed and finished product . there was no discernable change in flavor profile pectin . seed content of rejected stream was high with liquid reasonable low of about 1 % of line flow on a mass basis . pectin and seed were approximately 9 to 10 % of total mass flow the actual total mass flow was 12 , 200 pounds for 61 minutes . liquid reintroduction to pulp was successful with stationary weir functioning . post test inspection revealed little if any build up on screen surfaces table 1 summarizes the results . while embodiments of the invention have been illustrated and described , it is not intended that these embodiments illustrate and describe all possible forms of the invention . rather , the words used in the specification are words of description rather than limitation , and it is understood that various changes may be made without departing from the spirit and scope of the invention . | US-2749904-A |
devices and methods for treating degenerative , congestive heart disease and related dysfunction are described . passive and active cardiac support structures mitigate changes in ventricular structure and deterioration of global left ventricular performance related to tissue damage precipitating from ischemia , acute myocardial infarction or other abnormalities . cardiac efficiency is improved by providing reinforcement that restores or maintains an elliptical ventricular shape and mimics the position and positive inotropic effects of helical wound myofibrils to provide active contraction of the ventricle in synchrony with the metabolically required cardiac pace or output . in addition , the cardiac support structures compensate or provide therapeutic treatment for congestive heart failure and / or reverse the remodeling that produces an enlarged heart . the structures may be implanted in target heart regions using less invasive surgical techniques , such as those involving port access or small incisions into the thoracic cavity . | having described the characteristics and problems of congestive heart failure in the background and summarized hereto , the treatment method and apparati of the present invention will now be described in detail below . the variations of the invention described below may be used to provide a complete , comprehensive solution to treating congestive heart syndrome , and the contributing or associated co - morbid , anatomical , and physiological deficiencies . addressing the multiple factors that affect or cause congestive heart disease can retard or reverse the implicated remodeling thereby treating or mitigating the congestive heart disease and associated symptoms . with respect to these multiple factors the following applications are discussed in detail : muscle fiber helix restoring cardiac support structures , papillary muscle repositioning , active cardiac support structures and integrated multi - site pacing , and cardiac support structures with an integrated active compression mechanism . in connection with these completer or partial solutions , various cardiac support structure components , deployment approaches and structure materials and general fabrication methods for the devices are described . naturally , it is the intent that sometimes these solutions may be applied in a stand - alone fashion , and other situations in which any of the solutions will be utilized in any combination together for combined effect . before further discussion of the invention , however , it is to be understood that it is not limited to particular variations set forth and may , of course , vary . various changes may be made to the invention described and equivalents may be substituted without departing from the true spirit and scope of the invention . in addition , many modifications may be made to adapt a particular situation , material , composition of matter , process , process act ( s ) or step ( s ), to the objective ( s ), spirit or scope of the present invention . all such modifications are intended to be within the scope of the claims made herein . methods recited herein may be carried out in any order of the recited events which is logically possible , as well as the recited order of events . furthermore , where a range of values is provided , it is understood that every intervening value , between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention . also , it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently , or in combination with any one or more of the features described herein . all existing subject matter mentioned herein ( e . g ., publications , patents , patent applications and hardware ) is incorporated by reference herein in its entirety except insofar as the subject matter may conflict with that of the present invention ( in which case what is present herein shall prevail ). the referenced items are provided solely for their disclosure prior to the filing date of the present application . nothing herein is to be construed as an admission that the present invention is not entitled to antedate such material by virtue of prior invention . reference to a singular item , includes the possibility that there are plural of the same items present . more specifically , as used herein and in the appended claims , the singular forms “ a ,” “ and ,” “ said ” and “ the ” include plural referents unless the context clearly dictates otherwise . it is further noted that the claims may be drafted to exclude any optional element . as such , this statement is intended to serve as antecedent basis for use of such exclusive terminology as “ solely ,” “ only ” and the like in connection with the recitation of claim elements , or use of a “ negative ” limitation . unless defined otherwise herein , all 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 . with initial reference to fig1 a and 1b , an anterior view of a healthy heart in systole and diastole respectively is shown with directional arrows showing motion of the heart 186 . the preferred evolutionary anatomical shape of the left ventricle 18 assumes an elliptical form positioned in an oblique orientation from the base to the apex 242 . this ventricular shape ( in stark contrast to the spherical shape typically presented in later stage heart failure patients ) provides tangible benefits in contractile efficiency and valvular function by maintaining a desirable orientation relative to the helical wound myocardial fiber bundles and a desirable position of the subvalvular apparati . in fig1 b and 1c , perspective views are shown of a diseased ( enlarged ) heart in systole and diastole respectively . the infarcted or ischemic region 20 is shown to stretch from systole to diastole consistent with the progressive remodeling that occurs due to increased diastolic filling pressures exerted on the diseased tissue . a radial and axial expansion that is experienced by the heart leads to degenerative remodeling and concomitant organ enlargement . this enlargement can be localized along the anterior wall of the left ventricle 18 , can be located or extend septally , can include the right ventricle 24 , and / or can involve the mitral valve annulus 108 . this remodeling is exacerbated and accelerated by deterioration of associated anatomic structures such as the atria 74 and 58 , the aorta 162 , the pulmonary artery 72 , etc . which aid cardiac output in normal hearts by pulsating and augmenting the pumping action of the heart ventricles alone . accordingly it is evident that it would be desirable to maintain or at least restore the benefits of the preferred elliptical shape of the left ventricle 18 and to take advantage of the helical fibril bundle orientation in compromised hearts . fig1 e and 1f show perspective views of a diseased heart reinforced with a cardiac support structure 4 of the invention . these cardiac support structures 4 restore the preferred helical fiber orientation , and are secured in position on the surface of the heart to limit myocardial stretch or infarct expansion by locally reinforcing the infarcted / ischemic regions 20 or other diseased sections of tissue , and limiting the tension applied to the tissue regions 20 in conjunction with diastolic filling pressure exerted directly against this diseased section . in this example , a cardiac support structure 4 is shown deployed and secured to the left ventricle 18 in a helical pattern to restore the natural , healthy cardiac fiber orientation . fig2 a to 2 c show the natural helical myocardial fiber orientation 224 of a normal heart . the helical orientation involves the left 18 and right 24 ventricles and can be completely unraveled into a flat sheet . during unwanted remodeling of the heart associated with congestive heart failure , the myocardial fibers unwind as the heart enlarges thereby compromising efficient contractility and wall motion usually enabled by the natural helically oriented myocardial fiber orientation 224 . fig2 d shows a cardiac support structure embodiment of the invention designed to restore the myocardial fiber orientation by compressing the heart wall back into a helical shape . the compression applied by the structure depicted in the illustration can be instantaneously adjusted during intraoperative procedures , or can be adjusted over a period of time including post - discharge from the hospital . cardiac support structure aspects of the present invention comprise — individually , or in combination — components or devices including tensile member ( s ), anchor member ( s ) and deployment device ( s ). these components or devices are designed to be able to work alone or in concert in order to facilitate and provide palliative or therapeutic cardiac reinforcement in the following critical target areas of the heart : 1 ) papillary muscles ; 2 ) cardiac valve annulus ; 3 ) epicardium ; 4 ) apex of the heart ; 5 ) ventricular septum ; and / or 6 ) myocardium . the sub - sections broken - out below will further describe treatments addressing corresponding specific aspects of the invention . many of the embodiments described below incorporate a tensile member terminating at anchor mechanisms at each end . the embodiments described below are adapted or configured to be positioned into or through the myocardium and define anchor mechanisms augmented by the inherent structure and deployment process and / or can incorporate one or more anchors to aid in positioning and securing the cardiac support structures in place . fig3 a to 3 h show a cardiac support structure embodiment 84 that incorporates anchors 32 separately deployable from the tensile members . it should be noted , however , that the anchors can be advantageously be integrated and / or interconnected with the tensile members . fig3 c shows an anchor 32 that can be inserted through myocardium and incorporates notches 122 that fit in mating openings 142 of the tensile members to secure it firmly in position for chronic use throughout the necessary cyclic life of the device . the tensile members shown in fig3 a and 3b incorporate a spring component capable ( if desired ) of a pre - defined extension and contraction such that the tensile member 84 can be expanded during positioning and apply a compressive force against the heart to continuously urge and maintain the heart into the preferred helical orientation or any other orientation as defined by the operator during the implant procedure . tensile members 84 may comprise a tubing of raw material ( metal , alloy , polymer , etc .) cut into a helical spring . it should be noted that other tensile member configurations can be used including solid wire or tubing , mesh members , standard wound coil springs or other geometrical patterns that define the degree of elasticity , and rigidity . once the anchors are positioned , the tensile members such as those shown in fig3 a and 3b can be deployed locally and strategically arranged to provide the desired reinforcement and / or repositioning clinically desirable end effects . fig3 d and 3e show the engagement of the openings in the tensile members shown in fig3 a and 3b to the anchor shown in fig3 c . once the opening of the tensile member 84 is placed over the end of the anchor , the anchor end locks to the tensile member firmly securing the tensile member to the anchor . as shown in fig3 f to 3 h , tensile members can be connected to anchors at the ends of the tensile members , at the mid - region of the tensile members , or anywhere where a suitable anchoring opening along the length of the tensile member is located . fig4 shows a heart with an alternative cardiac support structure pattern utilizing the tensile members and anchors in fig3 a to 3 h described above with ribcage 226 superimposed over the subject system . in this embodiment , the cardiac support structures extend from the atrial - ventricular groove 178 to the apex of the heart 242 to maintain , facilitate or restore a desirable anatomical shape and relative positioning of heart subcomponents . at each of the extreme positions of the structure ( i . e ., adjacent atrial - ventricular groove 178 and apex 242 ), the anchors 32 are shown interconnected with locking anchor elements 124 , the purpose of which is to stabilize the structure by capturing the anchors . in the alternative , individual caps ( integrated with or interfacing with ) the end anchors may be provided in the variation of the invention . fig5 b shows cardiac support structures 4 as shown in fig5 a deployed through the myocardium of heart 186 . in the cardiac support structure embodiment 4 in fig5 a , a single tensile member 84 is shown with spaced apart tissue penetration ends 120 on one side and a connecting spring on the opposite side 126 . upon insertion of the tissue penetrating ends 120 of the tensile members 84 , a cardiac support structure anchor 124 can be placed over these ends to secure the member to the tissue surface or the ends of the tensile member can be tied to produce an axially - oriented tightening of the support structure 4 . still further , one free end of the tensile member can be subsequently inserted through myocardium at a spaced apart location to produce a three - dimensional , cinching effect . according to one aspect of the invention , multiple cardiac support structures are secured to the heart tissue to produce a helical pattern as shown in fig5 b , thereby maintaining or repositioning the myocardial fibers into a helical pattern . the array of tensioning structures may thereby maintain or restore a more optimal pattern of myocardial fiber contraction . it is this array , assemblage or pattern of spring elements that comprises an aspect of the invention ; so too do the methods of selecting the points / regions for positioning the tensioning members , the methods of emplacing the same , and even the methods of their operation once emplaced . actually , the tensioning structures shown in fig5 a and 5b are described in co - pending u . s . patent application no . 2003 / 0078465 , entitled , “ systems for heart treatment ,” to pai et al . incorporated by reference herein in its entirety for any purpose . many of the tensioning structures shown therein may be placed and used according to the present invention . under such circumstances where known tensioning structures are involved , the invention concerns the use to which the known devices are put . still , another aspect of the present invention involves the new tensioning structures disclosed herein . in any case , fig5 b , illustrates an aspect of the invention involving the helical placement of the tensioning structures as the units spiral around the whole of the heart muscle ( not just a surface patch ) in support of the underlying spiraling myocardial fibers 224 as illustrated in fig2 d . in this regard , support structures 4 on the opposite side of the heart from that facing the viewer are indicated in dashed line . further details as to the helical placement of support structures is provided below . before such discussion , however , some treatment is given to the manner in which the devices can be emplaced . delivery systems can be used to deploy the cardiac support structures via a thoracotomy , thoracostomy , sub - xiphoid access 228 , median sternotomy or other surgical access . in this manner , a deployment system 230 can access the heart along the epicardium ( or endocardium ) and position the cardiac support structures 4 at the desired locations in / on the heart . the delivery systems can be used to insert the anchors 32 ( e . g ., the embodiment shown in fig3 c ) of the cardiac support structures 4 into or through myocardium 34 where they engage the myocardium , the epicardium , or the endocardium and tensile members 84 to attach the cardiac support structures to the heart . once the anchors are positioned , the tensile members 84 such as those shown in fig3 a and 3b can be arranged to provide the desired reinforcement and / or repositioning clinical outcomes . fig3 d and 3e show the engagement of the openings in the tensile members shown in fig3 a and 3b to the anchor shown in fig3 c . once the opening of the tensile member is placed over the end of the anchor , the anchor end firmly locks to the tensile member securing the tensile member to the anchor . as shown in fig3 f to 3 h , tensile members can be connected to anchors at the ends of the tensile members , at the mid - region of the tensile members , or anywhere where a suitable anchoring opening is located . fig6 a to 6 d show a delivery system 230 capable of simultaneously and / or independently inserting components of a cardiac support structure 4 through or into myocardium via a sub - xiphoid 228 surgical approach . the discussion for this embodiment is described from a surgical approach initially inserting anchors for the cardiac support structures through the epicardium 68 to access the myocardium 34 ; although it should be noted that a catheter - based approach can be utilized with these embodiments if modified for percutaneous access and fluoroscopic visualization requirements facilitating insertion of the cardiac support structures either through the endocardial surface to access to or through the myocardium . one embodiment of the cardiac support structure deployment system of the invention is provided as step - by - step illustrations showing initial delivery and positioning , followed by release and secured anchoring of the device upon the heart at the operator chosen anatomical locations in fig6 a to 6 d . the delivery system embodiment shown in fig6 a to 6 d involves a sheath capable of compressing the components ( anchors and / or tensile members ) of the cardiac support structure into a sufficiently low profile for placement typically through a trocar . the delivery system embodiment in fig6 a and 6b also shows the components of the cardiac support structure compressed into a low profile inside a sheath having sufficient radial strength and column strength to straighten the tensioning structure 84 of support structure 4 . to facilitate deployment , a stylette ( not shown ) may be positioned within the sheath to engages the free end of the anchor and / or tensile member 84 of the cardiac support structure . an operator advances or retracts the anchor and / or tensile member 84 as the stylette is advanced or retracted from a proximal end of the deployment device . fig6 e and 7 show perspective views of two 3 - dimensional , helical , cinching , cardiac support structure 4 embodiments that utilize anchors 32 at each end of tensile members 84 to define the support structures 4 . the tensile members 84 are anchored into a helical pattern from the atrial - ventricular groove 178 towards the apex 242 . the cardiac support structure 4 embodiments in fig6 e and 7 are positioned along the epicardium of the left ventricle and extend from the anterior surface to the posterior surface of the heart . once positioned , the tensile members compress the heart wall into a helical orientation thereby maintaining or restoring the normal , helical pattern of the myocardial fibers . note that with the anchor 32 / tensile member 84 embodiment of the invention , the cardiac support structures constructed can be configured into any pattern as determined by the operator during the implant procedure . one pattern is the desired helical pattern partially or substantially around the anterior and posterior surfaces of the left ventricle 18 ; others include partially or completely around the left and right ventricles ( 18 and 24 ), along the left ventricle 18 from the anterior surface to the posterior surface along the ventricular septum 244 and back to the anterior surface , or other configuration . in any case , the pattern will generally be one that follows or coordinates with the directionality of underlying heart muscle fiber orientation . during deployment of tensile members whose anchoring mechanism involves inserting a loop of the cardiac support structure 4 through myocardium 34 ( as shown in fig8 , and 10 a ), each free end of the tensile member 84 may be placed through a holder of a puncturing device where the puncturing device ( s ) are compressed inside a deployment sheath . in a minimally invasive surgical approach , it is preferred that the two puncturing devices are placed in contact with the epicardial surface ( or alternatively can be placed into contact with the endocardial surface for catheter - based or open surgical procedures ). the puncturing devices may be designed to penetrate the epicardium with sharpened or beveled tips at spaced apart intervals . prior to inserting the puncturing devices , the tensile member can be placed through a pledget or other atraumatic surface ( e . g ., an eptfe patch , polyester patch , other synthetic patch , a piece of pericardium , muscle or other tissue ) to provide additional support at the anchor and to also provide additional strain relief to the underlying tissue once the tensile member is tightened . the puncturing devices are then typically advanced through the deployment sheath at which time they expand toward their preformed configuration channeling through myocardium to define a space for the tensile member to pass . alternatively , the puncturing devices can pass the tensile member 84 from the epicardial surface through the myocardium , past the endocardium , along the endocardium , and back to the epicardium . once the puncturing devices have advanced the ends of the tensile member through the heart wall and back past the epicardium , the ends of the tensile member will then be removed from the holder and the puncturing device is subsequently removed from the heart . the free ends of the tensile member are then tied or otherwise secured together thereby tightening and compressing a region of the heart wall . again , prior to tightening the free ends of the tensile member , they can also be inserted through pledgets or other atraumatic structure to provide additional support and strain relief at the tissue puncture sites . for a more detailed description of the applicable procedure , including illustrations applicable to the noted hardware , reference is again made to co - pending u . s . patent application no . 2003 / 0078465 , entitled , “ systems for heart treatment ,” to pai et al . incorporated herein by reference . fig8 , 10 a , and 10 b show perspective views of hearts with cardiac support structures 4 placed through the myocardium 34 in helical patterns . in fig8 , and 10 a , the solid lines demarcate the cardiac support structure located along the anterior surface of the heart , while broken lines demarcate the cardiac support structure looped into the myocardium and positioned along the posterior surface of the heart — both hidden from view . as shown , these cardiac support structure 4 embodiments pass through the myocardium along two spaced apart lines thereby producing a 3 - dimensional helical cinching tensioning structure mechanism 4 capable of tightening / compressing the heart wall to urge or restore the helical myocardial fiber orientation . the tension applied to the heart by the cardiac support structures can be adjusted as required to alter the helical orientation of the myocardial fibers and impact wall motion . the helical pattern around the heart may be defined substantially only upon its surface as shown in fig8 and 9 . in the alternative , the helical pattern may pass or carry through the heart to more selectively support a section of the heart such as the left ventricle as illustrated in fig1 a and 10b . it is additionally noted that the cardiac support structures can be oriented at or along other helical profiles relative to the heart thereby defining different tensioning patterns . the array of cardiac support structures previously discussed in reference to fig5 b illustrate one such alternative deployment system according to the present invention . in the embodiments of the invention in fig8 , 10 a and 10 b , a single tensile member 84 is shown deployed through the myocardium to define the support structure . in contrast , multiple cardiac support structures are positioned through heart tissue to produce a helical pattern in fig5 b to reposition the myocardial fibers into a helical pattern and restore a more optimal pattern of myocardial fiber contraction . in any case , the cardiac support structures 4 of the invention can be positioned about the ventricles and anchored through or into myocardium so as to reposition previously relaxed , damaged or stretched myocardial fibers and restore their helical orientation . restoring the helical myofibril orientation aids cardiac output by increasing the left ventricular ejection fraction and wall motion throughout the heart thereby improving efficiency and reducing the effects of congestive heart failure aiding the process of reverse remodeling . fig1 a and 11b shows a representative three - dimensional , cinching , cardiac support structure 4 capable of repositioning and compressing the chordae tendonae 110 and / or the papillary muscles 174 . these approaches may be employed in connection with the helical placement of support structures described above , on in isolation . a combined technique may be desire for many patients . also , it should be appreciated that the teaching regarding papillary muscle repositioning taught in “ systems for heart treatment ,” ( 2003 / 0078465 ) incorporated herein by reference and discussed above may be employed in connection with the additional teaching set forth herein . in any case , according to the present invention , the papillary muscles may be prefentially repositioned relative to each other if these structures have migrated laterally due ventricular dilatation . any pattern of cardiac support structures 4 can be used to provide the desired recovery or reverse remodeling response where the cardiac support structures extend between papillary muscles 174 . by compressing the papillary muscles 174 together along the lateral free wall of the heart ( or alternatively along the septal wall , not shown ) the orientation of the valve leaflets and the chordae tendonae 110 are influenced . by reducing tension on the chordae tendonae 110 and valve leaflets exerted by over - stretched papillary muscles 174 , valve leaflet apposition is improved thereby reducing mitral regurgitation and aiding reverse remodeling . the flexibility of the cardiac support structures 4 enable the physician to custom tailor the treatment options to the patient after careful analysis of the valve competency , ventricular wall motion , ejection fraction , and other diagnostic parameters . the free ends of these three - dimensional , cinching , tensioning structures 4 can be tied together permanently or secured to a mechanism capable of twisting the knotted regions or otherwise manipulating the free ends to adjust or tighten the tensioning structures 4 intraoperatively , during a follow - up procedure , or remotely post procedure . again , these adjustments can facilitate chronic maintenance of positive hemodynamic conditions . fig1 a and 12b show alternative three - dimensional , cinching , cardiac support structure patterns 4 incorporating multiple tensile members 84 and anchors 32 to reposition the papillary muscles 174 relative to each other . in these cardiac support structure embodiments , the tightening force is distributed at more than one location ( i . e ., the insertion and knotted sites ) thereby ensuring that a long , tightening structure will be capable of compressing tissue between the ends of the three - dimensional , cinching , tensioning structure 4 and repositioning the papillary muscles 174 closer together radially . in fig1 a and 13b , three - dimensional , cinching , cardiac support structures 4 are positioned and secured from the papillary muscles 174 to the atrial - ventricular groove 178 at the base of the heart . these cardiac support structure patterns reposition the papillary muscles 174 relative to the mitral valve annulus 108 thereby reducing tension placed on the chordae tendonae 110 and thereby reposition the valve leaflets for better apposition in order to reduce or eliminate mitral regurgitation . fig1 shows a three - dimensional , cinching , cardiac support structure that repositions the apex 242 of the heart relative to the papillary muscles 174 . such cardiac support structure patterns reshape the apex of the heart relative to the papillary muscles 174 reinforcing the apical region of the heart and preventing excess wall tension from enlarging the apex 242 and also maintains the optimal location of the subvalvular apparati thereby also reducing or eliminating mitral regurgitation . fig1 shows a heart with multiple , independent three - dimensional , cinching , cardiac support structures 4 strategically positioned and secured between the papillary muscles 174 and other heart regions to reposition the papillary muscles 174 and reinforce the heart . in this embodiment , cardiac support structures are positioned between papillary muscles 174 , from the papillary muscles 174 to the atrial - ventricular groove 178 at the base of the heart 186 , and from the papillary muscles 174 to the apex 242 . this configuration repositions the valve leaflets into more proximate apposition and reinforce the heart wall to encourage reverse remodeling . fig1 a shows a cardiac support structure 4 that incorporates multi - site pacing capabilities integrated into the cardiac support structure . as shown in fig1 b a set of two discrete wires are wound into spaced apart helical electrodes 232 . generally , wires fabricated from stainless steel , spring steel , titanium , titanium alloys , or other alloy may be wound in sections into one or more helices . the helical section ( s ) advantageously operate as spring member ( s ) as well as electrode ( s ). a covering 234 encapsulates the wires and electrode ( s ) 232 exposing the electrode ( s ) through windows opposite at least a portion of the electrodes in the covering . covering 234 ( e . g ., urethane , polyurethane , silicone , or other implantable polymer ) may be extruded , injection molded , or dipped around the wire ( s ) such that discrete regions of the wires are exposed to define the electrode ( s ). alternatively , laser cutting , chemical etching , or other removal process may be used to cut regions of covering to expose the electrode ( s ). the embodiment shown in fig1 a and 16b shows two discrete signal wires defining multiple electrodes 232 in the integrated cardiac support structure 4 to enable pacing ( or electrogram recording ) in bipolar mode between adjacent electrode pairs . fig1 c shows the cardiac support structure 4 with integrated multi - site pacing positioned and secured to the heart 186 in a helical pattern around the heart 186 thereby restoring the more physiologic myocardial fiber orientation and enabling pacing of the heart 186 at multiple sites along the heart 186 facilitating a patient specific , positive , inotropic response as required . the embodiment in fig1 c connects one signal wire thus the associated electrodes to the positive terminal on the implantable pacemaker 236 and the other signal wire to the negative terminal on the implantable pacemaker 236 . in other embodiments ( not shown ) where a single wire is used to define discrete electrodes , the pacing can be applied in unipolar mode from the electrodes to another reference electrode ( e . g ., the conductive cam of the pacemaker 236 or another electrode positioned within the body ). it should be noted that any combination of signal wire numbers , electrode numbers , electrode lengths , electrode diameters , and connection schemes can be used to tailor the integrated multi - site pacing lead and heart compression / reinforcement mechanism . indeed , the synergistic combination of multi - site pacing and cardiac reinforcement offered by the subject structure ( especially when configured for helical application to the heart ) with an integrated support structure takes advantage of the benefits in contractility demonstrated with multi - site pacing adapted to the patient &# 39 ; s specific needs and the mechanical compressing and reverse remodeling observed with tension reduction and volume reduction . fig1 and 18 show alternative embodiments of cardiac support structures integrating multi - site pacing capabilities . in fig1 , separate cardiac support structures with integrated electrodes are placed in helical patterns spaced apart . opposing structures are connected to either positive or negative terminals of the pacemaker 236 to induce a pacing pulse from electrodes on one structure to the electrodes on the adjacent structure . in fig1 , a single cardiac support structure integrating electrodes is wound around the heart 186 in a helical pattern and connected to a pacemaker that incorporates a cam electrode or is connected to a separate reference electrode ( not shown ) positioned in the body for the opposing terminal . fig1 a to 19 d show a cardiac support structure embodiment tension element 84 ( such as illustrated in fig3 a and 3b ) that can be caused to actively expand and / or compress in response to an energy source 238 such as through resistive heating ( e . g ., when using thermoelastic shape memory alloy materials ) or via applied potential / current ( e . g ., when using piezoelectric materials or electroactive polymers ). such active cardiac support structures could be arranged to work in synchrony with the requirements of the heart &# 39 ; s a - v node , an implantable pacemaker 236 or any prescribed or desired requirement as driven by an energy source 238 specifically designed to work with the structure . in any case , fig1 c and 19d show tensile member 84 in compressed and expanded states , respectively , with such action is driven by energy source 238 . as with cardiac support structures 4 employing multi - site pacing capabilities , the synergistic combination of active compression and cardiac reinforcement with an integrated support structures can be configured to provide a patient - specific active contractile assistance during systole while simultaneously providing the benefit of reverse remodeling observed with tension reduction and volume reduction . the structures can be configured to provide active contraction in synchrony with a pacemaker or similar controller to provide contraction as determined by the pacemaker circuitry algorithm or on demand as required . the various embodiments of the invention will generally be fabricated from various biological , metallic , and / or polymeric materials as typically employed by those with skill in the art . certain cardiac support structures comprise tensile members 84 ( e . g ., tube , ribbon , strand , or wire , which can limit elongation with satisfactory elasticity based upon the selection of material properties and cross sectional area ) incorporating at least one stress distribution feature such that the tensioning structure 4 can apply tension against tissue without damaging the contacted tissue regions . a variety of materials can be used as the tensile member 84 of the tensioning structure 4 , including ptfe , expanded ptfe , nylon , silicone , urethane derivatives , polyurethane , polypropylene , pet , polyester , superelastic materials ( e . g ., nickel titanium alloy ), other alloys ( e . g ., stainless steel , titanium alloy etc . ), metal ( e . g ., titanium ), biological materials ( e . g ., strips of pericardium , collagen , elastin , vascular tissue such as a saphenous vein or radial artery , tendons , ligaments , skeletal muscle , submucosal tissue etc .) other alternate materials having the desired properties , or a combination of these and other materials . the performance of the cardiac support structure will depend upon and can be tailored to the desired features . for example , when column strength is required , superelastic materials or other alloys or metals are preferred tensile member bodies 84 of the tensioning structure 4 . when pure tension is required and the cardiac support structure is to be deployed through tortuous access points , more flexible materials such as expanded ptfe , polyester , or other suture type materials may be preferred as tensile members . when absorption or biological integration is desired over a period of time , biological materials such as strips of pericardium or collagen , or absorbable materials are preferred . in instances where anchor members 32 are secured to one or more tensile member ( s ) 84 , the anchors may be fabricated from biocompatible materials commonly used in medical implants including nickel titanium ( especially , for self - expanding or thermally - actuated anchors ), deformable stainless steel ( especially for balloon - expanded anchors ), spring stainless steel , or other metals and alloys capable of being deformed using balloon catheters or other expansive means , or self - expanded to secure the tensioning structure 4 to the vasculature , myocardium , or other tissue . alternatively , the anchors 32 can be fabricated from superelastic polymers , flexible or deformable polymers such as urethane , expanded ptfe , or stiff materials such as fep , polycarbonate , etc . for self - expanding components of the embodiments ( e . g ., some tensile member embodiments ), those components are preferably fabricated from a superelastic , shape memory material like nitinol ( nickel titanium alloy ). these types of materials elastically deform upon exposure to an external force and return to their preformed shape upon reduction or removal of the external force . superelastic shape memory alloys enable straining of the material numerous times without plastic deformation . the repetitive strain capability facilitates a limited systolic stretch to enable adequate cardiac output while limiting or restricting the possibility of over stretch and continuation of the cyclic damage . various components of the cardiac support structures can be fabricated from shape memory alloys ( e . g ., nickel titanium ) demonstrating stress - induced martensite at ambient temperature . other shape memory alloys can be used and the superelastic material can alternatively exhibit austenite properties at ambient temperature . the composition of the shape memory alloy is preferably chosen to produce the finish and start martensite transformation temperatures ( mf and ms ) and the start and finish austenite transformation temperatures ( as and af ) depending on the desired material response . when fabricating shape memory alloys that exhibit stress induced martensite the material composition is chosen such that the maximum temperature that the material exhibits stress - induced martensite properties ( md ) is greater than af and the range of temperatures between af and md covers the range of ambient temperatures to which the support members are exposed . when fabricating shape memory alloys that exhibit austenite properties and do not transform to martensite in response to stress , the material composition is chosen such that both af and md are less than the range of temperatures to which the supports are exposed . of course , af and md can be chosen at any temperatures provided the shape memory alloy exhibits superelastic properties throughout the temperature range to which they are exposed . by way of example , nickel titanium alloy having an atomic ratio of 51 . 2 % ni to 48 . 8 % ti exhibits an af of approximately − 20 ° c . ; nickel titanium having an atomic ratio of 50 % ni to 50 % ti exhibits an af of approximately 10 ° c . melzer a , pelton a . superelastic shape - memory technology of nitinol in medicine . min invas ther & amp ; allied technol . 2000 : 9 ( 2 ) 59 - 60 . such superelastic components are able to withstand strain as high as about 8 to 10 % without plastically deforming . materials other than superelastic shape memory alloys can replace superelastic materials in appropriate cardiac support structure components provided they can be elastically deformed within the temperature , stress , and strain parameters required to maximize the elastic restoring force , thereby enabling the tensioning structures 4 to exert a directional force in response to an induced deflection . such materials include other shape memory alloys , bulk metallic glasses , amorphous beryllium , suitable ceramic compositions , spring stainless steel 17 - 7 , elgiloy ™ and related alloys , superelastic polymers , etc . the tensile members of various force transfer structure embodiments can be fabricated from at least one rod , wire , suture , strand , strip , band , bar , tube , sheet , ribbon or other such raw material having the desired pattern , cross sectional profile , dimensions , or a combination of cross - sections . these raw materials can be formed from various standard means including but not limited to : extrusion , injection molding , press - forging , rotary forging , bar rolling , sheet rolling , cold drawing , cold rolling , using multiple cold working and annealing steps , or casting . when using superelastic materials or other alloys as the tensile members , they can be cut into the desired pattern and thermally formed into the desired three - dimensional geometric form . the tensile members can then be cut into the desired length , pattern or other geometric form using various means including , but not limited to , conventional abrasive sawing , water jet cutting , laser cutting , edm machining , photochemical etching or other etching techniques . the addition of holes , slots , notches and other cut away areas on the support structure body facilitates the capability to tailor the stiffness of the implant . the tensile members , especially those that employ the use of tubular or wire raw materials , can also be further modified via centerless grinding means to enable tensile members that are tapered ( i . e ., have a cross - sectional diameter on the proximal end of the structure that progressively ramps down to a smaller cross - section on the opposite or distal end ). when fabricating superelastic tensile members from tubing , the raw material can have an oval , circular , rectangular , square , trapezoidal , or other cross - sectional geometry capable of being cut into the desired pattern . after cutting the desired pattern , the tensile members are formed into the desired shape , heated , for example , between 300 ° c . and 600 ° c ., and allowed to cool in the preformed geometry to set the shape of the tensile members . when fabricating superelastic tensile members from flat sheets of raw material , the raw material can be configured with at least one width , w , and at least one wall thickness , t , throughout the raw material . as such , the raw sheet material can have a consistent wall thickness , a tapered thickness , or sections of varying thickness . the raw material is then cut into the desired pattern , and thermally shaped into the desired three - dimensional geometry . opposite ends or intersections of thermally formed tensile members can be secured by using shrink tubing , applying adhesives , welding , soldering , mechanically engaging , utilizing another bonding means or a combination of these bonding methods . opposite ends of the thermally formed tensile members can alternatively be free - floating to permit increased flexibility . once superelastic tensile members are fabricated and formed into the desired three - dimensional geometry , the supports can be electropolished , tumbled , sand blasted , chemically etched , ground , or otherwise treated to remove any edges and / or produce a smooth surface . the previous discussions provide description of minimally invasive , cardiac support structures used to treat degenerative heart disease in patients suffering any stage of congestive heart failure . in addition , the described inventions provide methods and devices to provide restriction of continued enlargement of the heart , potentially progressively reducing heart size via reverse remodeling ( i . e ., application of compressive force during both systole and diastole ), improving atrial pump synchrony and efficiency thereby mitigating the morbidity and mortality effects of atrial fibrillation and finally decreasing valvular regurgitation associated with said enlargement . however , those skilled in the art should appreciate that at least certain ones of the structures described herein can be applied across a broad spectrum of organ structures to provide reinforcement and to limit enlargement facilitated by compensatory physiologic mechanisms . accordingly , the invention is not to be limited to the uses noted or by way of the exemplary description provided herein . numerous modifications and / or additions to the above - described embodiments may be applied ; it is intended that the scope of the present inventions extend to all such modifications and / or additions . the breadth of the present invention is to be limited only by the literal or equitable scope of the following claims . that being said , | US-99036104-A |
a blood vessel wall - defining device for repairing an abdominal aneurysm . the device comprises a percutaneously - insertable structural frame extending between first and second ends having an unexpanded diameter which is smaller than the diameter of the blood vessel to permit the structural frame to be placed into the blood vessel . the structural frame being expansible to form a cylindrical structural skeleton having a slightly larger diameter than the blood vessel to facilitate the securing of the skeleton in position in the blood vessel . the skeleton has a sheath of a tubular fabric . the said structural frame has a plurality of spaced coiled stents prior to expansion which are uncoiled under the aegis of a balloon catheter and locked into position by ratchet means . | attention is now directed to fig1 for a general view of the stent 10 of the present invention which is designed to be fitted into the abdominal aorta artery 11 in the area bordered at the top by the left renal artery 12 and the right renal artery 13 . at the bottom , it is defined by the bifurcated left iliac artery 14 and the right iliac artery 15 . the left and right renal arteries supply blood to the left kidney 16 and right kidney 17 , respectively . the abdominal aorta 11 may have an aneurysm or a ballooning out that may take various forms ; suffice it to say that it is an outcropping of the wall of the aorta 11 resulting in a considerable weakening of the aorta which may lead to a rupture . such weakening will have little or no affect on the patient until it actually bursts and may not be known to exist . sonograms can detect the aberration in wall disfiguration and outcropping . fig1 shows an expanding aorta . upon the bursting of the aorta &# 39 ; s wall , the patient will bleed internally often to a point of death . the stent shown in fig1 is fabricated of a skeleton of elongated flexible metal rods 20 which are shown to be eight in number . it is contemplated that the number of rods may be greater or lesser in number , eight is preferred which are equidistant from each other when positioned . the metal rods 20 are secured to a sheath 21 of fabric material which may elongatedly extend the entire length of the device or may terminate so that there is an open portion 22 while the rods 20 extend for an additional distance . the area unencumbered by the sheath provides fluid access between the rods so that branches off the abdominal aorta are supplied with blood . internally of the tube and rods is a series of ring stents 25 . these ring stents are coiled prior to percutaneous insertion and are uncoiled under the aegis of a balloon carried by a catheter in one embodiment or , in another embodiment , automatically when a retaining pin is retracted from the ring stents and the latter are constructed of coiled metal having spring qualities . [ 0042 ] fig2 is a fragmentary view showing a diagrammatic view of the sheath 21 in an expanded condition with rods 20 . the expansion is achieved by uncoiling ring stents 25 in either of the embodiments , both of which are shown in fig2 . a catheter 31 is shown in a fragmentary fashion which is the carrying means for the implantation of the device . the fig2 shows only a few of the ring stents 25 which are in a coiled position again . the ring stents are provided with a locking means which includes an elongated retractable pin 32 which is withdrawn from its locking position when the device 10 of the present invention is in place whereby the stent springs open , as stated , under its own accord when the stent is constructed of a material that has a spring memory whereby to assume an uncoiled configuration . when the ring stent , in the other embodiment , does not posses spring qualities , the unfurling must be assisted by means of a balloon in the catheter 31 . to accomplish this the catheter 31 has an elongated balloon 33 which is conventional to a balloon catheter and is normally employed to open a blocked artery . in this instance it is detailed to assist to unfurl the ring stent 25 and thereby the stent 10 of the present invention by inflating the balloon 33 to a desired position . [ 0044 ] fig3 shows a cross - section of the stent 10 of the present invention in a conventional tubular member 35 prior to percutaneous disposition in aorta being afflicted by an aneurysm . note therein the folded - up sheath tube 21 and the coiled ring stent 25 . the latter has a conventional plural ratchet locking means 34 for locking the ring stent 25 at selected positions in the progressively uncoiled position once the ring stent 25 has been expanded by balloon 33 supplied in a catheter 31 . in fig4 one can view the cross - sectional view similar to that shown by fig3 where the balloon 33 has uncoiled the ring stent 25 to its fullest position which is to the point of locking the ratchet lock or locks 34 as depicted . the ring stent in turn abuts outwardly radially against the sheath or fabric tube 21 with the attendant metal rods 20 . attention is now directed to fig5 which depicts another embodiment of the abdominal aortic stent system and shows the disposition thereof . a special single rod 20 a of the rods 20 carries a plurality of ring stents 25 in a fixed spaced relationship . each of the ring stents 25 has a compressible loop 25 a through which the rod 20 a is positioned . securement is accomplished by compressing the loop 25 a about the rod 20 a . it is contemplated that a suitable adhesive may accomplish the securing of the said rod 20 a to the ring stent 25 . as in one of the foregoing embodiments the insertable balloon catheter 31 has an attachment 36 adapted and constructed to slide along an elongated slide rail 32 a which has a distal attachment stop means 30 which is attached to the distal end portion of the rod 20 a and , as stated , to which the ring stents 25 are attached . another attachment means 37 is secured to the rod 20 a to which the ring stents 25 are attached at its proximate end portion and radially to the slide rail 32 a . the catheter , surrounded by a conventional tubular member 35 , is used to move the unfurled and undisposed stent 10 through the to - be treated aorta to a position opposite the aortic lesion . when properly positioned , the tubular member 35 is withdrawn . then the slide pin 32 is withdrawn from the stent 25 and the lead ring stent 25 . after all of the ring stents 25 have been permitted to uncoil and held in their respective places by retaining means , pin 32 is withdrawn from its attachment means 24 and removed with the catheter . it is contemplated that the catheter retracts from ring stent to ring stent . in the case of employing ring stents that do not unfurl of their own accord , a balloon catheter is employed in a known manner . the balloon 33 is inflated to uncoil the lead ring stent 25 , that is , as stated afore , when the stent is constructed of a material that wants to stay coiled and must be locked open to a position of abutment against the sheath 21 and in turn against the inner wall of the aorta . the lead ring stent remains locked open by the ratchets ; the balloon 33 may be then deflated . the balloon catheter is withdrawn sliding along a guide rail 32 a which acts as a guide for the balloon catheter so that the balloon can be reinflated at the next ring stent . in some embodiments it may be desirable to employ a balloon that has a suitable dimension that encompasses more than one ring stent 25 at a time . the sheath 21 is attached to the rods 20 or ribs as discussed heretofore . of course provision must be made for openings in the sheath 21 whereby the said loops 25 a of the individual ring stents 25 may protrude therethrough . one may construct various standardized sizes of the structural skeleton and thin walled flexible tubular member 35 for packaging into kits for use in the present invention . the devices 10 , as stated , may be preinstalled in the distal ends of respective catheters and may be injected by pusher devices similar to those employed to eject vena cava filters and the like . as stated , devices 10 are constrained by a tubular member 35 , which may be a known delivery sleeve . the distal ends of the rods 20 are rounded to hinder any undue abrasion against the aorta . various other modifications of the invention , within the spirit thereof and the scope of the claims , will occur to those skilled in the art . | US-615801-A |
a hitch mechanism for coupling an implement to a utility vehicle includes a coupling frame and six variable length links . the frame has couplers for coupling to the implement . each link has a first end coupled to the vehicle and a second end coupled to the coupling frame . the links are preferably arranged in the form of a hexapod , so that , in addition to the functions of known three - point hitches , the implement may be steered sideways or shifted sideways , and so that the motion of the coupling frame has six degrees of freedom . | referring to fig1 a front hitch 12 and a rear hitch 14 are mounted on an agricultural tractor 10 . the rear hitch 14 includes six variable length links 18 , 20 , 22 , 24 , 26 and 28 , and a frame 30 to which an implement 16 is coupled . details of the hitch mechanisms are shown in fig2 wherein the same or corresponding components are identified by the same reference numbers . preferably , the coupling frame 30 has a generally triangular shape . implement couplers , for the attachment of an implement , are mounted on the frame 30 , for example , in the region of its corners . a variety of known coupling means are available for selection . each link has a first end which is connected to the vehicle body 32 , for example , to the differential housing or to the vehicle frame . each link has a second end which is connected to the coupling frame 30 . the first ends of the links 18 - 28 are coupled in three pairs to a position near the corner points 34 , 36 , 38 of a vehicle - side triangle . one of these corner points 34 is located at a low level and in the center relative to the transverse direction of the vehicle . the corner points 36 , 38 are located together at the same elevation , above the low corner point 34 , and are arranged symmetrically about the transverse direction of the vehicle . the second ends of the links 18 - 28 are coupled in three different pairs to a position near the corner points 40 , 42 , 44 of a triangular - shaped frame 30 . one of these corner points 40 is located at a high elevation while the corner points 42 , 44 are located at the same elevation and below the high level corner point 40 . adjacent pairs of the links generally form a triangle or a closed chain . with such a hitch , all functions , among others , of a conventional three - point implement hitch can be provided . the triangles formed the link first ends and by the frame 30 may be equilateral triangles or isosceles triangles . isosceles triangles that extend relatively far in the vertical direction may be advantageous if particularly large vertical forces must be absorbed by the hitch . a first link 18 has one end connected in the vicinity of the low level vehicle - side corner point 34 and has its other end connected near corner point 42 . a second link 20 has one end connected near the low level vehicle - side corner point 34 and has its other end connected near corner point 44 . a third link 22 has one end connected near corner point 36 and has an other end connected near corner point 44 . a fourth link 24 has one end connected near corner point 36 and has an other end connected near corner point 40 . a fifth link 26 has one end connected near corner point 38 and has an other end connected near corner point 40 . a sixth link 28 has one end connected near corner point 38 and has an other end connected near corner point 42 . the links 18 - 28 are arranged so that adjacent pairs of links form , together with a portion of the vehicle - side triangle or with a portion of frame 30 , triangles . the vehicle - side corners 34 , 36 , 38 and the frame 30 both form triangles which are similar to each other , but which are rotationally shifted 180 degrees with respect to each other . the triangle formed by corners 34 - 38 is somewhat smaller than the triangle formed by frame 30 , so that pairs of the links have axis which converge in a forward direction of the tractor 10 . for example , the axis of links 26 and 20 converge at a point on a transverse horizontal line f . the axis of links 24 and 18 converge at a point on the horizontal line f which is spaced apart from the convergence point of links 20 and 26 . as best seen in fig1 line f is positioned forward of the hitch 14 and is forward of the rear wheel of tractor 10 and slightly rearward of the front wheel . furthermore , by changing the lengths of all or different combinations of the links 18 - 28 , the location of line f can be shifted vertically or in the fore - and - aft direction of the vehicle , and the location of the convergence points can be shifted . thus , it is possible to vary the effect on the rear axle of the load transmitted from an implement to the vehicle 10 . the vertical orientation of the coupling frame 30 can be maintained during the lifting and lowering of the implement 16 . this is particularly advantageous during ground breaking operations using power take - off shafts , since during the lifting and lowering of the implement the orientation of the vehicle - side power take - off shaft 46 and the orientation of the implement - side power take - off shaft 48 can be maintained , so that the angular velocity of the power take - off shaft does not change as a result of the lifting movement . the variable length links 18 - 28 are , for example , double - acting hydraulic cylinders or electromechanical repositioning elements . the links 18 - 28 are preferably connected via ball joints or universal joints so that they are free to pivot in all directions relative to the vehicle body 32 and to the coupling frame 30 . if the cylinders 22 and 28 are allowed to move freely , then the hitch can freely move ( float ) in response to forces acting on the hitch . if the links 18 , 20 , 24 , 26 are not allowed to float , then lateral movement of the hitch would be prevented and the hitch can move only in an up - and - down direction . as best seen in fig2 the coupling frame 30 has three legs which form a closed triangle . the six links 18 - 28 are coupled to locations near the corners of the frame 30 . upwardly opening hooks 52 , 54 , 56 are mounted on the side of frame 30 facing away from the vehicle , near its corner points . implements may be attached to these hooks . alternatively , or in addition , other coupling devices ( not shown ), as well as supply and measurement connections ( not shown ), can be mounted on the frame 30 . alternatively , in place of the closed frame of fig2 a so - called single - phase coupler ( not shown ) could also be used , that is , a coupler with two legs in the shape of an inverted v , such as with the lower leg of the frame 30 omitted . a correspondingly configured part of the frame of the implement can be hooked onto such a single - phase coupler and , if necessary , locked to it , thus stabilizing the legs of the v . with such a coupler , attachment hooks , as shown in fig2 can be omitted . a control system ( not shown ) may be provided for generating control signals for controlling the length of the links and calculating necessary lengths of the links on the basis of target value inputs , such as target values provided as inputs by an operator . alternatively , target values can be pre - set by an overriding control system , such as a positioning control system . while the present invention has been described in conjunction with a specific embodiment , it is understood that many alternatives , modifications and variations will be apparent to those skilled in the art in light of the foregoing description . for example , in the vicinity of a corner point several spatially separated connectors could also be provided , so that the links can be hooked selectively into one of these connectors . by means of such a change in the guide point positions various different configurations can be selected and used . accordingly , this invention is intended to embrace all such alternatives , modifications and variations which fall within the spirit and scope of the appended claims . | US-68580700-A |
an oven for heating food products on a conveyor includes two chambers . a conveyor belt circulates within each chamber and between the chambers . each chamber includes a drum oriented with a vertical axis , a motor for rotating the drum about the axis , and a conveyor belt having a length helically surrounding the drum . the conveyor belt has an infeed end and outlet end . a plenum is located within the chamber along an outer extent of the chamber and is curved substantially concentrically with the drum . the plenum forms a substantially closed air pathway having an inlet at one end and an outlet at an opposite end passing air into the first chamber . a fan is arranged to circulate air within the chamber and force air into the plenum inlet , through the plenum and out of the plenum outlet . a heat exchanger is arranged in the plenum to heat the air flowing within the plenum . | while this invention is susceptible of embodiment in many different forms , there are shown in the drawings , and will be described herein in detail , specific embodiments thereof with the understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the invention to the specific embodiments illustrated . u . s . pat . nos . 5 , 850 , 781 ; 7 , 107 , 899 and 5 , 329 , 916 are all herein incorporated by reference where not inconsistent with the present disclosure . fig1 illustrates an oven 30 having a housing 32 and conveyor infeed station 34 and a conveyor discharge station 36 . products , such as chicken pieces are loaded onto the conveyor infeed station , pass through the housing 32 and are output at the conveyor discharge station 36 . the housing includes a hood 40 that can be raise by four lifting jacks 43 . the housing 32 provides outside walls that substantially enclose the oven . fig2 and 6 illustrate the oven with the housing removed for viewing underlying components . the oven comprises a first drum 44 and a second drum 48 . preferably , drums 44 , 48 are solid cylinders . a conveyor belt 54 , such as a stainless steel wire mesh belt , is a continuous belt that moves from the product infeed , and helically wraps around the first drum 44 and the second drum 48 and passes to the discharge station 36 , and over a secondary drive 60 and back to the product infeed station 34 . the secondary drive 60 maintains a tension on the belt 54 . the drums 44 , 48 are rotated by a motor drive ( not shown ) and engagement of the drums and an inside edge of the belt 54 circulates the belts helically on the drums and between the infeed station 34 and the discharge station 36 and back . as shown in fig3 and 4 , each drum and associated length of spiral conveyor is arranged in a separate cooking volume of the housing . the drum 44 and a first associated length 54 a of spiral conveyor 54 are located in a first chamber 66 and the drum 46 and a second associated length 54 b of spiral conveyor are located in a second chamber 68 . the chamber 66 is heated by at least one ventilator or fan 70 contained in a substantially enclosed fan chamber 71 . the fan 70 is driven by a motor 70 m from outside the fan chamber . the fan 70 has a rotary axis approximately radially oriented to the circumference of the drum 44 . the fan 70 draws air from chamber 66 in a substantially radial direction r into an inlet 70 a . the fan 70 is mounted to the fan chamber 71 with the inlet 70 a in registry with a fan chamber inlet opening 71 a . the fan chamber inlet 71 a is preferably a funnel or flared inlet , tapered toward the fan inlet , to reduce pressure drop . the air is forced by the fan ( s ) 70 through an outlet 71 b of the fan chamber into a curved plenum 72 that has an inner curvature that substantially conforms to the outer circumference of the spiral belt 54 a within the chamber 66 . the plenum is curved substantially concentrically with the drum 44 . the air is moved through the plenum in a tangential direction t . a curved heat exchanger 76 is located within the plenum that conforms in curvature to the curvature of the plenum 72 to maximize heat exchange surface area in the compact oven . the heat exchanger 76 is preferably comprised of tubes which are transversely oriented and which carry hot heat transfer fluid . the heat exchanger 76 can be made up of vertically aligned exchanger banks 76 a , 76 b , 76 c , as shown in fig8 . the heat transfer fluid can be heated outside the oven by a gas or oil fired source , or an electric source , or the like . heat transfer fluid is conducted to and from the heat exchanger banks 76 a , 76 b , 76 c by pipes 77 . the plenum 72 is designed to output heated air into the chamber 66 in the tangential direction t so that the air is circulated substantially around the chamber before returning the inlet of the fan 70 . preferably two fans 70 are provided at different elevations but arranged identically when viewed from above , in plan . both fans force air into the plenum 72 in the same way . the chamber 68 is heated by at least one ventilator or fan 80 contained in a substantially enclosed fan chamber 81 . the fan 80 is driven by a motor 80 m from outside the fan chamber . the fan 80 has a rotary axis approximately radially oriented to the circumference of the drum 48 . the fan 80 draws air from chamber 68 in a substantially radial direction r into an inlet 80 a . the fan 80 is mounted to the fan chamber with the inlet 80 a in registry with a fan chamber inlet 81 a . the fan chamber inlet 81 a is preferably a funnel or flared inlet , tapered toward the fan inlet , to reduce pressure drop . the air is forced by the fan ( s ) 80 through an outlet 81 b of the fan chamber into a curved plenum 82 that has an inner curvature that substantially conforms to the outer circumference of the spiral belt 54 b within the chamber 68 . the plenum is curved substantially concentrically with the drum . the air is moved through the plenum in a tangential direction t . a curved heat exchanger 86 is located within the plenum that conforms in curvature to the curvature of the plenum 82 to maximize heat exchange surface area in the compact oven . the heat exchanger 86 is preferably comprised of tubes which are transversely oriented and which carry hot heat transfer fluid . the heat exchanger 86 can be made up of vertically aligned exchanger banks 86 a , 86 b , 86 c as shown in fig8 . the heat transfer fluid can be heated outside the oven by a gas or oil fired source , or an electric source , or the like . heat transfer fluid is conducted to and from the exchanger banks 86 a , 86 b , 86 c by pipes 87 . the plenum 82 is designed to output heated air into the chamber 68 in the tangential direction t so that the air is circulated substantially around the chamber before returning the inlet of the fan 80 . preferably two fans 80 are provided at different elevations but arranged identically when viewed from above , in plan . both fans force air into the plenum 82 in the same way . the drums 66 and 68 are rotated clockwise when viewed from above in fig3 . the belt 54 in the chamber 66 circulates helically up the drum 44 and the belt in the chamber 68 helically circulates helically down the drum 48 . the structure of the fans , heat exchangers and plenums are mirror image identical across a vertical center plane cp of the oven 30 . the air flow rotation direction in the chamber 66 is with the drum rotation and belt circulation direction , and the air flow rotation direction in the chamber 68 is counter to the drum rotation direction and belt circulating direction . the chambers 66 , 68 are defined by outside walls of the housing 32 and separated by inside walls 102 , 104 , 106 , 108 ( fig4 ) provided in the housing 32 . the walls 102 , 104 are curved and form side walls of the plenums 72 , 82 and extend vertically from a bottom wall of the housing to a top wall of the housing . opposite sidewalls 103 , 105 are curved and form side walls of the plenums 72 , 82 . different cooking temperatures and conditions can be maintained within the chambers 66 , 68 , for controlled cooking . products , such as chicken pieces are input into the infeed station 34 , move on the conveyor 54 up the drum 44 across to the drum 48 , down the drum 48 to the discharge station 36 . hot cooking gas , such as air is introduced into the first and second chambers 66 , 68 to cook the products while resident in the respective chambers 66 , 68 . fig7 illustrates that each chamber 66 , 68 includes an overhead cleaning manifold 202 , 204 . a pressurized water and soap mixture or solution is provided to the manifolds 202 , 204 and periodically , during a cleaning procedure , a plurality of nozzles 210 spray water and soap mixture or solution s into the respective chamber . fig8 , 10 and 11 illustrate construction of the exchangers 76 , 86 with the walls 102 , 104 removed in the figures . fig8 illustrates a further cleaning manifold 230 arranged above the exchanger 76 . a cleaning manifold 250 is arranged above the exchanger 86 and is a mirror image duplicate of the manifold 230 across the vertical center plane cp of the oven . the manifolds 230 , 250 contain a pressurized water and soap mixture or solution . the manifold 230 has a plurality of nozzles 210 for spraying water and soap mixture or solution s onto the top exchanger bank 76 a during a periodic cleaning procedure . further manifolds arranged between the banks can be used to spray water and soap mixture or solution s onto the banks 76 b and 76 c respectively . the manifold 250 has a plurality of nozzles 210 arranged to spray water and soap mixture or solution onto the top exchanger bank 86 a during a periodic cleaning procedure . further manifolds arranged between the banks can be used to spray water and soap mixture or solution onto banks 86 b and 86 c respectively . fig8 also shows an extension guide plate 260 and an adjustable spoiler plate 266 that is hinged by a plurality of hinges 270 to the extension guide plate 260 arranged between the heat exchanger 76 and the chamber 66 . the extension plate 260 and the spoiler plate 266 can be part of the respective wall 103 , 105 of an extension thereof and have a vertical length equal to the respective wall 103 , 105 . an identical extension guide plate and spoiler plate are arranged between the heat exchanger 86 and the chamber 68 , configured as a mirror image duplicate of the guide plate 260 and the adjustable spoiler plate 266 across the vertical center plane cp of the oven . the combination of the two plates 260 , 266 , with proper adjustment thereof allows for fine tuning of the air flow delivered by the fans 70 , 80 to the chambers 66 , 68 . the hinges 270 include a portion 271 fixed to the extension guide plate 260 and a portion 272 fixed to the spoiler plate 266 . the portions 271 , 272 are rotatable with respect to each other about a bolt 273 , when the bolt is loosened for adjustment of the angle between the plates 260 , 266 . one the angle is adjusted the bolt 273 is tightened which prevents any further rotation of the plates 260 , 266 . particularly , the air flows circumferentially around the respective drum 44 , 48 in the respective chambers 66 , 68 . fig1 and 11 illustrate a vertically arranged steam header 320 that is adjacent the heat exchanger banks 76 a , 76 b , 76 c . the header 320 contains pressurized steam . the header has a plurality of holes 320 a arranged spaced - apart in the vertical direction . a mirror image identical header 330 with holes 330 a is provided at the outlet of the exchanger 86 . steam under pressure is ejected from the holes 320 a , 330 a into the air stream downstream of the exchangers 76 , 86 such that a proper cooking humidity is maintained in the oven chambers 66 , 68 . the plenums 72 , 82 are mirror image identical across the vertical center plane cp of the oven . therefore , only the plenum 82 will be described in detail in fig1 . fig1 illustrates the plenum 82 . the plenum includes the curved vertical sidewalls 102 , 103 that are substantially concentric with the drum 48 . a top wall 400 substantially closes the space between the walls 102 , 103 at a top end thereof and a bottom wall 404 substantially closes the space between the walls 102 , 103 at a bottom end thereof . a fan chamber wall 408 provides at least one and preferably two outlets 81 b , 81 b for two fans 80 . although a flat wall 408 is shown in fig1 , it is beneficial to provide an expanding or funnel outlet 81 d , expanding in a direction away from the fans and toward the heat exchangers in the direction t ( fig3 ) as shown in fig7 , to minimize pressure drop . otherwise , the wall 408 closes an opening defined by the walls 102 , 103 , 400 , 404 . an outlet open face 412 defined by the walls 102 , 103 , 400 , 404 , at an end opposite the wall 408 , allows air to pass from the plenum 82 into the chamber 68 . the extension 260 , and the spoiler 266 , as an adjustable part of inside wall 103 , can be adjusted to most effectively direct forced air flow around the circumference of the drum 48 . the walls 102 , 103 , 400 , 404 form a curved rectangular tube for directing air in a curved path from the outlets 81 b , 81 b within the chamber 68 . the heat exchanger 86 is contained within the walls 102 , 103 , 400 , 404 . the walls 400 , 404 can be regions or portions of an overall housing hood and floor respectively . from the foregoing , it will be observed that numerous variations and modifications may be effected without departing from the spirit and scope of the invention . it is to be understood that no limitation with respect to the specific apparatus illustrated herein is intended or should be inferred . all references , including publications , patent applications , and patents , cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein , to the extent that the references are not inconsistent with the present disclosure . | US-201313750540-A |
an endoscope device wherein an observing optical system , illuminating optical system and channel are incorporated into respectively independent pipes which are then arranged as exposed out to form an endoscope inserting part and the above mentioned channel is formed to be of a noncircular cross - section so that , when a treating tool is inserted through the channel , a larger hollow gap may be made between the inner wall of the channel and the treating tool . | in fig3 to 5 , the reference numeral 11 represents an endoscope to be used as combined with a sheath 12 . in this endoscope 11 , an elongated inserting part 13 to be inserted into the sheath 12 is extended forward from a body part 14 on the handling side and , on the other hand , an eyepiece part 16 provided with an eyepiece part 15 is projected rearward from the outer periphery of the body part 14 . the above mentioned inserting part 13 is formed respectively independently of an optical pipe 18 provided internally with an observing opitcal system 17 transmitting an observed image to the end of the eyepiece 15 , light guide pipes 20 filled with light guides 19 for illuminating a position to be observed within a body cavity and a channel pipe 23 within which is formed a channel 22 through which a treating tool 21 is to be inserted . these pipes 18 , 20 and 23 are arranged as exposed out without being incorporated within an outer pipe . the above mentioned channel pipe 23 is formed to be of an elliptic cross - section and has the long diameter arranged horizontally . the optical system pipe 18 is arranged in the substantially central axis direction above the outer periphery of the long side of ths channel pipe 23 and the two light guide pipes 20 are arranged symmetrically above the outer periphery of the above mentioned channel pipe 23 on both sides of the optical system pipe 18 so that all the combined cross - sectional area of the channel pipe 23 , optical system pipe 18 and light pipes 20 may be compact . on the other hand , the body part 14 of the above mentioned endoscope 11 is provided on the outer periphery with a projecting light guide mouthpiece 24 for transmitting an illuminating light to the light guides 19 through a light guide cable from an external light source , is provided at the rear end with a treating tool inserting port 25 communicating with the channel 22 and is fitted with a cock 26 for opening and closing the channel 22 . this body part 14 is further provided with a sheath connecting part 27 and a cock 28 communicating with the channel 22 to feed an irrigating liquid . the sheath 12 in which the above mentioned endoscope inserting part 13 is inserted to be combined has in the rear a sheath body 29 on which are arranged an endoscope removably fitting part 30 to fit and connect the sheath connecting part 27 of the endoscope 11 to the sheath body 29 and a cock 32 communicating with the internal cavity 31 of the sheath to discharge the irrigating liquid . as the inserting part 13 is formed of the optical system pipe 18 , light guide pipes 20 and channel pipe 23 respectively independently arranged as mentioed above , such outer pipes as of the prior art examples shown in fig1 and 2 are not required , the outside diameter of the inserting part 13 can be made smaller by the thickness of various outer pipes and thus the outside diameter of the sheath 12 can be made smaller . further , as channel pipe 23 is elliptic in the cross - section , when the treating tool 21 is inserted through the channel 22 , the hollow space of the channel will be able to be taken to be large and the irrigated amount will be able to be well secured . thus , as compared with the prior art examples shown in fig1 and 2 , in case the outside diameter of the sheath 12 is set to be the same as in the prior art examples , the diameter of the channel pipe 23 will be able to be made larger at least by the thickness of the outer pipe made unnecessary , therefore the treating tool 21 of an outside diameter larger than in the prior art examples will be able to be used and the effect of the treatment will be able to be improved . in case the outside diameter of the treating tool 21 to be used is set to be the same as in the prior art example , the outside diameter of the sheath 12 will be able to be made smaller than in the prior art examples and therefore the pain to be given to the patient will be able to be reduced . further , in any of the above mentioned cases , even when the treating tool 21 is inserted through the channel 22 , the hollow space will be able to be taken to be large , therefore a sufficient irrigated amount will be secured , the visual field of the observing opitcal system 17 will not be obstructed , for example , by bleeding during the treatment and the treatment will be able to be made safely within a short time . by the way , the irrigation can be made always continuously by feeding the irrigating liquid through the channel 22 from the cock 28 communicating with the channel 22 and at the same time by discharging the irrigating liquid polluted with blood or the like through the cock communicating with the inner cavity 31 of the sheath 12 . fig6 shows the cross - section of the second embodiment of the present invention . in this embodiment , the channel pipe 23 is of a substantially semicircular cross - section and has the same effect as in the above mentioned first embodiment . though not illustrated , the channel pipe may be of an elliptic , semicircular or modified cross - section . fig7 shows an elevation of the third embodiment of the present invention . the eyepiece part 16 is arranged parallely with the inserting part 13 in the first embodiment but at an angle with the inserting part 13 in the third embodiment . by the way , this eyepiece part may be varied in the shape and arrangement . in this invention , it is apparent that working modes different in a wide range can be formed on the basis of this invention without departing from the spirit and scope of the invention . this invention is not restricted by any specific working mode except being limited by the appended claims . | US-85959186-A |
a wound dressing or therapy compress containing a fill material permanently loaded with an antimicrobial such as silver is used to cover and protect a wound while absorbing exudate , and may also provide and maintain a heated and / or a moist environment to promote the healing of wounds to promote a germ and microbial free environment approximate the shell and within the dressing or compress . | referring now to fig1 - 4 , and as best illustrated in fig1 , a dressing or compress 100 is illustrated having a lower shell 102 and a flexible upper backing 104 which are joined or otherwise fastened to one another to form a series of enclosures 106 therebetween . the enclosures are provided for the containment and relatively uniform distribution of a plurality of fill granules 108 placed therein . the enclosures may be fashioned as filled pods which are draped from the backing . the shell 102 forms the contact surface of the dressing or compress used to drape or form the bottom of the filled enclosures which are to be placed against the tissue to be treated , and to conform to the shape of the treatment area . the backing forms the smoother outer surface of the dressing or compress facing away from the treatment area . the enclosures 106 may be defined as hexagons using patterned seams 110 for local symmetry and efficient regular plane division . an illustrative hexagonal pattern 200 of enclosures 202 is illustrated in fig2 . the enclosures might also be fashioned as circles , octagons , or of any desired shape as may be appropriated for the desired treatment . the enclosures may be selectively sized as appropriate to the application . each hexagonal shaped enclosure 202 has a lengthwise dimension 204 extending from a first corner to an opposite second corner thereof . for example , and not by way of limitation , this dimension may be in the range of from approximately one inch to approximately four inches in length . large treatment areas such as the human torso or appendages may best be served with enclosures having a dimension 204 extending lengthwise for approximately 4 inches . highly contoured areas such as the face may best be served with enclosures having a dimension 204 of approximately 1 inch in length . an alternate dressing or compress 300 is illustrated in fig3 , having a plurality of hexagonal patterned enclosures 302 . each of the enclosures may also be formed as a channel - like rectangle , as illustrated in fig4 . the embodiment of the dressing or compress 400 is formed to have several channel enclosures 402 formed within a wrap compress having securing ties 404 . so constructed , the dressing or compress 400 may be provided for the treatment of soreness or strains of the human back . the size of the enclosures and overall dressing are selected to serve the desired treatment . selected single sites for treatment such as the eye may best be treated using a single enclosure dressing or compress appropriately sized and shaped to rest comfortably in the eye hollow of the human face . the dressing or compress may be shaped as a regular or irregular polygon , any smooth closed curve , or any closed combination of line segments and smooth curves . the invention is not limited to constructions conforming to or only serving the human body . the invention provides a potentially useful treatment for the ailments of mammals and any animals benefiting from the healing properties of moisture and / or heat therapy . a fluid - permeable , i . e ., a vapor - permeable and / or a liquid - permeable protective outer cover ( not illustrated ) may be provided to encompass the compress . this may be preferable to limit contamination of the dressing or compress . for the treatment of open wounds , an uncovered disposable dressing ( not illustrated ) may be preferred for optimal formable contact with , and healing of , the exposed tissues . the fill contained within the enclosure or enclosures may comprise a synthetic porous crystalline granular aluminosilicate zeolite , commonly used as a molecular sieve material , or other substances with similar properties . the fill material may further comprise other inert additives and physical matrices without affecting the antimicrobial and hydrous efficacies of the fill . silver loading of the fill may be attained by the process of ion - exchange , as known . in this process , a solution containing atomic silver or a composition of silver bathes , or is passed through , a bed of the fill granules 108 ( fig1 ). an ion - exchange column method , as known in the art , may be performed in which an aqueous solution containing atomic silver or a composition of silver may be passed through a column bed of the fill granules , and the eluted solution may again be passed through the bed or may receive additional silver and then be again passed through the bed . various ion - exchange schedules known in the art may be applied to produce retention of the silver . the final content by weight of the atomic silver or silver composition may be as high as twenty percent of the final loaded fill granules . the loaded fill granules produced by ion - exchange will exhibit high retention of the silver even under subsequent exposure to fluids and microwave irradiation . the fill granules may comprise a blend of both loaded and unloaded zeolite or a substance retaining silver . the presence of the atomic silver or silver composition will not interfere with the useful properties of the fill granules such as the moisture desorption and adsorption properties which may be desirable in the use of the dressing or compress . the inherent hydrophilic nature of the zeolite provides that a substantial water content is available therein by absorption from the atmosphere . the water so absorbed may be sufficient , or may be supplemented by manually added water , for providing the microwave responsive water content of the dressing or compress . the compositions of silver used may include but are not limited to , silver compounds , and silver salts such as silver chloride and silver nitrate . the presence of the silver within the fill granules contained in the enclosure of the invention provides anti - microbial properties to the dressing or compress . the ion - exchange loaded fill granules will retain the silver despite microwave heating as may be required in the use of the dressing or compress , which prevents the release of silver into a treated wound if the invention is used as a dressing . further , the retention of the silver within the fill granules provides assured antimicrobial performance in a reusable and potentially washable , if so desired , moist heat therapy compress . in the described embodiments of the invention , the lower shell and the upper backing are each constructed of materials known in the art . each may therefore be comprised of multilayered laminates , for example , with pore sizes selectable to meet the moisture transmission and retention properties desired for the specific treatment sought . the dressing or compress is adapted to be placed and to remain in intimate contact with the area to be treated to maintain a heated and / or moist environment thereabout . dressing or compress constructions using woven textiles of natural fibers have been found to have limited spatial conformance to the various shapes , dimples , wrinkles and joints offered by the human body , although these materials may be used if so desired . accordingly , preferred dressing or compress constructions will use formable woven and non - woven synthetic materials or combinations thereof which may include , but are not limited to , synthetic olefin , polyester , urethane , and nylon . the shell and the backing may be fastened together across the area of the dressing or compress with a fill material , the fill granules 108 , received therebetween . the shell and the backing may be fastened to one another by methods which may include , but are not limited to , adhesive attachment , rf welding , ultra - sonic attachment , sewing , or patterned heat application using a template or forming die to form a seal . to provide for the secure placement of the dressing or compress , peripheral or attachment fastening devices may be included which may comprise the desired number of velcro ®- type fasteners , adhesives , high tactility polymer materials , and / or material ties . throughout the construction of the dressing or compress , attention and care is taken in the selection of materials regarding thermal response to microwave heating . for design simplicity , all synthetic , microwave non - responsive materials may be selected to provide that the fill and / or water content of a moistened dressing or compress provide the only substantial thermal response to microwave irradiation . although several embodiments of the invention have been disclosed in the foregoing specification , it is understood by those skilled in the art that many modifications and other embodiments of the invention will come to mind to which the invention pertains , having the benefit of the teaching presented in the foregoing description and associated drawings . it is thus understood that the invention is not limited to the specific embodiments disclosed hereinabove , and that many modifications and other embodiments are intended to be included within the scope of the invention . moreover , although specific terms are employed herein , they are used only in a generic and descriptive sense , and not for the purposes of limiting the described invention . the words “ a ,” “ an ,” or “ the ” can mean one or more , depending upon the context in which the words are used hereinabove . | US-64965309-A |
disclosed is a backpack comprised of a flexible bag for containing a load to be carried and adjustable - length connection means extending across the interior of the bag and interconnecting the front and rear thereof . the volume of the bag can be adjusted to match variously - sized loads by adjusting the lengths of the connection means . | referring to fig1 - 4 , there is shown a backpack 10 in accordance with this invention comprising a flexible cloth bag for containing the major portion of a load to be packed . a pair of shoulder straps 20 and a waist belt 22 are connected to the front 16 of the bag and extend forwardly therefrom . the shoulder straps are each connected at the upper end thereof to the front of the backpack near its top and at the lower end thereof adjustably to the backpack near the bottom thereof as shown . secured to the sides 12 and top 18 of the bag are three small zippered compartments 24a , 24b and 24c useful for carrying small items of various sorts . a looped strap 28 , by which the pack can be hung up when not being worn , is secured at the top of the front of the bag and a second looped strap 30 , in which a tool such as an ice axe , fishing pole or the like can be secured , is positioned at the juncture of the back and bottom of the bag . exterior tie - down patches 31 are provided for securing gear to the back of the pack with straps ( not shown ). the sides 12 and back 14 of the bag are formed into a closed tubular shape having an opening in the upper portion of the back 14 . a zipper 26 , which may be opened from either end , extends around the sides and top of the opening . in one embodiment of this invention , ( shown best in fig3 and 4 ) the adjustable - length connection means or adjustment means comprises two straps 32a and 32b extending across the interior of the bag and interconnecting the front 16 and back 14 thereof . the straps 32a and 32b are spaced from the sides 12 , top 18 and bottom 19 of the bag and are spaced apart from one another . each strap is comprised of a first length of flexible nylon webbing 32a sewn at one end to the front 16 of the bag and a second , shorter length of nylon webbing 32b sewn at both ends to the back 14 of the bag to form a loop which passes through two metal rings 38 . the free end of the first length of webbing 32a extends through the two rings 38 and is looped back through one of them in a manner that causes the rings 38 to clamp the first length 32a when the strap is under tension and that allows the first length to slide through the rings when tension is released or when the free end of the first length is pulled . in another embodiment , a buckle may be substituted for the two rings 38 to adjustably secure the webbing at the desired location along its length , thereby defining the distance between the front and back of the pack . when the load to be carried substantially fills the bag to its capacity , the straps 32 can be tightened to compress the front 16 and back 14 of the bag tightly against the full load so as to minimize settling as the backpack 10 is agitated while being carried . when the load to be carried would only partially fill the bag if expanded to its maximum volume , the user can reduce the volume of the bag to substantially match that of the partial load by shortening the straps 32 to draw the front 16 and back 14 of the bag together . with the volume of the bag thus matched to the volume of the partial load , the center of gravity of the load will be positioned higher than it would be if the effective volume of the bag were not reduced . fig4 shows , in dotted lines , contraction of the bag from its substantially fully expanded volume to a volume matching that of a partial load contained therein . it can be seen that when the straps are tightly drawn against a load in the pack , the pack assumes a dimpled shape . the embodiments of fig5 and 6 are identical to that of fig1 - 4 except for the adjustable - length means interconnecting the front and back of the bags . in fig5 the adjustable - length connection means , comprising first and second vertically extending , partial septa 42a and 42b ( comprising strips of fabric , flexible nylon webbing , or other suitable material ), are sewn along their length to the front 16 &# 39 ; and back 14 &# 39 ; of the bag , respectively , approximately midway between the sides thereof . the partial septa 42a and 42b include eyelets 44 spaced - apart along their lengths and are interconnected by a lacing means 46 passing through the eyelets 44 . by varying the tightness of the lacing means 46 ( i . e ., the length of the connection means ), the spacing between the partial septa and hence the spacing between the front 16 &# 39 ; and back 14 &# 39 ; of the bag can be varied . the embodiment of fig5 further includes a partial compartmentalization of the interior of the backpack 10 by the septa 42a and 42b and the lacing means 46 extending therebetween . alternatively , the septa may extend completely across the bag interior to provide an interior wall substantially dividing the bag , which wall is adjustable in width by varying the tightness of the lacing means . referring now to the embodiment of fig6 the front 16 &# 34 ; and back 14 &# 34 ; of the bag are interconnected by two vertically spaced - apart cords 48a and 48b extending across the interior of the bag approximately midway between the sides thereof . one end of each cord 48a and 48b is firmly attached to the front 16 &# 34 ; of the bag and the other end passes through a hole 50 in one of two leather eyelets 52 sewn onto the back 14 &# 34 ; of the bag . the front 16 &# 34 ; and back 14 &# 34 ; of the bag can be drawn together simply by pulling on the free ends of the cords 48a and 48b and forming knots 54 ( which will not pass through the eyelets ) in the cords at locations which will maintain the desired separation between the front 16 &# 34 ; and back 14 &# 34 ; of the bag . the backpack shown herein provides adjustable - length connection means by varying the interior volume of the flexible bag by drawing a portion of the front of the pack toward a portion of the back of the pack . thus the bag can be reduced in volume in comparison to its fully expanded volume so that a load which would only partially fill the fully expanded bag , substantially fills the reduced volume of the bag . one variation of this invention provides interior separation or compartmentalization of the backpack while permitting free access to the interior and goods stowed therein . another embodiment provides exterior access to the adjustable - length connection means , eliminating the necessity of opening the pack to adjust the load . thus , convenience and usability of the pack is enhanced for loads of varying bulk and weight . other modifications and forms , such as further variations in the adjustable - length connection means and varying closure means will be apparent to one of ordinary skill in the art and are intended to be included within the scope of this invention . | US-71274176-A |
the present invention relates to a floor tool for a surface treating appliance including , a sole plate comprising a floor engaging surface having forward and rearward floor contacting edges and a suction opening , a head which is pivotable relative to the sole plate about an articulation axis between forward and rearward positions , the head having a front sole plate engaging edge and a back sole plate engaging edge , and a connecting arm comprising an outlet in communication with the suction opening , at least a portion of the floor engaging surface of the sole plate extends beyond the back sole plate engaging edge of the head when the head is in the rearward position . | fig1 shows a hand - held vacuum cleaner 100 . the hand - held vacuum cleaner 100 comprises a suction conduit 2 having a suction opening 4 in an attached floor tool 1 . the vacuum cleaner 100 also includes cyclonic separating apparatus 6 for separating dirt and dust from an airflow drawn in through the suction opening 4 . the cyclonic separating apparatus 6 is in communication with the suction conduit 2 and the suction opening 4 . the cyclonic separating apparatus 6 comprises an upstream cyclone 8 and a plurality of downstream cyclones 10 . the vacuum cleaner 100 further includes a motor housing 12 and a removable casing 14 having a plurality of exhaust vents 16 formed therein . an air flow path extends from the suction opening 4 , through the suction conduit 2 , the cyclonic separating apparatus 6 and the motor housing 12 to the exhaust vents 16 . a handgrip 18 is located below the motor housing 12 for manipulating the hand - held vacuum cleaner 100 when in use . the handgrip 18 is arranged so that the cyclonic separating apparatus 6 is located between the handgrip 18 and the suction opening 4 . the handgrip 18 includes a trigger switch 20 which is positioned on the side of the handgrip 18 closest to the suction opening 4 such that the trigger switch 20 can be manipulated by a user &# 39 ; s index finger . a power source 22 in the form of a lithium ion battery pack is connected to the handgrip 18 through a mounting portion 24 . when operating , an airflow generator ( not shown ) draws a flow of dirt - and dust - laden air into the suction opening 4 of the floor tool 1 , through the suction conduit 2 and into the cyclonic separating apparatus 6 . the cleaned air exits the cyclonic separating apparatus 6 and passes sequentially through a pre - motor filter if present and the airflow generator before being exhausted through the exhaust vents 16 . in order to clean a floor , the user grips the handle 18 and maneuvers the floor tool 1 across the floor surface . fig2 to 7 show a first embodiment of the floor tool 1 in greater detail . it can be seen that the floor tool 1 includes a head 25 , a sole plate 26 and a connecting arm 28 . the connecting arm 28 is rigidly attached to the head 25 , although it is possible that it could be pivotally connected to the head 25 if desired . the sole plate 26 is pivotally connected to the head 25 about an articulation axis a ( shown in fig3 and 6 ). the head 25 includes a barrel shaped body 29 in which a brush bar 30 is located . the brush bar 30 is rotatable about the same axis a that the sole plate 26 is rotatable about . the brush bar 30 may be of any suitable construction and may be either motor or turbine driven . the soleplate 26 faces a floor surface in use and includes a suction opening 4 . the suction opening 4 is in the form of a plurality of apertures 34 defined by a floor engaging surface 36 of the sole plate 26 . it can also be seen that the sole plate 26 further comprises upstanding front and rear walls ( only the front wall 38 can be seen ) which correspond in shape to the inner surface of the barrel shaped body 29 of the head 25 . these walls 38 ensure that as the head 25 rotates about the articulation axis a , a substantially airtight pathway is always provided between the suction opening 4 and the outlet 42 of the connecting arm 28 . the head 25 further comprises a front sole plate engaging edge 31 and a back sole plate engaging edge 33 . the front sole plate engaging edge 31 comes into contact with the sole plate 26 when the head 25 is in its forward position . the back sole plate engaging edge 33 comes into contact with the sole plate 26 when the head 25 is in the rearward position . this rearward position can be seen in fig2 to 6 . the floor engaging surface 36 of the sole plate 26 has forward and rearward floor contacting edges 44 , 46 . the sole plate 26 also further comprises and a front and rear lip 48 , 50 . the front and rear lips 48 , 50 have front and rear edges 52 , 54 respectively . it can be seen that the front lip 48 curves upwardly from the forward floor contacting edge 44 of the soleplate 26 and the rear lip 50 curves upwardly from the rearward floor contacting edge 46 of the sole plate 26 . in fig3 and 4 a portion 56 can be seen to extend from the rearward floor contacting edge 46 of the sole plate 26 beyond the back sole plate engaging edge 33 of the head 25 when the head 25 is in the rearward position . this extends the distance between the articulation axis a and the pivot point 47 which is located at the back edge of the portion 56 . increasing this distance makes it much harder to pivot the whole floor tool 1 during normal use thus helping to reduce skipping . without the portion 56 the floor tool 1 would pivot about the rearward floor contacting edge 46 of the sole plate 26 which would occur much more readily during normal use of the vacuum cleaner 100 . in the embodiment shown in fig2 to 7 it can be seen that there is a single portion 56 . it is of course possible to have a plurality of such portions 56 . such a portion 56 or portions may be located at any suitable position along the length of the rearward floor contacting edge 46 of the sole plate 26 . in fig3 to 6 it can be seen that the portion 56 curves upwardly to form a loop 58 . it can be seen in fig3 and 4 that the loop 58 connects a portion of the rear edge 54 of the rear lip 50 with the pivot point 47 at the rear edge of the portion 56 . the shape of the portion 56 is not important , the important feature is that the distance between the pivot point 47 of the floor tool 1 and the axis a is as large as possible . the loop 58 could therefore be solid and the edges could be angled rather than curved as long as there is a flat surface which lies in the same plane as the floor engaging surface 36 of the sole plate 26 and which extends rearwardly beyond the back sole plate engaging edge 33 of the head 25 when the head 25 is in the rearward position . for example the portion 56 could be planar , cuboidal , pyramidal or any other suitable shape . in the second embodiment shown in fig8 to 10 there is a single portion 56 . in this embodiment the portion 56 has a free end . in other words the portion 56 is not connected to a portion of the rear edge 54 of the rear lip 50 as in the first embodiment . in this second embodiment the portion 56 extends rearwardly in the same plane as the floor contacting surface 36 of the sole plate 26 for a distance beyond the back sole plate engaging edge 33 of the head 25 when the head 25 is in the rearward position . the portion 56 then curves upwardly . in the embodiment shown the curved portion 49 on portion 56 is larger than the rear lip 50 which extends from the rearward floor contacting edge 46 of the sole plate 26 on either side of the portion 56 . again the exact shape of the portion 56 is not important , the important feature is that the distance between the pivot point 47 of the floor tool 1 and the axis a is as large as possible . in the third embodiment shown in fig1 to 13 the portion 56 is an extension of the floor engaging surface 36 of the soleplate 26 along its entire length . again this portion extends rearwardly in the same plane as the floor contacting surface 36 of the sole plate 26 for a distance beyond the back sole plate engaging edge 33 of the head 25 and then a rear lip 50 curves upwardly . in fig1 to 13 it can be seen that the rear lip 50 is larger than the front lip 48 . in an alternative embodiment the rear lip 50 may be the same size or smaller than the front lip 48 . in another alternative embodiment there may only be one lip 48 , 50 or no lips . again the exact shape of the portion 56 is not important , the important feature is that the distance between the pivot point 47 of the floor tool 1 and the axis a is as large as possible . in this embodiment the pivot point 47 is also the rearward floor contacting edge 46 of the sole plate 26 . | US-70925210-A |
described herein is a pulsator device that can be used for generating a pulsed flow starting from a substantially constant flow , for example in reactors for cell growth and other applications in which it is desired to have available pulsed irroration flows . the device comprises a deformable body that is able to define a duct for passage of a substantially constant flow of a fluid subjected to pumping . associated to the deformable body is at least one actuation chamber that is selectively expandable between at least one contracted condition and at least one extended condition of pumping so as to produce a variation of the section for passage of said fluid through the duct . the variation of the section of passage through the duct is able to cause the generation of a pulsed flow of the fluid subjected to pumping . | in the figures of the drawings , the reference number 1 designates as a whole a pulsator device that can be used , for example , in ecc systems , in devices for cardiac assistance , or in biological reactors , in accordance with the criteria to which general reference has already been made in the introductory part of the present description , also considering wo - a - 01 / 43797 . the device 1 illustrated herein is configured as a tubular duct which is to be traversed by a flow of liquid , such as a biological liquid . in one embodiment of the present description , it will be assumed that said fluid is blood and that the flow through the respective pulsator 1 occurs , with reference to the point of observation of fig1 , from left to right . of course , the invention may be used in other fluids , and this example should not be interpreted as in any way limiting the scope of the invention . specifically , the block diagram of fig1 represents a flow modulator that uses a pulsator device 1 , which , thanks to its variable volume , receives a continuous flow coming from an ecc system 2 ( or other system ) and sends a pulsed flow to the patient ( or other load ), designated as a whole by p . as shown in fig2 , the pulsator 1 basically consists of a duct 10 , usually fundamentally inextensible but flexible , contained in a shell 12 , which is substantially rigid and equipped with connectors for inlet 12 a and outlet 12 b . the gap between the shell 12 and the duct 10 constitutes a closed space or volume , also around the connectors 12 a and 12 b , but equipped with a connector which enables controlled introduction or removal of a fluid ( the so called “ actuation fluid ”), which acts with variable and controllable pressure on the flexible duct 10 bringing about the desired variations of volume . set at output from the pulsator 1 is the sensor of a flowmeter 3 for measuring the blood flow ( or other flow ) delivered to the patient p . the flowmeter 3 can be of the ultrasound type and hence based upon a sensor without contact with the blood and which can be used a large number of times . in the example of embodiment illustrated , the flowmeter 3 is the only measuring instrument / sensor required , thanks to the original control logic which will be described hereinafter , for adequate operation of the flow modulator . a pump 4 , driven by a motor 4 a , such as for example a linear motor , enables the actuation fluid to be pushed into or removed from the gap of the pulsator , i . e ., it enables an actuation fluid to be transferred in a controlled way with respect to the pulsator 1 . this occurs via a closed fluid circuit 5 connected on one side to the pump 4 and on the other to the gap ( or actuation chamber ) of the pulsator 1 and containing the actuation fluid . a control unit 6 receives the signal of the flowmeter 3 ( and other possible optional sensors ) and controls the action of the pump 4 issuing a command to its motor 4 a on the basis of the logic described herein . electrical control components of a known type can prove useful for improving the performance and safety of the system used for the control unit 6 . one of these may , for example , be a pressure meter 7 with the sensor set in the gap of the pulsator 1 or in any other position of the closed circuit 5 containing the actuation fluid . this meter , indicated by dashed lines in the diagram of fig1 , makes available a redundancy of information useful for the purposes of safety and simplicity of the control . this also is not in contact with the blood and can be repeatedly used . another optional component ( not illustrated explicitly in the figures ) is a system for monitoring the volume of actuation fluid contained in the circuit 5 and for compensation of possible small leakages of fluid which may arise , for example , in the connections . said systems are widely known and used , for example , in intra - aortic - counterpulsation systems and in the ventricular assist devices ( vads ) of a pneumatic type . as has already been said , the pulsator 1 is basically constituted by a flexible duct 10 contained in a rigid shell 12 and equipped with connectors for inlet 12 a and outlet 12 b . one of the goals of this component is the low thrombogenicity . for this purpose , the solution described herein causes the blood flow within the pulsator to be as regular as possible , without any stagnation or turbulence , and the internal surface to be well “ washed ” by the flow to prevent any formation of deposits that may grow to significant dimensions and subsequently detach , forming emboli . to meet this goal , a geometry of the duct optimized from the fluid - dynamics standpoint is adopted like the ones known in the art for different types of pumps for blood , in particular for vads and for different models of artificial heart . for the present application , it proves particularly advantageous to use a flexible duct 10 having the configuration of a straight tube contained in a shell , which is also cylindrical and longitudinally anchored thereto along three directrices at 120 °, as may be seen more clearly in the cross sectional view of fig3 . an advantage of this configuration is that within it the flexible duct 10 can be long and have a relatively small diameter and thus be sized so as to form , in the completely expanded condition of the duct ( illustrated with a dashed line in fig2 and 3 ), a continuous tube with the ones that connect the ecc system with the patient p , thus guaranteeing optimal fluid - dynamics and washing of the surfaces . furthermore , the bends that the duct forms in the course of its deformation towards the condition of complete contraction of the duct ( illustrated by a solid line in fig2 and 3 ) remain basically aligned to the direction of the flow and thus enable maintenance of an effective washing of the surfaces also during the phases of deformation . the disposition at 120 ° of the lines of anchorage of the flexible duct 10 to the rigid shell 12 currently emerges as the preferred solution to arrive at a state of complete contraction characterized by a minimal but non - zero residual cross section . this enables minimization of the overall dimensions of the system ( for a pre - set maximum ejection volume ), while preventing possible problems of injury to the blood ( hemolysis ) which could arise if the internal surfaces of the flexible duct were to adhere due to collapse . in the currently preferred embodiment , the duct 10 is made as a tubular body of deformable material , for example silicone rubber or polyvinyl - chloride ( pvc ), nylon , pebax or polyurethane , compatible with usage in the medical field , surrounded by the body 12 , which is also made preferentially of plastic material , such as for example polycarbonate , polysulphone or pvc , with a wall having on a whole a cylindrical shape , gradually tapered in a position corresponding to the connectors 12 i a and 12 b . the cavities 14 , i . e ., the chambers for operation of the device in which the actuation fluid is introduced thus extend ( with possible not markedly appreciable discontinuities ) throughout the axial length of the pulsator device 1 . in the example of embodiment illustrated herein , corresponding to a currently preferred embodiment , the cavities or actuation chambers 14 are thus three in number , possibly interconnected . each actuation chamber assumes — in resting conditions — a general tile shape with an angular extension ( referred to the principal central axis of the duct 10 ) of a little less than 120 °. the structure just described is suited to being made with the use of plastic materials , such as the ones cited previously resorting to normal techniques of extrusion and / or molding . these techniques are widely experimented in the biomedical sector , as documented , for example , by ep - a - 0 512 359 , regarding the fabrication of balloon catheters . another important characteristic of the pulsator device 1 illustrated herein is that it is a non - valved device , i . e ., one in which there are not present valve elements designed to regulate , by opening and closing , the flow through the pulsator 1 . as will be seen more clearly from what follows , in fact , in the system described herein the pulsed character , of the outgoing flow is obtained only by controlling the operation of the pulsator . via the duct 5 , the pumping element 4 causes a pressurized fluid to flow into the cavities 14 in such a way as to cause the chambers defined by the cavities 14 to be able to swell , as a result of the as a whole flexible character of the material constituting the duct 10 of the pulsator device 1 , so as to be deformed towards the condition of maximum deformation of the cavities represented with solid line in fig2 and 3 . in said condition , the chambers corresponding to the cavities 14 swell , and the portion of wall comprised between each of these chambers and the duct 10 of the pulsator device 1 becomes arched , developing a more or less marked convexity directed towards the duct 10 . this movement of expansion and arching ( which occurs in a substantially identical way for all three cavities 14 ), with consequent contraction of the tubular duct 10 of the pulsator device 1 , underlies the phenomenon of modulation of the outgoing flow . as is illustrated more clearly in a schematic form in the diagram of fig4 , the expansion — and , in a dual way , the contraction — of the chambers 14 , controlled via the pump 4 , is able to cause in time a variation of the volume v = v ( t ) of the duct 10 of the pulsator . said variation enables a constant or substantially constant blood flow q 0 , which is sent at inlet to the pulsator device 1 ( on the left - hand side of the device 1 — as illustrated in fig4 ), to be converted at outlet from device 1 ( right - hand side of fig1 ) into a pulsating flow q ( t )= q 0 + dv ( t )/ d ( t ). the fact that mention was previously made of a “ substantially ” continuous flow rate at inlet to the pulsator aims at taking into account the fact that the continuous flow at outlet from certain pumping devices , such as for example the peristaltic pumps , may in fact present reduced fluctuations due to “ ripple ” phenomena ( linked to the intrinsic mechanism of the pumping action ) or resulting from variations in the pressure downstream . fig5 b ) represents , against the background of a corresponding incoming flow q 0 , a possible time evolution of a pulsating outgoing flow q ( t ) determined by variations in the internal volume of the pulsator , such as the ones represented schematically in fig5 a ). the pulsating flow q ( t ) is distinguished by a period t ( variable in time ), in which there is distinguishable a diastole phase t d , during which the volume of the duct 10 increases or remains constant and consequently with a value of the flow q ( t ) lower than or at the most equal to the incoming flow q 0 , and a systole phase t s , in which the volume of the duct 10 decreases and , consequently , the flow q ( t ) increases gradually towards a maximum value , to return then to the reduced value at a point corresponding to the start of the subsequent diastole phase . for simplicity of illustration , the diagram of fig5 a ) illustrates a possible variation in the volume of the duct 10 according to a rounded - triangular - wave law , while the diagram of fig5 b ) shows a possible corresponding modulation of the outgoing flow in the form of a square wave with rounded leading and trailing edges . a system of the type illustrated in fig1 is used , being interposed along the line that takes the blood from the outlet of the ecc system or the system providing assistance to the patient . otherwise , the modalities of application and connection of a system of the type illustrated in fig1 correspond — both as regards the surgical method of connection to the patient and as regards the accessory devices required to make such a connection — to data , information , and criteria to be deemed in themselves known in the art and , in any case , in themselves not important for an understanding and implementation of the invention . passing now to an even more detailed examination of the modalities of use of a system such as the one illustrated in fig1 , it should be recalled that , in order to meet as well as possible the requisite of low thrombogenicity , it is appropriate for the duct to reach at each cycle , at the end of the diastole phase t d , the position of complete expansion , thus assuming the configuration of a tube and hence enabling an optimal washing of its internal surface . this need can be met by intervening on the actuation and control unit 6 . passing now to an examination of various possible modalities and logics of actuation of the pulsator 1 , it will be noted that the deformation of the flexible duct 10 of the pulsator 1 occurs as a result of the difference in pressure between the blood inside it and the actuation fluid contained in the gaps ( chambers 14 ) of the pulsator 1 . the pressure and volume of this actuation fluid is varied by operating the pump 4 , which has precisely the function of transferring , in a controlled way ( by the unit 6 ), an actuation fluid with respect to the actuation chambers 14 of the pulsator 1 . the actuation fluid can be either a liquid or a gas . the use of a liquid , given its incompressibility , enables a more direct and immediate actuation and control ( volumetric control ). it involves , however , a greater weight and , principally , gives rise to reasons of possible critical aspects linked to factors of sterizability , packaging and transportation . the use of a gas such as air or , rather , co 2 or helium imposes the need for a pressure control , which is less direct . this is , on the other hand , feasible using known technologies , such as for example the ones used for actuation of intra - aortic counterpulsators . in general , actuation and control of the pulsator 1 start with a diastole phase , during which the control unit 6 measures , via the flowmeter 3 , the flow q ( t ) coming out of the duct 10 and imposes , by controlling the pump 4 during intake , the need for it to be approximately zero ( or only slightly positive ). this action can be performed using a normal control logic , for example of a pid type , up to complete filling of the pulsator 1 ( duct 10 completely expanded ). once said state of complete expansion and filling of the duct 10 has been reached , notwithstanding possible suction of the pump , the duct 10 , which is flexible but inextensible , will no longer be able to increase its own volume and accumulate blood . the flow q 0 entering the pulsator will hence traverse it and come out to reach the patient p . the flowmeter 3 will , at this point , indicate a relatively sharp increase in the flow rate , which the control unit 6 will be able to recognize ( either as it stands or as a difference between the desired flow rate and the measured flow rate ) as the end of the phase of filling of the duct 10 , accordingly issuing a command for arrest of the suction of the pump and enabling the start of the systole phase , which can be immediate or deferred when it is desired that the systole should start at instants determined by other conditions , such as for example the synchronism in counterpulsation with the natural heart ( in the terms described in greater detail in what follows ). when the state of complete filling of the pulsator 1 is reached , this can be detected by the control unit 6 also by monitoring the current for actuation of the motor 4 a of the pump and / or ( if the corresponding sensor is available ) the pressure of the actuation fluid . the former , on account of the unbalancing between the value of flow imposed and the value measured and on account of the inextensibility of the tubular duct 10 , will have a sharp increase . the latter , not compensated by the increase of volume of the flexible duct on account of the action of suction of the pump 4 , will undergo a sharp drop . said different modalities of detection of reaching the state of complete filling of the pulsator 1 can be used as an alternative or for the purpose of having a redundancy of information in order to insure greater safety . the control logic of the modulator in the phases of systole depends then upon the modalities of actuation that the user may wish to adopt . the tests so far conducted by the inventors have led to an identification of three basic operating modes , namely : said different possible modes of operation will now be described with reference to fig6 and 7 of the annexed plate of drawings . each of said figures contains two portions , designated , respectively , by a ) and b ). of these , the portion b ) reproduces , according to modalities similar to the ones adopted in fig5 b ), the time evolution of the pulsating flow q ( t ) at outlet from the pulsator 1 with direct reference to the incoming flow q 0 , which is substantially constant . the portion designated by a ) is a diagram representing the pumping action exerted by the pump 4 . supposing that the pump in question is a piston pump , the diagrams a ) of fig6 and 7 can be simply viewed as representing the position assumed in time by the piston of the pump itself . the minimum value of the corresponding curve represents the position of end of diastole , with the pulsator 1 “ full fill ”. of course , this representation can be transposed in an elementary way to pumps of different types . for the operating mode with pulsation synchronous with the heart beat , reference will moreover be made to fig8 , which contains a diagram exemplifying the synchronization between the external reference signal ( ecg ) and the phases of systole and diastole in the actuation of the pulsator . this operating mode , to which fig6 and 7 refer , is typically the one that can be used for improving , thanks to the pulsatility of the flow and of the pressure , the perfusion of the organs in the course of heart - surgery operations of long duration conducted in extracorporeal circulation . in this operating mode the aim is to have at each cycle ( period t ) the ejection volume to the patient corresponding to an adjustable pre - set value . of course , this may not be higher than the maximum volumetric range of the pulsator 1 plus the incoming mean flow multiplied by the duration of the systole phase t s . the systole phase starts , in this case , immediately after the complete filling of the pulsator and consists in operating the pump 4 in ejection with a pulse of pre - set form but with controlled amplitude and duration in such a way as to cause an ejection volume per cycle equal to the pre - set one . in the case where , as actuation fluid , a liquid is used , the variations in the internal volume of the pulsator correspond exactly to the volume displaced by the motion of the piston of the pump . in this case , a motion of ejection is imposed on the piston of the pump , starting from the position reached at the end of the diastole , which has a pre - set time evolution such as to generate an adequate waveform of the output flow rate . the amplitude of the motion is continuously adjusted by the control unit in such a way as to cause an ejection volume , determined by integrating the signal of the flowmeter 3 in the systole phase , equal to the one set , thus compensating for possible variations of the incoming flow q 0 . the duration of the systole phase can then be varied to keep it proportional ( for example equal ) to the duration of the diastole t d . for this purpose , since the value of the incoming flow q 0 is not known a priori , the control unit 6 corrects , at each cycle , the duration of the movement of compression , adapting it to the duration of the preceding diastole , which is in turn determined by the ejection volume imposed and by the incoming flow . once the systole phase terminates , a subsequent new diastole phase starts immediately . t s = k × t d ( for example k equal to 1 ) this operating mode with liquid as actuating fluid is illustrated in fig6 . in summary , in this operating mode , the incoming flow is imposed from the outside , the ejection volume and the ratio between the duration of the systole and that of the diastole are fixed , and the system automatically adapts in a simple way the amplitude and duration of the motion in compression of the piston to generate in the desired period of time a reduction in the volume of the pulsator such as to generate the ejection volume set . normally , when operating with fixed ejection volume , the endeavor is to get the pulsator 1 to work with a volumetric range close to the maximum ( condition defined as “ full fill - full empty ”), i . e ., with a range ( δv opt ) close to the maximum range allowed by the duct 10 between a condition of maximum extension and a condition of maximum contraction . this result can be achieved by adjusting manually the regulation of the ejection volume set or , rather , by adding to the control unit 6 ( operating according to criteria in themselves known ) an external and slow feedback loop based upon the comparison between the effective values of δv and δv opt . in the case where a gas is adopted as actuation fluid , the control logic is similar , it being , however , necessary to take into account the effects of the compressibility of the gas and the inertance of the masses of liquid ( blood ) that the pulsator must set in motion . the latter determines the need for a high pressure in the gap ( chambers 14 ) of the pulsator 1 at start of systole , in order to set the blood in motion towards the patient , and for a marked reduction in the pressure itself at the end of systole in order to slow down its motion . for the above reason , it may be expedient to use , for the systole phase , a control acting on the pressure in the actuation fluid , measured preferably in the gap of the pulsator or close thereto , instead of on the position of the piston . also in this case , one imposes to the piston of the pump 4 an actuation ( stroke or generated pressure ) based on a predetermined waveform having as adjustable variables the amplitude and the duration of the action of compression exerted by the pump . the adjustment of these variables is made by the control unit 6 on the basis of a logic similar to that of the previous case : the amplitude is varied to maintain the integral of the outgoing flow during the systole phase equal to the desired ejection volume , and the duration is modified to keep it proportional to the duration of the diastole . the waveform to be used in this case for the motion of the piston or for the pressure of the actuation fluid ( gas ) can be optimized on the basis of experimental tests and qualitatively has , on the basis of the tests conducted , the form indicated in the diagram of fig7 . in summary , in the asynchronous operating mode with predetermined ejection volume , the system operates , to maintain the outgoing flow zero , by drawing actuation fluid from the chambers 14 of the pulsator 1 until complete filling of the tubular duct and then by compressing the actuation fluid in the chambers with an action of amplitude such as to eject the desired volume of blood . the frequency of actuation , and hence the duration of the diastole and systole phases , are automatically determined and vary as the mean flow varies , said mean flow being set by the ecc system , and as the ejection volume , which is set , varies . if we wish to maintain the frequency of pulsation equal to a pre - set value , and hence with a predefined duration of the systole and diastole phases , it is possible to control the system exactly as illustrated for the previous operating mode but varying the ejection volume , and hence the amplitude of the actuation in the systole phase , in such a way as to maintain the desired frequency . of course , the pulsator 1 will no longer operate in a “ full fill - full empty ” way but in a “ full fill - partially empty ” way , i . e ., with a range between a condition of maximum extension and a condition of contraction that is only partial . the frequency set must be higher than what it would be in the case of operation in the mode with ejection volume mode fixed and optimized in order to ensure the “ full fill - full empty ” condition . this operating mode is of practical interest when , using the previous mode , there would be an excessively low frequency of pulsation on account of the low mean flow rate with respect to the maximum volumetric range of the pulsator 1 . this is the case , for example , of application of the system with patients in the pediatric age range or in any case small patients . also in this case , the systole phase starts immediately after complete filling of the pulsator and consists in operating the pump 4 in ejection with a pulse of predetermined duration in relation to the frequency of actuation desired and of amplitude initially equal to a predefined standard value . immediately after this systole phase a diastole phase starts , which is made to proceed up to complete filling of the duct 10 , detected as described previously . the time necessary to reach this condition is then compared with the desired duration of the diastole as a result of the desired frequency of actuation . if said time is longer or shorter than desired , the approach is to reduce or increase the amplitude of the action of actuation in the systole phase progressively so as to reduce or increase , respectively , the ejection volume ve and accordingly shorten or lengthen , respectively , the duration of the diastole . this progressive operation of control proceeds until a duration of the diastole , and hence a frequency of actuation , equal to the value desired and set is obtained and maintained . this operating mode is of interest when the system is used with patients whose heart beats regularly but does not have the force to sustain adequately the circulation of the blood and hence guarantee an adequate perfusion of the organs . typical examples of this situation are the so - called “ post - cardiotomy assistance ”, “ percutaneous cardiopulmonary assistance ” or “ extracorporeal membrane oxygenation ”. in the first case , they are patients subjected to heart - surgery operations in extracorporeal circulation whose heart , at the end of the intervention , does not recover an adequate functionality . in these cases , it is necessary to keep the extracorporeal circulation ( or any other procedure of assistance ) active for long periods of time ( some hours or a few days ) in the hope that the heart will recover from the trauma of the operation and will recover its own functionality . percutaneous assistance or ecmo are instead used in patients with serious cardiac insufficiency consequent to pathological conditions , usually of an acute nature ( e . g ., post - infarct shock ), in order to guarantee an adequate perfusion of the organs while awaiting other therapeutic interventions and / or recovery of the cardiac function . in all these cases , it is reasonable to envisage , also on the basis of scientific evidence that has emerged over the years , that the pulsatility of perfusion will have favorable effects but it is also necessary to be careful to prevent the pulsatility of artificial perfusion from being in opposition with that of the natural heart . for this purpose , the situation , defined as counterpulsation , in which the pressure wave generated by the system of assistance acts in the aorta during the diastole phase of the natural heart is considered optimal . in this case , in fact , the work done by the natural heart is minimized , and coronary perfusion is maximized . to be able to operate in this mode , a system of modulation of the blood flow as the one described herein receives ( through the unit 6 , usually already configured for this function ) an external synchronization signal , typically an ecg trace . from this signal the control unit 6 can readily obtain not only the frequency of actuation desired but also the timing for the start of the phases of systole t s and of diastole t d . this can occur , for example , by adopting the diagram shown in fig8 . in said figure the references tn , tn + 1 , tn + 2 , . . . designate the periods between the successive qrs signals of ecg trace while , in the lower part of the figure , the systole s and the diastole d are shown both for the natural heart nh and for the pulsator p . it is to be born in mind that the sum of the two coefficients of proportionality α and β indicated in the figure is smaller than 1 , for example α = 0 . 5 and β = 0 . 4 . in one embodiment , the ecg readings are inputted to unit 6 and used to adjust the pumping of the next pumping cycle based on ecg reading of the previous heart cycle . adjustments can be made to the timing of the pumping action , the amplitude of pumping pressure , the rising ramp of the pumping action , the falling ramp of pumping , the pressure wave form and other features as set forth herein . also in this case the system to operate in “ full fill - partially empty ” mode . starting the system by synchronizing the start of systole and the start of diastole with the external signal ( ecg ); monitoring , in the course of the diastole t d , the current to the motor 4 a of the pump 4 or the pressure in the gap ( chambers 14 ) of the pulsator 1 , interrupting the action of suction of the pump 4 when these signals indicate that the pulsator 1 is full ; operating the pump , in the systole phase t s , with a compression pulse having a form as described previously , duration equal to the one indicated by the external signal , and minimum amplitude . in these conditions , the pulsator always remains full , behaving essentially as a tube , and the flow remains basically constant ; increasing progressively the amplitude of the compression pulse applied in the course of the systole t s ; when this reaches an adequate value , the pulsator 1 starts to modulate the flow emptying a little , and then filling up again in the course of diastole ; monitoring , in the course of diastole , the outgoing flow , verifying the duration of the period during which the action of suction of the pump manages to maintain this flow practically zero ; continuing to increase slowly the amplitude of the compression pulse applied in the course of systole , thus increasing the amplitude of the modulation of flow , until it reaches the instant in which there is complete filling of the pulsator near the end of the diastole phase programmed ( e . g ., at 80 - 90 % of the duration set for the diastole ); once this condition has been reached , activating a control of the amplitude of the systole pulse that will maintain the duration of the phase of filling of the pulsator equal to the desired fraction ( e . g ., 80 - 90 %, and hence a substantial fraction ) of the duration of the diastole , bearing in mind that , if the pulsator finishes filling first , it means that , in the course of the previous systole , it had emptied less than was desired ( ejection volume smaller than the optimal ) and hence it is necessary to increase a little the amplitude of the systole pulse ; instead , if the time for filling is greater than what is desired , this means that with the previous systole the pulsator had emptied excessively and hence the amplitude of the systole pulse must be reduced : basically , the approach is to operate by increasing and decreasing the intensity of the transfer of the actuation fluid to the actuation chambers 14 in the course of systole according to whether , respectively , the phase of maximum extension of the cross section and hence of complete filling of the duct 10 tends to be anticipated or to be delayed . of course , without prejudice to the principle of the invention , the details of implementation and the embodiments may vary widely with respect to what is described and illustrated herein , without thereby departing from the scope of the present invention , as defined by the annexed claims . this applies , for example , to applications different from the systems of extracorporeal circulation and to devices of cardiac assistance , such as the so - called bioreactors for cell growth and other applications in which it is desired to have available pulsatile flows . all of the above u . s . patents , u . s . patent application publications , u . s . patent applications , foreign patents , foreign patent applications and non - patent publications referred to in this specification and / or listed in the application data sheet , are incorporated herein by reference , in their entirety . from the foregoing it will be appreciated that , although specific embodiments of the invention have been described herein for purposes of illustration , various modifications may be made without deviating from the spirit and scope of the invention . accordingly , the invention is not limited except as by the appended claims . | US-31764405-A |
a wire guide for feeding a medical catheter through the body passage of a patient to a distant target site within the body has a variably flexible distal portion . the distal portion facilitates threading the guidewire in a tortuous path through acute bends at branch junctions in the body passages of the patient . the wire guide end is able to feed into very delicate vessels such as ventricles of the brain and the spinal canal without puncturing the wall or damaging organs . | in this description , when referring to a deployment or treatment assembly , the term distal is used to refer to an end of a component which in use is furthest from the clinician during the medical procedure , including within a patient . the term proximal is used to refer to an end of a component closest to the clinician and in practice in or adjacent to an external manipulation part of the deployment or treatment apparatus . the novel wire guide 134 includes a cannula portion 100 , a flexible portion 108 , and a core wire 128 . the cannula portion 100 includes a series of cuts 106 to provide it with variable length . the flexible portion 108 includes a number of spheroidal members 112 that are displaced longitudinally at the distal end of a core wire 128 and within a covering 110 . the core wire 128 is displaced internally to both the cannula portion 100 and the beaded portion 108 , passing through a first lumen 104 within the cannula 100 , and a second lumen 126 defined by the apertures 124 in each of the spheroidal members 112 . the core wire 128 is affixed to the distal - most member 122 . the members 112 are separated from one another by variable gap distances 138 manipulated to alter the flexibility of the distal portion of the core wire . the core wire 128 can flex at points within the gaps 138 between the member 112 which allows the distal end 108 of the wire guide to bend at branch junctions and to conform to the curvature in the vessel duct . the member 112 can be fixed to the core wire 128 or they can move freely along the distal portion of the core wire 108 . also , member 112 freely sliding along the core wire 128 may be compressed against one another to control the flexibility and curvature of the distal portion 108 by manipulating the proximal end 136 of the core wire and inducing varying amounts of tension in cannula portion 100 , and thereby the flexible portion 6 , of the wire guide 134 . finally , the covering element 110 is disposed about the beaded portion 108 of the wire guide 134 and extends from a closed end 116 about the distal - most member 122 to the distal end of the cannula portion 102 , where it is affixed about 118 the distal end of the cannula 102 . an insertion tube is provided for initially feeding the flexible wire guide end into the body passage . [ lk 1 ] a first embodiment of the invention can be understood with reference to fig1 . the catheter wire guide 134 has a core wire 128 having a length to reach a distant target site when fed percutaneously from outside the body into the lumen of a bodily duct . the wire guide has a proximal end 136 that remains outside the body and is manipulated by a physician . generally , the core is flexible so as to be capable of threading through a branched bodily duct network along a tortuous path . the thickness , shape of cross section , and materials of construction of the core wire can vary along the length to provide different mechanical properties , such as flexibility and torsional strength . preferably , near or adjacent the proximal end , the core wire may be relatively stiff . moreover , the core wire near the proximal end may be relatively stiff . preferably , the proximal portion of the wire guide is less flexible because it usually resides in larger diameter , slightly curving sections of the duct network near the entry point . also the increased stiffness near the proximal end facilitates transmission of torque along the full length of the wire guide to aid in steering the tip at the distal end . preferably , wire guide flexibility increases along the length toward the distal end . throughout this specification reference will be made to a plurality of cuts 106 and a plurality of members 112 . unless otherwise stated , the term “ cuts ” shall hereinafter refer to a plurality of incisions on the cannula 100 which may be in any patterns designed to allow for longitudinal expansion and contraction of the cannula 100 . additionally , the term “ members ” shall hereinafter refer to a plurality of structures disposed between the distal end of the cannula 102 and the distal tip of the core wire 130 ; where the members 112 can be any shape with rounded edges that allow for movement against one another and smooth passage through the body duct . for example , each of the plurality of members 112 could be spherical , ovoid , ring - like , or any combination of such shapes or any other such rounded shape . the embodiments of this invention include at least two members . the at least first member 120 is affixed to the distal end of the cannula 102 , and a second member 122 is affixed to the distal tip 130 of the core wire 128 at an attachment region 132 . at its distal end , the core wire terminates at tip 130 on which is affixed a second member 122 . because the second member 122 at the distal tip of the core wire 130 leads the wire guide through the bodily duct , the second member 122 is a blunt form to reduce the risk of wall penetration . the second member 122 can have a spheroidal shape . the term “ spheroidal ” means that the shape can be imperfectly spherical as well as exactly spherical . spheroidal shapes can include spherical , elliptical , ovoid , and hemi - spheroidally - ended cylindrical shapes , as well as ring - like structures and round - ended semi - cylindrical structures . if conical , the forward and trailing ends should be blunted to remove any sharp edges which could provide a risk of penetration of the duct walls . to assure that the second member 122 does not separate from the core wire 128 , the second member 122 should be securely attached to the distal tip 130 of the core wire . the method of attachment is not critical to operation of the invention . for example , the second member 122 and the core wire 128 could be manufactured as a single piece , the second member 122 thereby being integral to the core wire 128 . alternative exemplary methods of attachment including cementing , thermally fusing , or crimping the second member 122 to the core wire 128 , fastening with clamps , pins and set screws , and any combination of these . the flexible portion 108 of the wire guide includes a plurality of spheroidal members 112 positioned sequentially along the core wire 128 . the members 112 are slidably disposed along the core wire 128 such that they can move relative to one another . the flexible portion 108 of the wire guide also includes a covering 110 having a closed end 116 at the distal tip 130 of the core wire , and an open end 114 that extends about , and is affixed to , the distal end 102 of the cannula 100 . the covering 110 encases the members 112 , such that they are prevented from separating from the core wire 128 and drifting through the patient &# 39 ; s vasculature . the members 112 also generally have smooth , rounded surfaces to prevent drag against the covering 110 or the duct walls during wire guide movement within the duct lumen . the flexible portion 108 of the wire guide is intended to lead the wire guide into the usually very small duct branches in the far reaches of the network . consequently , the diameter of the members 112 should be sufficiently small for the flexible portion 108 to slide easily through the narrowest ducts . the members 112 are spaced apart along the axis of the core wire 128 by a small distance which creates a gap 138 between adjacent members 112 . the core wire 128 can flex freely in the gaps . such flexing permits the distal portion to assume suitable curvature to advance the distal end of the device toward the target site through acute curves in a body duct network . furthermore , the gap 138 between members 112 is variable , and may be reduced such that the members 112 are touching one another , and the wire guide 134 is thereby stiffened . it is important that the flexible portion 108 not be too flexible , as under such a configuration , it could kink and jam within the body duct . members 112 of the novel wire guide will also be defined by a characteristic length . references to “ length ” should be interpreted to mean the maximum axial dimension of a member , such as the dimension 140 in fig3 , fig4 and fig5 . the aspect ratio of the members , that is , the ratio of the length relative to the diameter , can also influence the ability of the flexible portion to fold , kink , or jam within the body duct . members with too great an aspect ratio will cause the flexible portion to function as a straight , rigid rod , rather than a flexible wire guide . while this could be beneficial , in some embodiments , for navigating stenosed regions of the vasculature , such members would be incapable of navigating sharp curves within the patient &# 39 ; s body ducts . conversely , if the aspect ratio of the members is too small , the members may tend to bunch together and jam in the duct at bends or branch junctions . therefore , a variety of embodiments are contemplated such that the physician may choose a device with the appropriate flexibility and navigability characteristics for the particular procedure . some or all of the members 112 may also have magnetic properties , radiopaque characteristics , or both . members with radiopaque characteristics can be seen by using imaging technology known in the art , and can aid physicians in properly placing the wire guide 134 within the body of a patient . with reference to guidance , in some embodiments of the invention , some or all of the members 112 may have magnetic properties as well . in this invention , the term “ magnetic ” is used to refer to a composition that is a permanent magnet , a paramagnetic material , a diamagnetic material , or any other form of magnetic material . in instances where some or all of the members 112 comprise a magnetic material , the magnetic material can be used to assist a physician in guiding the wire guide 134 through the body of a patient . this may be accomplished by applying attractive or repulsive magnetic fields generated outside the body of the patient to the magnetic members 112 of the wire guide 134 . in some preferred embodiments of the invention only repulsive magnetic fields will be applied to members 112 of the wire guide 134 which have magnetic properties . in such cases , since the magnetic field strength falls off exponentially with the distance to the source , very fine control of the flexible portion 108 of the wire guide 134 may be accomplished . fig2 provides second view of the embodiment of fig1 , wherein the cannula 1 has been omitted so that the core wire 128 is visible along with the members 112 disposed about the flexible portion 108 of the wire guide . fig3 provides an enlarged view of an embodiment of the invention in which the covering 110 is shown surrounding each of the members 8 , and extending from a closed end 116 at the distal - most end of the second member 122 to the distal end 102 of the cannula 100 , including the entirety of the flexible portion 108 . the covering 110 is further shown to encapsulate a portion of the distal end 102 of the cannula 100 . this portion of the covering is affixed to the cannula 100 by clamping , gluing , bonding or any other electrical , mechanical or chemical means that is known in the art . furthermore , the first member 120 is affixed to the distal end 102 of the cannula 100 by clamping , gluing , bonding , or any other electrical , mechanical or chemical means known in the art . fig4 provides an enlarged view of a single member 112 of an embodiment of the invention in which the members 112 are spherical . the core wire 128 can be seen entering and exiting the apertures 124 defining the second lumen 126 within each member 112 . in this embodiment of the invention , the member 112 may slide along the core wire 128 . in addition , the member 112 in this embodiment can be spheroidal with an axial length 1240 equal to its diameter . this is not limiting , however , as noted earlier , a “ spheroidal ” member 112 could be any shape that may be imperfectly spherical as well as exactly spherical . spheroidal shapes can include spherical , elliptical , ovoid , and hemi - spheroidally - ended cylindrical shapes , as well as ring - like structures . fig5 depicts a partial section view of an embodiment of the invention in which the structures of fig4 are incorporated into a more complete depiction of the invention . in this embodiment of the novel wire guide , the wire guide includes a slender core wire 128 extending from a proximal end 136 to a distal tip 130 . the core wire 128 is affixed to the second member 122 at its distal tip 130 . the attachment may be carried out by clamping , gluing , bonding , or any other electrical , mechanical or chemical means known in the art . the cannula 100 is depicted having a first lumen 104 and the members 112 are shown having apertures 124 defining a second lumen 126 . the core wire 128 extends through both the first 104 and second 126 lumens , reaching from the proximal end 136 of the wire guide to the second body 122 . the length of the core wire 128 can vary with each embodiment of the invention , as it will be defined in part by the number of members 112 as well as their axial lengths 140 . more simply said , the length of the core wire 128 will vary with the length of the flexible portion 108 of the wire guide 134 . in addition , the flexible portion 108 of the wire guide 134 can have a variable length in each embodiment , as the amount of tension applied to the core wire 128 will vary the gaps 138 between the members 112 . the covering 110 is shown having an open end 114 at the distal end 102 of the cannula and extending around each of the members 112 and terminating in a closed end 116 surrounding the second body 13 . at the distal end 102 of the cannula , the open end 114 of the covering 110 is affixed in by clamping , gluing , bonding , or any other electrical , mechanical or chemical means known in the art . in this embodiment , the distal end 102 of the cannula is bonded to the open end 114 of the covering in a region denoted by the number 118 . fig6 a , fig6 b , fig6 c , and fig6 d depict partial views of two embodiments of the invention . in each of these diagrams , everything but the cannula 100 is omitted such that two different methodologies of providing cuts 106 to the cannula 100 are depicted . these depictions should not be construed as limiting , however , as they are merely intended to show that there are many methods available to provide the cannula 100 with a series of cuts 106 that create the potential for the cannula 100 to have a variable axial length . fig6 a and fig6 b depict a series of cuts 106 in the cannula 100 such that an “ scissors - lift - like ” length variation may be accomplished . fig6 c and fig6 d depict a series of cuts 106 in the cannula 100 that spiral about the cannula in such a way that a “ slinky - like ” length variation may be accomplished . fig7 depicts a partial section view of an alternate embodiment of the present invention , wherein the first member 120 has an alternate form , wherein the axial length 140 of the first member 120 has an axial length 140 that is different than its cross sectional diameter 142 . fig7 further includes the structures of fig4 , which are thus incorporated into a more complete depiction of the invention . in this embodiment of the novel wire guide , the wire guide includes a slender core wire 128 extending from a proximal end 136 to a distal tip 130 . the core wire 128 is affixed to the second member 122 at its distal tip 130 . the attachment may be carried out by clamping , gluing , bonding , or any other electrical , mechanical or chemical means known in the art . the cannula 1 is depicted having a first lumen 104 and the members 112 are shown having apertures 124 defining a second lumen 126 . the core wire 128 extends through both the first 104 and second 126 lumens , reaching from the proximal end 136 of the wire guide to the second body 122 . the length of the core wire 128 can vary with each embodiment of the invention , as it will be defined in part by the number of members 112 as well as their axial lengths 140 . more simply said , the length of the core wire 128 will vary with the length of the flexible portion 108 of the wire guide 134 . in addition , the flexible portion 108 of the wire guide 134 can have a variable length in each embodiment , as the amount of tension applied to the core wire 128 will vary the gaps 138 between the members 112 . the covering 110 is shown having an open end 114 at the distal end 102 of the cannula and extending around each of the members 112 and terminating in a closed end 116 surrounding the second body 122 . at the distal end 102 of the cannula , the open end 114 of the covering 110 is affixed in by clamping , gluing , bonding , or any other electrical , mechanical or chemical means known in the art . in this embodiment , the distal end 102 of the cannula is bonded to the open end 114 of the covering in a region denoted by the number 118 . in this embodiment , the first member 120 , comprises an alternate form , wherein its lumen 126 has a somewhat conical cross section . in certain aspects , the present invention provides unique wire guide devices 134 that can effectively traverse tortuous body passages atraumatically . in accordance with some forms of the invention , such wire guide devices 134 are configured to provide variable flexibility to the distal portion 108 of the device . in such devices , the wire guide 134 may include a cannula 100 provided with a series of cuts 106 , a plurality of spheroidal members 112 disposed within a covering 110 and fixed or slidably disposed about a core wire 128 ; the first member 120 being affixed to the distal end of the cannula 102 , and the distal - most member 122 being affixed to the distal tip 130 of the core wire 128 . in some forms of the invention , some of the members 112 may be radiopaque to allow for more precise guidance and placement within the vasculature . additionally , in some forms of the invention , some of the members 112 may have magnetic properties such that they may be guided through the vasculature by an externally - applied magnetic field . to provide for a smooth external surface of the flexible portion 108 , and to prevent the bead - like structures of this invention separating from the core wire while inside a patient &# 39 ; s vasculature , the entire flexible region of the wire guide is encapsulated within a covering which is closed at its most distal end , and affixed about the distal end of the cannula . although the invention has been described and illustrated with reference to specific illustrative embodiments thereof , it is not intended that the invention be limited to those illustrative embodiments . those skilled in the art will recognize that variations and modifications can be made without departing from the true scope and spirit of the invention as defined by the claims that follow . it is therefore intended to include within the invention all such variations and modifications as fall within the scope of the appended claims and equivalents thereof . | US-201514868827-A |
this invention describes a novel method of agricultural animal production that provides animals with optimum growth characteristics in a reliable and cost - effective manner . the invention utilizes a novel combination of nuclear transfer and embryonic stem cell technologies that improves the efficiency of delivering optimized animals and facilitates the introduction of genetic modifications into farm animals . | by “ animal ” is meant to include avians , mammals , reptiles and amphibians . preferred animals include avians and mammals as well as any animal that is an endangered species . preferred birds include domesticated birds ( e . g . quail , chickens . ducks , geese , turkeys , and guinea hens ) as well as other birds such as birds of prey ( e . g ., hawks , falcons , ospreys , condors . etc . ), endangered birds ( e . g ., parrots , california condor , etc . ), ostriches etc . preferred mammals include murine , caprine , ovine , bovine , porcine , canine , feline and primate . of these , preferred members include domesticated ungulates ( e . g ., cattle , buffalo , pigs , sheep , and goats ) and humans . by “ female surrogate ” is meant a female animal into which an embryo of the invention is inserted for gestation . typically , the female animal is of the same animal species as the embryo , but the female surrogate may also be of a different animal species . the embryo , as used herein , can include a complex of two or more cells . by “ cytoplast ” is meant the fragment of the cell remaining once the nucleus is removed . by “ enucleated oocyte ” is meant an animal egg which has had its endogenous nucleus removed or inactivated . by “ sperm ” “ semen ,” “ sperm sample ,” and “ semen sample ” are meant the ejaculate from a male animal which contains spermatozoa . a mature sperm cell is a “ spermatozoon ,” whereas the precursor is a “ spermatid .” spermatids are the haploid products of the second meiotic division in spermatogenesis , which differentiate into spermatozoa . the terms “ nuclear transfer ” or “ nuclear transplantation ” refer to a method of cloning , wherein the donor cell nucleus is transplanted into a cell before or after removal of its endogenous nucleus . the cytoplast could be from an enucleated oocyte , an enucleated es cell , an enucleated eg cell , an enucleated embryonic cell or an enucleated somatic cell . nuclear transfer techniques or nuclear transplantation techniques are known in the literature ( campbell et al ., theriogenology 43 : 181 ( 1995 ); collas et al ., mol . reprod . dev . 38 : 264 - 267 ( 1994 ); keefer et al ., biol . reprod . 50 : 935 - 939 ( 1994 ); sims et al ., proc . natl . acad . sci . usa 90 : 6143 - 6147 ( 1993 ); evans et al ., wo 90 / 03432 ; smith et al ., wo 94 / 24274 ; and wheeler et al ., wo 94 / 26884 . also u . s . pat . nos . 4 , 994 , 384 and 5 , 057 , 420 describe procedures for bovine nuclear transplantation . in the subject application , “ nuclear transfer ” or “ nuclear transplantation ” or “ nt ” are used interchangeably . the terms “ nuclear transfer unit ” and “ nt unit ” refer to the product of fusion between or injection of a somatic cell or cell nucleus and an enucleated cytoplast ( e . g ., an enucleated oocyte ), which is some - times referred to herein as a fused nt unit . by “ somatic cell ” is meant any cell of a multicellular organism , preferably an animal , that does not become a gamete . by “ differentiate ” or “ differentiation ” is meant to refer to the process in development of an organism by which cells become specialized for particular functions . differentiation requires that there is selective expression of portions of the genome . by , “ inner cell mass ” or “ icm ” is meant a group of cells found in the mammalian blastocyst that give rise to the embryo and are potentially capable of forming all tissues , embryonic and extra - embryonic , except the trophoblast . by “ feeder layer ” is meant a layer of cells to condition the medium in order to culture other cells , particularly to culture those cells at low or clonal density . by “ medium ” or “ media ” is meant the nutrient solution in which cells and tissues are grown . 2 ) tranfect such cells with an antibiotic resistance gene or any other gene that would allow the selection of these cells by positive selection . an example would be the use of the neomycin resistance gene . 3 ) take one of these cells and perform nuclear transfer to be able to have es cells from the somatic cells . 5 ) take some of these es cells between 2 to 20 , preferably 12 and inject them into a host mammalian embryo . such embryo should be in the stage between one to 200 cells preferably between 8 to 16 cells . the host embryo should not be resistant to the previously - mentioned selectable marker gene . 6 ) place the embryos is culture with a specific dosage of the selection substance , in the example of the neomycin resistance gene . g418 . 7 ) after 7 days in culture , embryos are transferred into the recipient females . iii . an alternative method for the production of es - derived cloned mammals 2 ) take one of these cells and perform nuclear transfer to be able to have es cells from the somatic cells . 4 ) take some of these es cells between 2 to 20 , preferably 12 and inject them into a host mammalian embryo . such embryo should be in the stare between one to 200 cells preferably between 8 to 16 cells . the host embryo should be incapable of development , being for example , a tetraploid embryo . 5 ) after 7 days in culture , embryos are transferred into the recipient females . 1 ) isolate es cells from a superior breeding stock of avian species . 2 ) scale cells up and cryopreserve large quantities of ampules of cells . 3 ) recipient eggs are prepared that are deficient in embryo production by genetic modification of the laying hen , or by exogenous means such as irradiation . the marketed avian or mammalian es cells may subsequently be modified by gene targeting or other means of genetic modification to introduce improved genetics of the final animal . the product envisioned is cryopreserved animal es cells that are stable for long periods of time , and can be stored inexpensively . when the final animal is in demand , the vials can he thawed and injected into the host embryo to produce the final animal . this allows the marketing of cryovials as opposed to live animals . the business model is to market clonal es cells to the final growers . the end customer will also be sold the injection equipment and allied supplies such as host embryos and eggs to produce the final animals . preferably , the nt units used to produce es - like cells will be cultured to a size of at least 2 to 400 cells , preferably 4 to 128 cells , and most preferably to a size of at least about 50 cells . in the present invention , embryonic stem cells , embryonic germ cells and embryonic stem - like cells can be produced according to the present invention . the present application refers to stem - like cells rather than stem cells because of the manner in which they are typically produced . i . e . by cross - species nuclear transfer . while these cells are expected to possess similar differentiation capacity as normal stem cells they may possess some insignificant differences because of the manner they are produced . for example , these stem - like cells may possess the mitochondria of the oocytes used for nuclear transfer , and thus not behave identically to conventional embryonic stem cells . based on the fact that human cell nuclei can be effectively transplanted into bovine oocytes , it is reasonable to expect that human cells maybe transplanted into oocytes of other non - related species , e . g . other ungulates as well as other animals . in particular , other ungulate oocytes should be suitable , e . g ., pigs , sheep , horses , goats . etc . also , oocytes from other sources should be suitable e . g . oocytes derived from other primates , amphibians , rodents , rabbits , guinea pigs , etc . further , using similar methods , it should be possible to transfer human cells or cell nuclei into human oocytes and use the resultant blastocysts to produce human es cells . therefore , in one embodiment , the present invention involves the transplantation of an animal or human cell nucleus or animal or human cell into an oocyte ( preferably enucleated ) of an animal species different from the donor nuclei , by injection or fusion . to produce an nt unit containing cells which may be used to obtain embryonic or stem - like cells and / or cell cultures . in another embodiment , a nucleus of an animal is injected or fused to an oocyte from the same animal species . enucleation ( removal of endogenous oocyte nucleus ) may be effected before or after nuclear transfer . for example , the invention may involve the transplantation of an ungulate cell nucleus or ungulate cell into an enucleated oocyte , e . g . another ungulate or non - ungulate , by injection or fusion , which cells and / or nuclei are combined to produce nt units and which are cultured under conditions suitable to obtain multicellular nt units , preferably comprising at least about 2 to 400 cells , more preferably 4 to 128 cells , and most preferably at least about 50 cells . the cells of such nt units may be used to produce eg cells , es cells , and es - like cells as well as cell colonies upon culturing . nuclear transfer techniques or nuclear transplantation techniques are known in the literature and are described in many of the references cited in the background of the invention . see , in particular , campbell et al . theriogenology , 43 : 181 ( 1995 ); collas et al , mol . report dev ., 38 : 264 - 267 ( 1994 ); keefer et al , biol . reprod ., 50 : 935 - 939 ( 1994 ); sims et al , proc . natl . acad . sci . usa , 90 : 6143 - 6147 ( 1993 ); wo 94 / 26884 ; wo 94 / 24274 , and wo 90 / 03432 , which are incorporated by reference in their entirety herein . also , u . s . pat . nos . 4 , 944 , 384 and 5 , 057 , 420 describe procedures for bovine nuclear transplantation . see , also cibelli et al , science , vol . 280 : 1256 - 1258 ( 1998 ). human or animal cells , preferably mammalian cells , may be obtained and cultured by well known methods . human and animal cells useful in the present invention include , by way of example , epithelial , neural cells , epidermal cells , keratinocytes , hematopoietic cells , melanocytes , chondrocytes , lymphocytes ( b and t lymphocytes ), other immune cells , erythocytes , macrophages , melanocytes , monocytes , mononuclear cells , fibroblasts , cardiac muscle cells , and other muscle cells . etc . moreover , the human cells used for nuclear transfer may be obtained from different organs . e . g . skin , lung , pancreas , liver , stomach , intestine , heart , reproductive organs , bladder , kidney , urethra and other urinary organs . etc . these are just examples of suitable donor cells . suitable donor cells , i . e ., cells useful in the subject invention , may be obtained from any cell or organ of the body . this includes all somatic or germ cells . preferably , the donor cells or nucleus would comprise actively dividing . i . e . non - quiescent ., cells as this has been reported to enhance cloning efficacy . also preferably , such donor cells will be in the g1 cell cycle . the resultant blastocysts may be used to obtain embryonic stem cell lines according to the culturing methods reported by thomson et al ., science , 282 : 1145 - 1147 ( 1998 ) and thomson et al ., proc . natl . acad . sci ., usa , 92 : 7544 - 7848 ( 1995 ), incorporated by reference in their entirety herein . in the example which follows , the cells used as donors for nuclear transfer were epithelial cells derived from the oral cavity of a human donor and adult human keratinocytes . however , as discussed , the disclosed method is applicable to other human cells or nuclei . moreover , the cell nuclei may be obtained from both human somatic and germ cells . it is also possible to arrest donor cells at mitosis before nuclear transfer , using a suitable technique known in the art . methods for stopping the cell cycle at various stages have been thoroughly reviewed in u . s . pat . no . 5 , 262 , 409 , which is herein incorporated by reference . in particular , while cycloheximide has been reported to have an inhibitory effect on mitosis ( bowen and wilson ( 1955 ) j . heredity , 45 : 3 - 9 ), it may also be employed for improved activation of mature bovine follicular oocytes when combined with electric pulse treatment ( yang et al ., ( 1992 ) biol . reprod ., 42 ( suppl . 1 ): 117 ). zygote gene activation is associated with hyperacetylation of histone h4 . trichostatin - a has been shown to inhibit histone deacetylase in a reversible manner ( adenot et al ., development ( 1997 ) 124 ( 22 ): 4615 - 4625 ; yoshida et al ., bioessays ( 1995 ) 17 ( 5 ): 423 - 430 ), as have other compounds . for instance , butyrate is also believed to cause hyper - acetylations of histones by inhibiting histone deacetylase . generally , butyrate appears to modify gene expression and in almost all cases its addition to cells in culture appears to arrest cell growth . use of butyrate in this regard is described in u . s . pat . no . 5 , 681 , 718 , which is herein incorporated by reference . thus , donor cells may be exposed to trichostatin - a or another appropriate deacetylase inhibitor prior to fusion , or such a compound may be added to the culture media prior to genome activation . additionally , demethylation of dna is thought to be a requirement for proper access of transcription factors to dna regulatory sequences . global demethylation of dna from the eight - cell stage to the blastocyst stage in preimplantation embryos has previously been described ( stein et al ., mol . reprod . & amp ; dev ., 47 ( 4 ): 421 - 429 ). also , jaenisch et al . ( 1997 ) have reported that 5 - azacytidine can be used to reduce the level of dna methylation in cells , potentially leading to increased access of transcription factors to dna regulatory sequences . accordingly , donor cells may be exposed to 5 - azacytidine ( 5 - aza ) previous to fusion , or 5 - aza may be added to the culture medium from the 8 cell stage to blastocyst . alternatively , other known methods for effecting dna demethylation may be used . the oocytes used for nuclear transfer may be obtained from animals including mammals , avians , reptiles , and amphibians . suitable mammalian sources for oocytes include sheep , bovines , ovines , pigs , horses , rabbits , goats , guinea pigs , mice , hamsters , rats , primates , humans , etc . in the preferred embodiments , the oocytes will be obtained from primates or ungulates , e . g ., a bovine . methods for isolation of oocytes are well known in the art . essentially , this will comprise isolating oocytes from the ovaries or reproductive tract of a mammal or amphibian , e . g ., a bovine . a readily available source of bovine oocytes is slaughterhouse materials . for the successful use of techniques such as genetic engineering , nuclear transfer and cloning , oocytes must generally be matured in vitro before these cells may be used as recipient cells for nuclear transfer , and before they can be fertilized by the sperm cell to develop into an embryo . this process generally requires collecting immature ( prophase i ) oocytes from animal ovaries . e . g . bovine ovaries obtained at a slaughterhouse and maturing the oocytes in a maturation medium prior to fertilization or enucleation until the oocytes attains the metaphase ii stage , which in the case of bovine oocytes generally occurs about 18 - 24 hours post - aspiration . for purposes of the present invention , this period of time is known as the “ maturation period .” as used herein for calculation of time periods . “ aspiration ” refers to aspiration of the immature oocyte from ovarian follicles . additionally , metaphase ii stage oocytes , which have been matured in vivo have been successfully used in nuclear transfer techniques . essentially , mature meta - phase ii oocytes are collected surgically from either non - superovulated or superovulated cows or heifers 35 to 48 hours past the onset of estrus or past the injection of human chorionic gonadotropin ( hcg ) or similar hormone . the stage of maturation of the oocyte at enucleation and nuclear transfer has been reported to be significant to the success of nt methods . ( see , e . g ., prather et al ., differentiation : 48 : 1 - 8 , 1991 ). in general , previous successful mammalian embryo cloning practices used metaphase ii stage oocyte as the recipient oocyte because at this stage it is believed that the oocyte can be or is sufficiently “ activated ” to treat the introduced nucleus as it does a fertilizing sperm . in domestic animals , and especially cattle , the oocyte activation period generally ranges from about 16 - 52 hours , preferably about 28 - 42 hours post - aspiration . for example , immature oocytes may be washed in hepes buffered hamster embryo culture medium ( hecm ) as described in seshagine et al ., biol . reprod ., 40 : 544 - 606 ( 1989 ) and then placed into drops of maturation medium consisting of 50 μl of tissue culture medium ( tcm ) 199 containing 10 % fetal calf serum which contains appropriate gonadotropins such as luteinizing hormone ( lh ) and follicle stimulating hormone ( fsh ), and estradiol under a layer of lightweight paraffin or silicon at 39 ° c . after a fixed time maturation period , which typically will range from about 10 to 40 hours , and preferably about 16 - 18 hours , the oocytes will typically be enucleated . prior to enucleation the oocytes will preferably be removed and placed in hecm containing 1 mg / ml of hyaluronidase prior to removal of cumulus cells . this may be effected by repeated pipetting through very fine bore pipettes or by vortexing briefly . the stripped oocytes are then screened for polar bodies , and the selected metaphase ii oocytes , as determined by the presence of polar bodies , are then used for nuclear transfer . enucleation follows . as noted above , enucleation may be effected before or after introduction of donor cell or nucleus because the donor nucleus is readily discernible from endogenous nucleus . enucleation may be effected by known methods , such as described in u . s . pat . no . 4 , 994 , 384 which is incorporated by reference herein . for example , metaphase ii oocytes are either placed in hecm , optionally containing 7 . 5 μg / ml cytochalasin b , for immediate enucleation , or may be placed in a suitable medium , for example cr1aa , plus 10 % estrus cow serum , and then enucleated later , preferably not more than 24 hours later , and more preferably 16 - 18 hours later . enucleation may be accomplished microsurgically using a micropipette to remove the polar body and the adjacent cytoplasm . the oocytes may then be screened to identify , those of which have been successfully enucleated . this screening may be effected by staining the oocytes with 1 μg / ml 33342 hoechst dye in hecm , and then viewing the oocytes under ultraviolet irradiation for less than 10 seconds . the oocytes that have been successfully enucleated can then be placed in a suitable culture medium . in the present invention , the recipient oocytes will typically be enucleated at a time ranging from about 10 hours to about 40 hours after the initiation of in vitro maturation , more preferably from about 16 hours to about 24 hours after initiation of in vitro maturation , and most preferably about 16 - 18 hours after initiation of in vitro maturation . enucleation may be effected before , simultaneous or after nuclear transfer . also , enucleation may be effected before , after or simultaneous to activation . a single animal or human cell or nucleus derived therefrom which is typically heterologous to the enucleated oocyte will then be transferred into the perivitelline space of the oocyte , typically enucleated , used to produce the nt unit . however , removal of endogenous nucleus may alternatively be effected after nuclear transfer . the animal or human cell or nucleus and the enucleated oocyte will be used to produce nt units according to methods known in the art . for example , the cells may be fused by electrofusion . electrofusion is accomplished by providing a pulse of electricity that is sufficient to cause a transient break down of the plasma membrane . this breakdown of the plasma membrane is ver , short because the membrane reforms rapidly . essentially , if two adjacent membranes are induced to break down , upon reformation the lipid bilayers intermingle and small channels will open between the two cells . due to the thermodynamic instability of such a small opening , it enlarges until the two cells become one . reference is made to u . s . pat . no . 4 , 997 , 384 , by prather et a )., ( incorporated by reference in its entirety herein ) for a further discussion of this process . a variety of electrofusion media can be used including , e . g ., sucrose , mannitol , sorbitol and phosphate buffered solution . fusion can also be accomplished using sendai virus as a fusogenic agent ( graham , wister inot . symp . monogr ., 9 : 19 , 1969 ). also , in some cases ( e . g . with small donor nuclei ) it may be preferable to inject the nucleus directly into the oocyte rather than using electroporation fusion . such techniques are disclosed in collas and barnes , mol . reprod . dev ., 38 : 264 - 7 ( 1994 ), and incorporated by reference in its entirety herein . preferably , the human or animal cell and oocyte are electrofused in a 500 μm chamber by application of an electrical pulse of 90 - 120v for about 15 μsec , about 24 hours after initiation of oocyte maturation . after fusion , the resultant fused nt units are preferably placed in a suitable medium until activation . e . g . one identified infra . typically activation will be effected shortly thereafter , typically less than 24 hours later , and preferably about 4 - 9 hours later . however , it is also possible to activate the recipient oocyte before or proximate ( simultaneous ) to nuclear transfer , which may or may not be enucleated . for example , activation may be effected from about twelve hours prior to nuclear transfer to about twenty - four hours after nuclear transfer . more typically , activation is effected simultaneous or shortly after nuclear transfer , e . g ., about four to nine hours later . the nt unit may be activated by known methods . such methods include , e . g ., culturing the nt unit at sub - physiological temperature , in essence by applying a cold , or actually cool temperature shock to the nt unit . this may be most conveniently done by culturing the nt unit at room temperature , which is cold relative to the physiological temperature conditions to which embryos are normally exposed . alternatively , activation may be achieved by application of known activation agents . for example , penetration of oocytes by sperm during fertilization has been shown to activate prefusion oocytes to yield greater numbers of viable pregnancies and multiple genetically identical calves after nuclear transfer . also , treatments such as electrical and chemical shock or cycloheximide treatment may also be used to activate nt embryos after fusion . suitable oocyte activation methods are the subject of u . s . pat . no . 5 , 496 , 720 , to susko - parrish et al . which is herein incorporated by reference . for example , oocyte activation may be effected by simultaneously or sequentially : this will generally be effected by introducing divalent cations into the oocyte cytoplasm , e . g ., magnesium , strontium , barium or calcium , e . g ., in the form of an ionophore . other methods of increasing divalent cation levels include the use of electric shock , treatment with ethanol and treatment with caged chelators . phosphorylation may be reduced by known methods , e . g . by the addition of kinase inhibitors , e . g ., serine - threonine kinase inhibitors , such as 6 - dimethylamino - purine , staurosporine , 2 - aminopurine , and sphingosine . alternatively , phosphorylation of cellular proteins may be inhibited by introduction of a phosphatase into the oocyte , e . g ., phosphatase 2a and phosphatase 2b . 1 — place oocytes in ionomycin ( 5 μm ) with 2 mm of dmap for 4 minutes ; 2 — move the oocytes into culture media with 2 mm of dmap for 4 hours ; 1 — place oocytes in ionomycin ( 5 μm ) with 2 mm of dmap for four minutes ; 2 — move the oocytes into culture media with 2 mm of dmap and 200 microm of roscovitin for three hours . 2 — move oocytes to culture media containing 5 μg / ml of cytochalasin b and 5 μg / ml of cycloheximide for five hours ; 1 — place eggs in mannitol media containing 100 μm cacl 2 ; 2 — deliver three pulses of 1 . 0 kvcm − 1 for 20 μsec . each pulse 22 minutes apart ; 3 — move oocytes to culture media containing 5 μg / ml of cytochalasin b for three hours . 2 — move oocytes to culture media containing 5 μg / ml of cytochalasin b and 5 μg / ml of cycloheximide for five hours ; 1 — inject oocytes with 10 to 12 picoliters of a solution containing 10 μm of adenophostine ; 1 — inject oocytes with 10 to 12 picoliters of sperm factor isolated , e . g ., from primates , pigs , bovine , sheep , goals , horses , mice , rats , rabbits or hamsters . 9 . activation by exposure to dmap followed by cycloheximide and cytochalasin b place oocytes or nt units , typically about 22 to 28 hours post maturation in about 2 mm dmap for about one hour , followed by incubation for about two to twelve hours , preferably about eight hours , in 5 μg / ml of cytochalasin b and 20 μg / ml cycloheximide . the above activation protocols are exemplary of protocols used for nuclear transfer procedures , e . g ., those including the use of primate or human donor cells or oocytes . however , the above activation protocols may be used when either or both the donor cell and nucleus is of ungulate origin , e . g ., a sheep , buffalo , horse , goat , bovine , pig and / or wherein the oocyte is of ungulate origin , e . g . sheet , pig , buffalo , horse , goal , bovine , etc ., as well as for other species . as noted , activation may be effected before , simultaneous , or after nuclear transfer . an general , activation will be effected about 40 hours prior to nuclear transfer and fusion to about 40 hours after nuclear transfer and fusion , more preferably about 24 hours before 10 about 24 hours after nuclear transfer and fusion , and most preferably from about 4 to 9 hours before nuclear transfer and fusion to about 4 to 9 hours after nuclear transfer and fusion . activation is preferably effected after or proximate to in vitro or in vivo maturation of the oocyte , e . g ., approximately simultaneous or within about 40 hours of maturation , more preferably within about 24 hours of maturation . activated nt units may be cultured in a suitable in vitro culture medium until the generation of embryonic or stem - like cells and cell colonies . culture media suitable for culturing and maturation of embryos are well known in the art . examples of known media , which may be used for bovine embryo culture and maintenance . include ham &# 39 ; s f - 10 supplemented with 10 % fetal calf serum ( fcs ), tissue culture medium - 199 ( tcm - 199 ) supplemented with 10 % fetal calf serum . tyrodes - albumin - lactate - pyruvate ( talp ), dulbecco &# 39 ; s phosphate buffered saline ( pbs ), eagle &# 39 ; s and whitten &# 39 ; s media . one of the most common media used for the collection and maturation of oocytes is tcm - 199 , and 1 to 20 % serum supplement including fetal calf serum , newborn serum , estrual cow serum , lamb serum or steer serum . a preferred maintenance medium includes tcm - 199 with earl salts , 10 % fetal calf serum , 0 . 2 m pyruvate and 50 μg / ml gentamycin sulphate . any of the above may also involve co - culture with a variety of cell types such as granulosa cells oviduct cells . brl cells and uterine cells and sto cells . in particular , human epithelial cells of the endometrium secrete leukemia inhibitory factor ( lif ) during the preimplantation and implantation period . therefore , the addition of lif to the culture medium could be of importance in enhancing the in vitro development of the reconstructed embryos . the use of lif for embryonic or stem - like cell cultures has been described in u . s . pat . no . 5 , 712 , 156 , which is herein incorporated by reference . another maintenance medium is described in u . s . pat . no . 5 , 096 , 822 to rosenkrans , jr . et al ., which is incorporated herein by reference . this embryo medium , named cr1 , contains the nutritional substances necessary to support an embryo . cr1 contains hemicalcium l - lactate in amounts ranging from 1 . 0 mm to 10 mm , preferably 1 . 0 mm to 5 . 0 mm . hemicalcium l - lactate is l - lactate with a hemicalcium salt incorporated thereon . also , suitable culture medium for maintaining human embryonic cells in culture as discussed in thomson et al ., science , 282 : 1145 - 7 ( 1998 ) and proc . natl . acad . sci . usa , 92 : 7844 - 8 ( 1995 ). afterward , the cultured nt unit or units are preferably washed and then placed in a suitable media , e . g ., cr1aa medium . ham &# 39 ; s f - 10 , tissue culture media - 199 ( tcm - 199 ). tyrodes - albumin - lactate - pyruvate ( talp ) dulbecco &# 39 ; s phosphate buffered saline ( pbs ), eagle &# 39 ; s or whitten &# 39 ; s , preferably containing about 10 % fcs . such culturing will preferably be effected in well plates which contain a suitable confluent feeder layer . suitable feeder layers include , by way of example , fibroblasts and epithelial cells e . g . fibroblasts and uterine epithelial cells derived from ungulates , chicken fibroblasts murine ( e . g . mouse or rat ) fibroblasts . sto and s1 - m220 feeder cell lines , and brl cells . in the preferred embodiment , the feeder cells will comprise mouse embryonic fibroblasts . means for preparation of a suitable fibroblast feeder layer are described in the example which follows and is well within the skill of the ordinary artisan . the nt units are cultured on the feeder layer until the nt units reach a size suitable for obtaining cells which may be used to produce embryonic stem - lire cells or cell colonies . preferably , these n units will be cultured until they reach a size of at least about 2 to 400 cells , more preferably about 4 to 128 cells , and most preferably at least about 50 cells . the culturing will be effected under suitable conditions . i . e . about 38 . 5 ° c . and 5 % co 2 with the culture medium changed in order to optimize growth typically about every 2 - 5 days , preferably about every 3 days . in the case of human cell / enucleated bovine oocyte derived nt units , sufficient cells to produce an es cell colony , typically on the order of about 50 cells , will be obtained about 12 days after initiation of oocyte activation . however , this may vary dependent upon the particular cell used as the nuclear donor , the species of the particular oocyte , and culturing conditions . one skilled in the an can readily ascertain visually when a desired sufficient number of cells has been obtained based on the morphology of the cultured nt units . in the case of human / human nuclear transfer embryos , or other embryos produced using non - human primate donor or oocyte , it maybe advantageous to use culture medium known to be useful for maintaining human and other primate cells in tissue culture . examples of a culture media suitable for human embryo culture include the medium reported in jones et al ., human reprod ., 13 ( 1 ): 169 - 177 ( 1998 ), the p1 - catalog # 99242 medium , and the p - 1 catalog # 99292 medium , both available from irvine scientific . santa ana , calif . and those used by thomson et al ., ( 1998 ) and ( 1995 ), which references are incorporated by reference in their entirety . another preferred medium comprises : acm , uridine , glucose , 1000 iu of lif . as discussed above , the cells used in the present invention will preferably comprise mammalian somatic cells ., most preferably cells derived from an actively proliferating ( non - quiescent ) mammalian cell culture . in an especially preferred embodiment , the donor cell will be genetically modified by the addition , deletion or substitution of a desired dna sequence . for example , the donor cell . e . g . a keratinocyte or fibroblast . e . g . of human , primate or bovine origin , may be transfected or transformed with a dna construct that provides for the expression of a desired gene product , e . g ., therapeutic polypeptide . examples thereof include lymphokines , e . g ., igf - i , igf - ii , interferons , colony stimulating factors , connective tissue polypeptides such as collagens , genetic factors , clotting factors , enzymes , enzyme inhibitors . etc . also , as discussed above , the donor cells may be modified prior to nuclear transfer , e . g . to effect impaired cell lineage development , enhanced embryonic development and / or inhibition of apoptosis . examples of desirable modifications are discussed further below . one aspect of the invention will involve genetic modification of the donor cell . e . g ., a human cell , such that it is lineage deficient and therefore hen used for nuclear transfer it will be unable to give rise to a viable offspring . this is desirable especially in the context of human nuclear transfer embryos , wherein for ethical reasons , production of a viable embryo may be an unwanted outcome . this can be effected by genetically engineering a human cell such that it is incapable of differentiating into specific cell lineages when used for nuclear transfer . in particular , cells may be genetically modified such that when used as nuclear transfer donors the resultant “ embryos ” do not contain or substantially lack at least one of mesoderm , endoderm or ectoderm tissue . this can be accomplished by . e . g . knocking - out or impairing the expression of one or more mesoderm , endoderm or endoderm specific genes . examples thereof include : the above list is intended to be exemplar and non - exhaustive of known genes which are involved in the development of mesoderm , endoderm and ectoderm . the generation of mesoderm deficient , endoderm deficient and ectoderm deficient cells and embryos has been previously reported in the literature . see , e . g . arsenian et al ., embo j ., 17 ( 2 ): 6289 - 99 ( 1998 ); saga . mech . dev ., 75 ( 1 - 2 ): 53 - 66 ( 1998 ). holdener et al . development . 120 ( 5 ): 1355 - 1346 ( 1994 ); chen et al ., genes dev . 8 ( 20 ): 2466 - 77 ( 1994 ): rohwedel et al . dev . biol ., 201 ( 2 ): 167 - 89 ( 1998 ) ( mesoderm ); morrisey et al . genes . dev . 12 ( 22 ): 3579 - 90 ( 1998 ); soudais et al . development , 121 ( 11 ): 3877 - 88 ( 1995 ) ( endoderm ); and lee et al ., proc . natl . acad . sci . usa , 95 ( 23 ): 13709 - 13 ( 1998 ); and radice et al ., development . 111 ( 3 ): 801 - 11 ( 1991 ) ( ectoderm ). in general , a desired somatic cell . e . g . a human keratinocyte , epithelial cell or fibroblast , will be genetically engineered such that one or more genes specific to particular cell lineages are “ knocked - out ” and / or the expression of such genes significantly impair ed . this may be effected by known methods , e . g . homologous recombination . a preferred genetic system for effecting “ knock - out ” of desired genes is disclosed by capecchi et al ., u . s . pat . nos . 5 , 631 , 153 and 5 , 464 , 764 , which reports positive - negative selection ( pns ) vectors that enable targeted modification of dna sequences in a desired mammalian genome . such genetic modification will result in a cell that is incapable of differentiating into a particular cell lineage when used as a nuclear transfer donor . this genetically modified cell will be used to produce a lineage - defective nuclear transfer embryo . i . e ., that does not develop at least one of a functional mesoderm , endoderm or ectoderm . thereby , the resultant embryos , even if implanted , e . g ., into a human uterus , would not give rise to a viable offspring . however , the es cells that result from such nuclear transfer will still be useful in that they will produce cells of the one or two remaining non - impaired lineage . for example , an ectoderm deficient human nuclear transfer embryo will still give rise to mesoderm and endoderm derived differentiated cells . an ectoderm deficient cell can be produced by deletion and / or impairment of one or both of rna helicase a or h beta 58 genes . these lineage deficient donor cells may also be genetically modified to express another desired dna sequence . thus , the genetically modified donor cell will give rise to a lineage - deficient blastocyst which , when plated , will differentiate into at most two of the embryonic germ layers . alternatively , the donor cell can be modified such that it is “ mortal .” this can be achieved by expressing antisense or ribozyme telomerase genes . this can be effected by known genetic methods that will provide for expression of antisense dna or ribozymes , or by gene knockout . these “ mortal ” cells , when used for nuclear transfer , will not be capable of differentiating into viable offspring . another preferred embodiment of the present invention is the production of nuclear transfer embryos that grow more efficiently in tissue culture . this is advantageous in that it should reduce the requisite time and necessary fusions to produce es cells and / or offspring ( if the blastocysts are to be implanted into a female surrogate ). this is desirable also because it has been observed that blastocysts and es cells resulting from nuclear transfer may have impaired development potential . while these problems may often be alleviated by alteration of tissue culture conditions , an alternative solution is to enhance embryonic development by enhancing expression of genes involved in embryonic development . for example , it has been reported that the gene products of the ped type , which are members of the mhc i family , are of significant importance to embryonic development . more specifically , it has been reported in the case of mouse preimplantation embryos that the q7 and q9 genes are responsible for the “ fast growth ” phenotype . therefore , it is anticipated that introduction of dnas that provide for the expression of these and related genes , or their human or other mammalian counterparts into donor cells , will give rise to nuclear transfer embryos that grow more quickly . this is particularly desirable in the context of cross - species nuclear transfer embryos which may develop less efficiently in tissue culture than nuclear transfer embryos produced by fusion of cells or nuclei of the same species . in particular , a dna construct containing the q7 and / or q9 gene will be introduced into donor somatic cells prior to nuclear transfer . for example , an expression construct can be constructed containing a strong constitutive mammalian promoter operably linked to the q7 and / or q9 genes , an ires , one or more suitable selectable markers , e . g ., neomycin . ada , dhfr , and a poly - a sequence , e . g ., bgh polya sequence . also , it may be advantageous to further enhance q7 and q9 gene expression by the inclusion of insulates . it is anticipated that these genes will be expressed early on in blastocyst development as these genes are highly conserved in different species , e . g ., bovines , goats , porcine , dogs cats and humans . also , it is anticipated that donor cells can be engineered to affect other genes that enhance embryonic development . thus , these genetically modified donor cells should produce blastocysts and preimplantation stage embryos more efficiently . still another aspect of the invention involves the construction of donor cells that are resistant to apoptosis . i . e ., programmed cell death . it has been reported in the literature that cell death related genes are present in preimplantation stage embryos ( adams et al ., science , 281 ( 5381 ): 1322 - 6 ( 1995 )). genes reported to induce apoptosis include e . g . bad . bok , bh3 , bik , hrk , bnip3 bim l , bad , bid , and egl - 1 . by contrast , genes that reportedly protect cells from programmed cell death include , by way of example , bcl - xl , bcl - w , mcl - 1 , a1 , nr - 13 , bhrf - 1 , lmw5 - hl , orf16 , ks - bel - 2 , e1b - 19k , and ced - 9 . thus , donor cells can be constructed wherein genes that induce apoptosis are “ knocked out ” or wherein the expression of genes that protect the cells from apoptosis is enhanced or turned on during embryonic development . for example , this can be effected by introducing a dna construct that provides for regulated expression of such protective genes , e . g ., bcl - 2 or related genes during embryonic development . thereby , the gene can be “ turned on ” by culturing the embryo under specific growth conditions . alternatively , it can be linked to a constitutive promoter . more specifically ., a dna construct containing a bcl - 2 gene operably linked to a regulatable or constitutive promoter , e . g . pgk , s140 cmv , ubiquitin , or β - actin , an ires , a suitable selectable marker , and a poly - a sequence can be constructed and introduced into a desired donor mammalian cell . e . g ., human keratinocyte or fibroblast . these donor cells , when used to produce nuclear transfer embryos , should be resistant to apoptosis and thereby differentiate more efficiently in tissue culture . thereby , the speed and / or number of suitable preimplantation embryos produced by nuclear transfer can be increased . another means of accomplishing the same result is to impair the expression of one or more genes that induce apoptosis . this will be effected by knock - out or by the use of antisense or ribozymes against genes that are expressed in and which induce apoptosis early on in embryonic development . examples thereof are identified above . cell death genes that may be expressed in the antisense orientation include bax . apaf - 1 , and capsases . additionally , a transgene may be introduced that encodes for methylase or demethylase in the sense or antisense orientation . dnas that encode methylase and demethylase enzymes are well known in the art . still alternatively , donor cells may be constructed containing both modifications , i . e ., impairment of apoptosis - inducing genes and enhanced expression of genes that impede or prevent apoptosis . the construction and selection of genes that affect apoptosis , and cell lines that express such genes , is disclosed in u . s . pat . no . 5 , 646 , 008 , which patent is incorporated by reference herein . many dnas that promote or inhibit apoptosis have been reported and are the subject of numerous patents . another means of enhancing cloning efficiency is to select cells of a particular cell cycle stage as the donor cell . it has been reported that this can have significant effects on nuclear transfer efficiency ( barnes et al ., mol . reprod . devel ., 36 ( 1 ): 33 - 41 ( 1993 )). different methods for selecting cells of a particular cell cycle stage have been reported and include serum starvation ( campbell et al ., nature 380 : 64 - 66 ( 1996 ); wilmut et al ., nature , 385 : 810 - 3 ( 1997 )), and chemical synchronization ( urbani et al ., exp . cell res ., 219 : 159 - 68 ( 1995 )). for example , a particular cyclin dna may be operably linked to a regulatory sequence , together with a delectable marker , e . g ., green fluorescent protein ( gfp ), followed by the cyclin destruction box , and optionally insulation sequences to enhance cyclin and marker protein expression . thereby , cells of a desired cell cycle can be easily visually detected and selected for use as a nuclear transfer donor . an example thereof is the cyclin d1 gene in order to select for cells that are in g1 . however , any cyclin gene should be suitable for use in the claimed invention . ( see , e . g ., king et al ., mol . biol . cell . 7 ( 9 ): 1343 - 57 ( 1996 )). however , a less invasive or more efficient method for producing cells of a desired cell cycle stale are needed . it is anticipated that this can be effected by genetically modifying donor cells such that they express specific cyclins under delectable conditions . thereby , cells of a specific cell cycle can be readily discerned from other cell cycles . cyclins are proteins that are expressed only during specific stages of the cell cycle . they include cyclin d1 , d2 and d3 in g1 phase , cyclin b1 and b2 in g2 / m phase and cyclin e , a and h in s phase . these proteins are easily translated and destroyed in the cytogolcytosol . this “ transient ” expression of such proteins is attributable in part to the presence of a “ destruction box ”, which is a short amino acid sequence that is part of the protein that functions as a tag to direct the prompt destruction of these proteins via the ubiquitin pathway ( adams et al ., science . 281 ( 5321 ): 1322 - 26 ( 1998 )). in the present invention , donor cells will be constructed that express one or more of such cyclin genes under easily detectable conditions , preferably visualization . e . g . by the use of a fluorescent label . for example , a particular cyclin dna may be operably linked to a regulatory sequence , together with a detectable marker . e . g . green fluorescent protein ( gfp ), followed by the cyclin destruction box , and optionally insulation sequences to enhance cyclin and / or marker protein expression . thereby , cells of a desired cell cycle can be easily visually detected and selected for use as a nuclear transfer donor . an example thereof is the cyclin d1 gene which can be used to select for cells that are in g1 . however , any cyclin gene should be suitable for use in the claimed invention . ( see , e . g . king et al . mol . biol . cell , 7 ( 9 ): 1343 - 57 ( 1996 )). as discussed , the present invention provides different methods for enhancing nuclear transfer efficiency , preferably a cross - species nuclear transfer process . while the present inventors have demonstrated that nuclei or cells of one species when inserted or fused with an enucleated oocyte of a different species can give rise to nuclear transfer embryos that produce blastocysts , which embryos can give rise to es cell lines , the efficiency of such process is quite low . therefore , many fusions typically need to be effected to produce a blastocyst the cells of which may be cultured to produce es cells and es cell lines . yet another means for enhancing the development of nuclear transfer embryos in vitro is by optimizing culture conditions . one means of achieving this result will be to culture nt embryos under conditions impede apoptosis . with respect to this embodiment of the invention , it has been found that proteases such as capsases can cause oocyte death by apoptosis similar to other cell types . ( see . jurisicosva et al ., mol . reprod . devel . 51 ( 3 ): 243 - 53 ( 1998 )). it is anticipated that blastocyst development will be enhanced by including in culture media used for nuclear transfer and to maintain blastocysts or culture preimplantation stage embryos one or more capsase inhibitors . such inhibitors include by way of example capsase - 4 inhibitor i , capsase - 3 inhibitor i , capsase - 6 inhibitor ii , capsase - 9 inhibitor ii , and capsase - 1 inhibitor i . the amount thereof will be an amount effective to inhibit apoptosis , e . g ., 0 . 00001 to 5 . 0 % by weight of medium , more preferably 0 . 01 % to 1 . 0 % by weight of medium . thus , the foregoing methods may be used to increase the efficiency of nuclear transfer by enhancing subsequent blastocyst and embryo development in tissue culture . after nt units of the desired size are obtained , the cells are mechanically removed from the zone and are then used to produce eg . es or es - like cells or cell lines . this is preferably effected by taking the clump of cells which comprise the nt unit , which typically will contain at least about 50 cells , washing such cells , and plating the cells onto a feeder layer . e . g ., irradiated fibroblast cells . typically , the cells used to obtain the stem - like cells or cell colonies will be obtained from the inner most portion of the cultured nt unit which is preferably at least 50 cells in size . however . nt units of smaller or greater cell numbers as well as cells from other portions of the nt unit may also be used to obtain es - like cells and cell colonies . it is further envisioned that a longer exposure of donor cell dna to the oocyte &# 39 ; s cytosol may facilitate the dedifferentiation process . this can be accomplished by re - cloning , i . e ., by taking blastomeres from a reconstructed embryo and fusing them with a new enucleated oocyte . alternatively , the donor cell may he fused with an enucleated oocyte and four to six hours later , without activation , chromosomes removed and fused with a younger oocyte . activation would occur thereafter . the cells are maintained in the feeder layer in a suitable growth medium , e . g . alpha mem supplemented with 10 % fcs and 0 . 1 mm β - mercaptoethanol ( sigma ) and l - glutamine . the growth medium is changed as often as necessary to optimize growth . e . g ., about every 2 - 3 days . this culturing process results in the formation of embryonic or stem - like cells or cell lines . in the case of human cell / bovine oocyte declined nt embryos , colonies are observed by about the second day of culturing in the alpha mem medium . however , this time may vary dependent upon the particular nuclear donor cell , specific oocyte and culturing to conditions . one skilled in the an can vary the culturing conditions as desired to optimize growth of the particular embryonic or stem - like cells . other suitable media are disclosed herein . alternatively , that such cells are actual human or primate embryonic stein cells will be confirmed based on their capability of giving rise to all of mesoderm , ectoderm and endoderm tissues . this will be demonstrated by culturing es cells produced according to the invention under appropriate conditions , e . g ., as disclosed by thomsen , u . s . pat . no . 5 , 843 , 780 , incorporated by reference in its entirety herein . alternatively , the fact that the cells produced according to the invention are pluripotent will be confirmed by injecting such cells into an animal , e . g ., a scid mouse , or large agricultural animal , and thereafter obtaining tissues that result from said implanted cells . these implanted es cells should give rise to all different types of differentiated tissues , i . e ., mesoderm , ectoderm , and endodermal tissues . the resultant es . eg . es - like cells and cell lines have numerous therapeutic and diagnostic applications . for example , such embryonic or stem - like cells may be used for cell transplantation therapies . human embryonic or stem - like cells have application in the treatment of numerous disease conditions . still another object of the present invention is to improve the efficacy of nuclear transfer , e . g ., cross - species nuclear transfer by introducing mitochondrial dna of the same species as the donor cell or nucleus into the recipient oocyte before or after nuclear transfer , before or after activation , and before or after fusion and cleavage . preferably , if the donor cell is human , human mitochondrial dna will be derived from cells of the particular donor . e . g ., liver cells and tissue . methods for isolating mitochondria are well known in the art . mitochondria can be isolated from cells in tissue culture , or from tissue . the particular cells or tissue will depend upon the particular species of the donor cell . examples of cells or tissues that may be used as sources of mitochondria include fibroblasts , epithelium , liver , lung , keratinocyte , stomach , heart , bladder , pancreas , esophageal lymphocytes , monocytes , mononuclear cells , cumulus cells , uterine cells , placental cells , intestinal cells , hematopoietic cells , and tissues containing such cells . for example , mitochondria can be isolated from tissue culture cells and rat liver . it is anticipated that the same or similar procedures may be used to isolate mitochondria from other cells and tissues . as noted above , preferred source of mitochondria comprises human liver tissue because such cells contain a large number of mitochondria . those skilled in the art will be able to modify the procedure as necessary , dependent upon the particular cell line or tissue . the isolated dna can also be further purified , if desired , known methods , e . g ., density gradient centrifugation . in this regard , it is known that mouse embryonic stem ( es ) cells are capable of differentiating into almost any cell type e . g ., hematopoietic stem cells . therefore , human es or es - like cells as well as that of other species produced according to the invention should possess similar differentiation capacity . the es . eg and eg - like cells according to the invention will be induced to differentiate to obtain the desired cell types according to known methods . for example , the subject es . eg and eg - like cells may be induced to differentiate into hematopoietic stem cells , muscle cells , cardiac muscle cells , liver cells , cartilage cells , epithelia ) cells , urinary tract cells , etc . by culturing such cells in differentiation medium and under conditions which provide for cell differentiation . medium and methods which result in the differentiation of embryonic stem cells are known in the art as are suitable culturing conditions . for example , palacios et al ., proc . natl . acad . sci . usa , 92 : 7530 - 37 ( 1995 ) teaches the production of hematopoietic stem cells from an embryonic cell line by subjecting stem cells to an induction procedure comprising initially culturing aggregates of such cells in a suspension culture medium lacking retinoic acid followed by culturing in the same medium containing retinoic acid , followed by transferral of cell aggregates to a substrate which provides for cell attachment . moreover , pedersen , j . reprod . fertil . dev ., 6 : 543 - 52 ( 1994 ) is a review article which references numerous articles disclosing methods for in vitro differentiation of embryonic stem cells to produce various differentiated cell types including hematopoietic cells , muscle , cardiac muscle , nerve cells , among others . further , bain et al ., dev . biol ., 168 : 342 - 357 ( 1995 ) leaches in vitro differentiation of embryonic stem cells to produce neural cells which possess neuronal properties . these references are exemplar of reported methods for obtaining differentiated cells from embryonic or stem - like cells . these references and in particular the disclosures therein relating to methods for differentiating embryonic stem cells are incorporated by reference in their entirety herein . thus , using known methods and culture medium , one skilled in the an may culture the subject embryonic or stem - like cells to obtain desired differentiated cell types , e . g . neural cells , muscle cells , hematopoietic cells , etc . in addition , the use of inducible bcl - 2 or bcl - x1 might be useful for enhancing in vitro development of specific cell lineages . in vivo , bcl - 2 prevents many , but not all , forms of apoptotic cell death that occur during lymphoid and neural development . a thorough discussion of how bcl - 2 expression might be used to inhibit apoptosis of relevant cell lineages following transfection of donor cells is disclosed in u . s . pat . no . 5 , 646 , 008 , which is herein incorporated by reference . the subject embryonic or stem - like cells may be used to obtain any desired differentiated cell type . therapeutic usages of such differentiated human cells are unparalleled . for example , human hematopoietic stem cells may be used in medical treatments requiring bone marrow transplantation . such procedures are used to treat many diseases , e . g ., late stage cancers such as ovarian cancer and leukemia , as well as diseases that compromise the immune system , such as aids . hematopoietic stem cells can be obtained , e . g ., by fusing adult somatic cells of a cancer or aids patient . e . g ., epithelial cells or lymphocytes with an enucleated oocyte , e . g ., bovine oocyte , obtaining embryonic or stem - like cells as described above , and culturing such cells under conditions which favor differentiation , until hematopoietic stem cells are obtained . such hematopoietic cells may be used in the treatment of diseases including cancer and aids . alternatively , adult somatic cells from a patient with a neurological disorder may be fused with an enucleated animal oocyte , e . g ., a primate or bovine oocyte , human embryonic or stem - like cells obtained therefrom , and such cells cultured under differentiation conditions to produce neural cell lines . specific diseases treatable by transplantation of such human neural cells include , by way of example , parkinson &# 39 ; s disease . alzheimer &# 39 ; s disease , als and cerebral palsy , among others . in the specific case of parkinson &# 39 ; s disease , it has been demonstrated that transplanted fetal brain neural cells make the proper connections with surrounding cells and produce dopamine . this can result in long - term reversal of parkinson &# 39 ; s disease symptoms . to allow for specific selection of differentiated cells , donor cells may be transfected with selectable markers expressed via inducible promoters , thereby permitting selection or enrichment of particular cell lineages when differentiation is induced . for example , cd34 - neo may be used for selection of hematopoietic cells , pwl - neo for muscle cells , mash - 1 - neo for sympathetic neurons , mal - neo for human cns neurons of the grey matter of the cerebral cortex . etc . the great advantage of the subject invention is that it provides an essentially limitless supply of isogenic or synegenic human cells suitable for transplantation . therefore , it will obviate the significant problem associated with current transplantation methods , i . e ., rejection of the transplanted tissue which may occur because of host versus graft or graft versus host rejection . conventionally , rejection is prevented or reduced by the administration of anti - rejection drugs such as cyclosporin . however , such drugs have significant adverse side - effects . e . g ., immunosuppression , carcinogenic properties , as well as being very expensive . the present invention should eliminate , or at least greatly reduce , the need for anti - rejection drugs , such as cyclosporine , imulan , fk - 506 , glucocorticoids , and rapamycin , and derivatives thereof . other diseases and conditions treatable by isogenic cell therapy include , by way of example , spinal cord injuries , multiple sclerosis , muscular dystrophy , diabetes , liver diseases , i . e ., hypercholesterolemia , heart diseases , cartilage replacement , burns , foot ulcers , gastrointestinal diseases , vascular diseases , kidney disease , urinary tract disease , and aging related diseases and conditions . also , human embryonic or stem - like cells produced according to the invention may be used to produce genetically engineered or transgenic human differentiated cells . essentially , this will be effected by introducing a desired gene or genes , which may be heterologous or removing all or pail of an endogenous gene or genes of human embryonic or stem - like cells produced according to the invention , and allowing such cells to differentiate into the desired cell type . a preferred method for achieving such modification is by homologous recombination because such technique can be used to insert , delete or modify a gene or genes at a specific site or sites in the stem - like cell genome . this methodology can be used to replace defective genes . e . g . defective immune system genes , cystic fibrosis genes , or to introduce genes which result in the expression of therapeutically beneficial proteins such as growth factors , lymphokines , cytokines , enzymes etc . for example , the gene encoding brain derived growth factor may be introduced into human embryonic or stem - like cells , the cells differentiated into neural cells and the cells transplanted into a parkinson &# 39 ; s patient to retard the loss of neural cells during such disease . previously , cell types transfected with bdnf varied from primary cells to immortalized cell lines , either neural or non - neural ( myoblast and fibroblast ) derived cells . for example , astrocytes have been transfected with bdnf gene using retroviral vectors , and the cells grafted into a rat model of parkinson &# 39 ; s disease ( yoshimoto et al ., brain research , 691 : 25 - 36 , ( 1995 )). this ex vivo therapy reduced parkinson &# 39 ; s - like symptoms in the rats up to 45 % 32 days after transfer . also , the tyrosine hydroxylase gene has been placed into astrocytes with similar results ( lundberg et al ., develop . neurol ., 139 : 39 - 53 ( 1996 ) and references cited therein ). however , such ex vivo systems have problems . in particular , retroviral vectors currently used are down - regulated in vivo and the transgene is only transiently expressed ( review by mulligan , science , 260 : 926 - 932 ( 1993 )). also , such studies used primary cells , astrocytes , which have finite life span and replicate slowly . such properties adversely affect the rate of transfection and impede selection of stably transfected cells . moreover , it is almost impossible to propagate a large population of gene targeted primary cells to be used in homologous recombination techniques . by contrast , the difficulties associated with retroviral systems should be eliminated by the use of human es and es - like cells and cell lines . it has been demonstrated previously by the subject assignee that cattle and pig embryonic cell lines can be transfected and selected for stable integration of heterologous dna . such methods are described in commonly assigned u . s . ser . no . 08 / 626 , 054 , filed apr . 1 , 1996 , now u . s . pat . no . 5 , 905 , 042 , incorporated by reference in its entirety . therefore , using such methods or other known methods , desired genes may be introduced into the subject es and es - like cells , and the cells differentiated into desired cell types , e . g ., hematopoietic cells , neural cells , pancreatic cells , cartilage cells . etc . genes which maybe introduced into the subject eg , es . es - like cells include , by way of example , epidermal growth factor , basic fibroblast growth factor , glial derived neurotrophic growth factor , insulin - like growth factor ( i and ii ), neurotrophin - 3 , neurotrophin - 4 / 5 , ciliary neurotrophic factor , aft - 1 , cytokine genes ( interleukins , interferons , colony stimulating factors , tumor necrosis factors ( alpha and beta ), etc . ), genes encoding therapeutic enzymes , collagen , human serum albumin , etc . in addition , it is also possible to use one of the negative selection systems now known in the art for eliminating therapeutic cells from a patient if necessary . for example , donor cells transfected with the thymidine kinase ( tk ) gene will lead to the production of embryonic cells containing the tk gene . differentiation of these cells will lead to the isolation of therapeutic cells of interest which also express the tk gene . such cells may be selectively eliminated at any time from a patient upon gancyclovir administration . such a negative selection system is described in u . s . pat . no . 5 , 698 , 446 , and is herein incorporated by reference . the subject es , es - like and ec cells may be used as an in vitro model of differentiation , in particular for the study of genes which are involved in the regulation of early development . also , differentiated cell tissues and organs using the subject embryonic or stem - like cells may be used in drug studies . further , the subject cells may be used to express recombinant dnas . still further , the subject embryonic or stem - like cells may be used as nuclear donors for the production of other embryonic or stem - like cells and cell colonies . also , cultured inner cell mass , or stem cells , produced according to the invention may be introduced into animals . e . g ., scid mice , cows , pigs , e . g ., under the renal capsule or intramuscular and used to produce a teratoma therein . this teratoma can be used to derive different tissue types . also , the inner cell mass produced by x - species nuclear transfer may be introduced together with a biodegradable , biocompatible polymer matrix that provides for the formation of 3 - dimensional tissues . after tissue formation , the polymer degrades , ideally just leaving the donor tissue , e . g ., cardiac , pancreatic , neural , lung , liver . in some instances , it may be advantageous to include growth factors and proteins that promote angiogenesis . alternatively , the formation of tissues can be effected totally in vitro , with appropriate culture media and conditions , growth factors , and biodegradable polymer matrices . we have developed a method , using nuclear transplantation , to produce transgenic embryonic stem ( es )- like cells from fetal bovine fibroblasts . these cells , when reintroduced into preimplantation embryos , differentiated into derivatives from the three embryonic germ layers , ectoderm , mesoderm , and endoderm , in 5 - month - old animals . six out of seven ( 86 %) calves born were found to be chimeric for at least one tissue . these experiments demonstrate that somatic cells can be genetically modified and then de - differentiated by nuclear transfer into es - like cells , opening the possibility of using them in differentiation studies and human cell therapy . embryonic stem ( es ) cells have been available for several strains of mice for many years and have been shown to be capable of contributing to each of the tissues of the animal when combined with a host embryo to form a chimera . techniques have been developed for inducing the differentiation of mouses es cells in vitro and successfully transplanting them into recipient mice . success in developing pluripotent cell lines from large animal species , such as bovine , has been minimal . production of putative bovine es cells vas first reported by saito et al ., and later , a similar type of stem - like cells w as reported to direct development through organogenesis . bovine es cells that are capable of complete differentiation to term , in vivo , have not been reported . little success has been achieved in inducing es cells to differentiate into a specified tissue in vitro or in the selecting specific cells , out of the many other types of cells that are present , following the induction of in vitro differention . the objectives of this study were to develop an efficient procedure for producing bovine es - like cells , to lest the pluripotency of these cells in vivo by forming chimeras with host embryos , and to develop an efficient method for genetic modification of the cells using somatic cell nuclear transplantation . results . production of transgenic embryo - derived pluripotent es - like cell colonies . as one approach to producing transgenic cattle , putative bovine es - like cells were derived from embryos . in vitro maturation and fertilization of oocytes and in vitro culture of the embryos to the blastocyst stage produced 49 embryos at day 7 . blastocysts were mechanically dissected and plated on mitotically inactivated fetal mouse fibroblast feeder layers . twenty - seven inner cell masses attached to the feeder layer grew as es - like cell colonies and successfully survived passaging over at least 12 months without differentiation . these colonies had well - defined edges . cells in these colonies had a high nuclear to cytoplasmic ratio and a high density of cytoplasmic lipid granules , and were negative for cytokeratin and vimentin . unlike mouse es cells , bovine es cells eventually formed single layer sheets ( fig1 a ) and were alkaline phosphatase negative . the method of producing transgenic bovine es - like cells also differed from procedures used for the mouse ( fig2 a ). bovine es - like cells , unlike mouse es cells , do not survive replating when trypsinization is performed ; therefore , mechanical passage was used instead . passage of the cells mechanically involves removing a group of cells , containing a minimum of 50 to 100 cells , and transferring these to fresh feeder layers . because single cell suspensions could not be passaged , it was not possible to use electroporation for dna transfection or to clonally propagate transgenic cells . therefore microinjection of dna into the nucleus of individual cells was used as an alternative method . approximately 500 to 1000 cells could be injected per hour , and injection volume vas based on nuclear swelling . three different cell lines ere used . a cytomegalovirus ( cmv )- β - galactosidase - neomycin ( β - geo ) cassette as delivered into the nucleus of es - like cells . five , three , and zero stable . g418 selected transgenic colonies were produced out of 3753 , 3508s and 3502 injected cells , respectively . we did not determine if these colonies were derived from single or multiple transgenic cells . during g418 selection the original colony essentially disappeared before growth of the transgenic cells began , indicating a possible clonal origin ; however , the possibility of having produced a transgenic colony from two or more closely placed transgenic cells cannot be ruled out . β - galactosidase expression as consistently high in all colonies , although not all cells within a colony expressed the gene ( fig1 b ). pcr amplification of a segment of the transgene also confirmed that the cells were transgenic ( fig1 e ). production of transgenic somatic cell - derived bovine pluripotent es - like cell colonies . although transgenic es - like cells can be produced by microinjection , the generation of a large number of transgenic es - like cells and clonal propagation was not achieved . therefore , we took another approach ( fig2 b ) that involved transfection of bovine fetal fibroblasts and fusion of the transgenic fibroblast cells to enucleated oocytes to produce blastocyst stage nuclear transplant embryos . these embryos were then plated on fibroblast feeder layers to produce transgenic es - like cell colonies . bovine fibroblasts were obtained from 55 day fetus , and grown and transfected by electroporation using standard methods ( fig1 c ). three hundred and thirty enucleated mature bovine oocytes were reconstructed with actively dividing fibroblasts . thirty - seven ( 11 %) blastocytes ( day 7 . 5 ) were obtained and es - like cell lines were established from 22 ( 59 %) of these . out of 22 cell lines , 21 were positive for the transgene after pcr amplification of the β - galactosidase fragment . the negative es - like colony could have originated from a neomycin - resistant fibroblast that lost the β - galactosidase gene . fibroblast - derived es - like cell colonies showed morphology and cytoplasmic marker characteristics identical to those of embryo - derived es - like cells ( fig1 d ). furthermore , colonies were passaged for several months without differentiation , even , in one case , when a colony as derived from a senescent , nondividing fibroblast cell line . production of chimeric calves . in order to determine the potency of bovine embryo - ( passage 10 ) and fibroblast - derived es - like cells ( passage 3 ) in vivo . 8 to 10 cells were introduced into day 3 in vitro produced embryos , cultured in vitro until day 7 . 5 and transferred into synchronized recipients . five calves were born from embryos that received transgenic embryo - derived es - like cells , and seven calves ere born from embryos that received transgenic nuclear - transfer ( nt )- derived es - like cells ( table 1 ). all the animals were phenotypically normal . all the animals were slaughtered at 5 months of age , with the exemption of calf 904 , which was killed at 45 days of age . genomic dna was isolated from a spectrum of tissues ( skin , muscle , brain , liver , spleen , kidney , heart , lung , mammary gland , intestine , and gonads ) from each animal , amplified using β - geo primers , and probed using standard - protocol southern blot analysis . results were positive in at least one tissue in nine calves and in two or more tissues in six calves . oocytes were found to be positive in one animal ( fig3 ). the limited presence of transgenic cells in the newborn animals could be attributed to the fact that not all the es - like cells were incorporated into the developing morulas ; moreover , among those cells that did incorporate , degree of pluripotency may have varied . fluorescent in situ hybridization ( fish ) analysis was performed in spleen tissue from calf 911 ( fig4 a ), and testis of calf 903 ( fig1 c ). positive hybridization signals were identified in both tissues . in the spleen . 32 % of nuclei ({ fraction ( 82 / 256 )}) exhibited green signals compared with negative spleen in which only 1 % of nuclei ({ fraction ( 2 / 231 )}) were classified as carrying green signals . testis specimens were not presented as a single monolayer of cells : therefore , percentage of positive cells was not assessed ; however , positive signals were detected inside the seminiferous tubules . discussion . the first objective of this study was to produce bovine pluripotent es - like cells . es - like cells are derived from an early stage embryo of the inner cell mass ( icm ) directly , and , therefore , should retain the morphology and cellular characteristics of the icm . in the mouse . es cells grow as colonies with a defined margin , and cells have high nuclear to cytoplasmic ratio and high density of lipid inclusions similar to the icm . our bovine cells derived both from embryos and nt fibroblasts , also retained these characteristics . the expression of various cytoplasmic markers has also been used to indicate an icm - like quality of mouse es cells . in the bovine , es - like cells derived either from embryonic or somatic cell sources , do not express differentiation markers such as vimentin and cytokeratin in a pattern similar to the icm ; however , these cells are alkaline phosphatase negative . the second characteristic of a pluripotent embryonic cell is that it can be grown over many passages without showing signs of differentiation . in this study , and other preliminary work ( 1 ), bovine icm - derived cells were passaged for over 1 year without losing the morphological and cellular similarities to the icm . the third and most important characteristic used to define es - like cells is that , upon introduction into a preimplantation ) embryo , they are able to colonize the ectodermal , mesodermal , and endodermal tissues and the germ line , as the host embryo develops and differentiates . in this study it was shown that both embryonic and fibroblast - derived es - like bovine ells are capable of giving rise to multiple tissues in 5 - month - old animals . our results demonstrate that cells derived from somatic and embryonic sources possess functional and phenotypic characteristics of pluripotent es - like cells . much work has been done in many different species toward developing methods of producing es cells ; how ever , little success has been reported at meeting all the criteria listed above . in rabbit ( 6 ) production of chimeric offspring was reported , but no chimerism in gonads was demonstrated . in hamster ( 7 , 8 ) and cow ( 3 , 4 ), cells were grown in vitro however , no chimeric animals were produced . this is the first published report demonstrating transgenic chimerism in full - term live mammals , including in gonadal tissue from a species other than a mouse . however , until germline transmission is demonstrated , we refer to our cells as “ pluripotent or es - like cells ” instead of es cells . the results in this study indicate that , although genetic modifications could be made in bovine es - like cells by microinjection , and transgenic cells could be selected by a standard neomycin resistance approach , limitations in the number of cells that can be microinjected , the slow growth of the cells , and our inability to clonally propagate the es - like cells limits the usefulness of this approach , particularly for gene targeting . this is one important difference between bovine es - like cells and mouse es cells . aside from the fact that care must be taken to prevent differentiation , mouse es cells can be readily grown in culture , clonally propagated , transfected by standard high - volume gene transfer methods , and in many cases , exhibit high - efficiency homologous recombination . in our system , the low transfection efficiency of bovine es - like cells prevents the possibility of using direct es - like cell transfection for gene targeting . an alternative method of making genetic modifications in bovine es - like cells is to genetically modify fibroblast cells and then produce embryos by nuclear transplantation . genetic modification is relatively simple with fibroblast cells , which are easy to grow , transfect and clonally propagate . furthermore , gene targeting and selection for homozygous lines in vitro have been successful in human fibroblast lines . this study demonstrates that es - like cells can be produced from bovine embryos , which can be cultured without a change in morphology for indefinite periods in vitro and retain the ability to give rise to tissues derived from all three gene layers in offspring . furthermore , using nuclear transplantation ., these cells can be produced from genetically modified fibroblasts . this system could be useful for the in vitro production of genetically modified bovine cells to be used for cell transplant therapies for many different human diseases . in vitro maturation of bovine oocytes . ovaries were recovered at a slaughterhouse , placed in warm phosphate - buffered saline ( pbs ) ( 34 ° c .) and brought to the laboratory within a limit of 8 h . each follicle of more than 2 mm in diameter was aseptically aspirated with an 18 gauge needle . search of oocytes was performed in modified tyrode &# 39 ; s medium ( tl hepes ). oocytes with a homogeneous cytoplasm , considerable perivitelline space and intact cumulus cells were placed in maturation medium m199 ( gibco , grand island , n . y . ), a 10 % fetal calf serum ( fcs ), 5 μl / ml bovine follicle - stimulating hormone ( nobl , sioux center , iowa ), 5 μl / ml bovine luteinizing hormone ( nobl ), and 10 μl / ml pen - strep ( sigma , st . louis , mo .) for 22 h at 38 . 5 ° c . and 5 % co 2 . in vitro fertilization of bovine oocytes . twenty - two hours post - maturation , oocytes were placed in fertilization medium ( 5 ml cr2 - specialty medium , stock solution 100 u / ml penicillin , 100 μg / ml streptomycin , 0 . 005 μg / ml phenol red , 30 mg bovine serum albumin fatty acid free , 5 μg / ml sodium heparin ). a unit of frozen semen was thawed and placed on top of a percoll layer that contains 90 % percoll ( sigma ) and one part 10 modified sperm tl plus , 45 % percoll ( one part of 90 % percoll stock solution and one part sperm ti , without bsa ). dead sperm were separated from live sperm by centrifugation at 700 g for 30 min . sperm pellet was resuspended at a final concentration of 500 , 000 sperm / ml . after 12 h in culture at 38 . 5 ° c . and 5 % co 2 , eggs were removed and placed in cr2 medium with 3 mg / ml bsa . embryo culture . during the first 3 days after fertilization , embryos were cultured in 500 μl well plates with mouse embryonic fibroblast ( mf ) feeder layers and cr2 with 6 mg / ml bsa . on day 4 , embryos were transferred to 500 μl well plates with mf feeder layers , cr2 with 6 mg / ml bsa , and 10 % fcs until blastocyst stage day 7 post - insemination ). es - like cell culture . blastocysts were placed in a 32 mm plate ( nunc , rochester , n . y .) with mitotically inactivated mf feeder layer and es medium ( alpha mem , 10 % fetal calf serum , 4 111 / ml antibiotic - antimycotic , 2 . 8 μl / ml 2 - mercaptoethanol , 0 . 3 mg / ml l - glutamine , and 1 μl / ml tylosin tartrate ) equilibrated a day in advance at 38 . 5 ° c . and 5 % co 2 . using a 22 gauge needle , blastocysts &# 39 ; zona pellucida and trophoblast were mechanically removed . the remaining icm was placed underneath the mf . after 1 week in culture , es - like cells were passaged to a fresh mitotically inactivated mf . inactivation of mf was performed by exposing them to gamma radiation ( 2956 rads ). es - like cells were passaged by cutting a small piece ( 50 to 100 cells ) of the colony and placed on top mf feeder layers using a pulled pasteur pipette . nuclear transplantation . eighteen hours post - maturation , oocytes were placed in a 100 μl drop of tl hecm - hepes under mineral oil ( sigma ). oocyte enucleation ( extraction of chromosomes ) was performed using a beveled glass pipette of 25 μm diameter . evaluation of enucleation was done by exposure of individual oocytes previously cultured for 15 min in 1 μg / ml of bisbenzimide ( hoechst 33342 ; sigma ) in tl hecm - hepes under ultraviolet light . donor cells were placed in the perivitelline space and fused with the egg &# 39 ; s cytoplasm at 23 h post - maturation . oocytes and donor cell were placed into 4 ml medium made of 50 % sor2 fusion medium ( 0 . 25 m d - sorbitol ( sigma ), 100 ( m caoac ( sigma ), 0 . 5 mm magnesium acetate ( sigma ), 1 . 0 g bsa ( sigma ), and 50 % hecm - hepes for 2 min . eggs were then placed between the electrodes of a 500 μm fusion chamber . once the eggs were aligned , a pulse of 90 v was administered over 15 μs . eggs were then returned to the 50 / 50 medium of sor2 and hecm / hepes for 2 min and , finally , placed into a 500 μl drop of cr2 at 38 . 5 ° c . and 5 % co 2 until activation . oocyte activation . activation was performed in general as described by forrester et al ., proc . natl , acad . sci . usa 88 : 7514 - 77 ( 1991 ) and palaclos et al ., dev . biol ., 92 : 7530 - 4 ( 1995 ). briefly , 25 to 27 h post - maturation oocytes were incubated in 5 μm ionomycin ( cal biochem , la jolla , calif . ), and 2 mm of 6 - dimethylaminopurine ( dmap ; sigma ) in cr2 with 3 mg / ml of bsa ( fatty acid free ; sigma ). after activation , eggs were washed in hecm / hepes five times and placed for culture in a 500 μl well of mf and cr2 with 3 mg / ml of bsa ( fatty acid free ) at 38 . 5 ° c . and 5 % co 2 . transgenic es - like cell production . five micrograms per milliliter of a β - geo cassette gene were microinjected into the nuclei of bovine es - like cells . twenty four to forth - eight hours after microinjection , 150 μg / ml of g418 was added to the culture medium . after 3 weeks under selection , a colony was considered transgenic upon dna screening by pcr and ethidium bromide gel , and by β - galactosidase staining . bovine fibroblast production and electroporation . bovine fibroblasts were produced from a 55 - day - old fetus as follows . under sterile conditions , the livers , intestines , and beads of the fetuses were discarded . the remaining parts of the fetuses were carefully minced and placed in a solution of dulbecco &# 39 ; s phosphate buffered saline ( dpbs ) with 0 . 08 % trypsin ( difco , detroit , mich .) and 0 . 02 % edta ( sigma ). after 30 min incubation at 37 ° c . the supernatant was discarded and the pellet resuspended with trypsin - edta / dpbs . after 30 min incubation , the supernatant was removed and centrifuged at 300 g for 10 min . the pellet of cells was then resuspended with es culture medium and plated in polystyrene tissue culture dishes ( 25010 ; corning , charlotte , n . c .). after two passages , cells were electroporated with a β - geo cassette gene with the protocol described by invitrogen ( san diego , calif .) for cos cells ( 11 ). after 3 weeks under 400 μg per ml of g418 selection , fibroblasts were considered transgenic upon dna screening by pcr and ethidium bromide gel , and by β - galactosidase staining . alkaline phosphatase staining . culture medium was removed from the plates and cells were fixed with 4 % paraformaldehyde for 20 min . cells were washed three times in tris - maleate buffer ( 3 . 6 g trizma base [ sigma ], in 1 l water , ph raised to 9 . 0 with 1 m maleic acid ) for 10 min each wash . the last wash was removed and the staining solution ( tris - maleate buffer , 200 μl of a 0 . 5 mm mgcl 2 , naphthol a5 - mx phosphate [ sigma ]), 0 . 4 mg / ml , fast blue [ sigma ], 1 mg / ml ) was added to the cells for 15 to 20 min . once blue cells were detected , the reaction was stopped by adding pbs which brought the ph to 7 . 4 chimera production . seventy - two hours after in vitro fertilization ( eight cell stage ), embryos were placed in manipulation medium ( hecm / hepes with 10 % fcs and 7 . 5 μg / ml of cytochalasin b [ sigma ]). es - like cells were dissociated using 0 . 08 % trypsin ( difco ) and 0 . 02 % edta in pbs during 25 to 30 min . using a 15 - 20 μl / ml diameter beveled pipette , 8 to 10 cells were introduced into the embryos . embryos were placed in a 500 μl culture drop ( mf feeder layer , cr2 with 6 mg / ml of bsa and 10 % fcs ). immunohistochemical studies . primary antibodies specific against cytokeratin 8 - 18 ( sigma ) and vimentin ( sigma ) were used in es - like cell cultures . cells were plated on sterile glass slides , fixed in 2 % paraformaldehyde , and extracted with cold (− 20 ° c .) acetone . cells were incubated with primary antibody dilutions in pbs containing 0 . 5 % bsa ( pbsa ) for 1 h at room temperature . slides were then rinsed three times in pbsa with changes of rinse solution every 10 min , and incubated for 1 h in fluorescein 5 - isothiocyanate ( fitc ) conjugated anti - mouse igg ( sigma ). after rinsing in pbsa for 30 min , cover slips were mounted in 50 % glycerol and observed under a fluorescence microscope ( 8 ). β - galactosidase staining . culture medium was removed from the plates , and cells were fixed with 2 % glutaraldehyde in pbs . then cells were washed three times with pbs and color substrate ( 5 mm k 3 fe ( cn ) 6 , 5 mm k 4 fe ( cn ) 6 , 1 mm mgcl 2 , 1 mg / ml x - gal in pbs , ph 7 . 0 - 7 . 5 ) was added for 3 h ( 12 ). pcr analysis and blot analysis . analysis of transfected cells and tissue from 5 - month - old animals was performed using a sense primer ( act3βgeo , a 21 base cgctgtggtacacgctgtgcg ) and antisense primer ( act4βgeo , 1 22 base caccatccagtgcaggagctcg [ amilof biotech , boston , mass .). reactions were run for 35 cycles ( 1 ) heated at 95 ° c . for 30 s ( 2 ) primers were annealed at 65 ° c . for 1 min , ( 3 ) extended for 2 min at 72 ° c ., followed by 10 min extension at 72 ° c . the amplified product was a 782 bp fragment . sample analysis was performed by separating by size in a ( 1 %) tae agarose gel electrophoresis containing ethidium bromide . products were sized by comparison with markers consisting of 1444 bp , 943 bp , 754 bp , 585 bp , 458 bp , 341 bp , 258 bp , 153 bp , and 105 bp . dna was then handled according to standard southern blot analysis protocols . briefly , dna was transferred to zetabind ( cuno , meriden , conn .) by capillary transfer and probed with a gel - purified 289 bp clai to ecorv fragment labeled with “ pdctp using random primed labeling kit ( boehringer mannheim , indianapolis , ind .). hybridization was done at 42 ° c . overnight . after washing , the blot was exposed to biomax film ( kodak , rochester , n . y .) overnight . nontransgenic fibroblasts and water were used as negative controls , and transgenic cells for β - geo and template were used as positive control . when oocytes were analyzed , ovarian follicles were aspirated with a syringe using an 18 gauge needle . eggs &# 39 ; granulose cells were removed by vortexing the oocyte / cumulus cell complex in 5 mg / ml of hyaluronidase ( sigma ) in pbs . oocytes were washed five times in pbs before dna isolation . fish analysis . samples were frozen and made onto slides either by slightly pressing the sample against the slide ( for spleen slides ) or by cryosections ( for testis slides ), βgeo dna was linearized with scai and biotin - labeled by nick translation reaction . an aliquot of the biotin - labeled dna was run on a gel and transferred to a membrane , and a streptavidin - alkaline phosphatase assay was performed to detect the size of labeled fragments and quantity of biotin incorporation . the labeled dna was then co - precipitated with salmon sperm dna as carrier . a number of single - target single - color fish assays were performed using varied concentrations of labeled dna as a probe ( 250 - 500 ng ). the specimens were washed in 70 % acetic acid and digested in pepsin ( 0 . 01 % in 0 . 01 m hcl at 37 ° c .) before denaturation . testis slides were incubated in pepsin at room temperature for 10 min before warming to 37 ° c . denaturation was performed at 75 ° c . for both chromosomal and probe dnas and hybridization was allowed to occur for approximately 60 h . post - hybridization washes included three 5 min washes in 50 % formamide / 2 × ssc and three 5 min washes in 2 × ssc at 43 ° c . immunochemical detection was achieved with consecutive incubations in fitc - avidin , biotinylated anti - avidin and fitc avidin ( vector , burlingame , vt .). chromatin was counter - stained with dapi ( 0 . 01 μg / ml on antifade ; boehringer mannheim ). after hybridization , slides were coded and blindly analyzed . analysis was performed in an olympus bx - 60 fluorescence microscope using interference filter sets for single band ( dapi and fitc ) and triple band ( dapi , fitc , texas red ). gray images were acquired using a ccd camera ( photometrics , phoenix , ariz .) and combined using the oncor ( gaithersburg , md .) image software . ( 1 ) forrester et al ., proc . natl . acad . sci . usa 88 : 7514 - 7577 ( 1991 ). ( 3 ) saito et al ., roux &# 39 ; s arch . dev . biol ., 201 : 134 - 141 ( 1992 ). although the present invention has been described in detail with reference to examples above , it is understood that various modifications can be made without departing from the spirit of the invention , and would be readily known to the skilled artisan . all cited patents and publications referred to in this application are herein incorporated by reference in their entirety . | US-27600103-A |
fertilizer or other liquid crop treatment is applied to the ground using a direct injection jet with a nozzle position closely adjacent the ground and forming a jet of the liquid directed into the ground . a solenoid controlled valve cyclically halts the flow of fluid to form short pulses of the fluid so that the fluid can be supplied in concentrate form while generating sufficient energy to achieve a depth of penetration in the range 2 to 4 inches . the solenoid controlled valve and nozzle is mounted on a skid member carried on a depth control wheel . the period of the pulses is arranged so that the length of a pulse is very short relative to the spacing between the pulses with the spacing between adjacent rows formed by adjacent heads being substantially equal to the spacing between the individual pulses . | the apparatus as shown schematically in fig1 includes a supply tank 10 mounted upon a suitable vehicle indicated schematically at 11 including ground wheels 12 by which the tank can be transported across the ground so the apparatus can apply a treatment liquid to the ground . mounted upon the rear of the vehicle and shown separately for convenience of illustration is a tool bar 13 upon which is mounted a plurality of injector heads each generally indicated at 14 . each injector head is shown in more detail in fig2 and 3 and will be described in more detail hereinafter . liquid drawn from a lower discharge point on the tank 10 is transmitted to a pump 15 arranged to generate a high pressure of the order of 6000 psi in a liquid forwarded from the pump along a line 16 . the pump is of a conventional type commercially available and accordingly will not be described in detail . the high pressure liquid on the line 16 passes to a pressure regulator 17 which maintains the pressure on the line 16 with any excess liquid being returned along the line 18 to the tank so that the pressure on the line at the point 16 is maintained at the required value regardless of the amount of liquid drawn from the line 16 to the heads 14 . an indicator is mounted in line 16 as shown at 19 . the line 16 divides into separate lines 16a , 16b and 16c for supplying the fluid under a constant common pressure to the heads 14 . a control device indicated at 20 acts to control the injection heads as will be described in more detail hereinafter . the control unit 20 receives power from a battery 21 and receives signals from a speed detector 22 coupled at a suitable location on the vehicle . two manually actuable dials are provided on the control unit 20 one of which is indicated at 23 and acts to control the pulse length as will be described hereinafter and another of which is indicated at 24 and acts to control the spacing between the pulses as described hereinafter . each of the injector heads mounted on the tool bar 13 comprises a trailing linkage 25 which connects to the hub 26 of a ground wheel 27 . the ground wheel 27 is thus free to raise and fall relative to the tool bar 13 in dependence upon ground height to maintain the hub or axle 26 at a set distance from the ground . the ground wheel 27 is of the type including a rubber tire while having a rather large diameter to more accurately control the height of the hub 26 . a bracket 28 is mounted on the linkage 25 and carries a vertical shaft 29 both of which are thus supported by the hub and maintained at a constant distance from the ground . the bottom end of the shaft 29 is welded to a skid plate 30 which extends forwardly therefrom lying in the plane of the grounds surface that is in the tangential plane to the lower most edge of the wheel 27 . the skid 30 includes an upwardly turned front end 31 to allow the skid to lift over small obstacles for example stones and soil clumps which are sufficiently small to avoid the general lifting action provided by the wheel 27 . the whole unit is self weighted so that both the wheel and the skid plate rest upon the ground with the undersurface of the skid plate is maintained accurately in contact with the ground without generating a furrow in the ground . attached to the vertical shaft 29 is an injector nozzle and solenoid control valve schematically indicated in fig2 at 32 . the unit includes a nozzle indicated at 33 which projects downwardly through an opening in the plate 30 indicated at 34 . turning therefore to fig3 the liquid supply line 16a communicates with a side of the nozzle body 33 through a threaded cap 35 which connects into suitable opening in the body 33 . the supplied liquid passes through a short bore 36 into a central bore 37 within the body 33 . the body is counterbored to define a wider section indicated at 38 for receiving a nozzle tip 39 having external screw thread for cooperating with an internal screw thread within the counter bore 38 . a parker o - ring 40 is provided on the outer surface of the nozzle tip 39 forming a seal between the counterbore 38 and the nozzle tip to accommodate the high pressure fluid injected from the line 16a . within an inner bore 41 of the nozzle tip is provided an insert 42 of a suitable hardened material for example tungsten carbide or aluminum oxide which is resistant to the high pressure corrosive materials forming the liquid to be injected into the ground . a lower most edge 43 of the insert 42 defines an orifice which is sized , as discussed hereinafter , to generate a jet of the liquid having a velocity and volume dependant upon the size of the orifice and the pressure of the liquid . at the end of the counterbore 38 above the nozzle body 39 is trapped a valve plate 44 which has a small central orifice 45 cooperating with a needle valve 46 . the needle valve 46 passes through a seal 47 in the base of the bore 37 and through an opening 48 at the upper edge of the body 33 . the needle valve 46 is actuated by a solenoid 49 of a conventional high - speed type which includes an armature 50 including a plate 51 mounted on the needle valve 46 . the needle valve is biased in a downward direction by a spring 52 operating upon a plate 53 at an upper end of the armature 50 . the solenoid 49 is housed within a bore of a solenoid housing generally indicated at 54 an upper end of which is closed by a plate 55 clamped by bolts 56 and cooperating nuts 57 . the spring 52 is mounted within a spring housing 58 closed by an end plate 59 and clamped by bolts 60 . in operation , movement of the vehicle across the ground is detected by the speed sensor 22 and is communicated to the control unit 20 . in dependence upon the manual setting of the controls 23 and 24 , the control unit 20 generates pulses to the solenoids 49 so that the needle valves 46 are drawn away from the valve plates 44 so that each of the injection heads generates a pulse of liquid which is allowed to pass from the respective line 16a , 16b , 16c into the nozzle body 39 and through the orifice 43 . the thickness of the skid plate 30 is arranged relative to the position of the orifice 43 that the surface of the ground indicated at 61 is approximately 1 / 4 inch from the orifice 43 . this spacing has been found to be the minimum practical spacing which can be achieved and is a spacing which avoids the induction into the jet flow of surrounding air . any such induction will tend to spread the liquid flow and thus increase the opening which must be generated in the soil by the movement of the liquid thus requiring a greater amount of energy to generate the opening . it is therefore necessary to maintain the orifice 43 at the required spacing from the ground , as far as possible within practical variations of soil level in order to minimize the amount of energy necessary to generate the opening through which the fluid jet passes into the ground . the size of the orifice is greater than and preferably in the range 0 . 015 inches to 0 . 050 inches . in order to generate sufficient energy for the liquid to reach a required depth of 2 to 4 inches it is necessary that the liquid jet carries sufficient energy to cut into the soil to that depth . in this case the size of the orifice must be greater than the above mentioned minimum in order to achieve that sufficient energy . it has been found that the depth of 2 to 4 inches can best be achieved by the orifice range stated above . an achieved depth of less than 2 to 4 inches is generally unacceptable since the fertilizer material is not placed in the required location for acceptability by the root structure of the plants . the spacing of each head from the next adjacent head is arranged to lie in the range 4 to 30 inches . the pulses in the jet flow are arranged to be very short relative to the spaces therebetween so as to generate fertilizer nests along the rows which are spaced in the range 4 to 30 inches . in order to achieve these spacings , the valve must operate in cycles of 10 to 30 cycles per second with valve openings for less than 5 . 7 milliseconds with periods between the openings being approximately 40 milliseconds . in order to achieve this , the opening of the valve must take place in less than 2 milliseconds . the use of the orifice size as defined above together with the pulse length cuts a slot shaped opening into the ground to a depth of the order of 2 to 4 inches with the liquid material injected remaining in a nest at the bottom of the cut slot . thus the arrangement of the spacing of the rows and pulses provides a pattern or grid of nests spaced across the ground which can be accessed by the root system of the plants . the injection of the material in pulses enables the generation of sufficient energy within those pulses to cause a liquid to reach the required depths . the fact that the material is supplied in pulses enables the actual amount of liquid to be reduced to a level such that a fertilizer material can be supplied in concentrate form without the necessity for water . the supply of water at levels previously necessary to achieve the required depths rendered the process unacceptable in view of the transportation requirements to carry the water across the ground and in addition the requirement for the actual water supply . for the first time therefore , the present inventor has generated an arrangement in which liquid can be injected directly into the ground obtaining the advantages set down hereinbefore while applying that liquid to the ground in a manner which enables the process to be commercially viable . since various modifications can be made in my invention as hereinabove described , and many apparently widely different embodiments of same made within the spirit and scope of the claims without departing from such spirit and scope , it is intended that all matter contained in the accompanying specification shall be interpreted as illustrative only and not in a limiting sense . | US-20821688-A |
the present invention relates to consumable film products and a method for producing same . more particularly , one aspect of the invention provides a method of making a consumable film by forming a composition into a ribbon , feeding the ribbon to one or more dies , cutting the ribbon into sections , and drying the sections . one or more ribbons may be simultaneously treated . the dies of the invention may be configured to produce an array of variously shaped products having a thickness of less than about ⅛ ″. another aspect of the invention provides single - layer films and multiple - layer films produced according to the disclosed methods . | in a conventional soft - gel manufacturing process , the gelatin mass and the center - fill medicinal mass are prepared separately . the gelatin mass may consist of a variety of materials including , for example , gelatin powder , glycerine , flavors , colors , and water . on the other hand , the center - fill , medicinal mass may include such compounds as oils , fats , waxes , excipients , and active ingredients . after the gelatin and medicinal masses are produced , they are transferred to a soft - gel encapsulator . in a typical encapsulation operation , molten gelatin is pumped to the encapsulator and two thin ribbons are formed on opposing sides of the encapsulator . these two ribbons then pass over a series of rollers and over a set of dies that determine the size and shape of the capsules . the medicinal mass , or fill , is fed to a positive displacement pump , which accurately transfers a predetermined amount of the fill and injects it between the two gelatin ribbons prior to the ribbons being sealed together by the application of heat and pressure . thereafter , the capsules are dried . according to the principles of the invention , a consumable film may be produced using the encapsulating device described above , which is normally used to prepare liquid center - filled , gelatin capsules or soft - gels . it has been found that the materials contained in the gelatin mass and medicinal mass , discussed above , may be blended together prior to being shaped . in one aspect , one or more active ingredients may be added . of course , a starch mass or another material may be substituted for or combined with the gelatin mass and active ingredients may or may not be employed according to the principles of the invention . thereafter , the composition may be fed to an encapsulator . it may be formed into one or more thin ribbons , which , in one embodiment , are located on opposing sides of the encapsulator , and then passed over a set of dies and rollers and formed into capsules without the injection of other material . in one aspect , the dies may be constructed such that the ribbons form thin , square or rectangular pieces of ribbon . any particular shaped or textured product including , but not limited to , circles , semicircles , triangles , parallelograms , fruit shapes , flower shapes , and the like , may be produced according to the principles of the invention by configuring the shape or texture of one or more of the dies . thereafter , the products of the encapsulation machine are dried and packaged as desired . in one aspect , a consumable film may be produced by forming a composition into a ribbon , cutting the ribbon into sections , and drying the sections . in another aspect , multiple ribbons may be formed and cut into sections . of course , both single - layer and multiple - layer films may be produced . preferably , the sections may be sized to render individual dosage units . the ribbon may be cut using one or more dies , which may be flat or rotary dies . in another aspect , the dies include a series of rollers and dies . fig1 provides a device 10 that is useful for producing a consumable film . in this example , ribbon 1 may be cast on a moving surface 20 , and transferred over roller 30 to a pair of cutting rollers 40 , and then collected and dried . in another aspect depicted in connection with fig2 , two ribbons 1 may be cast on moving surfaces 20 , and transferred over rollers 30 to a pair of cutting rollers 40 , and then collected and dried . of course , more than two ribbons may be cast , transferred , combined / cut , collected and dried . the equipment illustrated in fig1 may also be employed to produce a multiple - layer film by passing a previously cast film through cutting rollers 40 simultaneously with a ribbon 1 from roller 30 . fig3 illustrates a pair of rollers according to one aspect of the invention where cutting surfaces are disposed on roller 41 that engage roller 42 . in another aspect , rollers 43 are equipped with alternating cutting and non - cutting regions . as such , the rollers 43 may be arranged such that ribbon sections are cut using alternating cutting surfaces disposed on the rollers 43 as shown in fig4 . as described above , the dies disposed on the rollers 40 may be of any desired shape . for example , fig5 depicts rectangular shaped dies arranged on roller 44 that mate with roller 45 . while the products of the invention may be any shape , the depth of the dies may be restricted to be no more than about ⅛ ″. in another aspect the depth of the dies is limited to about 3 / 32 ″, and in yet another aspect the maximum depth of the dies is about 1 / 16 ″. the film produced by the inventive method may be made from any of a wide variety of materials , including water - soluble polymers , that provide a viscous solution that is flowable at normal operating conditions . the material may have a viscosity in the range of about 5 , 000 to about 25 , 000 cps at approximately 140 ° f . in another aspect the viscosity range is about 5 , 000 to about 12 , 000 cps at approximately 140 ° f . the materials that are useful for carrying out the invention include gelatins such as hydrolysed gelatin , acylated gelatin , and fish gelatin , zein , gluten , soy protein isolate , whey protein isolate , casein , starch , maltitol , maltitol syrup , glucose syrups , hydrogenated starch hydrolysate , saccharides , agar , acacia gum , sodium alginate , alginates , carrageenans , gellan , guar gum , karaya , locust bean gum , pectin , pullulan , polyethylene glycol , tragacanth gum , xanthan gum , arabic gum , polyacrylic acid , methylmethacrylate copolymer , carboxyvinyl polymer , amylose , high amylose starch , hydroxypropylated high amylose starch , polyvinyl pyrrolidone , polyvinyl alcohol , polystyrene sulphonate , dextran sulphate , chitosan derivatives , cellulose , hydroxypropylmethyl cellulose , hydroxyethyl cellulose , hydroxypropyl cellulose , carboxymethyl cellulose , cellulose derivatives , bentonite and diatomaceous earths , sorbitols , soribitans , polyhydric alcohols , mannitol , dextrin , pectin , chitin , chitosan , levan , elsinan , collagen , plasticizers such as glycerin , propylene glycol , and sorbital , coloring agents , preservative materials such as potassium sorbate and ethyl , methyl and propyl parabens , and water . the film may include one or more active ingredients , which may be added to the ribbon material during processing . typical ingredients include analgesics and anti - inflammatory agents , anthelmintics , anti - arrhythmic agents , anti - bacterial agents , anti - coagulants , anti - depressants , anti - diabetics , anti - epileptics , anti - fungal agents , anti - gout agents , anti - hypertensive agents , anti - malarials , anti - migraine agents , anti - muscarinic agents , anti - neoplastic agents and immunosuppressants , anti - parkinsonian agents , anti - protazoal agents , anti - thyroid agents , anxiolytic , sedatives , hypnotics and neuroleptics , β - blockers , breath freshening agents , cardiac inotropic agents , corticosteroids , diuretics , enzymes , gastro - intestinal agents , histamine h ,- receptor antagonists , lipid regulating agents , local anaesthetics , neuro - muscular agents , nitrates and other anti - anginal agents , nutritional agents , opioid analgesics , vaccines , sex hormones , spermicides , and stimulants . the active ingredients also include essential oils as antimicrobial agents , flavoring agents , sulfur precipitating agents , saliva stimulating agents , cooling agents , surfactants , stabilizing agents , emulsifying agents , thickening agents , binding agents , coloring agents , sweeteners , fragrances , and the like . the film may also include , for example , materials identified in u . s . pat . nos . 5 , 614 , 217 , 5 , 817 , 323 , and 6 , 596 , 298 , and u . s . provisional patent application ser . no . 60 / 467 , 339 , the disclosures of which are incorporated by reference in their entireties . while the invention has been described in detail and with reference to specific examples thereof , it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof . | US-11041205-A |
a patient support system to be used in conjunction with a standard linear accelerator , and other sources , is described that allows access of the treatment beam to the breast from up to 360 degrees . this support system places the patient in a prone position with the breast going through an aperture . the prone position increases the separation of the breast from the chest wall and other critical organs and reduces motion of the target tissue due to breathing . this invention offers up to 360 degree radiation beam access to the breast . this helps in skin sparing , better dose conformity , and allows one to use modern treatment techniques such as imrt and igrt . it also includes a provision for an imaging system . this invention can also be used with ct and mr imaging modalities . | this invention combines a unique support system with novel geometric motions to allow access to treat the breast in the prone position from up to 360 degrees . presently this range of access and motion is not possible with conventional linac couches or existing attachments . an anatomically designed patient support surface 10 with contour 12 provides a surface for the patient to lie on during positioning and treatment . the contour 12 of the support surface 10 combined with the shape and size of the aperture 11 allows the patient to lie comfortably in position during set - up and treatment while allowing the anatomical volume of interest to protrude through the aperture 11 . a series of inserts of different size , shape , and symmetry ( not shown ) can be provided to allow small breasts to be treated comfortably in one extreme , while a large , asymmetrically shaped aperture can allow the chest wall and other related anatomy such as the axilla to be accessed for treatment . the support system can be made in mirror - image versions with left and right versions of the apertures for treating the left and right breast to maximize patient comfort and anatomy accessibility . cushions can be provided for the support surface 10 and contour 12 to increase comfort during the procedure , which is typically 15 minutes with a beam - on time of 1 minute . the support surface 10 can be gently heated to increase patient comfort as well . a set of cushions that tilt the patient around the longitudinal axis can be provided to maximize access and comfort . the patient support system is shown in two basic configurations in fig1 a - c and 2 a - c as attachments . fig1 a - c have a triangular shaped support member 13 between the upper support surface 10 and bottom structure 14 . this provides unobstructed access to the breast over a wide range of angles , but not 360 degrees . this is a simple configuration that can be placed on an existing commercial linac treatment couch and provides much of the benefit of treating from a wide range of angles . as shown in fig7 a , because a treatment couch 21 and the patient support surface 10 interfere with the linac gantry 20 , a full range of angles is not physically accessible . the triangular support member 13 does not limit access by the radiation beam to the breast over the range of physically possible angles for a given combination of linac and couch . the upper support surface 10 is made of a stiff , radiolucent material such as carbon fiber over a foam or honeycomb core , which has sufficient torsional and longitudinal stiffness to support the patient in a cantilevered configuration without significant deflection . in this configuration , the invention consists of a simple , light add - on attachment to an existing treatment system , but provides much of the advantage of the more integrated , complex implementations also described here and included in the overall invention . a second level of performance and complexity is shown in fig2 a - c . a similar set of top patient support surface 10 and bottom structure 14 are separated by radiolucent spacers 15 with locations and orientations designed to minimize absorption of radiation . radiolucent spacers 15 that are cross shaped are shown , and the orientation of the supports is such that radiation will not traverse the long axis of the material on its way to the breast at isocenter . the cross shaped radiolucent spacers 15 project about 2 . 8 times the thickness of the material into the path of the beam . if the beam traverses two adjacent sections of the support at 45 degrees , the total thickness seen by the beam is 2 . 8 times the thickness of the material . a square tube has similar characteristics , but a round tube creates shadows where the beam traverses the edges of the round tube tangentially . the support system or a similar one of the same geometry is used in a ct machine prior to treatment to obtain a set of images used for treatment planning . these images can be used to create a set of digitally reconstructed radiographs ( drrs ) that can be used with an imaging system that is optionally part of this support system . these drrs are used to compare the patient &# 39 ; s position during set - up to insure correct positioning of the anatomy to be treated . the imaging system can consist of optical cameras mounted in one or more locations such as on the bottom of the bottom support structure 14 , out of the path of the treatment beam , on the linac gantry 20 , and on the walls of the room , mounted next to or coaxially with the alignment lasers typically installed in treatment rooms . the capability to acquire images , process the images and compare them to the treatment planning images is an optional part of this invention . fig3 a - d illustrate the support system with an additional longitudinal translation stage 16 and 17 , as well as an additional rotary stage 18 . the rotary stage 18 is fastened to the linac couch 21 of fig4 a - c , 5 a - c , 6 a - c , 7 a - c and 8 a - c and these two additional degrees of freedom allow the support system to orient the breast for access to the treatment beam through a full range of 360 degrees . the translation stage 16 and 17 and the additional rotary stage 18 allow the support system to move in a longitudinal axis of patient support system . in the positions shown in fig7 a - c , the support surface 10 would interfere with the linac gantry 20 if the support surface was not moved away from the linac treatment head using the translational stage 16 and 17 and rotary stage 18 shown in fig3 b and 3d . in the position shown in fig8 a - c , the distance from the patient &# 39 ; s breast to the patient &# 39 ; s feet is greater than the typical distance from the linac isocenter to the treatment head . it is necessary to use an increased sad for large treatment angles . the range of positions and angles are shown in fig4 a - c , 5 a - c , 6 a - c , 7 a - c and 8 a - c collectively . treatment with increased sad can be easily planned for once the geometrical limitations of the system are characterized . fig4 a - c show the patient support system in position to provide treatment on a linac at an angle which is defined as 90 degrees . the patient support system is at an angle of zero degrees when the long axis of the treatment couch 21 is parallel to the rotational axis of linac gantry 20 . the gantry 20 is rotated into a substantially horizontal position such that the upper surface of the radiation beam 24 is almost horizontal for this phase of treatment . all anatomy that projects through the aperture 11 can be treated in this configuration . additional treatments can be delivered to related sites such as the axilla , in which there are lymph nodes that may contain cancer cells that have migrated from the primary tumor . these are located under the arm near the armpit and are treated with radiation if they are found to be positive for cancer cells upon biopsy . fig4 a , 5 a , 6 a , 7 a and 8 a illustrate plan views of different rotations of the support surface 10 . fig4 b , 5 b , 6 b , 7 b and 8 b illustrate side views of the corresponding conditions . fig4 c , 5 c , 6 c , 7 c and 8 c illustrate isometric views of these configurations . fig4 a - c , 5 a - c , 6 a - c , 7 a - c and 8 a - c illustrate the different rotational angles of the support surface 10 . fig9 a - c , 10 a - c and 11 a - c are mirror images of fig5 a - c , 6 a - c and 7 a - c , respectively , which together in conjunction with rotating the linac gantry 20 describe 45 degree steps in a full 360 degree rotation to treat the breast from all angles . any given treatment may include treatment from one or more angles , and the most advanced version of treatment where the beam is on continuously during patient rotation is also possible . fig4 a - c , 5 a - c , 6 a - c and 7 a - c further illustrate a linac cabinet 19 , a treatment couch z axis motion 22 , a couch rotary base 23 and the radiation beam 24 . the support system can be made as an integral part of a custom couch instead of as an attachment . increased flexibility is obtained by integrating the structures instead of making an add - on attachment . better access to oblique angles departing from the substantially horizontal position is possible by eliminating duplicate structures and providing cut - outs in strategically located areas . a patient support system as described may additionally be mounted on a “ frog - leg ” jointed support or robotic arm 25 which increases performance and flexibility , as shown in fig1 a - d . an additional rotational motion can be incorporated into the add - on or integrated versions to allow tilting the patient support surface along the longitudinal axis , thus allowing greater comfort for the patient and creating better positioning for the left and right breasts . either version of this invention can be used with any radiation source including radioisotopes , linacs , ortho - or super - voltage x - ray generators or particle beam accelerators . the embodiments of the present invention can be used in conjunction with an already existing table , e . g ., a treatment couch , or incorporated into the design of an entirely new treatment couch . the patient support system of the present invention can be made out of materials making it ct and mr compatible for use with imaging modalities . the patient support system further includes one or more imaging components and associated software algorithms for patient registration . while the present invention has been particularly shown and described with reference to exemplary embodiments thereof , it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the following claims . | US-20541808-A |
the present invention provides an edible dosage form that incorporates optical elements , capable of producing unique optical effects and images in order to enable a user to better identify and differentiate the dosage forms , as well as to improve the detection of counterfeit production thereof , wherein the edible dosage forms may be made in a variety of ways to incorporate the optical elements therein . | it is believed that one skilled in the art can , based upon the description herein , utilize the present invention to its fullest extent . the following specific embodiments are to be construed as merely illustrative , and not limitative of the remainder of the disclosure in any way whatsoever . unless defined otherwise , 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 invention belongs . also , all publications , patent applications , patents , and other references mentioned herein are incorporated by reference . as used herein , all percentages are by weight unless otherwise specified . as used herein , “ structured surfaces ” may include any microreliefs and / or macroreliefs . as used herein , “ microrelief ,” or “ diffraction relief ” means a regular pattern of ridges 530 and grooves or gaps 531 , microstructures , and the like that may display a visual effect or optical information , covert or visible , to the human eye when exposed to suitable radiant energy . see e . g . fig6 b . examples of suitable radiant energy include , but are not limited to , normal illumination , i . e ., e . g ., incandescent and / or daylight , and / or special illumination , e . g . laser , and / or selected wavelenghts . microreliefs include both ( 1 ) patterns of microstructures or patterns of ridges and grooves produced through laser light interference and with other known techniques that can be subsequently transferred to a dosage form via , for example , molding , stamping or hot - embossing ; and ( 2 ) “ holograms ,” meaning , for example , the visual information , effects , and images produced by these patterns of ridges and grooves when supplied with light . holograms shall include the product of optical images , effects , and information on the dosage form , as well as their reconstruction via the use of either white , incoherent light or laser light . the microrelief should be “ stable ,” which means that it has a high resistance to degradation at high temperatures , e . g ., temperatures greater than about 70 ° c ., and to changes in shape ( in terms of microns ) due to applied mechanical forces . the microrelief should also not affect the efficacy of the pharmaceutical active ingredient , and should be economically compatible with current dosage form production equipment . in one embodiment , the microrelief may be a “ high resolution diffraction grating ,” meaning one that can diffract light and has at least about 100 lines per mm , e . g ., from about 100 lines per mm to about 5000 lines per mm , or about 100 lines per mm to about 2000 lines per mm , or about 200 lines per mm to about 1000 lines per mm . in this embodiment , the dimensions of the diffraction relief are proportional to the wavelength of light with which is it to interact . exemplary information that may be recorded and conveyed by this microrelief may be color , depth , image , auditory data , optical data , and / or a kinetic effect . in another embodiment , the microrelief may be a “ dovid ,” which is a diffractive optical variable image device , such as a hologram . in yet another embodiment , the microrelief may be a “ microetching ,” which is a structured surface that conveys information that is not visible to the human eye without the additional assistance of , for example magnification , i . e ., e . g . at least about 100 times , or at least about 250 times , or at least about 100 , 000 times . by contrast , “ macroreliefs ” as disclosed herein are similar in structure to microrelief gratings , but they function in a different way . in general , macroreliefs contain at least about 3 lines or “ lenticules ” per mm , i . e ., e . g ., from about 1 line per mm to about 10 lines per mm . as shown in , for example , fig1 , each lenticule may be a raised , curved ridge 920 . different types of “ macroreliefs ,” may be used in the present invention , and each type of macrorelief conveys different visual effects or animations ,. the simplest animation is referred to as a “ lenticular flip image ,” which is an animation wherein one image changes to another . a lenticular flip generally allows up to three separate images to be combined and viewed independently when viewed at different angles . another type of macrorelief is the “ lenticular 3d image ,” which is an animation that creates apparent depth on a flat surface image and typically requires about twelve images of the subject matter arranged in a horizontal , sequential manner . a “ lenticular morph image ” produces the effect of gradually changing one image into another through the use of multiple images generated via sophisticated computer algorithms . “ lenticular zoom imaging ” produces the effect of an image &# 39 ; s appearing to move closer or farther away in a series of animated positions , while “ lenticular full motion video imaging ” displays movement using multiple frames of a coherent action sequence . any two or more of the above type of effects or animations may be combined to produce a “ lenticular combination image .” as used herein , “ moiré ” shall mean the effect produced when two or more identical , repetitive patterns of lines , circles , or array of dots are overlapped with imperfect alignment as shown in , for example , fig1 b . as used herein , “ injection molding ” shall mean a process of forming a dosage form in a desired shape and size wherein a flowable material , which is in a fluid or flowable state form , enters a mold , then is solidified in the mold via a change in temperature ( either positive or negative ) before being removed therefrom . by contrast , “ compression ,” as used herein , shall mean a process of forming a dosage form in a desired shape and size wherein a material is compacted into a tablet between the surfaces of punches via an increase in pressure before being removed therefrom . as used herein , an “ exterior surface ” of a portion is a surface that comprises part of the exterior surface of the finished dosage form . as used herein , the term “ substantially conformably ” refers to the fact that the cavities of the first portion are defined by surfaces having peaks and valleys therein , and the second portion resides in the cavities and the second portion also has peaks and valleys in its surfaces , such that the peaks and valleys of the surfaces of the second portion correspond substantially inversely to the major peaks and valleys of the surfaces defined by the cavities . as used herein , the term “ compositionally different ” means having features that are readily distinguishable by qualitative or quantitative chemical analysis , physical testing , or visual observation . for example , the first and second materials may contain different ingredients , or different levels of the same ingredients , or the first and second materials may have different physical or chemical properties , different functional properties , or be visually distinct . examples of physical or chemical properties that may be different include hydrophylicity , hydrophobicity , hygroscopicity , elasticity , plasticity , tensile strength , crystallinity , and density . examples of functional properties which may be different include rate and / or extent of dissolution of the material itself or of an active ingredient therefrom , rate of disintegration of the material , permeability to active ingredients , permeability to water or aqueous media , and the like . examples of visual distinctions include size , shape , topography , or other geometric features , color , hue , opacity , and gloss . as used herein , the term “ dosage form ” applies to any ingestible forms , including confections . in one embodiment , dosage forms are solid , semi - solid , or liquid compositions designed to contain a specific pre - determined amount ( i . e . dose ) of a certain ingredient , for example an active ingredient as defined below . suitable dosage forms may be pharmaceutical drug delivery systems , including those for oral administration , buccal administration , rectal administration , topical , transdermal , or mucosal delivery , or subcutaneous implants , or other implanted drug delivery systems ; or compositions for delivering minerals , vitamins and other nutraceuticals , oral care agents , flavorants , and the like . in one embodiment , the dosage forms of the present invention are considered to be solid ; however , they may contain liquid or semi - solid components . in another embodiment , the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro - intestinal tract of a human . in yet another embodiment , the dosage form is an orally administered “ placebo ” system containing pharmaceutically inactive ingredients , and the dosage form is designed to have the same appearance as a particular pharmaceutically active dosage form , such as may be used for control purposes in clinical studies to test , for example , the safety and efficacy of a particular pharmaceutically active ingredient . “ active ingredients ,” as used herein , includes , for example , pharmaceuticals , minerals , vitamins and other nutraceuticals , oral care agents , flavorants and mixtures thereof . suitable pharmaceuticals include analgesics , anti - inflammatory agents , antiarthritics , anesthetics , antihistamines , antitussives , antibiotics , anti - infective agents , antivirals , anticoagulants , antidepressants , antidiabetic agents , antiemetics , antiflatulents , antifungals , antispasmodics , appetite suppressants , bronchodilators , cardiovascular agents , central nervous system agents , central nervous system stimulants , decongestants , diuretics , expectorants , gastrointestinal agents , migraine preparations , motion sickness products , mucolytics , muscle relaxants , osteoporosis preparations , polydimethylsiloxanes , respiratory agents , sleep - aids , urinary tract agents and mixtures thereof . suitable oral care agents include breath fresheners , tooth whiteners , antimicrobial agents , tooth mineralizers , tooth decay inhibitors , topical anesthetics , mucoprotectants , and the like . suitable flavorants include menthol , peppermint , mint flavors , fruit flavors , chocolate , vanilla , bubblegum flavors , coffee flavors , liqueur flavors and combinations and the like . examples of suitable gastrointestinal agents include antacids such as calcium carbonate , magnesium hydroxide , magnesium oxide , magnesium carbonate , aluminum hydroxide , sodium bicarbonate , dihydroxyaluminum sodium carbonate ; stimulant laxatives , such as bisacodyl , cascara sagrada , danthron , senna , phenolphthalein , aloe , castor oil , ricinoleic acid , and dehydrocholic acid , and mixtures thereof ; h2 receptor antagonists , such as famotadine , ranitidine , cimetadine , nizatidine ; proton pump inhibitors such as omeprazole or lansoprazole ; gastrointestinal cytoprotectives , such as sucraflate and misoprostol ; gastrointestinal prokinetics , such as prucalopride , antibiotics for h . pylori , such as clarithromycin , amoxicillin , tetracycline , and metronidazole ; antidiarrheals , such as diphenoxylate and loperamide ; glycopyrrolate ; antiemetics , such as ondansetron , analgesics , such as mesalamine . in one embodiment of the invention , the active ingredient may be selected from bisacodyl , famotadine , ranitidine , cimetidine , prucalopride , diphenoxylate , loperamide , lactase , mesalamine , bismuth , antacids , and pharmaceutically acceptable salts , esters , isomers , and mixtures thereof . in another embodiment , the active ingredient may be selected from analgesics , anti - inflammatories , and antipyretics : e . g . non - steroidal anti - inflammatory drugs ( nsaids ), including propionic acid derivatives : e . g . ibuprofen , naproxen , ketoprofen and the like ; acetic acid derivatives : e . g . indomethacin , diclofenac , sulindac , tolmetin , and the like ; fenamic acid derivatives : e . g . mefanamic acid , meclofenamic acid , flufenamic acid , and the like ; biphenylcarbodylic acid derivatives : e . g . diflunisal , flufenisal , and the like ; and oxicams : e . g . piroxicam , sudoxicam , isoxicam , meloxicam , and the like . in one embodiment , the active ingredient is selected from propionic acid derivative nsaid : e . g . ibuprofen , naproxen , flurbiprofen , fenbufen , fenoprofen , indoprofen , ketoprofen , fluprofen , pirprofen , carprofen , oxaprozin , pranoprofen , suprofen , and pharmaceutically acceptable salts , derivatives , and combinations thereof . in another embodiment of the invention , the active ingredient may be selected from acetaminophen , acetyl salicylic acid , ibuprofen , naproxen , ketoprofen , flurbiprofen , diclofenac , cyclobenzaprine , meloxicam , rofecoxib , celecoxib , and pharmaceutically acceptable salts , esters , isomers , and mixtures thereof . in another embodiment of the invention , the active ingredient may be selected from pseudoephedrine , phenylpropanolamine , chlorpheniramine , dextromethorphan , diphenhydramine , astemizole , terfenadine , fexofenadine , loratadine , desloratidine , doxilamine , norastemizole , cetirizine , mixtures thereof and pharmaceutically acceptable salts , esters , isomers , and mixtures thereof . examples of suitable polydimethylsiloxanes , which include , but are not limited to dimethicone and simethicone , are those disclosed in u . s . pat . nos . 4 , 906 , 478 , 5 , 275 , 822 , and 6 , 103 , 260 , the contents of each is expressly incorporated herein by reference . as used herein , the term “ simethicone ” refers to the broader class of polydimethylsiloxanes , including but not limited to simethicone and dimethicone . the active ingredient or ingredients are present in the dosage forms of the present invention in a therapeutically effective amount , which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art . in determining such amounts , the particular active ingredient being administered , the bioavailability characteristics of the active ingredient , the dosing regimen , the age and weight of the patient , and other factors must be considered , as known in the art . in one embodiment , the dosage form comprises at least about 85 weight percent of the active ingredient . the active ingredient or ingredients may be present in the dosage form in any form . for example , the active ingredient may be dispersed at the molecular level , e . g . melted or dissolved , within the dosage form , or may be in the form of particles , which in turn may be coated or uncoated . if the active ingredient is in form of particles , the particles ( whether coated or uncoated ) typically have an average particle size of about 1 micron to about 2000 microns . in one embodiment , such particles are crystals having an average particle size of about 1 micron to about 300 microns . in yet another embodiment , the particles are granules or pellets having an average particle size of about 50 microns to about 2000 microns , e . g . from about 50 microns to about 1000 microns or from about 100 microns to about 800 microns . in certain embodiments in which modified release of the active ingredient is desired , the active ingredient may optionally be coated with a known release - modifying coating . this advantageously provides an additional tool for modifying the release profile of active ingredient from the dosage form . for example , the dosage form may contain coated particles of one or more active ingredients , in which the particle coating confers a release modifying function , as is well known in the art . examples of suitable release modifying coatings for particles are described in u . s . pat . nos . 4 , 173 , 626 ; 4 , 863 , 742 ; 4 , 980 , 170 ; 4 , 984 , 240 ; 5 , 286 , 497 ; 5 , 912 , 013 ; 6 , 270 , 805 ; and 6 , 322 , 819 . commercially available modified release active ingredients may also be employed . for example , acetaminophen particles , which are encapsulated with release - modifying polymers by a coaccervation process , may be used in the present invention . such coaccervation - encapsulated acetaminophen is commercially available from , for example , eurand america , inc . or circa inc . if the active ingredient has an objectionable taste , and the dosage form is intended to be chewed or disintegrated in the mouth prior to swallowing , the active ingredient may be coated with a taste masking coating , as known in the art . examples of suitable taste masking coatings are described in , for example , u . s . pat . nos . 4 , 851 , 226 ; 5 , 075 , 114 ; and 5 , 489 , 436 . commercially available taste masked active ingredients may also be employed . for example , acetaminophen particles , which are encapsulated with ethylcellulose or other polymers by a coaccervation process , may be used in the present invention . such coaccervation - encapsulated acetaminophen is commercially available from eurand america , inc . or circa inc . the active ingredient or ingredients are typically capable of dissolution upon contact with a fluid such as water , stomach acid , intestinal fluid or the like . in one embodiment , the dissolution characteristics of the active ingredient meet usp specifications for immediate release tablets containing the active ingredient . in embodiments in which it is desired for the active ingredient to be absorbed into the systemic circulation of an animal , the active ingredient or ingredients should be capable of dissolution upon contact with a fluid such as water , gastric fluid , intestinal fluid or the like . in one embodiment , the dissolution characteristics of the active ingredient meet usp specifications for immediate release tablets containing the active ingredient . for example , for acetaminophen tablets , usp 24 specifies that in ph 5 . 8 phosphate buffer , using usp apparatus 2 ( paddles ) at 50 rpm , at least 80 % of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing , and for ibuprofen tablets , usp 24 specifies that in ph 7 . 2 phosphate buffer , using usp apparatus 2 ( paddles ) at 50 rpm , at least 80 % of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing . see usp 24 , 2000 version , 19 - 20 and 856 ( 1999 ). in another embodiment , the dissolution characteristics of the active ingredient may be modified : e . g . controlled , sustained , extended , retarded , prolonged , or delayed . in general , one embodiment of the present invention creates dosage forms having at least one filled - in , molded intagliation or cavity portion bearing a microrelief . these microreliefs may be formed in the filled - in , molded intagliation portion via stamping , etching , or molding using high - volume , high - speed dosage form production methods and apparatus . the active ingredient may be in the core , the filled in portions , and / or any coatings applied onto the dosage form . in one embodiment , the container in which the dosage form is carried , or the packaging therefor , may also contain a component , such as a cap , flap , sidewall , or the like , that facilitates special illumination , e . g ., a polarizing filter element or a color filter element . the dosage forms may contain at least one active ingredient , a first portion , which comprises one or more cavities , which optionally may further contain indentations on the cavity surface , and an exterior surface , and a second molded portion , which is inlaid into the cavities of the first portion and has an exterior surface . the first and second portions are in contact at an interface , the second portion comprises a solidified thermoplastic material bearing a microrelief , and the second portion resides substantially conformably upon the indentations of the first portion . alternatively , the dosage forms may contain at least one active ingredient , a core having an outer surface and a shell residing on at least a portion of the core outer surface , wherein the shell comprises a first shell portion and a second shell portion , and the second molded shell portion , which is inlaid into the first shell portion , bears a microrelief . in yet another embodiment of this invention , the dosage form may contain at least one active ingredient , a core , and a shell having a first molded shell portion which is discontinuous , and a second molded shell portion which is continuous and which bears a microrelief , such that the discontinuities of the first shell portion are due to the presence of the second molded shell portion , and the first and second shell portions are compositionally different . in another embodiment , the first molded shell portion is continuous and the second molded shell portion , which bears a microrelief , is discontinuous . in yet another embodiment of this invention , the dosage form may contain at least one active ingredient , a core , and a shell having a first molded shell portion which is continuous , and a second molded shell portion which is discontinuous and which bears a microrelief , such that the discontinuities of the second shell portion are due to the presence of the first shell portion , and the first and second shell portions are compositionally different . in certain embodiments , the first portion consists essentially of a single homogeneous layer . in other words , it may be a single molded composition ( e . g . core or stripe ) or a single compressed tablet . if the portion were divided into parts , each part would have the same density , porosity , color , crystallinity , etc . in embodiments in which the first portion is prepared via compression , suitable excipients include , but are not limited to , fillers , binders , disintegrants , lubricants , glidants , and the like . in embodiments in which the first portion is prepared via compression , suitable fillers include , but are not limited to , water - soluble compressible carbohydrates such as sugars , which include dextrose , sucrose , isomaltalose , fructose , maltose , and lactose , polydextrose , sugar - alcohols , which include mannitol , sorbitol , isomalt , maltitol , xylitol , erythritol , starch hydrolysates , which include dextrins , and maltodextrins , and the like , water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives , water - insoluble brittle fracture materials such as dicalcium phosphate , tricalcium phosphate and the like and mixtures thereof . in embodiments in which the first portion is prepared via compression , suitable binders include , but are not limited to , dry binders such as polyvinyl pyrrolidone , hydroxypropylmethylcellulose , and the like ; wet binders such as water - soluble polymers , including hydrocolloids such as alginates , agar , guar gum , locust bean , carrageenan , tara , gum arabic , tragacanth , pectin , xanthan , gellan , maltodextrin , galactomannan , pusstulan , laminarin , scleroglucan , gum arabic , inulin , pectin , whelan , rhamsan , zooglan , methylan , chitin , cyclodextrin , chitosan , polyvinyl pyrrolidone , cellulosics , starches , and the like ; and derivatives and mixtures thereof . in embodiments in which the first portion is prepared via compression , suitable disintegrants include , but are not limited to , sodium starch glycolate , cross - linked polyvinylpyrrolidone , cross - linked carboxymethylcellulose , starches , microcrystalline cellulose , and the like . in embodiments in which the first portion is prepared via compression , suitable lubricants include , but are not limited to , long chain fatty acids and their salts , such as magnesium stearate and stearic acid , talc , and waxes . in embodiments in which the first portion is prepared via compression , suitable glidants include , but are not limited to , colloidal silicon dioxide , and the like . in embodiments in which the first portion is prepared via compression , the dosage form of the invention may also incorporate pharmaceutically acceptable adjuvants , including , but not limited to preservatives , high intensity sweeteners such as aspartame , acesulfame potassium , cyclamate , saccharin , sucralose , and the like ; and other sweeteners such as dihydroalcones , glycyrrhizin , monellin ™, stevioside , talin ™, and the like ; flavors , antioxidants , surfactants , and coloring agents . an overall understanding of the dosage form of this invention may be obtained by reference to fig1 a , 1b , 2 a and 2 b . fig1 a and 1b depict one embodiment of the dosage form of this invention . in fig1 a , a dosage form 2 is depicted which comprises a first portion 4 . the first portion comprises a plurality of debossments or cavities , which in turn comprise inlaid second portions 6 . the exterior surfaces of one or more of the second portions 6 possess a microrelief 11 . in this embodiment , a first active ingredient may be located within first portion 4 and an optional second active ingredient may be located within inlaid second portions 6 , although in other embodiments only one of inlaid second portions 6 or first portion 4 may contain an active ingredient . the flowable material used in the second portions 6 bearing a microrelief 11 must be able to retain a fine micrograph pattern , when exposed to humidity and temperature variations typically encountered during storage , shipment , and use of the dosage forms worldwide . in addition , these flowable materials should easily and cleanly release from the mold or stamp change part , without damaging the microrelief , after the dosage form has cooled and set . fig1 b is a cross - sectional view of the dosage form 2 of fig1 a . as shown in fig1 b , inlaid second portions 6 may extend partially into the first portion 4 from both first upper or top surface 8 and second lower or bottom surface 10 . as shown , portions of the microreliefs 11 may be raised and protrude above the first surface 8 and the second surface 10 of the first portion 4 . alternatively , as shown in fig1 c and fig1 d , the microreliefs 11 may alternatively be recessed and extend partially into the first surface 8 or second surface 10 . although not shown , the tips or ridges 12 of the microreliefs 11 may also be at approximately the same level as the surface of the proximate first surface 8 or second surface 10 . in these embodiments , a first active ingredient may be located within inlaid second portions 6 and an optional second active ingredient ( which may be the same or different than the first active ingredient ) may be located within first portion 4 , although in other embodiments only one of inlaid second portions 6 or first portion 4 may contain an active ingredient . in one embodiment , the first and second portions together provide a prearranged pattern . in yet another embodiment , the second portion may comprise a flavoring agent or sensate . as used herein , a “ sensate ” is a chemical agent that elicits a sensory effect in the mouth , nose , and / or throat other than aroma or flavor . examples of such sensory effects include , but are not limited to , cooling , warming , tingling , mouth watering ( succulent ), astringent , and the like . sensate agents suitable for use in the present invention are commercially available and may be purchased from , for example , international flavor & amp ; fragrances . the dosage forms depicted in fig1 e and 1f further contain a clear or semi - transparent top coating 13 that resides on first surface 8 and second surface 10 . the top coating 13 may also partially ( not shown ) or fully reside on the micrograph - containing inlaid portions 6 of the dosage form . suitable polymers for inclusion in top coatings include polyvinylalcohol ( pva ); water soluble polycarbohydrates such as hydroxypropyl starch , hydroxyethyl starch , pullulan , methylethyl starch , carboxymethyl starch , pre - gelatinized starches , and film - forming modified starches ; water swellable cellulose derivatives such as hydroxypropyl cellulose ( hpc ), hydroxypropylmethyl cellulose ( hpmc ), methyl cellulose ( mc ), hydroxyethylmethylcellulose ( hemc ), hydroxybutylmethylcellulose ( hbmc ), hydroxyethylethylcellulose ( heec ), and hydroxyethylhydroxypropylmethyl cellulose ( hempmc ); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers , polyvinyl alcohol and polyethylene glycol copolymers , polyethylene oxide and polyvinylpyrrolidone copolymers ; polyvinylpyrrolidone and polyvinylacetate copolymers ; and derivatives and combinations thereof . suitable film - forming water insoluble polymers for inclusion in top coatings include for example ethylcellulose , polyvinyl alcohols , polyvinyl acetate , polycaprolactones , cellulose acetate and its derivatives , acrylates , methacrylates , acrylic acid copolymers ; and the like and derivatives , copolymers , and combinations thereof . suitable film - forming ph - dependent polymers for inclusion in top - coatings include enteric cellulose derivatives , such as for example hydroxypropyl methylcellulose phthalate , hydroxypropyl methylcellulose acetate succinate , cellulose acetate phthalate ; natural resins , such as shellac and zein ; enteric acetate derivatives such as for example polyvinylacetate phthalate , cellulose acetate phthalate , acetaldehyde dimethylcellulose acetate ; and enteric acrylate derivatives such as for example polymethacrylate - based polymers such as poly ( methacrylic acid , methyl methacrylate ) 1 : 2 , which is commercially available from rohm pharma gmbh under the tradename , “ eudragit s ;” and poly ( methacrylic acid , methyl methacrylate ) 1 : 1 , which is commercially available from rohm pharma gmbh under the tradename , eudragit l ; poly ( butyl methacrylate ( dimethylaminoethyl ) methacrylate , methyl methacrylate ), which is commercially available from rohm pharma gmbh under the tradename , “ eudragit e ;” and the like , and derivatives , salts , copolymers , and combinations thereof . in one embodiment , top coating 13 includes those coatings having a high rigidity , i . e ., e . g ., those coatings having a yield value sufficient to prevent deformation of the microrelief when exposed to normal manufacturing , handling , shipping , storage , and usage conditions . suitable top coatings having high rigidity include film formers , such as for example , the high tensile strength film - formers well known in the art . examples of suitable high tensile strength film - formers include , but are not limited to methacrylic acid and methacrylate ester copolymers ; polyvinylpyrrolidone ; cellulose acetate ; hydroxypropylmethylcellulose (“ hpmc ”), polyethylene oxide and polyvinylalcohol , which is commercially available from basf under the tradename , “ kollicoat ir ”; ethylcellulose ; polyvinyl alcohols ; and copolymers and mixtures thereof . in one embodiment , the top coatings may include the water - soluble high rigidity film formers selected from hpmc , polyvinylpyrrolidone , the aminoalkyl - methacrylate copolymers marketed under the trade mark , “ eudragit e ,” and copolymers and mixtures thereof . in embodiments wherein high clarity is of particular concern , the top coatings may include the high clarity high - rigidity film formers selected from the acrylates such as the aminoalkyl - methacrylate copolymers marketed under the trademark , “ eudragit e ” polyvinylpyrrolidone , cellulose acetate , polyethylene oxide and polyvinylalcohol , ethylcellulose , and polyvinyl alcohol shellac . in general , the thickness of the top coating may range from about 50 microns to about 200 microns , and the rigidity of the locating layer will increase as the thickness is increased . the dosage form may contain , based upon the total weight of the dosage form , from about 0 . 1 percent to about 10 percent of the top coating . the top coating 13 may be applied via any means known in the art such as , for example , spray coating as disclosed in , u . s . pat . nos . 4 , 683 , 256 , 4 , 543 , 370 , 4 , 643 , 894 , 4 , 828 , 841 , 4 , 725 , 441 , 4 , 802 , 924 , 5 , 630 , 871 , and 6 , 274 , 162 ; dip coating as disclosed in , u . s . pat . nos . 5 , 089 , 270 ; 5 , 213 , 738 ; 4 , 820 , 524 ; 4 , 867 , 983 ; and 4 , 966 , 771 ; or injection molding as disclosed in , us application 2003 - 0219484 a1 . in one embodiment , the refractive index of the topcoat is not equivalent to the refractive index of the core . the topcoat may also be clear or semi - transparent in fig2 a and 2b depict another embodiment of this invention . fig2 a depicts a dosage form 102 that comprises a core 104 . the core has a shell 105 residing on at least a portion of the exterior surface of core 104 . the shell 105 is shown in greater detail in fig2 b , which is a cross - sectional view of the dosage form of fig2 a . as shown in fig2 b , the shell 105 residing on the exterior surfaces 108 and 110 of core 104 comprises a first shell portion 107 having cavities , with molded inlaid second shell portions 106 residing in the cavities . at least one of the inlaid second shell portions 106 possesses micrographs 111 . these micrographs may protrude from , be substantially uniform with , or be recessed from the proximate shell portion exterior surface 107 ′. in this embodiment , a first active ingredient may be located within shell portion 107 and a second active ingredient may be located within inlaid second shell portions 106 , although in other embodiments only one of first shell portion 107 or inlaid second shell portions 106 may contain an active ingredient . core 104 may optionally also contain an active ingredient , which may be the same or different than the active ingredient contained in first shell portion 107 and inlaid second shell portions 106 . as depicted in fig2 b , the shell 105 may extend along the side portions 112 and 114 of core 104 , and inlaid portions 116 and 118 may reside in the cavities of shell 105 . in this embodiment , the cavities extend through the first shell portion up to the surface of the core ; however , in other embodiments the cavities may only extend through a part of the first shell portion . in alternative embodiments ( not shown ) the cavity may extend through either a portion or all of the core . the dosage form depicted in fig2 c further contains a clear or semi - transparent top coating 13 ′ that resides on the surface 107 ′. the top coating 13 ′ may also partially or fully reside on the micrograph - containing inlaid portions 106 of the dosage form . examples of suitable top coatings 13 ′ include any of those set forth above . the dosage form of this embodiment may contain , based upon the total weight of the dosage form , from about 1 percent to about 10 percent of the top coating 13 ′. the core ( or substrate ) may be any solid or semi - solid form . the core may prepared by any suitable method , for example the core be a compressed dosage form , or may be molded . as used herein , “ substrate ” refers to a surface or underlying support , upon which another substance resides or acts , and “ core ” refers to a material , which is at least partially enveloped or surrounded by another material . for the purposes of the suitable for use in a dosage form : i . e . the term “ core ” may also be used to refer to a “ substrate .” in one embodiment , the core comprises a solid , for example , the core may be a compressed or molded tablet , hard or soft capsule , suppository , or a confectionery form such as a lozenge , nougat , caramel , fondant , or fat based composition . in certain other embodiments , the core may be in the form of a semi - solid or a liquid in the finished dosage form . the core may be in a variety of different shapes . for example , in one embodiment the core may be in the shape of a truncated cone . in other embodiments the core may be shaped as a polyhedron , such as a cube , pyramid , prism , or the like ; or may have the geometry of a space figure with some non - flat faces , such as a cone , cylinder , sphere , torus , or the like . exemplary core shapes which may be employed include tablet shapes formed from compression tooling shapes described by “ the elizabeth companies tablet design training manual ” ( elizabeth carbide die co ., inc ., p . 7 ( mckeesport , pa .) ( incorporated herein by reference ) as follows ( the tablet shape corresponds inversely to the shape of the compression tooling ): 1 . shallow concave . 2 . standard concave . 3 . deep concave . 4 . extra deep concave . 5 . modified ball concave . 6 . standard concave bisect . 7 . standard concave double bisect . 8 . standard concave european bisect . 9 . standard concave partial bisect . 10 . double radius . 11 . bevel & amp ; concave . 12 . flat plain . 13 . flat - faced - beveled edge ( f . f . b . e .). 14 . f . f . b . e . bisect . 15 . f . f . b . e . double bisect . 16 . ring . 17 . dimple . 18 . ellipse . 19 . oval . 20 . capsule . 21 . rectangle . 22 . square . 23 . triangle . 24 . hexagon . 25 . pentagon . 26 . octagon . 27 . diamond . 28 . arrowhead . 29 . bullet . 30 . barrel . 31 . half moon . 32 . shield . 33 . heart . 34 . almond . 35 . house / home plate . 36 . parallelogram . 37 . trapezoid . 38 . fig8 / bar bell . 39 . bow tie . 40 . uneven triangle . the core or sub - core may optionally be at least partially covered by a compressed , molded , or sprayed sub - coating . however , in another embodiment , the core may be substantially free of the subcoating : i . e . there is no subcoating located between the outer surface of the core and the inner surface of the shell . any composition suitable for film - coating a tablet may be used as a subcoating according to the present invention . examples of suitable subcoatings include , but are not limited to , those disclosed in , for example , u . s . pat . nos . 4 , 683 , 256 , 4 , 543 , 370 , 4 , 643 , 894 , 4 , 828 , 841 , 4 , 725 , 441 , 4 , 802 , 924 , 5 , 630 , 871 , and 6 , 274 , 162 . additional suitable subcoatings may include one or more of the following ingredients : cellulose ethers such as hydroxypropylmethylcellulose , hydroxypropylcellulose , and hydroxyethylcellulose ; polycarbohydrates such as xanthan gum , starch , and maltodextrin ; plasticizers including for example , glycerin , polyethylene glycol , propylene glycol , dibutyl sebecate , triethyl citrate , vegetable oils such as castor oil , surfactants such as polysorbate - 80 , sodium lauryl sulfate and dioctyl - sodium sulfosuccinate ; polycarbohydrates , pigments , and opacifiers . in one embodiment , the subcoating and / or the top coating may comprise an effect pigment that acts to maximize the reflectance of the core . examples of suitable effect pigments include , but are not limited to , platy titanium dioxide , such as that disclosed in u . s . pat . no . 6 , 627 , 212 ; and transition metal oxide coated platy mica such as that commercially available from emd chemicals inc . under the tradename , “ candurin .” see also pfaff , g . and reynders , p ., “ angle - dependent optical effects deriving from submicron structures of films and pigments ,” 99 chem . rev . 1963 - 1981 ( 1999 ). in embodiments wherein the dosage form contains a subcoating , the dosage form may contain , based upon the total weight of the dosage form , from about 1 percent to about 5 percent of the subcoating . in embodiments wherein the core is a compressed dosage form , for example a compressed tablet , the core may be obtained from a compressed powder . the powder may contain an active ingredient , and optionally comprise various excipients , such as binders , disintegrants , lubricants , fillers and the like , as is conventional , or the powder may comprise other particulate material of a medicinal or non - medicinal nature , such as inactive placebo blends for tableting , confectionery blends , and the like . one particular formulation comprises active ingredient , as an excipient , a plastically deforming compressible material , and optionally other excipients , such as disintegrants and lubricants and is described in more detail in united states patent application publication no . 20030068373 . during compression , the plastically deforming compressible material assumes the shape of the microrelief from the upper and / or lower punch surface . suitable plastically deforming compressible materials for these embodiments include : microcrystalline cellulose , waxes , fats , mono - and di - glycerides , derivatives and mixtures thereof , and the like . in certain embodiments , wherein the plastically deforming compressible material is later caused to melt and be absorbed into the tablet , the plastically deforming compressible material may be selected from low - melting plastically deforming compressible materials , such as plastically deforming compressible powdered waxes , such as shellac wax and microcrystalline wax , polyethylene glycol , and mixtures thereof . the core may also optionally comprise a sub - core ( which may also be referred to as an “ insert ”), which may be made by any method , for example compression or molding , and which may optionally contain one or more active ingredients . in one embodiment of the invention , the dosage forms of this invention comprise a core made from a blend of powders having an average particle size of about 50 microns to about 500 microns . in one embodiment , the active ingredient has an average particle size of about 50 microns to about 500 microns . in another embodiment , at least one excipient has an average particle size of about 50 microns to about 500 microns , e . g . about 100 to about 500 microns . in one such embodiment , a major excipient , i . e . an excipient comprising at least 50 % by weight of the core , has an average particle size of about 50 microns to about 500 microns , e . g . about 100 to about 500 microns . particles in this size range are particularly useful for direct compression processes . in one embodiment of the invention , the core may be a directly compressed tablet made from a powder that is substantially free of water soluble polymeric binders and hydrated polymers . this composition is advantageous for maintaining an immediate release dissolution profile , minimizing processing and material costs , and providing for optimal physical and chemical stability of the dosage form . in embodiments in which the core is prepared by direct compression , the materials comprising the core , e . g . the active ingredient or ingredients and excipients , may be blended together , for example as dry powders , and fed into a cavity of an apparatus that applies pressure to form a core . any suitable compacting apparatus may be used , including for example a roller compactor such as a chilsonator or drop roller ; or a conventional tablet press . in one embodiment , the core may be formed by compaction using a rotary tablet press as known in the art . in general , a metered volume of powder is filled into a die cavity of the rotary tablet press , and the cavity rotates as part of a “ die table ” from the filling position to a compaction position . at the compaction position , the powder is compacted between an upper and a lower punch , then the resulting tablet is pushed from the die cavity by the lower punch . advantageously , the direct compression process enables the minimization or elimination of water - soluble , non - saccharide polymeric binders such as polyvinyl pyrrolidone , alginates , hydroxypropyl cellulose , hydroxypropylmethylcellulose , hydroxyethylcellulose , and the like , which could have a negative effect on dissolution . in another embodiment , the core may be prepared by the compression methods and apparatus described in united states patent application publication no . 20040156902 . specifically , the core may be made using a rotary compression module comprising a fill zone , insertion zone , compression zone , ejection zone , and purge zone in a single apparatus having a double row die construction as shown in fig6 of united states patent application publication no . 20040156902 . the dies of the compression module may then be filled using the assistance of a vacuum , with filters located in or near each die . the purge zone of the compression module includes an optional powder recovery system to recover excess powder from the filters and return the powder to the dies . in another embodiment , the core may be prepared by a wet - granulation method , in which the active ingredient or ingredients , appropriate excipients , and a solution or dispersion of a wet binder ( e . g . an aqueous cooked starch paste , or solution of polyvinyl pyrrolidone ) may be mixed and granulated . suitable apparatus for wet granulation include low shear , e . g . planetary mixers , high shear mixers , and fluid beds , including rotary fluid beds . the resulting granulated material may then be dried , and optionally dry - blended with further ingredients , e . g . adjuvants and / or excipients such as , for example , lubricants , colorants , and the like . the final dry blend is then suitable for compression by the methods described in the previous paragraph . methods for direct compression and wet granulation processes are known in the art , and are described in detail in , for example , lachman , et al ., the theory and practice of industrial pharmacy , chapter 11 ( 3rd ed . 1986 ). in one embodiment , the first portion or core may also be prepared by thermal setting injection molding using the method and apparatus in which the mold is maintained at approximately a constant temperature as described in united states patent application publication no . 20030124183 . in this embodiment , the first portion or core may be formed by injecting a starting material in flowable form into a molding chamber . the starting material may comprise an active ingredient and a thermally responsive material , which is introduced to the mold at a temperature above the glass transition temperature or set temperature of the thermally responsive material but below the decomposition temperature of the active ingredient . the starting material is then cooled and solidified in the molding chamber into a desired shaped form ( i . e . the shape of the mold ). the starting material , when at a temperature that is greater than its glass transition temperature or its set temperature , is sufficiently flowable to be easily injected or pumped into the molding chamber . as used herein , “ thermally responsive material ” shall include materials that , as the temperature applied to the material is increased , become softer , and as the temperature applied is reduced , the materials conversely becomes harder and have reduced flow . in the case of gels , “ set temperature ” shall mean the temperature at which a gel - forming material rapidly solidifies through the gelation process . in another embodiment , the first portion or core may be prepared by thermal cycle injection molding using the method and apparatus , in which the mold is cycled between at least two temperatures , as described in united states patent application publication no . 20030086973 . in this embodiment , the first portion or core may be formed by injecting a starting material in flowable form into a heated molding chamber . the starting material may comprise an active ingredient and a thermoplastic material at a temperature above the glass transition temperature or set temperature of the thermally responsive material but below the decomposition temperature of the active ingredient . the starting material is then cooled and solidified in the molding chamber into a desired shaped form ( i . e . the shape of the mold ). according to either of these molding methods , the starting material must be in flowable form . for example , it may comprise solid particles suspended in a molten matrix such as a polymer matrix . alternatively , the starting material may be completely molten or in the form of a paste . in one embodiment , the starting material may comprise an active ingredient dissolved in a molten material . alternatively , the starting material may be made by dissolving a solid in a solvent , which solvent may then be evaporated from the starting material after it has been molded . the starting material may comprise any edible material which is desirable to incorporate into a shaped form , including active ingredients such as those active ingredients previously described with respect to the core , nutritionals , vitamins , minerals , flavors , sweeteners , and the like . typically , the starting material comprises an active ingredient and a thermally responsive material . the thermally responsive material may be any edible material that is flowable at a temperature between about 37 ° c . and about 250 ° c ., and that is a solid or semi - solid at a temperature between about − 10 ° c . and about 35 ° c . when it is in the fluid or flowable state , the flowable starting material may comprise a dissolved or molten component , and optionally a solvent such as for example water or organic solvents , or combinations thereof . the solvent may be partially or substantially removed by drying . suitable flowable , starting materials include , but are not limited to those thermally responsive materials such as film forming polymers , gelling polymers , hydrocolloids , low melting hydrophobic materials such as fats and waxes , non - crystallizable carbohydrates , and the like . examples of suitable thermally responsive materials include , but are not limited to water - soluble polymers such as polyalkylene glycols , polyethylene oxides and derivatives , and sucrose - fatty acid esters ; fats such as cocoa butter , hydrogenated vegetable oil such as palm kernel oil , cottonseed oil , sunflower oil , and soybean oil ; free fatty acids and their salts ; mono - di - and triglycerides , phospholipids , waxes such as carnuba wax , spermaceti wax , beeswax , candelilla wax , shellac wax , microcrystalline wax , and paraffin wax ; fat - containing mixtures such as chocolate ; sugar in the form of an amorphous glass such as that used to make hard candy forms , sugar in a supersaturated solution such as that used to make fondant forms ; carbohydrates such as sugar - alcohols ( for example , sorbitol , maltitol , mannitol , xylitol and erythritol ), or thermoplastic starch ; and low - moisture polymer solutions such as mixtures of gelatin and other hydrocolloids at water contents up to about 30 %, such as for example those used to make “ gummi ” confection forms . in one embodiment , the thermally responsive material is a blend of fats and mono - and diglycerides . in one embodiment of the invention , the flowable materials may comprise a film former such as a cellulose ether , e . g . hydroxypropylmethylcellulose or a modified starch , e . g . waxy maize starch ; optionally a polycarbohydrate , e . g . maltodextrin ; optionally a hydrocolloid , e . g . xanthan gum or carrageenan , or a sugar , e . g . sucrose ; and optionally a plasticizer such as polyethylene glycol , propylene glycol , vegetable oils such as castor oil , glycerin , and mixtures thereof . any film former known in the art is also suitable for use as a thermally responsive material . examples of suitable film formers include , but are not limited to , polyvinylalcohol ( pva ), polyvinylpyrrolidone ( pvp ), hydroxypropyl starch , hydroxyethyl starch , pullulan , methylethyl starch , carboxymethyl starch , methylcellulose , hydroxypropylcellulose ( hpc ), hydroxyethylmethylcellulose ( hemc ), hydroxypropylmethylcellulose ( hpmc ), hydroxybutylmethylcellulose ( hbmc ), hydroxyethylethylcellulose ( heec ), hydroxyethylhydroxypropylmethyl cellulose ( hempmc ), methacrylic acid and methacrylate ester copolymers , polyethylene oxide and polyvinylpyrrolidone copolymers , gelatin , proteins such as whey protein , coaggulatable proteins such as albumin , casein , and casein isolates , soy protein and soy protein isolates , pre - gelatinized starches , and polymers and derivatives and mixtures thereof . one suitable hydroxypropylmethylcellulose compound is hpmc 2910 , which is a cellulose ether having a degree of substitution of about 1 . 9 and a hydroxypropyl molar substitution of 0 . 23 , and containing , based upon the total weight of the compound , from about 29 % to about 30 % methoxyl groups and from about 7 % to about 12 % hydroxylpropyl groups . hpmc 2910 is commercially available from the dow chemical company under the tradename , “ methocel e .” methocel e5 , which is one grade of hpmc - 2910 suitable for use in the present invention , has a viscosity of about 4 to 6 cps ( 4 to 6 millipascal - seconds ) at 20 ° c . in a 2 % aqueous solution as determined by a ubbelohde viscometer . similarly , methocel e6 , which is another grade of hpmc - 2910 suitable for use in the present invention , has a viscosity of about 5 to 7 cps ( 5 to 7 millipascal - seconds ) at 20 ° c . in a 2 % aqueous solution as determined by a ubbelohde viscometer . methocel e15 , which is another grade of hpmc - 2910 suitable for use in the present invention , has a viscosity of about 15000 cps ( 15 millipascal - seconds ) at 20 ° c . in a 2 % aqueous solution as determined by a ubbelohde viscometer . as used herein , “ degree of substitution ” shall mean the average number of substituent groups attached to a anhydroglucose ring , and “ hydroxypropyl molar substitution ” shall mean the number of moles of hydroxypropyl per mole anhydroglucose . as used herein , “ modified starches ” include starches that have been modified by crosslinking , chemically modified for improved stability , or physically modified for improved solubility properties . as used herein , “ pre - gelatinized starches ” or “ instantized starches ” refers to modified starches that have been pre - wetted , then dried to enhance their cold - water solubility . suitable modified starches are commercially available from several suppliers such as , for example , a . e . staley manufacturing company , and national starch & amp ; chemical company . one suitable modified starch includes the pre - gelatinized waxy maize derivative starches that are commercially available from national starch & amp ; chemical company under the tradenames , “ purity gum ” and “ filmset ,” and derivatives , copolymers , and mixtures thereof . such waxy maize starches typically contain , based upon the total weight of the starch , from about 0 percent to about 18 percent of amylose and from about 100 % to about 88 % of amylopectin . suitable tapioca dextrins include those available from national starch & amp ; chemical company under the tradenames “ crystal gum ” or “ k - 4484 ,” and derivatives thereof such as modified food starch derived from tapioca , which is available from national starch and chemical under the tradename , “ purity gum 40 ,” and copolymers and mixtures thereof . examples of suitable hydrocolloids ( also referred to herein as gelling polymers ) include but are not limited to alginates , agar , guar gum , locust bean , carrageenan , tara , gum arabic , tragacanth , pectin , xanthan , gellan , maltodextrin , galactomannan , pusstulan , laminarin , scleroglucan , gum arabic , inulin , pectin , whelan , rhamsan , zooglan , methylan , chitin , chitosan , and derivatives and mixtures thereof . suitable xanthan gums include those available from c . p . kelco company under the tradenames , “ keltrol 1000 ,” “ xantrol 180 ,” or “ k9b310 .” thermoplastic materials that can be molded and shaped when heated are suitable for use as the thermally responsive material , and include both water soluble and water insoluble polymers that are generally linear , not crosslinked , nor strongly hydrogen bonded to adjacent polymer chains . examples of suitable thermoplastic materials include : chemically modified cellulose derivatives such as hydroxypropyl cellulose ( hpc ), hydroxypropylmethyl cellulose ( hpmc ), methyl cellulose ( mc ), cellulose acetate ( ca ), ethyl cellulose ( ec ), cellulose acetate butyrate ( cab ), cellulose propionate ; vinyl polymers such as polyvinyl alcohol ( pva ) and polyvinyl pyrrolidone ( pvp ); thermoplastic starch ; thermoplastic gelatin , natural and chemically modified proteins such as gelatin , soy protein isolates , whey protein , myofibrillar proteins , and the milk derived caseinate proteins ; and derivatives and combinations thereof . any plasticizer known in the pharmaceutical art is suitable for use in the flowable material , and may include , but not be limited to polyethylene glycol ; glycerin ; sorbitol ; triethyl citrate ; tribuyl citrate ; dibutyl sebecate ; vegetable oils such as castor oil ; surfactants such as polysorbates , sodium lauryl sulfates , and dioctyl - sodium sulfosuccinates ; propylene glycol ; mono acetate of glycerol ; diacetate of glycerol ; triacetate of glycerol ; natural gums and mixtures thereof . in solutions containing a cellulose ether film former , an optional plasticizer may be present in an amount , based upon the total weight of the solution , from about 0 % to about 40 %. any thickener known in the art may optionally be added to the thermally responsive material . additional suitable thickeners include , but are not limited to , cyclodextrin , crystallizable carbohydrates , and the like , and derivatives and combinations thereof . suitable crystallizable carbohydrates include the monosaccharides and the oligosaccharides . of the monosaccharides , the aldohexoses e . g ., the d and l isomers of allose , altrose , glucose , mannose , gulose , idose , galactose , talose , and the ketohexoses e . g ., the d and l isomers of fructose and sorbose along with their hydrogenated analogs : e . g ., glucitol ( sorbitol ), and mannitol are preferred . of the oligosaccharides , the 1 , 2 - disaccharides sucrose and trehalose , the 1 , 4 - disaccharides maltose , lactose , and cellobiose , and the 1 , 6 - disaccharides gentiobiose and melibiose , as well as the trisaccharide raffinose are preferred along with the isomerized form of sucrose known as isomaltulose and its hydrogenated analog isomalt . other hydrogenated forms of reducing disaccharides ( such as maltose and lactose ), for example , maltitol and lactitol are also preferred . additionally , the hydrogenated forms of the aidopentoses : e . g ., d and l ribose , arabinose , xylose , and lyxose and the hydrogenated forms of the aldotetroses : e . g ., d and l erythrose and threose are suitable and are exemplified by xylitol and erythritol , respectively . the flowable material may optionally comprise adjuvants or excipients , which may comprise up to about 20 % by weight of the flowable material . examples of suitable adjuvants or excipients include detackifiers , humectants , surfactants , anti - foaming agents , colorants , flavorants , sweeteners , opacifiers , and the like . in one embodiment , the flowable material comprises less than 5 % humectants , or alternately is substantially free of humectants , such as glycerin , sorbitol , maltitol , xylitol , or propylene glycol . humectants have traditionally been included in pre - formed films employed in enrobing processes , such as that disclosed in u . s . pat . nos . 5 , 146 , 730 and 5 , 459 , 983 to ensure adequate flexibility or plasticity and bondability of the film during processing . humectants function by binding water and retaining it in the film . pre - formed films used in enrobing processes can typically comprise up to 45 % water . disadvantageously , the presence of humectant prolongs the drying process , and can adversely affect the stability of the finished dosage form . in another embodiment , the core may be a hollow or evacuated core . for example , the core may be an empty capsule shell . alternatively , a hollow core may be prepared for example by injection molding or shell molding . in one such method , flowable material is injected into a mold cavity , the cavity is brought to a temperature at which the outer surface of the core ( which is in contact with the mold ) begins to solidify or set . the excess flowable material from the center of the core is then withdrawn from the mold using suitable means , for example a piston pump . in another such method , an empty capsule is used as a sub - core , and a coating layer is formed thereon by methods known in the art such as , for example , spray - coating , dip - coating , injection cycle molding as described in , for example , united states patent application publication no . 20030086973 . in certain embodiments of the invention , the core may further comprise any of the aforementioned subcoatings applied by any method known in the art , for example spraying , compression , or molding . in certain other embodiments of the invention , the core may be substantially free of a subcoating . in another embodiment of the invention , the core contains at least in part one or more inserts . the inserts can be made in any shape or size . for instance , irregularly shaped inserts can be made , that is shapes having no more than one axis of symmetry . cylindrically shaped inserts may also be made . the insert may be made using conventional techniques such as panning , compression , or molding . in one embodiment , the insert is prepared using the injection molding methods and apparatus as described herein . in one embodiment of the invention , the insert may have an average diameter from about 100 to about 1000 microns . in another embodiment of this invention , the insert may have an average diameter or thickness from about 10 % to about 90 % of the diameter or thickness of the core . in yet another embodiment of this invention , the core may comprise a plurality of inserts . in another embodiment , the insert may have an average diameter , length , or thickness greater than about 90 % of the diameter or thickness of the core , for example the insert may have an average length greater than about 100 % of the thickness of the core . in another embodiment of the invention , the core , the insert ( if employed ), the inlaid portion or any combination thereof may comprise a microelectronic device ( e . g . an electronic “ chip ”) which may be used as an active component or to control , for example , the rate of release of active ingredients within the core or insert in response to an input signal . examples of such microelectronic devices are as follows : ( 1 ) integrated , self - regulating responsive therapeutic devices including biosensors , electronic feedback and drug / countermeasure release devices which are fully integrated . such devices eliminate the need for telemetry and human intervention , and are disclosed , for example , at www . chiprx . com / products . html , which is incorporated herein by reference ; ( 2 ) miniaturized diagnostic imaging systems which comprise a swallowable capsule containing a video camera , and are disclosed , for example , at www . givenimaging . com / usa / default . asp , which is incorporated herein by reference ; ( 3 ) subcutaneous glucose monitors which comprise implantable or insertable sensor devices which detect changes in glucose concentration within intestinal fluid , and communicate to an external detector and data storage device . such devices are disclosed , for example , at www . applied - medical . co . uk / glucose . htm , which is incorporated herein by reference ; ( 4 ) microdisplay vision aid devices encapsulated in an artificial intraocular lens . such devices include a receiver for power supply , data and clock recovery , and a miniature led array flip - chip bonded to a silicon cmos driver circuit and micro optics , and are disclosed , for example , at http :// ios . oe . uni - duisberg . de / e /, which is incorporated herein by reference . the microdisplay device receives a bit - stream + energy wireless signal from a high dynamic range cmos camera placed outside the eye which generates a digital black & amp ; white picture which is converted by a digital signal processing unit ( dap ) into a serial bit - stream with a data rate of approximately 1 mbit / s . the image is projected onto the retina ; ( 5 ) microchips used to stimulate damaged retinal cells , allowing them to send visual signals to the brain for patients with macular degeneration or other retinal disorders . the chip is 2 mm × 25 microns , and contains approximately 5 , 000 microscopic solar cells (“ microphotodiodes ”), each with its own stimulating electrode . these microphotodiodes convert the light energy from images into electrical chemical impulses that stimulate the remaining functional cells of the retina in patients with amd and rp . such microchips are disclosed , for example , at www . optobionics . com / artificialretina . htm , which is incorporated herein by reference ; ( 6 ) disposable “ smart needles ” for breast biopsies which display results in real time . the device fits into a 20 to 21 gauge disposable needle that is connected to a computer , as the needle is inserted into the suspicious lesion . the device measures oxygen partial pressure , electrical impedance , temperature , and light scattering and absorption properties including deoxygenated hemoglobin , vascularization , and tissue density . because of the accuracy benefits from the six simultaneous measurements , and real - time nature of the device , it is expected to exceed the accuracy levels achieved by the core needle biopsy procedure and approach the high level of accuracy associated with surgical biopsies . further , if cancer is found , the device can be configured to deliver various therapies such as cancer markers , laser heat , cryogenics , drugs , and radioactive seeds . such devices are disclosed , for example , at www . bioluminate . com / description . html , which is incorporated herein by reference ; and ( 7 ) personal uv - b recorders , which are instrument grade devices for measuring and recording uvb exposure and fit into a wrist - watch face . they may also be worn as a patch . in one embodiment of the invention , only the core comprises one or more active ingredients . in another embodiment of this invention , only the inlaid portion comprises one or more active ingredients . in yet another embodiment of this invention , only the insert comprises one or more active ingredients . in yet another embodiment of this invention , both the core and inlaid portion comprise one or more active ingredients . in yet another embodiment of this invention , one or more of the core , the inlaid portion , or the insert comprises one or more of the active ingredients . optionally , any of the coatings may further comprise one or more active ingredients . the shell and / or inlaid portion may be made from the aforementioned thermally responsive materials , which for food and pharmaceutical uses may be any material that has been approved for use in foods and pharmaceuticals and can be molded , including for example , film formers , low - melting hydrophobic materials , gelling polymers , thickeners , plasticizers , adjuvants , and excipients . in one embodiment , the inlaid portion comprises at least about 50 %, e . g . at least about 80 %, or at least about 90 % of a material selected from film formers , gelling polymers , low - melting hydrophobic materials , non - crystallizable sugars or sugar alcohols , and mixtures thereof . in another embodiment , the inlaid portion comprises at least about 50 %, e . g . at least about 80 % or at least about 90 % of a material selected from film formers , gelling polymers , low - melting hydrophobic materials , and mixtures thereof . in one embodiment of the invention , the flowable material comprises gelatin as a gelling polymer . gelatin is a natural , thermogelling polymer . two types of gelatin — type a and type b — are commonly used . type a gelatin is a derivative of acid - treated raw materials . type b gelatin is a derivative of alkali - treated raw materials . the moisture content of gelatin , as well as its bloom strength , composition and original gelatin processing conditions , determine its transition temperature between liquid and solid . bloom is a standard measure of the strength of a gelatin gel , and is roughly correlated with molecular weight . bloom is defined as the weight in grams required to move a half - inch diameter plastic plunger 4 mm into a 6 . 67 % gelatin gel that has been held at 10 ° c . for 17 hours . in one embodiment , the flowable material is an aqueous solution comprising 20 % 275 bloom pork skin gelatin , 20 % 250 bloom bone gelatin , and approximately 60 % water . in another embodiment of the invention , the inlaid portion of the dosage form comprises at least about 80 %, e . g . at least about 90 %, of a material selected from film formers , gelling polymers ( hydrocolloids ), thermoplastic materials , low - melting hydrophobic materials , non - crystallizable sugars , and mixtures thereof . the inlaid portion of the dosage form may be molded into the cavity of the dosage form via any molding means known in the art . in one embodiment of the invention , the inlaid portion is applied to the dosage form using thermal setting injection molding or thermal cycle injection molding as described above . as shown in fig4 a and fig4 b , the flowable material for insertion into the cavities may be kept in one or more reservoirs 500 until the desired time for filling the cavities 501 of the core or the shell of the dosage form 510 . the flowable material may then be transported from the reservoirs 500 to the desired location in the cavities 501 via one or more feedlines 503 connected to one or more injector ports 502 . fig4 b illustrates an embodiment wherein a multiple of reservoirs 500 , feedlines 502 , and injector ports 502 are used to fill multiple , discontinuous cavities 501 in the dosage form 510 . fig4 c illustrates another embodiment wherein a single feedline 502 is branched in a manifold configuration 530 in order to permit the flowable material to feed into multiple injector ports 502 . although not shown , it may be possible to fill such multiple cavities 501 in the dosage form through one of many other ways such as , for example , having concentric feedlines and / or concentric nozzle tips . one skilled in the art would readily appreciate that a method suitable for filling such multiple cavities depending upon , for example , the location of the cavities on the dosage form and the difference , if any , in the type of flowable material required for each respective cavity . as shown in greater detail in fig4 d , a tip or valve 504 located at the bottom of each injector port 502 passes through a hole 505 in the surface of the upper mold 506 that is in alignment with the respective cavity 501 therebelow . the desired amount of flowable material passes through the tip or valve 504 and into the cavity 501 . the valve 504 is then closed , which thus closes the hole 505 during the molding period . the location of the hole 505 is not critical , so long as it permits the flowable material to be injected into the appropriate cavity 501 of the dosage form 510 . see also fig5 , 53 , and 54 of wo03 / 028990 . the upper mold 506 is engaged with either a holder or “ collet ” for the dosage form or a lower mold 507 . although the upper mold 506 and the lower mold 507 are illustrated as moving in a longitudinal manner in order to produce the molded dosage form , the operational direction of these pieces is not critical so long as the microrelief on the interior surface 506 a of at least the upper surface is in alignment with the filled - in cavity portion 501 of the dosage form . in embodiments when the cavity is filled with gelatin , and the gelatin portion contains a microrelief , the gelatin generally shrinks vertically , e . g ., by about 50 % to about 75 % and laterally , e . g ., by about 1 % to about 10 %. in order to compensate for this shrinkage , the diffractive relief pattern molded into the wet gelatin is sized to be about 50 % to about 75 % larger in the vertical dimension and about 1 % to about 10 % larger in the horizontal dimension than the dimensions of the pattern in the final dried dosage form product . therefore , for example , if the final product has a diffractive grating of about 500 lines or grooves per millimeter , the diffractive pattern etched into the surface of the mold would be a negative pattern and have about 476 lines or grooves per millimeter . likewise in the vertical dimension , if the linear ridges making up the diffractive grating of the final , dried dosage form product are about ⅔ microns in height , then the diffractive pattern etched into the surface of the mold would be a negative pattern and have about 3 times the vertical dimension of the grating in the dried , finished product or approximately 2 microns . fig5 a shows an example of the plan view of the internal surface 506 a of the upper mold 506 , wherein a microrelief 512 , with ridges and grooves arranged in an exemplary shape , e . g . an overall “ y ” shape , is engraved into the internal surface 506 ′. in this example , the overall shape of the microrelief 512 may either correspond with the overall “ y - shaped ” cavity 513 as illustrated in fig5 b or may extend beyond the perimeter of the actual cavity ( not shown ). methods for etching the internal surface 506 ′, such as by use of a laser , mechanical scribing , or acid etching , in order to obtain the desired microrelief pattern in the desired location are well known in the art and disclosed in , for example , pages 17 - 18 of wo 03 / 005839 , u . s . pat . no . 6 , 410 , 213 b1 , and the publication , photonics spectra ( june 2004 ). in an alternative embodiment shown in fig6 a and 6d , a removable change - part 520 , 520 ′ such as a thin film or foil , containing the desired microrelief 512 may be inserted on to the internal surface 506 ′ of the upper mold , or in the internal surface of one of the dies used in a tablet press , via any known means for removably attaching the change - part such as , for example adhesives . in alternative embodiment shown in fig6 b and fig6 c , respectively , the removable change - part 520 may extend across the entire internal surface 506 ′ of the upper mold 506 ( see changepart 520 ″ in fig6 b ), or may be friction - fit into an opening in the upper mold 506 ( see changepart 520 ′″ in fig6 c ). advantageously , the changepart 520 used in this embodiment could easily be removed and replaced with another changepart having an alternative microrelief pattern with minimal cost and production cycle time loss . suitable changepart materials include any substance that is capable of holding a microrelief image , such as aluminum , tin , gold , silver , nickel , copper , and their alloys , plastics that are solid at temperature greater than 250 ° c ., and mixtures thereof . the size and thickness of the changepart may vary depending upon , for example , the surface area of dosage form and the desired microrelief pattern , but will generally have a thickness of from about 10 microns to about 5000 microns and a surface area of from about greater than 0 % to less than about 100 % of the dosage form face , e . g ., greater than about 10 % and less than about 90 % or greater than about 25 % and less than about 50 %. “ face ,” as used herein , is the portion of a compressed tablet formed by the upper and lower punch faces , and includes one - half of the overlap area of a rim as illustrated in united states patent application publication no . 20040109889 . in an alternative embodiment , the microrelief may be stamped into the molded inlaid portion 501 of the dosage form using conventional stamping means containing the desired microrelief pattern . these stamping means are well known in the art and disclosed in , for example , wo 01 / 10464 , begleiter , “ edible holography : the application of holographic techniques to food processing ,” 1461 spie practical holography v 102 - 109 ( 1991 ); wo 01 / 10464 ; and wo 03 / 00589 . in embodiments where the inlaid portion is formed by injection molding , the need for direct - compression filler - binders such as microcrystalline cellulose , spray - dried lactose , mineral salts such as calcium phosphate , crystalline sugars such as sucrose , dextrates and the like , may be minimized or eliminated . other known dosage forms , such as those produced via the inclusion of compression - coated shells , typically comprise at least about 30 % of such direct - compression filler - binders . see , e . g ., wo 00 / 18447 . disadvantageously , the inclusion of these materials would otherwise disadvantageously detract from the clarity and stability of the inlaid portion . advantageously in this embodiment , the inlaid portion of the present invention may comprise less than about 10 %, e . g . less than about 1 % or less than about 0 . 1 %, of such direct - compression filler - binders . in one embodiment wherein the cavity passes directly through the dosage form ( not shown ), the cavity may be filled with flowable material , then the microrelief may be applied to either the top surface and / or the bottom surface of the filled - in portion via any means known in the art . in this embodiment , the microrelief may be applied to one surface via injection molding or stamping as set forth herein . alternatively , in embodiments wherein it is desired to apply a microrelief to both the top surface and the bottom surface , the bottom dosage form collet may be replaced with a mold cavity having a microreliefed interior surface . after the mold is filled with the desired amount of flowable material , the closed mold may then be adjusted to an appropriate temperature and for a time sufficient to set the flowable material within the cavity 501 of the dosage form . although these parameters may vary depending upon , for example , the type and amount of flowable material , typically the molding temperature is from about 50 ° c . to about 120 ° c . and the molding time is from about 1 seconds to about 10 seconds . in one embodiment , the inlaid portion may be substantially free of pores having a diameter of about 0 . 5 microns to about 5 microns . as used herein , “ substantially free ” means that the inlaid portion has a pore volume of less than about 0 . 02 cc / g , e . g . less than about 0 . 01 cc / g or less than about 0 . 005 cc / g , in the pore diameter range of about 0 . 5 microns to about 5 microns . typical compressed materials have pore volumes of more than about 0 . 02 cc / g in this pore diameter range . pore volume , pore diameter and density may be determined using a quantachrome instruments poremaster 60 mercury intrusion porosimeter and associated computer software program known as “ porowin .” the procedure is documented in the quantachrome instruments poremaster operation manual . the poremaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non - wetting liquid ( mercury ), which involves evacuation of the sample in a sample cell ( penetrometer ), filling the cell with mercury to surround the sample with mercury , applying pressure to the sample cell by : ( i ) compressed air ( up to 50 psi maximum ); and ( ii ) a hydraulic ( oil ) pressure generator ( up to 60000 psi maximum ). intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure . the corresponding pore size diameter ( d ) at which the intrusion takes place is calculated directly from the so - called “ washburn equation ”: d =−( 4γ ( cos δ ))/ p where γ is the surface tension of liquid mercury , δ is the contact angle between mercury and the sample surface and p is the applied pressure . 1 . quantachrome instruments poremaster 60 . 2 . analytical balance capable of weighing to 0 . 0001 g . 3 . desiccator . 1 . high purity nitrogen . 2 . triply distilled mercury . 3 . high pressure fluid ( dila ax , available from shell chemical co .). 4 . liquid nitrogen ( for hg vapor cold trap ). 5 . isopropanol or methanol for cleaning sample cells . 6 . liquid detergent for cell cleaning . the samples remain in sealed packages or as received in the dessicator until analysis . the vacuum pump is switched on , the mercury vapor cold trap is filled with liquid nitrogen , the compressed gas supply is regulated at 55 psi ., and the instrument is turned on and allowed a warm up time of at least 30 minutes . the empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded . the cell is installed in the low pressure station and “ evacuation and fill only ” is selected from the analysis menu , and the following settings are employed : fine evacuation time : 1 min . fine evacuation rate : 10 coarse evacuation time : 5 min . the cell ( filled with mercury ) is then removed and weighed . the cell is then emptied into the mercury reservoir , and two tablets from each sample are placed in the cell and the cell is reassembled . the weight of the cell and sample are then recorded . the cell is then installed in the low - pressure station , the low - pressure option is selected from the menu , and the following parameters are set : mode : low pressure fine evacuation rate : 10 fine evacuation until : 200μ hg coarse evacuation time : 10 min . fill pressure : contact + 0 . 1 maximum pressure : 50 direction : intrusion and extrusion repeat : 0 mercury contact angle : 140 mercury surface tension : 480 data acquisition is then begun . the pressure vs . cumulative volume - intruded plot is displayed on the screen . after low - pressure analysis is complete , the cell is removed from the low - pressure station and reweighed . the space above the mercury is filled with hydraulic oil , and the cell is assembled and installed in the high - pressure cavity . the following settings are used : mode : fixed rate motor speed : 5 start pressure : 20 end pressure : 60 , 000 direction : intrusion and extrusion repeat : 0 oil fill length : 5 mercury contact angle : 140 mercury surface tension : 480 data acquisition is then begun and graphic plot pressure vs . intruded volume is displayed on the screen . after the high pressure run is complete , the low - and high - pressure data files of the same sample are merged . in one embodiment , the dosage form contains a core having two faces and a belly band therebetween , and a shell having a thickness from about 100 microns to about 400 microns that substantially covers the one face surface . the other face surface is compositionally different from the shell . the shell , which may contain , based upon the total weight of said shell , less than about 50 percent crystallizable sugar , bears a microrelief . another embodiment of the present invention is directed to a dosage form wherein the core is comprised of a powder blend containing a plastically deforming compressible material . in this embodiment as illustrated in fig7 , the core 704 may be formed by first adding the powder blend into the desired mold arrangement , such as one with an upper punch 702 and a lower punch 703 . at least one internal surface 705 , 705 ′ of the molding arrangement contains at least one micrograph 701 with a positive image engraved into its internal surface , such as that illustrated in fig5 a . these punches may be used in any conventional compression tablet press ( not shown ) having an upper punch and a lower punch known in the art , wherein the interior surface of the upper and / or lower punch contains at least one micrograph . as used herein , “ plastically deforming compressible material ” shall mean any excipient added to core materials , which during compression , flows and assumes the shape of the microrelief engraved in the punch face . examples of suitable plastically deforming compressible materials include polyethylene glycol , fats , waxes , and mixtures thereof . after the powder blend is compressed via a compression tablet press , a non - opaque , e . g ., clear or semi - transparent , top coating 13 may then be applied to the surface 706 of the resulting core 704 , which contains a micrograph 707 as illustrated in fig7 b , via any of the above - described coating application methods and at a temperature below the melting temperature of the plastically deforming compressible material . typically , such temperature may range from about 5 ° c . to about 120 ° c . the top coating 13 should also be applied to the core 704 at the location of the micrograph 707 . examples of suitable top coating 13 materials include , but are not limited to aminoalkyl methacrylate copolymers , which are commercially available under the tradename , “ eudragit e ,” and polymethylmethacrylate . the coated dosage form may contain , based upon the total weight of the dosage form , from about 1 percent to about 10 percent of the top coating 13 . after the top coating 13 is set on the core 705 such that the internal surface 720 of the top coating 13 possesses a negative image 721 of the micrograph pattern 707 formed on the exterior surface 706 of the core 704 , the coated dosage form may then optionally be heated to a temperature sufficient to melt at least the surface of the core 705 . although this temperature may vary depending upon , for example , the composition of the powder blend , typically the temperature may range from 20 ° c . to about 200 ° c . in this embodiment , the core material may optionally contain , based upon the total weight of the core , from about 10 to about 50 , of an absorbent excipient having a porous structure such as dicalcium phosphate , tricalcium phosphate , calcium silicate , and mixtures thereof . the dosage form may then be cooled to ambient temperature . the resulting dosage form uniquely possesses a top coating 13 with an internal surface 720 containing at least one micrograph 721 in the internal surface of the top coating as illustrated in fig7 c . in yet another embodiment as shown in fig9 a , a tablet core 800 comprised of a powder blend containing a plastically deforming compressible material may be produced via injection molding or compression as aforementioned , wherein the surface of the resulting core does not possess a micrograph . optionally , the tablet core 800 may also contain the aforementioned absorbent excipient . a waxy layer 801 may then be applied to the surface of the core either via pan coating or via any of the aforementioned molding methods . a micrograph 802 may then be applied to the outer surface 803 of the waxy layer 801 either by stamping the pan - coated waxy layer surface with the desired micrograph pattern or via injection molding the micrograph pattern into the waxy layer 801 with a mold portion having a patterned inner surface . the dosage form 850 of this embodiment may contain , based upon the total weight of the coated dosage form 850 , from about 1 percent to about 10 percent of the waxy layer 801 . the waxy layer 801 may be comprised of any material that will retain the image of the micrograph , but have a lower melting temperature than the melting temperature of the adjacent top coat 810 . examples of suitable materials for the waxy layer 801 include , but are not limited to , aliphatic polyesters ; ascorbyl palmitate ; hydrogenated castor oil ; cetosteryl alcohol ; cetyl alcohol ; cetyl esters ; sterols such as cholesterol ; ethyl glycol palmitostearate ; mono and di - glycerides ; saturated polyglycolized glycerides , paraffin , poloxamer , polyethylene glycol ; polyethylene oxide ; sorbitan esters , polyoxyethylene stearates ; suppository bases ; stearyl alcohol , stearic acid ; hydrogenated vegetable oil ; waxes such as yellow , white , carnauba , sterotex , anionic emulsifying , microcrystalline , nonionic emulsifying waxes ; and mixtures thereof . a top coat 810 , which is not opaque , may then be applied to the surface 803 of the waxy layer 801 via any means known in the art such as , for example , spraying , molding , or dipping . advantageously , the top coating 810 should either partially or fully reside on the micrographed portion 802 of the waxy layer 801 , and be comprised of a material that is rigid or not flowable at a temperature less than about 100 ° c ., e . g ., less than about 70 ° c . examples of suitable top coatings 810 include those set forth above such as , for example , a blend of acrylate and hydroxypropylmethyl cellulose . the dosage form of this embodiment 850 may contain , based upon the total weight of the dosage form , from about 1 percent to about 10 percent of the top coating . after the top coating 810 is dried , the resulting dosage form 850 may then be heated to a temperature in excess of the melting temperature of the waxy layer 801 . in one embodiment , the temperature may also be less than the melting temperature of the core 800 . as a result , the waxy layer 801 is substantially absorbed by the core 800 , leaving the interior surface 811 of the top coating 810 with a negative image 802 ′ of the microrelief 802 , and the formation of an air gap 820 between the outer surface 830 of the core 800 and the inner surface 811 of the top coating 810 as illustrated in fig9 b . the presence of the air gap creates an interface between the core 800 and the diffractive relief pattern 802 ′ in the interior surface 811 of the top coating 810 . the resulting change in the index of refraction through this interface causes a reflection of a portion of the incident light and thus a reconstruction of the holographic microrelief image 802 ′ in the top coating 810 . the portion of the light transmitted through the microrelief 802 ′ also brightens the core surface 800 located in the background of the microrelief upon the light &# 39 ; s reflecting from the core surface 800 . see u . s . pat . no . 4 , 921 , 319 . in the embodiment wherein the core 800 also contains a printed image , this reflected light also permits the visualization of that printed image , with the result being a superimposition of a diffractive image over a printed image . advantageously , this embodiment is particularly suitable for providing a user with a visual quality control indication on the dosage form that would visibly change if the dosage form were exposed to adverse humidity or temperature conditions . for example , a micrograph pattern , such as the word , “ expired ,” may be placed into the waxy layer of the dosage form . then , so long as the waxy layer is made from a composition that melts at least at a temperature and or humidity that would also affect the efficacy of the pharmaceutical active ingredient , the micrograph pattern would not become visible to the user until the waxy layer was absorbed into the core . yet another embodiment of the present invention is directed to flakes or “ glitter ” comprised of film containing microreliefs that may be subsequently cut into smaller , desired shapes and sizes . films suitable for use in this embodiment may be prepared from a polymeric mixture containing , based upon the total weight of the polymeric mixture , from about 5 percent to about thirty percent of a water insoluble , film forming polymer , and from about 70 percent to about 95 percent of an organic solvent . suitable water insoluble polymers include , but are not limited to cellulose acetate , ethylcellulose , and derivatives , copolymers and mixtures thereof . suitable ph - dependent polymers include , but are not limited to methyl acrylate copolymers , such as those commercially available from rohm pharma gmbh , under the tradenames , “ eudragit l ” or “ eudragit s .” suitable organic solvents include , but are not limited to ethanol , acetone , methylene chloride , ethyl acetate , diethyl ether , hexane , and the like and combinations thereof . the polymeric mixture may optionally contain other ingredients such as , for example , preservatives , colorants , flavors , plasticizers , detackifiers , defoaming agents , and the like in amounts readily known by one of ordinary skill in the art . in general , the water insoluble , film forming polymers may be dissolved in the solvent with stirring at ambient temperature such that the solution contains , based upon the total weight of the solution , from about 10 % to about 25 % of the water insoluble , film forming polymers . the components of the polymeric mixture may be mixed until all components are dissolved and / or dispersed in the solvent . temperature is not critical . the mixture may then be made into film via any known apparatus for making film . for example , the polymeric mixture may be spread onto a film casting system as illustrated in fig8 a , which is comprised of at least two rotating rollers 902 a and 902 b having a movable belt 903 thereon set to a temperature of about 20 ° c . to about 50 ° c . see also park , w . r . r ., plastic film technology , ch . 2 ( 1969 )( fig2 . 12 ). in this embodiment , the flowable material 963 may exit a holding tank 960 through a nozzle 961 and be spread across the width of the belt 903 with the assistance of the spreading bar 962 . alternatively ( not shown ), the spreading bar 962 may be in the form of upper rollers , plates , or the like that produce a substantially uniform , downward pressure on the flowable material . one skilled in the art would readily appreciate that if the film is exposed to a pressure less than atmospheric pressure , then the overall production cycle time should be reduced in order to compensate for the increased the rate of evaporation . alternatively ( not shown ), the flowable material may be sprayed or spread on to the belt . the belt 903 advances the flowable material 963 , from left to right , at a linear velocity of from about 100 fpm to about 1000 fpm . a microrelief pattern 901 may be engraved into the surface of a supporting change part or mold , such as , for example the belt 903 itself as illustrated in fig8 a . after the flowable material 963 is spread onto the belt 903 containing a microrelief pattern 901 on its upper surface 903 a and the solvent from the flowable material is permitted to be evaporated therefrom , the exiting material is dried to form a film 905 . as the film continuously advances , the lower surface 907 of the exiting film 905 will possess a negative image of the microrelief pattern 901 . examples of such film casting systems are well known in the art and disclosed in , for example , park , w . r . r ., plastic film technology , ch . 2 ( 1969 )( see p . 22 ). in yet another embodiment as shown in fig8 b , the polymeric mixture , which is at a temperature equal to or greater than room temperature , may alternatively be dropped onto a roller 950 having an outer surface that possesses a microrelief pattern 951 , which is the negative image to that which is formed in the adjacent film surface 952 of the exiting film 953 . the roller is set to a temperature sufficient to evaporate the solvent , e . g , typically from about 20 ° c . to about 50 ° c ., and the tangential velocity of the roller is from about 1 fpm to about 100 fpm . although not shown , the polymeric mixture may also alternatively be spread onto a belt or other supporting change part , plate , or mold without microrelief patterns in its surface . a microrelief pattern may then be added to the upper and / or the lower surfaces of the films cast from these belts via methods known in the art such as via stamping or rolling ( rotary embossing ). details of these methods are known in the art and disclosed in , for example , u . s . pat . nos . 6 , 349 , 639 ; 6 , 143 , 386 ; and 6 , 694 , 872 . the thickness of the resulting films may vary depending upon , for example , the size and detail of the microrelief desired , but generally may vary from about 10 microns to about 500 microns . the microrelief pattern may be adjusted such that only desired wavelength of light may be reflected therefrom . for example , by adjusting the depth and angle of the ridges and grooves of the microrelief in the molding portion , it may be possible to reflect one color from the resulting microrelief in the film , and with further adjustment of the microrelief in the molding portion , it may be possible to reflect multiple colors from the resulting microrelief in the film . the resulting films containing microrelief patterns may then be cut to a desired shape and size under ambient conditions via any cutting means known in the art , including but not limited to millers , shears , knives , or choppers , in order to form microreliefed flakes or “ glitter ” desired weight and thickness . optionally , the cut flakes maybe sieved to desired flake size . in this embodiment , it would be possible to collect a multitude of similar flakes having a certain microrelief and a certain size . this is particularly beneficial when a certain color in the wavelength reflected from the microrelief is desired . the resulting flakes may then be added to any media , such as liquids or semi - solids , including but not limited to oral pharmaceutical suspension vehicles such as those disclosed in for example , u . s . pat . nos . 5 , 272 , 137 and 5 , 374 , 659 . in one embodiment , the resulting microreliefed glitter may be comprised of flakes , which have , for example , different sizes and / or different microrelief patterns , that are dispersed in the media , thereby enabling the light reflected from the flakes &# 39 ; surfaces to appear in a spectrum of colors . by contrast , if only one type and size of microreliefed glitter was dispersed in a media , then the light reflected therefrom would appear to be a more uniform color . the resulting glitter - containing media may then be applied to dosage forms via methods known in the art such as , for example , dip coating or molding . advantageously , such coatings possess several refractive particles that not only give the dosage form a unique appearance , but are also suitable for human ingestion unlike other , known inorganic interference pigments . in another embodiment , the flakes may be combined with the above - described powder blend components in order to produce a core with the flakes dispersed throughout the core matrix . the glitter may be used in a variety of products so long as the glitter remains insoluble therein . examples of ingestible product uses include those liquids and semi - solids in the fields of pharmaceutical , nutritional , or food . in one embodiment , the glitter may be added to the pharmaceutical powder dosage forms , which may then be added to a pharmaceutically acceptable vehicle . examples of non - ingestible uses for the glitter include , but are not limited to : 1 ) cosmetic bases such as body powders , perfumes , blush , eye shadow , and the like ; 2 ) hair care products such as gels , shampoos , conditioners ( rinse - out or leave - in ), mousses , sprays , and the like ; 3 ) other personal , cosmetic , healthcare , and / or toiletry products such as nail polish , bandages , soap bars , baths , shower gels , wipes , washes , sticks , balms , sachets , pillows , mousses , sprays , lotions , creams , cleansing compositions , powders , oils , bath oils and other bath compositions which may be added to a bath . personal care compositions may also include , but are not limited to , aerosols , and candles . another method for producing a dosage form containing unique visual properties includes the application of lines , or fine dots arranged in a line , in a desired pattern onto the surface of a core , which optionally may be a pattern 610 on the interior surface 602 ′ of a core cavity 602 as shown in fig3 , followed by the application of a coating containing a macrorelief pattern thereon . any method known in the art for applying lines to a substrate surface may be used such as , for example : a ) applying a striped film coating to the dosage form via any of the methods described herein ; b ) applying a decal or the like containing the striped pattern to the surface of the dosage form ; or c ) printing strips directly onto the surface of a core via a high resolution printer , such as those commercially available from harknett , inc . when the lines are printed on the dosage form as a regularly spaced pattern of lines and overlayed with an identical pattern of lines that is slightly misaligned with the first pattern , an interference - producing , moiré pattern may be obtained . in one embodiment as shown in fig1 , the surface of a dosage form 201 may contain a first printed pattern 202 , and a second film 203 , which optionally may possess at least one macroreliefed surface , may be overlayed thereon to yield a moiré pattern effect . a macrorelief - containing coating may be applied to the striped core surface in a manner similar to those disclosed herein for applying a microreliefed coating to cores . examples of suitable coatings include , but are not limited to , those comprising gelatin , methacrylic acid and methacrylate ester copolymers , polyvinylpyrrolidone , cellulose acetate , hpmc , polyethylene oxide and polyvinylalcohol copolymers , ethylcellulose , polyvinyl alcohols , and derivatives , and copolymers and mixtures thereof . as a result , when light passes through the lenticules 920 of a microrelief coating on a core 921 as illustrated in fig1 , it is reflected from an underlying surface , i . e ., e . g ., the tablet surface that contains printed information or an image . the lenticule refracts the returning light and magnifies the underlying information or image . the information or image , which underlies the lenticules and is arranged in stripes 902 , 903 , is appropriately aligned so that all of the stripes for particular information / image are refracted to the same point in order to create a single image . as the orientation of the lenticular surface is changed in relation to the line of sight by an observer , different image stripes can then be seen as complete images . fig1 illustrates a dosage form having the appearance of two different colors . the dosage form may appear to be one color ( fig1 a ) based upon the refraction of light from a first set of strips 902 , and a second color ( fig1 c ) based upon the refraction of light from a second set of strips 903 after the orientation of the lenticular surface is changed . in one embodiment as illustrated in fig1 , the printed information may be arranged into a plurality of strips , with at least a first set of strips 902 and a second set of strips 903 . at least one of the first set of strips 902 and at least one of the second set of strips 903 are arranged directly on the surface 922 of the core 921 , or alternatively on a decal attached to the tablet surface , in an alternating , juxtaposed manner as shown in fig1 b , such that a plurality of strip pairs 901 are formed . each strip pairs 901 , respectively , is in substantial vertical alignment beneath one of the plurality of lenticules 920 , and is comprised of a first strip 902 and a second strip 903 . in this embodiment , the first strips 902 are of one visual distinction , e . g ., a first color , and the second strips 903 are of a different visual distinction , e . g ., a different color . when an observer looks down directly upon the top surface of the resulting dosage form as shown in fig1 a , the dosage form may appear to be striped . in another embodiment as illustrated in fig1 , the surface of the dosage form may either have the appearance of the term , “ 500 ,” or alternatively the term , “ tylenol .” as shown in fig1 a and 12d , each of these two terms may be divided into a plurality of strips . the strips are then arranged in an alternating manner to form strip pairs 901 on the surface of the core 921 . when an observer directly looks down upon the top surface of the resulting dosage form , the dosage form may have the appearance as shown in fig1 e . however , as the orientation of the lenticular surface 920 is changed in relation to the line of sight by an observer , the different image stripes can then be seen as one of two complete images , i . e ., e . g ., as either the “ 500 ” ( fig1 c ) or the “ tylenol ” ( fig1 b ). each of the plurality of lenticules 902 may have a substantially uniform width of from about 0 . 1 mm to about 1 mm , and in one embodiment , each of the first strips and the second strips , respectively have a substantially uniform width that is not more than about half the width of each respective lenticule . as shown in fig1 b , each lenticule possesses a tip or ridge 930 , with a gap 931 between each pair of proximate ridges 930 . the strips may be comprised of any ink or pigment , and optionally may contain an effect pigment . examples of suitable inks and pigments are those disclosed in , for example , u . s . pat . nos . 5 , 435 , 840 ; 5 , 006 , 362 ; and 6 , 468 , 561 ; united states patent application no . 20040175463 ; and wo 2004073582 . examples of suitable effect pigments include , but are not limited to those providing a nacreous or pearlescent quality to various products and containing titanium oxide and / or iron oxide on a base of mica or flakes of al 2 o 3 , sio 2 , or tio 2 , such as those commercially available from merck kgaa under the tradename , “ candurin ®.” see also wo 2004 / 073582 a2 . in embodiments wherein the strips are directly printed onto the core surface , the core surface may first be coated with a subcoat , which may be comprised of , for example , any of the aforementioned film forming materials . the subcoating may be applied to the core via any means known in the art such as , for example , spray coating , pan coating , and dip coating . the subcoating should be applied at least to the area selected for printing , and the amount of subcoating used should be , based upon the total weight of the subcoated core , from 0 . 1 percent to about 10 percent . in one embodiment , the strips may be directly applied to the core surface while the core is held in an appropriate orientation by a holding means , such as a collet , in order to provide a backing to the core during the printing process . the core then may be fed into an ink - jet printer , a flexoprinter , a silk - screener , or other suitable device that enables the edible ink to be applied onto , and adsorbed by the core surface . although the color of the ink is not critical , in one embodiment relatively opaque ink may be used to ensure an effective contrast with the surrounding , non - imprinted core areas . in one embodiment , the printed information may be presented in two or more colors . in embodiments wherein a decal is used , the decal may be comprised of a film such as cellulose acetate , hydroxypropylmethylcellulose , any of the film formers aforementioned , and mixtures thereof , and may be adhered to the core surface by , for example , a known adhesive such as a water and / or alcohol - soluble material or via wet surface tension . examples of suitable adhesives include , but are not limited to those that are heat - activated , such as starch , vegetable gum or wax . a liquid adhesive may be pre - formed using adhesive in an amount , based upon the total weight of liquid adhesive , from about 1 percent to about 10 percent , and a solvent in an amount appropriate to solubilize the adhesive . suitable solvents include , but are not limited to , water , alcohol , acetone , and mixtures thereof . in one embodiment , the decal may contain an adhesive on the non - printed surface , then either the adhesive or the surface of the core may be wetted with solvent prior to its application . alternatively , either the non - printed surface of the adhesive or the surface of the core may be wetted with liquid adhesive prior to application of the decal thereto . the thickness of the decal may vary , but typically will be from about 50 microns to about 250 microns . in one embodiment , the dosage form may possess a subcoating layer between the core and the decal . the subcoating layer may be comprised of , for example , any of the aforementioned subcoatings . in one embodiment , the subcoating may be comprised of , based upon the total weight of subcoating , from about 2 percent to about 8 percent , e . g . from about 4 percent to about 6 percent , of a water - soluble cellulose ether ; and from about 0 . 1 percent to about 1 percent of castor oil , as disclosed in u . s . pat . no . 5 , 658 , 589 . in another embodiment , the subcoating may be comprised of , based upon the total weight of the subcoating , from about 20 percent to about 50 percent , e . g ., from about 25 percent to about 40 percent of hpmc ; from about 45 percent to about 75 percent , e . g ., from about 50 percent to about 70 percent of maltodextrin ; and from about 1 percent to about 10 percent , e . g ., from about 5 percent to about 10 percent of peg 400 . the subcoating may be applied to the core via any means known in the art such as , for example , spray coating and dip coating . the dried subcoating typically is present in an amount , based upon the dry weight of the core , from about 0 percent to about 5 percent . an alternative method for producing a dosage form containing unique visual properties includes applying to a dosage form either a film that possesses at least one microreliefed surface or a film containing the aforementioned microreliefed flakes . in one embodiment , cores , which may optionally contain at least one cavity and which may further optionally be comprised of sugar in the form of an amorphous glass , may be enrobed with either of these films via the vacuum forming apparatus and processing conditions disclosed in united states patent application no . us 2003 / 215585 a1 . the amount of vacuum applied to the film during processing may depend upon , for example , the thickness of the film , the temperature of the film , the depth of the cavity in the dosage form , and the desired amount of air gap in the dosage form , but typically may range from about 0 . 005 torr to about 700 torr . in embodiments using a film having at least one microreliefed surface , the film can touch the cavity - free core surface so long as the microreliefed surface is proximate to the core to form a plurality of airgaps . fig3 illustrates one embodiment of the resulting dosage form 604 of the present invention , wherein the core 601 is enrobed with a film 603 having a microreliefed surface 620 and an air gap generated between the inner surface of the film 605 and the bottom interior surface 602 ′ of the cavity 602 . in an alternative embodiment ( not shown ), the inner surface 605 or both the inner surface 605 and the exterior surface 606 of the film 603 may possess a microreliefed portion over at least a portion of the cavity 602 . as a result , incident light 623 is partially reflected as reflected light 625 at the interface between the bottom surface 605 of the film and the air within the cavity 602 , and the microreliefed surface 620 appears brighter than that of similar dosage forms enrobed with microreliefed films but lacking an air gap . in another embodiment , the interior surface of the cavity 602 may also optionally possess a printed image or pattern 610 . in this embodiment , the reflected light 625 could be viewed with the printed pattern 610 in the background , thus resulting in the superimposition of a diffractive image over a printed image . the image or pattern , which may be applied to the dosage form via any of the aforementioned methods , may be in substantial vertical alignment below the structured surface . in one embodiment ( not shown ), the printed image may be in the form of a plurality of strips , with the gaps of the structured surface not being in substantial vertical alignment with the strips . one of the advantages of this invention is that in the embodiments wherein the dosage forms have an inlaid portion , the inlaid portion may not only have a complex geometry or pattern , but is the dosage form is further rendered unique by virtue of the microrelief pattern within the inlaid portion . for example , inserts or inlaid portions previously disclosed in the prior art typically have been limited to simple shapes , e . g . shapes having circular cross - sections . using prior art techniques , it would be extremely difficult to press fit a complex logo , for example an intagliation that causes or requires discontinuities in the surface of the substrate , core , or first portion into which it must fit . however , because the insert or inlaid portion of the present invention is obtained using a flowable material , it may be used to fill any depression in any shape or continuous pattern , or even a discontinuous pattern if multiple nozzles are employed . the resulting dosage form is further differentiable from other dosage forms due to the unique micrograph inserted into the inlaid portion . another particular advantage of the embodiments of the present invention wherein the dosage form has an inlaid portion is that the inserts or inlaid portions may be larger in cross - section ( in at least one portion ) than the cavity , which contains the insert or inlaid portion . for example , in one embodiment in which a second molded portion is inlaid into one or more cavities in the exterior surface of a first portion of the dosage form , the area of at least one cross - section of the second molded inlaid portion is greater than the cross - sectional area of the cavity at the surface of the first portion . in contrast , in the prior art an insert must be no larger in cross - section than the opening of the cavity , which contains the insert . this may also be expressed in terms of the “ draft angle ” of the insert or inlaid portion . as used herein , the term “ draft angle ” refers to the angle defined by the side wall of the cavity and a line perpendicular to the face of the first portion , as described for example in rosato et al ., injection molding handbook , pp . 601 - 04 , ( 2d ed . 1995 ), the disclosure of which is incorporated herein by reference . advantageously , the dosage forms produced in accordance with the embodiments of the present invention may possess a unique logo , diffractive color pattern or other product identifying appearance , which not only help the user to identify the brand but also help to control and detect counterfeit dosage forms . further , the dosage forms may also advantageously provide unique visual and color effects and images to dosage forms , as well as to other toiletry , cosmetic , healthcare , and foodstuffs , such that they possess a unique appearance without the use of inedible metal , dye , color , and ink pigments . in one embodiment , the brightness of the logo or diffractive color pattern of the microrelief on a dosage form may further be enhanced by using a core having a shiny light colored , e . g . white , reflective surface . as used herein , “ shiny ” or “ highly glossy ” means that the core , substrate , or dosage form possesses a surface gloss of at least 200 , for example between about 200 to about 300 . “ surface gloss ,” as used herein , refers to the amount of light reflectance as measured at a 60 degree incident angle using the method set forth in example 7 of united states patent application publication no . 20030072731 . for example , in embodiments wherein a highly glossy effect is desired , the core may be comprised of a polyol such as sorbitol , xylitol , mannitol , and the like , or may be coated with a subcoating comprised of , for example , pullulan and other subcoatings as disclosed in u . s . pat . nos . 6 , 248 , 391 ; 6 , 274 , 162 ; 5 , 468 , 561 ; 6 , 448 , 323 ; 6 , 183 , 808 ; and 5 , 662 , 732 ; and wo 2004 073582 . in addition , the dosage forms of the present invention beneficially may be made with apparatus and processes that are not only economical to use , but also are compatible with current production techniques . this invention will be further illustrated by the following examples , which are not meant to limit the invention in any way . acetaminophen tablets having the formula set forth in table a below are compressed on a rotary tablet press . the tablet press is equipped with compression tooling that is designed to deboss the upper surface of the pressed tablet with the letter “ y .” see fig5 a and 5b . the compression tooling is keyed such that the orientation of the debossed lettering is the same for all tablets and is in proper alignment with the molding cavities of the injection molding apparatus . table a debossed tablet core formulation ingredient mg / tablet core paracetamol dc273n ( p . g . s . )- us * 529 . 1 sodium starch glycolate nf - explotab 25 . 0 magnesium stearate nf 2 . 0 total core 556 . 1 * granulation available from mallinckrodt once formed , the tablet containing the debossed “ y ” in its surface is transferred to an injection molding apparatus , where the tablet is placed in a mold cavity such that the portion of the debossed tablet bearing the letter “ y ” is located under an injector tip . the surface of the mold cavity that is located above the debossed tablet face contains an insert , which also bears the letter “ y ” and is in vertical alignment with the debossed “ y ” in the tablet face . the area within the letter “ y ” on the insert is etched with a diffractive relief pattern having about 500 lines per mm . an aqueous gelatin solution ( 35 % solids ) at 50 ° c . is then injected through the injector tip of the molding apparatus into the void of the debossed “ y ” in the tablet surface . the gelatin is permitted to fill the void until the gelatin is contacts the surface of the mold bearing the diffractive relief pattern , which is maintained at a temperature of about 10 ° c . upon cooling to room temperature in the mold , the gelatin solution forms a gel that fills the void in the tablet and , along its exterior surface , assumes the reverse image of the diffractive relief pattern in the mold . during drying , the gelatin shrinks vertically , e . g ., by about 65 % and laterally , e . g ., by about 5 %. in order to compensate for this shrinkage , the diffractive relief pattern molded into the wet gelatin is sized to be about 65 % larger in the vertical dimension and about 5 % larger in the horizontal dimension than the dimensions of the pattern in the final dried product . the resulting dried product has a diffractive grating of 500 lines or grooves per millimeter , and the diffractive pattern etched into the surface of the mold is a negative pattern having 476 lines or grooves per millimeter . likewise in the vertical dimension , the resulting dried product has a diffractive grating of about ⅔ microns in height , and the diffractive pattern etched into the surface of the mold is a negative pattern having a vertical dimension of about 2 microns . acetaminophen tablets having the formulation set forth below in table b are prepared using a rotary tablet press of example 1 . table b tablet core formulation ingredient mg / tablet core paracetamol dc273n ( p . g . s . )- us * 400 . 0 microcrystalline wax ** 150 . 0 magnesium stearate nf 2 . 0 total core 552 . 0 * commercially available from mallinckrodt ** plastically deforming agent the upper punch face of the tablet press is engraved with a series of parallel lines of about 500 lines per millimeter to yield a diffractive pattern in the shape of the letter “ y ”. after compression , the resulting tablet surface has a coating of the plastically deforming agent bearing a negative impression of the microrelief . this example shows that during compression of the core granulation , the plastically deforming agent at the surface of the tablet flows under pressure and molds to the contour of the micro relief . after compression , the flow of the plastically deforming agent ceases , which then leaves the tablet surface with a coating of the plastically deforming agent bearing a negative impression of the punch face micro relief . compressed tablets , which are made in accordance with the procedure set forth in example 2 , are warmed to a temperature of about 30 ° c ., then thinly coated with a poly ( butyl methacrylate , ( 2 - dimethylaminoethyl ) methacrylate , methyl methacrylate ) polymeric dispersion , which is commercially available from rohm pharma gmbh under the tradename , “ eudragit epo ” via a spray gun . spray rate , inlet air quantity and inlet air temperature are adjusted in such a way that spraying can be performed continuously . the tablets are maintained at a temperature of about 25 ° c . to about 35 ° c . during coating . the coating weight gained is , based upon the original weight of the uncoated compressed tablet , from about 2 percent to about 5 percent . coated tablets bearing a microrelief and an air gap between the coating laver and the tablet surface acetaminophen tablets having the formulation set forth below in table c are prepared using the rotary tablet press of example 1 . table c tablet core formulation ingredient mg / tablet core paracetamol dc273n ( p . g . s . )- us * 529 . 1 avicel ph 101 200 . 0 magnesium stearate nf 2 . 0 total core 731 . 1 * commercially available from mallinckrodt the resulting tablets are then transferred to a mold cavity within an injection molder apparatus . the upper inner face of the mold cavity contains an insert , which is etched with a diffractive relief pattern in the form of a “ y .” the diffractive relief pattern consists of parallel grooves of about 500 grooves per millimeter . a saturated polyglycolized glyceride waxy thermoplastic material available from gattefosse under the tradename , “ gelucire 39 / 01 ,” which has a melting temperature of about 39 ° c ., is injected as a liquid at a temperature of about 50 ° c . into the mold and onto the surface of the tablet therein . the liquid thermoplastic material is solidified in the mold , which is set at a temperature of about 20 ° c . as a result , a coating is formed on the tablet bearing the reverse image of the diffractive relief pattern of the mold surface . after the tablets are then warmed to a temperature of about 30 ° c ., the tablets are then thinly coated with a poly ( butyl methacrylate , ( 2 - dimethylaminoethyl ) methacrylate , methyl methacrylate ) polymeric dispersion , which is commercially available from rohm pharma gmbh under the tradename , “ eudragit epo ” via a spray gun . spray rate , inlet air quantity and inlet air temperature are adjusted in such a way that spraying can be performed continuously . the tablets are maintained at a temperature of about 25 ° c . to about 35 ° c . during coating . the coating weight gained is , based upon the original weight of the uncoated compressed tablet , is about 10 percent . the tablets are then heated to about 50 ° c . for a time sufficient to melt the waxy , gelucire layer , which is substantially absorbed by the tablet core . as a result , an air gap is formed between the and core and the eudragit layer . the inner surface of the eudragit layer , which faces the tablet core surface , retains the reverse image of the diffractive relief pattern formerly in the gelucire layer . a cellulose acetate ( ca ) polymer solution at 15 % w / w solids in acetone is cast into a film over a steel belt supporting substrate . the upper surface of the substrate contains a diffractive microrelief having about 500 lines or grooves per millimeter . after evaporating the solvent away , the dried ca film , which is about 1 micron to about 5 microns in thickness and bears the microrelief pattern on its lower film surface , is peeled off of the substrate then cut / chopped to the desired size and shape of the flakes , i . e ., 0 . 5 mm 2 . b . method for coating tablets with gelatin solution containing microrelief flakes : about 5 % w / w of the ca micro relief film flakes produced in accordance with example 5a above are dispersed into a 35 % w / w gelatin aqueous solution . the resulting gelatin solution is then dip coated onto the tablets produced in accordance with the procedure of example 1 . the coating weight gained is , based upon the original weight of the uncoated tablet , about 5 . 3 % percent . the resulting coating on the tablet contains light diffractive flakes that giving a sparkly appearance to the resulting dosage form . acetaminophen tablets having the formulation set forth below in table d are prepared using the rotary tablet press of example 1 . the tablet surface or portion of the resulting tablets is sufficiently smooth to allow for fine printing thereon . table d tablet core formulation ingredient mg / tablet core paracetamol dc273n ( p . g . s . )- us 529 . 1 sodium starch glycolate nf - explotab 25 . 0 magnesium stearate nf 2 . 0 total core 556 . 1 the resulting , flat - faced tablets are then transported to a tablet printer having a resolution of at least 0 . 15 mm . one face of the tablet is then printed with a series of alternating red and yellow strips 0 . 15 mm in width to form a lenticular split image / pattern . the printed tablets are then positioned in a molding apparatus of example 4 such that the colored lines are in parallel alignment with the lenticular grooves located above in the mold cavity . the grooves in the mold cavity are about 0 . 315 mm wide and about 0 . 225 mm in height in order to compensate for shrinkage of a 35 % w / w gelatin solution on the final dried dosage form . the mold then closes over the tablet , and a 35 w / w % gelatin solution is then injected and solidified over the printed tablet . after the tablet is removed from the mold and dried , the gelatin coating forms an edible lenticular lens layer on the tablet surface . the final , dried dosage form displays a lenticular split image which , in this case , is a flip image that transitions between red and yellow when the tablet is viewed at different angles . acetaminophen tablets having the formulation set forth below in table e are prepared using the rotary tablet press of example 1 . the tablet surface or portion of the resulting tablets is sufficiently smooth to allow for fine printing thereon . table e tablet core formulation ingredient mg / tablet core paracetamol dc273n ( p . g . s . )- us 529 . 1 sodium starch glycolate nf - explotab 25 . 0 magnesium stearate nf 2 . 0 total core 556 . 1 the resulting , flat - faced tablets are then transported to a tablet printer having a resolution of at least 0 . 15 mm . the tablet logo and dosage strength are then printed as a lenticular split image on the tablet face surface . one face of the tablet is then printed with a series of alternating red and blue strips , each of which are about 0 . 15 mm in width , of the words , “ tylenol ” and “ 500 ” superimposed in the form of a lenticular split image . the printed tablets are then positioned in a molding apparatus of example 4 such that the colored lines are in parallel alignment with the lenticular grooves located above in the mold cavity . the grooves in the mold cavity are about 0 . 315 mm wide and about 0 . 225 mm in height in order to compensate for shrinkage of a 35 % w / w gelatin solution on the final dried dosage form . the mold then closes over the tablet , and the gelatin solution is then injected and solidified over the printed tablet . after the tablet is removed from the mold and dried , the gelatin coating forms an edible lenticular lens layer on the tablet surface . the final , dried dosage form displays a lenticular split image which , in this case , is a flip image that transitions between the words “ tylenol ” in red and “ 500 ” in blue when the tablet is viewed at different angles . although this invention has been illustrated by reference to specific embodiments , it will be apparent to those skilled in the art that various changes and modifications may be made which clearly fall within the scope of this invention . | US-23604105-A |
a surgical suturing apparatus includes a needle , a needle holder which also serves as a support for suturing material , and an elongate handle . the needle defines a passageway through which the suturing material extends . the passageway has an outlet at the distal end of the needle . | for ease of reference , as used herein the term “ distal ” will refer to that part of the instrument which is farthest for the surgeon , and the term “ proximal ” refers to that part of the apparatus which is closest to the surgeon . turning now to the drawings and referring specifically to fig1 and 2 , the surgical suturing apparatus of the present invention 10 generally includes a needle portion 11 , a conic portion 12 , a spool 13 , a spool cover 14 and a handle 15 . fig2 shows the needle portion that includes a coil with a plurality of loops . alternatively the needle portion may include only one loop or even one half of a loop . the distal end of a needle portion 11 includes a tip 16 with an opening for the passage of suture material . the opening is made in such a way that it is on the top of the outside radius of the needle portion for a better presentation and easier grasping of the suture material . the proximal end of stem of the needle portion is made under an angle and travels from the axial center of the coil , laterally toward the outside radius of the coil . the angle is equivalent to the angle of a channel 17 in the conic portion 12 in which the proximal end of the needle is secured . fig3 shows the conic portion 12 including a shaft 18 and a conic end 19 that defines the channel 17 and an opening 20 . the conic portion 12 is made in different outside diameter to be suitable for different passages . in the conic portion 12 , the channel 17 travels from the tip , extending into the proximal horizontal portion of the conus under the angle that is the same as the angle of the proximal portion of the needle 11 . the opening 20 of the channel 17 on the proximal horizontal surface of the conus is placed in the space between the circular portion of the distal end of the spool 13 and the spool cover 14 in such a way that it will allow free advancement of the suture material . the shaft 18 of the conic portion 12 is placed in the central line of the handle 15 and serves as an axle for the spool 13 and the spool cover 14 . the very end is threaded for attachment to the handle 15 . fig4 shows the spool 13 which is made in such a way that the distal end is of smaller outside diameter than the inside diameter of the spool cover 14 to allow space for suture material to freely advance through the needle and also for the spool 13 to freely turn around the shaft 18 . the proximal end of the spool is of the same outside diameter as the inside diameter of the spool cover with minimal tolerance to allow the spool to freely turn when covered . the length of the longitudinal portion 15 and the length of the spool 13 will depend on the type and amount of suture material needed ( ie . the more suture material needed , the longer the spool and shaft ). fig5 shows the spool cover 14 which is made to cover the spool 13 with suture material and to be of the same outside diameter as the conic portion 12 . the distal end of the cover 14 is open and the proximal end has a central hole that is of the same diameter as the outside diameter of the handle 15 at the location . fig6 shows the handle 15 which includes a shaft portion 15 a and hand - piece 15 b . the shaft portion 15 a is of the same outside diameter as the spool cover 14 , and conic portion 12 . on the tip of the shaft portion 15 a there is a threaded bore 15 c for the attachment of the conic portion 12 . the hand - piece 15 b is made to be suitable for an argonomic grasp by the surgeon &# 39 ; s hand . while the above description and the drawing disclose and illustrate one embodiment , one should understand , of course , that the invention is not limited to this embodiment . those skilled in the art to which the invention pertains may make other embodiments employing the principles of this invention , particularly upon considering the foregoing teachings . therefore , by the appended claims , the applicant intends to cover any modifications and other embodiments as incorporate those features which constitute the essential features of this invention . | US-24408599-A |
the invention is directed to an inverting device which takes one or more articles from a first device , inverts the article , and discharges the article onto a second device that may be at essentially the same relative height as the first device . the inverting device has a rotating device with two opposed surfaces that are spaced apart a distance slightly greater than the height of the article . once the article has been moved into position in the rotating device , the rotating device rotates 180 degrees about a transverse axis , resulting in the inversion of the article . the new orientation of the article may facilitate further processing in a manufacturing environment , such as cleaning , filling , labeling , stacking or any other activity that relies on a specific product disposition . | it is desirable to be able to quickly and reliably invert baking pans 10 in the wholesale baking industry , whether such inversions turn the pans upside down or right - side - up . to facilitate this process , the invention is directed to a pan inverting apparatus or device 100 which can be placed in the baking line . in many applications , two pan inverting devices are used in the same line . the first pan inverting device turns pans upside down after the baked product has been removed from the pan , and the second pan inverting device turns pans right - side - up so that they may be filled with dough . however , in some applications , e . g ., those in which the pans are to be stacked , only one pan inverting device may be utilized . as shown in fig1 through 8 , each pan inverting device 100 has a rotating device 110 which is rotatably mounted within a static frame 112 , such as to permit the entire rotating device 110 to rotate about a transverse axis 114 ( fig5 ) of the rotating device 110 . the rotating device may be trunnion - mounted to the frame 112 . generally , rotation of the rotating device 110 occurs in 180 degree increments . rotation of the rotating device 110 in either direction about the transverse axis 114 is possible . the transverse axis 114 preferably extends through the center of the rotating device 110 , relative to both the length and height dimensions . although two successive rotations of 180 degrees in the same rotational direction are possible , it is preferable for practical reasons that the rotating device 110 is first rotated 180 degrees in one direction and then next rotated back in the opposite direction . regardless , the rotating device 110 will always rotate about the transverse axis 114 , or rotatably reciprocate about the transverse axis 114 , such that the rotating device 110 remains substantially in the same position within the frame 112 at all stopped positions . rotation of the rotating device 110 is generated by a suitable motor 116 ( fig1 ), such as for example , an electrical servo or step motor . as is shown in fig1 , the rotating device 110 is supported on the frame 112 or any other structure capable of supporting the weight of the rotating device 110 and allowing the rotating device 110 to rotate about a transverse axis . the rotating device 110 has a first wall 120 , a second wall 122 and two sidewalls 124 which connect the first wall 120 to the second wall 122 . in the position shown in fig1 and 5 , the first wall 120 is the bottom wall and the second wall 122 is the top wall . alternatively , as best shown in fig1 , the first and second walls may be removed and replaced by support members which extend between the sidewalls . the motor 116 is mechanically connected to a respective sidewall 124 by a shaft ( not shown ) or the like . the shaft is positioned at the center of the sidewall 124 at the transverse axis 114 , thereby allowing the rotating device 110 to rotate about the transverse axis 114 as shown in the drawings . extending from the first wall 120 is a first conveyor 140 . the first conveyor 140 has a belt 142 which moves in a conventional manner about conveyor supports 144 . the first conveyor has a first pan - engagement mechanism which will engage the baking pan and cause the baking pan to be maintained in position on the first conveyor belt as the rotating device is rotated and the baking pan is inverted . in the embodiment shown , the first conveyer 140 produces a magnetic force which will attract the pans 10 . the magnetic force may be generated by the use of conventional magnets 146 ( fig9 ) which are located proximate the belt 142 , or the belt 142 may be made of material which can exhibit magnetic properties . extending from the second wall 122 is a second conveyor 150 . the second conveyor 150 has a belt 152 which moves in a conventional manner about conveyor supports 154 . the second conveyor has a second pan - engagement mechanism which will engage the baking pan and cause the baking pan to be maintained in position on the second conveyor belt as the rotating device is rotated and the baking pan is inverted . in the embodiment shown , the second conveyer 150 produces a magnetic force which will attract the pans 10 . the magnetic force may be generated by the use of conventional magnets 156 ( fig9 ) which are located proximate the belt 152 , or the belt 152 may be made of material which can exhibit magnetic properties . the first conveyor 140 and the second conveyor 150 may be essentially mirror images of each other . the first conveyer 140 and the second conveyor 150 have opposed pan - receiving surfaces 148 , 158 ( fig5 - 8 ) which are spaced from each other a distance x which is slightly greater than the height y of the largest pan 10 to be used in the baking line in which the rotating device 110 is positioned . the magnets 146 , 156 may include , but are not limited to , permanent magnets , electromagnets or a combination thereof . the force generated by the magnets must be sufficiently strong to attract the metal baking pans 10 fed on the first conveyor 140 or second conveyor 150 and retain the pans 10 in place as the rotating device 110 is rotated , thereby inverting the pans 10 . if permanent magnets are used , the motion of the conveyors 140 , 150 , when actuated , must be sufficient to dislodge the pans 10 from their fixed position , such as to allow them to be displaced along the pan - receiving surfaces 148 , 158 while still being maintained in physical engagement with the pan - receiving surfaces 148 , 158 . if electromagnets are used , the amount of magnetic force produced can be controlled by an electric rheostat or the like to produce a variable magnetic force to allow the pans 10 to be displaced along the pan - receiving surfaces 148 , 158 while still being maintained in physical engagement with the pan - receiving surfaces 148 , 158 . in operation , a first respective pan 10 a is advanced from the feed belt 200 of the baking line to the first conveyor 140 . the first respective pan 10 a is advanced to the position shown in fig1 . as the feed belt 200 and the first conveyor 140 are in the same plane , the first respective pan 10 a is easily moved from the feed belt 200 to the first conveyor 140 . this facilitates the continuous movement of the pans 10 as required in many applications in the baking industry . as the first respective pan 10 a is moved onto the first conveyor 140 , the magnetic force generated by the magnets 146 of the first conveyor 140 causes the first respective pan 10 a to be attracted to the pan - receiving surface 148 of the belt 142 of the first conveyor 140 . once the first respective pan 10 a is properly positioned , a sensing mechanism ( not shown ) recognizes that the first respective pan 10 a is properly positioned and sends a message to a controller ( not shown ) that controls the rotating device 110 . the controller then causes the motor to rotate the rotating device 110 about the transverse axis 114 , as shown in fig2 ( and fig6 ). as the rotation occurs , the magnetic force of the first magnets 146 of the first conveyor 140 cooperates with the first respective pan 10 a to maintain the first respective pan 10 a in engagement with pan - receiving surface 148 of the belt 142 of the first conveyor 140 . as the first respective pan 10 a is provided on an inside surface of the first conveyor 140 relative to the arc of rotation , the forces associated with the rotation of the rotating device 110 force the first respective pan 10 a toward the belt 142 , thereby applying additional forces to maintain the first respective pan 10 a in engagement with the pan - receiving surface 148 of the belt 142 of the first conveyor 140 . the rotation of the rotating device 110 is continued until the first conveyor 140 reaches the position shown in fig3 ( and fig7 ), in which the first respective pan 10 a has been rotated 180 degrees . in this position , the first wall 120 is now the top wall and the second wall 122 is the bottom wall . consequently , the first respective pan 10 a on the pan - receiving surface 148 of the belt 142 of the first conveyor 140 is now inverted ( or upside down as shown in fig3 ). due to the magnetic force generated by the magnets 146 of the first conveyor 140 , the first respective pan 10 a is maintained on the pan - receiving surface 148 of the belt 142 of the first conveyor 140 . once this position is reached , the controller advances the belt 142 of the first conveyor 140 , causing the inverted first respective pan 10 a to be moved toward the removal belt 210 ( as shown in fig8 ). as this occurs , the magnetic force exerted on the first respective pan 10 a will lessen , as less surface area of the first respective pan 10 a remains in contact with the belt 142 of the first conveyor 140 . additionally , if the magnetic force is an electromagnetic force , the intensity of the force can be controlled , as was previously described . consequently , as the first respective pan 10 a is discharged from the first conveyor 140 , the weight of the first respective pan 10 a will cause the first respective pan 10 a to transfer from the first conveyor 140 onto the removal belt 210 . the removal belt 210 may be padded at the point of impact , thereby preventing damage to the first respective pan 10 a as it transfers to the removal belt 210 . as shown in fig4 , the first respective pan 10 a is then moved away from the rotating device 110 to continue with the other processes involved in the baking line . it should be noted that an initial portion 210 a of the removal belt 210 may also be magnetized and positioned at the same level as the first conveyor 140 , as is shown in fig1 . in this case , when the first conveyor 140 discharges the first respective pan 10 a , the first respective pan 10 a would be engaged by the magnetized removal belt 210 a , causing the first respective pan 10 a to have its baking surface 20 , into which all the baking ingredients are inserted , downwardly exposed . this would allow the exposed baking surface 20 of the first respective pan 10 a to be cleaned by cleaning devices ( not shown ) positioned below the removal belt 210 a . once the cleaning is accomplished , the first respective pan 10 a would be moved beyond the magnetized removal belt 210 a . as this occurs , the magnetic force exerted on the respective first pan 10 a would lessen , as less surface area of the first respective pan 10 a remains in contact with the magnetic portion of the removal belt 210 a . consequently , as the first respective pan 10 a is moved from the magnetized portion of the removal belt 210 a , the weight of the first respective pan 10 a would cause the first respective pan 10 a to transfer from the magnetized portion of the removal belt 210 a onto the conventional portion of the removal belt . the conventional portion of the removal belt may be padded at the point of impact , thereby preventing damage to the first respective pan 10 a as it transfers . simultaneously with the advancement of the first respective pan 10 a to the removal belt 210 , a second respective pan 10 b is advanced from the feed belt 200 to the second conveyor 150 ( as best shown in fig8 ). the second respective pan 10 b is advanced to the position shown in fig4 ( which is identical to the position of the first respective pan 10 a in fig1 ). as the feed belt 200 and the second conveyor 150 are in the same plane , the second respective pan 10 b is easily moved from the feed belt 200 to the second conveyor 150 . as previously stated , this facilitates the continuous movement of the pans 10 as required in many applications in the baking industry . as the second respective pan 10 b is moved onto the second conveyor 150 , the magnetic force generated by the magnets 156 of the second conveyor 150 causes the second respective pan 10 b to be attracted to the pan - receiving surface 158 of the belt 152 of the second conveyor 150 . once the second respective pan 10 b is properly positioned , the sensing mechanism recognizes that the second respective pan 10 b is properly positioned and sends a message to the controller . the controller also recognizes when the first respective pan 10 a has been properly discharged to the removal belt 210 . the controller then causes the motor to rotate the rotating device 110 , as shown in fig2 , and the process or sequence recited above with respect to the first respective pan 10 a is repeated for the second respective pan 10 b . this repetition occurs until all of the pans 10 have been properly fed through the pan inverting device 100 . as previously recited , the opposed pan - receiving surfaces 148 , 158 of the first conveyer 140 and the second conveyor 150 are spaced from each other a distance x which is slightly greater than the height y of the largest pan to be used in the baking line in which the rotating device 110 is positioned . as the first respective pan 10 a is discharged by the first conveyor 140 and the second respective pan 10 b is fed onto the second conveyor 150 , the first respective pan 10 a and the second respective pan 10 b are always laterally offset from each other , thereby allowing the spacing x between the first conveyor and the second conveyor to be minimized . referring to fig5 through 8 , the pan inverting apparatus 100 , feed belt 200 and removal belt 210 are identical to that shown in fig1 through 4 . however , in fig5 through 8 , different sizes and types of baking pans 10 are shown . this exemplifies the universal natures of the pan inverting apparatus 100 . while baking pans 10 of various configurations are shown , this is for illustrative purposes . in use , pans of different sizes would not be fed into the pan inverting apparatus 100 at the same time . in particular , this illustrates that the opposed pan - receiving surfaces 148 , 158 of the first conveyer 140 and the second conveyor 150 are spaced from each other a distance x which is greater than the height y of the largest pan to be used in the baking line in which the rotating device 110 is positioned . as the rotating device 110 can accommodate all sizes and shapes of baking pans used , no down time is required to change the configuration of the rotating device 110 as different types of baking pans are introduced . the pan inverting apparatus or device 100 is part of a pan inverting station which is incorporated into the baking line . the feed belt 200 and removal belt 210 are positioned at the same relative height to the rotating device 110 , thereby allowing the baking pans 10 to enter and leave the pan inverting station at the same relative height , thereby facilitating the movement of the baking pans in a baking line in which the pan inverting device 100 is positioned . as previously discussed , the rotating device 110 can also take upside down pans and rotate them to the right - side - up position . the process is essentially identical to that described above , except that the pans are delivered by the feed belt 200 in the upside down position and are inverted by the rotating device 110 and discharged to the removal belt 210 in the right - side - up position . during this operation , cleaning of the pans 10 would generally not occur , as the pans 10 are in the right - side - up position upon discharge . the rotating device 110 also allows the pans to be inverted regardless of the orientation in which the pans 10 are fed from the feed belt 200 . for example , if the pans 10 are fed in a longitudinally extending direction , the rotating device 110 will invert the pans 10 and advance them to the removal belt 210 in the same longitudinal orientation . similarly , if the pans 10 are fed in a transversally extending direction , the rotating device 110 will invert the pans 10 and advance them to the removal belt 210 in the same transverse orientation . as the rotating device 110 is in - line in a complete baking line , it is likely that the pans 10 need not be inverted with each pass through the rotating device 110 . in such cases , the pans 10 are fed by the feed belt 200 to the first conveyor 140 or second conveyor 150 , whichever conveyor is in the plane of the feed belt 200 . in this instance , the conveyor performs as a typical conveyor and merely advances the pan through the rotating device 110 to the removal belt 210 . in such cases , the rotating device 110 does not invert the pans 10 . in a continuous baking line , it can be important for the feed belt 200 and removal belt 210 to be positioned at the same relative height , as it can be difficult to design a continuous baking line in which all of the belts are at different heights . the design of the pan inverting device 100 described herein allows the pans 10 to enter and leave the rotating device 110 at the same height , thereby facilitating the overall function of the baking line . as the feed belt 200 and the respective conveyor onto which the pan 10 is being fed are also in the same plane , the pan 10 is properly supported on its bottom surface . this reduces the possibility of a misfeed or improper alignment of the pans 10 when moving from the feed belt 200 to the respective conveyor , thereby allowing for the continuous feed of the pans 10 without interruption . the configuration of the rotating device 110 and the conveyors 140 , 150 provides for proper position of the pans 10 during rotation of the rotating device 110 . as previously discussed , the magnetic force and the forces associated with the rotational movement of the rotating device 110 all act in the same direction to keep the pan 10 properly seated . as the pans 10 are positioned on an inside surface of the conveyors 140 , 150 relative to rotation , the rotational forces caused by the rotation of the rotating device 110 act to keep the pan 10 seated , rather than acting to pull the pan away from the belt 142 , 152 ( as in the prior art ). consequently , smaller magnets 146 , 156 may be used . in applications in which the pan engagement mechanisms are vacuum heads which can create suction , clamps driven by pneumatic cylinders , or with other types of devices to hold the objects in place , the size of the devices may be reduced as the pans are positioned on an inside surface of the conveyors relative to rotation , thereby allowing the rotational forces caused by the rotation of the rotating device to act to keep the pan seated , rather than acting to pull the pan away from the belt . the use of the magnets 146 , 156 or the magnetic conveyors eliminates the need to have other types of guides , clamps or other restraints to hold the pans 10 in place as the pans 10 are inverted . this allows for a more continuous flow of the pans 10 . this also allows the pan inverting device 100 and the rotating device 110 to be universally used for all types of pans of all sizes . in the baking industry it is common to use the same line to bake different products , i . e . different breads , rolls , etc . previously , this often required equipment change - over to allow for the use of the different pans . however , with this pan inverting device 100 , the conveyors 140 , 150 do not use special clamps and are spaced apart to allow for the use of many types of pans 10 with no change - over required . the adaptability and programmability of the rotating device 110 is also advantageous . as previously described , the rotating device 110 can be used to invert pans 10 or simply feed the pans 10 through without inverting . this allows the inversion of the pans 10 , and therefore , the cleaning of the pans 10 , to occur only as needed , rather than during every cycle . if a pan or article has a magnetic bottom surface but a non - magnetic top surface ( or insufficient mass on its top surface to be held by a magnet ), the top conveyer could be used as the first conveyor when the pan is to be inverted from it “ upside - down ” orientation to its “ right - side - up ” orientation . in this application , the feed belt would be elevated or inclined by an appropriate amount such that the feed belt ( which supports the pan from underneath ) discharges onto the bottom magnetic belt of the upper or first conveyor . when the rotating device is turned 180 degrees , the pan can be discharged from the first conveyor , which is now on the bottom , directly onto the removal belt . although the inverting device 100 is described herein with respect to baking pans 10 , it is to be understood that other uses of the inverting device are possible , within the food preparation industry or in industries unrelated to food preparation . while the invention has been described with reference to the drawings , it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention . as an example , the invention may be used with non - magnetic objects by altering the configuration of the rotating device or by replacing the magnets with vacuum heads which can create suction or with other types of devices to hold the objects in place . as another example , multiple pans or other items may be positioned in the rotating device at the same time . 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 . the particular configuration of the rotating device may vary and the manner of rotation may vary without departing from the invention . therefore , it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention , but that the invention will include all embodiments falling within the scope of the appended claims . | US-71248510-A |
a bread product including oat bran , a thickened product and egg whites is disclosed . the bread product is a nutritional food item having about 10 grams of protein per serving . the bread product is dense taking form as a pita and is not cakey like a pancake or muffin . | the present invention describes a bread product made of oat bran , egg whites and a thickened product . in one embodiment the bread product is made using 2 tablespoons of the thickened product , ¼ cup egg whites and 2 tablespoons oat bran . the bread product is nutritious having , in one serving of the bread , about 98 . 75 calories with 11 . 25 calories coming from fat . 1 . 3125 g of fat and 0 . 1875 g of saturated fat , 102 . 875 mg sodium , 90 mg potassium , 10 . 5625 g of carbohydrates , 0 . 5625 g of sugar , 2 . 25 g fiber and 10 . 0625 g protein . in another embodiment the bread product has about 17 . 6 % oat bran , about 65 . 7 % egg whites and about 16 . 7 % thickened product . the bread is made by mixing together the oat bran , egg whites and thickened product all at once . the thickened product can include yogurt such as but not limited to greek yogurt , tofu or cream cheese . to make one serving the mixture will have about 1 ½ to 3 tablespoons ( 15 g dry weight ) of oat bran , about ¼ to ½ cup or 2 - 4 egg whites and about 14 . 1875 g of thickened product . in one embodiment , the method to make the bread is by making it on a stove top burner cooked or generally fried on a cooking device such as but not limited to a pan . the pan is preheated on the stove top burner to high , a first temperature , then the bread batter poured therein . in some embodiments the pan may be coated with a non - stick spray or other non - stick cooking oil if necessary . the batter is made by mixing all together in a bowl such as a glass bowl the oat bran , egg whites and thickened product to be a thick and creamy batter . the quantity of each the oat bran , egg whites and thickened product are notable as is the mixing of each ingredient all at once . the egg whites are not foamed as such a process would defeat the dense character of the bread . after mixing the three ingredients together to form the batter , it is poured slowly into the pre - heated pan and the stove top temperature is turned to medium - low , a second temperature . the slow pour of the batter into the hot pan is notable as the technique together with the thick , creamy consistency of the batter keeps the batter in the center of the pan and prevents the batter from seeping to the sides of the pan . the batter is cooked at medium - low for 2 - 3 minutes or until air bubbles show on top . the bread is then flipped and the stove top temperature under the pan is turned down again to a low temperature , a third temperature . the bread is cooked at this third temperature for about three minutes . the bread is flipped one last time and the temperature is turned down again to a fourth temperature for cooking for about one minute . the bread is then taken off the pan and cooled for 10 - 15 minutes on a cooling rack . the resulting bread product is dense and nutritious . the bread is both gluten - free and wheat free , provides a good source of protein and is low in sodium . the bread is dense like a pita . in one embodiment , the bread can be made in any shape such as a pita - shape where it can be cut in the middle and used like a pita sandwich bread . while the present invention has been described in conjunction with specific embodiments , those of normal skill in the art will appreciate the modifications and variations can be made without departing from the scope and the spirit of the present invention . such modifications and variations are envisioned to be within the scope of the appended claims . | US-201213654601-A |
the present invention relates to a tool for adhering an orthodontic bracket , comprising : a pair of bracket holding portions for holding a bracket to be bonded to teeth while approaching or separating from each other ; and a pair of handle portions connected to the pair of bracket holding portions , for controlling the bracket holding portions to allow the same to approach or separate from each other , wherein a scale for measuring the height of a bracket for the end of teeth is formed in at least any one of the pair of bracket holding portions . therefore , an operation is convenient , measurement is easy and measurement time can be reduced since the tool has a simple and uncomplicated structure . in addition , it is possible to improve the effectiveness of orthodontic treatment since a bracket can be bonded by precisely setting the height of the bracket . | the present invention has been made in view of the above problems , and provides an orthodontic bracket attaching tool that can conveniently perform a surgical operation due to a simple structure and in which measurement can be easily performed because measurement is performed from an end portion of a bracket base on the same plane as that of an end portion of teeth to an end portion of teeth and in which horizontality can be easily maintained and that can save a time because a tweezer and a measuring gauge function are simultaneously performed and that can fix the bracket by accurately setting a height of the bracket and that can thus improve orthodontic efficiency . in accordance with an aspect of the present invention , an orthodontic bracket attaching tool includes : a pair of bracket holding portions that hold a bracket to be attached to teeth while approaching each other or separating from each other ; and a pair of handle portions connected to the pair of bracket holding portions to manipulate the bracket holding portion to approach each other or separate from each other , wherein in an end portion of at least one of the pair of bracket holding portions , a scale that measures a height of the bracket to an end portion of the teeth is formed , and an end portion indication portion that indicates an end portion of the teeth is installed . preferably , the bracket holding portion is disposed at an end portion of the teeth to have a polygonal section shape in which a latch jaw that forms a measurement reference is formed , and in the bracket holding portion , an end portion indication portion that indicates an end portion of the teeth is formed . preferably , the scale is formed in at least one side of the bracket holding portion . preferably , the bracket includes : a bracket base to which an adhesive is attached : a slot into which an orthodontic wire is inserted ; and a stem disposed between the bracket base and the slot , wherein the bracket holding portion in which the scale is formed measures a distance between one side of the bracket base or the stem and the teeth end portion . preferably , the orthodontic bracket attaching tool further includes a guide that guides an approaching or separating operation of the pair of bracket holding portions . preferably , the guide includes : a first guide provided in an area of the pair of bracket holding portions ; and a second guide provided in an area of the pair of handle portions . preferably , both the first and second guides each include : a guide protrusion ; and a guide groove that guides the guide protrusion . preferably , the bracket holding portion has a stepped polygonal shape having a width that reduces or enlarges as advancing to an end portion or a protruded shape having a protruded one side . according to the present invention , due to a simple structure , a surgical operation can be conveniently performed and measurement can be easily performed , a measurement time can be shortened , a bracket can be attached by accurately setting a height thereof , and orthodontic efficiency can be thus improved . fig1 is a schematic diagram illustrating an orthodontic state ; fig2 is a side view illustrating an orthodontic bracket attaching tool according to a first exemplary embodiment of the present invention ; fig3 is a top plan view illustrating the orthodontic bracket attaching tool of fig2 ; fig4 is a diagram illustrating an example of measuring a height between a bracket stem and a teeth end portion illustrating a use example of the orthodontic bracket attaching tool of fig2 ; fig5 is a side view illustrating an orthodontic bracket attaching tool according to a second exemplary embodiment of the present invention ; fig6 illustrates a use example of an orthodontic bracket attaching tool according to a third exemplary embodiment of the present invention ; and fig7 illustrates various modified examples of an orthodontic bracket attaching tool . hereinafter , an exemplary embodiment of the present invention will be described in detail with reference to the accompanying drawings . fig1 is a schematic diagram illustrating an orthodontic state . fig1 illustrates a state in which a bracket 10 is mounted in each tooth for orthodontic and in which an orthodontic wire 20 is installed in the bracket 10 . the bracket 10 is attached to a bracket attaching location b / p of teeth by an adhesive 30 ( see fig4 ). as shown in fig4 , the bracket 10 includes a bracket base 11 to which the adhesive 30 is attached , a slot 12 into which the orthodontic wire 20 is inserted , and a stem 13 disposed therebetween . as the orthodontic wire 20 is inserted into the slot 12 ( see fig4 ) of the well attached bracket 10 , a fixing force is transferred to teeth and thus a desired teeth movement can be performed . when irregular teeth are straightened with a method of fig1 , after a surgical operation , teeth are regularly arranged and thus an aesthetic function , a pronunciation function , and a mastication function can be enhanced . fig1 illustrates a case of attaching the brackets 10 to a labial side , i . e ., an outside lip ( or cheek ) of teeth and latching and extending the orthodontic wire 20 to the bracket 10 as a labial side orthodontic treatment . however , the present invention is not limited thereto . that is , the present invention can be applied to an orthodontic treatment of the tongue side that is not shown from the outside . in a method of performing orthodontic of fig1 , to accurately measure a bracket attaching location b / p to teeth and to attach the bracket 10 to the bracket attaching location b / p are the most important . for this , conventionally , a separate gauge was used , but because the bracket 10 was attached to an inaccurate location or a surgical operation was uncomfortable , the present invention provides an orthodontic bracket attaching tool 100 . because the orthodontic bracket attaching tool 100 according to the present invention has a more simple structure than that of the conventional art , a surgical operation is convenient , and because the bracket 10 can be attached by accurately setting an end portion of teeth and a height of the bracket 10 , orthodontic efficiency can be improved . fig2 is a side view illustrating an orthodontic bracket attaching tool according to a first exemplary embodiment of the present invention , fig3 is a top plan view illustrating the orthodontic bracket attaching tool of fig2 , and fig4 is a diagram illustrating a use example of the orthodontic bracket attaching tool of fig2 . referring to fig2 to 4 , the orthodontic bracket attaching tool 100 of the present exemplary embodiment includes a pair of bracket holding portions 110 and a pair of handle portions 130 that manipulate a pair of bracket holding portions 110 . the pair of bracket holding portions 110 perform a function of holding the bracket 10 to be attached to teeth while approaching each other or separating from each other . the pair of handle portions 130 are connected to the pair of bracket holding portions 110 to perform a function of manipulating the pair of bracket holding portions 110 to approach each other or separate from each other . a portion in which a surgical operator actually holds by a hand is a pair of handle portions 130 . for reference , the orthodontic bracket attaching tool 100 of the present exemplary embodiment is a tweezer type . in the orthodontic bracket attaching tool 100 of a tweezer type , when approaching the pair of handle portions 130 by applying a force in an arrow direction shown in fig2 a , the pair of bracket holding portions 110 are separated from each other , and when removing a force applied to the pair of handle portions 130 , the pair of bracket holding portions 110 approach each other , as shown in fig2 b . the present invention can be applied to a pincette type orthodontic bracket attaching tool in which a pair of bracket holding portions 110 also approach each other , when a pair of handle portions 130 approach each other and in which a pair of bracket holding portions 110 are also separated from each other , when a pair of handle portions 130 are separated from each other . as largely shown in fig3 , the circumferential side of the bracket holding portion 110 may have a straight shape , and adjacent circumferential sides may cross . in consideration of such a shape , an entire shape of the bracket holding portion 110 may have a quadrangular section shape . when the bracket holding portion 110 has a quadrangular section shape and the circumferential side thereof has a straight shape , it is advantageous in view of horizontally maintaining the bracket 10 relative to teeth . that is , in a state that holds the bracket 10 , because horizontality level may be adjusted through the circumferential side of a straight shape , it is advantageous in view of horizontally maintaining the bracket 10 relative to teeth . in such a bracket holding portion 110 , a height of the bracket 10 to an end portion a ( see fig4 ) of teeth , particularly , as a means that measures a height to the bracket attaching location b / p in which the bracket 10 is to be attached to the end portion a ( see fig4 ) of teeth , a scale 111 is used . a scale 111 is used for measuring , and a unit thereof may be millimeter mm or centimeter cm . as shown in fig3 , such a scale 111 may be formed at one side of an end portion of the bracket holding portion 110 , i . e ., at a first side of the front side toward teeth . by such a structure , after an adhesive is applied to the bracket , by applying a force in an arrow direction shown in fig2 a , in a state in which a pair of bracket holding portions 110 are separated each other , the bracket 10 is held between the pair of bracket holding portions 110 and is disposed at one side surface of teeth , as shown in fig2 a . thereafter , in order to locate the bracket 10 at a desired height of teeth , a location of the bracket 10 is adjusted at a surface of teeth using the scale 111 of the bracket holding portion 110 . that is , after the bracket holding portion 110 is disposed upward from a lower portion of the stem 13 of the bracket 10 , the scale 111 measures a height to the bracket attaching location b / p to which the bracket 10 is to attach to the end portion a ( see fig4 ) of teeth using the scale 111 of the bracket holding portion 110 . when measurement is complete , by adjusting a location of the bracket 10 , the bracket 10 is attached to teeth of the bracket attaching location b / p . according to the present exemplary embodiment having such a structure and that can perform operation thereof , due to a simple structure , a surgical operation can be conveniently performed , measurement can be easily performed , and a measurement time can be shortened , and the bracket 10 can be attached by accurately setting an end portion a of teeth and a height of the bracket 10 and thus orthodontic efficiency can be improved . fig5 is a side view illustrating an orthodontic bracket attaching tool according to a second exemplary embodiment of the present invention . referring to fig5 , in an orthodontic bracket attaching tool 200 of the present exemplary embodiment , when a bracket holding portion 210 approaches or separates , guides 250 a and 250 b that guide the bracket holding portion 210 to prevent the bracket holding portion 210 from deviating are further provided . the guides 250 a and 250 b may include a first guide 250 a provided in an area of a pair of bracket holding portions 210 and a second guide 250 b provided in an area of a pair of handle portions 230 . the first and second guides 250 a and 250 b have only a location difference and may include a guide protrusion 251 and a guide groove 252 that guides the guide protrusion 251 . in this way , when the guides 250 a and 250 b are provided , an approaching operation of the bracket holding portion 210 can be stably guided and thus the bracket 10 can be stably held without a numerical value . fig6 illustrates a use example of an orthodontic bracket attaching tool according to a third exemplary embodiment of the present invention . referring to fig6 , in an orthodontic bracket attaching tool 300 of the present exemplary embodiment , a bracket holding portion 310 has a polygonal section shape having a latch jaw 315 disposed at an end portion of teeth to form a reference of measurement , for example , a protruded shape ( structure ), i . e ., an l - shaped section shape in which an area of the latch jaw 315 is protruded to one side . in the bracket holding portion 310 , as a means that measures a height to a bracket attaching location b / p in which a bracket 10 is to be attached to an end portion a of teeth , i . e ., a height from a lower portion of a bracket base 11 to an end portion a of teeth , a scale 311 is formed . in this case , in the bracket holding portion 310 , an end portion indication portion 312 that indicates the end portion a of teeth may be formed , thereby accurately and easily measuring a height . that is , when putting the latch jaw 315 at the end portion a of teeth , a height from a base of the bracket base 11 to an end portion of teeth can be easily measured . fig7 illustrates various modified examples of an orthodontic bracket attaching tool . fig7 a illustrates a case in which a scale 411 is formed in both of two opposing sides 410 b and 410 c of a bracket holding portion 410 , and fig7 b illustrates a case in which a scale 511 is formed in the entire of circumferential sides 510 a - 510 c of a bracket holding portion 510 . fig7 c and 7d illustrate a case in which bracket holding portions 610 and 710 have a stepped polygonal shape having a reducing or enlarging width as advancing a free end portion of the bracket holding portions 610 and 710 instead of a quadrangular section shape . even if the bracket holding portions 610 and 710 have the same shape as that of fig7 a to 7d or a shape similar to that of fig7 a to 7d , an effect of the present invention can be provided . for example , the bracket holding portions 610 and 710 may have a protruded shape described in fig6 . for reference , a scale is not shown in fig7 c and 7d , but a scale may be formed in fig7 c and 7d . further , the foregoing exemplary embodiment illustrates a tweezer type orthodontic bracket attaching tool , but an orthodontic bracket attaching tool according to the present invention can be applied to a pincette type . although exemplary embodiments of the present invention have been described in detail hereinabove , it should be clearly understood that many variations and modifications of the basic inventive concepts herein taught which may appear to those skilled in the present art will still fall within the spirit and scope of the present invention , as defined in the appended claims . | US-201314375796-A |
a specimen retrieval device includes an outer shaft defining a bore , an inner shaft slidably disposed within the bore of the outer shaft , a pouch detachably coupled to a distal end of the inner shaft , and a pouch retention mechanism configured to selectively retain the pouch at the distal end of the inner shaft . | embodiments of the present disclosure will now be described in detail with reference to the drawings , in which like reference numerals designate identical or corresponding elements in each of the several views . as used herein , the term distal refers to the portion of the instrument which is farthest from the user , while the term proximal refers to that portion of the instrument which is closest to the user . in the following description , well - known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail . as used herein with reference to the present disclosure , the terms laparoscopic and endoscopic are interchangeable and refer to instruments having a relatively narrow operating portion for insertion into a cannula or a small incision in the skin . they also refer to minimally invasive surgical procedures . it is believed that the present disclosure may find use in any procedure where access to the interior of the body is limited to a relatively small incision , with or without the use of a cannula , as in minimally invasive procedures . with reference to fig1 - 8 , and initially with reference to fig1 , a specimen retrieval device 10 according to an embodiment of the present disclosure is illustrated . specimen retrieval device 10 includes a housing 12 , an outer shaft 14 and an inner shaft 16 ( inner shaft 16 is shown in fig2 ). specimen retrieval device 10 ( and components associated therewith ) may be formed from any suitable biocompatible material , e . g ., plastic . in an embodiment , an injection molding manufacturing process may be utilized to form housing 12 , outer shaft 14 and inner shaft 16 . continuing with reference to fig1 , housing 12 includes a generally elongated configuration and may be formed as a unitary component or as two separate half components that are coupled to one another by one or more suitable coupling methods ( e . g ., one or more suitable adhesives ). in the latter instance , an indent / detent configuration ( not explicitly shown ) may be utilized to facilitate coupling the two separate half components . in an assembled configuration , housing 12 may serve as a handle for a user to grasp to facilitate manipulation of specimen retrieval device 10 . referring to fig2 , one or more stops are provided on housing 12 and are configured to engage one or more corresponding release mechanisms that are provided on inner shaft 16 . specifically , a first stop ( e . g ., a stop pin 22 ) is provided at a proximal end of housing 12 and is configured to engage a corresponding first release mechanism ( e . g ., a leaf spring 24 ) provided at a proximal end of inner shaft 16 . in the illustrated embodiment , stop pin 22 is press fit into a recess ( not explicitly shown ) provided on housing 12 and extends within housing 12 to contact leaf spring 24 . other devices and / or components ( e . g ., a detent ) may be utilized in place of stop pin 22 to engage leaf spring 24 . stop pin 22 is configured to contact leaf spring 24 so as to prevent inner shaft 16 from translating distally past the point at which the leaf spring 24 engages the stop pin 22 . moreover , a second stop ( e . g ., an inner flange 26 formed along an inner wall 28 of housing 12 ) is located distally with respect to stop pin 22 and is configured to selectively engage a second release mechanism ( e . g ., a retention pin 30 ) that is operably coupled to inner shaft 16 . engagement between retention pin 30 and flange 26 prevents distal translation of retention pin 30 relative to the outer shaft 16 past a predetermined longitudinal position while allowing the inner shaft 16 to continue to move distally relative to the outer shaft 14 so as to allow a pouch 18 to uncouple from inner shaft 16 . accordingly , and unless otherwise noted , the operable components and / or features of specimen retrieval device 10 will be described in terms of use with pouch 18 . continuing with reference to fig2 and with reference to fig3 - 4 , an actuation mechanism 32 of suitable configuration is provided at a proximal end of housing 12 and is configured to selectively engage leaf spring 24 to move leaf spring 24 out of engagement with stop pin 22 . in the illustrated embodiment , for example , actuation mechanism 32 is in the form of a spring loaded push - button 34 including a contact pad 36 that is configured to contact leaf spring 24 when push - button 34 is depressed . a notch or groove 38 a of suitable configuration is provided at a proximal end 41 of inner shaft 16 and is configured to allow leaf spring 24 to pivot therein when push - button 34 is depressed . the depth of groove 38 a is adequate to allow leaf spring 24 to translate beneath stop pin 22 as inner shaft 16 is moved distally . proximal and distal apertures of suitable configuration ( not explicitly shown ) are provided at respective proximal and distal ends 11 , 13 of housing 12 ( fig2 ). specifically , the distal aperture of housing 12 is configured to receive a proximal end of outer shaft 14 and the proximal aperture of housing 12 is configured to receive inner shaft 16 therethrough . since inner shaft 16 is positioned within outer shaft 14 and outer shaft 14 does not extend to the proximal end of housing 12 , the proximal aperture of housing 12 may be smaller than the distal aperture of housing 12 . the proximal aperture of housing 12 is large enough to allow proximal and distal translation of inner shaft 16 including leaf spring 24 therethrough . outer shaft 14 extends distally from housing 12 and includes a generally tubular configuration having a longitudinal axis “ a - a ” defined therethrough . longitudinal axis “ a - a ” is oriented in a different , e . g ., a substantially perpendicular or orthogonal direction , with respect to a longitudinal axis “ b - b ” that is defined through one of the aforementioned pouches ( e . g ., pouch 18 ) when pouch 18 is in a deployed state ( see fig7 a - 7b for example ). outer shaft 14 is dimensioned for insertion through a trocar cannula ( or natural body orifice ) for endoscopic or laparoscopic procedures . moreover , an aperture 9 ( fig1 ) of suitable configuration is provided at a distal end of outer shaft 14 and is configured to allow ingress and egress of inner shaft 16 including pouch 18 therethrough . outer shaft 14 operably couples to housing 12 via one or more suitable coupling methods ( e . g ., one or more suitable adhesives ). outer shaft 14 , however , may be monolithically formed with housing 12 . inner shaft 16 includes a generally elongated configuration and is positioned within outer shaft 14 . inner shaft 16 is translatable within outer shaft 14 to move pouch 18 to a retracted configuration wherein pouch 18 is disposed within outer shaft 14 for positioning specimen retrieval device 10 through an access port ( fig9 shows pouch 18 in a partially retracted configuration ). moreover , inner shaft 16 may be utilized to move pouch 18 to an extended or deployed configuration wherein pouch 18 is disposed outside of outer shaft 14 for positioning target tissue within pouch 18 , see fig7 a - 7b for example . further , inner shaft 16 is translatable to move pouch 18 to a “ release ” configuration for uncoupling pouch 18 from inner shaft 16 . to these ends , a handle assembly 40 is provided at proximal end 41 of inner shaft 16 and is configured to move inner shaft 16 between the retracted , extended and release configurations . handle assembly 40 may be coupled to inner shaft 16 via one or more suitable coupling methods , e . g ., one or more suitable adhesives . alternatively , handle assembly 40 may be formed monolithically with inner shaft 16 . handle assembly 40 includes a distal end 42 having an ergonomic configuration that facilitates grasping by a user . specifically , distal end 42 includes two generally arcuate portions 44 a , 44 b that are configured for grasping by a user . arcuate portions 44 a , 44 b are configured to accommodate fingers of the various contemplated users . a proximal end 46 of handle assembly 40 is configured to releasably couple to a cinch puller 48 . with this purpose in mind , proximal end 46 of handle assembly 40 includes a generally arcuate configuration that complements a generally arcuate configuration of cinch puller 48 . a pair of relatively flexible finger portions 50 a , 50 b are provided at proximal end 46 and are configured to releasably couple to a pair of corresponding indents 52 a , 52 b that are provided on cinch puller 48 ( as best seen in fig2 ). moreover , an indent / detent interface may be utilized to facilitate aligning cinch puller 46 with handle assembly 40 . specifically , a pair of detents 56 a , 56 b may be provided at proximal end 46 and configured to engage a pair of corresponding indents 58 a , 58 b that may be provided at a distal end 60 of cinch puller 48 ( fig4 ). cinch puller 48 is configured to close pouch 18 after a tissue specimen is positioned therein . to this end , a cinch ( e . g ., a suture “ s ,” thread , wire , cable or the like ) is threaded through an aperture 59 that extends through cinch puller 48 . a knot “ k ” ( fig2 ) of suitable configuration ( e . g ., a knot sized not to fit through aperture 59 ) is provided at a distal end of suture “ s ” and is configured to connect suture “ s ” to cinch puller 48 . as can be appreciated , other devices ( e . g ., a tab ) may be utilized in place of knot “ k ” to connect suture “ s ” to the cinch puller 48 . the distal end of suture “ s ” is feed through aperture 59 and is positioned within one or more grooves 55 defined through a side surface of handle assembly 40 and into a corresponding groove 38 b on inner shaft 16 to couple to pouch 18 ( fig4 ). an optional cutting mechanism 51 that may be provided on handle assembly 40 . specifically , cutting mechanism 51 ( as best seen in fig2 ) may be a part of handle assembly 40 and may be configured to sever suture “ s ” after tissue is positioned within pouch 18 and pouch 18 is closed . in the illustrated embodiment , for example , cutting mechanism 51 is in the form of cutting blades 53 that are seated within a recess ( not explicitly shown ) defined in handle assembly 40 . cutting blades 53 may include a “ butterfly ” configuration that allows cutting blades 53 to be installed in handle assembly 40 without the need for riveting or gluing . that is , cutting blades 53 may be press - fit within the recess . as can be appreciated , this may decrease the overall manufacturing cost of specimen retrieval device 10 . a central aperture 57 of suitable configuration ( e . g ., having a diameter slightly smaller than a diameter of suture “ s ”) is provided between cutting blades 53 and is configured to grasp a portion of suture “ s ” that is left coupled to pouch 18 ; this allows a clinician to maintain control of suture “ s ” including pouch 18 after pouch 18 is closed . continuing with reference to fig2 - 4 , groove 38 b and a groove 38 c may be provided on inner shaft 16 and may extend along a length of inner shaft 16 to receive respective suture “ s ” and retention pin 30 therein . grooves 38 b , 38 c maintain respective suture “ s ” and retention pin 30 in a relatively fixed orientation therein such that suture “ s ” and retention pin 30 do not hinder translation of inner shaft 16 with respect to outer shaft 14 when inner shaft 16 is moved to deploy and / or retract pouch 18 . one or more bridges ( not shown ) may extend across grooves 38 a - 38 c and may be utilized to maintain leaf spring 24 , suture “ s ” and retention pin 30 in respective grooves 38 a - 38 c . moreover , one or more o - rings 39 ( see fig6 a - 6b for example ) are provided at a distal end 43 of inner shaft 16 are also configured to facilitate maintaining leaf spring 24 , suture “ s ” and retention pin 30 in their respective grooves 38 b , 38 c . o - rings 39 seat within corresponding recesses ( not explicitly shown ) that are defined on an outer surface of inner shaft 16 . o - rings 39 are also configured to provide adequate clearance between outer shaft 14 and inner shaft 16 so as to allow unhindered translation of inner shaft 16 with respect to outer shaft 14 when inner shaft 16 is translated in the proximal and / or distal directions . moreover , o - rings 39 also provide a fluid tight seal to maintain insufflation gases in a working space , e . g ., within a peritoneal cavity of a patient . referring now to fig5 , 6 a and 6 b , retention pin 30 is configured to releasably couple to pouch 18 and engage flange 26 when leaf spring 24 is moved distally past stop pin 22 . to these ends , retention pin 30 is configured to releasably couple to pouch 18 so as to allow a user to move pouch 18 and also so as to allow a user to selectively disconnect pouch 18 from the inner shaft 16 . specifically , a proximal coupling portion 35 of pouch 18 has an opening or aperture 35 a through which the retention pin 30 is initially passed . the inner shaft 16 has near its distal end 43 a notch 433 which defines a proximal notch face 431 and a distal notch face 432 . in its initial position , the retention pin 30 extends fully between the notch faces such that the pouch 18 is attached to the distal end 43 of the inner shaft 16 and will not inadvertently become disengaged therefrom . retention pin 30 has at its proximal end a radially - extending tip 36 ( fig2 and 5 ) that is configured to engage flange 26 . specifically , tip 36 engages flange 26 when leaf spring 24 disengages from stop pin 22 and inner shaft 16 is moved a predetermined distance “ d ” distally , as best seen in fig2 . in accordance with the instant disclosure , with tip 36 engaged with flange 26 and inner shaft 16 moved distally a distance “ d ,” the retention pin 30 is moved proximally relative to the inner shaft 16 such that the distal most end of the retention pin 30 becomes spaced apart from the distal notch face 432 . as a result of this retraction of the retention pin 30 , the pouch 18 can be uncoupled from retention pin 30 , e . g ., proximal movement of inner shaft 16 causes pouch 18 to uncouple from a pair of resilient fork members 64 , 66 of pouch support mechanism , e . g ., a spring 62 . referring to fig6 a - 6b , spring 62 operably couples to a distal end 43 of inner shaft 16 via one or more suitable coupling methods and includes two flexible or resilient members 64 and 66 that form an open fork configuration ( fig1 and 6 a - 6 b ). in the illustrated embodiment , inner shaft 16 at distal end 43 thereof is overmolded to a proximal end 68 of spring 62 . other coupling methods may also be utilized to couple spring 62 to distal end 43 . for example , one or more pins , rivets or the like may be utilized to couple proximal end 68 to distal end 43 . resilient members 64 , 66 are configured to move from a stressed or non - expanded state ( e . g ., when pouch 18 is in a retracted configuration , see fig9 for example ) to an unstressed or expanded state ( e . g ., when pouch 18 is deployed from outer shaft 14 ( see , e . g ., fig1 , 6 a - 6 b and 8 ). in the unstressed or expanded condition , resilient members 64 , 66 collectively form a generally u - shaped configuration for supporting a periphery of an opening 15 of pouch 18 , see fig7 a for example . in accordance with the instant disclosure , resilient members 64 , 66 are configured to releasably couple to pouch 18 . specifically , resilient members 64 , 66 are feed through a tubular portion or sleeve 17 of suitable configuration that is provided on pouch 18 ( fig8 ). accordingly , subsequent to pouch 18 being uncoupled from retention pin 30 , proximal movement of inner shaft 16 within outer shaft 14 causes a portion of pouch 18 , e . g ., sleeve 17 , to contact a distal end of outer shaft 14 , which , in turn , results in resilient members 64 , 66 sliding out from sleeve 17 and pouch 18 uncoupling from resilient members 64 , 66 . referring to fig7 a - 8 , pouch 18 may be made from any suitable biocompatible materials ( e . g ., nylon ) capable of forming an impermeable flexible membrane . pouch 18 includes a generally tubular or elongated configuration that is defined by an openable and closable upper portion or mouth 19 and closed lower portion 21 . upper portion 19 includes circumferential sleeve 17 that is configured to receive resilient members 64 , 66 therein and a distal end of suture “ s .” sleeve 17 may be formed on pouch 18 via any suitable forming methods . in embodiments , for example , a top portion of pouch 18 may be folded into an interior thereof and , subsequently , glued thereto . as noted above , suture “ s ” is configured to close pouch 18 when cinch puller 48 is pulled proximally . thus , unlike resilient members 64 , 66 which are releasably coupled to pouch 18 , suture “ s ” is intended to remain connected to pouch 18 by virtue of the fact that the suture is looped through the slot / sleeve 17 of the pouch . unlike conventional pouches that typically include a proximal edge having a profile that is generally straight and perpendicular to the longitudinal axis a , pouch 18 may , in various embodiments , include a proximal edge 23 that has a curved profile 29 . for example , in an embodiment , the proximal edge of the pouch 18 is initially at a very obtuse angle , nearly 180 degrees , relative to the longitudinal axis at or near the mouth of the pouch 18 . the proximal edge of the pouch 18 gradually becomes closer to being orthogonal relative to the longitudinal axis near to the bottom of the pouch 18 . this curvature profile at the proximal edge of the pouch 18 may have any such curvature , but in an embodiment , may define a concave curvature at or near the mouth of the pouch 18 and may further define a convex curvature at or near the bottom portion 21 of the pouch 18 . the above - described features may facilitate retraction of pouch 18 within outer shaft 14 by reducing the force required to be exerted by a user in order to move inner shaft 16 proximally relative to the outer shaft 14 . moreover , unlike conventional specimen retrieval devices that are typically shipped for use with a pouch that is folded or rolled and stored within the outer shaft , specimen retrieval device 10 may be shipped for use with pouch 18 in an unfolded and deployed configuration . as can be appreciated , a pouch that is folded or rolled and stored within the outer shaft during shipping may result in undesirable memory wrinkles being formed thereon , which , in turn , may make it difficult for a clinician to open the pouch when it is deployed from the applicator . such a disadvantage may be avoided by an arrangement as described herein . the pouch 18 may have any of a variety of different configurations . fig1 is a perspective view of a specimen retrieval device in accordance with an embodiment of the present disclosure with a pouch in a deployed configuration . in this configuration , the pouch 18 has an hourglass shape . specifically , the pouch 18 , in this embodiment , has a region having a waist “ w ”. the waist may have a dimension in the radial direction , e . g ., a direction that is in a plane generally parallel to the plane defined by the patient &# 39 ; s tissue wall being traversed , that is less than the dimension of the mouth of the pouch 18 . in this way , when the pouch is deployed into an incision , the waist of the pouch 18 may be arranged within the laparotomy site , while the portions of the pouch 18 that are above the waist may remain outside of the incision . likewise , when the pouch is deployed into an incision and the waist of the pouch 18 is arranged within the laparotomy site , the portions of the pouch 18 that are below the waist may remain fully inside of the surgical space , e . g ., below the incision . such an arrangement may allow for easier morcellation . furthermore , such an arrangement may allow for easier access to the contents of the pouch 18 after the inner shaft and the pouch support mechanism has been removed . for example , when the pouch support mechanism has been removed from a conventional specimen retrieval product , the mouth of the pouch 18 is positioned within the surgical space , making it difficult for a user to access the mouth , e . g ., for the purposes of inserting a morcellation instrument or the like . in contrast , the arrangement shown in fig1 permits a user to readily access the mouth of the pouch 18 even when the pouch support mechanism has been detached from the pouch 18 and removed therefrom , because the mouth of the pouch 18 is positioned outside of the surgical space . the pouch 18 may be fabricated in various different manners . advantageously , the pouch 18 is made from a single piece of material , e . g ., rip - stop nylon , polyurethane , etc ., that , prior to fabrication , is in the form of a flat sheet . fig1 a - c are top views of a pouch for a specimen retrieval device in accordance with another embodiment of the present disclosure , with the pouch in a pre - fabricated state . the pouch 18 is shown as being symmetrical about a vertical ( in this view ) midline . this vertical midline will be the location of a fold . the upper portion of the pouch 18 ( in this view ) provides the mouth of the pouch 18 , and is advantageously folded over and welded in place so as to form a slot around the mouth of the pouch 18 . of course , joining methods other than welding may also be employed , e . g ., gluing , mechanically fastening , etc . in this embodiment , this upper portion tapers towards the vertical midline at a single angle . the right and left sides of the pouch ( in this view ) form a complex curve that , as described in further detail hereinabove , provides a curved proximal edge that is more easily pulled by the inner shaft into the outer shaft during use . in an embodiment , the right and left sides of the pouch 18 are brought together during fabrication by the pouch 18 being folded about the vertical midline , with the right and left sides of the pouch being welded or otherwise joined together in a sealing manner . this folding method of fabrication reduces the linear length of welding that needs to occur in order to provide a pouch that is fully sealed around its edges ( except for the mouth ). fig1 a , b , and c are similar to each other and differ from each other only in the angles 13 formed by the edges . fig1 d is a side view of a pouch for a specimen retrieval device in accordance with the embodiment shown in fig1 a and c , with the pouch in a fabricated state , illustrating the bag fold line and the complex curve provided by the weld on the proximal sides . as mentioned previously , fig1 a is a top view of a pouch for a specimen retrieval device in accordance with another embodiment of the present disclosure , with the pouch in a pre - fabricated state . similar to the embodiment shown in fig1 a - d , the pouch 18 of fig1 a and b are shown as being symmetrical about a vertical ( in this view ) midline . this vertical midline provides the location of a fold . the right and left sides of the pouch ( in this view ) form a complex curve that , as described in further detail hereinabove , provides a curved proximal edge that is more easily pulled by the inner shaft into the outer shaft during use . like the embodiment of fig1 a - d , the right and left sides of the pouch 18 are brought together during fabrication by the pouch 18 being folded about the vertical midline , with the right and left sides of the pouch 18 being welded or otherwise joined together in a sealing manner . again , this folding method of fabrication reduces the linear length of welding that needs to occur in order to provide a pouch that is fully sealed around its edges ( except for the mouth ), thereby reducing manufacturing complexity and lowering the cost of manufacturing the pouch . the pouch 18 of fig1 a and b differs from the embodiments shown in fig1 a - d in that each side of the upper portion of the pouch 18 ( in this view ) that provides the mouth of the pouch 18 forms a compound angle α . each side of the mouth is advantageously folded over and welded in place so as to form a slot around the mouth of the pouch 18 . the significance of this compound angle along the upper portion is illustrated in fig1 b , which is a side view of a pouch for a specimen retrieval device in accordance with the embodiment shown in fig1 a , with the pouch in a fabricated state . as shown in fig1 b , the increased angle provides for an opening in the pouch that more easily accepts a specimen . more specifically , during a surgical procedure in which the pouch 18 is positioned by a user to receive a specimen , the mouth of the pouch 18 is presented to a user at an angle that is more conducive to receiving the specimen . in use , handle assembly 40 may be moved proximally to move inner shaft 16 including pouch 18 to a retracted configuration . thereafter , outer shaft 14 may be inserted through a natural or man made orifice on a patient and positioned adjacent target tissue . subsequently , handle assembly 40 may be moved distally to move inner shaft 16 including pouch 18 to a “ normal use ” configuration , e . g ., leaf spring 24 is in contact with stop pin 22 . in the “ normal use ” configuration , target tissue may be dissected and positioned within pouch 18 . a user may selectively and repeatedly move between the normal use and retracted configurations so as to collect various different tissue portions at different times during a surgical procedure , while temporarily pulling the entire mouth of the pouch 18 ( along with the pouch support mechanism ) into the distal end of the outer shaft 14 between such different times so as to ensure that the contents of the pouch are not spilled between such fillings . when a user is satisfied that all of the tissue to be collected has been placed within pouch 18 , a user may depress push - button 34 to disengage leaf spring 24 from stop pin 22 and move handle assembly 40 distally , e . g ., a distance “ d .” as a result thereof , tip 36 engages flange 26 , which , in turn , causes retention pin 30 to move proximally relative to the inner shaft 16 , thereby enabling the de - coupling of pouch 18 from the inner shaft 16 . once the pouch 18 has been de - coupled from the inner shaft 16 , a user may detach the cinch puller 48 from the handle portion of the inner shaft and use the cinch cutter 53 to cut the suture “ s .” the entire inner shaft 16 may then be withdrawn out of the outer shaft 14 , taking with it the pouch retention mechanism 30 , the leaf spring 24 , the pouch support mechanism of the resilient forks ( which retract out of the slot 17 at the mouth of the pouch , etc . with the inner shaft 16 completely removed , the remaining portion of the cinch extends longitudinally through the outer shaft 14 . by pulling the suture “ s ,” the mouth of the pouch 18 is caused to close . the outer shaft 14 may then also be withdrawn from out of the surgical site , leaving just the closed pouch 18 within the surgical site and a portion of the suture “ s ” extending through the incision . as set forth above , in an embodiments , one or more stop mechanisms may be employed to facilitate detachment of the pouch 18 from the pouch support mechanism at the distal end of the inner shaft 16 . in other embodiments , the stop mechanisms may be eliminated and a different type of mechanism may be employed to facilitate detachment of the pouch 18 from the pouch support mechanism at the distal end of the inner shaft 16 . fig1 a - c illustrate several views of an embodiment which replace the retention pin 30 with a pair of sliding retention fingers 153 . fig1 a - c , on the other hand , illustrate several views of embodiments which replace the stop mechanisms with a movable member , e . g ., a pivotable ring , which functions as an actuator for selectively moving the pair of sliding retention fingers 153 . turning first to fig1 a - d , there is provided an arrangement for a pouch retention mechanism that facilitates selective detachment of the pouch 18 from the pouch support mechanism at the distal end of the inner shaft 16 . an advantage of the pouch retention mechanism described herein below may be the ease with which the pouch retention mechanism facilitates selective detachment of the pouch 18 from the pouch support mechanism . conventional pouch retention mechanisms that enable detachment of the pouch 18 from the pouch support mechanism typically do so only when the pouch retention mechanism has been moved distally to a location that is distal relative to the distal end of the outer shaft . in order to prevent inadvertent detachment of the pouch from the pouch support mechanism , conventional pouch retention mechanisms may rely on various stop mechanisms to prevent the pouch retention mechanism from being moved distally to a location that is distal relative to the distal end of the outer shaft . in various embodiments , the arrangement described hereinbelow may eliminate the need for such stop mechanisms . for example , as described in further detail below , the arrangement of the presently described devices may include a pouch retention mechanism that permits selective detachment of the pouch from the pouch support mechanism while the pouch retention mechanism is still within the outer shaft 16 . by eliminating the conventional stop mechanisms , the device may be simplified and require fewer steps to be performed by a user during a surgical procedure . in addition , the cost of the device may be reduced as a result of there being fewer components , thereby decreasing component costs and simplifying manufacture . as in the previously described embodiments , the pouch 18 has holes 152 defined by the pouch material and being adjacent to the proximal end of the mouth . instead of these holes 152 having a single retention pin 30 positioned through them , each one of the holes 152 in this embodiment has positioned therethrough a protrusion 151 of the inner shaft 16 . each one of these protrusions 151 protrudes laterally from an outer surface of the inner shaft 16 . each one of the protrusions 151 is engaged by a respective one of a pair of sliding retention fingers 153 that slide longitudinally relative to the inner shaft 16 , e . g ., along an outside surface of the inner shaft 16 . it should be recognized that , in other embodiments , the retention fingers 153 may move in various different ways , not merely by sliding , e . g ., by pivoting , rotating , etc . it should also be recognized that , while these members are described herein as being elongated finger - type structures , other structures may also be employed . when each one of the pair of sliding retention fingers 153 is in a distal most position relative to the inner shaft 16 , the distal end of the sliding retention finger 153 abuts the protrusion 151 such that the hole 152 of the pouch that is positioned through the protrusion 151 is prevented from being disengaged from , e . g ., slipping off of , the protrusion 151 . when the sliding retention finger 153 is actuated in a proximal direction relative to the inner shaft 16 by a user , the sliding retention fingers 153 no longer abut the protrusions 151 . a separating force that is exerted on the inner shaft 16 relative to the pouch 18 at this point enables the hole 152 to be disengaged from the protrusion 151 and thus enables the pouch 18 to be detached from the pouch support mechanism at the distal end of the inner shaft 16 . such a separating force may be generated by a user pulling proximally on the handle at the proximal end of the inner shaft 16 . for example , once the hole 152 of the pouch 18 is no longer locked onto the protrusion 151 by the sliding retention finger 153 , pulling the inner shaft 16 proximally does not pull the pouch 18 and pouch support mechanism back into the outer shaft 14 ( as it did when the hole 152 of the pouch 18 was locked onto the protrusion 151 by the sliding retention finger 153 ), but rather the pouch support mechanism is caused to slide out of the slots around the mouth of the pouch 18 , until the pouch support mechanism is no longer supporting the pouch 18 . this disengagement of the pouch 18 from the pouch support mechanism occurs because the friction experienced between the pouch 18 and the outer shaft 14 by the unfolded pouch 18 attempting to be pulled into the small cross - sectional area of the outer shaft 14 is greater than the frictional force that holds the pouch support mechanism in the slots around the mouth of the pouch 18 . in the embodiment shown , the sliding retention fingers 153 are attached to a cinch , e . g ., suture , attachment mechanism 154 . the sliding retention fingers 153 may be separate components from the cinch , e . g ., suture , attachment mechanism 154 and may be attached thereto by any suitable method , e . g ., overmolding , friction fit , snap - lock fitting , welding , etc . alternatively , the sliding retention fingers 153 may be integrally formed with the cinch , e . g ., suture , attachment mechanism 154 . as shown , the cinch , e . g ., suture , attachment mechanism 154 defines an opening 155 through with the cinch , e . g ., suture , 156 may be positioned and secured . a force exerted on the cinch , e . g ., suture , 156 , e . g ., by a user actuating an actuator ( described in further detail below ), exerts a force on the cinch , e . g ., suture , attachment mechanism 154 which , in turn , exerts a force on the sliding retention fingers 153 to move the sliding retention fingers 153 proximally relative to the inner shaft 16 . in an embodiment , the inner shaft 16 and the sliding retention fingers 153 may have corresponding features that prevent the sliding retention fingers 153 from inadvertently moving proximally relative to the inner shaft 16 . as shown , the sliding retention fingers have an indent 157 and the inner shaft 16 has corresponding detents 158 that are frictionally engaged thereby . the force required to be exerted on the sliding retention fingers 153 to move the sliding retention fingers 153 proximally relative to the inner shaft 16 should be higher than the frictional force between the indent 157 of the sliding retention fingers 153 and the corresponding detents 158 of the inner shaft 16 . of course , it should be recognized that , while the embodiment shown and described hereinabove employs an arrangement in which the pouch 18 has two holes 152 , two protrusions 151 and two sliding retention fingers 153 , other embodiments may employ a different number of these components , e . g ., either one or more than two . for example , in accordance with an embodiment , an arrangement may be provided whereby the pouch 18 has only one hole 152 , the inner shaft 16 having only a single protrusion 151 which is positioned through the hole 152 , the protrusion 151 being engaged by a single sliding retention finger 153 . in such an embodiment , the pouch 18 is maintained on the distal end of the inner shaft 16 by protrusion 151 protruding through the hole 152 and by the sliding retention finger 153 engaging the protrusion such that the hole 152 is prevented from being disengaged by the protrusion 151 . the pouch 18 is selectively detached from the distal end of the inner shaft 16 by the actuation of the sliding retention finger 153 in a proximal direction relative to the inner shaft 16 , thereby permitting the hole 152 to be disengaged from the protrusion 151 . still further , it should be recognized that these components need not be equal in number , e . g ., a single protrusion 151 may be positioned through a plurality of holes 152 , a single sliding retention finger 153 may engage a plurality of protrusions 151 and / or holes 152 , a plurality of sliding retention fingers 153 may engage a single protrusion 151 and / or hole 152 , etc . fig1 d illustrates a bottom perspective view of the distal end of the inner shaft 16 . an underside of the inner shaft 16 shows a track 160 for the cinch , e . g ., suture , 156 . the cinch , e . g ., suture , 156 resides within the track 160 and extends from the pouch 18 , along the underside of the inner shaft 16 , then up and through the middle of the inner shaft 16 , then through the opening 155 in the cinch , e . g ., suture , attachment mechanism 154 and then it continues proximally along the top of the inner shaft 16 . as set forth above , fig1 a - c illustrate several views of embodiments which replace the stop mechanisms with a movable member , e . g ., a pivotable ring , which functions as an actuator for selectively moving the pair of sliding retention fingers 153 . for example , fig1 a - b illustrate several views of an embodiment which employ a movable member , e . g ., a pivotable ring , which is connected to a proximal end of the cinch , e . g ., suture , 156 and that functions as an actuator for selectively moving the pair of sliding retention fingers 153 . fig1 c , on the other hand , illustrates an embodiment which employs a pivotable ring that is connected to a proximal end of the cinch , e . g ., suture , 156 and that functions for the same purpose . referring to fig1 a and b , there is provided an actuator for selectively moving the pair of sliding retention fingers 153 . in this embodiment , the actuator is a pivotable ring 170 . the pivotable ring 170 is pivotably attached at its proximal end to a handle 171 . in an embodiment , the proximal end of the pivotable ring 170 is snap - fit into a groove 172 on the handle 171 . the handle 171 is attached to the proximal end of the inner shaft 16 and is configured to be gripped by a user for moving the inner shaft 16 longitudinally relative to the outer shaft 14 . the distal end of the pivotable ring 170 is connected to the cinch , e . g ., suture , 156 . when a user determines that he or she has placed all of the tissue that is desired to be placed in the pouch 18 , the user may pivot the distal end of the ring 170 by lifting it up and pivoting it relative to the handle 171 . this pivoting movement pulls on the cinch , e . g ., suture , 156 so as to actuate the sliding retention fingers 153 and thereby permit the detachment of the pouch 18 from the pouch support mechanism , as described previously . with the pouch 18 detached from the pouch support mechanism , e . g ., with the resilient forks 64 and 66 withdrawn from out of the slots around the mouth of the pouch 18 , the cinch , e . g ., suture , 156 may be cut , which allows the inner shaft 16 to be retracted from out of the outer shaft 14 . with the inner shaft 16 retracted from out of the outer shaft 14 , a user may pull on the proximal end of the cinch , e . g ., suture , 156 in order to cinch the mouth of the pouch 18 closed . the outer shaft 14 may then be withdrawn from out of the incision , leaving just the cinch , e . g ., suture , 156 passing through the incision with the pouch 18 inside of the incision . the contents of the pouch 18 may be morcellated , if desired ( either through the outer shaft 14 prior to the outer shaft 14 being withdrawn , or through the incision if the outer shaft 14 has already been withdrawn ), and the pouch 18 may then be withdrawn through the incision . in the embodiment shown in fig1 a and b , the ring 170 overlaps with the handle 171 except for a region of the ring 170 that is radially within a void 173 of the handle 171 . thus , in order to cause the ring 170 to pivot relative to the handle 171 , a user reaches through the void 173 and presses upwardly against the ring 170 so as to pivot it relative to the handle 171 . in the embodiment shown in fig1 c , the ring 170 overlaps with the handle 171 except for a region of the ring 170 that is proximal to the handle 171 . thus , in order to cause the ring 170 to pivot relative to the handle 171 , a user places his or her fingers on the proximal end of the handle and presses upwardly against the ring 170 so as to pivot it relative to the handle 171 . the embodiment shown in fig1 a and b may be advantageous in that there may be less likelihood that a user will inadvertently pivot the ring 170 relative to the handle 171 since the user needs to place his or her fingers in a region of the handle 171 , e . g ., through the void 173 defined by the handle 171 , which is different from the region of the handle 171 that his or her fingers are already in to move the handle 171 and the inner shaft 16 proximally and distally relative to the outer shaft 14 . the ability of the specimen retrieval device 10 to be repeatedly moved into and out of the distal end of the outer shaft 14 enables the device to be shipped with pouch 18 in an unfolded and deployed configuration , e . g ., outside of the outer shaft 14 . such an arrangement may overcome an aforementioned drawback typically associated with conventional specimen retrieval devices , e . g ., the likelihood of memory wrinkles being formed on pouch 18 is reduced , if not eliminated . from the foregoing and with reference to the various figure drawings , those skilled in the art will appreciate that certain modifications can also be made to the present disclosure without departing from the scope of the same . for example , one or more devices or components may be utilized to indicate to a user when forks 64 and 66 are completely within the outer shaft 14 . such an indication may be useful so that a user will know that the mouth of the pouch 18 , which is being supported by the forks 64 and 66 , is also captured within the outer shaft 14 , ensuring that the contents of the pouch 18 will not inadvertently spill out of the mouth of the pouch 18 . specifically , with reference to fig1 and 11 a specimen retrieval device 110 according to an alternate embodiment of the present disclosure is illustrated . specimen retrieval device 110 is similar to specimen retrieval device 10 . accordingly , only those features unique to specimen retrieval device 110 are described herein . an inner shaft 116 includes one or more indication mechanisms 180 thereon that are configured to indicate to a user when forks 64 and 66 are positioned within an outer shaft 114 . in an embodiment , indication mechanism ( s ) 180 may be in the form of indicia that are visible to a user when forks 64 and 66 are fully within the outer shaft 14 . in one particular embodiment , for example , indicia may include one or more markings “ m ” on inner shaft 116 that are visible to a user when forks 64 and 66 are fully within the outer shaft 14 . when the forks 64 and 66 are not fully within the outer shaft 14 , the indicia may be hidden by the housing . alternatively , indication mechanism ( s ) 180 may be a structure that provides an audible sound perceivable to a user when forks 64 and 66 are fully within the outer shaft 14 ( fig1 ). in this particular embodiment , one or more components may be provided on inner shaft 116 and / or outer shaft 114 and may be configured to provide an audible “ click ” that is perceivable to a user to indicate when forks 64 and 66 are fully within the outer shaft 14 . alternatively , indication mechanism ( s ) 180 may be a tactile feature “ t ” that is perceivable to user when forks 64 and 66 are fully within the outer shaft 14 ( fig1 ). in this particular embodiment , one or more components , e . g ., an indent / detent configuration , may be provided on inner shaft 116 and / or outer shaft 114 and may be configured to provide an tactile “ feel ” that is perceivable to a user when forks 64 and 66 are fully within the outer shaft 14 . with reference to fig1 a - 17b , a specimen retrieval device 110 according to another embodiment of the present disclosure is illustrated . specimen retrieval device 110 is configured for use with the pouch 18 and is substantially similar to specimen retrieval device 10 . accordingly , only those features that are unique to specimen retrieval device 110 are described in detail herein . a housing 112 including a pair of optional finger loops 112 a , 112 b that are configured to receive the fingers of a clinician is provided at a proximal end of the outer shaft 114 . finger loops 112 a , 112 b are configured to allow the clinician to grasp the housing 112 and move an inner shaft 116 from the extended or “ normal use ” position ( fig1 a ) to the retracted position . a cinch handle or puller 148 couples to the inner shaft 116 via a press or friction fit and is positioned between a handle 140 of the inner shaft 116 and finger loops 112 a , 112 b of housing 112 . cinch puller 148 is configured to contact a proximal end of the housing 112 to limit distal translation of the inner shaft 116 with respect to outer shaft 114 to maintain the distal most end of the retention pin 130 between notch faces 133 a , 133 b ( fig1 b ). as noted above , with the distal most end of the retention pin 130 positioned between notch faces 133 a , 133 b , the pouch 18 is attached to the distal end of the inner shaft 116 and is prevented from inadvertently becoming disengaged therefrom . in accordance with the instant disclosure , when a tip 136 of the retention pin 130 engages a flange ( not explicitly shown ) provided in the outer shaft 114 ( see description of distal tip 36 above for example ) and inner shaft 116 is moved distally a distance “ d ,” the retention pin 130 is moved proximally relative to the inner shaft 116 such that the distal most end of the retention pin 130 becomes spaced apart from the notch faces 133 a , 133 b . as a result of this retraction of the retention pin 130 , the pouch 18 can be uncoupled from the retention pin 130 in a manner as described above . the cinch handle 148 may have a suture ( not shown ) coupled thereto which extends therefrom to couple to the pouch 18 for cinching the pouch 18 . the suture may couple to the cinch handle 148 via one or more suitable coupling methods , e . g ., adhesive , knot , etc . moreover , the housing 112 and / or handle 140 may include a cutting mechanism ( e . g ., the cutting mechanism 51 ) thereon to cut the suture . in use , handle assembly 140 may be moved proximally to move inner shaft 116 including pouch 18 to a retracted configuration . thereafter , outer shaft 114 may be inserted through a natural or man made orifice on a patient and positioned adjacent target tissue . subsequently , handle assembly 140 may be moved distally to move inner shaft 116 including pouch 18 to a “ normal use ” configuration , e . g ., cinch handle 148 contacts the proximal end of the housing 112 . in the “ normal use ” configuration , target tissue may be dissected and positioned within pouch 18 . a user may selectively and repeatedly move between the normal use and retracted positions so as to collect various different tissue portions at different times during a surgical procedure , while temporarily pulling the entire mouth 15 of the pouch 18 ( along with the resilient members 64 , 64 ) into the distal end of the outer shaft 114 between such different times so as to ensure that the contents of the pouch 18 are not spilled between such fillings . when a user is satisfied that all of the tissue to be collected has been placed within pouch 18 , a user may remove cinch handle 148 from the inner shaft 116 and move handle assembly 140 distally , e . g ., a distance “ d .” as a result thereof , the tip of the retention pin 130 engages the flange in the housing 112 , which , in turn , causes retention pin 130 to move proximally relative to the inner shaft 116 , thereby enabling the de - coupling of pouch 18 from the inner shaft 116 in a manner as described above . the pouch 18 may then be de - coupled from the inner shaft 116 , cinched and removed from the patient in a manner as described above . as can be appreciated , the specimen retrieval device 110 overcomes the aforementioned drawbacks typically associated with conventional specimen retrieval devices , e . g ., the likelihood of memory wrinkles being formed on pouch 18 is reduced , if not eliminated . with reference to fig1 - 28 , a specimen retrieval device 210 according to still another embodiment of the present disclosure is illustrated . specimen retrieval device 210 is configured for use with the pouch 18 and is substantially similar to the previously described specimen retrieval devices . accordingly , only those features that are unique to specimen retrieval device 210 are described in detail herein . specimen retrieval device 210 includes an outer shaft 214 that is configured to house an inner shaft 216 and a retention pin 230 therein . unlike the previously described outer shafts , however , outer shaft 214 does not include one of the aforementioned housings . one of the aforementioned housings may , however , be utilized . moreover , the proximal coupling portion 35 that is configured to mechanically interface with the distal most end of the retention pin 30 may be omitted . the retention pin 230 is coupled to the inner shaft 216 and is moveable within the outer shaft 214 as the inner shaft 216 is moved between the retracted position ( fig2 and 23 - 24 ) and extended position ( fig1 , 20 and 22 ). a proximal end 231 of the retention pin 230 is configured to contact a proximal end of the outer shaft 214 ( fig1 , 20 and 22 ). proximal end 231 includes a generally arcuate configuration and is configured to be received within a corresponding recess 241 ( fig2 ) provided on handle assembly 240 of the inner shaft 216 when the handle assembly 240 is moved to the extended configuration ( fig2 - 24 ). a distal most end of the retention pin 230 is configured to releasably couple the retention pin 230 to a proximal portion 235 of a pouch 218 , as will be described in greater detail below . a cinch 248 releasably couples to the handle assembly 240 of the inner shaft and extends through the outer shaft 214 for coupling to the pouch 218 . specifically , a distal end of the cinch 248 fixedly couples to one end of the pouch 218 via an anchor nut 7 ( or other suitable device ) and extends through the sleeve 17 ( see fig1 ) around a periphery of the pouch 218 and out the other end of the pouch 218 . prior to extending the cinch 248 through the outer shaft 214 , the cinch 248 is wrapped around the distal most end of the retention pin 230 to form a first loop 242 a ( fig1 ) that is tightened around the distal most end of the retention pin 230 and the proximal end of the pouch 218 to releasably secure the retention pin 230 to the pouch 218 . various loop configurations may be utilized to releasably secure the retention pin 230 to the pouch 218 . a proximal end of the cinch 248 includes a second loop 242 b ( fig1 ) that is configured to facilitate pulling the cinch 248 for cinching the pouch 218 . a knot “ k ” may be provided adjacent the second loop 242 b and may be configured to releasably couple to a corresponding slit 243 disposed at a proximal end of the handle assembly 240 . the knot “ k ” may be utilized to releasably secure the second loop 242 b of the cinch to the proximal end of the handle assembly 240 . in use , handle assembly 240 may be moved proximally to move inner shaft 216 including pouch 218 to a retracted configuration ( fig2 ). thereafter , outer shaft 214 may be inserted through a natural or man made orifice on a patient and positioned adjacent target tissue . subsequently , handle assembly 240 may be moved distally to move inner shaft 216 including pouch 218 to a “ normal use ” configuration , e . g ., the proximal end 231 of the retention pin 230 contacts proximal end of the outer shaft 214 ( fig2 ). in the “ normal use ” configuration , target tissue may be dissected and positioned within pouch 218 . a user may selectively and repeatedly move between the normal use and retracted positions in a manner as described above . to uncouple the pouch 218 from the distal end of the retention pin 230 , handle assembly 240 is moved distally into contact with the proximal end 231 of the retention pin 230 , which , in turn , causes the first loop 242 a to move out of engagement with ( or uncouple from ) the distal most end of the retention pin 230 , thereby enabling the de - coupling of pouch 218 from the inner shaft 216 in a manner as described above ( fig2 ). when a user is satisfied that all of the tissue to be collected has been placed within pouch 218 , a user may remove the cinch 248 from the handle assembly 240 of the inner shaft 216 ( fig2 ). the pouch 218 may then be cinched and removed from the patient in a manner as described above ( fig2 ). as can be appreciated , the specimen retrieval device 210 overcomes the aforementioned drawbacks typically associated with conventional specimen retrieval devices , e . g ., the likelihood of memory wrinkles being formed on pouch 218 is reduced , if not eliminated . fig2 illustrates an alternate retention pin and outer shaft configuration that may be utilized with the specimen retrieval device 210 . specifically , a retention pin 270 may be provided within the outer shaft 214 and a proximal end 271 of the retention pin 270 may be configured to engage an internal stop , e . g ., an internal flange 226 , that is defined along an interior wall of the outer shaft 214 . in use , a user may selectively and repeatedly move between the normal use and retracted positions in a manner as described above . to uncouple the pouch 218 from the distal most end of the retention pin 270 , handle assembly 240 is moved proximally until the proximal end 271 of the retention pin 270 engages the flange 226 , which , in turn , causes the first loop 242 a to move out of engagement with the distal most end of the retention pin 270 , thereby enabling the de - coupling of pouch 218 from the inner shaft 216 in a manner as described above . one or more indicators ( not shown ) may be provided on the inner shaft 216 and utilized to indicate to a clinician how far the inner shaft 216 has been moved before the inner shaft 216 releases the pouch 218 . fig2 - 28 illustrate an alternate retention pin and outer shaft configuration that may be utilized with the specimen retrieval device 210 . specifically , a retention pin 280 may include a bifurcated configuration having right and left leg members 280 a , 280 b that are configured to releasably couple to the proximal portion 235 of pouch 218 . specifically , right and left leg members 280 a , 280 b are configured to squeeze or compress the proximal portion 235 of pouch 218 with a compressive force that , along with the first loop 242 a , is capable of maintaining pouch 218 between leg members 280 a , 280 b as pouch 218 is moved between the retracted and extended configurations . leg members 280 a , 280 b are joined at a proximal end to form a proximal end ( not explicitly shown ), such as , for example , a proximal end similar to proximal end 231 and / or proximal end 271 that is configured to engage flange 226 and / or proximal end of outer shaft 214 . to uncouple the pouch 218 from the distal end of the retention pin 280 , handle assembly 240 is moved proximally until the proximal end of the retention pin 280 engages the flange 226 and / or the proximal end of the outer shaft 214 , which , in turn , causes the first loop 242 a to move out of engagement with the distal most end of the retention pin 280 , thereby enabling the de - coupling of pouch 218 from the inner shaft 216 in a manner as described above . with reference to fig2 a - 29c , a specimen retrieval device 310 according to another embodiment of the present disclosure is illustrated . specimen retrieval device 310 is configured for use with either of the pouches 18 or 218 and is substantially similar to aforementioned specimen retrieval bags . accordingly , only those features that are unique to specimen retrieval device 310 are described in detail herein . in accordance with the instant disclosure , specimen retrieval device 310 includes a cinch handle 348 that is in accessible to a clinician when an inner shaft 316 is in the extended position ( fig2 a ). as can be appreciated , this may prevent the clinician from mistakenly cinching the pouch 18 prior to retracting the spring 62 , which may lead to the specimen retrieval device not functioning in a manner as intended . to this end , cinch handle 348 includes a generally elongated configuration having a pair of proximal and distal tabs 349 a , 349 b . a protuberance 346 is provided on an underside of the cinch handle 348 and is configured to facilitate uncoupling the cinch handle 348 from the inner shaft , as will be described below . a suture “ s ” may be coupled to the cinch handle 348 , e . g ., a knot “ k and aperture configuration , adhesive , etc . suture “ s ” may extend along a top surface 345 of the cinch handle 348 and through the housing 312 and outer shaft 314 to couple to the pouch 18 . housing 312 includes a pair of arm portions 313 a , 313 b that serve as a handle for a user to grasp . an outer shaft 314 couples to the housing 312 and extends distally therefrom . housing 312 and outer shaft 314 are configured to allow a user to move the inner shaft 316 from the retracted configuration ( fig2 a and 29b ) to the extended configuration . the inner shaft 316 of the specimen retrieval device 310 includes a pocket 317 that is disposed at a proximal end of the inner shaft 316 adjacent a handle assembly in the form of a finger loop 318 that is configured to receive a finger of a clinician . as can be appreciated , finger loop 318 can be replaced with one of the aforementioned a handle assemblies . pocket 317 includes a pair of proximal and distal cut - outs 319 a , 319 b that are configured to releasably engage the pair of proximal and distal tabs 349 a , 349 b that are provided on the cinch handle 348 . a recess or detent 320 ( fig2 c ) is defined within the pocket 317 and is configured to receive the protuberance 346 ( fig2 b - 1 ) that is provided on an underside of the cinch handle 348 . depending on which pouch is utilized , the specimen retrieval device 310 may include one more of the aforementioned retention pin configurations ( not explicitly shown in fig2 a - 29c ) to uncouple the pouches 18 , 218 from resilient members 64 , 66 . in the normal use configuration , the cinch handle 348 will be seated within the pocket 317 and the tabs 349 a , 349 b of the cinch handle 34 engaged with the cut - outs 319 a , 319 b ( fig2 a ). in this configuration , the top surface 345 of the cinch handle 348 will be flush with an exterior of the inner shaft 316 to allow a user to repeatedly move the pouch 18 ( or pouch 218 ) in and out of the outer shaft 314 . a user can uncouple the pouch 18 ( or pouch 218 ) from the resilient members 64 , 66 in accordance with one of the aforementioned embodiments described above . thereafter the user can cinch the pouch 18 ( or pouch 218 ). specifically , a user can move the tab 349 a out of engagement with the cut - out 319 a , which , in turn , simultaneously causes the protuberance 346 to rotate within the recess 320 and the tab 349 b of the cinch handle 348 to pivot about the cut - out 319 b of the inner shaft 316 ( fig2 b ). a user can then remove the cinch handle 348 from the pocket 317 of the inner shaft 316 and pull the cinch handle 348 proximally to cinch the pouch 18 ( fig2 c ). with reference to fig3 a - 30c , a specimen retrieval device 410 according to another embodiment of the present disclosure is illustrated . specimen retrieval device 410 is configured for use with either the pouch 18 or pouch 218 and is substantially similar to aforementioned specimen retrieval bags , e . g ., specimen retrieval device 310 . accordingly , only those features that are unique to specimen retrieval device 410 are described in detail herein . a pocket 417 is provided on an inner shaft 416 and includes a protrusion 421 that releasably couples via a press or friction fit to an aperture or indent 444 ( fig3 c ) provided on a cinch handle 448 . the suture “ s ” may be coupled to the cinch handle 448 via one of the aforementioned coupling methods . moreover , one or more optional cut outs and / or tab members ( see discussion above for example ) may be utilized to facilitate coupling the cinch handle 448 within the pocket 417 . in the normal use configuration , the cinch handle 448 will be seated within the pocket 417 ( fig3 a ). in this configuration , a top surface 445 of the cinch handle 448 will be flush with an exterior of the inner shaft 416 to allow a user to repeatedly move the pouch 18 ( or pouch 218 ) in and out of the outer shaft 414 . a user can uncouple the pouch 18 ( or pouch 218 ) from the resilient members 64 , 66 in a manner as described above . thereafter the user can cinch the pouch 18 ( or pouch 218 ). specifically , a user can rotate the cinch handle 448 about the protuberance 346 to place the cinch handle 448 in a position for allowing a clinician to uncouple the cinch handle 448 from the pocket 417 of the inner shaft 416 ( fig3 b ). a user can then remove the cinch handle 448 from the pocket 417 of the inner shaft 416 and pull the cinch handle 448 proximally to cinch the pouch 18 ( or pouch 218 ), fig3 c . in accordance with the instant disclosure , other cinch handles may utilized with the specimen retrieval devices 310 , 410 . for example , fig3 - 32 illustrate a cinch handle 548 that includes two generally arcuate lateral portions 549 a , 549 b and an elongated medial portion 547 that extend at least partially along a length of the cinch handle 548 . the medial portion 547 is configured to seat within a corresponding indent or groove ( not explicitly shown ) that may be defined within the pockets 317 , 417 . the lateral portions 549 a , 549 b are relatively flexible and configured to snap into place along an exterior of the inner shafts 316 , 416 . accordingly , the lateral portions 549 a , 549 b should extend beyond a center of the inner shafts 316 , 416 ( see fig3 for example ). a user can uncouple the cinch handle 548 from the pockets 317 , 417 of the inner shafts 316 , 416 , respectively , via grasping ( or squeezing ) the lateral portions 549 a , 549 b of the cinch handle 548 while simultaneously rotating ( or pulling ) the cinch handle 548 until the cinch handle 548 uncouples from the pockets 317 , 417 of the respective inner shafts 316 , 416 . with reference to fig3 - 34 , an alternate embodiment of the spring 62 is illustrated and is designated spring 662 . spring 662 is similar to spring 62 and configured for use with any of the aforementioned specimen retrieval devices and pouches . accordingly , only those features that are unique to spring 662 are described in detail herein . spring 662 includes two resilient fork members 664 , 666 having respective distal tips 667 a , 667 b with generally arcuate medial portions 669 a , 669 b that form a nested configuration when the resilient fork members 664 , 666 are in a compressed configuration , see fig3 for example . in embodiments , such as the illustrated embodiment , the distal tips 667 a , 667 b are monolithically formed with resilient fork members 664 , 666 . alternatively , distal tips 667 a , 667 b may be formed as separate components and , subsequently , coupled to resilient fork members 664 , 666 via one or more suitable coupling methods , e . g ., adhesive , mechanical interface , or the like . the complementary geometry distal tips 667 a , 667 b allows the resilient fork members 664 , 666 to nest on each other , as opposed to overlapping or moving over one another ( commonly referred to in the art as “ fork scissoring ”) as with conventional springs . this fork scissoring may damage the sleeve 17 of the pouches 18 , 218 and / or may increase the likelihood of uncontrolled bunching of the pouch 18 , 218 as the pouch 18 , 218 is moved between the extended and retracted positions . in accordance with the instant disclosure , the nesting of the resilient fork members 664 , 666 may help to reduce withdrawal force associated with the pouch 18 , 218 and may help to promote better withdrawal into the previously described outer shafts of specimen retrieval devices . in use , when the pouch 18 is positioned within one of the aforementioned shafts , e . g ., outer shaft 114 , and being moved therein , resilient fork members 664 , 666 are guided to the nested configuration as a result of the complementary geometry distal tips 667 a , 667 b . while several embodiments of the disclosure have been shown in the drawings , it is not intended that the disclosure be limited thereto , as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise . therefore , the above description should not be construed as limiting , but merely as exemplifications of particular embodiments . those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto . | US-201414443079-A |
a self - expanding bone screw anchor assembly adapted to allow the screw body to engage the bone and the anchor to attach thereto . the anchor assembly is adapted to be universally deployed with a variety of installation tools . | referring to fig1 a and 1b , the anchor assembly comprises elongate body 1 , defining lumen 2 therethrough . the lumen provides a bore through the device having an inner diameter that allows for the insertion of a screw body such as bone ( pedicle ) screws or setting rods and seating therein . elongate body 1 has a partially open cylindrical design with a shaft extending between proximal and distal ends 3 and 4 . at least two opposing vertical slots 5 and 6 are disposed along the shaft body , through which helical turns of a screw body may protrude to engage surrounding bone , thereby stabilizing the screw within the bone . slots 5 , 6 extend vertically to about ⅔ to ¾ the length of the elongate body and circumferentially to up to 75 % of the body diameter . the remaining material forms opposing walls of the shaft body 7 and 8 , which walls are curved ( e . g ., in substantially a “ c ” shape ). at the distalmost end ( below line a - a of fig1 a ), walls 7 , 8 are tapered inwardly as well as outwardly deflectable on insertion of a bone screw ; i . e ., the ends can extend away from body 1 to form wings 10 and 11 . as discussed further hereinbelow , wings 10 , 11 may be symmetrical or asymmetrical , as shown in expanded state in fig2 a and 2b . in either configuration , the wings are outwardly deflectable from the anchor body to form an angle therefrom of 10 to 60 °, most preferably between 25 and 45 °. as detailed in fig3 and 4 , to strengthen the deflectable wings while holding preventing distortion of the shaft walls , to maximize the deflecting force exerted on the wings , a deflectable collar 9 is provided within the interior diameter of elongate body 1 proximal to wings 10 , 11 . prior to insertion of a screw through lumen 2 , collar 9 rests in an unexpanded inverted shape that is preferably concave in its center ( forming a loose fig8 ) at the vertical openings of the shaft to minimize the hole diameter into which the anchor must be seated in the bone . insertion of the screw through the collar exerts compressive force against the internal surface of the collar , causing it to expand and stiffen , forming a shape ( preferably circular ) which protrudes from vertical slots 5 , 6 , thereby engaging surround bone and reinforcing the shaft walls above wings 10 and 11 . most preferably , the sides of collar 9 are slightly offset from horizontal ; i . e ., by between 5 ° and 10 ° ( for example , by 8 ° as shown in fig3 ). alternatively , when unexpanded , the collar may assume any shape ( e . g ., straight parallel walls ) whose walls do not protrude through vertical slots 5 , 6 prior to expansion , and through which a bone screw may be inserted . wings 10 , 11 may be deflectable in response to a compressive force exerted by insertion of the screw through lumen 2 , wherein the deflection is provided by virtue of flexibility in the material used in body 1 as described below . preferably , however , wings 10 , 11 are each provided with a hinge 12 for controlled outward expansion on insertion of a bone screw through the length of lumen 2 . as shown in fig2 a , wings 10 , 11 are symmetrical in placement and length on body 1 . alternatively , wings 10 , 11 may be asymmetrically disposed on body 1 as illustrated in fig2 b . the asymmetrical configuration allows wings 10 , 11 to be displaced at specific and independent distances and angles in the superior , inferior , medial , and lateral directions . to allow for deflectability of wings 10 and 11 , elongate body 1 is preferably a biocompatible polymer with a degree of flexibility . those of ordinary skill in the art will be familiar with materials available for use in bone screw anchors which include , without limitation , a medical grade polymer or titanium . numerous medical grade polymers exist such as nylon , polyetheretherketone ( peek ), high density polyethylene , ultra - high molecular weight or high modulus polyethylene , polyethylene glycol , polyvinyl chloride ( pvc ), polymethyl methacrylate ( pmma ), polyvinyl alcohol ( pva ), etc . additional materials of use in the invention include titanium , nitinol and stainless steel . if hinged , however , deflection of wings 10 , 11 may occur by rotation of hinge 12 at each wing . hinge 12 attach wings 10 , 11 to walls 7 , 8 . hinge 12 may secured to walls 7 , 8 by any means suitable for deployment in an implantable medical device , including a biocompatible metal or polymer pin , groove and socket hinges , and similar structures . referring to fig3 and 4 , collar 9 may be formed of the same material or a more elastic one , having sufficient rigidity to retain the unexpanded concavity described herein while being expandable on insertion of a screw body therethrough . such materials include , without limitation , those described above with respect to suitable materials for body 1 , including wings 10 , 11 . in an alternative embodiment which provides additional stability to the anchor ( especially for use with significantly degraded bone ), body 1 is further stabilized within the bone on insertion by engagement of flanges along body 1 with surrounding bone . to that end , one or more pairs of opposing outwardly deflectable flanges 13 and 14 are provided along walls 7 , 8 ( see fig6 and 7 ), situated on body 1 above line a - a ( see fig1 a ). to minimize the outer diameter of elongate body 1 during insertion into bone , one or more pairs of flanges 13 , 14 are retracted within lumen 2 so as not to extend beyond the outer diameter of body 1 until insertion of a screw body through lumen 2 . as it passes through lumen 2 , the screw body pushes each flange pair 13 , 14 deflect outwardly to engage the surrounding bone . each flange 13 , 14 is attached to walls 7 , 8 by a hinge 12 for controlled outward expansion on insertion of a screw body through lumen 2 . the wings are outwardly deflectable from the anchor body to form an angle therefrom of 10 to 60 °, most preferably between 25 and 45 °. to allow for universal application of the anchor , a screw head or nut 15 is provided per fig8 a and 8b to facilitate insertion of the anchor into bone using any suitable installation tool ( e . g ., a surgical screwdriver ). anchor head 15 is made of a deformable material , such as a polymer with elastic properties such as rubber , or any of the materials described with regard to the composition of body 1 . head 15 has a oval - shaped bore 16 therethrough that includes opposing slits 17 and 18 at the opposing ends of the oval , which allows bore 16 to stretch in diameter and shape to accommodate different sizes and shapes of installation devices and bone screws . to minimize the volume occupied by the anchor assembly ( including the screw ) after installation , anchor head 15 may be a removable nut ; i . e ., one that is reversibly threaded onto the proximal end of the anchor and can be removed after the anchor and screw are fully introduced into the bone . on insertion and rotation of a screw body through lumen 2 , the rotation can exert a rotation force on body 1 . engagement of wings 10 , 11 and flanges 13 , 14 with surrounding bone will stabilize the anchor position . to further stabilize the anchor assembly during its implantation , anchor head 15 may be further provided with a pair of opposing recesses 21 and 22 , as shown in fig8 b . recesses 21 , 22 provide a structure for engagement of a retaining tool , such as a hemostat , to hold the anchor assembly in place as it is being deployed . following insertion of a bone screw into the anchor body , the helical turns of the screw face will engage surrounding bone , stabilizing the anchor and screw in place within the bone . the inner diameter of lumen 2 is therefore adapted to allow for insertion of a screw through lumen 2 whereby the helical turns of the screw face will protrude from vertical slots 5 , 6 to engage with surrounding bone . it will be appreciated that the outer surfaces along body 1 , wings 10 , 11 and flanges 13 , 14 can be treated to be especially well suited to a particular application ( e . g ., fixation or stabilization of bone at various levels of the spine ). for example , the surfaces may be smooth , sanded , or micro - abrasive blasted to create a rough surface finish . a rough surface finish has the advantage of significantly increasing the friction coefficient between the device - bone interface . additionally , said porous surfaces can promote bone growth and further strength the device - bone interface . the anchor assembly may also be coated with a material , drug , or biologic to increase bone growth . for example , the device may be coated with hydroxyapatite , small molecules , or stem cells . the invention having been fully described , its construction and use is illustrated by the examples below . the scope of the invention , however , is not limited by the examples but is defined instead by the appended claims . the device must be constrained to the dimensions of the anatomy of human vertebrae in order to attain a beneficial interaction . thus , dimensions of an anchor assembly in accordance with the invention adapted for use in an average human l3 ( lumbar level 3 ) vertebrae are provided in figures illustrating each element of the anchor assembly . it will be appreciated that the dimensions illustrated are representative , and may be altered to accommodate variance in patient size , variance in level of the vertebra , and variance in pedicle screw size . 1 . surgeon inserts a 4 mm gear shift ( pedicle probe ) into pedicle and vertebral body to create a pilot hole . during this step , the surgeon assesses the quality of the patient &# 39 ; s bone . 2 . surgeon determines that the quality of the patient &# 39 ; s bone is poor . 3 . surgeon decides to augment the pedicle screw fixation by application of the device to reconstruct the strength of the pedicle . 4 . surgeon expands the pilot hole with a 6 mm gear shift . 6 . surgeon locks the device in proper orientation by attaching tool or tapping with mallet . 7 . surgeon inserts a pedicle screw into the device , causing the wings and , if present , flanges of the device to displace outward and improve the fixation strength of the pedicle screw . | US-201013505602-A |
a modular and customizable tie bar system comprises a tie bar base , one or more tie bar covers , and a fastener . the tie bar base cooperates with a user &# 39 ; s tie and comprises at least a mounting surface . each tie bar cover comprises a cover plate and optional side walls . each tie bar cover is preferably sized to cover and cooperate with the mounting surface of the tie bar base , has a decorative outer surface , and has an inner surface for facilitating attachment to the base . to facilitate removable attachment of the covers to the base , one or more fasteners such as magnets attach to the inner surface of the cover or to mounting surface of the base or to both . preferably , several covers with differing decorative outer surfaces cooperate with a single base to allow for interchangeability and customization depending on the user &# 39 ; s aesthetic preferences . | the present invention comprises a modular and customizable tie bar system 10 that comprises one or more interchangeable tie bar covers and a tie bar base . as shown in fig1 - 5b , a modular and customizable tie bar system 10 comprises a tie bar base 20 , one or more tie bar covers 30 , and a fastener 40 . preferably , the tie bar system 10 is a kit 12 comprising one tie bar base 20 and two or more tie bar covers 30 where the tie bar covers are interchangeable and removably attach to the tie bar base with the fastener 40 . more preferably , the kit 12 comprises three or more tie bar covers 30 and the covers vary in their external appearance or in the material from which they are made such that no two tie bar covers are identical , as shown in fig6 . the tie bar base 20 can be a pinch clasp , jaw - type clasp , split pin , r - pin , or any other type of clasp or slide that cooperates with a user &# 39 ; s tie and shirt . preferably , the tie bar base comprises a jaw or pinch clasp . more preferably , the tie bar base 20 comprises a gripping unit 22 pivotally attached to a first bar 24 with a pin 26 , hinge , or other fastener and an optional torsion spring 28 or other type of bias member . alternatively , the first bar 24 is integral with gripping unit 22 and comprises of a resilient material that allows for some flexibility , such as a split pin or r - pin design . the first bar 24 comprises a mounting surface 24 a and a bar extension 24 b , and the gripping unit 22 comprises one or more teeth 22 a and a finger grip extension 22 b . finger grip extension 22 b may optionally include ridges or indentations 22 c as shown in fig1 - 3 . first bar 24 further preferably defines at least one opening 24 c configured to cooperate with a pin 26 or other fastener . as shown in the figures , opposing openings 24 c are defined by bar extension 24 b . similarly , gripping unit 22 also defines one or more openings 22 d , that align with openings 24 c to cooperate with pin 26 or another fastener when pin 26 is inserted through the gripping unit openings 22 d and the bar openings 24 c , as shown in fig2 . pin 26 , which is sized to cooperate with bar openings 24 c and gripping unit openings comprises a simple pin or a spring pin and preferably includes a pin head at each end ( not separately labelled ) to prevent it from slipping out of the openings and is further preferably surrounded by a torsion spring 28 as shown in fig2 . optionally , the tie bar base 20 further comprises a torsion spring 28 or similar bias member or spring that is biased to position the finger grip extension 22 b in an up position and the teeth 22 a in a down or closed position . the spring 26 is further positioned and attached such that when a user pushes the finger grip extension 22 b to a down position , the teeth 22 a shift to an up or open position . when the teeth 22 a are in an up or open position , the tie bar can be moved or repositioned . when the teeth 22 a are in a down or closed position , the tie bar substantially grasps or secures material positioned between the tie bar base first bar 24 and the tie bar gripping unit 22 . each tie bar cover 30 comprises a cover plate 32 and optionally one or more side walls 34 . optional side walls can be integral with cover plate 32 or fixedly attached thereto . each tie bar cover 30 is preferably sized such that it substantially covers the tie bar base first bar 24 when attached to , positioned next to , or fastened to the plate . each cover plate 32 has an outer surface 32 a and an inner surface 32 b . the outer surface 32 a comprises decorative or additional functional elements while the inner surface 32 b cooperates with the fastener 40 and first bar 24 . fastener 40 preferably comprises one or more magnets 42 configured to magnetically cooperate with additional magnets 42 disposed on the tie bar base or to magnetically cooperate with the tie bar base directly . the magnets 42 are preferably attached to the tie bar cover 30 and optionally to the tie bar base 20 with adhesive . alternatively , they can be attached with snaps , hooks and loops , slots and inserts , wedges , or other fasteners , as is known in the art . preferably , magnets 42 are permanently fixed to either the tie bar cover inner surface 32 b , the tie bar first bar 24 , or both . where the tie bar first bar 24 is magnetic and the cover plate 32 is not magnetic , magnet 42 only needs to be attached to cover plate inner surface 32 b . where the cover plate 32 is magnetic and the tie bar first bar 24 is not magnetic , magnet 42 only needs to be attached to tie bar first bar 24 . where neither the cover plate 32 nor the tie bar first bar 24 are magnetic , cooperating magnets 42 should be attached to both the tie bar first bar 24 and the cover plate inner surface 32 b . fig1 - 5a illustrate an embodiment where only one magnet is needed . fig5 b illustrates an embodiment where cooperating magnets are needed . cover 30 as shown in the figures is substantially rectangular in shape with rounded edges . more particularly , cover 30 is shown with rounded edges where the outer surface of cover plate 32 transitions to walls 34 , which is the preferable configuration for cover 30 . alternatively , however , cover 30 may have sharp edges , may have less than four walls , may have no walls , may have an irregular perimeter , or may have an oval , circular , or other shape perimeter . for example , cover 30 may be rectangular , may be elliptical , or may have an overall shape that looks like an airplane or a race car . additionally , cover 30 may have a convex outer surface , a concave outer surface , or an irregular outer surface . cover 30 may also have additional components permanently affixed to it , integral with it , or removably attached to it . cover 30 may be a solid color , may have multiple colors , may have a smooth texture , may have a rough , soft , or other textures , and may include text , images , patterns , or other designs . cover 30 may be made from a variety of materials . additionally , it may be one element or may be several elements of varying materials or of like materials that are permanently attached or integrally formed . for example , cover 30 may be comprised of stainless steel , steel alloy , copper , environmental copper , other metals , wood , leather , suede , ceramic , plastic , semi - precious stone , silk - screen prints , enamel overlays , or any other similar material , coating , or combination of materials and coatings . for example , cover 30 may be comprised of stainless steel with a wood overlay , plastic with a suede overlay , plastic with wood embellishments , stainless steel with leather embellishments , environmental copper with a silk - screen print and enamel overlay or any other combination of materials . a kit 12 , for example , may include four covers where a first cover is a rectangular stainless steel cover , a second cover is a rectangular gold or gold - plated cover , a third cover is a rectangular metal cover with a leather overlay , and a fourth cover is a rectangular wood cover , as is generally shown in fig6 . the dimensions of the various components can vary depending on how small or large of a tie bar is desired . fig7 illustrates dimensions in inches for a preferred embodiment of tie bar system 10 , but is not intended to limit the scope of tie bar system 10 to these dimensions or to the specific dimensional relationships . for example , while tie bar system 10 is illustrated with a generally rectangular cover 30 that is 1 . 5 inches long and 0 . 25 inches wide , it can be further elongated or it can be shortened to more of a square shape . additionally , it can be circular or irregularly shaped as well . similar changes to the tie bar base 20 , fastener 40 , or other components are also within the scope of this invention . fig7 includes dimensions for the cover 30 , pin 26 , and gripping unit 22 as shown in section 100 , for the tie bar base 20 as shown in section 110 , and the magnet 42 as shown in section 120 . to use the tie bar system 10 individually or as a kit 12 , a user first selects a first cover that he wishes to use based on his selected outfit or his individual preferences . then , if necessary , the user removes a second cover from the tie bar base . once the tie bar base has no cover , the user then attaches the first cover to the base . after the cover has been attached , the user can then apply the tie bar to his tie and shirt as desired . if the tie bar system uses a clasp - type base as described in detail above , the user presses the finger extension to open the jaw or gripping unit , slides the tie bar base with cover attached into place on his outfit , and then releases the finger extension to close the jaw or gripping unit . to remove the tie bar base with cover attached from his outfit , the user again presses the finger extension to open the jaw or gripping unit , slides the tie bar base with cover attached off of his outfit , and then releases the finger extension to close the jaw or gripping unit . while there has been illustrated and described what is at present considered to be the preferred embodiment of the present invention , it will be understood by those skilled in the art that various changes and modifications may be made and equivalents may be substituted for elements thereof without departing from the true scope of the invention disclosed , but that the invention will include all embodiments falling within the scope of the claims . | US-201514796342-A |
in at least one embodiment , a method for diagnosing vascular disease is provided , the method comprising the steps of obtaining a vessel image showing a vasculature of a vessel , identifying at least two measurements from the vasculature of the vessel , the measurements relating to at least two parameters , calculating a relationship between the at least two parameters from the at least two measurements to generate one or more vasculature data points , and comparing the one or more vasculature data points to data relative to a model vasculature to determine the extent of vascular disease . in an another embodiment , a method for diagnosing vascular disease in a patient &# 39 ; s vascular tree is provided , the method comprising the steps of generating a model vascular tree from a minimum energy hypothesis calculation , and comparing the patient &# 39 ; s vascular tree with the model vascular tree to determine the extent of vascular disease . | the disclosure of the present application applies concepts from biomimetics and microfluidics to analyze vascular tree structure , thus improving the efficacy and accuracy of diagnostics involving vascular diseases such as dcad . scaling laws are developed in the form of equations that use the relationships between arterial volume , cross - sectional area , blood flow and the distal arterial length to quantify moderate levels of diffuse coronary artery disease . for the purposes of promoting an understanding of the principles of the present disclosure , reference will now be made to the embodiments illustrated in the drawings , and specific language will be used to describe the same . it will nevertheless be understood that no limitation of the scope of the present disclosure is thereby intended . biomimetics ( also known as bionics , biognosis , biomimicry , or bionical creativity engineering ) is defined as the application of methods and systems found in nature to the study and design of engineering systems and modern technology . the mimic of technology from nature is based on the premise that evolutionary pressure forces natural systems to become highly optimized and efficient . some examples include ( 1 ) the development of dirt - and water - repellent paint from the observation that the surface of the lotus flower plant is practically unsticky , ( 2 ) hulls of boats imitating the thick skin of dolphins , and ( 3 ) sonar , radar , and medical ultrasound imaging imitating the echolocation of bats . microfluidics is the study of the behavior , control and manipulation of microliter and nanoliter volumes of fluids . it is a multidisciplinary field comprising physics , chemistry , engineering and biotechnology , with practical applications to the design of systems in which such small volumes of fluids may be used . microfluidics is used in the development of dna chips , micro - propulsion , micro - thermal technologies , and lab - on - a - chip technology . regarding the minimum energy hypothesis , the architecture ( or manifolds ) of the transport network is essential for transport of material in microfluid channels for various chips . the issue is how to design new devices , and more particularly , how to fabricate microfluidic channels that provide a minimum cost of operation . nature has developed optimal channels ( or transport systems ) that utilize minimum energy for transport of fluids . the utility of nature &# 39 ; s design of transport systems in engineering applications is an important area of biomimetics . biological trees ( for example , vascular trees ) are either used to conduct fluids such as blood , air , bile or urine . energy expenditure is required for the conduction of fluid through a tree structure because of frictional losses . the frictional losses are reduced when the vessel branches have larger diameters . this comes with a cost , however , for the metabolic construction and maintenance of the larger volume of the structure . the question is what physical or physiological factors dictate the design of vascular trees . the answer is that the design of vascular trees obeys the “ minimum energy hypothesis ”, i . e ., the cost of construction and operation of the vascular system appears to be optimized . the disclosure of the present application is based on a set of scaling laws determined from a developed minimum energy hypothesis . equation # 1 ( the “ volume - length relation ”) demonstrates a relationship between vessel volume , the volume of the entire crown , vessel length , and the cumulative vessel length of the crown : in equation # 1 , v represents the vessel volume , v max the volume of the entire crown , l represents the vessel length , l max represents the cumulative vessel length of the entire crown , and ε ′ represents the crown flow resistance , which is equal to the ratio of metabolic to viscous power dissipation . equation # 2 ( the “ diameter - length relation ”) demonstrates a relationship between vessel diameter , the diameter of the most proximal stem , vessel length , and the cumulative vessel length of the crown : in equation # 2 , d represents the vessel diameter , d max represents the diameter of the most proximal stem , l represents the vessel length , l max represents the cumulative vessel length of the entire crown , and ε ′ represents the crown flow resistance , which is equal to the ratio of metabolic to viscous power dissipation . equation # 3 ( the “ flow rate - diameter relation ”) demonstrates a relationship between the flow rate of a stem , the flow rate of the most proximal stem , vessel diameter , and the diameter of the most proximal stem : in equation # 3 , q represents flow rate of a stem , q max represents the flow rate of the most proximal stem , v represents vessel diameter , v max represents the diameter of the most proximal stem , and ε ′ represents the crown flow resistance , which is equal to the ratio of metabolic to viscous power dissipation . regarding the aforementioned equations , a vessel segment is referred to as a “ stem ,” and the entire tree distal to the stem is referred as a “ crown .” the aforementioned parameters relate to the crown flow resistance and is equal to the ratio of maximum metabolic - to - viscous power dissipation . two additional relations were found for the vascular trees . equation # 4 ( the “ resistance - length and volume relation ”) demonstrates a relationship between the crown resistance , the resistance of the entire tree , vessel length , the cumulative vessel length of the crown , vessel volume , and the volume of the entire crown : in equation # 4 , r , represents the crown resistance , r max represents the resistance of the entire tree , l represents vessel length , l max represents the cumulative vessel length of the entire crown , v represents vessel volume , v max represents the volume of the entire crown , and ε ′ represents the crown flow resistance , which is equal to the ratio of metabolic to viscous power dissipation . resistance , as referenced herein , is defined as the ratio of pressure differenced between inlet and outlet of the vessel . equation # 5 ( the “ flow rate - length relation ”) demonstrates a relationship between the flow rate of a stem , the flow rate of the most proximal stem , vessel length , the cumulative vessel length of the entire crown : in equation # 5 , q represents flow rate of a stem , q max represents the flow rate of the most proximal stem , l represents vessel length , and l max represents the cumulative vessel length of the entire crown . in at least one embodiment of the disclosure of the present application , the application of one or more of the aforementioned equations to acquired vessel data may be useful diagnose and / or aid in the diagnosis of disease . by way of example , the application of one or more of the aforementioned equations are useful to diagnose dcad . for such a diagnosis , the applications of equations # 1 -# 3 may provide the “ signatures ” of normal vascular trees and impart a rationale for diagnosis of disease processes . the self - similar nature of these laws implies that the analysis can be carried out on a partial tree as obtained from an angiogram , a computed tomography ( ct ) scan , or an magnetic resonance imaging ( mri ). hence , the application of these equations to the obtained images may serve for diagnosis of vascular disease that affect the lumen dimension , volume , length ( vascularity ) or perfusion ( flow rate ). additionally , the fabrication of the microfluidic channels can be governed by equations # 1 -# 5 to yield a system that requires minimum energy of construction and operation . hence , energy requirements will be at a minimum to transport the required microfluidics . in one exemplary embodiment , the application of the volume - length relation ( equation # 1 ) to actual obtained images is considered as shown in fig1 . first , images ( angiograms in this example ) of swine coronary arteries were obtained . the application of equation # 1 on various volumes and lengths from the angiograms resulted in the individual data points shown within fig1 ( on a logarithmic scale ). the line depicted within fig1 represents the mean of the data points ( the best fit ) among the identified data points . in fig2 , the mean of the data ( solid line ) is compared to an animal with diffuse disease at three different vessel sizes : proximal ( 1 ), middle ( 2 ), and distal ( 3 ). the reductions in volume shown on fig2 correspond to approximately 40 % stenosis , which is typically undetectable with current methodologies . at each diffuse stenosis , the length remains constant but the diameter ( cross - sectional , and hence , volume ) changes . the length is unlikely to change unless the flow becomes limiting ( more than approximately 80 % stenosis ) and the vascular system experiences vessel loss ( rarefication ) and remodeling . it is clear that a 40 % stenosis deviates significantly from the y - axis ( as determined by statistical tests ) from the normal vasculature , and as such , 40 % stenosis can be diagnosed by the system and method of the disclosure of the present application . it can be appreciated that the disclosure of the present application can predict inefficiencies as low as about 10 %, compared to well - trained clinicians who can only predict inefficiencies at about 60 % at best . this exemplary statistical test compares the deviation of disease to normality relative to the variation within normality . the location of the deviation along the x - axis corresponds to the size of the vessel . the vessel dimensions range as proximal & gt ; mid & gt ; distal . hence , by utilizing the system and method of the disclosure of the present application , the diagnosis of the extent of disease and the dimension of the vessel branch is now possible . similar embodiments with other scaling relations as described herein can be applied similarly to model and actual vascular data . the techniques disclosed herein have tremendous application in a large number of technologies . for example , a software program or hardware device may be developed to diagnose the percentage of inefficiency ( hence , occlusion ) in a circulatory vessel or system . regarding the computer - assisted determination of such diagnoses , an exemplary system of the disclosure of the present application is provided . referring now to fig3 , there is shown a diagrammatic view of an embodiment of diagnostic system 300 of the present disclosure . in the embodiment shown in fig3 , diagnostic system 300 comprises user system 302 . in this exemplary embodiment , user system 302 comprises processor 304 and one or more storage media 306 . processor 304 operates upon data obtained by or contained within user system 302 . storage medium 306 may contain database 308 , whereby database 308 is capable of storing and retrieving data . storage media 306 may contain a program ( including , but not limited to , database 308 ), the program operable by processor 304 to perform a series of steps regarding data relative of vessel measurements as described in further detail herein . any number of storage media 306 may be used with diagnostic system 300 of the present disclosure , including , but not limited to , one or more of random access memory , read only memory , eproms , hard disk drives , floppy disk drives , optical disk drives , cartridge media , and smart cards , for example . as related to user system 302 , storage media 306 may operate by storing data relative of vessel measurements for access by a user and / or for storing computer instructions . processor 304 may also operate upon data stored within database 308 . regardless of the embodiment of diagnostic system 300 referenced herein and / or contemplated to be within the scope of the present disclosure , each user system 302 may be of various configurations well known in the art . by way of example , user system 302 , as shown in fig3 , comprises keyboard 310 , monitor 312 , and printer 314 . processor 304 may further operate to manage input and output from keyboard 310 , monitor 312 , and printer 314 . keyboard 310 is an exemplary input device , operating as a means for a user to input information to user system 302 . monitor 312 operates as a visual display means to display the data relative of vessel measurements and related information to a user using a user system 302 . printer 314 operates as a means to display data relative of vessel measurements and related information . other input and output devices , such as a keypad , a computer mouse , a fingerprint reader , a pointing device , a microphone , and one or more loudspeakers are contemplated to be within the scope of the present disclosure . it can be appreciated that processor 304 , keyboard 310 , monitor 312 , printer 314 and other input and output devices referenced herein may be components of one or more user systems 302 of the present disclosure . it can be appreciated that diagnostic system 300 may further comprise one or more server systems 316 in bidirectional communication with user system 302 , either by direct communication ( shown by the single line connection on fig3 ), or through a network 318 ( shown by the double line connections on fig3 ) by one of several configurations known in the art . such server systems 316 may comprise one or more of the features of a user system 302 as described herein , including , but not limited to , processor 304 , storage media 306 , database 308 , keyboard 310 , monitor 312 , and printer 314 , as shown in the embodiment of diagnostic system 300 shown in fig3 . such server systems 316 may allow bidirectional communication with one or more user systems 302 to allow user system 302 to access data relative of vessel measurements and related information from the server systems 316 . it can be appreciated that a user system 302 and / or a server system 316 referenced herein may be generally referred to as a “ computer .” the disclosure of the present application also relates to the design and fabrication of micro - fluidic chambers for use in research and development , thereby designing a chamber that maximizes flow conditions while minimizing the amount of material needed to construct the chamber . many other uses are also possible and within the scope of the disclosure of the present application . the foregoing disclosure of the exemplary embodiments of the present application has been presented for purposes of illustration and description and can be further modified within the scope and spirit of this disclosure . it is not intended to be exhaustive or to limit the present disclosure to the precise forms disclosed . this application is therefore intended to cover any variations , uses , or adaptations of a device , system and method of the present application using its general principles . further , this application is intended to cover such departures from the present disclosure as may come within known or customary practice in the art to which this system of the present application pertains . many variations and modifications of the embodiments described herein will be apparent to one of ordinary skill in the art in light of the above disclosure . the scope of the present disclosure is to be defined only by the claims appended hereto , and by their equivalents . further , in describing representative embodiments of the present disclosure , the specification may have presented the method and / or process of the present disclosure as a particular sequence of steps . however , to the extent that the method or process does not rely on the particular order of steps set forth herein , the method or process should not be limited to the particular sequence of steps described . as one of ordinary skill in the art would appreciate , other sequences of steps may be possible . therefore , the particular order of the steps set forth in the specification should not be construed as limitations on the claims . in addition , the claims directed to the method and / or process of the present disclosure should not be limited to the performance of their steps in the order written , and one skilled in the art can readily appreciate that the sequences may be varied and still remain within the spirit and scope of the present disclosure . | US-52235008-A |
the present invention pertains to a portable apparatus that is placed into a covered outdoor grill that facilitates cooking food by indirect heat . the outdoor grill has a charcoal , electric , or gas heat source which provides the direct heat that is transformed into an indirect heat by a raised cooking grill with a heat shield that is selectively locatable between the food and the heat source . | the apparatus of this invention is referred to generally in fig1 - 5 by the reference number 10 and is intended to provide an indirect heat cooking apparatus 10 for outdoor grill 32 cooking . it should be understood that the indirect heat cooking apparatus 10 may be used to cook many different types of foodstuffs . fig1 is a perspective view of the indirect heat cooking apparatus 10 and includes , in the preferred embodiment , four support legs 12 connected to two cross members 13 . the cooking grill 16 consists of two side retaining members 14 , a plurality of transverse rods 17 which are arranged in parallel and the ends of which are fixed to the side retaining members 14 in regularly spaced intervals . a handle 18 consists of two short parallel rods 19 each perpendicularly connected to a single rod 21 at a first end 11 thereof . the handle 18 is rotatably fastened to the cooking grill 16 by forming the opposite ends 23 of the short parallel rods 19 into small loops 25 and attaching the rods 19 to the outer most parallel rod 17 of the cooking grill 16 . a storage hook 20 consists of a small rod 205 and is rigidly connected at one end 210 thereof to an approximate center point of one cross member 13 . fig2 is a cross - sectional view of the indirect heat cooking apparatus 10 , but further illustrates a heat shield receptacle 22 and a heat shield 24 . the heat shield receptacle 22 consists of a flat bottom wall 29 with vertically inclined side walls 27 extending upwards from the bottom wall 29 . the heat shield 24 is contained in the heat shield receptacle 22 , the bottom wall 29 constituting the heat shield 24 when the heat shield receptacle 22 does not contain a liquid such as water , or the like . the handles 18 can rotate for convenient carrying . fig3 is a perspective view of an alternate embodiment of the indirect heat cooking apparatus 10 and includes , in its preferred embodiment , four support legs 12 connected to two cross members 13 . a heat shield rack 26 comprises two rods 31 perpendicularly connected to the support legs 12 with a plurality of parallel members 33 approximately equally - spaced and connected at each end thereof to the rods 31 . fig4 is a cross - sectional view of the alternate embodiment of the invention , but further including the heat shield receptacle 22 and the heat shield 24 . fig5 is a perspective view of an outdoor grill 32 , a lid 28 thereof , and a cooking grid 30 thereof . the outdoor grill 32 in fig5 is only one example of the various types of outdoor grills available to which the indirect heat cooking apparatus 10 of the invention may be employed . therefore , the outdoor grill 32 is only described generally herein . referring to fig5 , the outdoor grill 32 has a general box shaped configuration that is common to many outdoor grills of the prior art . although the indirect heat cooking apparatus 10 of the invention is described herein as being used with a box - shaped outdoor grill 32 , it should be understood that the indirect heat cooking apparatus 10 of the invention can be modified for its use in outdoor grills of other shapes , for example outdoor grills that have circular or rounded configurations . the source of heat may be burning fuel such as gas , electricity , charcoal , or briquettes . for illustrative proposes , the source of heat in fig5 is gas . referring to fig1 , the heat resistant support legs 12 provide a stable base to the elevated cooking grill 16 which can be used with varying types of a heat shields 24 . the heat resistant cross members 13 are rigidly connected to the support legs 12 , such as by welding , and provide stability to the support legs 12 . the length of the plural support legs 12 determines the overall height of the cooking grill 16 . the heat resistant cooking grill 16 provides an area for food to be placed for cooking . the cooking grill 16 , which is generally perpendicular to the support legs 12 , is at an adequate height that allows the lid 28 of the outdoor grill 32 to close without coming into contact with the indirect heat cooking apparatus 10 or the selected food ( not shown ). the overall width and length of the cooking grill 16 can accommodate a large amount of food , while insuring that the lid 28 of the outdoor grill 32 can be closed without coming into contact with the indirect heat cooking apparatus 10 or the selected food . this indirect heat cooking apparatus 10 can be used in an outdoor grill 32 that uses charcoal bricks , briquettes , electricity or gas as a heat source . referring to fig2 , the plural , rotatable , heat resistant handles 18 are linked at opposite sides of the cooking grill 16 and rotate up vertically for transporting the apparatus and rotate down naturally by gravity to the sides of the indirect heat cooking apparatus 10 when not being carried . to limit the rotated downward movement of the handle 18 the length of the single rod 21 extends to , and rest upon at least one support leg 12 . to limit the lateral movement of the handle 18 , the ends 23 of the short parallel rods 19 are attached to the cooking grill 16 outer - most traverse rods 17 and as close as possible to the support legs 12 without limiting up and down rotation of the handle 18 . the heat resistant storage hook 20 is located in the approximate center of a cross member 13 and is upwardly angled . the storage hook 20 is used for hanging the indirect heat cooking apparatus 10 for storage when not in use . the distance between the bottom of the cooking grill 16 and the top of the cooking grid 30 allows a heat shield receptacle 22 thereunder , while ensuring that the lid 28 of the outdoor grill 32 can be closed without coming into contact with the indirect heat cooking apparatus 10 or the selected food . the distance between the cooking grill 16 and the heat shield 24 can be varied and depends upon the selected length of each support leg 12 . the heat shield receptacle 22 is a vessel for containing a liquid or solid heat shield 24 while also catching any liquids produced in the cooking process . the heat shield receptacle 22 can be made of various heat resistant materials such as , but not limited to , aluminum or metal . the heat shield receptacle 22 is removable , leak proof , sized to fit under the cooking grill 16 . a heat shield 24 can be comprised of , but not limited to , water and flavor enhancing liquids . the heat resistant heat shield 24 can be composed of various solid materials such as , but not limited to , fire clay , refractory ceramic , or sand . the removable heat shield 24 is used for creating a heat barrier between the cooking heat and the food . referring to fig3 and 4 , the heat resistant heat shield rack 26 provides a platform for a raised heat shield 24 . in such an embodiment , the distance between the bottom of the cooking grill 16 and the top of the heat shield rack 26 allows enough height for the heat shield receptacle 22 . the distance between the bottom of the heat shield rack 26 and the top of the cooking grid 30 also allows the heat shield receptacle 22 . the overall height of such an embodiment is such as to ensure that the lid 28 to the outdoor grill 32 can be closed without coming into contact with the indirect heat cooking apparatus 10 or the selected food . the distance between the cooking grill 16 and the heat shield 24 can be varied by selecting the length of the support legs 12 . referring to fig5 , the indirect heat cooking apparatus 10 is housed in the cooking chamber of the outdoor grill 32 . the plural support legs 12 are placed directly upon the cooking grid 30 of an outdoor grill 32 . the plural cross members 13 are placed directly upon the cooking grid 30 of an outdoor grill 32 . the area where the support legs 12 and the cross members 13 are rigidly connected provides an adequate width to insure that the indirect heat cooking apparatus 10 , and the support legs 12 thereof , do not slip between the cooking grid members 30 of the outdoor grill 32 . the length of the storage hook 20 is relatively short so as not to interfere with the heat shield 24 container when it is slid under the cooking grill 16 and on the cooking grid 30 of outdoor grill 32 . the heat shield 24 is manually inserted into the heat shield 24 container . the handle 18 is rotatably fastened to the cooking grill 16 . referring to fig2 , the distance between the top of the cooking grill 16 and a heat shield 24 can vary , depending on the length of the support legs 12 . an ideal distance between the top surface of the cooking grill 16 and the top surface of the cooking grate is between one inch to seven inches . different textures on the food can be obtained by using different heat shield 24 materials at different heights of support legs 12 . fig2 shows a heat shield 24 container that can be placed directly below the cooking grill 16 . while using a liquid heat shield 24 , the food is subjected to a humidifying effect . with a liquid heat shield 24 in close proximity to the food , the heat source slowly cooks the surface of the food on the cooking grill 16 and gradually bakes or cooks by convection the opposite surface of the food . the food &# 39 ; s outer surface will have a moist texture , compared to that of when using a solid heat shield 24 . a moist texture is desirable for certain foods such as but not limited to boneless chicken . due to evaporation , the liquid heat shield 24 may need to be replenished periodically to retain the heat shielding properties . liquid drippings produced in the cooking process will fall directly into and mix with the liquid heat shield 24 and can be easily disposed of . with the heat shield 24 container placed directly upon the cooking grid 30 of the outdoor grill 32 , and while using a solid heat shield 24 , the food is subjected to a dry heat . with a solid heat shield 24 in such close proximity to the food , the heat source slowly cooks the surface of the food on the cooking grill 16 and gradually bakes or cooks by convection the opposite surface of the food . the food &# 39 ; s outer surface will have a hard crust texture , compared to using a liquid heat shield 24 . a hard crust texture is desirable for certain foods such as tri - tip . liquid drippings produced in the cooking process will fall directly into the heat shield 24 receptacle . liquid drippings produced in the cooking process can penetrate solid heat shield 24 materials such as fire clay or sand , causing the loss of the heat shielding properties over time . by encapsulating a solid heat shield 24 within a foil pouch ( not shown ), for example , such as large size “ hot bags ” manufactured by reynolds , a business of alcoa inc . of richmond , va ., the heat shield 24 can be protected from the drippings and be used multiple times . the heat shield 24 can also be encapsulated by forming an envelope of aluminum foil . the vertically inclined side walls 27 of the heat shield receptacle 22 extend above the heat shield 24 , enough to provide an adequate space for the heat shield 24 and a protective liner ( not shown ). by placing a disposable protective liner such as aluminum foil over the encapsulated solid heat shield 24 the drippings can be easily disposed of and the heat shield 24 and the heat shield receptacle 22 come into minimal contact with the drippings . with the embodiment shown in fig4 , the heat shield receptacle 22 may be placed in a raised position upon the heat shield rack 26 . while using a liquid heat shield 24 in this position the food is subjected to a humidifying effect . with a liquid heat shield 24 in such close proximity to the food , the heat source slowly cooks the surface of the food on the cooking grill 16 and gradually bakes or cooks by convection the opposite surface of the food . the food &# 39 ; s outer surface will have a very moist texture , compared to using a liquid heat shield 24 at a lower level . a very moist texture is desirable for certain foods such as but not limited to fish . alternately , the heat shield receptacle 22 can be placed directly upon the cooking grid 30 of the outdoor grill 32 , that is , in the lower position . while using a liquid heat shield 24 in this position the food is subjected to less of a humidifying effect , compared to when the liquid heat shield 24 is in the raised position . the heat source cooks the surface of the food on the cooking grill 16 at a faster rate compared to when the liquid heat shield 24 is in the raised position , and bakes or cooks by convection the opposite surface of the food . the food &# 39 ; s outer surface will have a moist texture . a moist texture is desirable for certain foods such as but not limited to ribs . with the heat shield 24 in the lower position , the liquid evaporates at a faster rate . due to evaporation , the liquid heat shield 24 may need to be replenished periodically to retain the heat shielding properties . liquid drippings produced in the cooking process fall directly into and mix with the liquid heat shield 24 and can be easily disposed of . with the heat shield receptacle 22 placed in the raised position upon the heat shield rack 26 , and while using a solid heat shield 24 in this position , the foodstuffs are subjected to a dry heat . with a solid heat shield 24 in such close proximity to the food , the heat source slowly cooks the surface of the food on the cooking grill 16 and gradually bakes or cooks by convection the opposite surface of the food . the food &# 39 ; s outer surface will have a hard crust texture , compared to using a liquid heat shield 24 . a hard crust texture is desirable for certain foods such as whole chicken or sausages . the heat shield receptacle 22 may also be placed directly upon the cooking grid 30 of the outdoor grill 32 . while using a solid heat shield 24 in this position the foodstuffs are subjected to less of a heat barrier , compared to when the solid heat shield 24 is in the raised position . as such , the heat source cooks the surface of the food on the cooking grill 16 at a faster rate and bakes or cooks by convection the opposite surface of the food . liquid drippings produced in the cooking process fall directly into the heat shield 24 receptacle 22 . thus , the alternate embodiment of the invention allows more subtle cooking texture options that can be imparted upon selected foods . it is feasible , as well , to use a solid heat shield 24 without utilizing a heat shield receptacle 22 . the indirect heat cooking apparatus 10 shown in fig1 & amp ; 3 are just one example of the various shapes available to which the indirect heat cooking apparatus 10 of the invention may be employed . additional shapes of an indirect heat cooking apparatus 10 which could be used are , but not limited to , square , round , oval and the like . to seal the juices in food before cooking , searing a hard crust onto the outer surface of food is sometimes desirable . searing is accomplished by subjecting the food to high direct heat . removing the heat shield receptacle 22 , adjusting the outdoor grill 32 to a high temperature , and placing the selected food directly upon the hot cooking grill 16 accomplishes this desired result . likewise , it is sometimes desirable to impart a hard crust texture on the outer surface after the food is cooked . removing the heat shield receptacle 22 , adjusting the temperature of the outdoor grill 32 to a high temperature , and flipping the food achieves this objective . cleaning the indirect heat cooking apparatus 10 is possible by removing the heat shield receptacle 22 , adjusting the outdoor grill 32 to a high temperature and using a cleaning implement such as a wire brush or a scraper to remove any cooking residues from past use . cooking with direct heat on a raised cooking grill 16 is sometimes desirable . direct heat cooking is accomplished by removing the heat shield receptacle 22 , adjusting the outdoor grill 32 to the desired temperature , placing food on the cooking grill 16 , and flipping food until the desired result is achieved . the lid 28 of the outdoor grill 32 can be up or down . it is possible to use the indirect heat cooking apparatus 10 as a portable cooking grill 16 . cooking with direct heat outside of the cooking chamber , on a raised cooking grill 16 is sometimes desirable . a method is to place a heat source such as charcoal , briquettes of wood upon the ground or in a container , position the indirect heat cooking apparatus 10 over the heat source and cooking the food accordingly . indirect heat cooking temperatures are usually low . the lower the temperature , the longer the cooking duration . a method to keep the temperature of the cooking chamber very low would be to adjust a single burner to the lowest setting . with a heat shield 24 between the heat source and the food , it is possible to increase the temperature which speeds up the cooking duration without overcooking or burning the food . since other modifications and changes can be imparted to the invention to fit particular operating requirements and environments , as will be apparent to those skilled in the art , the invention is not considered limited to the example chosen for purposes of disclosure . it should be understood that the invention covers all changes and modifications which do not constitute departures from the true spirit and scope of this invention . having thus described the invention , what is desired to be protected by letters patent is presented in the subsequently appended claims . | US-30800606-A |
a ski boot binding for snowboards includes a base to which a back piece is pivotally mounted . the back piece extends upward from the base and supports the user &# 39 ; s ankle . the degree to which the back piece flexes affects an amount of support which it provides to the user &# 39 ; s ankle . a reinforcement is mounted on a central part of a rear face of the back piece . the reinforcement is adjustably mounted for vertical movement relative to the back piece to adjust the flexibility of the back piece , hence the amount of rearward ankle support . | a snowboard is shown with two bindings 2 a , 2 b , also called mountings for keeping on the upper surface the two boots of the user . the two bindings are mounted on the upper surface across the snowboard with their plane of symmetry p disposed on the bias relative to an axis xx ′ along the board as is shown in fig1 . below is described the ski boot bindings 2 a , 2 b , that are designated under the common reference number 2 . [ 0038 ] fig1 is a side lateral view showing the binding 2 according to the invention that includes a base plate 4 that gives support extending horizontally from a front end 5 to a back end 6 at which a back piece 10 is mounted on the base plate . the base plate 4 limits lateral displacement to each side by lateral sides 7 a , 7 b , including a left lateral side 7 a and a right lateral side 7 b . each of the sides is advantageously made up by a vertical wall designed to retain the boot against lateral movement and to support retention means 16 , 17 . the two lateral sides are connected by an arcuate back 8 . it is to be understood that at the rear , a back piece 10 is found , which back piece extends toward the top ha and is pivotally disposed on the lateral sides 7 a , 7 b on a transverse axis 9 . the ski boot 11 of the user has a relatively supple ankle support section 12 that extends upward from the bottom part 13 which extends from a front end 14 to a rear end 15 where a heel disposed toward the rear ar against the arcuate back 8 . the ski boot 11 according to the illustrated embodiment , is retained on the base plate 4 by a front retention mechanism 16 which holds the front of the ski boot and by a rear retention mechanism 17 which holds the ski boot at the top of the foot . the front holding mechanism 16 and the rear holding mechanism 17 preferably include an adjustment means for adapting their dimensions to the size of the ski boot . of course , all other means of retention for the ski boot are also contemplated , others than those with flexible adjustable straps like , for example , without straps and notably of the type of automatic mounting and demounting mechanism known as “ step in ” such as are illustrated schematically in fig2 and like , for example , those described in prior published french patent no . 2 , 742 , 997 . it will be noted that the rear piece 10 is designed to serve as a support piece at the back of the ankle support section 12 of the boot . to this end , the rear support piece 10 extends towards the top ha for holding the back 18 of the ankle section 12 . the back piece 10 is advantageously formed with a central part 19 extending laterally between two lateral or horizontal parts 20 a , 20 b , one a left horizontal part 20 a and one a right horizontal part 20 b . the back piece 10 is articulated or pivoted relative to the base by lower ends 200 a , 200 b of each of the lateral sides 20 a , 20 b of the rear support piece 10 that is understood each of these has a hole 100 which receives , for example , a rivet 21 for attachment and pivoting . the rear piece 10 pivots relative to the base plate in a forward direction r 1 and can , in the absence of a boot , be , for example , pivoted completely flat for transport . of course , it is important for the back ankle support piece to pivot on the base , but pivoting on the base by any other means of articulation is also contemplated like , for example , a resilient , deformable binding . according to another characteristic of the invention , the ankle support includes on its central wall part 19 a reinforcement 22 which extends from the bottom to the top and conversely . it will be understood that by reinforcing the whole piece , the rigidity is improved and the resistance to the ankle support pieces deflecting rearward , insures the user of better ankle support while snowboarding while allows the user better control of his trajectory . the reinforcement 22 is , according to the invention , adjustable in vertical position relative to the ankle support piece . for this purpose , the aforementioned reinforcement is an independent , separate part from the ankle support 10 and is fixed in place by a means for adjusting and locking its vertical position . this means permits the user to adjust the vertical position of the reinforcement to a selected position relative to the ankle support piece 10 and to lock it in the selected position . the locking and adjusting means includes at least a nut and screw or bolt system 23 , 24 designed to lock the reinforcement 22 on the ankle support piece 10 and at least one oblong hole or adjusting window 25 a , 25 b which permits the reinforcement to be moved vertically relative to the ankle support . additionally , the framework of the invention includes other locking means such as , for example , those which do not require tools and in particular , a cam system or the like . thus , the ankle support piece 10 includes a vertical plane of symmetry p , the two windows 25 a , 25 b being disposed one above the other while the vertical reinforcement 22 includes two holes 26 a , 26 b disposed one above the other . each of the holes 26 a , 26 b is designed to hold a screw or bolt 23 while each of the windows 25 a , 25 b is designed to hold a nut 24 that includes a flange or collet 26 to prevent rotation . the reinforcement is a piece made out of plastic whose length l 1 is longer than its width l 2 while the length l 1 is at least as high as half of the height l 3 of the central wall part 19 of the ankle support piece 10 which is disposed near the back of the boot . the invention &# 39 ; s binding , in addition , includes a means to guide the vertical displacement of the reinforcement 22 relative to the ankle support piece 11 . to this end , the ankle support piece 10 includes along the back of its central wall part 19 , a rectangular vertical guide projection 27 . while the reinforcement 22 includes a corresponding groove 29 which extends vertically and is designed to receive the aforementioned guidance projection . thus , the reinforcement can be moved vertically by a vertical sliding motion along the guide track . a means of indexing the position of the reinforcement includes a succession of cooperating teeth or detents . thus , on the lower part of the guide track of the ankle support piece 10 are disposed a succession of teeth or detents designed to cooperate with the corresponding teeth 31 arranged at the bottom of the groove 29 of the reinforcement 22 . in addition , the exterior cross - section of the reinforcement 22 can take various forms and can be constant or changing in form or dimension . according to one preferred embodiment which is illustrated most clearly in fig4 , 11 , 12 , 13 , and 14 , the cross - section of the reinforcement varies by gradually decreasing in width l 2 and thickness l 4 toward the top . in addition , the reinforcement section 22 is advantageously trapezoidal in shape . according to another preferred embodiment , the reinforcement 22 is curved and the center of curvature of the curve extends along an inner face int . of course , the reinforcement can have a rectangular or square section , even cylindrical . the dimensions can be constant or variable like those illustrated respectively in fig1 , 16 , 17 , 18 , 19 , and 20 . according to an alternate embodiment of fig1 and 15 a , the shape of the reinforcement is square . according to an alternate embodiment of fig1 and 16 a , the shape of the reinforcement is rectangular . according to an alternate embodiment of fig1 and 17 a , the shape of the reinforcement is semi - cylindrical . according to another alternate embodiment of fig1 and 18 a , the shape of the reinforcement is square and its dimensions are progressively smaller toward the top . according to an alternate embodiment of fig1 and 19 a , the shape of the reinforcement is rectangular and the dimensions are progressively smaller toward the top . according to the alternate embodiment of fig2 and 20 a , the cross - section of the reinforcement is semi - circular and the dimensions get progressively smaller toward the top . in addition , a general plane of symmetry p 1 of the reinforcement can be in the general plane of symmetry p of the ankle support piece 10 such as shown in fig1 - 20 . but , it can be different such as the alternative shown in fig2 . according to this alternative embodiment , the general symmetry plane p 1 of the reinforcement converges with the general symmetry plane p of the ankle support which can diverge toward the top and towards an inside face int of the boot . it is to be understood that due to the possibility of sliding motion of the reinforcement on the ankle support and the locking means , it is possible to readjust the reinforcement against the ankle support piece 10 either toward the top f 1 or toward the bottom f 2 to allow the user to adapt the stiffness of his needed ankle support . in addition , the lower end 32 of the reinforcement defines a stop designed to rest against and be supported by an upper edge 33 of the rear arch 8 . this stop system is designed to pivot towards the back of the ankle support which allows the user to have good rearward flexibility of the ankle support portion 12 of the boot . the position of the reinforcement being adjustable , the user can modify the angular position of his ankle support piece . the reinforcement 22 can be of an identical or different material than that of the ankle support piece . [ 0065 ] fig2 and 23 show another alternate embodiment in which the reinforcement is a small rail of composite material in an adjustable vertical position . it can be fixed to the ankle support by its ends while the remainder of its length can slide . [ 0066 ] fig2 shows another means for attachment to the ski boot of a type in which the binding for the ski boot on the base 4 is not achieved by straps 16 , 17 as described before , but a central device 160 like , for example , that described in prior french patent no . 2 , 742 , 997 . thus , the back binding piece 10 is mounted on its own base 4 ′ different from the base 4 of the ski boot binding . of course , the invention is not limited to the embodiments described and shown by way of example , but also includes all of the equivalent technologies and combinations thereof . having thus described the preferred embodiment , the invention is now claimed to be : | US-97245501-A |
a cochlear implant or other auditory prosthesis utilizes an external portion worn on a recipient &# 39 ; s head and an internal portion implanted therein . both portions include an associated coil that transmits a signal between the two portions . the external coil has a form factor substantially similar to the implantable coil . this form factor allows the external portion to be manufactured with a smaller footprint , since components that may otherwise interfere with signal transmission may be installed closer to the external coil . | while the technologies disclosed herein have particular application in the cochlear implant devices depicted in fig1 , it will be appreciated that the systems , methods , and apparatuses disclosed can be employed in other types of hearing prostheses . for example , the embodiments disclosed herein can be used to power active transcutaneous bone conduction devices , passive transcutaneous devices , or other devices that include an external coil and an internal or implantable coil . furthermore , the embodiments disclosed herein can be utilized to transmit signals to medical devices other than hearing prostheses . the technologies disclosed herein will be described generally in the context of external portions of medical devices where the external portions utilize a coil for transmission of data or other signals . such signals can also include signals sent by a charging coil that charges a totally - implantable cochlear implant or other medical device . for clarity , however , the technology will be described in the context of cochlear implant auditory prostheses and , more specifically , the external portions and coils used therewith . fig1 is a perspective view of an auditory prosthesis 100 , in this case , a cochlear implant , including an implantable portion 102 and an external portion 104 . the implantable portion 102 of the cochlear implant includes a stimulating assembly 106 implanted in a body ( specifically , proximate and within the cochlea 108 ) to deliver electrical stimulation signals to the auditory nerve cells , thereby bypassing absent or defective hair cells . the electrodes 110 of the stimulating assembly 106 differentially activate auditory neurons that normally encode differential pitches of sound . this stimulating assembly 106 enables the brain to perceive a hearing sensation resembling the natural hearing sensation normally delivered to the auditory nerve . the external portion 104 includes a speech processor that detects external sound and converts the detected sound into a coded signal 112 through a suitable speech processing strategy . the coded signal 112 is sent to the implanted stimulating assembly 106 via a transcutaneous link . the signal 112 is sent from an external coil 114 located on the external portion 104 to an implantable coil 116 on the implantable portion 102 , via a radio frequency ( rf ) link . the signal 112 can be data , power , audio , or other types of signals , or combinations thereof . these coils 114 , 116 are typically both circular in shape to maximize the coupling of magnetic flux . the efficiency of power transfer and integrity of the data transmission from one coil to the other is affected by the coil coupling coefficient ( k ). coil coupling coefficient k is a unitless value that indicates the amount of the shared magnetic flux between a first coil and a second , coupled ( associated ) coil . as the amount of shared magnetic flux decreases ( i . e ., as the coil coupling coefficient k decreases ), efficient power transfer between the two coils becomes increasingly difficult . therefore it is advantageous to maximize the coil coupling coefficient k in a system where power and / or data are transferred between two coils . the stimulating assembly 106 processes the coded signal 112 to generate a series of stimulation sequences which are then applied directly to the auditory nerve via the electrodes 110 positioned within the cochlea 108 . the external portion 104 also includes a battery and a status indicator 118 . permanent magnets 120 , 122 are located on the implantable portion 102 and the external portion 104 , respectively . in the depicted device , the external portion includes a microphone port 124 connected to a microphone that receives sound . the microphone is connected to one or more internal processors that process and convert the sound into stimulation signals that are sent to the implantable portion 102 . fig2 - 3 are perspective views of an external portion 200 of an auditory prosthesis and are described simultaneously . the external portion 200 includes a body 202 and an external coil 204 connected thereto . the body 202 can include a permanent magnet 206 as described above . the external portion 200 can include an indicator 208 such as a light emitting diode ( led ). a battery door 210 ( depicted removed in fig3 ) covers a receptacle 212 that includes a battery 214 that provides internal power to the various components of the external portion 200 and the implantable portion . the battery 214 is matingly received in the receptacle 212 . a microphone 216 receives sound that is processed by components within the external portion 200 . as can be seen , the battery 214 is installed proximate the coil 204 , generally above the coil 204 itself . it is desirable that auditory prostheses maintain a high coil quality factor ( q ). coil quality factor q is a unitless value that indicates the how much energy is lost relative to the energy stored in the resonant circuit that includes the coil . a higher coil quality factor q indicates a lower rate of energy loss relative to the stored energy of the resonant circuit . coil quality factor q can be calculated for an ideal series rlc circuit as depicted in equation i : here , l is the measured inductance of the coil , r is the measured resistance of the coil , and ω 0 = 2 × pi × frequency . as the coil quality factor q decreases , it becomes increasingly difficult to transfer power efficiently from one coil to an associated coil . therefore , it is advantageous to maximize the coil quality factor q in a system where power is transferred between two coils . a high coil quality factor q is desirable , even while the electronics and batteries are in close proximity to the coil , as depicted in fig2 and 3 . placing metallic components , e . g ., a battery 214 , above the coil 204 , as depicted in fig2 and 3 , has an adverse effect on coil q , but does keep to a minimum the effective length l cb of the coil / battery arrangement which is directly related to the size of the external portion 200 . in fig3 , the effective length lcb is limited to the outer diameter of the coil 204 . a reduced coil q , however , results in a lower efficiency rf link , which ultimately results in a shorter battery life . to address this in the configuration depicted in fig2 and 3 , a shielding material such as ferrite may be disposed between the battery 214 and coil 204 . this can help alleviate the adverse effect on coil q , but adds weight and size to the device , which is also undesirable , since the external portion 200 is worn on the head of a recipient . fig4 a - 4b depict schematic views of external portions 300 of auditory prostheses . in fig4 a , the external portion 300 a includes an external coil 302 a and , in this case , two batteries 304 a . in contrast to the device of fig2 and 3 , the external portion 300 a of fig4 a is arranged such that the batteries 304 a are disposed next to the coil 302 a , where a center 308 a of the coil 302 a is a distance da from a center 310 a of the battery 304 a . this configuration results in an increase in coil q as compared to the device of fig2 and 3 , but also a significant increase in the effective length la of the coil / battery arrangement . in testing , it has been discovered that the depicted arrangement has a coil q of about 89 . 3 when the coil is made to resonate at about 5 mhz . thus , in equation i , l = 5 . 288 μh , r = 1 . 86 ohms , and frequency = 5 mhz . this coil also has a coupling coefficient k to a second coil of about k = 0 . 25 when the two coils are separated by about 3 . 0 mm . however , as apparent from fig4 a , this configuration ultimately increases the total footprint of a housing 306 a of the external portion 300 a , which is undesirable . in fig4 b , the batteries 304 b are arranged so as to only partially overlap the coil 302 b , where a center 308 b of the coil 302 b is a distance db from a center 310 b of the battery 304 b . here , the distance db is less than the distance da of the device depicted in fig4 a . this shorter distance db decreases the effective length lb of the coil / battery arrangement ( relative to the effective length la of fig4 a ) and thus the housing 306 b size . however , due to the proximity of the batteries 304 b and the coil 302 b , the drop in coil q is significant and undesirable . in testing , it has been discovered that the depicted arrangement has a coil q of about 36 . 4 when the coil is made to resonate at about 5 mhz . thus , in equation i , l = 5 . 1 μh , r = 4 . 4 ohms , and frequency = 5 mhz . the coupling coefficient k is largely unchanged in this configuration because the size , shape , and relative position of the two coils has not changed . fig5 a - 5b depict schematic views of external portions 400 c , 400 d of auditory prostheses in accordance with embodiments of the present disclosure . in fig5 a , the external portion 400 c includes an external coil 402 c and two batteries 404 c . the centers 408 c , 410 c , respectively , are a distance dc from each other . notably , this distance dc is the same as the distance db depicted in fig4 b , above . in this embodiment , however , the batteries 404 c do not overlap the coil 402 c . instead , the outer perimeter of the coil 402 c has been modified to decrease the total perimeter length as compared to the coils 302 a , 302 b depicted above , by including a curved ( in this case , substantially circular ) portion 412 c and a substantially linear portion 414 c . coil 402 c has a truncated circle shape . this modification from the round coils 302 a , 302 b depicted above enables the effective length lc of the coil / battery arrangement to be substantially the same as the effective length lb , which results in a similarly - sized housing 406 c . it has been discovered that , by eliminating overlap between the coil 402 c and batteries 404 c , coil q is substantially increased in comparison to the arrangement of fig4 b . in testing , the depicted embodiment of external device 400 c has a coil q of about 74 . 6 when the coil is made to resonate at about 5 mhz . thus , in equation i , l = 5 . 268 μh , r = 2 . 22 ohms , and frequency = 5 mhz . this increase in coil q is in excess of 200 %, or double that the coil of fig4 b . a coil with the shape of 402 c has a slightly smaller coupling coefficient k than a round coil . in testing , it has been discovered that the depicted arrangement has a coupling coefficient to a second coil of about k = 0 . 24 when the two coils are separated by about 3 . 0 mm . by utilizing a truncated circular coil shape as depicted in fig5 a , instead of a round coil as depicted in fig4 b , coil quality factor q has more than doubled , while but the coil coupling coefficient k has only reduced by about 4 % ( from about 0 . 25 to about 0 . 24 ). the resulting power transfer efficiency increase is a significant benefit of the coil shape 402 c . in fig5 b , the external portion 400 d includes a coil 402 d and two batteries 404 d . the centers 408 d , 410 d , respectively , are a distance dd from each other . notably , this distance dd is the same as the distance db depicted in fig4 b , above . in this embodiment , the outer perimeter of the coil 402 d also has been modified to decrease the total perimeter length , by including a curved ( in this case , substantially circular ) portion 412 d and two substantially linear portions 414 d . this modification enables the effective length ld of the coil / battery arrangement to be substantially the same as the effective length lb , which results in a similarly - sized housing 406 d . it has been discovered that , by eliminating overlap between the coil 402 d and batteries 404 d , coil q is substantially increased in comparison to the arrangement of fig4 b . coil q is anticipated to be similar to that of the prosthesis 400 c . in the external portions 400 c , 400 d , a shielding material such as ferrite may be disposed between the batteries and coil to further increase q , although , as described above , this may increase weight of the external portion 400 c , 400 d . fig6 a - 6b depict a top view and a side sectional view , respectively , of a bobbin 500 utilized in embodiments of the present disclosure , and are described together . the bobbin 500 is used as a base about which to wind a wire 510 to form an external coil 512 to be utilized in an auditory prosthesis . the bobbin 500 includes a base plate 502 with a ring 504 extending therefrom . a second plate 506 is disposed parallel to the base plate 502 so as to form a channel 508 at least partially defined therebetween . the channel 508 is configured so as to receive the wire 510 that is wound about the ring 504 , in a particular arrangement , so as to form the coil 512 . in the depicted embodiment , the wire 510 is a 40 strand , 46 awg wire having a diameter of about 420 μm , and is wound ten times to form the coil 512 . wires having other diameters or sizes can be utilized to form a coil , which can have greater than or fewer than ten turns . in certain embodiments , the shape of the bobbin 500 and the coil 512 contained therein , can be defined by the geometric structure thereof . the depicted bobbin 500 ( and therefore , the coil 512 ) has a shape of a truncated circle 501 . in other embodiments , the bobbin can be a d - shape . in the depicted embodiment , the diameter d represents an interior diameter of the bobbin 500 and , therefore , the interior diameter of the coil 512 . the diameter d ( or radius r ) defines a curved portion 512 of the truncated circle shape of the perimeter . in the depicted embodiment , the curved portion 512 is called the primary arc portion and has a primary arc length s 1 . the truncated circle 501 is also defined by a substantially straight portion 514 or a chord . the substantially straight portion 514 can connect to the curved portion 512 at a curved or sharp interface 520 , although a curved interface can be more desirable to reduce or prevent damage , stress , or kinks to the coil 512 . in the depicted embodiment , the chord 514 is a distance r t from a line parallel to the substantially straight portion 514 that also intersects the center c of the truncated circle 501 . the substantially straight portion 514 has a chord length c l . the truncated circle 501 can also be defined by the absent circular segment 516 partially defined by the substantially straight portion 514 and a secondary arc portion length s 2 . a center point of the secondary arc portion 518 is a distance r s from the substantially straight portion 514 . the radius of the curved portion 512 of the truncated circle can be defined as equation ii : in certain embodiments , the primary arc portion length s 1 can be about 70 % to about 90 % of the total length of the perimeter , which is the sum of the primary arc portion length s 1 and the chord length c l . in other embodiments , the primary arc portion length s 1 is about 75 % of the total length of the perimeter . the truncated circle and the circular segment 516 define areas bound by , respectively , the primary arc portion 512 and chord 514 , and the secondary arc portion 518 and chord 514 . in embodiments , the area of the circular segment 516 can be between about 5 % and about 25 % of the area of a complete circle ( which includes the area of the truncated circle 501 and the circular segment 516 ). in other embodiments , the area of the circular segment 516 is about 10 % of the area of the complete circle . fig7 depicts an auditory prosthesis 100 , including an implantable portion 102 , an external control portion 104 , and an external modified portion 104 ′ in accordance with an embodiment of the present disclosure . the various elements depicted are described generally in fig1 , and thus generally are not described further . the implantable portion 102 includes an implantable coil 116 that , in this embodiment , has a generally circular base form factor . the implantable coil 116 has a radius r i and an area a i defined by the radius r i . the external control portion 104 includes an external control coil 114 . that also has a generally circular form factor . the external control coil 114 has a radius r c and an area a c defined by the radius r i . in certain embodiments , r c can be greater than r i to help ensure adequate data transmission from the external control coil 114 to the implantable coil 116 . fig7 also depicts an external modified portion 104 ′, which is an external portion of the auditory prosthesis 100 . the external modified portion 104 ′ includes the same components as the external control portion 104 , e . g ., a magnet 122 ′, an indicator 118 ′, and so on . the coil 114 ′, however is a modified coil , in that it has a modified base form factor substantially similar to the base form factor of the implantable coil 116 , and that has a radius r m and an area a m defined at least in part by the radius r m . the substantial similarity stems from the condition that the implantable coil 116 has a circular base form factor , while the modified base form factor of the modified external coil 114 ′ is a truncated circle . in certain embodiments , the radius r m of the modified external coil 114 ′ is larger than the radius r c of the control coil 114 . however , due to the truncated circle shape of the modified external coil 114 ′, the area a m of the modified external coil 114 ′ is less than the area a c of the external control coil 114 . in other embodiments , the radius r c of the external control coil 114 is substantially the same as the radius r m of the modified external coil 114 ′. fig8 depicts a comparison plot of coil coupling coefficient k between coils having different form factors . for the auditory prosthesis depicted in fig7 above , where an implantable coil is utilized with an external control coil or a modified external coil , the coil coupling coefficient k can be measured between the implanted coil and either external coil ( i . e ., the control coil or the modified coil ). as can be seen from the plot , the coil coupling coefficient k between an implanted coil and a truncated circle coil is between about 92 % to about 96 % of the coil coupling coefficient k between an implanted coil and a full coil , at various implant distances . fig9 depicts a top view of another bobbin 600 utilized in embodiments of the present disclosure . as with the embodiment of fig7 , the bobbin 600 includes a base plate 602 with a ring 604 extending therefrom . a second plate ( not shown in this view ) is disposed parallel to the base plate 602 so as to form a channel 608 . the bobbin 600 is substantially oval in shape , and thus may be defined by a primary radius r p and a secondary radius r s . it has been discovered that bobbins ( and thus coils ) having a form factor such as an oval can also be utilized with an implanted coil having a circular form factor while still maintaining acceptable coil quality q and coil coupling k . additionally , the non - round coils described herein need not be formed by wrapping a wire about a bobbin . for example , a non - round coil may be formed by traces on a printed circuit board . this disclosure described some embodiments of the present technology with reference to the accompanying drawings , in which only some of the possible embodiments were shown . other aspects can , however , be embodied in many different forms and should not be construed as limited to the embodiments set forth herein . rather , these embodiments were provided so that this disclosure was thorough and complete and fully conveyed the scope of the possible embodiments to those skilled in the art . although specific embodiments were described herein , the scope of the technology is not limited to those specific embodiments . one skilled in the art will recognize other embodiments or improvements that are within the scope of the present technology . therefore , the specific structure , acts , or media are disclosed only as illustrative embodiments . the scope of the technology is defined by the following claims and any equivalents therein . | US-201414542286-A |
a pair of pointed , rearwardly toothed wedge members are pivotally mounted at their rear or blunt ends to spaced positions on a drive handle head , whereby they may be successively and alternatingly driven into a saw cut in a tree by pumping the handle . | fig1 - 3 illustrate a first embodiment of the wedge arrangement . the wedge arrangement 1 comprises a first upper wedge member 2 and a second lower wedge member 3 . the two wedge members 2 and 3 have mutually opposing abutment surfaces 4 and 5 respectively . the abutment surfaces are planar and smooth so that the two wedge member 2 , 3 are able to slide against each other with the least possible amount of friction and one or both of said wedge members may have arranged therein a channel which opens in the planar surface and through which grease or lubricating oil can be passed to the two mutually co - operating surfaces 4 and 5 . one such channel 6 is indicated in fig3 and extends from one side surface 7 of the wedge member 2 . the back , working surfaces of the two wedges 2 , 3 are provided with rearwardly extending teeth , for example teeth 8 , 9 , 10 and 11 which extend across the whole of the width of each wedge member , as shown in fig3 . alternatively , narrower teeth can be provided which lie in rows across the worksing surfaces of the wedge members . arranged on the rear end portions of each said wedge member remote from the wedge points 12 and 13 respectively of said members are two lugs , as will best be seen from fig3 in which figure the lugs 14 and 15 of the wedge member 2 are shown . fig1 illustrates one lug 16 of the lower wedge member 3 . extending through the lugs of respective wedge members are bearing holes 17 and 18 respectively , said holes being mutually aligned relative to one another . a lever 19 having holes 20 and 21 is journalled between the lugs on the two wedge members by means of shafts 22 and 23 . the shaft 22 extends through the holes 17 in the lugs 14 and 15 and through the hole 20 of the lever 19 . the shaft 23 passes through the hole 18 of the lugs , for example 16 , and through the hole 21 of the lever 19 . in the embodiment of fig1 the holes in the upper wedge member 2 are of oval shape so that when the wedge arrangement 1 is used the shaft 22 will not exert a separating force on the wedge members 2 , 3 . the holes 18 may also be elongate in a direction approximately perpendicularly to the surface 4 , 5 or provision may be made for relative movement between the wedge member and the attachment end of the lever in a direction towards and away from the surfaces 4 , 5 by elongating one or both holes in the end portion of the lever 19 . as will be seen from fig1 the points 12 , 13 of the wedge members are relatively thin so that the wedge arrangement can be inserted into a relatively narrow slot or the like between two surfaces 24 , 25 to be separated by means of said wedge arrangement , and the size of the teeth preferably increase from the point of respective wedge members towards the end portions thereof , as illustrated in fig1 and 3 . in the illustrated embodiments , angle members 26 and 27 are fixedly arranged , for example by means of screws , to respective side surfaces of the lower wedge member 3 , said angle members being intended to hold the two wedge members 2 and 3 together . each angle member is provided with an inwardly extending flange 28 and 29 respectively ( fig3 ) which engages a co - operating groove in the side surface of the upper wedge member 2 . in fig1 only one groove 30 is shown . when using the described wedge arrangement , the two wedge members 2 and 3 are inserted into the gap found between the bodies or surfaces 24 , 25 to be separated from each other , with the handle 19 occupying the position shown in fig1 . the wedge members are inserted so that the teeth on said members positively grip the surfaces . the handle 19 is thereupon moved upwardly as viewed in the figure , and the wedge member 3 is prevented from sliding out of engagement between the rearwardly extending teeth of the wedge member and the surface 25 . thus , the shaft 23 forms a pivot axis for the lever 19 and the shaft 22 forms a pushing member which urges the upper wedge member further into the space between the surfaces 24 and 25 . as a result of the wedge angle of the wedge member 2 , the surfaces 13 and 25 will be urged slightly apart . when the handle 19 is thereafter moved downwardly , the rearwardly directed teeth of the upper wedge member 2 will grip into the surface 24 and prevent the wedge member 2 from being withdrawn . thus , in this case the shaft 22 forms a pivot axis for the lever 19 and the shaft 23 forms a pushing member which forces the lower wedge member further into the space between the surfaces 22 and 25 and expands the space therebetween . this sequence of operation is repeated until the two wedge members 2 , 3 have been &# 34 ; pumped &# 34 ; sufficiently far into the slot to separate the surfaces 24 and 25 to the extent desired . in order for the teeth to penetrate into the surface 24 and 25 to the requisite extent , the teeth must be harder than the material of said surfaces . in certain instances the fact that the points 12 , 13 do not form any form of support for the two members 2 , 3 and thus do not contribute to preventing the wedge members from moving askew in the space between the surfaces 24 , 25 is a disadvantage . from this aspect the embodiment shown in fig4 - 6 is more suitable , since it permits the wedge members to swing away from each other . in fig4 - 6 the upper wedge member is referenced 31 . the wedge member 31 has two wedge fingers 33 and 34 projecting from a central wedge body and , as with the previously described embodiment , the upper working surface of the wedge member 31 is provided with rearwardly extending , edge - like teeth , for example teeth 35 and 36 . the end portion of the fingers 33 and 34 have an under abutment surface 37 , which is preferably provided with rearwardly extending teeth . the rear end of the wedge member 31 is provided with two lugs 38 and 39 respectively , which have lower bearing holes for fixedly receiving two mutually aligned , inwardly turned bearing pins 40 and 41 respectively . in this case the lever 19 is fork - shaped having two arms 42 and 43 . each of the arms 42 and 43 has a hole 44 and 45 respectively . the peg 40 is loosely mounted in the hole 44 , which has a larger diameter than the peg 40 . the peg 41 is loosely mounted in the hole 45 , which also has a larger diameter than the peg 41 . the lower wedge member 32 is a mirror image of the wedge member 31 and thus has a rear wedge body from which extend two wedge fingers 46 and 47 . the two fingers 46 and 47 are freely pivotable in the spaces between the fingers of the upper wedge member 31 . on its outwardly turned surface , the wedge member 32 is provided with rearwardly extending teeth or other gripping means comparable therewith , such as the teeth 48 and 49 and the inner surface of the point portion of said wedge member forms an abutment surface 50 which is preferably provided with rearwardly extending teeth . the outer end portion of the wedge member 32 has a central lug 51 having a through passing peg 52 projecting outwardly on both sides of said lug . the two free ends of the peg 52 are freely mounted in upper holes 53 and 54 in respective arms 42 , 43 of the fork lever 19 . the central bodies of the two wedge members 31 , 32 have planar mutually conforming surfaces 55 and 56 respectively , which enable the wedge members to be placed together so that the surface 50 lies against the surface 24 and the surface 37 lies against the surface 25 to form a guide into the space for the wedge arrangement . to maintain the two wedge members in a normal position with the points on the wedge fingers lying in a common plane , there may be provided a resilient element , for example a rubber ball 57 , in a groove 58 in the lower wedge member 32 . this rubber ball presses against the under surface of the wedge member 31 . for the purpose of guiding the wedge members 31 and 32 relative to one another there is provided a bolt 59 which is screwed into the lower wedge member 32 and the head of which is slidable arranged in a groove 60 in the upper wedge member 31 . when the lever 19 of the embodiment according to fig4 and 6 is moved downwardly subsequent to bringing the wedge members firmly between the surfaces 24 and 25 , the lower wedge member 32 will be firmly locked by its rearwardly extending teeth and the shaft 52 will form a fixed pivot point for the forked arms 42 , 43 of said lever . as the lever 19 is moved downwardly , the pegs 40 and 41 will urge the upper wedge member 31 forwardly and at the same time swing the pointed surface 37 of said wedge member into abutment with the surface 25 . when the lever is subsequently moved upwards , the upper wedge member 31 will be prevented from sliding upwardly and the pegs 40 , 41 form a fixed axis of rotation . the shaft 52 thus forms a means for inserting the lower wedge member 32 further into the gap , this wedge member being swung upwardly during its inward movement until the abutment surface 50 engages the surface 24 . this sequence of operation is repeated until the wedge arrangement has been &# 34 ; pumped &# 34 ; far enough in between the surfaces 24 and 25 for the surfaces to be separated to the intended amount . as will be readily understood , the manually operated handle by means of which the aforedescribed alternate insertion movement of the two wedge members is achieved , can be replaced by a drive means , comprising two hydraulic or pneumatic pistons which will move the wedge members alternately into the space between the surfaces to be separated , or by pistons that are operated with other means than air or hydraulic fluid . the aforedescribed wedge arrangement is operated by means of a head . when the head is pivoted by means of , for example , a lever , the wedge members are only lifted a small distance apart . in many cases , it has been found that the wedge members must be lifted further apart in order for , for example , a tree to be felled satisfactorily . fig7 illustrates a modified embodiment of the wedge arrangement in which the connection between the head and the two wedge members is such that in addition to permitting the wedge members to be driven in to a cleft between two surfaces to be separated enables the separation of said surfaces to be effected by means of the head , whereupon a tree can be felled more readily . the modified embodiment shown in fig7 comprises an upper wedge member 61 which comprises two parts and which is provided with teeth 62 arranged to grip one of the two surfaces to be separated , and a lower wedge member 63 having teeth 64 engaged to grip the other surface to be separated . the two surfaces to be separated from each other are not shown but , as will be understood , may be the opposing surfaces of a sawcut made in the trunk of a tree . the wedge member 61 is pivotally mounted on a head 65 by means of a shaft 66 , and the wedge member 63 is pivotally mounted on a shaft 67 which extends through two lugs on the head 65 , of which lugs only one , 68 , is shown . the head 65 is provided with a lever 69 . the wedge members 61 and 63 are shown in a lifted position , i . e . the end portions of respective wedge members have been lifted away from each other . the rear portions of the wedge members can be further parted by further rotating the head 65 anticlockwise until its shafts 66 and 67 lie on one line with each other , this line being substantially vertical . in this latter case , the lever 69 is brought to a position in which it is inclined more anticlockwise that its illustrated position in the figure . the angle which is generated by rotating the head 65 to the illustrated position is , however , sufficient to fell a tree into which the wedge arrangement has been driven . whilst the wedge members are being driven alternately into said cleft by pumping the lever 69 , the lever lies obliquely downwardly , the shaft 67 being located approximately in the position shown at 67 &# 39 ;. whilst pumping the handle , the shaft 67 is moved from the position 67 &# 39 ; alternatively with the shaft 66 in the direction of arrows a and b respectively . as soon as the wedge members have been driven in to the intended depth in the sawcut and are well locked therein , the handle 69 is swung counterclockwise to the position shown in the figure , whereupon the wedge members 61 and 63 , which were in close abutment with each other whilst being driven in the said cleft are moved to the position shown in the figure , i . e . the wedge angle is greatly increased to exert an additional wedge force causing the tree to fall . it is essential that the pivot connections 66 , 67 are so arranged on the head 65 that said head can adopt a first position with the wedge members close to each other to enable them to be driven into said cleft , and a second position in which the wedge members are moved apart to greatly increase the wedge angle . the fork - like wedge member 61 may be divided into two separate wedge sections on either side of the central wedge member 63 and each such separate wedge sextion is journalled on a lug 68 by means of a shaft 66 . it is also possible to change the bearing points so that the central wedge member 63 is journalled in the head 65 on the shaft 66 and the further wedge members or member , for example the wedge section 61 , is journalled on the shaft 67 . | US-84331077-A |
a backpack frame comprising a plurality of flexible support members wherein each of the plurality of flexible support members further comprise a top end and a bottom end , a pack further comprising a first tensioner attachment point and a second tensioner attachment point , and a plurality of tensioners wherein each of the plurality of tensioners further comprises a tension length . one of the plurality of tensioners is attached to the first tensioner attachment point and also attached to the second tensioner attachment point . one of the plurality of flexible support members extends substantially between the first tensioner attachment point and the second tensioner attachment point . the tension length of one of the plurality of tensioners is located between the first tensioner attachment point and the second tensioner attachment point . the tension length may be adjusted . | the present invention will now be described more fully hereinafter with reference to the accompanying drawings , in which preferred embodiments of the invention are shown . this invention may , however , be embodied in many different forms and should not be construed as limited to the embodiments set forth herein . rather , these embodiments are provided so that this disclosure will be thorough and complete , and will fully convey the scope of the invention to those skilled in the art . those of ordinary skill in the art realize that the following descriptions of the embodiments of the present invention are illustrative and are not intended to be limiting in any way . other embodiments of the present invention will readily suggest themselves to such skilled persons having the benefit of this disclosure . like numbers refer to like elements throughout . in this detailed description of the present invention , a person skilled in the art should note that directional terms , such as “ above ,” “ below ,” “ upper ,” “ lower ,” and other like terms are used for the convenience of the reader in reference to the drawings . also , a person skilled in the art should notice this description may contain other terminology to convey position , orientation , and direction without departing from the principles of the present invention . referring to fig1 , a backpack frame 100 is shown . as depicted , there is a pair of flexible support members 101 . these flexible support members 101 may be constructed of a material that flexes . specifically , the flexible support members 101 may be constructed of a lightweight material that resiliently flexes when exposed to lateral stress . suitable materials for the flexible support members include , but are not limited to , carbon fiber , aluminum , wood , or the like . in one embodiment of the inventive concept , the flexible support members 101 may be constructed from carbon fiber rods , blades , or the like . the flexible support members 101 may be solid or hollow . each flexible support member 101 may have a top end 102 and a bottom end 103 . the flexible support members 101 may remain rigid when exposed to forces that extend through the flexible support member 101 directly between the top end 102 and the bottom end 103 . the flexible support members 101 may flex or bow into an essentially arcuate shape when exposed to lateral forces that deflect the area of the flexible support member 101 disposed between the top end 102 and the bottom end 103 while applying force to bring the top end 102 and the bottom end 103 in closer proximity to one another . when these forces are removed , the flexible support member 101 may return to its original , essentially planar shape . each flexible support member 101 may be connected to a pack 104 by a top capture 105 and a bottom capture 106 . the top capture 105 or the bottom capture 106 may be a rivet , a snap , an adhesive , hooks and loops , a zipper , or any like fastener known to those skilled in the art . in one embodiment , the top capture 105 or bottom capture 106 may be constructed from fabric that is secured to the pack 104 on the left side and the right side of the flexible support member 101 and retains the flexible support member 101 against the pack 104 . the fabric may be constructed from cotton , nylon , polyester , polyethylene , or the like . in another embodiment , the top capture 105 or bottom capture 106 may be constructed from fabric that is secured to the pack 104 on the left side and the right side of the flexible support member 101 as well as above the top end 102 for a top capture 105 and below the bottom end 103 for a bottom capture 106 . fig2 a depicts one embodiment of a top capture 205 in which the flexible support member 201 is secured to the pack 204 by a piece of fabric 211 which is connected to the pack 204 by stitches 212 on either side of the flexible support member 201 . fig2 b depicts an embodiment of the top capture 205 in which the flexible support member 201 is secured to the pack 204 by a piece of fabric 211 which is connected to the pack 204 by stitches 212 on either side of the flexible support member 201 and also above the flexible support member 201 . the top capture 105 or bottom capture 106 may removably connect the flexible support member 101 to the pack . this may be achieved by connection methods including , but not limited to , hooks and loops , snaps , rivets , buttons , zippers , pockets , or the like . in the embodiment depicted in fig3 a and 3 b , the flexible support member 201 may be removed from or inserted into the pocket formed by the connection of the fabric 211 to the pack 204 . returning to fig1 , the pack 104 may be any backpack , duffel , purse , case , sack , or the like known in the art . in one embodiment of the inventive concept , the pack 104 may be a backpack with multiple pockets , straps , or other securing means for containing equipment . the backpack may have two shoulder straps that are worn across the wearer &# 39 ; s shoulders . each shoulder strap may connect to a low point and a high point on the backpack . the backpack may also have a waist strap that is secured to the wearer &# 39 ; s waist and distributes a significant amount of the weight of the backpack and contents to the wearer &# 39 ; s torso . a tensioner 108 may connect to two tensioner attachment points 107 . the tensioner 108 may be a rope - like structure constructed from a synthetic material that resists elongation when subject to tensile stress . suitable materials for the tensioner 108 may include , but are not limited to , polyester , nylon , polyethylene , cotton , or the like . materials with properties identical to or similar to brand name dyneema ® may be used to construct the tensioner 108 . the tensioner 108 may have a tension length that is measured as the length of tensioner 108 disposed between the two tensioner attachment points 107 to which the tensioner 108 is connected . a tensioner attachment point 107 may be disposed on the pack 104 . the tensioner attachment point 107 may be disposed in close proximity to each top end 102 and each bottom end 103 . the tensioner attachment point 107 may connect to the pack 104 at the same location as the top capture 105 or bottom capture 106 . two tensioner attachment points 107 may be disposed on the pack 104 for each flexible support member 101 that is present . the tensioner 108 may be connected to the pack 104 in such a way that adjusting the length of the tensioner 108 may exert stress on the flexible support member 101 and shortening the tensioner 108 may cause the flexible support member 101 to bow away from the pack wearer &# 39 ; s body . when the flexible support members 101 are bowed , they may support the weight of the pack 104 and its contents away from the wearer &# 39 ; s body . lateral force may be applied to the flexible support member 101 to deflect the midsection of the flexible support member 101 before the tensioner 108 may be shortened . the tensioner length may be adjusted to manipulate the shape of the flexible support member 101 across which the tensioner 108 is disposed . when the tensioner length is at maximum length , which is any length longer than the length of the flexible support member 101 across which the tensioner 108 is disposed , the flexible support member 101 may maintain a substantially planar shape . when the tensioner length is adjusted to activating length , which is any length shorter than the length of the flexible support member 101 across which the tensioner 108 is disposed , the flexible support member 101 may be subject to forces that draw the top end 102 and the bottom end 103 closer together and cause the flexible support member 101 to assume an arcuate shape . fig3 depicts the pack on a wearer &# 39 ; s back with the tensioners 108 at the activating length . the tensioner 108 may be connected to the tensioner attachment point 107 by threading the tensioner 108 through a first opening of an attachment apparatus and a second opening of an attachment apparatus . the tensioner 108 may pass through the first opening substantially 180 ° opposed to the direction at which it may pass through the second opening . the tensioner 108 may be secured in place by the attachment apparatus through friction , clamping , or the like . the tensioner length may be adjusted by pulling on either free end of the tensioner 108 . the force exerted by the attachment apparatus may be removed from the tensioner 108 to allow the tension length to increase . fig4 depicts one embodiment of the tensioner attachment point 407 in more detail . the tensioner 408 is connected to the tensioner attachment point through an attachment apparatus 413 . the free end 414 of the tensioner 408 may be pulled to shorten the tension length . the attachment apparatus 413 may be adjusted to lengthen the tension length . lateral stress may be applied to the flexible support member 401 to allow the flexible support member 401 to flex and provide the ability to shorten the tension length . fig4 depicts an embodiment of the tensioner attachment point 407 in proximity to the top capture 405 . embodiments of the tensioner attachment point 407 in proximity to the bottom capture may be identical or similar to that shown in fig4 . fig5 a depicts the tensioners 508 adjusted to the activating length . when the tensioners 508 are at the activating length , the tension length is shorter than the length of the portion flexible support member 501 that is disposed between the two tensioner attachment points 507 that connect the tensioner 508 to the pack . the tension length may be shortened by pulling on the free end 514 of the tensioner 508 . adjusting the tensioner 508 to the activating length , may cause the flexible support member 501 to bow away from the tensioner 508 . fig5 b depicts the tensioners 508 adjusted to the maximum length . when the tensioners 508 are at the maximum length , the tension length is longer than the length of the portion flexible support member 501 that is disposed between the two tensioner attachment points 507 that connect the tensioner to the pack . in one embodiment of the inventive backpack frame 100 , as depicted in fig1 , there may be two flexible support members 101 , two tensioners 108 , two top captures 105 , two bottom captures 105 , and four tensioner attachment points 107 . in such an embodiment , the tension length of each tensioner 108 may be adjusted independently . in some embodiments , the tension length of each tensioner 108 may be adjusted dependent on each other . in embodiments with two flexible support members 101 , they may be disposed substantially parallel to one another . the two flexible support members 101 may be substantially identical in length . the top captures 105 may be disposed at substantially the same height on the pack 104 and the bottom captures may be disposed at substantially the same height on the pack 104 . a cross - member 109 may extend between two or more flexible support members 101 . in embodiments utilizing a cross - member 109 , the cross - member 109 may connect substantially orthogonally to each flexible support member 101 . the cross - member 109 may be constructed from a material similar to that of the flexible support member 101 . however , it may not be necessary for the cross - member 109 to flex . the cross - member 109 may be resiliently flexible or rigid . in some embodiments of the inventive backpack frame 100 , a cross - member 109 may connect two flexible support members 101 at or near the top ends 102 while a second cross - member 109 may connect the two flexible support members 101 at or around their mid - points . the cross - member 109 may connect to the pack 104 and to the flexible support member 101 by attachment structures similar to the top capture 105 or bottom capture 106 . fig2 c depicts a cross - member capture 215 . in this embodiment of the cross - member capture 215 , the flexible support member 201 may be surrounded by the fabric 211 . alternatively the fabric 211 may extend over the flexible support member 201 and be secured to the pack 204 by stitching along the side of the flexible support member 201 that is opposed to the side of the flexible support member 201 that is adjacent to the cross - member 209 . the fabric 211 may be secured to the pack 204 with stitches 212 along either side of the cross - member 209 . a mesh structure 110 may extend substantially between two or more tensioners 108 . the mesh structure 110 may be substantially planar and provide a breathable surface to come into contact with a wearer &# 39 ; s back when the backpack is in use . the mesh structure 110 may extend less than the entire length of the tensioner 108 and may be less than the shortest possible activating length . the mesh structure 110 may be removably attached to the tensioners 108 . the mesh structure 110 may be an area of mesh , lightweight , or breathable fabric disposed between the tensioners 108 . the foregoing examples have been provided in the interest of clarity to illustrate an embodiment of the present invention in substantial detail . a person of skill in the art will appreciate that one or more of the above provided embodiments may be included in the use of the backpack frame of the present invention . additionally , a person of skill in the art will appreciate additional embodiments that would be included within the scope and spirit of the present invention , after having the benefit of this disclosure . furthermore , a skilled artisan will appreciate that the operations described above , along with additional operations that would be apparent to those in the art , may be performed exclusively , incrementally , sequentially , simultaneously , or any other operative configuration . many modifications and other embodiments of the invention will come to the mind of one skilled in the art having the benefit of the teachings presented in the foregoing descriptions and the associated drawings . therefore , it is understood that the invention is not to be limited to the specific embodiments disclosed , and that modifications and embodiments are intended to be included within the scope of the appended claims . | US-201313917724-A |
an adjustable deck - chair comprises a frame having two lateral frame portions interconnected by a cross - bar . a seat - back assembly is pivotably supported by the lateral portions of the frame and is movable between an upright position in which the back is substantially perpendicular to the seat and a reclined position in which the seat and the back enclose an angle approximating 180 °. the seat - back assembly is arrested in the upright position by a force exerted on the seat by a friction and detent member which is pivotably supported on the cross - bar and frictionally and wedgingly engages a portion of the seat frame . the lateral portions of the frame may be collapsible . | discussing now the drawing in detail , and firstly fig1 to 3 thereof , it will be seen that these figures give an overall view of a first embodiment of the deck - chair according to the invention . in this context , it is to be understood that while the invention is being described as applied in a deck - chair , it is not limited to this application but can be utilized in other kinds of reclining or convertible chairs , chaise longues or similar pieces of furniture or garden or pool accessories . the illustrated embodiment of the invention comprises a seat 1 and a back 2 which are pivotably connected to one another by a pivot or pin 3 so as to form a seat - back unit . the seat 1 and the back 2 can either be of unitary construction , such as plates of wood , plywood or synthetic plastic material or , as illustrated in the drawing , comprise a rigid supporting structure or frame and have a system of interwoven straps , a piece of cloth or felt connected to the supporting structure and spanning the space therebetween ; all these expedients are well known in the art and do not necessitate further elaboration . in the currently preferred embodiment of the invention , a cushion is placed on the seat - back assembly , this cushion being shown in dash - dotted lines . if so desired , this cushion can be attached to the supporting structure by conventional attachment means . the seat - back assembly 1 to 3 is pivotably supported on a frame which , in the embodiment illustrated in fig1 to 3 , comprises two lateral portions 5 which are rigidly connected to one another at least by means of a cross - bar 6 so that the two lateral portions 5 and the cross - bar 6 form a rigid frame . a pivot 4 connects the back 2 to the two lateral portions 5 of the frame . there may either be provided two pivots 4 , each of which pivotably connects the back 2 to one of the lateral portions 5 of the frame , or there may be provided only one pivot extending between the two lateral portions 5 and rigidly attached thereto , which expedient affords the frame increased stability . in the latter case , the back 2 is pivotably supported on the through pivot and is free to rotate with respect thereto . the seat 1 , in addition to being connected to the back 2 , is also supported on the cross - bar 6 in a manner which will be described later on when discussing the other figures ; for the present purposes it is sufficient to point out that the seat 1 is free to move in the forward and rearward direction of the deck - chair and to tilt within a limited range with respect to the cross - bar 6 . fig1 shows the deck - chair in its upright position , that is the position assumed when the occupant desires to use the deck - chair as a chair , while fig3 shows the same deck - chair in its reclined position , that is a position which it assumes when used as a cot , a bed or the like . the seat - back assembly 1 to 3 may be freely moved between these two positions by a simple expedient of shifting the center of gravity of the occupant or by his bracing his feet against the ground . when the seat - back assembly is to be moved from its upright into its reclined position , the center of gravity is shifted rearwardly , so that a force is applied to the back 2 forcing the same to move in the clockwise direction as shown in the drawings . as a result of this movement of the back 2 , the seat 1 is pushed in the forward direction -- in the drawings toward the left --, with simultaneous lifting of the rear end of the seat 1 . the seat - back assembly may be stopped in any desired position beyond the upright position , and will remain in this selected position as a result of friction as will be described later on . if the center of gravity is shifted again to a sufficient extent to overcome the friction , the seat - back assembly may be moved to any other desired position , including the upright and fully reclined positions . the lateral portions 5 of the frame of the currently preferred embodiment of the deck - chair as illustrated in fig1 to 3 are of tubular material which is bent so as to provide the desired profile . the lateral portions 5 may be provided with , and interconnected by , a conventional arm rest which is shown in dash - dotted lines . the deck - chair is provided with an adjusting and arresting mechanism which will now be described in detail with reference to fig4 to 14 which illustrate various embodiments of the mechanism . for the sake of clarity , the same or corresponding parts of the mechanism have been assigned the same reference numerals throughout . the adjusting and arresting mechanism includes a friction and detent member 7 which is freely rotatably supported on the cross - bar 6 and which may be made of natural or synthetic rubber or other natural or synthetic plastic material . what is important is that the material of the friction and detent member have pronounced frictional properties and be elastically yieldable to at least some extent . such materials are well known in the art . the friction and detent member 7 cooperates with a bracket 8 which is attached to the seat 1 by any suitable attachment means , such as screws , bolts , welding , soldering and so on , and possibly also with the structure of the seat 1 itself . the mode of cooperation will be discussed in connection with the various embodiments of the friction and detent mechanism ; it is only to be pointed out that in the embodiments illustrated in fig4 to 13 , the bracket 8 extends through a passage 71 provided in the friction and detent member 7 . the brackets 8 which are illustrated in fig1 , 4 and 6 to 14 are so configurated that the distance between the seat 1 and the bracket 8 increases in the rearward direction of the deck - chair , that is toward the right as shown in the drawings . in other words , the operative portion of the bracket 8 encloses an acute angle with the seat 1 , so that the distance between the corresponding portions of the seat 1 on one hand and the bracket 8 on the other hand increases in the rearward direction . thus , when the seat - back assembly is moved from its upright position toward the fully reclined position thereof , not only does the seat 1 move forwardly , but the portion thereof which is supported on the cross - bar 6 via the friction and detent member 7 and the bracket 8 is also lifted . this , of course , is in addition to the lifting of the rear end of the seat 1 which results from the circular motion of the pivots 3 about the pivot or pivots 4 . as a result of this expedient , the seat 1 is slightly inclined downwardly and rearwardly when the seat - back assembly is in its upright position , while , when the seat - back assembly assumes its fully reclined position , at least the seat 1 extends substantially horizontally . of course , in all these explanations , it is assumed that the deck - chair is situated on a level ground so that the lower portions of the lateral portions 5 of the frame ( fig1 to 3 ) and the cross - bar 6 extend substantially horizontally which , incidentally , is the suggested position in which the deck - chair is to be utilized . the advantage of this arrangement is that it affords the occupier a comfortable accommodation in both the upright and the fully reclined positions and also in any intermediate position . contrarily thereto , the embodiment illustrated in fig5 includes a bracket 8 whose operative portion extends in parallel to the seat 1 . if the same advantages as in the previous embodiments are to be achieved , the pivot 4 has to be located at substantially the same level as the cross - bar 6 . in this embodiment , the front portion of the seat 1 only slides with respect to the cross - bar 6 without being lifted with respect thereto , while the rear part is being lifted due to the fact that the pivot 3 conducts circular movement about the pivot 4 as the seat - back assembly is being moved towards the fully reclined position thereof . advantageously , in all of the above - mentioned embodiments , the seat - back assembly , when in its fully reclined position , assumes a horizontal plane , or at least substantially so . as already mentioned , the bracket 8 is accommodated in the passage 71 of the friction and detent member 7 . at least when the deck - chair is being occupied , there exists a frictional force between the bracket 8 and the surfaces delimiting the passage 71 of the friction and detent member 7 , the magnitude of the frictional force being directly proportional to the force with which the bracket 8 is pressed against the afore - mentioned surfaces of the member 7 . the frictional force is of such a magnitude as to prevent unintentional movement of the seat - back assembly , but also sufficiently small as to be easily overcome when the occupier purposely transfers his center of gravity with the intention to change the position of the seat - back assembly . as a result of this , the frictional force retains the seat - back assembly in any selected position until the occupier decides to change the position thereof . when the occupier of the deck - chair decides to leave the same , he has to move the center of gravity of his body forwardly , which results in an automatic movement of the seat - back assembly into the upright position , that is the seat 1 moves rearwardly and the back 2 in the counterclockwise direction . in order that , after the occupier has left the seat , the seat - back assembly does not assume any other than the upright position thereof , there are provided means for retention of the seat - back assembly in its upright position , which means will now be described with reference to the various embodiments of the adjusting and arresting mechanism as illustrated in the various figures . in the embodiments illustrated in fig4 and 5 , the brackets 8 are preferably made of flat steel strips , and they are provided with tongues 81 which are bent out of the plane of the operative portion of the bracket 8 , the operative portion in this and other embodiments being that portion which cooperates with the surfaces of the member 7 which define the passage 71 therein . the tongues 81 are preferably partially punched out of the strip - shaped bracket 8 and form a wedge . advantageously , the passage 71 has a corresponding wedge - shaped configuration . when the occupier is in the act of leaving the deck - chair and standing up , the center of gravity of his body moves in the forward direction which results in rearward movement of the seat 1 -- that is to the right in the drawings --, until the seat - back assembly assumes the upright position thereof . as a result of this movement , the tongues 81 of the brackets 8 enter the wedge - shaped passages 71 of the friction and detent member 7 , and the material of the member 7 and / or the tongues 71 are elastically deformed to such an extent that the bracket 8 is arrested in this position by friction between the surfaces thereof and the tongues 81 and the surfaces bounding the passage 71 of the member 7 . once the deck - chair is again occupied , this frictional force may be volitionally and intentionally overcome by transferring the center of gravity of the body of the occupier . it is evident that this retention of the seat - back assembly in the upright position thereof can also be obtained by other means . so , for instance , in the embodiment illustrated in fig6 a leaf spring 9 is connected to the friction and detent member 7 , whose free end has a substantially semiannular configuration . the bracket 8 is provided with a recess 82 , and when the seat - back assembly assumes its upright position , the free end of the leaf spring 9 enters the recess 82 and is retained therein , so that the seat - back assembly is prevented from leaving its upright position . fig7 shows a different embodiment of the adjusting and arresting mechanism , in which a separate tongue 10 is provided which is attached to the bracket 8 and is provided , at one of its ends , with a semi - annular projection . when the seat - back assembly is moved into its upright position , that is when the seat 1 and the bracket 8 move toward the right in the drawings , the projection of the tongue 10 enters the passage 71 and deforms the walls bounding this passage , thus arresting the seat - back assembly in its upright position . in the embodiment illustrated in fig8 the seat - back assembly is retained in its upright position in such a manner that a recess 82 is provided in the forward end portion of the bracket 8 , and that a biconvex rubber or synthetic plastic body 11 is accommodated in the recess 82 and attached to the bracket 8 . during the movement of the seat - back assembly into its upright position , the bracket 8 moves toward the right as seen in the drawing until the body 11 enters the passage 71 of the friction and detent member 7 and the bracket 8 and thus the seat - back assembly is arrested in this position due to the friction between the body 11 and the surfaces bounding the passage 71 of the member 7 . in the embodiment illustrated in fig9 the friction and detent member 7 is provided on its upper side with a recess 72 . in addition thereto , a ball - shaped pin 12 is mounted in a vertical bore provided in the seat 1 and biased in the downward direction as shown in the drawing . when the seat 1 is moved toward the right , that is into the upright position of the seat - back assembly , the pin 12 enters the recess 72 and prevents movement of the seat - back assembly out of its upright position until sufficient force is exerted on the seat 1 to overcome the resilient deformation of the member 7 and / or the biasing force acting upon the ball - shaped pin 12 . in the embodiment of fig1 , a flat , convexly configurated body 13 of rubber or synthetic plastic material is attached to the lower surface of the bracket 8 . here , the body 13 is located to the other side of the friction and detent member 7 than the bodies or tongues of the other embodiments . the dimensions of the body 13 are such as to permit passage of the body 13 through the passage 71 of the member 7 after overcoming the friction between the surfaces bounding the passage 71 of the member 7 and the surface of the body 13 . so , when the seat 1 and the associated bracket 8 are moved to the right due to the movement of the seat - back assembly into the upright position thereof , the body 13 enters into and passes through the passage 71 of the member 7 until it emerges on the other side thereof , that is it assumes the illustrated position . once this happens , the seat - back assembly can be displaced out of its upright position only by overcoming the friction force between the member 7 and the body 13 . according to the embodiment illustrated in fig1 , the friction and detent member 7 is provided on its upwardly directed side with a rib 73 , and a member 14 is attached to the lower side of the seat 1 and has a portion which contacts the rib 73 of the member 7 as the seat 1 moves to the right , that is in the direction of the upright position of the seat - back assembly , or vice versa . thus , when the seat 1 moves to right , shortly before the upright position of the seat - back assembly is reached , the projecting portion of the member 14 contacts the rib 73 and further movement is only possible when one or both of the projecting portions of the member 14 and rib 73 of the member 7 are deflected so as to permit the passage of the member 14 beyond the member 7 . once in this position , that is in the upright position of the seat - back assembly , a sufficient force is needed to again deflect one or both of the projecting portions of the members 14 and 7 , respectively . thus , the seat - back assembly is effectively arrested in its upright position . it is also possible , by appropriately shaping and dimensioning the projecting portions of the member 14 and 7 , as illustrated in fig1 to achieve a situation in which larger force is needed for overcoming the force of deflection when the seat 1 moves in one direction than in the opposite direction . a further embodiment of the adjusting and arresting mechanism according to the invention is shown in fig1 and 13 . the friction and detent member 7a of this embodiment is provided with two elastic projections 74 which are located mirror - symmetrically to the two sides of the member 7 . a projection 75 is provided in the passage 71 of the member 7 approximately midway of the two opposite sides of the member 7 . the bracket 8 of this embodiment is provided with a succession of holes 83 . when the deck - chair is unoccupied , the projections 74 force the bracket 8 upwardly , so that the projection 75 enters a selected one of the successive holes 83 corresponding to the instantaneous position of the seat - back assembly . however , once the seat is occupied , the weight of the occupant forces the seat 1 and thus the bracket 8 downwardly , so that the projection 75 emerges out of the respective hole 83 and the projections 74 are elastically deformed . thus , when the seat is occupied , the only force retarding or preventing the movement of the seat - back assembly is the friction force between the bracket 8 and the contacting surfaces bounding the passage 71 and of the projections 74 , any action of the projection 75 being discontinued . thus , the force which is necessary to bring about the movement of the seat - back assembly is always the same regardless of the instantaneous position of the seat - back assembly , while in the other embodiments a larger force is needed for bringing the seat - back assembly out of its upright position , while a smaller force is needed for moving the seat - back assembly between an intermediate and fully reclined position or between two intermediate positions . it is to be pointed out that , when the projection 75 and the respective hole 83 are perfectly aligned , the projection 75 enters the hole 83 immediately upon the occupant &# 39 ; s leaving the chair , while only a slight movement of the seat - back assembly is necessary for the projection 75 to enter the hole 83 when the projection 75 is not aligned with any of the holes 83 , due to the relatively small distance between any two adjacent holes 83 . this is further aided by the fact that the holes 83 may diverge in the upward direction of the bracket 8 . herein , fig1 shows the mechanism in the position it assumes when the deck - chair is occupied or when force is exerted on the seat 1 , while fig1 shows the same mechanism in its arresting position . it is evident that in this embodiment the seat - back assembly may be arrested in any desired position , not only in the upright position thereof . still another embodiment of the adjusting and arresting mechanism according to the invention is illustrated in fig1 . in this embodiment a simple upper roller 7b of rubber or elastic synthetic plastic material and a similar lower roller 7c are rotatably supported on the cross - bar 6 of the frame of the deck - chair , and serve as support rollers for the seat 1 , particularly for the seat supporting structure . a wave - shaped bracket 8b of flat steel strip material is connected to the seat 1 and is situated downwardly of the roller 7b and thus of the cross - bar 6 . in this manner , the cross - bar 6 and the roller 7b rotatably supported thereon are prevented from leaving the region defined by the seat 1 and the bracket 8b . the forward -- in the drawing the left -- portion of the bracket 8b extends in parallelism with the seat 1 and has a distance therefrom which is smaller than the diameter of the roller 7b . when the seat and the bracket are moved to the right in the drawing , that is in the rearward direction of the deck - chair -- which movement ensues when the seat - back assembly is moved into its upright position , the roller 7b enters the relatively narrow gap between the bracket 8b and the seat 1 , whose dimension is smaller than the outer diameter of the roller 7b , so that the roller 7b is deformed causing a marked increase in the frictional force between the roller 7b and the surfaces of the elements 8b and 1 bounding the gap . thus , the seat - back assembly is securely retained in its upward position until sufficient force is exerted upon the same to overcome this frictional force . moreover , the wave - shaped configuration of the bracket 8b cooperating with the rollers 7b and 7c renders possible to hold the seat - back assembly in a plurality of intermediate positions , should this be necessary or desired . it is to be understood that while only one adjusting and arresting mechanism has been described , it will be advantageous to arrange one such mechanism to each side of the deck - chair , that is in its region adjacent to the lateral portions 5 of the frame . this expedient provides for a better distribution of forces and stresses and improves the overall stability and operation of the deck - chair . the aforementioned adjusting and arresting mechanism is also suitable for utilization in other types of chairs . so , for instance , fig1 and 16 show a different deck - chair in which the mechanism can find useful application . the deck - chair according to this embodiment of the invention is collapsible , that is it may be folded if so desired in order to reduce the amount of space taken up by the deck - chair for the purposes of storage , transportation or the like . the lateral portions of the frame of this deck - chair consist of two sections 15 and 16 each or , alternatively , as shown in the drawings , the two corresponding sections 15 , preferably of tubular cross - section , and the two corresponding sections 16 are connected by , or made in one piece with , transverse bars so that each of the sections 15 and 16 , respectively , has an approximately u - shaped configuration . the sections 15 and 16 are pivotably interconnected by a through pin or two separate pins 17 to each side of the deck - chair . preferably , the sections 15 and 16 are curved . a connecting section 18 is pivotably connected to the section 16 by the pivot 4 which also pivotably connects the seat - back assembly to the section 16 . a cushion -- shown in dash - dotted lines -- may be provided on and attached to the seat - back assembly 1 to 3 , and similarly represented arm rest may be attached to the connecting section 18 in any conventional manner . the connecting section 18 is so configurated that , when the deck - chair is in its position illustrated in fig1 , that is in the assembled position , the free end of the connecting portion bluntly abuts the free end of the section 15 . preferably , these bluntly abutting ends of the sections 15 and 18 are rigidly but dismountably interconnected by means of a spreading device . a spreading device which is particularly suitable for the present purpose is illustrated in fig1 and 18 , and comprises two spreading elements 19 and 20 of substantially semi - cylindrical configuration , which may be of metallic or synthetic plastic material . an internal thread 21 is provided in the spreading element 19 centrally thereof , and is adapted for accepting a screw 22 which is accessible from the exterior of the deck - chair . preferably , the head 22a of the screw 22 is provided with a hexagonal recess 22b for accepting a tightening tool . the bluntly abutting ends of the sections 15 and 18 are provided with semi - circular cutouts 23 and 24 for permitting unobstructed passage of the stem of the screw 22 therethrough . when the deck - chair is to be assembled , it is merely necessary to insert the spreading elements 19 and 20 into the tubular end portions of the sections 15 and 18 in such a manner that the head 22a of the screw 22 is accommodated in the cutouts 23 and 24 . subsequently thereto , the screw 22 is tightened , that is rotated in such a sense that the free end of the screw 22 abuts against the element 20 and thus spreads the elements 19 and 20 apart until sufficient friction force is achieved between the outer surfaces of the spreading elements 19 and 20 and the inner surfaces of the tubular end portions of the sections 15 and 18 to prevent unintentional dislodging of the spreading device or disassembly of the connection formed thereby . the advantage of this particular connecting arrangement is that when the deck - chair is assembled , only the relatively small heads 22a of the screws 22 are visible and accessible from the outside of the deck - chair , so that the appearance of the latter is not impaired . when the deck - chair is to be folded , that is when it is to be brought into the position illustrated in fig1 , it is only necessary to slightly loosen the screws 22 so as to eliminate the friction between the spreading elements 19 and 20 and the end portions of the sections 15 and 18 , whereupon the sections 15 and 18 are taken apart and the deck - chair folded so that the space requirement for storing and / or transporting the deck - chair is significantly reduced . it is to be understood that in all other respects the deck - chair according to the second embodiment thereof is similar to the first embodiment of the deck - chair , including the possibility to move the seat - back assembly between the upright and the reclined positions thereof and to arrest the same in the former position . the deck - chair of the present invention is particularly suitable for campoing purposes because of the wide range of application thereof . it is to be noted that this deck - chair can be easily adapted to serve as a cot or foldable bed by the simple expedient of providing conventional means for arresting the seat - back assembly in its fully reclined position . it will be understood that each of the elments described above , or two or more together , may also find a useful application in other types of furniture or garden equipment differing from the types described above . while the invention has been illustrated and described as embodied in a deck - chair , 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 . 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 . | US-43505674-A |
a sandal comprises a sole and a strap connected to the sole for securing the sandal to the foot the sole includes a cleat attachment hole for fixing a cleat on a bottom surface thereof . the sole includes a middle sole and a covering sole disposed on a lower surface of the middle sole . the coveting sole includes a window for exposing a portion of the middle sole , and at least two cleat attachment holes are disposed in the window for fixing a cleat to a bottom surface of the sole so that the cleat does not extend below the lowermost surface of the sole . | fig1 is a fight side view of a particular embodiment of a sandal according to the present invention . fig2 is a top view of the sandal , and fig3 is a bottom view of the sandal . a left sandal is shown in the figures , but the right sandal is merely a mirror image of the left sandal so a separate description of the right sandal will be omitted . as shown in fig1 - 3 , a sandal 0 comprises a sole 1 and a foot - securing band or strap 2 affixed to the sole 1 for securing sole 1 to the cyclist &# 39 ; s foot . the bottom of the sole 1 has cleat attachment holes 11 for fitting in a cleat 3 ( fig3 ). the cleat attachment holes 11 are located in front of the sole center and are shaped as recessions in the sole surface . in this embodiment , the lower surface of cleat 3 does not extend below the ground - contacting surface of the sole 1 . as a result , the wearer experiences no discomfort in the area of the foot sole during walking . the sole 1 comprises a middle sole 4 and covering soles 5 . middle sole 4 is formed of a hard resin , metal , or some other material of comparatively poor elasticity . covering soles 5 are joined to the upper and lower surfaces of the middle sole 4 . covering soles 5 provide an elastic cover for the middle sole 4 and are formed of hard rubber or a soft material with comparatively good flexibility . the foot - supporting band 2 comprises a heel - securing band 2a , a toe - securing band 2b , and a connecting band 2c . heel - securing band 2a is a back strap for securing the heel area of the foot , toe - securing band 2b is a front strap for securing the toe area of the foot , and connecting band 2c connects the heel - securing band 2a and the toe - securing band 2b in the longitudinal direction of the foot . the heel - securing band 2a comprises a left heel - securing band 2al and a right heel - securing band 2ar . the left end of the left heel - securing band 2al is affixed to the sole 1 , while the other end can be released . similarly , the right end of the right heel - securing band 2ar is affixed to the sole 1 , while the other end can be released . the toe - securing band 2b comprises a left toe - securing band 2bl and a right toe - securing band 2br . the left end of the left toe - securing band 2bl is affixed to the sole 1 , while the other end can be released . similarly , the right end of the right toe - securing band 2br is affixed to the sole 1 , while the other end can be released . in the left sandal , the connecting band 2c connects the left heel - securing band 2al and the left toe - securing band 2bl in the longitudinal direction . the heel - securing band 2a is provided with a heel - coupling means 6 for coupling the releasable side of the left heel - securing band 2al and the releasable side of the right heel - securing band 2ar . in this embodiment , the heel - coupling means 6 may be a ring provided with a slit and affixed to the releasable end of the right heel - securing band 2ar by sewing or other means . similarly , the toe - securing band 2b is provided with a toe - coupling means 7 for coupling the releasable side of the left toe - securing band 2bl and the releasable side of the right toe - securing band 2br . in this embodiment , the toe - coupling means 7 may be a ring provided with a slit and affixed to the releasable end of the right toe - securing band 2br by a stitch or other means 8 . for example , the releasable end of the right toe - securing band 2br can be folded back , and a looped stitched portion 9 can be formed by sewing . the ring 7 is passed through this stitched portion 9 . the left heel - securing band 2al rises from the left side of the sole 1 for the left sandal , passes through the heel - coupling means 6 , and folds back . a hook - and - loop fastener ( such as a velcro ® fastener ) is affixed to the facing surfaces of the folding portion on the releasable side of the left heel - securing band 2al . similarly , the left toe - securing band 2bl rises from the left side of the sole 1 for the left sandal , passes through the toe - coupling means 7 , and folds back . a hook - and - loop fastener ( such as a velcro ® fastener ) is affixed to the facing surfaces of the folding portion on the releasable side of the left toe - securing band 2bl . as shown in fig1 and 5 , the middle sole 4 is slightly curved downward in a convex fashion ( with the exception of an area on the heel side ). in this embodiment , the entire middle sole 4 is curved , having a point of inflection p . the curving forms a curved surface that follows the lower surface of the foot . cleat attachment holes 11 for fitting in a cleat are formed at positions near the lower end point of this convex surface . as shown in fig3 a window 12 is formed in the lower - side portion of the covering soles 5 , and the lower surface of the middle sole 4 is exposed . the cleat attachment holes 11 are formed in the exposed portion 4a of the middle sole 4 . the cleat 3 ( whose upper - end surface is bonded under pressure to the lower - end surface ) is movably and rotatably secured to the exposed portion 4a . the cleat 3 is affixed to the middle sole 4 with a plurality of hexagonal - head bolts 13 and with nuts ( the latter are not shown ) in a well known manner . the cleat 3 can be attached while allowed to move in the longitudinal direction with respect to the sole 1 , and the angle with respect to the longitudinal direction can be varied somewhat . as noted above , in this embodiment the cleat 3 does not extend below the lowermost surface of the sole 1 . as shown in fig4 the cleat attachment holes 11 are shaped as slits extending in the longitudinal direction of the footwear . the cleat attachment holes 11 may comprise two slits arranged in a row . of course , the two cleat attachment holes 11 are not limited to slits and can be round holes , circular holes , or elliptical holes arranged in the form of islands in the longitudinal direction . the parts of the two cleat attachment bolts 13 that pass through the cleat attachment holes 11 are narrower ( in the transverse direction that is orthogonal to the longitudinal direction ) than the corresponding cleat attachment holes 11 . the pitch of the row of two holes , that is , the distance between the centers of the two holes in the row in the transverse direction , is set at 14 mm . or less . in this embodiment , the distance between the front end of the sole and the central point in the longitudinal direction of the row of holes is set at 25 to 45 percent of the distance between the front and back ends of the sole , and the distance between the holes in the row is set at no more than 25 percent of the width of the sole in the vicinity of this row of holes . as a result , the surface area of the cleat attachment holes 11 is small , and the strength of the sole does not suffer . in addition , the pitch remains small when the cleat 3 is secured to the sole at an angle , thus making it possible to make the angle between the cleat 3 and the cleat attachment holes 11 relatively large even when only a small gap is formed between the cleat attachment bolts 13 and the cleat attachment holes 11 . adjusting the securing position by means of such a large attachment angle is convenient for the cyclist . fig4 - 11 elaborate on the structure of the middle sole 4 . fig5 is a cross section taken along line v -- v in fig4 . fig6 - 10 are cross sections taken along lines vi -- vi , vii -- vii , viii -- viii , ix -- ix , and x -- x , respectively , in fig1 . as shown in fig5 the middle sole 4 has maximum thickness in an area near the point of inflection p ( or near a horizontal line containing the point of inflection p ). as shown in fig6 and 7 , the middle sole 4 has maximum width in the front portion ( in the portion closer to the toes and farther from the point of inflection p ). as shown in fig9 and 10 , the middle sole 4 has minimum width in the back portion ( in the portion closer to the heel and farther from the point of inflection p ). the middle sole 4 is concave overall . specifically , the left and right sides are raised as shown in fig6 through 10 . the cleat attachment holes 11 for cleat coupling are provided at the position of maximum width . the middle sole is thicker in a linear region 21 extending in the longitudinal direction on the underside of the central region than on the left or right sides thereof . in the longitudinal region near the point of inflection p , the middle sole 4 is thinner on the inside ( on the downside in fig1 ) than on the outside . to use the sandal , the cyclist inserts his or her foot into the sandal , and the free end of the releasable portion of the left toe - securing band 2bl is passed through the toe - coupling means 7 and folded back . the left toe - securing band 2bl and the right toe - securing band 2br can be joined and tightened by aligning the hook and loop fasteners on the facing sides of the folded left toe - securing band 2bl . the degree of tension can be adjusted by varying the folding position . the free end of the releasable portion of the left heel - securing band 2al is then passed through the heel - coupling means 6 and folded back . the left heel - securing band 2al and right heel - securing band 2ar can be joined and tightened by aligning the fasteners on the facing sides of the folded left heel - securing band 2al . the degree of tension can be adjusted by varying the folding position . adjusting the degree of tension in such a manner allows the heel - securing band 2a and the toe - securing band 2b to snugly secure the toe area and the heel area of the foot against the sole 1 . after the sandals are secured to the cyclist &# 39 ; s foot , the cyclist inserts the cleats 3 into the bicycle pedals at predetermined positions . the pedaling force acts to further bend the sole 1 around the point of inflection , but the magnitude of this force varies periodically from high to low , and the fact that the middle sole 4 is hard and hence rigid allows the sole to rapidly regain its original shape as soon as the pedaling force decreases . such a bending force also acts to bend the middle sole 4 and to stretch the connecting band 2c , but the deformation of the middle sole 4 is suppressed by the tension of the connecting band 2c , which is made of a material that is hard to stretch . as noted above when discussing the structures shown in fig6 through 10 , the central portion is thicker than the left or right side , and thus generally functions as a stiff structural member while preserving its elasticity . resistance to bending is also high because of the considerable thickness of the central bending portion . thus , the cleated sandal of this invention has only minor energy losses because it is rigid and easily restores its original state . the cleat , which does not extend below the lower - end surface of the sole 1 , does not impede walking when the rider gets off the bicycle and walks . thus , the sandal can be used for both cycling and walking . because the sandals have good ventilation , they can be used as sporting footwear , and particularly sporting footwear for summer use . the degree of tension is easy to adjust , and the range of cleat adjustment angles is large . while the above is a description of various embodiments of the present invention , further modifications may be employed without departing from the spirit and scope of the present invention . thus , the scope of the invention should not be limited by the specific structures disclosed . instead , the true scope of the invention should be determined by the following claims . of course , although labeling symbols are used in the claims in order to facilitate reference to the figures , the present invention is not intended to be limited to the constructions in the appended figures by such labeling . | US-66542096-A |
the invention relates to a device for developing hands muscles , formed by a body comprising a partially or fully hollow container fitted with an upper movable cover having one hole or a series of holes provided at one o more points along the periphery thereof for the coupling of transparent flexible tubes which are open at both ends . according to the invention , the lower end of the tube is used for the insertion of a pail having a surface that is fully or partially covered , especially in the peripheral area thereof , with longitudinal segments in the forms of pins or needles inclined in the same direction with a variable degree of inclination . the ends os said longitudinal segments are kept in contact with the inner face or wall of the tube . the device can be used for therapeutic uses , as a piece of gym equipment or as a toy . | the invention described in this utility model is a device whose primary function is to act as a means for reinforcing the musculature of the hands , whether for medical reasons , i . e ., recovery of motor strength in people with reduced mobility or strength , or with illnesses that diminish the motor capabilities of the fingers , such as occurs with the loss of sensation in people with diabetes , or to increase , musculature like other gym devices , or to be used for recreational purposes . in all these possible applications , the device is apt for children and adults of any age , with no limitations , and can be used individually or in groups . specifically , this device for developing muscular strength in the hand and fingers has been conceived as a device that focuses on the continuous repetition of two actions , squeeze and release , which requires concentrating the force specifically in the hand and very particularly in the joint action of all the fingers . the device is structured around a central body , which is a container that is partially or completely hollow and optionally provided with a top cover enabling to access the inside . at one or more points of its perimeter , this container has one or more orifices into which similar flexible transparent tubular segments can be fitted and adjusted . these are open at both ends and can be fixed to the container like tentacles . the second basic element of this device is a part that is of the proper size to be inserted inside the described tube . this piece is preferably elongated and cylindrical and its surface is completely or partially covered , particularly its perimeter , by long segments like spikes or needles , which are all positioned obliquely with respect to the piece itself , always all tilted in the same direction and able to vary the degree of inclination . the diameter and / or thickness of these needles can be varied . in their rest position these needles have an inclination of approximately between 80 ° and 88 ° with respect to the longitudinal axis of the cylinder or “ hedgehog ”. the operation of this device is very simple , and as has already been mentioned , is based on the continued repetitive squeezing and releasing of the tubular body using the hand and fingers . the aim is to defeat the resistance of the flexible tube and needles or flexible spikes on the cylinder , in a way that the cylinder is moved along the tube until the end is reached , and it falls into the container . as stated , the cylindrical piece with spikes , or “ hedgehog ”, is positioned inside the flexible transparent tube in such a way that each of the spikes or needles , when at rest , has its tip brushing the interior surface of the tube , thus acting as means for retaining the cylinder , which remains immobilised inside the tube . when the user applies a certain pressure , squeezing the point at which the cylinder is by hand , the flexible tube gives in , narrowing its original diameter , and pressing on the spikes or needles of the cylinder , which are flexible and therefore also give in and change their tilt angle to become approximately between 5 °/ 18 ° degrees , pushing the cylinder forward . at this moment , when the cylinder or “ hedgehog ” moves forwards , some of the needles , specifically those at the end , stay in contact with the tube &# 39 ; s internal wall , acting as a means of retention and forcing the “ hedgehog ” to move exclusively forwards and not allowing it to move backwards . when the user releases the pressure applied by their hand , the flexible tube returns to its original diameter and , consequently , the spikes or needles also return to their original inclination and position , but at a point further down the tube with regard to the previous point . as this squeezing and releasing process is continuously repeated , the cylinder is moved along the described tube until it reaches the end , where it falls into the mentioned container . as mentioned above , the number of flexible tubes varies , although four is considered a reasonable number to allow using the device in groups . the container can take many shapes as long as the perimeter orifices for inserting the flexible tubes are maintained . in the same way , and with the aim of achieving maximum visibility , it is envisaged that the device as a whole , including the container may be transparent so that the movement of the cylinder can be observed and even its position inside the container , although it could likewise be opaque . at its bottom , the container could also include some means of anchoring it to a supporting surface or stand , such as a table or similar item , so that it stays fixed and immobilised under the pressure and force applied on its various tubes or tentacles . the device can incorporate electronic or other elements such as optics or sounds , which enable to monitor the position and movement of the cylinders or “ hedgehogs ”, the time intakes to move it or other variables . the cylindrical parts or “ hedgehogs ”, whilst maintaining a basically cylindrical shape , can take on , particularly and their ends , different shapes , imitating animals , objects etc ., or can be painted in different colours . for example , one possibility is to imitate heads and animal tails , which is particularly applicable when used as a game . as per this description , it is obvious that the claimed device has many advantages over other similar devices ; it is useful , from a recreational point of view , both for personal enjoyment and for competing against other people ; it enables to exercise the musculature of both hands simultaneously , which is particularly important in cases of recovering motor skills or muscular dysfunction in people showing an imbalance between the right and left sides of the body ; it is equally effective as a gym equipment ; it can be used by adults or children , where the only difference is the length or thickness of the needles or spikes , as the thicker they are , the greater their resistance , and the thinner , the lower their resistance , which means it can be adapted to levels of force for children , women or men . at this point is should be noted that the thickness and diameter of the tube , and its degree of flexibility can be varied according to the end user in order to increase its degree of resistance when squeezed . likewise , the perimeter orifices of the container include the adjustment means needed to attach tubes of different diameters , making these interchangeable so that the user can change them to carry out exercises at different levels . to better understand what is described in this patent , a set of drawings are attached , which should only be analysed and considered as examples , with no intention to limit or restrict . fig2 .— detailed view of the mobile element or cylinder at rest fig3 .— detailed view of the mobile element or cylinder in the forwards moving position fig4 .— detailed view of the advancing process of the mobile element or cylinder these figures show the configuration of the claimed muscle exercising device , which , as can be seen in fig1 , is comprised of a body acting as a container ( 1 ) that is partially or totally hollow and optionally provided with a removable top lid ( 2 ) or dome that allows access to the inside . at one or more points of its perimeter , the container ( 1 ) includes a series of orifices into which flexible and , transparent tubes ( 3 ) are coupled , and are open at both ends . through the lower end ( 4 ) of the tube ( 3 ), the second element of the device is inserted , which is a preferably elongated and cylindrical piece ( 5 ), with its surface completely or partially covered , and particularly its perimeter , with long segments such as spikes or needles ( 6 ). these spikes ( 6 ), which can be seen in greater detail in fig2 , are positioned obliquely with respect to the cylinder ( 5 ), with an approximate degree of inclination between 80 ° and 88 ° with respect to the cylinder &# 39 ; s ( 5 ) longitudinal axis . fig2 and fig3 show the detail of this cylinder ( 5 ), which in fig2 is in the rest position , so the end of each spike or needle ( 6 ) rubs and is in contact with the inside of the tube ( 3 ), acting as a means of retention for the piece that is fixed and immobile . fig3 shows how squeezing and releasing the flexible tube ( 3 ) makes it give in and in turn presses on the cylinder ( 5 ), forcing the spikes or needles ( 6 ) to change their degree of inclination , which becomes approximately between 5 ° and 18 ° with respect to the cylinder &# 39 ; s ( 5 ) longitudinal axis . at this time , the cylinder ( 5 ) moves and shifts . when pressure on the flexible tube ( 3 ) is no longer applied , the tube returns to its original diameter and the spikes ( 6 ) on the cylinder ( 5 ) also return to their original inclination , as can be seen in the aforementioned fig2 . fig4 shows , in a comparison of the flexible tube ( 3 ) and the cylinder ( 5 ) in the rest or released position , at the top , and in a squeezed position at the bottom , how the tips ( 8 ) of the needles or spikes ( 6 ) are kept in contact with the inner wall or face of the tube ( 3 ) at the same point , acting as a means of retention and forcing the cylinder ( 5 ) to always move forward . also visible in fig4 is the advance movement of the cylinder ( 5 ) inside the flexible tube ( 3 ). by squeezing the cylinder ( 5 ), it stays in the advanced position thanks to the needles or spikes ( 6 ) that do not change their degree of inclination and thus stop the cylinder ( 5 ) from moving backwards . it is not considered necessary to provide a more detailed description so that any expert in the field can understand the scope of the invention and , the , advantages derived from it . the materials , form , size and layout of the elements can be varied provided that this does not alter the essential nature of the invention . the terms in which this report has been written should always be understood in a broad sense and not a limiting one . | US-99409609-A |
methods for making a balloon catheter device comprising a solvent - swellable polymer are provided . the method includes providing a balloon , wherein a wall of the balloon or a coating over the balloon comprises a polymer , wherein the polymer is swellable in an organic solvent . in certain embodiments of the invention , the polymer on the balloon is exposed to a mixture of said solvent and a therapeutic agent ; and the solvent is thereafter removing , leaving the therapeutic agent in the polymer . | catheter devices of the present invention use an expandable balloon for delivering a therapeutic agent to a target site in the body . the balloon is designed to be insertable in the body via a catheter . the therapeutic agent can be associated with the balloon in any of various ways , as further described below . any of various mechanisms conventionally used for the delivery , actuation , or expansion ( e . g ., by inflation ) of balloon catheter devices may be used in the present invention . the balloon catheter may be designed similar to those that have been known in the art , including but not limited to angioplasty catheters , stent delivery catheters , inflation catheters and / or perfusion catheters . the catheter devices of the present invention may be used in conjunction with other drug delivery devices , such as stents . referring to fig1 a and 1b , in certain embodiments , a balloon catheter 20 comprises a catheter body 22 having a balloon 24 mounted thereon . in fig1 a , the balloon is in a deflated state ; in fig1 b , the balloon is in an inflated state . the body of the balloon can be single - layered or multiple - layered . in one aspect of the present invention , a balloon comprises a solvent - swellable polymer . the solvent - swellable polymer may have a therapeutic agent incorporated therein and may be used to form a wall of the balloon or to form a coating disposed over the balloon . preferably , the polymer is swellable upon exposure to an organic solvent . the organic solvent can be polar or non - polar . preferably , the organic solvent has a low boiling point . preferably , the organic solvent has a boiling point of about 90 ° c . or less , about 80 ° c . or less , or about 70 ° c . or less . solvents with low boiling points can be removed relatively easier than those with high boiling points . non - limiting examples of organic solvents include dichloromethane , chloroform , carbon tetrachloride , ethyl acetate , tetrahydrofuran , acetonitrile , hexane , and cyclohexane . optionally , the solvent - swellable polymer is a semi - crystalline polymer . the semi - crystalline polymer can form a polymer matrix having crystalline portions and amorphous portions . when the polymer matrix is exposed to a mixture of a suitable organic solvent and a therapeutic agent , the solvent and the therapeutic agent diffuses into and swells preferentially the amorphous regions of the polymer matrix . the crystalline portions of the polymer matrix are more resistant to swelling , and therefore form a stable structure that maintains the physical structure of the polymer - containing balloon wall or coating . when the solvent is removed , the polymer matrix contracts to its original conformation , entrapping the therapeutic agent within the polymer matrix . for example , referring to the schematic illustration shown in fig2 a - 2c , a catheter device comprises a balloon comprising a solvent - swellable , semi - crystalline polymer . fig2 a shows a polymer matrix 70 on the wall of the balloon prior to solvent exposure . polymer matrix 70 has crystalline regions 72 , which are represented schematically by the lines , and amorphous regions 74 , which are represented schematically by the spaces . referring to fig2 b , upon exposure to a mixture of a solvent and a therapeutic agent , amorphous regions 74 absorb the solvent and therapeutic agent 76 , causing polymer matrix 70 to swell . referring to fig2 c , upon removal of the solvent , polymer matrix 70 contracts to its original conformation such that therapeutic agent 76 is retained within polymer matrix 70 . optionally , the solvent - swellable polymer is a partially cross - linked polymer . preferably , the cross - linking density is low to allow at least a portion of the polymer to swell in an organic solvent . the cross - linking can be done using any known methods . for example , the cross - linking may be induced by uv irradiation or electron beam irradiation . the cross - linked portions of the polymer serve as the stable structure , while the non - crosslinked portions of the polymer swell upon exposure to an organic solvent and entrap the therapeutic agent previously mixed with the solvent after the solvent is removed . optionally , the solvent - swellable polymer is grafted onto the surface of the balloon through chemical bonding . in this case , the balloon wall base itself serves as the stable structure , while the polymer swells upon exposure to an organic solvent and entraps the therapeutic agent previously mixed with the solvent after the solvent is removed . non - limiting examples of solvent - swellable polymers include block copolymers of styrene - ethylene / butylene - styrene (“ sebs ”), block copolymers of styrene - ethylene / propylene - styrene (“ seps ”), block copolymers of styrene - butadiene - styrene (“ sbs ”), block copolymers of styrene - isoprene - styrene (“ sis ”), polyolefins such as polyethylene and polypropylene , polyurethane , polyoxymethylene - acetyl copolymers , polyamide block copolymers , and copolymers of acrylates and methacrylates . the sebs , seps , sbs , and sis copolymers can be commercially - available copolymers , such as those sold under the trade names kraton g and kraton d . preferably , the solvent - swellable polymer has unsaturated bonds to allow for cross - linking or grafting . after the therapeutic agent is loaded into the polymer , the solvent may be removed by any known method , for example , evaporation or vacuum drying . preferably , the solvent is removed without heating . preferably , the solvent is removed by evaporation . in operation , the balloon comprising a therapeutic agent - containing polymer is inserted into the body and delivered to the target site . the balloon is then inflated , causing the polymer ( in the case of a semi - crystalline polymer being used , polymer matrix 70 ) in the balloon wall to undergo expansion by mechanical force . by enlarging the space within the polymer ( e . g . polymer matrix 70 ), the therapeutic agent ( e . g . therapeutic agent 76 ) is released from the wall of the balloon . because the therapeutic agent is preferably loaded through diffusion , it tends to locate near the surface of the wall or coating and can be easily released after the balloon catheter device is delivered to the target site . medical devices of the present invention may also include a vascular stent mounted on the balloon . the vascular stent may be any of those known in the art , including those with or without coatings that contain a therapeutic agent . the stent may also be biostable , bioerodable , or biodegradable . the balloons of the present invention may also be coated with a low - molecular weight carbohydrate , such as mannitol . the carbohydrate may be a separate coating or be blended with the therapeutic agent . the balloons of the present invention may also be coated with a radiocontrast agent ( ionic or non - ionic ), such as iopromide . the contrast agent may be a separate coating or be blended with the therapeutic agent . the therapeutic agent used in the present invention may be any pharmaceutically acceptable agent ( such as a drug ), a biomolecule , a small molecule , or cells . example drugs include anti - proliferative agents or anti - restenosis agents such as paclitaxel , sirolimus ( rapamycin ), tacrolimus , everolimus , and zotarolimus . other example drugs include those that are anti - spasmodic agents and vasodilators . example biomolecules include peptides , polypeptides and proteins ; antibodies ; oligonucleotides ; nucleic acids such as double or single stranded dna ( including naked and cdna ), rna , antisense nucleic acids such as antisense dna and rna , small interfering rna ( sirna ), and ribozymes ; genes ; carbohydrates ; angiogenic factors including growth factors ; cell cycle inhibitors ; and anti - restenosis agents . example small molecules include hormones , nucleotides , amino acids , sugars , and lipids and compounds have a molecular weight of less than 100 kd . example cells include stem cells , progenitor cells , endothelial cells , adult cardiomyocytes , and smooth muscle cells . a double - layered balloon is manufactured . the inner layer is made of high density polyethylene and the outer layer is made of sebs ( kraton g , kraton polymers , houston , tex .). the sebs in the outer layer is crosslinked by electron beam irradiation . the balloon is then immersed in a mixture of cyclohexane and paclitaxel for drug loading . after the balloon is taken out , the cyclohexane is removed by evaporation . the balloon is then assembled onto a balloon catheter device . the foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting . each of the disclosed aspects and embodiments of the present invention may be considered individually or in combination with other aspects , embodiments , and variations of the invention . modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art and such modifications are within the scope of the present invention . | US-39953209-A |
disclosed is a blood pressure measurement apparatus in which a waveform discrimination method is used in the recognition of korotkoff sounds in the measurement of blood pressure by auscultation . in processing executed by the apparatus , the minimum point or maximum point of a signal waveform indicative of the sound or vibration produced by a blood vessel is detected , and a maximum value or minimum value point is detected within a predetermined time region the final instant of which is the point . if a level difference between the point and the point is within a predetermined range , there is detected a minimum value or maximum value point within a predetermined time region the final instant of which is . if a level difference between the point and the point is within a predetermined range , there is detected a maximum value or minimum value point within a predetermined time region the starting instant of which is the point . it is then discriminated whether a level difference between the point and the point falls within a predetermined range . control proceeds in successive fashion when each of these conditions is satisfied , with a korotkoff sound being recognized in the signal waveform when all of these conditions are satisfied . | an embodiment of the present invention will now be described in detail with reference to the drawings . fig1 is a block diagram illustrating the basic construction of an embodiment of the present invention . the arrangement includes a microphone 1 for picking up korotkoff sounds ( hereafter referred to as &# 34 ; k - sounds &# 34 ;) and for producing an analog output signal indicative thereof . the input analog signal between range of 0 . 3v and 2 . 0v is converted into a 8 bit digital signal every 4 milliseconds ( ms ) by an analog - digital ( a / d ) converter 2 before being applied to an arithmetic circuit 3 . the latter serves as recognition means and is adapted to recognize a k - sound by processing a series of sound data signals obtained in digital form from the a / d converter 2 . the arithmetic circuit 3 comprises a one - chip cpu having a ram and a rom and is so illustrated that the various functions implemented by executing a program stored in the rom are shown in block form . the present invention is capable of implementing these functions efficiently with the limited memory and limited processing time given the cpu . numeral 4 denotes a display unit for displaying the fact that a k - sound has been recognized , for displaying other information as well . the arithmetic circuit 3 includes a data read - in unit 5 for reading the digital output signal from the a / d converter 2 into the arithmetic circuit 3 , a threshold value setting unit 6 which compares the newly read digital signal data from the data read - in unit 5 and the threshold value determined based upon the most recent k - sound . the arithmetic circuit 3 further includes a time generator for generating time information , and a memory ( ram ) 9 for storing a digital data as well as the time information prevailing at the instant of detection . the threshold value which is to be held in the threshold value setting unit 6 is calculated from the most recent k - sound in a k - sound recognition unit 15 in accordance with the following equation , if the newly read digital signal is larger than the most recent threshold value , the sign bit is set to &# 34 ; 1 &# 34 ;. this sign bit is included in the output 106 . if , on the contrary , the new data is smaller than the threshold value , the sign bit is set to &# 34 ; 0 &# 34 ;. after completion of this operation , the digital data signal containing the sign bit is delivered to the memory 9 as digital signal data 106 . the sign bit is referred to by a c3 detector 10 in order to determine whether to produce a signal on line 113 or not . before continuing with the description of the functional blocks of the apparatus shown in fig1 let us discuss typical patterns of the k - sounds which are to be recognized by the apparatus . fig2 ( a ) is a typical pattern of a k - sound waveform recognized by the apparatus of the illustrated embodiment , and fig2 ( b ) illustrates the pattern when the signal level is inverted . as it is possible that the input waveform may represent two opposite waveforms , drawings illustrating the respective waveforms , for example , fig2 ( a ) and 2 ( b ), are provided in this application . the characteristic points of the k - sound waveform are the four points c1 - c4 shown in fig3 ( a ), ( b ). in order to help understanding of the present invention , level differences dp1 to dp3 and time regions t 1 to t 3 are labeled in fig3 a . they will be referred to in the following discussion . in the illustrated embodiment , a k - sound is recognized on the basis of the relationship among these four points . in fig3 ( a ), ( b ), the point c3 is defined as the point where the signal level attains an absolute extreme valve , i . e ., the highest peak or lowest valley , and is a portion which has great significance for the purpose of k - sound recognition , described below . specifically , once the characteristic point c3 has been found , the characteristic points c1 , c2 , c4 are each obtained by a prescribed analytical method which starts from the point c3 . each of the functional blocks described below constitutes means for recognizing the abovementioned k - sound waveform patterns both reliably and efficiently . returning to fig1 numeral 10 is the c3 detector for detecting a relative ( local ) extreme valve , i . e ., a maximum value or minimum value in the digital signal data read out of the memory 9 . numeral 11 designates a level inverter which , for the purpose of k - sound recognition , inverts the level of the signal waveform data , which is read out of the memory 9 , whenever necessary . a characteristic point detector 12 performs a predetermined calculation with regard to the signal waveform data read out of the memory 9 and time data to check for the presence of a waveform located at each of the characteristic points c2 , c2 , c4 . the characteristic point detector 12 comprises a time region setting unit 13 for generating prescribed time region data , and a k - sound discriminator 14 for discriminating whether sound data of a signal level forming a characteristic is present within the time region , and is adapted to detect each characteristic point in accordance with a predetermined calculation procedure , described below , when a signal indicating that the c3 point has been detected is received from the c3 detector 10 . the output of the k - sound discriminator 14 is applied to a k - sound recognition unit 15 , which examines the positional relationship among a collection of characteristic points found by the characteristic point detector 12 , in order to recognize a k - sound . the operation of the present embodiment comprising the foregoing elements will now be described . the output of the microphone 1 is an analog electric signal 101 indicative of a k - sound picked up by the microphone . the signal 101 is converted into a digital signal 102 at every 4ms sampling instant by the a / d converter 2 . the digital signal 102 at the output of the a / d converter 2 is read into the arithmetic circuit 3 by the data read - in unit 5 and is applied to the threshold value setting unit 6 as a series of digital signal data 103 in a time series . the threshold value setting unit 6 sets a threshold value in dependence upon a signal 117 from the k - sound recognition unit 15 indicative of the magnitude of a k - sound which appeared last in accordance with equation 1 . by setting the threshold value to | c3 - p o |· βl , the unit 6 reduces the influence of noise contained in the waveform data 103 . in order to suitably deal with a signal pattern input of any amplitude whatsoever at the start of measurement , no threshold value is set when measurement starts after measurement starts , however , a threshold value is set upon predicting , from the magnitude of an immediately preceding k - sound , the smallest magnitude capable of being traversed by the next k - sound . more specifically , in a case where a k - sound has already appeared in the course of measurement , the threshold value setting unit 6 sets a threshold value in dynamic fashion in dependence upon the signal 117 from the k - sound discriminator 15 indicative of the magnitude of the threshold | c3 - p o |· βl , thereby making it possible to detect the c3 point accurately and rapidly . accordingly , the threshold value setting unit 6 in the apparatus of the illustrated embodiment is different in nature from threshold value setting means in the conventional comparator method , in which a threshold value is set that is fixed with respect to the amplitude of the k - sound . the threshold value setting unit 6 delivers the digital signal data 106 to the memory 9 each 4 ms interval and also delivers timing signal 105 to the time generator 8 each sampling instant at the a / d converter 2 . the time generator 8 is a unit which cyclically counts timing information that increases every millisecond , by way of example . when the timing signal 105 is received from the threshold value setting unit 6 , the time generator 8 successively counts up a write - in address 120 of the memory 9 so that the digital signal data 106 from the threshold value setting unit 6 and prevailing clocked time information 107 are written into the memory in accordance with the counted up address . thus , the digital signal value data 106 and the time information 107 prevailing at the moment of detection are stored in the memory 9 . the time generator 8 also outputs a read - out address 120 of the memory 9 at a predetermined time interval and produces a read enable signal 121 when a read - out becomes possible . the digital signal data 106 stored in memory 9 is read by the c3 detector 10 and characteristic point detector 12 in accordance with the read enable signal 121 , whereby k - sound recognition processing is performed . in order that the memory 9 can be read from any address when k - sound recognition processing is executed , the characteristic point detector 12 provides the time generator 8 with an address designating signal 122 for designating a read - out address from which a read - out is to be started . the k - sound recognition processing will now be described with reference to the flowchart of fig4 ( a ) and 4 ( b ). in accordance with the read enable signal 121 from the time generator 8 , the c3 detector 10 reads sound data 108 out of the memory 9 in accordance with the successively stored time series , examines these data in regular order and executes processing for detecting the c3 point in the signal pattern shown in fig3 ( a ) or fig3 ( b ). in the first step s90 of the flowchart shown in fig4 ( a ) and ( b ), an inversion flag 10a internally of the c3 detector 10 is set to &# 34 ; 0 &# 34 ;. when the inversion flag 10a is &# 34 ; 0 &# 34 ;, an inversion indicating signal 109 is reset ; when the flag 10a is &# 34 ; 1 &# 34 ;, the inversion designating flag 109 is set . when the inversion indicating signal 109 is in the reset state , the level inverter 11 delivers read - out data 110 from memory 9 directly to the characteristic point detector 12 as output data 111 . when the inversion indicating signal 109 is in the set state , the level inverter 11 inverts the read - out data from the memory 9 and delivers the result to the characteristic point detector 12 as the output data 111 . initially , the inversion flag 10a is set to &# 34 ; 0 &# 34 ; and the inversion designating signal 109 is reset . consequently , the read - out data from memory 9 is applied as such to the characteristic point detector 12 . next , at a step s91 , the c3 detector 10 , in accordance with the read enable signal 121 , reads the digital signal data 106 from the threshold value setting unit 6 stored successively in memory 9 via , the a / d converter 2 out of the memory in the same order in which it was stored and compares this with digital signal data 106 read out immediately before . the time generator 8 exercises read - out control separate from the write - in of the digital signal data 106 . the reading of data from the memory 9 can be performed immediately by writing in the digital signal data 106 by means of the threshold value setting unit 6 . extreme value detection processing is executed from step s92 onward and is performed by a level comparison of digital signals at three consecutive points in the sound data 108 . thus , at the step s92 , digital signals at three consecutive points are compared to determine whether a valley point has been detected , that is , to check whether the level difference between adjacent ones of the points changes from a decreasing value to an increasing value . if a valley pont is detected and this valley point is given a sign bit &# 34 ; 1 &# 34 ;, that is the newly obtained digital signal data is determined by the c3 detector 10 to be larger than the current threshold value , this point is treated as being the characteristic point c3 and the program proceeds from the step s92 to a step s94 , at which the inversion flag 10a is set to &# 34 ; 1 &# 34 ; and the inversion indicating signal 109 is delivered to the level inverter 11 . the program then proceeds to a step s95 . when the inversion indicating signal 109 is delivered to the level inverter 11 , k - sound detection is performed . to this end , the level of each item of waveform data 110 corresponding to the characteristic points c1 - c4 in fig3 ( b ) and read out of the memory 9 is inverted with regard to a base line [ level p o shown in fig5 ( d ), ( e )] that will turn these levels into the signal pattern shown in fig3 ( a ). the inverted levels are delivered to the characteristic point detector 12 . if a valley point is not detected at the step s92 , the program proceeds to a step s93 , at which it is determined whether a peak c3 has been detected , that is , whether the level difference between adjacent ones of the three consecutive points changes from an increasing value to a decreasing value . if a peak is detected , this peak is determined as to whether the peak is exceeding the threshold value with referring to the sign bit included in the digital signal data 106 . if the peak is exceeding the threshold value , the peak is treated as being the characteristic point c3 and the program proceeds to a step s95 . if a peak is not detected at the step s93 , the program returns to the step s91 , the next item of digital signal data is read and processing for detecting a characteristic point c3 is performed again . if a peak point is detected at the step s93 , the inversion flag 10a remains at &# 34 ; 0 &# 34 ; and the program proceeds to the step s95 . this step calls for a characteristic point detection signal 113 to be sent from the c - point detector 10 to the characteristic point detector 12 to indicate that the detected point is a characteristic point . the program then proceeds to a step s104 . if a k - sound is recognized , what is detected first is the peak point . an example of the state in which the initial peak is detected is illustrated in fig5 ( a ). in response to the characteristic point detection signal 113 from the c3 detector 10 indicating that the c3 point has been detected , the characteristic point detector 12 initiates detection of each characteristic point of the digital signal data constituting a k - sound . this being performed by processing from step s104 onward . when the characteristic point detection signal 113 is received , the characteristic point detection circuit 12 produces the address designating signal 122 so that data stored in the memory 9 prior to detection of the characteristic point are read out of the memory sequentially in the same order that the data were stored . these data are stored in a ram . in other words , each item of data from c1 to c3 is stored every 4 ms sampling period in the ram at the instant c3 is detected . the step s104 calls for the time region setting unit 13 to set a predetermined time region t 1 the final instant of which is the position of c3 . the unit 13 produces a time region signal 114 indicative of this time region and applies the signal to the k - sound discriminator 14 . the setting of this time region can be accomplished by storing in a rom a predetermined value in accordance with the figures given in below . the set time region t 1 is illustrated in fig5 ( b ). according to the embodiment of the present invention , each time region t 1 , t 2 and t 3 have the values t 1 = 10 , t 2 = 15 and t 3 = 15 [× 4ms ]. and these time region data have been stored previously in the rom which is constituting the time region setting unit 13 . next , the program proceeds to a step s105 , at which the k - sound discriminator 14 reads digital signal data within the time region t 1 set by the time region setting unit 13 and stored in the ram , detects a minimum value within the read data and treats this value as c2 [ fig5 ( c )]. the minimum level point is detected by comparing the levels of two points in the output data 111 from the level inverter 11 . next , a step s106 calls for a decision as to whether the level difference ( dp2 ) between c2 and c3 falls within a predetermined range . the upper and lower limits of this range are stored beforehand in the rom in accordance with the below table . according to the embodiment of the present invention , each level difference dp1 , dp2 and dp3 is given as follows . ______________________________________ lower limit upper limit______________________________________dp2 15 -- dp1 dp2 × α1 dp2 × α2dp3 dp1 × α3 dp2 × α4______________________________________ in the above table , the unit is 0 . 7v / 256 and also , the level differences illustrated in fig3 a , dp1 , dp2 and dp3 , are given below . in fig5 ( c ), the level difference is not within the predetermined range , so that the program returns to the step s90 for detection of the next characteristic point . a valley point shown in fig5 ( d ) is detected by subsequent c3 detection processing . the program proceeds from the step s92 to the step s94 , the inversion flag 10a is set and , in the data read out of the memory 9 and stored in the ram , the input signal level is level - converted from p to 2p o - p ( where p o is a reference level ) by the level inverter 11 , thereby giving the waveform shown in fig5 ( e ). thus , the signal waveform is apparently inverted next , the minimum point c2 is detected within the set time region t 1 through the steps s104 , s105 [ fig5 ( f )]. the decision step s106 now finds that the point c2 lies within the predetermined limits , so that the program proceeds from this step to a step s107 , where the time region setting unit 13 sets a predetermined time region t 2 the final instant whereof is the position of c2 . a signal 114 indicative of this time region is delivered to the k - sound discriminator 14 . the set time region t2 is shown in fig5 ( g ). next , the program proceeds to a step s108 , at which the point ( value ) of a maximum level is detected within the time region t 2 and treated as c1 . the detection of the maximum level is performed by comparing the level between two points . this is followed by a step s109 , at which it is determined whether the level difference dp1 between c1 and c2 lies with a predetermined range . in fig5 ( h ), detection of c1 , c2 , c3 is judged to be improper and the program returns to the step s90 . the characteristic point detected next is c3 shown in fig5 ( i ) and no inversion is made of the read waveform by the level inverter 11 . at the step s104 , the time region t 1 is set as shown in fig5 ( j ), the characteristic point c2 shown in fig5 ( k ) is detected at the step s105 , the time region t 2 having the characteristic point c2 as its final instant is set at the step s107 , as shown in fig5 ( l ), and the maximum value c1 is detected within the time region t 2 shown in fig5 ( m ) at the step s108 . this is followed by the level decision step s109 , at which it is judged that detection of c1 , c2 , c3 is proper . the program then proceeds to a step s110 , at which the time region setting unit 13 sets a time region t 3 the final instant of which is the position of c3 , as shown in fig5 ( n ). next , at a step s111 , a digital signal data 103 within the time region t 3 is read out of the memory 9 , the point of a minimum level is detected and the point is treated as being c4 . this is shown in fig5 ( o ). this is followed by a step s112 , at which it is determined whether the level difference dp3 between c3 and c4 falls within a predetermined range . if the level difference does not fall within the predetermined range , the program returns to the step s90 . if the level difference does fall within the predetermined range , the signal is recognized to be a k - sound at a step s113 . since the present method is a very simple method of detecting the characteristic points c1 , c2 , c3 , c4 , it is suited to real - time processing performed by a one - chip cpu . furthermore , since the maximum value of a peak or the minimum value of a valley is detected within each predetermined time period , the influence of noise ( fig7 ) produced in the vicinity of extreme values of the k - sound waveform is almost nil . when the k - sound discriminator 14 successively detects the positions c3 , c2 , c1 and c4 , an output 115 is produced so as to inform the k - sound recognition unit 15 that the digital signal data should be treated as a k - sound . when the k - sound is recognized by the unit 15 , the unit performs a computation adapting equation 1 to obtain and to deliver the new threshold value to the threshold value setting unit 6 in order to renew the current threshold value . the recognized k - sound is delivered from the k - sound recognition unit 15 to the display unit via line 116 . in the illustrated embodiment , an example has been described in which characteristic points are detected upon inverting peaks and valleys of the signal waveform as reference characteristic points whenever necessary . however , it is permissible to execute processing without making the inversion or to treat a reference characteristic point solely as the waveform peak . in such case , the inversion flag and level inverter 11 can be deleted . according to the present invention as described above , the characteristics of a k - sound waveform are investigated directly . as a result , it is unnecessary to place a restriction upon the frequency band characteristic of a filter or to set a threshold value fixed with respect to the amplitude of a k - sound , as in the prior art . moreover , measurement precision is not readily influenced by the frequency component constituting the k - sound or by the effect of a disparity in the amplitude of the k - sound . further , according to the present invention , the maximum value or minimum value capable of being traversed by a k - sound signal constituent is detected within each set time region , unlike the conventional method in which maximum and minima are detected one by one while traversing the waveform in regular order . accordingly , the detection of candidates for characteristic points can be readily performed by a very short program and measurement precision is not influenced by fine ripple produced in the vicinity of extreme values of a k - sound waveform , particularly ripple due to a conversion error which readily occurs after the a / d conversion . according to the present invention , a plurality of signal patterns indicative of k - sounds can be recognized efficiently on a real - time basis in the limited memory and processing time given a one - chip cpu by using simple software programmed in such a manner that typical patterns of k - sound waveforms are recognized . by adopting an arrangement in which level inverting means is provided , a plurality of patterns can be recognized by a short program . as many apparently widely different embodiments of the present invention can be made without departing from the spirit and scope thereof , it is to be understood that the invention is not limited to the specific embodiments thereof except as defined in the appended claims . | US-20687388-A |
a head - hair cover comprises a body defining a chamber and an opening in the body . the opening has a peripheral edge and permits communication between the chamber and outside of the cover . an adjustment mechanism is provided at or near the peripheral edge for selectively varying the dimensions of the opening . additionally , a constricting band is provided and associated with the peripheral edge for gently crimping at least a portion of the peripheral edge . | with reference to the drawings , there is shown various perspectives of a head and hair cover in accordance with the present invention . the head and hair cover contains a number of features which facilitate putting on the cover , and adjusting it in a manner which is comfortable , and assumes the shape of the user &# 39 ; s head and hair . the head and hair cover of the invention is intended to keep the hair contained therewithin , but without disturbing the style of the hair . the head and hair cover of the invention may be used in a number of contexts . it may be used when sleeping to keep the hair from spreading or losing its shape , or it may be used as a sanitary cover ( such as when the user is preparing food ), or a protector when the user is operating machinery in which the hair may become entangled , thus posing a danger to the user . fig1 of the drawings shows a side view of the head and hair cover 10 in accordance with the invention . the cover 10 is essentially comprised of two identical panels , which are mirror images of each other . thus , there is provided a first lateral panel 14 and a second lateral panel 16 ( clearly illustrated in fig3 of the drawings ), the two panels 14 and 16 being of substantially identical shape , and overlying each other . each panel 14 and 16 comprises a back edge 18 , a base edge 20 , and a front edge 22 . each of the first and second lateral panels 14 and 16 is comprised of preferably a soft and light - weight fabric , such as nylon , polyester , cotton and the like , although any suitable material may be used . further , a preferred embodiment of the invention would be one where each of the first and second lateral panels 14 and 16 is comprised , at least in part , of a material which has some elastic properties , so that it is capable of , at least to a small extent , expanding and contracting back to its normal size depending upon use requirements . each of the first and second lateral panels 14 and 16 is connected to each other preferably by stitching along the back edge 18 thereof , from approximately point 24 to the point 26 . further , the base edges 20 of each of the first and second lateral panels 14 and 16 are also connected to each other , preferably by stitching , between the points 26 and 28 . with respect to the front edge 22 , the first and second lateral panels 14 and 16 are partially attached to each other , once more preferably by stitching . the front edges 22 of the first and second lateral panels 14 and 16 are attached to each other between the point 28 , near the base edge 20 , and the point 30 , about midway up the length of the front edge 22 . therefore , it will be appreciated that the first and second lateral panels 14 and 16 are sewn together along substantially their entire periphery , from point 24 to 26 , point 26 to 28 , and point 28 to 30 . however , the front edge 22 of the first and second lateral panels 14 and 16 respectively remains unattached between points 24 and 30 , creating an opening 34 . the opening 34 provide access to a chamber 36 , which is of a generally tube - like shape . the opening 34 is defined by first peripheral edge 38 , which forms part of the front edge 22 of the first lateral panel , and the second peripheral edge 40 , which forms part of the front edge 22 of the second lateral panel 16 . each of the first and second peripheral edges 38 and 40 comprises a hem 44 , each hem 44 having a sealed or closed end 46 and an open end 48 . the hem 44 defines a channel 50 between the sealed end 46 and open end 48 respectively . a cord 52 , which generally comprises a fabric strip , is located within the channel 50 , and has one inside end 54 fastened near the sealed end 46 . the inside end 54 is preferably fastened near the sealed end by appropriate stitching . the cord 52 extends through the channel 50 , through the open end 48 , so that outside portion 56 of the cord 52 hangs loosely . the outside portion 56 of each cord 52 along the first and second peripheral edges 38 and 40 respectively can be used , as will be described in further detail below , to tighten or loosen the cover 10 , thereby varying the size of the opening 34 so as to be customized and comfortable for the user . the first peripheral edge 38 and second peripheral edge 40 each have an elastic band 60 extending therealong from points 62 and 64 respectively down to the point 30 . the elastic bands 60 are sewn along the peripheral edges 38 and 40 , or may be contained within a hem formed along this portion of the edge . it is not important to the invention exactly how the elastic band 60 is fastened along the edge , only that it is present . the purpose of the elastic band 60 is to provide a light pressure , tending to gather or fold slightly the peripheral edges 38 and 40 along the length at which they , the elastic bands 60 , are located , providing a small , but comfortable and effective , pressure tending to close the opening 34 . as will be described below , the elastic band 60 , together with the cords 52 , provide an advantageous mechanism for adjusting the size of the opening 34 to the precise requirements of the wearer . in use , the cover 10 of the invention is designed and configured to carefully hold the hair , and to fit about the head in a comfortable and proper location . this is achieved by the overall configuration of the cover 10 , as well as the features defining the opening 34 , and the mechanisms for adjusting the size of the opening 34 to desired dimensions . in use , the wearer &# 39 ; s hair is carefully lifted and inserted through the opening 34 so that it will be contained within the chamber 36 . the size of the chamber 36 can , of course , be determined according to the size and shape of the first and second lateral panels 14 and 16 . these panels 14 and 16 can therefore be cut and dimensioned in different ways , to suit the needs of different users . the hair passed through the opening 34 and into the chamber 36 will remain there , and , depending upon the length of the hair , may extend all the way to the base edge 20 , or it may simply hang without the ends touching the base edge 20 . the cover 10 is therefore essentially divided into a head portion 68 and a hair container portion 70 . the hair , when passing through the opening 34 , enters the head portion 68 of the chamber 36 , and then , according to the length of the hair , will fall , to some extent or another , within the hair container portion 70 . the cover 10 is then pulled over the head such that the point 24 is approximately on the forehead of the wearer , while the point 30 rests more or less on the back of the neck of the wearer . the first and second peripheral edges 38 and 40 extend from the forehead , across the cheeks , either in front or behind the ears , and towards the back of the neck . fig3 of the drawings shows in phantom outline the face 74 of the user relative to the cover 10 . the cover 10 remains comfortable on the head , and the tightness thereof , and particularly the opening 34 , can be adjusted . first , the elastic band 60 tends to crimp or fold the peripheral edges 38 and 40 so as to draw the opening 34 tightly around the head and face . however , the cover 10 is still loose enough , and can be elastically extended , so as to make the opening 34 bigger or smaller for putting on or removing . in addition , the user is able to pull the cord 52 along the first and second peripheral edges 38 and 40 , thus gathering the hem 34 and thereby constricting the opening 34 until a comfortable sized opening 34 has been achieved . at that point , the outside portions 56 of the cord 52 are knotted or bowed to keep the cords held and tensioned in the desired position . thus , between the operation of the elastic bands 60 , and the cords 52 , appropriately joined and connected to each other , the size of the opening 34 can be carefully and comfortably adjusted by the user . while the cover 34 worn , the hair is contained within the soft and somewhat elasticized lateral panels 14 and 16 , and the hair is able , to a large extent , to hang substantially naturally within the hair container portion 70 . one potential advantage of the cover 10 is therefore that the hair will not be flattened or pressed into undesired positions by the action of the cover 10 , which , in one embodiment , essentially surrounds and contains the hair without significantly altering its position . variations of the invention are possible . for example , instead of having first and second lateral panels 14 and 16 , a single piece may be used , and stitched together , or molded as a tube , to the desired shape . further , the elastic bands 60 may not necessarily be only , or even , at the lower portion of the opening 34 , but can be effectively located at one or more points along the periphery of the opening . further still , the cords 52 may be near the bottom of the opening , or at the side thereof , rather than at the top . the cords may also be kept together and fastened by means of a clip or other device instead of the requirement that they be knotted or tied by their loose ends only . further , the position of the cords 52 and elastic band 60 may be reversed , so that the elastic is at the top , and the cords at the bottom . | US-97461604-A |
there is provided a tampon or similar device or product in which there is disposed at least one surface active agent . a broad feature of the present invention provides a fibrous absorbent article for absorbing body fluids made up of a fibrous material defining a structure suitable for absorbing the body fluids , and disposed in or on the structure , an effective amount of at least one surface active agent , so as to adsorb malodor associated with these bodily fluids . | the present invention is directed to a fibrous absorbent article , such as a tampon or feminine pad , with at least one surface active agent disposed on or in the fibrous absorbent article . the at least one surface active agent has the property of adsorbing onto surfaces or interfaces to alter the surface or interfacial free energies of the interface . the term “ interface ”, as used herein , refers to a boundary between phases including , but not limited to , liquid - liquid phase boundaries , liquid - solid phase boundaries , liquid - gas phase boundaries , and gas - solid phase boundaries . when vaginal malodor compositions come into contact with a fibrous absorbent article , such as a tampon , the phase boundary area between the malodor and fiber surface is large relative to the volume of the system . therefore , the total mass of the system is present at the boundaries . the behavior of the fiber system is determined to a large degree by the interfacial processes . the at least one surface active agent can play an important role in the process . surface active agents have a molecular structure with a structural group that has little attraction for the solvent phase ( lyophobic ) and a group that has a strong attraction for the solvent phase ( lyophilic ). when surface active agents are added to the surface of fibers of a tampon , the presence of the lyophobic group causes a distortion of the solvent liquid structure , thus increasing the free energy of the system . in the presence of an aqueous solution of a surface active agent , this distortion of the malodor ( water ) phase by the lyophobic group , and the resulting increase in the free energy of the system , results in less energy required to bring a surface active agent , rather than a water molecule , to the surface . therefore , the at least one surface active agent concentrates on the surface of the fibrous absorbent article . the presence of the lyophilic group prevents the surface active agent from being expelled from the solvent phase . as a result , the surface active agent concentrates at the surface and orients itself so that the hydrophilic group is in the aqueous phase ( malodor phase ) and the hydrophobic group is oriented away from the aqueous phase . the malodorous components are therefore chemically bound ( ionic and / or covalent ) by the surface active agents onto the surface at the fiber - liquid interface . the chemical structure of the at least one surface active agent suitable for this application can vary with the nature of the fiber chemistry , malodor phase and the conditions of use . in the presence of a polar solvent phase such as vaginal malodor , ionic or highly polar groups may act as the lyophilic groups . in the presence of electrolytes or organic additives as in vaginal malodor , several surface active agents may be needed to maintain surface activity at a suitable level . for surface activity ( adsorption of malodor ) to be effective , the at least one surface active agent molecule must have a chemical structure that is amphipathic in the malodor phase under the conditions of use . suitable surface active agents for use with the present invention include , but are not limited to , one or more surfactants , polymers , or any combinations thereof . suitable surfactants include , but are not limited to , one or more anionic , nonionic , cationic , amphoteric , silicone - based , polymeric , or any combinations thereof . suitable anionic surfactants that may be used in the present invention include , but are not limited to , sodium alkyl aryl ethoxy sulfate , alkylalkoxylated phosphate ester sodium salt , dioctylester of sodium sulfosuccinic acid , dioctyl sulfosuccinate , ammonium salt of polycarboxylic acid , potassium salt of complex organic phosphate ester , ammonium lauryl ether sulfate , or any combinations thereof . suitable nonionic surfactants that may used in the present invention include , but are not limited to , polyoxyethylene , polyoxyethylene stearic acid , polyoxyethylene 40 hydrogenated castor oil , alkanolamides , isostearyl alcohol , polyoxyethylene / polyoxypropylene block copolymer , glycerol mono / dioleate , glycerol mono / distearate , ethoxylated linear alcohols ( 50 % ethoxylated ), peg - 2 stearate , polyoxyalkylated isostearyl alcohol , polyoxyethylene sorbitan monostearate , triglycerol monooleate , polysorbate 80 , glyceryl monostearate , diglyceryl diisostearate , polyoxyethylene 20 , polyoxyethylene 20 sorbitan monooleate , silicone glycol copolymer , polyglyceryl ester , glycol distearate , ethoxylated alcohols ( ceteareth - 20 ), glycol esters ( peg 400 ditallate ), or any combinations thereof . suitable cationic surfactants that may be used in the present invention include , but are not limited to , trimethyl coco quaternary ammonium chloride , distearyl dimonium chloride , benzalkonium chloride , benzethonium chloride , or any combinations thereof . suitable amphoteric surfactants that may be used in the present invention include , but are not limited to , coconut - based ( imidazoline , dicarboxylate , sodium salt ), coco amido betaine , betaine derivatives ( oleyl betaine ), octyl dipropionate , cocamphoglycinate , or any combinations thereof . suitable silicone - based surfactants that may be used in the present invention include , but are not limited to , cetyl dimethicone copolyol , dialkoxy dimethyl polysiloxane , polysiloxane polyalkyl copolymers , or any combinations thereof . suitable polymer that may be used in the present invention includes , but is not limited to , acrylates / c10 - 30 alkyl acrylate crosspolymer . in order to achieve the odor adsorption properties of the present invention , the at least one surface active agent is present in an amount about 0 . 001 percentage by weight ( wt . %) to about 30 wt . % and preferably about 0 . 01 wt . % to about 5 wt . %, based on the total weight of the fibrous absorbent article . the following example demonstrates the effectiveness of the use of a surface active agent on a tampon to reduce and / or eliminate malodor . a study was conducted to identify and rate the aroma attributes and intensities of malodor treated non - deodorant tampons with varying levels / types of malodor adsorbing / neutralizing treatments , including one with a surface active agent according to the present invention . samples were prepared using unscented tampons according to a detailed protocol . each sample included a 15 % malodor applied to the unscented tampon . the samples prepared are indicated below in table 1 . the samples in table 1 were prepared and tested on three separate occasions . sample b — non - deodorant tampon + 15 % malodor solution + zeolite ( 0 . 7 wt . % to 2 . 63 wt . %) sample c — non - deodorant tampon + 15 % malodor solution + glycerin ( 0 . 92 wt . % to 3 . 61 wt . %) sample d — non - deodorant tampon + 15 % malodor solution + glycerin ( 0 . 92 wt . % to 1 . 81 wt . %)+ polyoxyethylene ( 20 ) ( 0 . 64 wt . % to 1 . 25 wt . %) evaluation of the samples was performed in a well - ventilated room having an exhaust fan available . five objective sensory experts , trained experienced , and calibrated in aroma analysis , evaluated the samples on the date of receipt . each panelist received a complete set of samples with the control and non - deodorant products . all panelists evaluated a sample at the same time , and consensus results of the characteristics and intensities were recorded . panelists waited at least 30 minutes between evaluations and were allowed to smell a neutral substrate ( paper napkin or back of arm ) between and within samples as needed to prevent acclimating to the malodor or fragrance . for each session , one sample was randomly repeated as a check of intensity results . the repeated sample was generally one for which variable results were detected within jar from a single sample treatment . the intensity of the sensory characteristics were rated on a 15 point intensity scale with 0 = none and 15 = very strong . data is reported as consensus data . it is noted that panelists are able to see small differences and can often detect aroma differences as small as 0 . 2 units on the 15 - point scale used . panelists commonly detect differences of 0 . 5 units . table 2 provides mean results over three replications . when reviewing table 2 , it is noted that for attributes having a range in intensity across jars within a sample , the highest values were used to calculate means . as is evident from table 2 , sample d , with the surface active agent according to the present invention , exhibited the lowest overall malodor intensity of the samples tested . the at least one surface active agents may be incorporated in a fibrous absorbent article in any of the following methods , including but not limited to , application during fiber processing , post - processing fiber surface treatment , deposited on the inside of the article , applied to the exterior of the article , included in a coverstock material , included in the removal string or other removal device , included as part of the applicator , encapsulated and applied in above - referenced ways , or any combinations thereof . application methods may include but are not limited to spraying of surfactant in a patterned or random arrangement , deposited in droplets , or any combinations thereof . the present invention having been thus been described with particular reference to the preferred forms thereof , it will be obvious that various changes and modifications may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims . | US-12004402-A |
neuroprobes that include rhenium , manganese , and technetium for use in mapping monoamine reuptake sites are disclosed . non - radioactive tricarbonylrheniumcyclopentadienyl or non - radioactive tricarbonylmanganesecyclopentadienyl phenyltropane analogs are synthesized for use as testing surrogates for radioactive technetium congeners . ferrocenyl analogs of phenyltropane are disclosed as useful precursors for the preparation of novel tricarbonyltechnetiumcyclopentadienyl phenyltropane analogs in radioactive form . | the examples which follow describe methods for preparing tricarbonylrheniumcyclopentadienyl ( trcp ) or tricarbonylmanganesecyclopentadienyl ( tmcp )- tagged phenyltropane analogs . methods are also described for preparing novel ferrocenyl precursors or tricarbonyltechnetiumcyclopentadienyl ( ttcp )- tagged phenyltropane analogs and their transformation to ttcp compounds labelled with 99m tc for use in biological systems . as shown in fig1 mmol 3β -( 4 - iodophenyl )- 2β -( carbomethoxy ) tropane ( β - cit ( 1 )) is dissolved in 25 ml ethyl ether at 0 ° c ., and 2 equivalents of lithium borohydride ( libh 4 ) are added . the temperature is raised to room temperature , and stirring is continued for approximately 2 hr . the reaction is quenched with water and the aqueous phase of the mixture is extracted with methylene chloride . the organic phase is collected and dried over magnesium sulfate and the solvent is removed to give 2β - hydroxymethyl - 3β -( 4 - iodophenyl ) tropane free base ( 2 ) in quantitative yield . 2β - hydroxymethyl - 3β -( 4 - iodophenyl ) tropane was fully characterized as d - tartaric acid : mp = 90 °- 92 ° c ., α ! d 20 - 66 . 3 ° c . ( c , 0 . 525 , meoh ). 1 h nmr ( 250 mhz , cdcl 3 ): δ 7 . 59 ( d , j = 8 . 4 hz , 2h ); 6 . 99 ( d , j = 8 . 4 hz , 2h ); 3 . 76 ( dd , j = 11 . 06 hz ; 1h ); 3 . 44 ( d , j = 4 . 59 hz , 1h ); 3 . 32 ( m , 2h ); 3 . 01 ( m , 1h ); 2 . 47 ( td ; j = 2 . 88 hz , j = 12 . 74 hz ; 1h ); 2 . 20 ( s , 3h ); 2 . 16 ( m , 2h ); 1 . 70 ( m , 2h ); 1 . 65 ( m , 1h ), 1 . 46 ( m , 1h ). anal . ( c 15 h 20 no 1 ) ( c 4 h 6 o 6 ): chn . the produce prepared in step a above ( compound 2 ) is dissolved in toluene ( 1 g / 10 ml ) and 1 . 1 equiv . of triethylamine and 1 . 1 equiv . of cyclopentadiencarbonyl chloride tricarbonylrhenium are added under nitrogen . after heating at reflux for 30 min ., the solvent is removed and the residue is passed through a silica gel column equilibrated with hexane / ether / triethanolamine ( 50 / 50 / 5 ) to produce 3β -( 4 - iodophenyl )- 2β -( tricarbonylrheniumcyclopentadienylcarboxymethyl ) tropane ( 3 ) ( rbi - 211 ) in 76 % yield . mp : 161 °- 162 ° c . ; 1 h nmr ( 250 mhz , cdcl 3 ): δ 7 . 59 ( d , j = 8 . 4 hz , 2h ); 6 . 99 ( d , j = 8 . 4 hz , 2h ); 5 . 80 ( m , 1h ); 5 . 62 ( m , 1h ); 5 . 30 ( m , 2h ); 4 . 48 ( dd , j = 7 . 57 hz , j = 11 . 03 hz ; 1h ); 53 . 86 ( dd ; j = 5 . 86 hz ; j = 10 . 93 hz , 1h ); 3 . 26 ( m , 1h ); 3 . 20 ( m , 1h ); 3 . 07 ( m , 1h ); 2 . 22 ( s ; 3h ); 2 . 10 ( m , 3h ); 1 . 61 ( m , 3h ) ms ( fab ): 720 ( 29 %): 718 ( 23 %); 340 ( 100 %); anal . ( c 24 h 23 no 5 ire ): chn . as shown in fig2 to a solution of 2β - hydroxymethyl - 3β -( 4 - iodophenyl ) tropane ( 1 ) in toluene ( 1 g / 10 ml ), 1 . 1 equiv . of triethylamine and 0 . 5 equiv . of 1 , 1 &# 39 ;- ferrocenedicarbonyl chloride ( 4 ) are added under nitrogen . after heating at reflux for 30 min . the solvent is removed , and the residue passed through a silica gel column with hexane / ether / tea : 50 / 50 / 5 to give 1 , 1 &# 39 ;- bis - 3β -( 4 - iodophenyl ) tropane - 2β - ylmethoxycarbonyl ! ferrocene ( 5 ) in 82 % yield . mp : 74 °- 75 ° c . 1 h nmr ( 250 mhz , cdcl 3 ): δ 7 . 59 ( d , j = 8 . 4 hz , 4h ); 6 . 99 ( d , j = 8 . 4 hz , 4h ); 4 . 57 ( s , 4h ); 4 . 36 ( m , 6h ); 3 . 85 ( m , 2h ); 3 . 30 ( m ; 4h ); 3 . 06 ( m , 2h ); 2 . 29 ( s ; 6h ; 2 . 17 ( m , 8h ); 1 . 68 ( m , 2h ). anal . ( c 42 h 46 feno 4 i 2 re ): chn . as shown in fig3 - bromobutan - 1 - one - cyclopentadiene tricarbonylrhenium ( 6 ) ( 0 . 4 mmol ) and ki ( 10 mg ) are added to a solution of nor - β - cct ( 7 ) ( 0 . 27 mmol ) and triethylamine ( tea , 46 mmol ) in toluene ( 10 ml ). the mixture is refluxed under nitrogen for 3 hours and the progress of the reaction is monitored with thin layer chromatography ( tlc ). the solvent is removed under reduced pressure and the residue is passed through a silica gel column ( equilibrated with a mixture of hexane / ether / triethylamine : 50 / 50 / 5 ) to give n -( tricarbonylrheniumcyclopentadienylbutan - 1 - one - 4 - yl )- 2β - carbomethoxy - 3β -( 4 - chlorophenyl ) nortropane ( 8 ) ( rbi - 235 ) in 64 % yield , as a brown oil . anal . ( c 27 h 27 no 6 clre ) 3 ( h 2 o ): chn 1 h nmr : ( 250 mhz cdcl 3 ): δ 7 . 19 ( dd , j = 7 . 15 hz , j = 7 . 62 hz , 4h ); 6 . 11 ( s , 1h ); 5 . 05 ( s , 1h ); 5 . 39 ( m , 2h ); 3 . 69 ( m ; 1h ); 3 . 49 ( m ; 5h ); 3 . 36 ( m , 1h ); 2 . 89 ( m , 3h ); 2 . 62 ( m , 1h ); 2 . 29 ( m ; 2h ); 2 . 05 ( m , 1h ); 1 . 71 ( m , 3h ); 1 . 21 ( m , 2h ). as shown in fig3 n -( tricarbonylmanganesiumcyclopentadienylbutan - 1 - one - 4 - yl )- 2β - carbomethoxy - 3β -( 4 - chlorophenyl ) nortropane ( 10 ) is prepared using similar procedures as described in example 3 . 4 - bromobutan - 1 - one - cyclopentadienetricarbonyl manganese ( 9 ) ( 0 . 4 mmol ) and ki ( 10 mg ) are added to a solution of nor - β - cct ( 7 ) ( 0 . 27 mmol ) and triethylamine ( tea , 46 mmol ) in toluene ( 10 ml ). the mixture is refluxed under nitrogen for 3 hours and the progress of the reaction is monitored with thin layer chromatography ( tlc ). the solvent is removed under reduced pressure and the residue is passed through a silica gel column ( equilibrated with a mixture of hexane / ether / triethylamine : 50 / 50 / 5 ) to give n -( tricarbonylmanganesecyclopentadienylbutan - 1 - one - 4 - yl )- 2β - carbomethoxy - 3β -( 4 - chlorophenyl ) nortropane ( 10 ) ( rbi - 233 ) in 64 % yield , as an oil . anal . ( c 27 h 27 no 6 clmn ) 3 ( h 2 o ) 2 : chn . 1 h nmr ( 250 mhz , cdcl 3 ): δ7 . 21 ( m , 4h ); 4 . 84 ( s , 2h ); 3 . 69 ( br , 1h ); 3 . 49 ( br , 3h ); 3 . 36 ( br , 1h ); 2 . 90 ( m , 2h ); 2 . 80 ( m , 1h ); 2 . 61 ( m , 2h ); 2 . 27 ( m ; 2h ); 2 . 03 ( m , 2h ); 1 . 71 ( m , 4h ); 1 . 22 ( m , 1h ). as shown in fig4 to a solution of n -( 2 - hydroxypropyl )- 2β - carbomethoxy - 3β -( 4 - chlorophenyl ) tropane ( 11 ) in toluene ( 1 g / 10 ml ) is added 1 . 1 equiv . of triethylamine ( tea ) and 1 . 1 equiv . of cyclopentadienecarbonyl chloride tricarbonylrhenium ( 12 ) under nitrogen . after heating at reflux for 30 min ., the solvent is removed and the residue passed through a silica gel column with hexane / ether / tea : 50 / 50 / 5 to give n -( tricarbonylrheniumcyclopentadienylcarboxypropyl )- 2β - carbomethoxy - 3β -( 4 - chlorophenyl ) nortropane ( 13 ) ( rbi - 232 ) in 45 % yield . 1 h nmr ( 250 mhz , cdcl 3 ): δ7 . 26 ( m , 4h ); 6 . 01 ( m , 2h ); 5 . 36 ( m , 2h ); 4 . 31 ( m ; 2h ); 3 . 67 ( br , 1h ); 3 . 47 ( s , 3h ); 3 . 36 ( m , 1h ); 2 . 90 ( m , 2h ); 2 . 51 ( m , 2h ); 2 . 35 ( m , 2h ); 2 . 10 ( m , 2h ); 1 . 71 ( m , 4h ). anal . ( c 27 h 27 no 7 clre ) ( h 2 o ) 3 : chn . as shown in fig5 a solution of n -( 2 - hydroxypropyl )- 2β - hydroxymethyl - 3β -( 4 - chlorophenyl ) tropane ( 14 ) in toluene ( 1 g / 10 ml ) is combined with 1 . 1 equiv . of triethylamine and 1 . 1 equiv . of cyclopentadienecarbonylchloride tricarbonylrhenium ( 12 ) under nitrogen . after heating at reflux for 30 min ., the solvent is removed and the residue passed through a silica gel column equilibrated with hexane / ether / tea ( 50 / 50 / 5 ) to give 3β -( 4 - chlorophenyl )- 2β - tricarbonylrheniumcyclopentadienylcarboxymethyl ) tropane ( 15 ) ( rbi - 219 ) in 81 % yield . mp = 149 °- 150 ° c . 1 h nmr ( 250 mhz , cdcl 3 ): δ7 . 26 ( d , j = 8 . 1 hz , 2h ); 7 . 14 ( d , j = 8 . 1 hz , 2h ); 5 . 82 ( m , 1h ); 5 . 66 ( m , 1h ); 5 . 33 ( m , 2h ); 4 . 48 ( dd , j = 7 . 57 hz , j = 11 . 03 hz ; 1hy ); 3 . 86 ( dd ; j = 10 . 93 hz , 1h ); 3 . 26 ( m , 1h ); 3 . 20 ( m , 1h ); 3 . 07 ( m , 1h ); 2 . 22 ( s ; 3h ); 1 . 61 ( m , 3h ). anal . ( c 24 h 23 no 5 clre ): chn . radiolabeling of ferrocenyl precursors can be carried out using standard procedures known in the art ( see wenzel et al ., j . label . comp . radiopharm . 31 , 641 - 650 ( 1992 ); wenzel et al ., j . label . comp . radiopharm . 34 , 981 - 987 ( 1994 )). in one embodiment shown in fig6 a ferrocene compound such as 1 , 1 &# 39 ;- bis - 3β -( 4 - iodophenyl ) tropan - 2β - ylmethoxycarbonyl ! ferrocene from example 2 above ( 5 ) ( 2 mg ) and mn ( co ) 5 br are mixed in equimolar ratios in thf , methanol or dmf in a test tube . an equivalent amount of 99m tco 4 - eluate ( 0 . 5 - 10 mci , eluted from a technetium - 99m generator ) is added . the tube is sealed and heated to 150 ° c . for 1 h , after which the reaction mixture is purified by semipreparative hplc ( rp - 18 ), and eluted with 0 . 5 ml h 2 o and 0 . 5 ml methanol to isolate the 99m tc !- labelled compound , and to remove insoluble black particles and unwanted 99m tco 2 . other related ferrocene compounds may also be labelled with 99m tc using similar procedures known in the art in combination with the skills of the ordinary skilled practitioner . each of the compounds synthesized above may be tested for binding to various reuptake sites found in homogenates of brain tissue . each compound is mixed with a crude membrane fraction of homogenates of rat brain corpus striatum ( for the dopamine transporter ) or frontoparietal cerebral cortex ( for the serotonin and norepinephrine transporters ). each compound is tested at six concentrations and in duplicate . each mixture is incubated in tris buffer ( ph 7 . 4 ) containing na + ( 120 nm ), following previously reported methods as described in , e . g ., neumeyer et al ., j . med . chem . 37 : 1558 - 1561 ( 1994 ); anderson , j . neurochem . 48 : 1887 - 1896 ( 1987 ); kula et al ., neuropharmacol . 30 : 89 - 92 ( 1992 ); habert et al ., eur . j . pharmacol . 118 : 107 - 114 ( 1985 ); and tejani - butt , j . pharmacol . exp . ther . 260 : 427 - 436 ( 1992 ). for the dopamine transporter assay , the radioligand was 3 h ! gbr - 12935 ( 13 ci / mmol ; kd = 1 . 0 nm ) at a test concentration ( l )= 0 . 4 nm ( for 45 min at 4 ° c . ), with or without 30 μm methylphenidate used to define nonspecific binding ( blank ). for the serotonin transporter assay , l = 0 . 2 nm 3 h ! paroxetine ( 20 ci / mmol ; kd = 0 . 15 nm 3 h ! paroxetine ( 20 ci / mmol ; kd = 0 . 15 nm ( for 60 min at 20 ° c . ); and 1 μm fluoxetine ( lilly labs ., indianapolis , ind .) as the blank agent . for the norepinephrine transporter assay , l = 0 . 8 nm 3 h ! nisoxetine ( 50 ci / mmol ; kd = 0 . 8 nm ( for 180 min at 4 ° c . ); and 2 μm desipramine ( marion merrel dow , kansas city , mo .) as the blank agent . all radioligands were from dupont - nen , boston , mass . concentration - inhibition curves were computer - fit to determine ic 50 ± sem , and converted to k i values from the relationship ki = ic 50 /( 1 + l / kd !). to evaluate the binding affinities and selectivity of ttcp - tagged phenyltropane analogs for the monoamine transporters , initially , the trcp or tmcp surrogates were prepared to test their ability to selectively bind to desired transporters in radioreceptor assays using the above - described procedure . the resulting affinities and selectivity of the compounds on transporter sites are comparable to the affinity value of β - cit used as a reference standard to establish the design of targeted ferrocenyl precursors for 99m tc - radiolabeling . trcp and tmcp - tagged phenyltropane analogs were evaluated using the above - described radioreceptor binding assay . the results are illustrated in table 1 and compared to results with β - cit . in table 1 , selectivity is defined as the ratio of k i for the dopamine transporter to the k i for the serotonin transporter . table 1______________________________________affinity of β - cit analogs for thedopamine and seratonin transporter dopamine serotonin transporter ( da . sub . t ) transporter ( 5 - ht . sub . t ) da . sub . t / 5 - ht . sub . tcompound ( k . sub . i , nm ) ( k . sub . i , nm ) selectivity______________________________________rbi - 211 7 . 22 ± 1 . 06 34 . 6 ± 3 . 4 0 . 21rbi - 219 4 . 41 ± 0 . 76 11 . 9 ± 1 . 7 0 . 37rbi - 232 2 . 66 ± 0 . 33 0 . 56 ± 0 . 08 4 . 75rbi - 233 1 . 67 ± 0 . 39 0 . 84 ± 0 . 06 2rbi - 235 1 . 29 ± 0 . 1 0 . 37 ± 0 . 04 3 . 49β - cit 1 . 40 ± 0 . 2 0 . 46 ± 0 . 06 3 . 04______________________________________ although the invention has been shown and described with respect to an illustrative embodiment thereof , it should be appreciated that the foregoing and various other changes , omissions , and additions in the form and detail thereof may be made without departing from the spirit and scope of the invention as delineated in the claims . | US-66265696-A |
an intra - abdominally adjustable organ positioning system . the system includes a cord for lifting an organ , such as the liver , during endoscopic surgery , tissue connectors , and an adjustable locking mechanism which allows tightening and loosening of the cord . | fig1 shows one embodiment 12 of the apparatus for intra - abdominal moving a first internal organ to a position away from a second internal organ and then holding the first internal organ in the position without manual input . as stated earlier , the apparatus 12 is constructed of component parts that are often used in laparoscopic instruments and procedures as well as other types of surgical instruments and procedures . because such component parts are known , the component parts that make up the apparatus 12 of the invention will be described herein using their common understood names and functions , without going into the details of the particular constructions of the component parts . as is conventional with laparoscopic apparatus , the component parts of the apparatus are dimensioned to be inserted through an incision in the abdominal wall or through a cannula extending through the abdominal wall to position the apparatus in the abdominal cavity . the basic construction of the apparatus 12 of the invention includes a length of cord . in the example of fig1 the cord length is 10 inches , but the size of the apparatus 12 could change depending on the size of the patient in which the apparatus is used . in the embodiment shown in fig1 , the cord is comprised of a first cord segment 14 having a flexible length with opposite first 16 and second 18 ends , and a second cord segment 22 having a flexible length with opposite first 24 and second 26 ends . the cord segments 14 , 22 could be provided by lengths of suture , lengths of tubing such as iv tubing , lengths of umbilical tape or elastic strips , or other equivalent cord constructions . the tubing or tape configurations of the cord segments have the advantage of being less likely to dig into or cut into the first internal organ in use of the apparatus to be described . the first 14 and second 22 cord segments could be separate cord segments that are attached directly together , or separate cord segments that are attached by way of a further cord segment 28 or some other component part of the apparatus , or two cord segments of a single continuous length of cord such as the two cord segments 14 a , 22 a shown in fig2 . first 32 , second 34 , and third 36 separate tissue connectors are attached to the first 14 and second 22 cord segments . the tissue connectors 32 , 34 , 36 can be any type of known tissue connector that can be manually manipulated to connect to body tissue , and then manually manipulated to be removed from the body tissue without leaving any significant damage to the body tissue . in addition , the tissue connectors 32 , 34 , 36 could be biocompatible tissue connectors that are designed to be left in the abdominal cavity after the surgical procedure is completed . some examples of tissue connectors include suture needles , “ t ” bars , surgical graspers , barbed needles , hooks , clasps , rivet assemblies , or any other equivalent type of connector . in the apparatus of the invention , it is not necessary that all three tissue connectors 32 , 34 , 36 be the same type of tissue connector . because various different types of tissue connectors may be employed with the apparatus 12 of the invention , the three tissue connectors 32 , 34 , 36 of the apparatus 12 are represented schematically in the drawing figures . the first 32 and third 36 tissue connectors are attached to the opposite ends of the first cord segment 14 . the third tissue connector 36 is also attached to one end of the second cord segment 22 , with the second tissue connector 34 being connected to the opposite end of the second cord segment 22 . this positions the first 32 and second 34 tissue connectors at the opposite ends of the combined lengths of the first 14 and second 22 cord segments , and positions the third tissue connector 30 at an intermediate position of the combined length of the first 14 and second 22 cord segments . in fig1 , the first 32 and second 34 tissue connectors are shown connected to the respective first end 16 of the first cord segment 14 and the first end 24 of the second cord segment 22 through the intermediary of additional cord segments 38 , 40 . the third tissue connector 36 is shown connected to the second end 18 of the first cord segment 14 and the second end 26 of the second cord segment 22 through the intermediary of a further cord segment 28 . fig2 shows the apparatus 12 with the first 32 and second 34 tissue connectors connected directly to the respective first end 16 of the first cord segment 14 and the first end 24 of the second cord segment 22 , fig2 also shows the third tissue connector 36 connected directly to the second ends 18 , 26 of the first cord segment 14 and the second cord segment 22 . fig4 and 5 illustrate an example of the use of the apparatus 12 of fig1 according to the method of the invention . in use , the apparatus 12 is first manually passed through the abdominal wall 42 , for example through an incision or a cannula 44 in the abdominal wall 42 , and is positioned in the abdominal cavity 46 in the area of the first 48 and second 50 internal organs . in fig4 , the first internal organ 48 represented is the human liver , and the second internal organ 50 represented is the human stomach . the third tissue connector 36 of the apparatus is then manually connected to tissue 52 adjacent the first internal organ 48 and between the first 48 and second 50 internal organs . in the example shown in fig4 , the tissue 52 is the crus of the diaphragm . connection of the third tissue connector 36 to the tissue 52 positions the second ends 18 , 26 of the first 14 and second 22 cord segments connected to the third tissue connector 32 between the first 48 and second 50 internal organs and on an opposite side of the first internal organ 48 from the abdominal wall 42 . the first tissue connector 32 attached to the opposite end 16 of the first cord segment 14 from the third tissue connector 36 is then manually moved causing the length of the first cord segment 14 to move and engage across the first internal organ 48 . continued movement of the first tissue connector 32 causes the first cord segment 14 engaging across the first internal organ 48 to move the first internal organ toward a position away from the second internal organ 50 . the first tissue connector 32 is then manually connected to the inner abdominal wall 42 . the second tissue connector 34 attached to the opposite end 24 of the second cord segment 22 from the third tissue connector 36 is then manually moved causing the second cord segment 22 to move and engage across the first internal organ 48 . continued movement of the second tissue connector 34 causes the second cord segment 22 engaging across the first internal organ 48 to move the first internal organ 48 toward the position away from the second internal organ 50 . the second tissue connector 34 is then manually connected to the inner abdominal wall 42 . with the apparatus 12 connected between the tissue 52 and the inner abdominal wall 42 in the manner discussed above , the first cord segment 14 and the second cord segment 22 engage across the first internal organ 48 and hold the first internal organ 48 at the position away from the second internal organ 50 without further manual input . this provides surgical access to the second internal organ 50 . without requiring manual holding or restraining of the first internal organ 48 in the position away from the second internal organ 50 . fig6 is a representation of the apparatus of fig2 that has been connected between the tissue 52 and the inner abdominal wall 42 according to the same method as the apparatus of fig1 described above . in a further embodiment of the apparatus of the invention shown in fig3 , the apparatus 54 is comprised of a single cord 56 having a continuous flexible length with opposite first 58 and second 60 ends . a tissue connector in the form of a needle 62 is attached to the first end 58 of the length of cord 56 . at the opposite second end 60 of the length of cord 56 , the cord is formed in a knot 64 . the method of using the embodiment of the apparatus 54 shown in fig3 is illustrated in fig7 . the apparatus 54 is first positioned inside the abdominal cavity in the same manner as the previously described embodiments . the knotted end 64 of the length of cord is then connected to the tissue 52 adjacent the first internal organ 48 by first passing the needle 62 through the tissue 52 and then manually pulling the needle 62 and the attached length of cord 56 through the tissue 52 . this attaches the knotted second end 64 of the length of cord 56 to the tissue 52 between the first 48 and second 50 internal organs . the needle 62 is then passed through the inter - abdominal wall 42 and the needle 62 and the attached length of cord 56 are pulled from the insertion site 72 back into the abdominal cavity 46 . this causes a first segment 74 of the cord length 56 to move into engagement with and across the first internal organ 48 . the engagement of the first cord segment 74 with the first internal organ 48 moves the first internal organ 48 toward the position away from the second internal organ 50 . the needle 62 is then again inserted through the inter - abdominal wall 42 at a second insertion location 76 spaced from the first insertion location 72 . the needle 62 and the attached length of cord 56 are pulled manually through the second insertion 76 into the abdominal cavity 46 until an intermediate section of cord 78 extends between the two insertion sites 72 , 76 . the needle 62 and the attached length of cord 66 are then passed through the knot 64 formed at the opposite end of the length of cord 56 and are pulled tight . this causes a second cord segment 82 of the length of cord 56 to engage across and move the first internal organ 48 toward the position away from the second internal organ 50 . the length of cord 56 is pulled tight and a knot is tied between the opposite ends of the cord at the knot 64 on the cord second end 60 . the portion of the length of cord 54 extending from the knot 64 to the needle 62 is then cut and removed from the abdominal cavity . the length of cord 54 left in the abdominal cavity forms a triangular loop with the first 56 and second 82 cord segments extending across the first internal organ 48 and holding the first internal organ in the position away from the second internal organ 50 without manual input . in this manner , surgical access is provided to the second internal organ 50 without manually holding the first internal organ 48 in its retracted position . fig8 a - 8e represent one method of inserting the apparatus of the invention into the abdominal cavity and the method of using the apparatus . the embodiment of the apparatus 12 shown in these drawing figures has a pair of keith needles 80 , 82 as the first and second tissue connectors , and a “ t ” bar 84 as the third tissue connector . the apparatus 12 is first positioned inside an insertion device 86 in the form of a hollow narrow tube . the insertion device 86 is then inserted through a trocar or cannula 44 that has been positioned in the abdominal wall 42 in a conventional manner . once inside the abdominal cavity 46 , the apparatus 12 is removed from the interior of the insertion device 86 and the insertion device is removed from the abdominal cavity through the cannula 44 . the “ t ” bar 84 or the third tissue connector is then passed through the body tissue 52 , i . e ., the right diaphragm crus as described earlier . once the “ t ” bar 84 is passed through the tissue 52 , it is rotated to its substantially 90 degree position relative to its pathway through the tissue 52 as shown in fig8 c . the apparatus 12 is then pulled from the keith needles 80 , 82 . as represented in fig8 , the keith needles 80 , 82 are then passed through the abdominal wall 42 and the apparatus is pulled tight against the first internal organ 48 , i . e ., the liver . the needles 80 , 82 are then pulled at the exterior of the abdominal wall 42 , causing the apparatus to move the first internal organ 48 away from the second internal organ , i . e ., the stomach . a pair of tension clasps 88 , 90 are attached to the respective first 14 and second 22 cord segments of the apparatus on the exterior of the abdominal wall 42 to hold the apparatus in its position across the first internal organ 48 in the abdominal cavity 46 . fig9 a - 9e represent a method of using an embodiment of the apparatus 12 that is similar to that shown in fig8 a - 8e and described above . in this example , the apparatus 12 also employs the “ t ” bar 84 as its third tissue connector . however , there is no needle provided on the first cord segment 14 and there is no needle provided on the second cord segment 22 . in this embodiment of the apparatus 12 , the first cord segment 14 is a length of suture having a free end 92 opposite the “ t ” bar 84 and the second cord segment 22 is a length of suture also having a free end 94 opposite the “ t ” bar 84 . the apparatus 12 is shown in fig9 a as being positioned in the abdominal cavity 46 using the insertion device 86 in the same manner described earlier with reference to the method of fig8 a - 8e . the apparatus 12 of fig9 a is also initially used according to the same method of fig8 a - 8e in that the “ t ” bar 84 is passed through the body tissue 52 and is positioned substantially 90 degrees relative to the pathway through the tissue . a pair of granee needles 96 , 98 are then passed through the abdominal wall 42 . one of the granee needles 96 grabs the suture free end 92 of the first cord segment 14 and the other granee needle 98 grabs the suture free end 94 of the second cord segment 22 . the granee needles 96 , 98 are then withdrawn through the abdominal wall 42 pulling the suture free ends 92 , 94 through the abdominal wall . the suture free ends 92 , 94 are then secured to the abdominal wall using a pair of clamps 88 , 90 as was done in the previously - described embodiment of fig8 a - 8e . fig1 a and 10b are a representation of the method of the invention practiced using an endo stitch ® device marketed by united states surgical corporation . fig1 a represents the distal end of the endo stitch ® 102 being inserted through the cannula 44 in the abdominal wall 42 to a position adjacent the diaphragm crus 52 . as is conventional , the pair of jaws 104 , 106 at the endo stitch ® distal end 102 hold a needle 108 and a length of suture 110 . the endo stitch ® 102 is manually actuated to pass the needle 108 through the tissue 52 of the crus from one jaw 104 of the endo stitch ® to the opposite jaw 106 of the endo stitch ®. the length of suture 110 is then removed from the abdominal cavity 46 through the cannula 44 and is pulled tight , causing the length of suture 110 to move and hold the first internal organ away from the second internal organ in substantially the same manner as described earlier . fig1 a and 11b represent a further embodiment of the apparatus 12 and its method of use . the embodiment of the apparatus 12 shown in fig1 a and 118 and its method of use are substantially the same as that of earlier - described embodiments , except that the “ t ” bar of the previously - described embodiments is replaced by a “ j ” hook locking clasp 112 . fig1 a shows the locking clasp 112 in its open position prior to the hook portion of the clasp being passed through the tissue 52 of the diaphragm crus . fig1 shows the locking clasp 112 after the hook of the clasp has been passed through the tissue 52 and the clasp has been locked . the method of further using the apparatus to move and hold an internal organ is substantially the same as that of earlier - described embodiments . fig1 a and 126 show a further embodiment of the apparatus 12 and its method of use . the construction of the embodiment of the apparatus 12 shown in fig1 a and 126 is substantially the same as earlier described embodiments , except that the “ t ” bar or locking clasp is replaced by a barbed needle 114 . the method of using the embodiment of the apparatus shown in fig1 a and 126 is substantially the same as that of earlier described embodiments , except that the barbed needle 114 is passed through the tissue 52 of the diaphragm crus until the barb of the needle emerges from the tissue as shown in fig1 b . this secures the apparatus to the tissue 52 . further use of the apparatus to move and hold an internal organ is substantially the same as that of earlier - described embodiments . fig1 a and 13b show a further embodiment of the apparatus 12 of the invention that is substantially the same as that as earlier - described embodiments except that the third tissue connector or “ t ” bar is replaced by a resilient biased clasp 116 . in the method of using the apparatus of fig1 a and 13b , the opposite arms 118 , 120 of the clasp 116 are compressed to open the jaws 122 , 124 of the clasp as shown in fig1 a . the jaws 122 , 124 are then positioned around the tissue 52 of the diaphragm crus and are allowed to close , thereby securing the clasp 116 to the tissue 52 . the subsequent method of using the apparatus shown in fig1 a and 13b is substantially the same as that of previously - described embodiments of the apparatus . fig1 a - 14c show a further embodiment of the apparatus 12 that is substantially the same as that of previously - described embodiments except that the third tissue connector is a two - piece rivet assembly . the assembly is comprised of a pin 126 having an enlarged point 128 and a cap 130 having a circular center opening 132 . in the method of using the apparatus of fig1 a - c , the pin 126 is first inserted through the tissue 52 of the diaphragm crus until the point 128 projects from the opposite side of the tissue . the point 128 is then inserted through the center opening 132 of the cap 130 , thereby securing the pin 126 and the cap 130 to the tissue 152 . the subsequent steps of using the apparatus of fig1 a - 14c is substantially the same as that of earlier - described embodiments of the apparatus . fig1 a and 15b show a further embodiment of the apparatus 12 that has substantially the same construction of earlier - described embodiments of the apparatus except for the first and second tissue connectors being a pair of “ j ” shaped hooks 134 , 136 . in the method of using the embodiment of the apparatus shown in fig1 a and 15b , the first cord segment 14 and the second cord segment 22 are secured to the inner abdominal wall 42 by passing the hooks 134 , 136 through the tissue of the inner abdominal wall . apart from this , the method of using the apparatus shown in fig1 a and 15b is substantially the same as that of earlier - described embodiments of the apparatus . fig1 a and 16b represent a further embodiment of the apparatus and its method of use that are substantially the same as that of previously - described embodiments , except for the first and second tissue connectors being a pair of “ j ” hook locking clasps 138 , 140 . in the method of using the apparatus of fig1 a and 166 , the hook portions of the locking clasps 138 , 140 are passed through the tissue of the inner abdominal wall 42 and then are locked closed . this secures the first cord segment 14 and the second cord segment 22 to the inner abdominal wall . apart from this , the method of using the apparatus of the invention shown in fig1 a and 16b is substantially the same as that of earlier - described embodiments of the apparatus . fig1 shows a representation of an embodiment of the apparatus where the first and second tissue connectors are provided as a pair of resilient , biased clasps 142 , 144 that have substantially the same construction of the earlier - described clasp 116 . the clasps 142 , 144 are secured to the inner abdominal wall 42 by first opening the clasps and positioning tissue of the inner abdominal wall between the open jaws of the clasps , and then allowing the jaws of the clasps to close over the tissue . this secures the first cord segment 14 and the second cord segment 22 to the inner abdominal wall . apart from this , the method of using the apparatus represented in fig1 is substantially the same as that as earlier - described embodiments of the apparatus . fig1 a and 18b show an embodiment of the apparatus and its method of use that is substantially the same as that of fig7 . the embodiment of fig1 a and 18b differs from that of the fig7 embodiment in that the free ends 146 , 148 of the length of suture 150 are tied in a knot completing the triangular loop configuration of the length of suture 150 at a location that is displaced from the portion of the suture 150 passed through the tissue 52 of the diaphragm crus . apart from this , the method of using the apparatus of the invention shown in fig1 a and 18b is substantially the same as that of the embodiment of the apparatus shown in fig7 . fig1 a and 19b show a further embodiment of the apparatus and its method of use . the apparatus shown in these drawing figures is comprised of a length of cord 152 with a circular pledget 154 secured at one end of the cord and a needle , for example a keith needle 156 , secured to the opposite end of the cord . the cord 152 could be a length of suture or other similar material . in the method of using the apparatus shown in fig1 a and 19b the needle 156 is first passed through the abdominal wall 42 and into the abdominal cavity 46 . the needle 156 is then passed through the tissue 52 of the diaphragm crus . the needle 156 is then again passed through the abdominal wall 42 to the exterior of the abdomen and is pulled tight . this results in the length of cord 152 engaging against and moving the first internal organ away from the second internal organ in substantially the same manner as previously - described embodiments . the tight length of cord 152 is then secured in place by a clasp 158 attached to the length of cord 152 against the exterior of the abdominal wall 42 . fig2 a and 20b show a representation of a further embodiment of the apparatus and its method of use . in fig2 a , the apparatus is shown comprised of a length of cord 160 having a circular pledget 162 at one end and a needle , for example a keith needle 164 , at the opposite end . the apparatus also includes a second shorter length of cord 166 with a “ t ” bar 168 at one end and a loop 170 formed in the opposite end . in the embodiment , the cords 160 , 166 may be suture or other similar materials . the method of using the apparatus is represented in fig2 b . the “ t ” bar 168 is first secured to the tissue 52 of the diaphragm crus . the needle 164 is then passed through the tissue of the inner abdominal wall 42 , through the loop 170 and then through the abdominal wall 42 to the exterior of the abdomen . pulling the needle 164 on the exterior of the abdomen pulls the cord 160 tight across the internal organ to move and hold the internal organ in substantially the same manner as that of previously - described embodiments of the apparatus . fig2 a and 21b show a further embodiment of the apparatus that is substantially the same as that of the embodiment of fig2 a and 20b , except that the needle 164 is removed from the end of the length of cord 160 , leaving a free end 172 of the cord . the method of using this embodiment of the apparatus is substantially the same as that of the previously - described embodiment except for the step of passing the cord free end 172 through the abdominal wall 32 . a granee needle ( not shown ) may be used to perform this step of the method . fig2 a and 22b show a further embodiment of the apparatus that is substantially the same as that of the previously - described embodiment , except that it is comprised of only the length of cord 160 having the circular pledget 162 at one end and a free end 172 of the cord at the opposite end . in the method of using this embodiment of the apparatus , the suture free end 172 is first passed through the inner abdominal wall 42 , then through the tissue 52 of the diaphragm crus , and then through and out of the abdominal wall 42 . as in the previously - described embodiment , the suture free end 172 can be passed through the tissue of the abdominal wall 42 and the crus 52 using a granee needle or other similar instrument . the length of cord 160 is pulled tight to move and hold the first internal organ relative to the second internal organ in substantially the same manner as previously - described method embodiments of the apparatus . fig2 shows a further embodiment of the apparatus that is substantially the same as that of earlier - described embodiments except for the first and second tissue connectors being “ j ” hook locking clasps 174 , 176 that incorporate one - way clutch mechanisms . the ends of the cord segments 14 , 22 can be pulled through the clutch mechanisms of the clasps 174 , 176 in one direction , but are prevented by the clutch mechanisms from being pulled through the clasps 174 , 176 in the opposite directions . fig2 a - 24c show representations of a “ j ” hook locking clasp such as that shown in fig2 , with a one - way clutch mechanism . the one - way clutch mechanism is comprised of a rotatable pulley 178 and a “ v ” shaped groove 180 positioned adjacent the pulley 178 . an end portion of the cord 182 is threaded through the “ v ” shaped groove 180 and then around the pulley 178 . when the end of the cord 182 extending from the pulley 178 is pulled tight , the relative positions of the pulley 178 and the groove 180 cause the portion of the cord 182 to wedge and become locked in the bottom of the groove 180 . fig2 shows a further representation of the embodiment of the apparatus employing a “ j ” hook locking clasp 184 with a one - way clutch mechanism . the one - way clutch mechanism is comprised of a pair of pivoting cams 186 , 188 having opposing ratchet tooth surfaces 190 , 192 . a portion of the apparatus cord 194 is threaded between the opposed tooth surfaces . the portion of cord 194 can be pulled through the spacing between the cam ratchet tooth surfaces 190 , 192 in one direction , for example to the left in fig2 , but the cams 186 , 188 pivot toward each other and their ratchet tooth surfaces 190 , 192 clamp the cord portion 194 between the surfaces when the cord portion is pulled in the opposite direction , for example to the right as shown in fig2 . fig2 shows a representation of a further embodiment of the “ j ” hook clasp 196 having a one - way clutch mechanism . in this embodiment , the one - way clutch mechanism is comprised of a toothed wheel 198 that engages with the cord portion 20 pulled through the claps 196 . the tooth wheel 198 also has a smaller ratchet wheel 202 at its center . the ratchet wheel 202 engages against a resilient pawl 204 . the ratchet wheel 202 and resilient pawl 204 function in the conventional manner allowing the toothed wheel 198 to rotate in one direction when the cord portion 200 is pulled through the clutch mechanism , for example to the right as shown in fig2 , but prevent the rotation of the toothed wheel 198 and the movement of the cord portion 200 when the cord portion is pulled in the opposite direction , for example to the left as shown in fig2 . fig2 - 32 show several different representations of the possible constructions of the cord segments 14 , 22 , 38 of the apparatus of the invention . in fig2 - 32 the first and second tissue connectors are represented by needles , for example keith needles 80 , 82 . the third tissue connector is represented by a “ t ” bar 84 . it should be understood that these are only examples of only three tissue connectors that could possibly be used with the apparatus of the invention , and that other forms of tissue connectors , for example the types described herein could be used as the three tissue connectors on the apparatus . fig2 shows the first 14 , second 22 and third 38 cord segments as being constructed of suture material . fig2 shows the first 14 and second 22 cord segments being part of a single length of surgical tape or strap , and the third cord segment 38 being constructed of suture . fig2 shows the first 14 and second 22 cord segments being constructed of lengths of suture inserted through lengths of surgical tubing . the third cord segment 38 is constructed of suture . fig3 shows the apparatus as having first 14 and second 22 cord segments constructed of combinations of surgical tape and suture connected end to end . the third cord segment 38 is constructed of suture material . fig3 shows the apparatus being constructed of first 14 and second 22 cord segments formed from a single length of suture material inserted through a single length of surgical tubing . the third cord segment 38 is constructed of suture material . fig3 shows the apparatus as having the first 14 and second 22 cord segments constructed of a single continuous length of surgical tape having lengths of suture at opposite ends . the third cord segment 38 is constructed of suture material . fig3 - 45 show examples of some of the various different types of tissue connectors that could be used as any one of the tissues connectors 32 , 34 , 36 of the apparatus . these are only some of the possible types of tissue connectors , and the connectors shown in fig3 - 45 should not be interpreted as limiting the apparatus to the particular tissue connectors shown . fig3 shows a “ t ” bar 84 as one example of any one of the three tissue connectors 32 , 34 , 36 . fig3 shows a barbed needle 114 as any one of the three tissue connectors 32 , 34 , 36 . fig3 shows the two - piece rivet pin 126 and cap 30 connector that can be used as any one of the three tissue connectors 32 , 34 , 36 . fig3 shows the “ j ” hook locking clasp 112 that can be used as any one of the three tissue connectors 32 , 34 , 36 . fig3 shows the resilient , biased clasp 116 that could be used as any one of the three tissue connectors 32 , 34 , 36 . fig3 shows a cross - section of an embodiment of a “ j ” hook locking clasp . the embodiment shown is comprised of a cylindrical housing 206 that contains the “ j ” hook 208 and a coil spring 210 that biases the “ j ” hook 208 to its closed position . fig3 a - 39c show a variation of the “ j ” hook locking clasp of fig3 where the coil spring 210 is replaced by a spiral band spring 212 . fig3 b shows the spiral and spring 212 in its extended configuration , and fig3 c shows the spring in its compressed configuration . fig4 a and 40b show a tissue connector clasp that is comprised of a pair of resilient jaws 214 , 216 that project from one end of a hollow housing 218 , and a pin 220 connected to the jaws that projects from the opposite end of the housing . a spring 22 contained in the housing 218 biases the pin 220 and the jaws 214 , 216 to the left as shown in fig4 a . this causes the resilient jaws to move to their open position shown in fig4 a . pulling the pin 220 to the right against the bias of the spring 222 causes the housing to slide against the opposite sides of the jaws 214 , 216 and move the jaws to their closed position . fig4 shows a side view of the resilient biased clasp 116 described earlier . compressing the opposite arms 118 , 120 of the clasp 116 causes the jaws 122 , 124 to separate . releasing the compression force causes the jaws 122 , 124 to move together under the bias of the resilience of the clasp 116 . fig4 shows an embodiment of a clasp comprised of a first jaw 224 and first arm 226 connected by a pivot connection 228 to a second jaw 230 and second arm 232 . an oblong cam 234 on a toothed cam wheel 236 is positioned between the pair of arms 226 , 232 . a toothed actuator wheel 238 meshes with the toothed cam wheel 236 . rotation of the actuator wheel 238 will cause rotation of the cam wheel 236 and the cam 238 . rotation of the cam 234 to its position shown in fig4 pushes the pair of arms 226 , 232 away from each other which in turn causes the pair of jaws 224 , 230 to move toward each other . rotation of the cam 234 90 degrees or one - quarter turn from its position shown in fig2 will cause the jaws 242 , 230 to move away from each other . fig4 shows an embodiment of a clasp comprised of a first jaw 240 and first arm 242 connected by a pivot connection 244 to a second jaw 246 and second arm 248 . a spring 250 is positioned between the pair of arms 240 , 248 and biases the arms away from each other . this in turn biases the first jaw 242 and second jaw 246 toward each other . the jaws 242 , 246 are opened by applying a compression force to the opposite sides of the first arm 240 and second arm 248 that compresses the spring 250 . fig4 a - 44b show a side - sectioned view of a construction of the rivet assembly described earlier . as seen in the drawing figures , the pin head 128 is slightly larger in diameter than the cap hole 132 . when the pin 126 is attached to the cap 130 , there is a fixed gap or maximum distance between a circular head 252 of the pin 126 and the cap 130 . fig4 a - 45e show a further embodiment of a rivet assembly . in this assembly , the rivet pin 254 has several notches 256 along its length between the pin head 258 and the pin point 260 . the rivet cap 262 is similar in construction to that of the previously - described embodiment with a center opening or hole 264 extending through the cap . however , the cap 262 is also formed with a transverse slot 266 that intersects the center hole 264 and a parallel slot 268 that extends into the cap 262 parallel to the center hole 264 and intersects the transverse slot 266 . a locking tab 270 with a pin hole 272 and a spring hole 274 is inserted in the transverse slot 266 for sliding movement therein . a resilient wire spring 276 is inserted downwardly into the parallel slot 268 and through the tab pin hole 272 . inserting the rivet pin 254 into the cap center hole 264 and through the tab pin hole 272 causes the pin to slide the tab to the left as shown in fig4 a against the bias of the wire spring 276 . as a pin notch 256 passes through the tab hole 272 , the bias of the spring 276 causes the tab 270 to move to the right and into the notch 256 . this locks the pin 254 in place relative to the cap 262 . with the pin 254 having a number of notches , and in the example of fig4 a having three notches , the position of the pin head 258 relative to the cap 262 can be adjusted between three positions . this provides an adjustable gap or an adjustable distance between the pin head 258 and the cap 262 . fig4 a - 46e represent a further embodiment of the apparatus of the invention . this embodiment is comprised of a length of cord 278 having a needle 280 at one end and a loop 282 formed at the opposite end . a circular pledget 284 is provided on the length of cord 278 toward the loop end of the cord . the apparatus also includes a locking collar having a hollow cylindrical housing 286 that contains a tubular one - way suture lock 288 . the suture lock 288 is basically cylindrical but is formed with a resilient tab 290 that projects toward the center of the cylindrical configuration of the suture lock . fig4 e shows a cross - section representation of the collar cylindrical housing 286 containing the one - way suture lock 288 and a portion of the length of cord 278 extending through the collar . the method of using this embodiment of the apparatus is shown in fig4 c . in use in the abdominal cavity 46 , the needle 280 is first passed through the tissue 52 in the area of the diaphragm crus , and then is passed a first time through the inner abdominal wall 42 . the needle 280 is then moved across the inner abdominal wall 42 and is again passed a second time through the inner abdominal wall . the needle is then inserted through the loop 282 and is pulled tight . this causes the length of cord 278 to form a triangular loop in the abdominal cavity that moves the first internal organ away from the second internal organ and holds the first internal organ in the displaced position in the same manner as previously - described methods of using the apparatus of the invention . the needle 280 is then passed through the collar cylindrical housing 286 and the housing 286 is moved tight against the cord loop 282 . the cord loop 282 is smaller than the housing 286 so that the housing cannot pass through the loop 282 . as the length of cord 278 is pulled through the collar housing 286 , the locking tab 290 engages against the side of the cord 278 as shown in fig4 e . this allows the cord 278 to move through the collar housing 286 in the direction to the right shown in fig4 e , but prevents movement of the cord to the left as shown in the figure . in this manner , the apparatus of fig4 a - 46e holds the length of cord tight in its triangular loop configuration . fig4 a and 47b show a further embodiment of the apparatus of the invention and its method of use . the apparatus is comprised of a length of cord 294 having a pledget 296 secured at one end and a needle 298 secured at the opposite end . the apparatus also includes a one - way locking mechanism 300 having a pair of channels 302 , 304 through the mechanism dimensioned to receive the length of cord 294 . one of the channels 302 allows the length of cord 294 to move through the channel in one direction , but prevents the opposite direction of movement . the other channel 304 allows the length of cord 294 to move through the channel in one direction , but also prevents the opposite direction of movement of the cord 294 . as represented in fig4 a , the method of using the apparatus first involves the needle 298 passing through the inner abdominal wall until the pledget 296 is positioned up against the wall . the needle 298 then passes through the tissue 52 in the area of the diaphragm crus . the needle 298 is then inserted through the first channel 302 of the one - way locking mechanism 300 . the needle 298 is then against passed through the inner abdominal wall at a location spaced from the first insertion site and is then passed through the second channel 304 of the one - way locking mechanism 300 . the needle 298 with the length of cord 294 are then pulled tight and the locking mechanism 300 is moved up against the inner abdominal wall at the second needle insertion site . this causes the length of cord 294 to move the first internal organ and hold the first internal organ in its moved position away from the second internal organ in a similar manner to that of earlier - described embodiments . fig4 c and 47d show the interior of one embodiment of the one - way locking mechanism 300 . the mechanism 300 includes a housing first half 306 and a second half 308 that are connected together by a living hinge 310 . the open position of the locking mechanism is shown in . fig4 d . the interior of the two halves 306 , 308 of the locking mechanism are formed with grooves 312 , 314 that form the two channels 302 , 304 through the locking mechanism when the two halves 306 , 308 of the locking mechanism are pivoted about the living hinge 310 and snapped together . a “ u ” shaped spring member 316 is positioned in the first locking mechanism half 306 . the spring member 316 has a pair of arms 318 , 320 that project from opposite sides of the spring member . each arm 318 , 320 in turn has a resilient locking tab 322 , 324 that projects outwardly at an angle from its respective arm 318 , 320 . the resilient tabs 322 , 324 are positioned to engage in sliding engagement along portions of the cord 294 that pass through the channels 302 , 304 . as shown in fig4 d , the one tab 322 will allow the cord 294 to slide across the tab in a direction from right to left as shown in the drawing figure , but will prevent the reverse sliding movement of the cord . the other tab 324 will allow sliding movement of the cord 294 across the tab 324 in a left to right direction as shown in fig4 d , but will prevent the reverse movement of the length of cord 294 . fig4 a - 48d show a variant embodiment of the one - way locking mechanism 300 . as shown in fig4 a , the length of cord is passed through the locking mechanism 328 in much the same manner as the earlier - described locking mechanism 300 . however , the second channel 330 of the locking mechanism 328 of fig4 a has a block 332 with a hole 334 positioned along the channel . an inclined tooth 336 is positioned in the block hole 334 . the portion of the cord length 338 that extends through the locking mechanism channel 330 also extends through the block hole 334 . a spring 340 in the locking mechanism 328 biases the block 332 and the tooth 336 toward the portion of cord 338 extending through the locking mechanism channel 330 . due to the inclination of the tooth 336 , with the spring 340 biasing the tooth 336 into engagement with the cord portion 338 , the cord portion 338 can slide over the tooth 338 as it is moved in a left to right direction as shown in fig4 c , but is prevented from moving in the opposite direction . pressing the block 332 into the locking mechanism 328 against the bias of the spring 340 disengages the tooth 336 from the cord portion 338 and permits the cord portion to move in either direction through the locking mechanism 328 . fig4 a and 49b show a further embodiment of a cord locking mechanism 344 that is similar to that of fig4 a . a cross - section of a channel 346 extending through the locking mechanism 344 is shown in fig4 a . the channel 346 is formed with pairs of ridges 348 , 350 on opposite sides of the channel . a wave form spring 352 is positioned in the channel 346 . the spring 352 has grooves 354 formed through peaks formed in the wave form spring . the portion of the cord 356 passing through the locking mechanism channel 346 also passes through the grooves 354 in the wave form spring 352 . a button hole 358 is provided in the top of the cord locking mechanism 344 and a release button 360 is positioned in the hole . when the release button 360 is pressed in the hole 358 , it engages with the wave form spring 352 and compresses the spring to the position shown in fig4 a . in this position of the spring 352 the cord 356 is free to move in opposite directions through the locking mechanism 344 . when the button 360 is released , the spring 352 moves upwardly from its position shown in fig4 a and portions of the spring 362 engage with the cord portion 356 extending through the lock mechanism channel 346 and hold the cord portion against the ridges 348 at the top of the channel 346 . this locks the cord portion 356 in the locking mechanism 344 . fig5 a and 50b show a further embodiment of a one - way cord locking mechanism . the mechanism includes a housing 364 having a hole 366 extending through the housing that is defined by a cone - shaped interior surface 368 . a pair of lock members 370 , 372 are positioned in the housing hole 366 . each of the lock members 370 , 372 have exterior surfaces 374 , 376 that when the locking members are positioned together , define a truncated cone shape that fits within the cone - shaped interior surface 368 of the housing 364 . the opposing interior surfaces 378 , 380 of the lock members 370 , 372 are formed with mating peaks and valleys . as shown in fig5 b , a spring 382 biases the two lock members 370 , 372 into the cone - shaped interior surface 368 of the housing 364 , thereby causing the lock member interior surfaces 378 , 380 to move toward each other . a portion of a cord length 384 extending through the opposing interior surfaces 378 , 380 of the lock members 370 , 372 is prevented from moving in the upward direction as shown in fig5 b due to the bias of the spring 382 . however , when the cord portion 384 is moved in the opposite downward direction as shown in fig5 b , the movement of the cord portion 384 causes the lock members 370 , 372 to compress the spring 382 . this allows the lock member interior surfaces 378 , 380 to move away from each other and release the portion of the cord 384 for movement through the lock mechanism . fig5 a - 51e show one method of inserting the apparatus of the invention into the tubular insertion device 86 described earlier . as shown in these drawing figures , a length of suture 386 is looped around the apparatus and is then pulled through the interior of the insertion device 86 . the first 14 and second 22 cord segments are folded flat against each other and the additional cord segment 38 is folded over parallel with the first cord segment 14 and second cord segment 22 . the apparatus is then pulled by the suture loop 386 into the interior of the insertion device 86 to the position shown in fig5 e . fig5 a and 52b show a further embodiment of an insertion device 390 . the insertion device 390 has the configuration of an elongate narrow rod with a pair of opposed grooves 392 , 394 extending up one side of the rod from a distal end 396 of the rod . a third groove 398 is formed in a side of the rod toward a proximal end of the rod . the third groove 398 is positioned between the opposed pair of grooves 392 , 394 . according to the method of using the insertion device 390 , the first cord segment 14 and second cord segment 22 of the apparatus 12 are positioned in the opposed pair of grooves 392 , 394 that extend from the insertion device distal end 396 . the additional cord segment 38 of the apparatus 12 is positioned in the third groove 398 in the side of the rod . with the cords of the apparatus held in these grooves , the insertion device 390 is then inserted through a cannula 44 to insert the apparatus 12 into the abdominal cavity . fig5 shows a representation of a further embodiment of the insertion device 402 that is similar in construction to the previously - described embodiment of the insertion device 390 . the insertion device 402 of fig5 is also comprised of a pair of opposed grooves 404 , 406 that receive the first 14 and second 22 cord segments of the apparatus 12 , and a third groove 408 that receives the additional cord segment 38 of the apparatus . fig5 shows a still further embodiment of an insertion device 410 . the insertion device 410 has a rod - shaped length with a hollow distal end . the rod distal end is comprised of a first half 412 and a second half 414 that are connected together by a living hinge assembly 416 . according to the method of using the insertion device 410 of fig5 , the apparatus 12 is positioned in the interior of the first half 412 with the first cord segment 14 and second cord segment 22 extending parallel to each other , and the third cord segment 38 folded aver the first cord segment 14 and second cord segment 22 . the second half 414 of the insertion device is then folded over the hinge assembly 416 and snapped closed to prepare the insertion device 410 for insertion of the apparatus 12 . fig5 a - 55c show a mesh apparatus 420 that is designed to be used as a part of the apparatus of the invention . the mesh apparatus 420 is basically comprised of a generally rectangular or trapezoidal - shaped panel of surgical mesh 422 with a pair of axially aligned tubes 424 at one side and a pair of axially aligned tubes 426 at the opposite side . as shown in fig5 b , the mesh apparatus 420 can be rolled up around the pairs of tubes 424 , 426 to reduce the size of the apparatus for insertion through a cannula and into the abdominal cavity . fig5 c shows the mesh apparatus 420 positioned in the abdominal cavity 46 and held in place against the first internal organ 48 by one of the previously - described embodiments of the apparatus . it should be understood that any of the previously - described embodiments of the apparatus may be employed according to the method of the invention to hold the surgical mesh 420 in its position as shown in fig5 c . as various modifications could be made in the constructions of the apparatus and the methods herein described and illustrated without departing from the scope of the invention , it is intended that all matter contained in the foregoing description or shown in the accompanying drawings shall be interpreted as illustrative rather than limiting . thus , the breadth and scope of the present invention should not be limited by any of the above - described exemplary embodiments , but should be defined only in accordance with the following claims appended hereto and their equivalents . | US-201615171850-A |
a customizable organizational and internal communications system comprises several interconnected modules , wherein the modules therein can be firmly interlocked and easily interchanged . the organizational system comprises multiple rectangular modules having longitudinal channels at all corners , each module being formed by four rectangular panels having alternating rectangular crenellations and rectangular recesses which are inversely configured on two opposite edges ; multiple interlocking pins having a shape which is fitted into hollow space defined by the corner channels of adjacent modules so as to keep them from moving apart ; and an optional rectangular box frame surrounding the assembly of multiple rectangular modules . accessory panels having various functions , such as calendar , key holder , can be inserted in each module to provide for desired functionality customized by the end user . | referring now to fig1 and 2 , the key inventive concept of the present inventive system 10 lies in rectangular modules 12 formed by four identical rectangular panels 16 having alternating rectangular crenellations 23 , 24 and rectangular recesses which are inversely configured on two opposite edges 22 , height of the crenellations being essentially equal to thickness of the panels . in an exemplary embodiment , fig4 and 5a shows inner and outer surfaces 28 , 30 respectively of the panel 16 . the term “ alternating ” here means that on each of the two opposite edges , the crenellations 24 , 26 and recesses 22 appear alternately , i . e ., each crenellation is next to a recess and each recess is next to a crenellation . the term “ inversely configured ” here means , as compared to the configuration on the first edge ( bottom edge ), crenellations 24 , 26 and recesses 22 on a second edge ( top edge ), which is opposite to the first edge , appear in a totally inverse manner . namely , if one first crenellation 24 appears on the first edge , its corresponding location on the second edge will be one second recess 22 having the same width as the first crenellation 24 ; while if one first recess appears on the first edge , its corresponding location on the second edge will be one second crenellation having the same width as the first recess . the fold symmetry is such that rotation by 180 ° provides the identical shape . with these features , two adjacent panels 16 can be well assembled vertically by engaging first crenellations 24 , 26 of one panel into second recesses 22 of the adjoining panel to form the module corner . fig9 and 10 show how crenellations 24 , 26 and recesses of four panels are assembled in an end - to - end way , so as to form a module . fig4 and 5a show one preferred embodiment wherein the panel 16 has two crenellations 24 , 26 and two recesses 22 alternating on each edge . the present invention can further encompass other embodiments with panels having various numbers of crenellations and recesses . for example , in another embodiment ( not shown ), the panel may have only one crenellation and one recess on each of the opposite edges , which are inversely configured . in another embodiment ( not shown ), the panel may have three crenellations and three recesses alternating on each of the opposite edges , which are inversely configured . in another embodiment ( not shown ), the panel may have four crenellations and four recesses alternating on each of the opposite edges , which are inversely configured , and so on . more crenellations and recesses may provide better engagement , but at the sacrifice of structural strength . alternatively , the present invention can further encompass other embodiments with panels having different numbers of crenellations and recesses on each edge . for example , in another embodiment ( not shown ), the panel may have two first crenellations and one first recess alternating on the first edge , as well as one second crenellation and two second recesses alternating on the second edge opposite to the first edge , which are inversely configured . in this case , there is not the same symmetry and will require different panels 16 . in another embodiment ( not shown ), the panel may have three first crenellations and two first recesses alternating on the first edge , as well as two second crenellations and three second recesses alternating on the second edge opposite to the first edge , which are inversely configured . in another embodiment ( not shown ), the panel may have four first crenellations and three first recesses alternating on the first edge , as well as three second crenellations and four second recesses alternating on the second edge opposite to the first edge , which are inversely configured , and so on . in the preferred embodiment as shown in fig4 and 5a , all the crenellations 24 , 26 and recesses 22 possess the same width . however , a skilled person in the art will readily understand that the crenellations and recesses on one edge do not necessarily possess the same width . as long as each crenellation has a width essentially identical with the recess at the corresponding location on the opposite edge , they can be perfectly engaged ( since height of the crenellations is equal to thickness of the panels ) when four panels are vertically assembled in an end - to - end way to form a module . in a detailed embodiment ( not shown ), a crenellation may have a width greater than the recess next thereto ; while on its opposite edge , a crenellation may have a width shorter than the recess next thereto . the interlocking pin according to the present invention has four round - shaped corner beads for holding the modules by being slid into the circle - shaped corner channels , so its cross - section has four symmetric axes and one symmetric center . when four modules are arranged in a 2 × 2 grid as shown in fig8 , the shape of the interlocking pin 40 is always identical to the hollow space defined by the four adjacent corner channels . depending on the position / size of module corner channels and its outwardly facing opening , the above - mentioned hollow space and corresponding interlocking pin can be variously shaped . fig3 a to 3d show several embodiments of interlocking pins 40 which can match the embodiment as described in fig9 and 10 ( wherein fig1 clearly shows how interlocking pins 40 are fitted into the corner channels of an assembled module ). the interlocking pins 40 in these figures have four round - shaped corner beads 44 and one central spine 46 . the central spine 46 a in fig3 a is hollow , for the purpose of such as weight reduction and wire routing . at the front surface ( facing the user ) of the central spine 46 b , cuboid projection 48 b in fig3 b and cuboid hole 42 c in fig3 c are for the purpose of securing an interlocking pin cap or a box frame front cover ( which will be discussed below ). the central spine 46 d in fig3 d is solid , providing greater strength . the following description of the assembly of panels into a module where the corner channels for the module provide for receiving the interlocking pin bead 44 that connects that module corners of adjacent panels so that the modules retain their rigid configuration when assembled . fig9 clearly shows four longitudinal channels 32 at all corners of the module . the cross - section of each channel 32 is substantially circle - shaped and has an outwardly facing opening . it is important that the outwardly facing opening is no more than one - third circle , so that the module can be firmly held by sliding the corner bead 44 of the interlocking pin 40 into the channel 32 . if the opening occupied more than one - third of the whole circle , it can be imagined that the corner bead 44 will easily fall out of the channel 32 . fig9 also clearly shows that each corner channel 32 is formed by several channel segments on the first crenellations 24 , 26 of one panel 16 and the second crenellations 24 , 26 of its adjacent panel 16 , as they are perfectly engaged . as stated above , no matter which kind of configuration of crenellations and recesses is applied ( such as the configuration in the preferred embodiment as shown in fig4 , the configuration with different numbers of crenellations and recesses , or the configuration with different widths of crenellations and recesses ) to achieve a perfect engagement at a corner , all the channel segments on the involved crenellations should be completely aligned to form a longitudinal channel 32 with an outwardly facing opening , and the opening having a center that projects at a 45 ° angle from the surface 30 . optionally , a box frame is provided to surround the assembly of multiple rectangular modules 12 with interlocking pins 40 , wherein the box frame 60 has multiple longitudinal channels 62 on its inner surface 65 , so as to form , with the corner channels 32 of adjacent modules , multiple hollow spaces having the same shape as the interlocking pins 30 and fitting them in . fig2 shows one embodiment with a box frame 60 , wherein two adjacent module corner channels in the top row form an w - shaped space to fit in the bottom half ( i . e ., two beads 44 ) of the interlocking pin 40 ( which is enlarged in fig7 ). correspondingly , the box frame 60 as shown in fig2 also has an inverted w - shaped channel 64 to fit in the top half of the interlocking pin 40 , i . e ., the hollow space here , having the shape identical to the interlocking pin 40 , is formed by two adjacent module corner channels 32 in the top row as well as the w - shaped channel 64 on the inner surface of the box frame 60 . similar situations occur at the bottom row and two side columns . at each corner of the box frame , because only one corner channel 32 is provided by the module to contain one bead 44 of the interlocking pin 40 , the inner surface of the box frame corner will have to provide cover channels 62 to contain the remaining three beads 44 of the interlocking pin 40 . that is to say , the hollow space here , having the shape identical to the interlocking pin 40 , is formed by one module corner channel 32 as well as the club - shaped space on the inner surface of the box frame corner . the box frame 60 according to the present invention does not necessarily consist of one piece . fig6 shows another embodiment , wherein the box frame 160 comprises four separate walls 162 , 164 , 166 , 168 . the interlocking pins 40 at four corners of the box frame 160 in this embodiment also serve to hold two adjacent pieces of walls , e . g ., walls 166 , 168 , together , in addition to securing the corner module 12 to the box frame 60 . the securing manner at top and bottom rows as well as two side columns is identical to the previous paragraph . furthermore , the box frame serves to mount the whole assembly of organizational system into or onto the standing wall 11 . fig1 shows an in - wall mounting manner with two wall studs 13 ( dotted lines ) for mounting the organizational system . fig6 shows an on - wall mounting configuration . the mounting may be effected by means of corner brackets 49 attached to the studs 13 , within the wall surface 11 , by an appropriate means such as wood screws 51 , as shown in fig6 . a skilled person in the art can readily understand that the mounting manner depends on actual demand , regardless of whether the box frame consists of one piece or multiple pieces . in addition to the embodiment where a single square module is formed by four regular panels ( i . e ., one square long ) as shown in fig9 and 10 , the organizational system according to the present invention can also comprise a multiple - square module comprising end - to - end or vertically connected module sections to form a unitary storage space , as shown in fig6 a and 13 . for instance , fig6 a shows three - square modules 84 for use as mailbox and a two - square - width two - square - high module 86 for use as calendar . such multiple - square module , which is as at least two times long ( such as two times , three times , four times , or other integer times ) in width and / or height as the single square module as shown in fig9 , can be formed with longer panels . alternatively , the panels may be joined end to end to provide a 2 × or 3 × length of panel as shown in fig5 b , described below . in an exemplary embodiment of mailbox module as shown in fig6 , the top and bottom panels are both three - square - long , whereas the two side panels are regular ones ( i . e ., one square long ). here , an important thing lies in that these three - square - long panels have w - shaped channels on the outer surface at their points of trisection , so as to form hollow space with above - defined shape for receiving interlocking pins . in another exemplary embodiment of calendar module as shown in fig6 , the two - square - long panels also have w - shaped channels at their outer surface at their midpoints , so as to form hollow space with above - defined shape for receiving interlocking pins . similarly , it is not difficult to imagine that if a four - square module is formed by two four - square - long panels and two regular panels , these four - square - long panels will have w - shaped channels on the outer surface at their points of quadrisection , so as to form hollow space with above - defined shape for receiving interlocking pins . another way to form a multiple - square module is shown in fig1 . in this embodiment , three panels 16 are disposed lengthwise horizontally end to end to form a top surface and three more panels 16 are disposed to provide for a bottom surface of a three - unit module . of course , the ends of this module are defined by two vertical panels 20 , all the panels cooperatively interfitting at their crenelated edges as in the other embodiments described above . certain manipulations or alterations to the interconnecting pin ( not shown ) may be required to accommodate the dimensions of a specific three - unit module when it takes up the space of three separate one unit modules , but that can be done by judicious use of the interconnecting pin structure . in the preferred embodiment , as shown , each assembled module could contain one or more functional accessories which may be mounted on rectangular inserts 80 ( fig9 ). these inserts 80 may include any desirable functional elements , such as an envelope holder , key holder , cell phone or other electronic device charger , writing / display board , calendar , and mirror . however , the discerning user could conceivably provide for additional functional inserts ( not shown ) and this invention is not to be considered as being limited by the enumerated functional inserts . one common element in all of the insert 80 embodiments having functional accessories is the accessory tab slots 34 , preferably being centrally disposed on the crenellated edge 22 of each panel 16 , so as to firmly hold the functional accessories by fitting the accessory tabs into the accessory tab slots . fig1 shows one exemplary design of such combination of accessory tabs 81 and accessory tab slots 34 , wherein the accessory tab slots 34 are located among the crenellations and recesses at two opposite edges of the panel , while the accessory tabs 81 are located at each corner of the key holder accessory 80 . accessory tab channels 90 having an outwardly facing opening are present on each accessory tab 81 , so that when the accessory tab 81 is fitted into accessory tab slots 34 during module assembly , these accessory tab channels 90 will be perfectly aligned to other channel segments forming the channel 32 on the adjacent crenellations to form a complete channel 32 for fitting in a corner bead of interlocking pins 40 . this structurally is a more robust configuration in that both the tab slots 34 and the interlocking pins 40 retain the accessary 80 . there are other designs to locate the accessory tab slots in different manners . in one embodiment where the accessory tab slots are in the middle of each panel , the accessory tabs are correspondingly located at the middle of each edge of the accessory , so that the machining process can be simplified . in another embodiment where the number of the accessory tab slots is not intendedly limited , each panel can have more than one ( such as two , three , four , etc .) slots in the middle ; correspondingly , the same number of accessory tabs are located at the middle of each edge of the accessory , so that the strength can be improved . it is not difficult to imagine that , in another embodiment , the accessory tab slots can be located both at two opposite edges and in the middle of the panel , while the accessory tabs are correspondingly located both at each corner ( with accessory tab channels as above stated ) and at the middle of each edge of the accessory . fig1 and 2 show that a box frame front cover 70 , as an optional element of the organizational system 10 , is in front of the other parts for structural and aesthetical purpose . it can be seen from the exploded view in fig2 that if the interlocking pins 40 a , 40 c of fig3 a and 3c are applied , the back side of the box frame front cover 70 can have cuboid projections at corresponding locations to be inserted into the hollow central spines 46 a or into the cuboid holes 46 c of the central spines 42 c ; while if the interlocking pins 40 b of fig3 b are applied , the back side of the box frame front cover 70 can have cuboid holes to fit in the cuboid projections 48 b of the central spines 42 b . in addition , if the interlocking pins 40 d of fig3 d are applied , the back side of the box frame front cover may be flat and glued onto the front surface of the central spines 46 d . different from the box frame front cover 70 which is secured to the outermost interlocking pins , fig8 shows an interlocking pin cap 52 which is secured to a middle interlocking pin 40 among modules . here , although an interlocking pin 40 a , 40 c of fig3 a or 3c is shown , a skilled in the art can readily understand that this cap 52 can be secured in similar manners as set forth for box frame front cover 70 if another type of interlocking pin 40 is applied . as shown in fig1 , the modules may optionally have inconsecutive bars at their rear edge 20 ( the surface not facing the user ), and the gap between the bars of adjacent modules can allow wire routing , so as to provide power supply to the modules ( such as , phone charging ). the bars and the space therebetween can be at any length and height according to the actual demand , which can be readily selected by an ordinary person in the art . the organizational system according to the present invention will have excellent interchangeability and customizability . more specifically , as shown in fig6 a , each module can be removed independently by pulling out the involved interlocking pins 40 , and then , for example , this removed module can be added or substituted with any needed accessory . alternatively , two or more consecutive modules can be replaced by a multi - unit or multiple square module according to the user &# 39 ; s desire . referring to fig6 a , for instance , the four single square modules in the right column can be removed and replaced by a four - square module for use as umbrella storage , in case the weather becomes rainy ; or , the calendar module 86 and the two single square modules adjacent thereto can be removed and replaced by two extra three - square modules 84 for use as mail holder , in the case that two additional residents desire to receive mail at the house . due to the above - stated structural features , all the removal and replacement work can be easily done without any tooling and within a few minutes without destroying the integrity of the whole organizational system . the detailed re - assembling steps will be described below . in order to change the module next to the calendar module as shown in fig6 a , for example , as a key holder module ( not shown ), four interlocking pins 40 are first pulled out , then the whole module is also removed by sliding it out the four panels comprising the module . then , the removed module is disassembled into the four constituent panels 16 , and by plugging accessory tabs 81 into accessory tab slots 34 , a key holder accessory 80 is inserted in the middle of and re - assembled with the four panels 16 in the manner as shown in fig1 . next , the assembled key holder module can be pushed back into the vacant position next to the calendar module , as shown , and the four interlocking pins 40 are also pushed back to secure the key holder module to adjacent panel corners of adjoining modules . for the purpose of weight reduction and cost saving , the panels and interlocking pins in the present invention can be made of wood , bamboo or plastic . for the purpose of providing strength , the panels and interlocking pins in the present invention can be made of metal , such as steel , copper or aluminum . for either purpose , in preferred embodiments as exemplified in fig1 to 14 , the center part of the panel is made of wood , bamboo or plastic , whereas the crenellated edges 122 of the panel are made of metal . an appropriate means is necessary to bind the two together . the invention herein has been described and illustrated with reference to the specific embodiments , but it should be understood that the features and operation of the invention as described is susceptible to modification or alteration without departing significantly from the spirit of the invention . for example , the dimensions , size and shape of the various elements may be altered to fit specific applications . accordingly , the specific embodiments illustrated and described herein are for illustrative purposes only and the invention is not limited except by the following claims . | US-201615247741-A |
an exercise machine for strengthening the foot and for treating plantar fasciitis includes a foot pad for receiving a patient &# 39 ; s foot and a resistance member associated with the foot pad . as the patient pivots the foot pad on a pivot pin located near the heel section of the foot pad , a resistance is applied to the toe section of the foot pad thereby providing strengthening for the plantar fasciitis band of tissue . | one embodiment of the present invention is shown in fig1 - 3 . a weight machine 10 similar to those found in commercial gyms , includes a weight stack 12 comprising movable five - pound plates 14 . the plates 14 can be any incremental weight such as two pounds , four pounds , five pounds , or any combination of these increments , depending upon the total amount of weight required for a particular patient . the plates 14 are supported and can move vertically ( up and down ) along one or more support rods 15 . a first pulley 16 and a second pulley 18 are connected together by a cable 20 . a first end of the cable is attached to the weight stack and the second end of the cable is attached to rotating platform 22 . alternatively , a third pulley ( not shown ) can be used to change the direction of the cable from vertical to horizontal . a foot sleeve 24 is positioned on the rotating platform and is configured to receive a person &# 39 ; s foot for use during the exercises . preferably , the foot sleeve includes a heel support 26 which remains stationary during the exercising . in this embodiment , the rotating platform 22 is supported by and rotates on pedestal 27 . the pedestal 27 is positioned beneath the heel support 26 so that the heel of the foot remains stationary as the platform 22 rotates or pivots on the pedestal 27 . the pedestal 27 is anchored to a base of the machine . the rotating platform 22 includes indexed holes 28 , with a pin extending through the holes , in order to adjust the amount of lateral movement of the rotating platform . a pull - pin 30 extends through the indexed holes in order to limit the amount of lateral movement of the rotating platform . alternatively , the range of rotation or pivoting can be unlimited . in use , a patient will place their foot through the foot sleeve 24 and rest their foot on the rotating platform 22 . the patient uses the other foot for support . the patient &# 39 ; s heel will be supported by heel support 26 which remains substantially stationary throughout the exercise . the patient selects the appropriate amount of weight on the weight stack 12 and then moves the foot in the foot sleeve in a lateral direction ( fig3 ) along an arc line that is circular against the resistance of the weight stack . importantly , the heel of the foot remains substantially stationary in the heel support 26 while the rest of the foot moves in a lateral right to left and left to right motion , with resistance from the weight stack in both directions . the motion of the toes is substantially circular , while the foot pad and platform rotate or pivot at the heel . the pull - pin 30 can be placed in any of the indexed holes 28 in order to adjust the starting point for the rotating platform . preferably , the patient will keep their shoes on ( gym shoes or tennis shoes ) during the exercise for added support . the shoes are not necessary , however , it is preferable . support arms 30 extend from the machine 10 so the patient can hold onto the arms and maintain balance during the exercise . after the patient completes a number of repetitions with one foot , he can remove that foot from the foot sleeve 24 and insert the other foot and continue the repetitions . the device strengthens the foot in general and the plantar fascia in particular to a point of total rehabilitation as long as the user is faithful to the exercises prescribed . in another embodiment , as shown in fig4 - 15 , a foot exercise machine 50 includes a base 52 which typically is placed on the floor and provides support for the foot exercise machine . a frame 54 extends upwardly from the base 52 and has a foot pad 56 mounted on the top of the frame 54 . the foot pad 56 includes a heel section 58 and a toe section 60 and has a flange 62 extending around the foot pad . in use , the patient places their foot on top of the foot pad 56 with the heel of the foot being in the heel section 58 and the toe of the foot being in the toe section 60 . the flange 62 that extends around the foot pad helps to keep the foot positioned on the foot pad during use . a restraint 64 also can be placed on the foot pad in order to hold the foot on the foot pad during use . the restraint 64 can include a strap , sleeve or any type of securing restraint in order to hold the foot on the foot pad 56 during use . the foot pad also has a heel edge 66 and a toe edge 68 which define the longitudinal extremities of the foot pad 56 and through which longitudinal axis 70 extends . the foot pad is attached to mounting plate 71 which in turn is attached to the frame 54 . a first pivot pin 72 extends through the mounting plate 71 and provides the basis for the foot pad 56 to pivot during use . it is contemplated that the foot pad 56 can be mounted with a quick release ( not shown ) in order to substitute different sized foot pads for different sized feet . also , it is contemplated that the length and width of foot pad 56 be adjustable to accommodate different sized feet . with further reference to fig4 - 15 , the foot exercise machine also includes a resistance member 80 which can be any type of resistance member that provides a resistance to the foot pad during use . in this embodiment , a coil spring 82 is positioned in a bore in the frame and surrounds the first pivot pin 71 . the coil spring 82 is restrained at its top and bottom by a top compression plate 84 and a bottom compression plate 86 . the coil spring 82 is further restrained by coil spring restraint arm 88 which extends from the bottom compression plate 86 into the base 52 of the machine in order to keep the coil spring in a compressed configuration and to provide the appropriate resistance to the foot pad 56 . in one embodiment , an adjustment screw 90 is provided through the base 52 of the machine in order to adjust the resistance of the coil spring 82 . a resistance gauge 92 is indexed in pounds and can range from one pound up to eighty pounds in any increments determined to be appropriate for a particular patient . for example , turning the adjustment screw 90 either clockwise or counterclockwise , will increase or decrease the length of coil spring 82 , thereby adjusting the amount of resistance the coil spring will apply to the foot pad 56 during use . the location of the first pivot pin 71 with respect to the foot pad 56 is one important aspect of the invention that will determine not only how much lateral movement is applied to the toe section 60 , but also the location of the application of force to the toe section . for example , in one embodiment , the first pivot pin 72 is located along longitudinal axis 70 in the heel section 58 of the foot pad 56 . the first pivot pin 72 is located anywhere along the longitudinal axis extending from heel edge 66 up to about four inches along the longitudinal axis 70 moving toward the toe section . importantly , the first pivot pin 72 will be located on the foot pad closer to the heel edge 66 than to the toe edge 68 . in one embodiment , the first pivot pin 72 is located on the foot pad along the longitudinal axis 70 within two inches of heel edge 66 . in another embodiment of the invention , as shown in fig1 - 18 , the foot pad 56 is mounted so that the foot pad can tilt to accommodate someone sitting in a chair . in this embodiment , one or more tilt plates 100 support the foot pad and allow the foot pad to tilt up to 90 ° by rotating on second pivot pin 102 . as can be seen in fig1 , for example , the dotted line shows the foot pad elevating from a horizontal toward a vertical position and up to 90 ° in order to accommodate someone sitting in a chair . the toe edge 68 will be higher than the heel edge 66 when the foot pad 56 is rotated upwardly on pivot pin 102 . a locking knob 104 is used to prevent the foot pad from tilting , and when unscrewed , allows the foot pad to tilt upwardly and then knob 104 is turned to lock the foot pad in the tilted angular position . an arcuate slot 106 in the tilt plates 100 allow the foot pad to move along the arcuate path as described . the second pivot pin 102 extends through bore 108 and is positioned near the heel section 58 of the foot pad 56 . while not shown in the drawings , it is contemplated that foot pad 56 can be mounted on the frame so the foot pad can tilt in any direction including with the toe section being above the heel section , or laterally from side to side . in use , the foot exercise machine 10 as shown in fig4 - 18 is used to generally strengthen the foot and in particular to treat plantar fasciitis . a patient places their foot on the foot pad 56 and adjusts the restraint 64 on the foot pad to firmly secure the foot to the foot pad . a suitable amount of resistance is selected so that the patient can do multiple repetitions moving to the right or to the left . the longitudinal axis 70 represents a neutral position where there is no resistance on the foot pad or the patient &# 39 ; s foot . as the patient moves his foot to the right , for example , he will encounter resistance as the foot pad pivots at the pivot point located closer to the heel section than the toe section of the heel pad . the patient can move the foot up to 120 ° to the right and encounter resistance throughout the movement to the right . when the patient completes the movement to the right , he will then move the toe section along the arc line back toward the neutral position . in moving left back to the neutral position , the patient also encounters resistance on the foot . similarly , the foot pad can be moved to the left through an arc of 120 ° encountering resistance moving both to the left and back to the right . again , there is no resistance at the neutral position . the flange 62 on the foot pad helps to secure the patient &# 39 ; s foot during the lateral movements to the right and the left during use . if the patient is unable to stand during the exercise routine , the patient can sit in a chair and the foot pad 56 can be tilted at an angle to accommodate the patient &# 39 ; s sitting position . thus , referring to fig1 - 18 , the patient , from a seated position , places his foot on foot pad 56 and attaches the restraint 64 as previously described . using locking knob 104 , the locking knob is turned thereby releasing the foot pad so that it can tilt by pivoting on second pivot pin 102 along an arcuate slot 106 in tilt place 100 . the foot pad can tilt up to an angle of about 90 ° to accommodate the seated patient . after tilting the tilt pad 56 so that the toe section 60 is higher than the heel section 58 , the locking knob is returned to a closed position thereby locking the foot pad at an angle and so that the patient can then begin the exercise . the above - described apparatus and use is not limited to a device for use in a gym or health club , but also can be used and modified for use at home . further , while a weight stack has been described , it is contemplated that other forms of resistance can be substituted for the weights , such as stretchable bands , hydraulic pistons , and the like . also , references herein to a patient is broadly defined so that anyone seeking to strengthen their foot , whether or not they have plantar fasciitis . | US-201414540397-A |
this invention provides compounds of formula ## str1 ## wherein the substituents are described in the specification . the compounds of formula are plant fungicides . | throughout this document , all temperatures are given in degrees celsius and all percentages are weight percentages , unless otherwise stated . the term halo , used alone or in combination with other terms , refers to f , cl , or br . the term &# 34 ; branched alkyl &# 34 ; refers to all alkyl isomers containing the designated number of carbon atoms , except the straight chain isomers . the term &# 34 ; alkoxy &# 34 ; refers to a straight or branched chain alkoxy group . the term &# 34 ; halo alkyl &# 34 ; refers to a straight or branched alkyl group , substituted with one or more halo atoms . the term &# 34 ; halo alkoxy &# 34 ; refers to an alkoxy group , substituted with one or more halo atoms . the term &# 34 ; halo alkylthio &# 34 ; refers to a straight or branched alkylthio group , substituted with one or more halo atoms . the term &# 34 ; substituted phenyl &# 34 ; refers to phenyl substituted with up to three groups selected from halo , c 1 - c 10 alkyl , branched c 3 - c 6 alkyl , halo c 1 - c 7 alkyl , hydroxy c 1 - c 7 alkyl , c 1 - c 7 alkoxy , halo c 1 - c 7 alkoxy , phenoxy , phenyl , no 2 , oh , cn , c 1 - c 4 alkanoyloxy , or benzyloxy . the term &# 34 ; substituted phenoxy &# 34 ; refers to a phenoxy group substituted with up to three groups selected from halo , c 1 - c 10 alkyl , branched c 3 - c 6 alkyl , halo c 1 - c 7 alkyl , hydroxy c 1 - c 7 alkyl , c 1 - c 7 alkoxy , halo c 1 - c 7 alkoxy , phenoxy , phenyl , no 2 , oh , cn , c 1 - c 4 alkanoyloxy , or benzyloxy . the term &# 34 ; substituted phenylthio &# 34 ; refers to a phenylthio group substituted with up to three groups selected from halo , c 1 - c 10 alkyl , branched c 3 - c 6 alkyl , halo c 1 - c 7 alkyl , hydroxy c 1 - c 7 alkyl , c 1 - c 7 alkoxy , halo c 1 - c 7 alkoxy , phenoxy , phenyl , no 2 , oh , cn , c 1 - c 4 alkanoyloxy , or benzyloxy . the term &# 34 ; substituted phenylsulfonyl &# 34 ; refers to a phenylsulfonyl group substituted with up to three groups selected from halo , i , c 1 - c 10 alkyl , c 3 - c 6 branched alkyl , halo c 1 - c 7 alkyl , hydroxy c 1 - c 7 alkyl , c 1 - c 7 alkoxy , halo - c 1 - c 7 alkoxy , phenoxy , phenyl , no 2 , oh , cn , c 1 - c 4 alkanoyloxy , or benzyloxy . the term &# 34 ; unsaturated hydrocarbon chain &# 34 ; refers to a hydrocarbon chain containing one to three multiple bond sites . the term &# 34 ; carbocyclic ring &# 34 ; refers to a saturated or unsaturated ring of four to seven carbon atoms . while all the compounds of this invention have fungicidal activity , certain classes of compounds may be preferred for reasons such as greater efficacy or ease of synthesis . these preferred classes include those compounds of formula ( 1 ), above , wherein r 1 - r 4 are independently h , halo , or c 1 - c 4 alkyl , or more preferably halo ; v is ch or c 1 - c 4 alkyl , and a is a phenyl group of formula ( 2 ), above , wherein r 9 r 13 are independently halo , c 1 - c 4 alkyl , or halo c1 - c7 alkyl , or more preferably a phenyl group of formula ( 2 ) above , wherein r 9 r 13 is independently halo ; a pyridyl or substituted pyridyl group ; or a pyrimidinyl or substituted pyrimidinyl group . the compounds of formula ( 1 ) have been found to control fungi , particularly plant pathogens . when employed in the treatment or prevention of plant fungal diseases , the compounds are applied to seeds or plants in a disease - inhibiting and phytologically - acceptable amount . the term &# 34 ; disease - inhibiting and phytologically - acceptable amount &# 34 ;, as used herein , refers to an amount of a compound of the invention which kills or inhibits the plant disease for which control is desired , but is not significantly toxic to the plant . this amount will generally be from about 1 to 1000 ppm , with 10 to 500 ppm being preferred . the exact concentration of compound required varies with the fungal disease to be controlled , the type of formulation employed , the method of application , the particular plant species , climate conditions , and the like . the compounds of this invention may also be used to protect stored grain and other non - plant loci from fungal infestation . the following tests were performed to determine the fungicidal efficacy of the compounds of this invention . the compounds of the present invention have been found to control fungi , particularly plant pathogens . when employed in the treatment of plant fungal diseases , the compounds are applied to the plants in a disease inhibiting and phytologically acceptable amount . as used herein , the term &# 34 ; disease inhibiting and phytologically acceptable amount &# 34 ;, refers to an amount of a compound of the present invention which kills or inhibits the plant disease for which control is desired , but is not significantly toxic to the plant . this amount will generally be from about 1 to 1000 ppm , with 10 to 500 ppm being preferred . the exact concentration of compound required varies with the fungal disease to be controlled , the type formulation employed , the method of application , the particular plant species , climate conditions and the like . a suitable application rate is typically in the range from about 0 . 10 to about 4 lb / a . the compounds of the invention may also be used to protect stored grain and other non - plant loci from fungal infestation . the following experiments were performed in the laboratory to determine the fungicidal efficacy of the compounds of the invention . the test compounds were formulated for application by foliar spray . the following plant pathogens and their corresponding plants were employed . ______________________________________ designation in following pathogen table host______________________________________erysiphe graminis tritici pmw wheat ( powdery mildew ) ______________________________________ wheat c . v . monon was grown in the greenhouse from seed in a soil - less peat - based potting mixture (&# 34 ; metromix &# 34 ;). the seedlings were used for testing at the 1 . 5 leaf stage . compound formulation was accomplished by dissolving technical materials in acetone , with serial dilutions then made in acetone to obtain desired rates . final treatment volumes were obtained by adding nine volumes 0 . 011 % aqueous triton x - 100 , resulting in test solutions with 10 % acetone and 0 . 01 % triton x - 100 . test rates were 400 , 100 , 25 , and 6 . 25 ppm . in a high volume foliar application , plants were sprayed to runoff ( using two opposing spraying systems 1 / 4jaupm air atomization nozzles operated at approximately 138 kpa . test inoculum for wheat powdery mildew ( e . graminis f . sp . tritici ) was produced in vivo on stock plants in the greenhouse . the test plants were inoculated by dusting spores from stock plants on test plants 24 hours after spray application after inoculation the test plants were kept in the greenhouse for seven days , until disease on the untreated control plants was fully developed . seven days after inoculation , the disease incidence on the leaves was assessed visually . the following table presents the activity of typical compounds of the present invention when evaluated in these experiments . the effectiveness of test compounds in controlling disease was rated using the following scale . ______________________________________compound rate number ( ppm ) pmw______________________________________1 400 + 1 100 + 1 25 + 1 6 . 25 + 2 400 + 2 100 - 2 25 - 2 6 . 25 - 3 400 + 3 100 + 3 25 + 3 6 . 25 + 4 400 + 4 100 + 4 25 + 4 6 . 25 + 5 400 - 5 100 - 5 25 - 5 6 . 25 - 6 400 - 6 100 - 6 25 - 6 6 . 25 - 7 400 + 7 100 + 7 25 - 7 6 . 25 - 8 400 - 8 100 - 8 25 - 8 6 . 25 - 9 400 + 9 100 + 9 25 + 9 6 . 25 - 10 400 + 10 100 + 10 25 + 10 6 . 25 - 11 400 - 11 100 - 11 25 - 11 6 . 25 - 12 400 + 12 100 + 12 25 + 12 6 . 25 + 13 400 + 13 100 + 13 25 - 13 6 . 25 - 14 400 - 14 100 - 14 25 - 14 6 . 25 - 15 400 + 15 100 + 15 25 - 15 6 . 25 - 16 400 + 16 100 + 16 25 + 16 6 . 25 - 17 400 + 17 100 + 17 25 + 17 6 . 25 + 18 400 + 18 100 + 18 25 + 18 6 . 25 + 19 400 + 19 100 + 19 25 + 19 6 . 25 - 20 400 + 20 100 + 20 25 + 20 6 . 25 + 21 400 + 21 100 + 21 25 + 21 6 . 25 + 22 400 + 22 100 + 22 25 - 22 6 . 25 - 23 400 + 23 100 + 23 25 - 23 6 . 25 - 24 400 + 24 100 + 24 25 + 24 6 . 25 - 25 400 - 25 100 - 25 25 - 25 6 . 25 - 26 400 + 26 100 + 26 25 - 26 6 . 25 - 27 400 + 27 100 + 27 25 + 27 6 . 25 - 28 400 + 28 100 - 28 25 - 28 6 . 25 - 29 400 - 29 100 - 29 25 - 29 6 . 25 - 30 400 - 30 100 - 30 25 - 30 6 . 25 - 31 400 - 31 100 - 31 25 - 31 6 . 25 - 32 400 - 32 100 - 32 25 - 32 6 . 25 - 33 400 + 33 100 + 33 25 - 33 6 . 25 - 34 400 + 34 100 + 34 25 + 34 6 . 25 + 35 400 + 35 100 + 35 25 + 35 6 . 25 + 36 400 + 36 100 + 36 25 + 36 6 . 25 - 37 400 + 37 100 + 37 25 + 37 6 . 25 - 38 400 + 38 100 + 38 25 - 38 6 . 25 - 39 400 - 39 100 - 39 25 - 39 6 . 25 - 40 400 - 40 100 - 40 25 - 40 6 . 25 - 41 400 - 41 100 - 41 25 - 41 6 . 25 - 42 400 - 42 100 - 42 25 - 42 6 . 25 - 43 400 + 43 100 - 43 25 - 43 6 . 25 - 44 400 - 44 100 - 44 25 - 44 6 . 25 - 45 400 - 45 100 - 45 25 - 45 6 . 25 - 46 400 - 46 100 - 46 25 - 46 6 . 25 - 47 400 - 47 100 - 47 25 - 47 6 . 25 - 48 400 - 48 100 - 48 25 - 48 6 . 25 - 49 400 - 49 100 - 49 25 - 49 6 . 25 - 50 400 - 50 100 + 50 25 - 50 6 . 25 - 51 400 - 51 100 - 51 25 - 51 6 . 25 - 52 400 - 52 100 - 52 25 - 52 6 . 25 - 53 400 + 53 100 + 53 25 + 53 6 . 25 + 54 400 + 54 100 - 54 25 - 54 6 . 25 - 55 400 + 55 100 + 55 25 + 55 6 . 25 + 56 400 + 56 100 + 56 25 + 56 6 . 25 - 57 400 + 57 100 + 57 25 + 57 6 . 25 + 58 400 + 58 100 + 58 25 + 58 6 . 25 + ______________________________________ nt = not tested against specific organism 0 = 0 % control - = 1 - 49 % control + = 50 - 100 % control the compounds of this invention are made using well known chemical procedures . the required starting materials are commercially available , or readily synthesized utilizing standard procedures , several of which are disclosed in u . s . pat . no . 5 , 145 , 843 . the compounds of formula ( 1 ) are then prepared by treatment of the corresponding 4 - v substituted lepidine derivative with the appropriate -- z -- a containing derivative . 4 - bromomethyl - 8 - chloroquinoline ( 0 . 8 g , 3 . 11 mmol ) was dissolved with stirring in dry thf ( 10 mls ) and sodium hydride ( 0 . 15 g , 60 % dispersion in mineral oil , 6 . 23 mmol ) added . the mixture was stirred at room temperature for 15 minutes and 4 - fluorophenol ( 0 . 52 g , 3 . 11 mmol ) added . the mixture was stirred at room temperature overnight and worked up to provide the product ( 0 . 46 g , 51 . 2 %) as a white solid , mp 144 - 5 ° c . a mixture of 4 - bromo - 7 - chloroquinoline ( 24 . 3 g , 0 . 1 mol ), styrene ( 12 . 0 g , 0 . 125 mol ), tri ( o - tolyl ) phosphine ( 0 . 4 g , 1 . 3 mmol ), palladium acetate ( 0 . 2 g , 0 . 89 mol ) and triethylamine ( 120 mls ) was charged into a 300 ml stirred pressure vessel and heated at 120 ° c . for 17 hours . the mixture was cooled , filtered to remove triethylamine hydrobromide , and the solids washed with ethyl acetate ( 250 ml ). solvents were evaporated under reduced pressure and the residue dissolved in ethyl acetate ( 500 ml ). the solution was washed with water and brine , and dried over anhydrous sodium sulphate . evaporation of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate : hexane gave the product ( 13 . 5 g , 51 %) as an orange solid , mp 120 - 122 ° c . found : c , 76 . 50 ; h , 4 . 62 ; n , 5 . 38 %; calculated : c , 76 . 84 ; h , 4 . 55 ; n , 5 . 27 % 4 - hydroxymethyl - 7 - chloroquinoline ( 0 . 6 g , 3 . 12 mmol ) was dissolved with stirring in dry thf ( 20 mls ) and sodium hydride ( 0 . 15 g , 60 % dispersion in mineral oil , 3 . 75 mmol ) added . the mixture was stirred at room temperature for one hour and 2 - chloro - 3 - trifluoromethylpyridine ( 0 . 62 g , 3 . 42 mmol ) added . the mixture was stirred overnight and worked up to provide the product ( 0 . 9 g , % as a tan solid , mp 125 - 7 ° c . found : c , 56 . 68 ; h , 2 . 90 ; n , 8 . 17 %; calculated : c , 56 . 74 ; h , 2 . 98 ; n , 8 . 27 % bromine ( 15 ml , 0 . 30 mol ) was dissolved in acetonitrile ( 200 ml ) and added dropwise to a suspension of 4 - hydroxy - 5 , 7 - dichloroquinoline ( 60 g , 0 . 28 mol ) ( swiss pat . ch 93 - 3640 931207 ) and triphenylphosphite ( 78 ml , 0 . 30 mol ) in acetonitrile ( 1 l ) over three hours . the reaction was left to stir for 24 hours at which point it was filtered to collect the precipitate . the solid was suspended between water ( 1 l ) and dichloromethane ( 500 ml ) and neutralized with sodium bicarbonate . extractions were performed periodically as the aqueous layer neared neutral and finally at ph 10 to give a total of 5 × 500 ml aliquots . the organics were combined , dried ( magnesium sulfate ), filtered through a plug of silica gel , and concentrated under vacuum to a total volume of 1 l , then heated until solid dissolved and left to crystallize 12 hours . filtration gave analytically pure product ( 46 g , 65 %) while concentration of the mother liquor gave spectroscopically clean product ( 14 g , 20 %, mp 131 ° c .). ## str11 ## a solution of 4 - bromo - 5 , 7 - dichloroquinoline ( 5 . 7 g , 21 mmol ), palladium ( ii ) acetate ( 0 . 93 g , 4 . 2 mmol ), tri - o - tolylphosphine ( 2 . 5 g , 8 . 2 mmol ), styrene ( 5 ml , 26 . 2 mmol ), copper iodide ( 0 . 80 g , 4 . 2 mmol ), and triethylamine ( 4 ml , 28 mmol ) in acetonitrile ( 41 ml ) was heated at reflux for three hours . after cooling to ambient temperature , the reaction was diluted with ethyl acetate and filtered through a plug of silica gel . this material was used as is minus an analytical sample ( 178 mg , mp 242 ° c .) used for characterization . the resulting solid was taken up in methanol , dichloromethane solution ( 1 : 1 , 600 ml ) and cooled to - 78 ° c . ozone was passed through the system until the reaction was complete as determined by gcms . thiourea was added ( 5 g , 600 mmol ) and left to warm to ambient temperature , filtered through a plug of silica and rinsed with through with dichloromethane . the solvent was removed under vacuum with slight heat until a white solid precipitated . the solid was collected as several crops to give the desired aldehyde ( 2 . 1 g , 45 % over 2 steps , mp 154 ° c . ). analytical samples were obtained by recrystalization from ethylacetate . ## str12 ## the aldehyde ( 100 mg , 0 . 44 mmol ) was dissolved in toluene ( 6 ml ) and cooled to 0 ° c . methylmagnesium bromide ( 1 . 4 m in toluene / tetrahydrofuran ) was dripped in until the starting material was exhausted as judged by tlc . the reaction was diluted with ethylacetate ( 50 ml ) and 0 . 5 n hcl ( 50 ml ) and allowed to warm to ambient temperature . the organic layer was additionally extracted with 0 . 5 n hcl ( 3 × 50 ml ). the aqueous layers were combined and neutralized with sodium bicarbonate and extracted with ethylacetate ( 4 × 50 ml ) the organics were dried ( magnesium sulfate ), filtered and concentrated to give clean product ( 101 mg , 94 %, mp 112 ° c .) ## str13 ## neat diethyl azodicarboxylate ( 0 . 30 ml , 1 . 9 mmol ) was added to a solution of secondary alcohol ( 300 mg , 1 . 25 mmol ), triphenylphosphine ( 600 mg , 2 . 3 mmol ), and 4 - fluorophenol ( 200 mg , 1 . 7 mmol ) in chloroform ( 6 ml ) over 15 minutes . the reaction was allowed to stir for two hours , concentrated under vacuum and purified by medium pressure chromatography , ( 10 : 1 , heptane / ethyl acetate ), the resulting solid was recrystalized from pentane to give the phenoxy lepidine ( 325 mg , 78 %, mp 101 ° c .). 5 , 7 - dichloroquinoline - 4 - carboxaldehyde ( 500 mg , 2 . 2 mmol ) and 4 - fluoroaniline ( 246 mg , 2 . 2 mmol ) were combined in 20 ml benzene with magnetic stirring . the flask was fitted with a dean - stark trap and heated to reflux overnight . reaction was monitored by tlc and shown to be complete after 16 hours . the benzene was removed in vacuo and the resulting solid recrystallized from ethyl acetate / heptane . yield : 0 . 5 g ( 71 %), mp 153 ° c . ## str15 ## the product above ( 600 mg , 1 . 9 mmol ) was dissolved in 10 ml ethanol . sodium borohydride ( 90 mg , 2 . 4 mmol ) was added and the reaction magnetically stirred overnight at room temperature under nitrogen atmosphere . reaction was monitored by tlc and shown to be complete . the reaction was diluted with water and extracted with ethyl acetate . the organic layer was dried over magnesium sulfate , filtered and evaporated in vacuo . the resulting solid was recrystallized from ethyl acetate / heptane . yield : 180 mg ( 30 %), mp 166 . 5 ° c . a solution of 4 - bromo - 5 , 7 - dichloroquinoline ( 5 . 7 g , 21 mmol ), palladium ( ii ) acetate ( 0 . 93 g , 4 . 2 mmol ), tri - o - tolylphosphine ( 2 . 5 g , 8 . 2 mmol ), styrene ( 5 ml , 26 . 2 mmol ), copper iodide ( 0 . 80 g , 4 . 2 mmol ), and triethylamine ( 16 ml , 115 mmol ) in acetonitrile ( 41 ml ) was heated at reflux for three hours . after cooling to ambient temperature , the reaction was diluted with ethyl acetate and washed with dilute hydrochloric acid and brine . the organic layer was dried ( mgso 4 ) and concentrated to a white solid . the solid was taken up in a methanol / dichloromethane solution ( 1 : 1 , 400 ml ) and cooled to - 78 ° c . ozone was passed through the system until the reaction was complete as determined by gcms . thiourea was added ( 5 . 0 g , 600 mmol ) and left to warm to ambient temperature . the reaction was diluted with dichloromethane and filtered through a plug of silica gel eluting with methanol / dichloromethane ( 1 : 1 ). the solution was cooled to 0 ° c . and sodium borohydride was added as a solid over one hour until the reaction was deemed complete by gcms . the reaction was quenched and washed with 1n hydrochloric acid . the aqueous layers were combined and filtered through a plug of cotton and then neutralized with sodium bicarbonate . the solid was collected by filtration and air dried to give the desired product ( 2 . 8 g , in & gt ; 80 % purity . an analytical sample was prepared via recrystalization from ethyl acetate / methanol ( mp 196 ° c .). a 200 ml stainless steel autoclave was loaded with 4 - bromo - 7 - chloroquinoline ( 1 . 2 g , 5 . 0 mmol ) ( can . pat . ca 94 - 2133620 941004 ), bis ( triphenylphosphine ) palladium chloride ( 0 . 1 g ), triethylamine ( 3 ml ) and ethanol ( 40 ml ) and pressurized to 200 psi with carbon monoxide . the autoclave was heated at 120 ° c . for 12 hours , cooled , and vented . solids were removed by filtration through celite and the mother liquor concentrated in vacuo . the residue was taken up in chloroform ( 50 ml ), washed with water ( 3 × 50 ml ), saturated brine ( 50 ml ), and dried ( na 2 so 4 ). filtration and removal of solvent left 1 . 3 g of a brown liquid . flash chromatography on silica using 1 vol % ch 3 cn in ch 2 cl 2 as eluent afforded product as a colorless syrup which solidified to a waxy solid . this solid was dissolved in methanol ( 50 ml ) and sodium borohydride was added over two hours until judged complete by tlc . the reaction was diluted with water and acidified with 1n hydrochloric acid and then neutralized with sodium bicarbonate . the resulting solid was recovered via filtration , dissolved in ethyl acetate and dried ( mgso 4 ). filtration and concentration afforded the desired compound ( mp : 160 ° c ., 0 . 66 g , 68 % over two steps ). commercially available 2 - chloroaniline ( 200 g , 1 . 56 mol ) was dissolved in 600 ml ethanol , and dry hcl gas was bubbled through for 10 minutes to give 2 - chloroaniline hydrochloride . a new flask was charged with 2 - chloroaniline hydrochloride ( 130 g , 0 . 793 mol ), ferric chloride hexahydrate ( 25 . 7 g , 0 . 095 mol ), anhydrous zinc chloride ( 10 . 9 g , 0 . 0799 mol ) and 500 ml 2b ethanol . the mixture was heated to 60 ° c . for 10 minutes and 1 , 3 , 3 - trimethoxy butane was added dropwise over a period of one hour . the mixture was then refluxed for two hours and allowed to stand overnight at room temperature . most of the alcohol was removed by distillation and the residue was made alkaline with 25 % sodium hydroxide solution . the reaction was cooled , filtered , and the filter pad washed with toluene . the toluene was concentrated to dryness . the product was recrystallized from dichloromethane / pentane to obtained a spectroscopically pure sample ( mp : 110 ° c ., 37 . 0 g , 25 % overall yield ). the 8 - chlorolepidine ( 20 . 0 g , 0 . 113 mol ) and n - bromosuccinimide , ( 20 . 0 g , 0 . 113 mol ) were dissolved in 200 ml dry carbon tetrachloride and the mixture stirred under nitrogen for three hours , while being exposed to a 250 watt high intensity sun lamp . the solution was cooled to room temperature , filtered , and evaporated to dryness . the residue was placed over a silica gel column using ethyl acetate / pentane , to give the bromomethyl lepidine ( 10 . 8 g , 37 . 4 % yield , mp : 92 ° c .) 4 - carboxaldehyde - 7 - chloro quinoline ( 1 . 00 g , 5 . 22 mmol ) was dissolved in 12 . 5 ml of a 0 . 5 m solution of trimethyl ( trifluoromethyl ) silane in tetrahydrofuran in an oven dried , nitrogen swept 100 ml round bottomed flask , and the resulting solution was cooled to 0 ° c . under nitrogen . with stirring , tetra - n - butyl ammonium fluoride trihydrate ( 0 . 014 g , 0 . 052 mmol ) was added as a solid and the mixture allowed to warm slowly to room temperature over two hours by which time thin layer chromatography ( hexanes : ethyl acetate / 2 : 1 ) indicated complete consumption of the starting material . the reaction mixture was cooled to 0 ° c . and 10 % aqueous hydrochloric acid ( 3 ml ) was added and the mixture stirred at room temperature until cleavage of the trimethyl silyl ether was complete as indicated by thin layer chromatography ( 1 h ). the reaction mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate , the layers separated and the aqueous layer extracted with an additional portion of ethyl acetate . the combined organic layers were dried ( mgso 4 ) filtered and concentrated to dryness . purification by flash silica gel chromatography ( hexanes : ethyl acetate / 2 : 1 ) provided 7 - chloro - α -( trifluoromethyl )- 4 - quinolinemethanol ( 1 . 32 g , 96 %) as a yellow solid . an analytical sample was prepared by recrystallization from ethyl acetate : hexanes . ( mp 161 ° c .). n -( 2 , 3 , 3 - trifluoro - 1 - propenyl ) trimethylammonium iodide ( 10 . 0 g , 35 . 6 mmol ) ( tetrahedron lett . 1995 , 36 ( 9 ), 1527 ) was dissolved in 70 ml of acetonitrile in a oven dried nitrogen swept 250 ml round bottomed flask . with stirring , diethylamine ( 15 . 6 g , 213 mmol ) was added via syringe , the flask was fitted with a reflux condenser and stirred under nitrogen at 75 - 80 ° c . for one hour . the mixture was allowed to cool to room temperature and 2 - methyl - 2 - thiopseudourea sulfate ( 19 . 8 g , 71 . 2 mmol ) and sodium methoxide ( 3 . 80 g , 71 . 2 mmol , 15 ml of a 25 % solution in methyl alcohol ) were added with stirring and the mixture heated to reflux for six hours . the cooled reaction mixture was poured into water , the layers separated , the aqueous phase extracted with methylene chloride ( 3 × 50 ml ) and the combined organics were dried ( sodium sulfate ), filtered and concentrated to low volume . purification by flash silica gel chromatography ( hexanes : ethyl acetate / 10 : 1 ) provided the volatile 5 - fluoro - 2 -( thiomethyl ) pyrimidine , which was immediately dissolved in 100 ml of methylene chloride in a 500 ml round bottomed flask , and treated at 0 ° c . with 3 - chloroperoxybenzoic acid ( 21 . 6 g , 125 mmol ) with good stirring . after stirring for 15 hours at room temperature , the oxidation was judged complete by thin layer chromatography ( hexanes : ethyl acetate / 1 : 2 ). the reaction mixture was poured into saturated sodium hydrogen carbonate , the layers separated and the aqueous phase extracted with methylene chloride and the combined organics washed with saturated sodium hydrogen carbonate and dried ( naso 4 ), filtered and concentrated . purification by flash silica gel chromatography ( hexanes : ethyl acetate / 1 : 2 ) provided 5 - fluoro - 2 -( methylsulfonyl ) pyrimidine ( 4 . 3 g , 68 % ( from n -( 2 , 3 , 3 - trifluoro - 1 - propenyl ) trimethylammonium iodide ) as colorless oil : p analysis calcd for c 5 h 5 f 1 n 2 o 2 s : c , 34 . 09 ; h , 2 . 86 ; n , 15 . 9 ; s , 18 . 2 . found : c , 34 . 09 ; h , 2 . 79 ; n , 15 . 81 ; s , 18 . 3 . 7 - chloro - α -( trifluoromethyl )- 4 - quinolinemethanol ( 0 . 25 g , 0 . 96 mmol ) was dissolved in 5 ml of tetrahydrofuran in a oven dried , nitrogen swept 25 ml round bottomed flask and the resulting solution was cooled to 0 ° c . under nitrogen . with stirring , nah ( 0 . 042 g , 1 . 1 mmol , 60 % dispersion in mineral oil ) was added all at once . after 15 minutes , 5 - fluoro - 2 -( methylsulfonyl ) pyrimidine ( 0 . 17 g , 0 . 96 mmol ) was added dropwise via syringe as a solution in tetrahydrofuran ( 2 . 5 ml ) over 5 minutes . an additional 2 ml of tetrahydrofuran was used to rinse the flask containing the sulfone and the syringe . the milky solution was allowed to warm to room temperature and stir for 15 hours by which time thin layer chromatography ( hexanes : ethyl acetate / 1 : 1 ) indicated complete consumption of the starting materials . the reaction mixture was partitioned between water and ethyl acetate , the layers separated and the aqueous layer extracted with an additional portion of ethyl acetate . the combined organic layers were dried ( mgso 4 ) filtered and concentrated to dryness . purification by flash silica gel chromatography ( hexanes : ethyl acetate / 2 : 1 ) provided 7 - chloro - 4 -[ 2 , 2 , 2 - trifluoro - 1 -[( 5 - fluoro - 2 - pyrimidinyl ) oxy ] ethyl ] quinoline ( 0 . 32 g , 94 %) as a white solid . an analytical sample was prepared by recrystallization from hexane . ( mp 92 ° c .). the following table identifies compounds of formula ( 1 ) prepared analogous to the various processes illustrated in the preceding examples . __________________________________________________________________________cmpd m . p no . r . sup . 1 - r . sup . 4 x y v z a (° c .) __________________________________________________________________________ 1 7 - cl ch ch chch . sub . 3 o 4 - fluorophenyl 104 - 106 2 7 - cl ch ch chc . sub . 6 h . sub . 13 o 4 - fluorophenyl 38 - 40 3 7 - cl ch ch chcn o 4 - fluorophenyl 118 - 123 4 7 - cl ch ch chch ═ ch . sub . 2 o 4 - fluorophenyl 186 - 190 5 7 - cl ch ch ch . sub . 2 o 2 , 5 - trifluoro - 83 - 85 methyl - 6 - pyridinyl 6 7 - cl ch ch ch . sub . 2 o 4 , 6 - methoxy - 2 - 134 - 136 pyrimidinyl 7 5 , 7 - ch ch ch . sub . 2 o 2 - trifluoro - 108 . 1 - 110 . 1 dicl methyl - 6 - pyridinyl 8 5 , 7 - ch ch ch . sub . 2 o 4 - methoxy - 6 - 166 - 167 dicl methyl - 2 - pyrimidinyl 9 7 - cl ch ch ch . sub . 2 o 4 - methoxy - 6 - 114 - 116 methyl - 2 - pyrimidinyl 10 5 , 7 - ch ch ch . sub . 2 nch . sub . 3 4 - fluorophenyl 118 - 122 dicl 11 5 , 7 - ch ch ch . sub . 2 o 2 - trifluoromethyl - 176 . 1 - 178 . 1 dicl 6 - pyridinyl 12 5 , 7 - ch ch ch . sub . 2 o 4 - methoxy - 2 - 211 . 1 - 213 . 1 dicl pyrimidinyl 13 5 , 7 - ch ch chch . sub . 2 ch . sub . 3 o 4 - fluorophenyl 102 - 103 dicl 14 5 , 7 - ch ch ch . sub . 2 o 4 , 6 - dimethyl - 1 , 3 - 169 . 4 - 170 . 4 dicl pyrimidinyl 15 7 - cl ch ch ch . sub . 2 o 4 - trifluoromethyl - 99 - 101 2 - pyridinyl 16 7 - cl ch ch ch . sub . 2 o 4 , 6 - dimethyl - 1 , 3 - 145 - 147 pyrimidinyl 17 7 - cl ch ch ch . sub . 2 o 4 - methoxy - 2 - 125 - 127 pyrimidinyl - 18 7 - cl ch ch ch . sub . 2 o 61 - 63 ## - 19 7 - cl ch ch ch . sub . 2 o 110 - 112 - 20 5 , 7 - dicl ch ch ch . sub . 2 o 134 . 5 - 136 . 5 - 21 7 - cl ch ch ch . sub . 2 o 2 - chloro - 4 - fluoro - 116 . 3 - 117 . 3 phenyl 22 7 - cl ch ch ch . sub . 2 o 2 - trifluoromethyl - 112 - 115 phenyl - 23 7 - cl ch ch ch . sub . 2 o 125 - 127 - 24 7 - cl ch ch ch . sub . 2 o 152 - 153 - 25 8 - f ch ch ch . sub . 2 o 2 - chlorophenyl 122 - 123 26 8 - f ch ch ch . sub . 2 o 4 - fluorophenyl 124 - 125 27 7 - cl ch ch ch . sub . 2 o 2 , 4 - fluorophenyl 83 . 5 - 85 . 5 - 28 7 - cl ch ch ch . sub . 2 o 104 . 5 - 106 - 29 7 - cl ch ch ch . sub . 2 o 2 - chlorophenyl 143 - 144 - 30 h ch ch ch . sub . 2 o 93 . 5 - 94 . 5 - 31 h ch ch ch . sub . 2 o 2 - trifluoromethyl - 107 . 5 - 108 . 5 phenyl 32 h ch ch ch . sub . 2 o 2 - chlorophenyl 92 . 5 - 94 . 5 - 33 8 - f ch ch ch . sub . 2 o 78 - 81 ## - 34 8 - cl ch ch ch . sub . 2 o 2 - chlorophenyl 122 - 123 35 5 , 7 - ch ch chch . sub . 3 o 4 - fluorophenyl 104 . 5 - 105 . 5 dicl 36 7 - cl ch ch ch . sub . 2 o 4 - fluorophenyl 133 - 135 37 5 , 7 - ch ch ch . sub . 2 o 2 - chloro - 4 - fluoro - 142 - 143 dicl phenyl 38 8 - f ch ch ch . sub . 2 o phenyl 101 - 103 39 8 - f ch ch ch . sub . 2 o 2 - trifluoromethyl - 128 - 131 phenyl 40 8 - f ch ch ch . sub . 2 o 2 , 4 - fluorophenyl 98 - 100 - 41 8 - f ch ch ch . sub . 2 o 96 - 98 ## - 42 8 - f ch ch ch . sub . 2 o 2 - chloro - 4 - fluoro - 117 . 5 - 121 . 5 phenyl 43 5 , 7 - ch ch ch . sub . 2 o 4 - phenoxyphenyl 153 - 155 dicl 44 5 , 7 - ch ch ch . sub . 2 o 4 - t - butylphenyl 136 - 137 dicl - 45 8 - cl ch ch ch . sub . 2 o 107 - 109 - 46 8 - cl ch ch ch . sub . 2 o 2 , 4 - difluorophenyl 156 - 158 47 8 - cl ch ch ch . sub . 2 o phenyl 100 - 102 48 8 - cl ch ch ch . sub . 2 o 2 - trifluorophenyl 146 - 148 49 8 - cl ch ch ch . sub . 2 o 4 - fluorophenyl 144 - 145 50 h ch ch ch . sub . 2 o 2 - chloro - 4 - fluoro - 125 . 5 - 126 . 5 phenyl - 51 8 - cl ch ch ch . sub . 2 o 120 - 122 - 52 8 - cl ch ch ch . sub . 2 o 2 - chloro - 4 - fluoro - 132 - 135 phenyl - 53 5 , 7 - dicl ch ch o 4 - fluorophenyl 110 - 112 - 54 h ch ch ch . sub . 2 o 4 - fluorophenyl 111 - 113 55 5 , 7 - ch ch ch . sub . 2 n 4 - fluorophenyl 167 dicl 56 5 , 7 - ch ch ch . sub . 2 o 2 - trifluoromethyl - 145 - 146 dicl phenyl 57 5 , 7 - ch ch ch . sub . 2 o 2 , 4 - difluorophenyl 154 - 156 dicl 58 5 , 7 - ch ch ch . sub . 2 o 4 - fluorophenyl 133 - 134 dicl__________________________________________________________________________ the compounds of this invention are applied in the form of compositions , which are important embodiments of the invention , and which comprise one or more compounds of formula ( 1 ) with a phytologically - acceptable inert carrier . the composition may optionally include fungicidal combinations which comprise at least 1 % of one or more compounds of formula ( 1 ) with another fungicide . the compositions are either concentrated formulations which are dispersed in water for application , or are dust or granular formulations which are applied without further treatment . the compositions are prepared according to procedures which are conventional in the agricultural chemical art , but which are novel and important because of the presence therein of the compounds of this invention . some description of the formulation of the compositions will , however , be given to assure that agricultural chemists can readily prepare any desired composition . the dispersions in which the compounds are applied are most often aqueous suspensions or emulsions prepared from concentrated formulations of the compounds . such water - soluble , water suspendable , or emulsifiable formulations are either solids usually known as wettable powders , or liquids usually known as emulsifiable concentrates or aqueous suspensions . wettable powders , which may be compacted to form water dispersible granules , comprise an intimate mixture of the active compound , an inert carrier and surfactants . the concentration of the active compound is usually from about 10 % to 90 %. the inert carrier is usually chosen from among the attapulgite clays , the montmorillonite clays , the diatomaceous earths , or the purified silicates . effective surfactants , comprising from about 0 . 5 % to about 10 % of the wettable powder , are found among the sulfonated lignins , the naphthalenesulfonates , alkylbenzenesulfonates , the alkyl sulfates , and non - ionic surfactants , such as , for example , ethylene oxide adducts of alkyl phenols . emulsifiable concentrates of the compounds comprise a convenient concentration of a compound , such as from about 10 % to about 50 % of liquid , dissolved in an inert carrier , which is either a water miscible solvent or a mixture of water - immiscible organic solvents , and emulsifiers . useful organic solvents include aromatics , especially the high - boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha . other organic solvents may also be used , such as , for example , terpenic solvents , including rosin derivatives , aliphatic ketones , such as cyclohexanone , and complex alcohols , such as 2 - ethoxyethanol . suitable emulsifiers for emulsifiable concentrates are chosen from conventional nonionic surfactants , such as those mentioned above . aqueous suspensions comprise suspensions of water - insoluble compounds of this invention , dispersed in an aqueous vehicle at a concentration in the range from about 5 % to about 50 %. suspensions are prepared by finely grinding the compound , and vigorously mixing it into a vehicle comprised of water and surfactants chosen from the same types discussed above . inert ingredients , such as inorganic salts and synthetic or natural gums , may also be added , to increase the density and viscosity of the aqueous vehicle . it is often most effective to grind and mix the compound at the same time by preparing the aqueous mixture , and homogenizing it in an implement such as a sand mill , ball mill , or piston - type homogenizer . the compounds may also be applied as granular compositions , which are particularly useful for applications to the soil . granular compositions usually contain from about 0 . 5 % to about 10 % of the compound , dispersed in an inert carrier which consists entirely of in large part of clay or a similar inexpensive substance . such compositions are usually prepared by dissolving the compound in a suitable solvent , and applying it to a granular carrier which has been pre - formed to the appropriate particle size , in the range of from about 0 . 5 to 3 mm . such compositions may also be formulated by making a dough or past of the carrier and compound , and crushing and drying to obtain the desired granular particle . dusts containing the compounds are prepared simply by intimately mixing the compound in powdered form with a suitable dusty agricultural carrier , such as , for example , kaolin clay , ground volcanic rock , and the like . dusts can suitably contain from about 1 % to about 10 % of the compound . | US-90428297-A |
this invention relates to a selectorized dumbbell having a handle that can be dropped down between nested left and right stacks of weight plates . the weight plates can comprise individual weights or a pair of weight plates , one from each stack , can be connected together to form a single weight . a selector is provided to allow the user to select a desired number of weight plates from each stack and couple such weight plates to the handle to provide an adjustable weight dumbbell . each weight includes a weight frame having at least one carrier to which a commodity weight can be fastened . the dumbbell can be shipped by the manufacturer with empty weight frames to reduce shipping costs . when the dumbbell with empty weight frames reaches a destination , the dumbbell can be completed by securing commodity weights to the carriers on the respective weight frames . | referring first to fig1 - 5 , a first embodiment of a selectorized dumbbell is illustrated generally as 2 . dumbbell 2 as shown herein is similar to an existing product known as the big block which is manufactured and sold by intellbell , inc . of owatonna , minn ., and which is shown in the applicants &# 39 ; u . s . pat . no . 5 , 769 , 762 , which is hereby incorporated by reference . a summary description of dumbbell 2 will be provided herein only as needed to understand this invention . reference may be had to u . s . pat . no . 5 , 769 , 762 for a fuller and more complete description of dumbbell 2 . basically , dumbbell 2 includes a handle 4 and three nested weights 6 which can be selectively coupled to handle 4 using a selector 8 , namely a pin 10 that can be moved between three different positions on handle 4 to pass through one of three holes 12 on handle 4 . weights 6 are provided with various sets of holes 14 and slots 16 in different combinations , a middle set c having three holes 14 c , a far right set b having two holes 14 b and one slot 16 b , and a far left set a having two slots 16 a and one hole 14 a . see fig3 which illustrates the various sets a - c of holes 14 and slots 16 in the various weights 6 . a desired number of weights 6 can be selectively coupled to handle 4 depending upon how selector 8 is used . if selector 8 is inserted through the middle hole 12 in handle 4 and through the middle set c of holes and slots , then all three weights 6 are coupled to handle 4 . if selector 8 is inserted through the far left hole 12 in handle 4 and thus through the far left set a of holes and slots , then only one weight 6 is coupled to handle 4 . if selector 8 is inserted through the far right hole 12 on handle 4 and thus through the far right set b of holes and slots , then two weights 6 are coupled to handle 4 . if selector 8 is not inserted through any holes 12 on handle 4 , then no weights 6 are coupled to handle 4 and handle 4 can be used by itself with the weight provided by handle 4 comprising the only exercise mass . the various sets a , b and c of holes and slots are further described in the applicants &# 39 ; u . s . pat . no . 5 , 769 , 762 . in dumbbell 2 of this invention , each weight 6 comprises an elongated weight frame 20 formed from an upwardly facing u - shaped channel 22 having a bottom wall 24 and front and rear walls 26 and 28 . in addition , each channel 22 includes an upwardly extending carrier 30 at each end that extends well above channel 22 . carrier 30 is in the form of an upwardly extending tongue . see fig4 . channel 22 and carriers 30 are formed of metal , such as steel , with carriers 30 being formed of extended portions of bottom wall 24 that are bent upwardly relative to channel 22 . the various holes 14 and slots 16 in each set a , b and c thereof are duplicated in the opposed front and rear walls 26 and 28 of channel 22 as taught in the applicants &# 39 ; u . s . pat . no . 5 , 769 , 762 . a pair of commodity weights 32 are secured to carriers 30 of weight frame 20 , with one weight 32 being secured to each carrier 30 . in this regard , each carrier 30 includes a hub 34 that is punched out of each carrier 30 at the top of carrier 30 . hub 34 sticks inwardly relative to carrier 30 to point towards the interior of weight frame 20 . hub 34 is sized to be received in a central hole 36 of commodity weight 32 . hub 34 also includes a hole 38 at the center of hub 34 to allow an attachment bolt 40 to pass therethrough . a clamping member 42 is used on the other side of commodity weight 32 to clamp or secure commodity weight 32 on hub 34 of carrier 30 when attachment bolt 40 is tightened by a nut 43 . clamping member 42 includes a protruding , saucer shaped central portion 44 and an annular peripheral rim 46 surrounding central portion 44 . fig5 shows hub 34 on carrier 30 passing into central hole 36 on commodity weight 32 . saucer shaped portion 44 of clamping member 42 passes into central hole 36 on commodity weight 32 opposite to hub 34 to be able to abut and mate with hub 34 . attachment bolt 40 passes through both clamping member 42 and hub 34 to firmly clamp the clamping member 42 to hub 34 when nut 43 is tightened . when so clamped , commodity weight 32 is held in the annular channel formed between peripheral rim 46 of clamping member 42 and the portions of carrier 30 surrounding hub 34 . thus , a commodity weight 32 may be easily clamped to each carrier 30 of weight frame 20 using hub 34 provided on carrier 30 and a clamping member 42 . fig7 illustrates a typical commodity weight 32 of the type that is often used on traditional barbells or dumbbells . in such traditional barbells or dumbbells , a simple bar is used and a plurality of separate commodity weights 32 are provided . each commodity weight 32 comprises a circular weight plate 35 having a central hole 36 . hole 36 in commodity weight 32 allows commodity weight 32 to be slipped over one end of the bar . after a desired number of weights 32 have been so installed on each end of the bar , weights 32 can be held in place by a locking collar that is then placed and secured on each end of the bar . in using traditional barbells or dumbbells of this type , the user adjusts the exercise mass by loosening and removing the locking collars from the ends of the bar and by then removing weights 32 from each end of the bar or by adding additional weights 32 to the bar . each gym has a number of such weights 32 on hand simply for use on a bar to add weight to the bar . weights 32 are referred to herein as “ commodity weights ” since they are a low cost commodity product typically manufactured in low wage , developing countries , such as china . weights 32 are cast in large quantities from iron , currently more than 10 million pounds per year . they are shipped in large quantities from their country of origin and are readily available all around the world in standard weights , such as 1 . 25 pounds , 2 . 5 pounds , 5 pounds , and so on . the applicants have discovered that commodity weights 32 of this type are so inexpensive that the cost to purchase the weights locally is not much more or about the same as the cost to ship the same weights from the united states . moreover , as shipping costs rise , the costs to ship relatively heavy dumbbells is expected to increase . accordingly , in a preferred method of manufacturing dumbbell 2 , weight frames 20 would be manufactured and shipped as part of dumbbell 2 but without any commodity weights 32 being attached thereto . the distributor , retailer or purchaser of the product would receive dumbbell 2 in this “ unweighted ” form . the distributor , retailer or purchaser of the product would then purchase a sufficient number of commodity weights 32 locally wherever the distributor , retailer or purchaser resides and would add such weights 32 to each weight frame 20 to complete dumbbell 2 . in this regard , dumbbell 2 would be shipped with enough clamping members 42 , bolts 40 and nuts 43 to allow a sufficient number of commodity weights 32 to be clamped to all the different weight frames 20 to complete dumbbell 2 . the net result of this preferred manufacturing method of this invention is a lower cost product in the hands of the end user . the cost to purchase the product by the end user will be reduced by the costs that would have been incurred to manufacture or purchase custom weight plates as well as by the costs to ship all of the weights . this cost reduction will more than offset the cost at the other end to complete dumbbell 2 by having to purchase a sufficient number of commodity weights 20 . essentially , at least the shipping costs that are usually associated with shipping the dumbbell should by and large be saved . this is an advantage to the user of dumbbell 2 by lowering the cost to own dumbbell 2 . in addition , commodity weights 32 of different weights , such as 1 . 25 pounds or 2 . 5 pounds , typically have smaller diameters but a central hole 36 that is the same diameter to allow each weight 32 to be slipped onto the bar of a conventional barbell or dumbbell . thus , the user can determine the incremental amount of adjustability for dumbbell 2 by selecting which sized commodity weight 32 to attach to carriers 30 . if a 1 . 25 pound commodity weight 32 is attached to carriers 30 , then dumbbell 2 will adjust in 2 . 5 pound increments . if a 2 . 5 pound commodity weight 32 is attached to carriers 30 , then dumbbell 2 will adjust in 5 pound increments . in addition , dumbbells 2 constructed with lighter commodity weights 32 will be dimensionally smaller in height and width than dumbbells 2 constructed with heavier commodity weights 32 . using commodity weights 32 to complete dumbbell 2 gives the end user a great deal of flexibility in custom tailoring dumbbell 2 to the user &# 39 ; s desires . if a user wants a smaller , lighter dumbbell 2 that adjusts in smaller increments , the user completes dumbbell 2 with lighter commodity weights 32 . if a user wants a larger , heavier dumbbell 2 that adjusts in larger increments , the user completes dumbbell 2 with heavier commodity weights 32 . moreover , the user can upgrade dumbbell 2 from a lighter to a heavier version simply by replacing the currently used commodity weights 32 with heavier commodity weights 32 without having to buy a set of new weight frames 20 . commodity weights 32 of the same size are available in slightly different thicknesses . for example , 2 . 5 pound weights 32 are currently made in 50 or so different foundries worldwide and vary in thickness from 0 . 565 inches to 0 . 615 inches . weight frames 20 have to be manufactured to accommodate the thickest weight 32 in a particular size or range of sizes that are intended for use on weight frames 20 . in other words , clamping member 42 has to clamp to hub 34 and be able to receive the thickest commodity weight 32 . a compressible foam washer or other material could be supplied to use with thinner weights 32 to take up any play or gaps between thinner weights 32 and clamping member 42 . handle 4 of dumbbell 2 is shown in fig1 - 5 as having a pair of commodity weights 32 secured to either end thereof . in the case of handle 4 , weight frame 20 includes a downwardly facing u - shaped channel 48 instead of an upwardly facing u - shaped channel 22 . an upwardly facing u - shaped cradle 50 having spaced apart carriers 30 is fixed to the upper surface of downwardly facing channel 48 . a hand grip 52 extends between carriers 30 as shown in fig1 and 3 . hand grip 52 carries a resilient cushion or cover to allow the user to better grip hand grip 52 of handle 4 . in the case of handle 4 , carriers 30 will be formed with outwardly , rather than inwardly , extending hubs 34 which are inserted into central holes 36 of weights 32 . a similar clamping member 42 is used on the outside of carrier 30 to clamp weight 32 to carrier 30 . instead of a bolt 40 and nut 43 for tightening clamping member 42 to hub 34 , a machine screw is used which can be screwed into a threaded bore ( not shown ) in the end of hand grip 52 to tighten clamping member 42 on carrier 30 of handle 4 . thus , handle 4 can itself be provided with a pair of commodity weights 32 to allow handle 4 to be used for exercise by itself without any weights 6 being coupled to handle 4 by selector 8 . alternatively , handle 4 could be formed without any provision for coupling any commodity weights 32 to handle 4 . in this case , carriers 30 of handle 4 could simply be planar and solid without any outwardly protruding hub 34 for mounting a weight 32 . in this configuration , at least one weight 6 would normally be coupled to handle 4 to provide a minimum exercise mass . the exercise mass would be adjusted by selectively coupling additional weights 6 to handle 4 using selector 8 . other ways of coupling weights 32 to each end of weight frame 20 could be used . fig6 shows one such alternative coupling . referring to fig6 , each end of upwardly facing channel 22 of each weight frame 20 is no longer provided with an upwardly extending carrier 30 . instead , each front and rear wall 26 and 28 of channel 22 is provided with a vertical slot 54 sized to receive the thickness of commodity weight 32 within slot 54 . bottom wall 24 of channel 22 includes a tang 56 having a hole 58 in the top end of tang 56 . a flexible tie 60 is used to tie weight 6 in place in channel 22 with tie 60 passing through hole 58 in tang 56 and encircling the lower side of weight 32 with tie 60 being secured to itself by a connector 61 within central hole 36 of weight 32 . such flexible ties 60 and connectors 61 as well as the tools used to secure the ends of tie 60 together at connector 61 are well known in the fastener art . fig8 - 12 show an alternative form of selectorized dumbbell 2 ′ according to this invention . the type of dumbbell 2 ′ shown in fig8 - 12 is similar to an existing product known as the power block , which is manufactured and sold by intellbell , inc . of owatonna , minn ., and which is shown in the applicants &# 39 ; u . s . pat . no . 5 , 637 , 064 , which is hereby incorporated by reference . a summary description of dumbbell 2 ′ will be provided herein only as needed to understand this invention . reference may be had to u . s . pat . no . 5 , 637 , 064 for a fuller and more complete description of dumbbell 2 ′. basically , dumbbell 2 ′ includes a handle 4 ′ and a plurality of nested weights 6 ′ which can be selectively coupled to handle 4 ′ using a selector 8 ′. in the dumbbell 2 ′, each weight 6 ′ includes a pair of spaced apart weight plates 70 that are rigidly joined together by a pair of side rails 72 . beginning with the innermost weight 6 ′, each weight 6 ′ has the weight plates 70 spaced apart a progressively greater distance and the side rails 72 located progressively lower to allow the weights 6 ′ to be nested together . the selector 8 ′ comprises a double pronged pin which can be slid beneath the side rails 72 of a selected weight 6 ′ by sliding the prongs of the pin into a selected groove 74 on each end of handle 4 ′. with selector 8 ′ so positioned , when the user lifts up on handle 4 ′, all weights 6 ′ whose side rails 72 are above selector 8 ′ will be lifted with handle 4 ′. in the dumbbell 2 ′ as shown in the 064 patent , the individual weights 6 ′ were manufactured by taking two custom made weight plates 70 and by welding the side rails 72 to either side of the weight plates . in the embodiment of dumbbell 2 ′ of this invention as shown in fig8 - 12 , each weight 6 ′ is now made as a relatively lightweight weight frame 20 ′ that removably accept and retain a pair of commodity weights 32 . thus , each weight 6 ′ when completed will comprise a weight frame 20 ′ with a commodity weight 32 in either end of weight frame 20 ′. each weight frame 20 ′ for each weight 6 ′ comprises a pair of planar , generally vertical carriers 30 ′ that are spaced apart the required distance to allow weight 6 ′ to be nested with the other weights 6 ′. carriers 30 ′ are preferably molded or formed as a single piece out of a lightweight material , such as plastic . each carrier 30 ′ has downwardly facing shoulders 64 along either side . shoulders 64 of adjacent weights 6 ′ are at progressively lower elevations as shown in fig8 , again to allow the completed weights 6 ′ to nest together . carriers 30 ′ are rigidly connected together by a pair of connecting rods or side rails 72 , preferably made of metal for durability . as shown in fig1 , the end of each side rail 72 is simply bolted or screwed to shoulder 64 of the carrier by a screw or bolt 78 . the head of screw or bolt 78 is received in a recess 80 in carrier 30 ′ so that screw or bolt 78 does not protrude beyond the face of carrier 30 ′. when each end of side rail 72 is screwed to shoulders 64 on the same side of both carriers 30 ′, side rail 72 will extend between and unite the two carriers 30 ′ together in much the same way as the welded side rails joined the pair of weight plates shown in the 064 patent . there are two such side rails 72 for each weight 6 ′, one on either side of carrier 30 ′, uniting shoulders 64 provided on each side of carrier 30 ′. the need for shoulders 64 that are progressively lower on adjacent weights is to allow side rails 72 to nest beneath one another as shown in fig8 . while three weights 6 ′ have been shown in fig8 , more could be provided with weights 6 ′ lying progressively outside of the three weights 6 ′ that are shown with such additional weights 6 ′ having progressively lower shoulders 64 and side rails 72 . as many weights 6 ′ could be provided as there are grooves 74 in each end of handle 4 , grooves 74 being suited for holding selector 8 ′ at different levels to couple different numbers of weights 6 ′ to handle 4 ′. each carrier 30 ′ includes a cavity 84 for receiving one commodity weight 32 therein . as shown most clearly in fig1 , cavity 84 is provided in an inner face of carrier 30 ′ and is circular in shape . cavity 84 includes a central , cylindrical hub 86 that is sized to be received within central hole 36 of commodity weight 32 . hub 86 includes a central bore 88 for receiving a fastener 90 such as a bolt . cavity 84 is deep enough to accommodate the thickest weight 32 in a size or range of sizes intended to be used on carriers 30 ′. again , foam washers or rings or other material could be used in cavity 84 around hub 86 to accommodate any play if thinner weights 32 are used . dumbbell 2 ′ as shown herein , when completed with commodity weights 32 , will desirably have a snug fit of commodity weights 32 in cavity 84 to avoid excess rattling and clanking and to impart a feeling of quality and safety to the end user . referring further to fig1 , a commodity weight 32 is attached to carrier 30 ′ simply by lying weight 6 into cavity 84 with central hole 36 of weight 32 being concentrically received around the cylindrical central hub 86 in cavity 84 . a clamping member 42 ′, such as a flat washer 92 , is then abutted against the inner side of commodity weight 32 . bolt 90 can be inserted through washer 92 , through central hole 36 in commodity weight 32 , and through central bore 88 of hub 86 . a nut 94 can be tightened on the free end of bolt 90 to tighten and clamp washer 92 against commodity weight 32 to hold commodity weight 32 in place in cavity 94 . referring to fig1 , when commodity weight 32 is assembled to carrier 30 ′ in this fashion , the combined thicknesses of the various parts does not exceed the thickness of carrier 30 ′ to allow proper nesting of the various weights 6 ′ against one another . for example , nut 94 is received in a recess 96 in carrier 30 ′ so that it does not protrude beyond the adjacent face of carrier 30 ′. when tightened , washer 92 is flush or slightly inside of the other face of carrier 30 ′. thus , each carrier 30 ′ on each weight 6 ′ can be abutted flush against the carriers 30 on the adjacent inside and outside weights 6 ′ in the nested array of weights 6 ′. if nut 94 or bolt 90 should become loose , the fact that cavity 84 is in the inner face of carrier 30 ′ is beneficial . weight 32 will still be trapped or retained between carrier 30 ′ and the outer face of carrier 30 ′ on the adjacent weight frame 20 ′ lying to the inside . this enhances safety of dumbbell 2 ′. the alternative embodiment of a selectorized dumbbell 2 ′ as disclosed in fig8 - 12 has the advantages of the previous embodiment in that it can be completed by using readily available , low cost commodity weights 32 . thus , dumbbell 2 ′ can also be shipped by the manufacturer with handle 4 ′, the various weight frames 20 ′ of the different weights 6 ′, selector 8 ′, and the necessary clamping washers 92 , bolts 90 and nuts 94 . once dumbbell 2 ′ reaches a destination in the hands of a distributor , retailer or purchaser , it can be completed by purchasing the required number of commodity weights 32 locally and by clamping each commodity weight 32 in a cavity 94 of one carrier 30 ′. following completion in this manner , dumbbell 2 ′ is ready for use in the normal method . the result is a dumbbell that is less expensive to manufacture and for the user to purchase . various modifications of this invention will be apparent to those skilled in the art . for example , the use of commodity weights 32 is not limited to selectorized dumbbells 2 , 2 ′ as shown herein , but could be used in any selectorized dumbbell including selectorized dumbbells where the selector is simply a movable part on the handle that cooperates with a recess , detent , cam lobe , etc . on each weight . in this event , the weights can still be manufactured as a weight frame that will receive a commodity weight 32 with commodity weight 32 supplying the mass that is needed as long at the weight frame carries the recess , detent , cam lobe , etc . that is required for cooperation with the selector . moreover , while the applicants believe that it is most advantageous to purchase and unite commodity weights 32 to weight frames 20 , 20 ′ after weight frames 20 , 20 ′ are first shipped by the manufacturer to another destination , this is not necessary for every aspect of this invention . weights 32 could be added to weight frames 20 , 20 ′ prior to shipment by the manufacturer as this still permits using readily available , low cost commodity weights 32 in the manufacture of selectorized dumbbells 2 , 2 ′. low cost , cast iron commodity weights manufactured for use on traditional barbells or dumbbells are a preferred type of commodity weight that can be used with respect to dumbbells 2 , 2 ′. however , large and heavy steel washers which are also readily available and relatively low cost can also comprise commodity weights 32 . thus , the scope of this invention is to be limited only by the appended claims . | US-78666210-A |
a rolling jump cup for use with an adjustable equestrian barrier includes a body with rollers surrounding an equestrian barrier post , and a jump cup for holding a rail . | referring to fig1 , a prior art horse jump is generally indicated by reference numeral 10 . horse jump 20 includes a pair of upright standards 22 and 24 which are each typically constructed of an upright 4 ″× 4 ″ pressure treated post and a base 26 and 28 . a rail 30 extends between standards 22 and 24 and rests in jump cups 32 and 34 . rail 30 may be vertically adjusted by removing the rail pins ( not shown ) which extend through apertures 38 and 40 in jump cups 32 and 34 and apertures 42 and 44 in standards 22 and 24 and moving the jumps cup 32 and 34 to the desired height and reinserting the pins to secure the jump cup at the desired height . apertures 42 and 44 are typically spaced three inches apart to allow incremental manual adjustment of the height of rail 30 above the ground . referring to fig2 , the remotely adjustable equestrian barrier of the present invention is generally indicated by reference numeral 50 . remotely adjustable equestrian barrier 50 includes a primary motor control housing 52 and a secondary motor housing 54 which are secure to posts 22 and 24 . rail 30 extends between rolling jump cups 56 and 58 which are linked to primary control housing 52 and secondary motor housing 54 by lines 60 and 62 respectively . a power and control wire 64 extends from the primary motor control housing 52 to the secondary motor housing 54 . typically wire 64 is covered with a thin layer of earth or otherwise concealed between posts 22 and 24 so at to make it invisible to the horse and rider . referring to fig3 and 4 , primary motor control housing 52 is attached to the top of post 22 . a line 60 extends from housing 52 and attaches to rolling jump cup 56 . jump cup 56 includes a generally u - shaped bracket 57 , four rollers 66 extending between the legs of bracket 57 and which freely ride on the outside surfaces of post 22 , a rail support cup 68 and aperture 70 , which allows the jump cup 56 to be used in the conventional manner and temporarily secured to post 22 using a locking pin ( not shown ). jump cup 56 may be constructed from a 5 ″× 5 ″ square tube with four pairs of rollers on the inside of all sides ( not shown ). referring to fig5 - 7 , primary motor control housing 52 includes a motor 80 and shaft 82 , an encoder wheel 84 , and encoder wheel shaft 85 , a rotation sensor 86 and a controller circuit board 90 . the controller circuit board 90 includes a microprocessor 112 , a primary motor controller 92 , a secondary motor controller 94 , a rf receiver / decoder 96 and a signal booster 97 . a post mounting bracket 98 secures the housing 52 to the top of a post 22 . secondary motor housing 54 includes a motor 100 and shaft 102 , a rotation sensor 104 , encoder wheel 106 and an encoder wheel shaft ( not shown ). primary and secondary housings 52 and 54 may be constructed of plywood or other material such as high - strength plastic . in the typical equestrian arena , jumps are typically made of wood or plastic to protect the horses and riders . referring to fig8 , the controller circuit 90 receives power from a 12 - volt dc battery 110 . controller circuit 90 includes a microprocessor 112 with a memory 114 . microprocessor 112 receives commands from receiver / decoder 96 from antenna 116 to change the height of a rail , for example . microprocessor 112 sends “ up ” or “ down ” commands to the primary motor controller 92 and the secondary motor controller 94 which direct the rotation of motors 80 and 100 . motors 80 and 100 rotate shafts 82 and 102 which turn encoder wheels 84 and 106 on encoder shaft 85 and the secondary encoder shaft ( not shown ) respectively . as the encoder wheels 84 and 106 turn , rotation sensors 86 and 108 detect the marks on the encoder wheels 84 and 106 which are counted by microprocessor 112 to determine the incremental distance a rail has moved . when the desired position is reached , microprocessor 112 disables the motor controller 92 and 94 which in turn stop motors 80 and 100 . encoder wheels 84 and 106 may be secured directly to shafts 82 and 102 eliminating the need for a second encoder shaft . in the preferred embodiment , processor 112 may be a basicx bx - 24 processor chip for example . a bx - 24 development board may be used to mount the processor 112 and rf receiver 96 . an x10 rf transmitter may be used to transmit rf to the signal booster 97 and receiver 96 . in small arenas signal booster 97 may not be needed . these transmitters provide digitally encoded signals , are inexpensive and come in several sizes from a key chain attachable unit to desktop size units . a saturn l - series windshield motor may be used for drive motors 80 and 100 . the saturn windshield motor includes a 90 degree worm gear drive shaft and is capable of forward and reverse operation . stepper motors may also be used obviating the need for the rotational sensors 86 and 108 and encoder wheels 84 and 106 . a dacron ® line may be used to link the drive shafts to the rolling jump cups . chain , wire or other string may also be used . the motor housings 52 and 54 may be glued or otherwise fastened together . two high power h - bridge drives available from robotics hk of hong kong may be used to control the motors . referring to fig9 and 10 , remote control units 130 and 132 are illustrated . remote control unit 130 provides eighteen position buttons 134 and a 2 - position selector switch 136 . when one of the buttons 134 is depressed , position transmitter 130 sends an encoded signal to antenna 116 and receiver / decoder 116 in the primary motor control housing 52 . when the selector switch 136 is in the a - position and the button pushed is button 3 through 16 , the encoded signal is interpreted by the microprocessor 112 as incremental direction information . when selector switch 136 is in the b - position , the encoded signal is interpreted as position information or a store command to save the current position for a particular button 134 . remote control unit 132 is a smaller , compact transmitter with buttons 138 which may be used in a similar way as remote control unit 130 . remote control unit may be more conveniently carried by a rider to dynamically change the height of a jump while riding a horse during a training or practice session . remote control units 130 and 132 are preferably radio frequency ( rf ) transmitters . however , other transmitters such as optical or infrared transmitters or a hardwired data link for a fixed system may be used . referring to fig9 the selector switch 136 may be set to either the “ a ” or “ b ”. referring to fig1 there is no selector switch and the unit is always in the “ a ” mode . when the jump unit is first powered up the microprocessor sets the system to mode 0 ( zero ). no controller functionality is available other than mode selection until a mode is actually selected by pressing either button 1 or button 2 . when a button is depressed a digital signal is sent from the transmitter 130 or 132 to the receiver 96 . embedded within this signal is not only the identity of the particular button pressed but also the setting of the a / b selector switch . every button press transmits the position of the a / b selector switch . buttons 1 and 2 on the controllers 130 and 132 may be used to set the mode under which the microprocessor operates . when the selector switch 136 is in the “ a ” position mode 2 or 1 may be selected by pressing either button 1 or button 2 . when the selector switch is in the “ b ” position mode 3 or 4 may be selected by pressing button 1 or button 2 . controller 132 lacks a selector switch and is therefore in the “ a ” mode and thus only modes 1 or 2 may be selected . when the power is first turned on the system is in the mode 0 state . there are a total of four operational modes plus the startup mode that exists until one of the modes is selected . button 1 or 2 ( in either selector switch position “ a ” or “ b ” position ) may be pressed to activate one of the four modes of operation . buttons 3 through 18 may have no functionality until an operational mode is selected . once a mode is selected buttons 3 through 16 provide different functionality depending on which mode is selected . once a mode is selected buttons 17 and 18 buttons provide the same functionality in all four operational modes . button 17 being depressed causes the jump rail to be lowered in three - inch increments . button 18 being depressed causes the jump rail to rise in three - inch increments . with the selector switch 136 is in position “ a ” when button 1 is depressed the microprocessor program enters mode 2 . mode 2 is a set up mode . it is used to make two different adjustments to the jump rail 30 ( fig2 ). first , the rail may be adjusted so that the rail is at the top of the range of movement that it will attain in all other modes of operation . this is the zero position . once the zero position is established , the rail may not move any higher . second , the position of the two cups 56 and 58 ( fig2 ) may be adjusted so that each jump cup is of equal distance above the ground and so that the rail 30 will be generally parallel to the ground . if the ground is not level , the jump cups 56 and 58 may be independently adjusted so that the rail 30 is generally level . the height of the jump cups 56 and 58 may also be established using a laser or laser range finder ( not shown ) mounted on the housings 52 and 54 pointing at the top of rail 30 or mounted on the lower side of each jump cup pointing at the ground or the bases 26 and 28 , for example . input from the laser in the form of digital data may be used by the microprocessor 112 to calculate the height of the rail 30 and to adjust it accordingly . while in mode 2 the jump cups may be adjusted together in a downward direction by depressing buttons 13 , 15 or 17 . button 13 causes both cups 56 and 58 to descend by one increment of the rotational sensor . button 15 causes both cups to descend by one inch as detected by the rotational sensors . button 17 causes both cups to descend by three inches as detected by both rotational sensors . the buttons directly adjacent to buttons 13 , 15 and 17 are respectively buttons 14 , 16 and 18 . buttons 14 , 16 and 18 being depressed cause both cups to raise by 1 increment , 1 inch and 3 inches respectively . by using these buttons one can precisely position both cups at the top of the range of motion that will be allowed in other modes of operation . while in mode 2 the cup 56 attached to the primary controller box 52 ( fig2 ) is adjusted in a downward direction by depressing buttons 3 , 5 , and 7 . button 3 causes cup 56 to descend by one increment of the rotational sensor . button 5 causes cup 56 to descend by one inch as detected by the rotational sensor . button 7 causes cup 56 to descend by three inches as detected by the rotational sensor . the buttons directly adjacent to buttons 3 , 5 and 7 are respectively buttons 4 , 6 and 8 . buttons 4 , 6 and 8 being depressed will cause cup 56 to raise by 1 increment , 1 inch and 3 inches respectively . by using these buttons one can precisely align cup 56 so that it is at the same level above the ground as cup 58 . in mode 2 buttons 9 through 12 have no function and the microprocessor ignores the signals received when any of these buttons is depressed . once the two cups 56 and 58 are at an equal distance above the ground and at the extreme top of the range of movement button 2 is pressed to enter mode 1 . with the selector switch in position “ a ” depressing button 2 enters mode 1 . mode 1 is the run or operational mode and the buttons of the controller when depressed cause both jump cups 56 and 58 to move . in mode 1 buttons 17 and 18 cause both jump cups to lower or rise in three - inch increments respectively . the jump cups will rise to the upper limit of movement that is set in mode 2 and will lower all the way to the ground . buttons 3 through 16 being depressed will cause both cups to move to a preprogrammed height . if the jump is set in mode 2 so that 4 ′ 3 ″ is the top of the range of motion the depressing of buttons 3 through 16 may cause the cups to move to various heights above the ground between 4 ′ 3 ″ and 1 ′ 0 ″, for example . if the jump is set in mode 2 so that 5 ′ 3 ″ is the top of the range of motion the depressing of buttons 3 through 16 may cause the cups to move to various heights above the ground between 5 ′ 3 ″ and 2 ′ 0 ″, for example . the incremental distance moved when a button is depressed is typically in sets of 3 ″ as this is the traditional increment used for most horse jumps . moving the selector switch to position “ b ” and depressing the 1 button enters mode 4 . in mode 4 buttons 17 and 18 cause the two jump cups to move up and down in three - inch increments . when buttons 3 through 16 are depressed in mode 4 they record the present height of the jump in association with the specific button pressed . thus , the jump cups may be moved to any height above the ground using buttons 17 and 18 and then associate a specific button with that height above the ground . all of the buttons may be programmed to register different heights , the same height or any combination of different and same heights . the buttons may be programmed independently of each other . when power to the jump is shut off or when a different mode is entered the button settings as programmed in mode 4 are saved . with the selector switch in position “ b ” depressing the 2 button fig9 causes the microcomputer / jump to enter mode 3 . in mode 3 when a button ( 3 through 16 ) is depressed the jump cups move to the height that was associated with the specific button during mode 4 programming . buttons 17 and 18 still function to either raise or lower the cups in 3 - inch increments . referring to fig1 - 14 , the control software for microprocessor 112 is illustrated . generally , the software operates in a continuous loop to position the rail based on commands received from a remote control unit 130 or 132 . in position a , run mode , pressing one of the position buttons 3 through 16 causes the system to move the rail to a preset height . for example , pressing button 3 may move the rail to four feet . pressing button 4 may move the rail to four feet three inches . pressing button 5 may move the rail to three feet six inches . pressing button 6 may move the rail to three feet nine inches . pressing button 17 may move the rail down three inches and pressing button 18 may move the rail up three inches from the present location . if the rail is at the correct height , for example two feet , and the button assigned to two feet ( button 11 ) is pressed again , the system “ nods ” by moving the rail down an inch and then back up to the correct height of two feet to let the rider know that the signal was received . when the system starts , the rail moves to a preset position corresponding to two feet , for example . the typical post height is 66 inches , so the rail may move from ground level up to approximately 66 inches . the operator measures the height of the rail and then adjusts the height using the remote until the rail is level and at two feet , for example . once the preset position is established , the height of the rail may be changed by pushing the buttons on the remote 130 or 132 which moves the jump to the position associated with the button pushed . a button may be associated with a specific height of the jump such as eighteen inches , for example . or a button may be associated with an incremental adjustment of the jump height , such as up or down three inches . in the preferred embodiment , the system starts as indicated by block 200 , and looks for a signal from a remote , block 202 . if no input signal is present , decision block 204 , the system loops back and waits for an input signal . if an input signal is present , the signal is decoded , block 206 . with each push of a button on the remote , both the position of the selector switch and the identity of the button is transmitted . if the selector switch is in the a - position , decision block 208 , the identity of the button is determined . if button 1 is pressed , decision block 210 , the system enters the programming mode 2 and the target height , rail height primary and rail height secondary variables are set to a value of 500 , which is a preset position of three feet , block 212 , for example . in the programming mode 2 , the rail height is moved to the preset position , measured and adjusted if necessary and then set and stored in the memory to orient or calibrate the microprocessor . if button 1 is pressed , decision block 210 , then the other buttons are used to position and level the rail . if button 2 is pressed , decision block 214 , the settings are saved , the variables are set to zero and the system enters the run mode , block 216 . if button 3 is pressed , decision block 218 , one is added to the rail height primary variable , block 220 . if button 4 is pressed , decision block 222 , one is subtracted from the rail height primary variable , block 224 . if button 5 is pressed , decision block 226 , the scaling factor is added to the rail height primary variable , block 228 . if button 6 is pressed , decision block 230 , the scaling factor is subtracted from the rail height primary variable , block 232 . if button 7 is pressed , decision block 234 , three times the scaling factor is added to the rail height primary variable , block 236 . if button 8 is pressed , decision block 238 , three times the scaling factor is subtracted from the rail height primary variable , block 240 . in this manner , adjusting the height of the primary side of the rail independently from the secondary side of the rail , the rail may be leveled . if button 13 is pressed , decision block 242 , one is added to the target height variable , block 244 . if button 14 is pressed , decision block 246 , one is subtracted from the target height variable , block 248 . if button 15 is pressed , decision block 250 , the scaling factor is added to the target height variable , block 252 . if button 16 is pressed , decision block 254 , the scaling factor is subtracted from the target height variable , block 256 . if button 17 is pressed , decision block 258 , three times the scaling factor is added to target height variable , block 260 . if button 18 is pressed , decision block 262 , three times the scaling factor is subtracted from target height variable , block 264 . once the rail height is adjusted and leveled and button 2 is pressed , decision block 214 , the mode is set to normal , and the target height , rail height primary and rail height secondary variables are set to zero , block 216 and processing returns to block 202 . if a signal is received , block 202 , the signal is decoded , block 206 , and if it is in position a , decision block 208 and not button 1 , decision block 210 , then the system next determines which button has been pressed , continuation “ a ”. the distance to move the rail is determined by the spacing of the segments on the transparency or slotted wheel 88 and the diameter of the encoder wheel shaft 85 ( see fig6 ). based on these parameters , a scaling factor ( sf ) is established which corresponds to a distance increment in order to move the rail up or down . for example , a ½ ″ diameter shaft has a circumference of approximately 1 ½ ″. if the transparency wheel 88 has six segments , then each transition on the encoder wheel is equivalent to approximately ¼ movement of the rail . in this example , the scaling factor is six . a higher degree of accuracy may be obtained by increasing the number of segments on the transparency wheel . for example , if the circumference of the shaft is approximately one inch , a transparency wheel having sixty - four segments provides a resolution of 1 / 64 ″. in this example , the scaling factor is sixty - four . referring to fig1 , if button 17 is pushed , decision block 266 , then three times the scaling factor sf is added to the current target height variable trghgt , block 268 , to move the rail down three inches . if button 18 is pressed , decision block 270 , then three times the scaling faction is subtracted from the target height variable , block 272 , to move the rail up three inches . the system sequentially checks each button until the pressed button is determined and then continues to “ b ” in the flowchart . for each button pressed , target height variable is set to a multiple of the scaling factor . for example , if button 3 is pressed , decision block 274 , the target height variable is set to three times the scaling factor , block 276 , and processing continues to b to adjust the height of the rail . if button 4 is pressed , decision block 278 , the target height variable is set to zero times the scaling factor , block 280 , or the top of the post . if button 5 is pressed , decision block 282 , then the target height variable is set to nine times the scaling factor , block 284 . if button 6 is pressed , decision block 286 , the target height variable is set to six times the scaling factor , block 288 . if button 7 is pressed , decision block 290 , then the target height variable is set to fifteen times the scaling factor , block 292 . if button 8 is pressed , decision block 294 , then the target height variable is set to twelve times the scaling factor , block 296 . if button 9 is pressed , decision block 298 , then the target height variable is set to twenty - one times the scaling factor , block 300 . if button 10 is pressed , decision block 302 , then the target height variable is set to eighteen times the scaling factor , block 304 . if button 11 is pressed , decision block 306 , then the target height variable is set to twenty - seven times the scaling factor , block 308 . if button 12 is pressed , decision block 310 , then the target height variable is set to twenty - four times the scaling factor , block 312 . if button 13 is pressed , decision block 314 , then the target height variable is set to thirty - three times the scaling factor , block 316 . if button 14 is pressed , decision block 318 , then the target height variable is set to thirty times the scaling factor , block 320 . if button 15 is pressed , decision block 322 , then the target height variable is set to thirty - nine times the scaling factor , block 324 . if button 16 is pressed , decision block 326 , then the target height variable is set to thirty - six times the scaling factor , block 328 . once the button pressed has been determined , processing continues to “ b ” to block 330 , fig1 . because the target height does not equal the rail height primary or secondary , decision block 330 , the system determines the direction of movement , block 332 . if the target height is greater than the rail height ( primary or secondary ), then the direction of travel is down . if the target height is less than the rail height ( primary or secondary ), then the direction of travel is up . the duty cycle is set to 20 % for each motor to slowly rotate the motors to raise or lower the rail , block 334 . the microprocessor directs the motor control circuit of the primary motor to turn in a direction to lower or raise the rail and the rail height primary variable is decremented or incremented by one for each change in the output state of the primary rotation sensor , block 336 . likewise , the microprocessor directs the motor control circuit of the secondary motor to turn in the same direction as the primary motor to lower or lower the other side of the rail and the rail height secondary variable is decremented or incremented by one for each change in state of the secondary rotation sensor , block 338 . if the primary rotational sensor does not change in a predetermined period , which indicates that the primary motor has stalled , decision block 340 , then the duty cycle setting for the primary motor is checked . if the duty cycle for the primary motor is 100 %, decision block 342 , then both the primary and secondary motors are turned off , block 346 . processing returns to block 202 ( fig1 ). if the duty cycle for the primary motor is not 100 %, decision block 342 , then the duty cycle for the primary motor is increased by 10 %, block 344 . if the secondary rotational sensor does not change in a predetermined period , which indicates that the secondary motor has stalled , decision block 348 , then the duty cycle setting for the secondary motor is checked . if the duty cycle for the secondary motor is 100 %, decision block 350 , then both the primary and secondary motors are turned off , block 346 , and processing returns to block 202 ( fig1 ). if the duty cycle for the secondary motor is not 100 %, decision block 350 , then the duty cycle is increased by 10 %, block 352 , and processing continues to “ d ”. if the rail height of the primary equals the target height , decision block 354 , the primary motor is turned off , block 356 . if the rail height of the secondary equals the target height , decision block 358 , the secondary motor is turned off , block 360 , and processing returns to “ c ” to the beginning ( fig1 ). if the rail height of the primary does not equal the target height , decision block 354 , the secondary height is checked . if the secondary height is equal to the target height , decision block 362 , the secondary motor is turned off block 364 and processing returns to “ e ” ( fig1 ). in operation , a rider may adjust the height of the rail without dismounting his or her horse and without disrupting a training session by simply pointing the remote at the jump and pressing the desired button to raise or lower the rail . referring to fig1 , 15 - 17 , if the selector switch is in the b position , decision block 208 , processing goes to “ f ”. if button 1 was pressed , decision block 372 , the system enters into programming mode 4 and sets the target height , rail height primary and rail height secondary to 500 , block 374 . if button 2 is pressed , decision block 376 , programming mode exits and the system saves the programmed variables for each button , sets the program variables to zero and returns to “ c ” to the start ( fig1 ). if button 2 is not pressed , decision block 376 , processing continues to “ h ”. in programming mode 4 , specific rail heights are assigned to the remote control buttons . for example , button 3 may not be set to 2½ feet , button 4 is set to 2 feet and button 5 set to 3 feet , 3 inches . the height of the rail is adjusted using button 17 , decision block 380 , to move the rail down , block 382 , and button 18 , decision block 384 to move the rail up , block 386 . once the target height is reached , this rail height is assigned to a remote control button by pushing the desired button . for example , if button 3 is pressed , decision block 388 , button 3 is assigned to the current rail height and stored , block 390 . if button 4 is pressed , decision block 392 , button 4 is assigned to the current rail height and stored , block 394 . if button 5 is pressed , decision block 396 , button 5 is assigned to the current rail height and stored , block 398 . if button 6 is pressed , decision block 400 , button 6 is assigned to the current rail height and stored , block 402 . if button 7 is pressed , decision block 404 , button 7 is assigned to the current rail height and stored , block 406 . if button 8 is pressed , decision block 408 , button 8 is assigned to the current rail height and stored , block 410 . if button 9 is pressed , decision block 412 , button 9 is assigned to the current rail height and stored , block 414 . if button 10 is pressed , decision block 416 , button 10 is assigned to the current rail height and stored , block 418 . if button 11 is pressed , decision block 420 , button 11 is assigned to the current rail height and stored , block 422 . if button 12 is pressed , decision block 424 , button 12 is assigned to the current rail height and stored , block 426 . if button 13 is pressed , decision block 428 , button 13 is assigned to the current rail height and stored , block 430 . if button 14 is pressed , decision block 432 , button 14 is assigned to the current rail height and stored , block 434 . if button 15 is pressed , decision block 436 , button 15 is assigned to the current rail height and stored , block 438 . if button 16 is pressed , decision block 440 , button 16 is assigned to the current rail height and stored , block 442 . once the button ( s ) has been programmed , the programming mode may be exited by pressing button 2 , decision block 376 , and control returns to “ c ” to the start . in operation in the b position , the rail height goes to the value stored for the programmed button using the same control algorithms as shown in fig1 and 14 . in an arena with a plurality of jumps , each jump may be programmed to a different height associated with a single button . for example , button 3 may be programmed to eighteen inches for jump 1 , twenty - one inches for jump 2 , thirty - six inches for jump 3 and thirty inches for jump 4 . by pressing button 3 , each of the four jumps will move to the programmed height for that jump associated with button 3 . for a large arena , the motor controllers may be linked directly to a personal computer via an rs - 232 , usb port , ethernet port , or com port connection for example , which may be used to control the height of each jump , or the computer may be connected to a transmitter to wirelessly control each jump . referring to fig1 , the remotely adjustable equestrian barrier 50 may be used with an expandable rail 31 which includes slats 33 connected together and to rail 31 . slats 33 fold and unfold when rail 31 is lowered and raised . referring to fig1 , motor control housing 52 may be adapted to be located at the base of post 22 and connect to rolling jump cup 56 with line 60 over pulleys 51 and 53 secured to the top corners of post 22 . other configurations may be used to connect the motor control housings to the jump cups using lines or screws internal to the posts ( not shown ). it is to be understood that while certain forms of this invention have been illustrated and described , it is not limited thereto except insofar as such limitations are included in the following claims and allowable equivalents thereof . | US-91586704-A |
systems , methods and computer - accessible mediums can be provided that can establish particular parameters for electric pulses based on a characteristic of the tissue , and control an application of the electric pulses to tissue for a plurality of automatically controlled and separated time periods to ablate the tissue through mediation of membrane potential and through inducing the cells through a plurality of charge — discharge cycles such that an electroporation of a majority of the tissue is prevented or reduced . | the exemplary system , method and computer - accessible medium , according to an exemplary embodiment of the present disclosure , can utilize bioelectric responses and cellular processes to perform a controlled injury , or to kill the cells . according to one exemplary embodiment , the atp exhaustion can be induced in the cell if the external electric field can be applied for carefully pre - determined periods of time with timing such that the time between the waveform alterations can be sufficient to facilitate the cell to regain resting values before being hyper or depolarized again . based on the sign of the electric field , the exemplary system , method and computer - accessible medium , according to an exemplary embodiment of the present disclosure , can be used to impair the functioning of specific ion channels . this can lead to loss of osmotic and ionic balance . furthermore , the combination of atp exhaustion and ionic imbalance can reduce the cell &# 39 ; s ability to maintain membrane potential , and therefore , can disrupt basic cellular processes . this repeatedly induced external electric field can also cause mechanical damage to the membrane and other electro - sensitive structures . the generation of current flow through the cell can induce creation of reactive oxygen species (“ ros ”) in the intra and inter cellular spaces which can degrade cellular structures . the repeated passage of current through the cell can also be used to cause highly localized heating . this cascade of events , following exposure to an electric field , can cumulatively or separately cause the cell to lose viability and die . ( see , e . g ., fig3 ). as illustrated in fig3 , a cell exposed to an external voltage 210 imposed upon it for a short duration of time using electrodes 305 in order to depolarize or hyperpolarize the cell can elicit a variety of reactions , which can include , for example i ) atp exhaustion 310 : where the atp within the cell can be consumed in order to maintain osmotic balance and to regain the cell &# 39 ; s normal resting membrane potential ; ii ) ion flow and imbalance 315 : the polarization can also lead to ion influx into the cell ( e . g ., na 2 + or ca 2 ) and the loss of certain ions ( e . g ., k + ); iii ) reactive oxygen species (“ ros ”) damage and infiltration 320 : the flow of current can induce an electrolysis and / or an ros formation near the membranes ; iv ) electro - confirmational protein / gate / channel change 325 : electrically sensitive membrane proteins , including cells having an abundance ion channels and gates , can undergo electric field induced deformation and damage ; and v ) osmotic swelling 330 : the disruption of membrane potential can also lead to loss of homeostasis , which can lead to osmotic swelling . this process can be defined to be electrically induced stress or estress for short . estress can operate as an in - vivo tissue ( e . g ., tissue type or cell type ) ablation technique . through the working principle of estress ( element 400 ), the waveform of the external electric field can induce one of several biological effects on cells in vivo including transient cellular injury ( element 405 ), increased metabolic rates ( element 410 ), increased vulnerability to immune processes and can also cause immediate and complete cell death ( element 420 ). ( see , e . g ., fig4 ). cells from element 410 or 425 that can be exposed , e . g ., to only a limited cycle polarization can typically survive and continue to function normally . the estress waveform used to cause any of these effects can be carefully attuned to attain a specific outcome . the estress waveform can be defined by several parameters including applied voltage , sign of the electric field , type of waveform , length of each exposures , relative field strengths and current density , duty cycle , and intermittent or repeat exposures . ( see , e . g ., fig5 ). while similar waveforms can be in use for experimental techniques and other physiological processes , the selection of waveforms to induce estress can be non - trivial . incorrect choice of even one parameter can lead to undesirable or unexpected outcomes . the voltage to be applied to achieve estress can be based on the configuration of electrodes used , and the biology of the target cells . the size , shape and morphology of the cells can determine the threshold membrane potential induced on the cell . the exemplary transmembrane potential induced on exposure to an external electric field can be determined using the schwann equation , where cell shape and size can be key determinant factors . the exemplary voltage applied upon the cells can be high enough to cause transient rise in membrane potential but can be lower than the electroporation threshold for the cell . while this can be based on cell type , representative values for mammalian cells can be the voltage that can cause increase in transmembrane potential in the range of about 100 - 300 mv . these values can likely be lower for larger skeletal muscle cells , and higher for smaller cells . various exemplary statistical methods can be used to determine values for a population of cells where processes such as neoplasia or dysplasia can cause variations in the cell size and general morphology . for example , fig6 a illustrates a current density map 600 including electrodes 605 and an exemplary boundary of the effect of the exemplary estress 610 . fig6 b illustrates an electric field map 615 having electrodes 605 and a boundary of electroporation 620 . the treatment voltage can be applied to the cell in a variety of waveforms , including square 701 , sawtooth or triangle 703 , trapezoidal 704 , exponential or sinusoidal pulses 705 - 709 . ( see , e . g ., fig7 ). these waveforms can be applied to the cell in monopolar , dc shifted or bipolar fashions . in case of sinusoidal or similar waveforms , the frequency of application can be limited by root mean squared (“ rms ”) voltage value , which can be larger than the cell charging time . in case of monopolar application , the sign of the waveform can determine the predominant current channel affected by it , for example either inward or outward current , and also the type of ion depletion caused . ( see , e . g ., na + or k + ). the exemplary waveform can be shifted from a positive to a negative direction , or vice versa , to maximize stress induced on the cell . the bipolar waveform can offer additional advantages such as reducing stimulation of non - targeted cells , which can lead to effects such as minimal to no nerve or muscle activation , for example . the dc shifted waveform can provide the benefit of low level heating and generation of reactive oxygen species that can increase the stress on the cell , making it more vulnerable to death or other extra - cellular processes . transient localized hyperthermia can also provide the added benefit of reducing the voltage used to induce desired transmembrane potential . other waveforms , such as exponential waves , can also be used to provide a gradient for driving ros species towards the cell , and interfering with cell &# 39 ; s ability to return to resting potential . a single exposure can be defined by the exemplary waveform that can induce increase of transmembrane potential to a desired value , and the period which can facilitate the cell to return to its natural resting state . the number of exposures that the cell goes through can be the primary determinant of the nature of injury to the cell . at optimal voltage values and without considering other expedient factors , it can be estimated that the cell can undergo at least 500 - 1000 exposures to cause permanent injury that can lead to eventual cell death . the number of exposures to achieve cell death can be based on the biology of the cell ( e . g ., ion channels present on the cell membrane ), and / or its relative age and metabolism . given a known cell type and optimal voltage value , empirical data can be used to construct a statistical model , like a peleg - fermi formulation , to determine the number of exposures that can be used to cause 99 % or more cell death in a given population . ( see , e . g ., fig9 ). the exemplary waveform used to induce estress in cells can be resolved into two functional components . at least one portion of the exemplary waveform , where the voltage can be applied to elevate the transmembrane voltage , can be called the “ active ” portion of the exemplary waveform , and the portion of the exemplary waveform where the external voltage can be turned off to facilitate the cell to return to resting values can be called the “ passive ” portion of the exemplary waveform . ( see , e . g ., fig8 ). the active portion of the exemplary waveform can be longer than the membrane charging time of the cell , which can typically be between about 1000 ns to about 100 μs in length . in case of sinusoidal or similar waveforms , the half or quarter cycle / wavelength of the exemplary waveform can fall within this range . the actual active portion can be a smaller portion of about 100 μs , with the remaining portion of the exemplary waveform used to induce mild hyperthermia , generate ros , cause electrophoretic or other effects . conversely , the active portion can be optimized to provide a narrow range of temperature increase in the targeted area . the passive portion of the exemplary waveform can correspond to the time used by the cell to return to resting potential values from the elevated values due to exposure to the active portion of the waveform . the length of the passive portion can be dictated by the cell biology , and electrochemical transport processes . for example , this value can range from a lower range of about 10 μs for cells with rapid response time to about 100 ms for cells that can have slower processes . the passive portion can extend to many seconds for certain other cell types . the passive portion may not be constant , but can increase as the exposure progresses because of cell fatigue , and accelerating stress on the cell . the passive portion can also be monitored and altered to stop the buildup of membrane potential which can eventually lead to undesired electroporation of the cell . the waveform can be applied to a target area continuously or as fractionated treatment . the fractionation can serve two purposes . ( see , e . g ., fig9 ). first , fractionation can facilitate for the recovery of non - target cells which can undergo transient estress because of proximity to treatment zone . second , fractionation can facilitate pre - stressing of cells , where cells can be stressed by a first set of treatments , facilitating completion by following sets of treatment which can now be delivered at a lower energy setting . this fractionation can also be performed between sets of electrodes ( e . g ., spatially or temporally ). during spatial fractionation , a set of electrodes can be used to surround a target that can be embedded well within non - target tissue that can be spared . in this case , each pair or set of electrodes can deliver a portion of the total desired energy . while the energy passes through non - target tissue , it can spare it from injury as it may only be a fraction of what can be used to cause cell death or permanent injury . however , in combination from all the electrodes , the target tissue can receive a larger and more complete portion of the energy leading to the desired treatment effect in this location only . the same effect can also be achieved by temporally fractionating the treatment , by either delivering treatment from a different pair of electrodes at different time points , or by a single set of electrodes but over different time points . ( see , e . g ., fig1 ). the current density and field strength generated in a tissue experiencing estress can be dependent on the applied voltage and the configuration of electrodes used . globally , current density and field strength can be inter - related parameters , calculated by the applied voltage and electrical impedance of the target tissue . unlike electroporation and related techniques like irreversible electroporation and supraporation which can be driven by target field strength , estress can be mediated by current density imposed on the cells . the impact of estress on a target tissue can in turn be determined by the total charge that can be moved through the cell , which in turn can be computed as the temporal integration of current density in the tissue over the course of treatment . the field strength and current density can be numerically computed by solving the laplace equation of the voltage distribution over the domain of the target tissue . ( see , e . g ., fig1 ). the exemplary estress can utilize the exposing of a cell to a pre - determined sequence of exposures to electric fields . cells in regions receiving fewer exposures that can be insufficient to induce cell death can be expected to survive ( e . g ., lines 1005 ). as shown in fig1 , estress can be delivered using electrode pairs , where tissue 1010 surrounding the common current source 1010 can experience maximum exposure to electric fields , which can lead to tissue ablation 1015 . the target tissue 1020 surrounding each current sink 1025 can experience only a fraction of the total exposures provided from the current source ( see e . g ., fractional estress zone 1030 ). through this exemplary approach , maximum effect of estress can be limited to a single region while sparing tissue in the surrounding areas . different types of waveforms can be combined to either enhance the effects of estress or to achieve adjuvant effects . for example , radiofrequency waves can be combined prior to delivering the exemplary estress waveform to use hyperthermia to increase the sensitivity of the cell to the effects of estress . alternately , the same effect can be achieved by a monopolar or bipolar square waveform . waveforms or pulses typically used for causing electroporation can also be combined with estress . for example , estress can be used to alter the metabolic activity of the cell , following which electroporation can be used to introduce agents into the cell that can exploit the altered state of the cell . additionally , exponential waveforms can be used to induce a combination of hyperthermia and ros molecules that can further weaken the cell . estress can be induced , or treatment can be delivered to tissue or cells , through the delivery of electrical energy . this exemplary procedure , system , device , etc ., according to an exemplary embodiment of the present disclosure , can use at least two electrodes , for example , one positive and the other for return pathway of the electrical current . beyond this basic condition , the actual delivery of estress to cells or tissue can be achieved through many different exemplary electrode arrangements . for in - vivo applications , this can be broadly classified into five exemplary approaches . the first exemplary approach can be a percutaneous approach where needles or long thin probes can be introduced into a target region through skin punctures . the second exemplary approach can be a catheter directed approach where long tubular probes with integrated electrodes can be delivered through bodily vascular other natural lumen to the target region . the third exemplary approach can be an endoscopic or laparoscopic approach , where natural or clinically created orifices or lumen used to direct specifically designed probes for therapy to a target region . the fourth exemplary approach can be a cutaneous approach where surface electrodes can be used to target regions that can be in proximity or at a superficial depth to the skin surface . the fifth exemplary approach can be one where a ring of electrodes can be deployed on the skin , in a non - invasive fashion , such that they surround a deeper target for therapy . each of these exemplary approaches is described in further detail below . common to all exemplary approaches , therapy can be achieved by embedding or placing multiple electrodes in proximity of or surrounding a target , where at least one electrode can be positive and one other can provide a return path to the current . alternately , the electrodes can also be paired , where each positive electrode can be paired with a corresponding return electrode . in this exemplary configuration , permutations of pairs can also be chosen ad - hoc to deliver estress . the polarity of the electrodes can be alternated as treatment can progress to reduce electrochemical buildup . the alteration of polarity of the electrodes can also facilitate a reduced activation of electrically sensitive tissue such as nerves or muscles . another exemplary configuration can be utilized when a multitude of current sources can be paired with a single grounding pad , or where the return path which can be attached on the skin surface distal to the treatment region . ( see , e . g ., fig1 and 13 ). fig1 illustrates that the total exemplary electric charge transferred through the target tissue can also be used to track the effectiveness of estress for ablation . element 1120 is the surface of the electrode from which the electric field can be deposited into the tissue . element 1105 represents the boundary where the charge can pass through cells and where the number of exposures can be sufficient to ablate the cells . elements 1110 and 1115 represent isolines of constant current density . the exemplary charge density of fig1 can be expected to be highest in proximity to the electrodes , and therefore , cells at that location can be expected to undergo damage even with few exposures to the electric field . repeated cycles can grow the boundary of injured / uninjured tissue , and can be used to achieve the desired volume of ablation . as illustrated in fig1 , the exemplary can be conducted using a multitude of electrode pairs 1205 , where the current source and sink can be , but do not have to be equal in number . when an exemplary therapeutic waveform can be delivered with one pair of electrodes at a given time , the combination ( s ) of electrodes use for treatment delivery to untreated tissue 1210 can be varied to achieve any shape / volume of ablation ( e . g ., element 1215 ) in the exemplary treated tissue 1220 . fig1 illustrates a further exemplary configuration of the exemplary estress . a varying number of needle electrodes 1305 can act as a current source 1310 ( e . g ., a catheter - directed electrode ), and can be used in combination with a single distally placed ground pad 1315 to provide a return circuit . the distribution of current density , and the period over which the exemplary waveform can be delivered , can determine success of estress . for a given set of electrical properties for a target tissue , the current density can be determined by the distribution of electrodes in the tissue , the cross sectional shape and geometry of the electrode , the relative position of the electrodes with respect to each other , and the distance between each source — ground pair . the current density at any point in the tissue can be numerically calculated solving the laplace equation . ( see , e . g ., fig1 ). the cumulative charge moved through a given cell , a factor of induced current density and the period over which the waveform can be applied can be used to determine magnitude of injury to the cell . this can be minor , transient or permanent . referencing the exemplary percutaneous approach , the probes can be designed as thin long needles with different prismatic cross sections which can be used to facilitate current density distribution in the surrounding regions ( e . g ., square 1405 , pentagonal 1410 , circular 1415 and / or star 1420 ). as illustrated in fig1 , percutaneous probes ( e . g ., insulated probe 1505 ) can also be tined , with the tines being used to enhance current distribution from current source 1510 , create a faraday cage effect ( e . g ., through current return 1515 ) or to inject fluid media that can alter local conductivity properties to enhance the effects of estress . ( see , e . g ., fig1 ). percutaneous probes can also be fashioned such that they can perform a core biopsy of tissue immediately followed by delivery of estress treatment . ( see , e . g ., fig1 ). the exemplary probes can be arranged in pairs with mathematical models used to determine treatment coverage , or they can also be arranged in a fashion such that a central source can be enclosed by a ring of ground or return electrodes . this latter exemplary configuration can facilitate the protection of electrically sensitive tissue just beyond the target zone from unnecessary stimulation . an integrated bipolar configuration can also be created for the percutaneous probe where both the source and return can be designed into a single probe device . this exemplary device can also follow a tined configuration where the tines can act as a ground , enclosing the target region with a homogenous dosage of estress . electrodes can also be structured and / or configured for vascular or non - vascular endoluminal access . in either case , the exemplary electrodes can be distributed over a catheter like device , with at least one source and one return electrode . alternately , the return electrode can also be a grounding pad that can be placed distal to the target or treatment region . ( see , e . g ., fig1 ). the electrode on the catheter - like device can be provided using conductive wires in forms such as coils , baskets or tines . ( see , e . g ., fig1 ). in these exemplary cases , the exemplary configuration of the electrodes can be fashioned to provide ablations with radial depth , or along a helical or longitudinal cross section of the lumen . in addition to these exemplary configurations , the electrode can be or can include a conductive substrate running the length of the catheter , or can be placed on a balloon that can be used to increase contact with the surface of the lumen . alternately or in addition , the source and ground electrodes can be placed on two separate catheters that can be introduced to the target region separately . the endoluminal devices can be configured to achieve focal , spot , or circumferential lesions by altering the electrode placement on the catheter . fig1 illustrates an even further electrode configuration where core biopsy needles 1605 can be modified to serve as electrodes for ablation . ablation with estress can be performed after biopsy to prevent needle tract seeding . in this exemplary configuration , the biopsy needles can be used for performing an ablation ( a ), while sparing surrounding healthy non - targeted tissue ( b ), and subsequently can be used to extract core samples for histological assessment . fig1 illustrates an exemplary delivery of estress using catheter electrodes where the catheter can function as either a monopolar electrode with a grounding pad 1710 ( e . g ., element 1705 ) or in a bipolar configuration ( e . g ., element 1710 ). the return element for completing the electric circuit ( element 1710 ) can be placed on the skin surface 1720 . lumen wall 1725 can represent the target location upon which treatment is to be performed . this can include various endoluminal locations in the body ( e . g ., blood vessel , bile duct , gastrointestinal duct and urinary system ). the expected treatment boundary 1735 achieved from application of pulses is illustrated by element 1740 . according to one exemplary embodiment of the present disclosure , catheters or similar flexible devices can be delivered to a target site using either percutaneous access or access established through natural orifices . in case of a natural orifice , the access can be established using a flexible endoscope , or some similar device , which can provide visual guidance to perform the procedure . in such exemplary cases , the electrodes that deliver estress can be placed at the tip of long flexible devices to deliver the exemplary therapy . the tip can be in the shape of loops , button electrodes or flat surface applicators . inner portions of large organs like the stomach , uterus and gut , and some other lumen , can potentially be targeted using this exemplary approach . ablations can typically be directed on the surface of the organ with endoscopic visual guidance . this approach and configuration of electrodes can also be beneficial for use during laparoscopic or minimally invasive robotic surgery , where the probe with the electrode at the tip can be used to clear up margins of tissue surrounding the surgical region . using estress to perform this procedure provides the distinct benefits of preserving tissue integrity in the margins , and the ablation of tissue without emission of smoke or similar particulate matter . ( see , e . g ., fig1 a and 19b ). fig1 a and 19b illustrate examples of laparoscopic friendly flexible electrodes . the electrodes ( e . g ., element 1905 ) can be mounted on a flexible shaft ( e . g ., element 1910 ) that can facilitate transport through a narrow working guide of a endoscopic instrument . the exemplary design can conform to the inner circumference of a lumen ( see , e . g ., fig1 a ) to facilitate uniform ablation . the exemplary device can also be designed to deform and place the electrodes flatly against the target surface to direct ablation . estress can be applied for cutaneous or subcutaneous targets using various electrode configurations . when targeting skin protrusions , the target can be surrounded or captured using a pair of plate electrodes , or as part of a caliper electrode . this electrode configuration can minimize seepage of therapeutic waveforms or current into surrounding non - targeted tissue . for subcutaneous targets such as sweat glands or adipose tissue , estress can be applied using fine needle arrays , where individual electrode needles can be of about 25 g or smaller in size . needles in the array can be paired to provide localized treatment effects , or groups of needles can be assigned polarity to ablate a larger region . alternately , in this exemplary configuration the needles at the boundary and the center of the array can be of an opposite polarity , facilitating capture of delivered energy within the targeted region . in other exemplary configurations , arrays of button or ring electrodes can also be employed to deliver electrical energy to the target region . ( see , e . g ., fig2 ). fig2 illustrates exemplary devices that can be used for subcutaneous delivery of the exemplary estress . the body of the exemplary device ( e . g ., element 2005 ) can be constructed using an insulating material to support the electrodes ( e . g ., element 2010 ). the electrodes can consist of a number of current sinks in the periphery with a single central current source ( e . g ., element 2015 ), or the electrodes can be constructed as plate electrodes that can be repositioned to vary the size of the resultant ablation ( e . g ., element 2020 ). as described above , estress can be amenable to summation of treatment energy in both temporal and spatial fashions . for example , a location deep in the viscera , such as a location within the brain or inside some solid organ such as the lung or the liver , can be targeted using a ring of electrodes placed on the skin surface such that they cumulatively form a perimeter or surround the target location . ring , plate , gel or other forms of electrodes can be used create this configuration . in this exemplary configuration , estress can be delivered between pairs or groups of electrodes such that the each group of electrodes can deliver a small portion of the total therapeutic dose of the energy waveform . the delivery could be sequenced such that all electrodes can be used within a finite period of time . such spatial and temporal distribution of estress can facilitate delivery of therapeutic energy through non - targeted tissue such that the target can receive the full dose of therapy , but surrounding non - targeted tissue can be completely spared of the effects , or can undergo only transient injury . similar effects can also be achieved through percutaneous needles or subcutaneous electrode arrays that can be deliberately placed in a manner similar to that described above . ( see , e . g ., fig1 , 21a and 21b ). as illustrated in fig2 a , a number of current sinks 2105 ( e . g ., which can be placed subcutaneously ) can be combined with a single current source 2110 , to be placed within the target area 2115 , can be combined to achieve a targeted ablation while sparing tissue under the current sinks . a tumor 2120 ( e . g ., a deep seated tumor ) can be targeted using a multitude of current sinks 2105 and current sources 2110 placed on the skin surface . ablation can be achieved by distributing fractions of exposure between different pairs of electrodes . for a known biological target and tissue type , the exemplary mathematical procedures can be used to precisely plan the dose of estress to a given target while entirely sparing , or only transiently injuring , surrounding non - targeted tissue . the effects of estress can be modulated by agents and chemicals that can be introduced during the therapeutic procedure . these agents can alter the local biology , or influence overall electrical properties in the targeted region to facilitate estress , or in other exemplary cases , to protect non - targeted tissue . for example , wet electrodes can be created and / or provided by introducing saline of a different tonicity to modulate the delivery of estress into a large lumen such as colon , esophagus or bronchus . the use of the wet electrode can protect the lumen from thermal effects that can arise due to direct tissue contact with a metal electrode delivering large values of current . additionally , the fluid used to create the wet electrode can also be used to induce effects such as osmotic shock , or agents in the fluid can be used to protect one region of the tissue while facilitating deeper penetration of the therapeutic energy . in addition , chemical compounds , such as ion channel blockers , or other pharmaceutical agents , can be used as part of the wet electrode to improve targeting of a select set of cells using estress . similar wet electrodes in the form of a conductive gel can also be used with subcutaneous electrodes to improve targeted delivery of estress to targets on the skin . ( see , e . g ., fig2 ). fig2 illustrates an exemplary device 2200 ( e . g ., using a catheter ) that can be used to deliver the exemplary estress to a treatment zone 2205 by using into a bodily lumen 2210 where a permeable balloon 2115 ( e . g ., a weeping balloon ) can be used locally deliver a medium 2120 ( e . g ., a fluid ) that can modulate the estress treatment zone . as illustrated in fig2 , exemplary circuitry used for generation of the exemplary estress waveforms can include electrical equipment capable of generating sustained power high voltage waveforms ( e . g ., through exemplary power supply 2305 ). this can be achieved through multiple procedures , including use of a step up transformer coupled with an arbitrary waveform generator 2310 and a rectifier circuit , or a combination of a capacitor bank and fast acting switches 2315 . current and power monitoring circuitry can be built in to the generator 2305 to ensure that the waveform generated can be specific to the desired estress effect . a number of sensors 2320 and 2325 can be used to monitor and to modulate or control the estress waveform being delivered using computer control unit 2330 in combination with signal conditioning unit 2335 . this can include temperature sensors to regulate or minimize thermal effects on sensitive structures , and electrical impedance or conduction circuitry to track or control the effect of the exemplary waveform from estress as compared to other effects such as thermal ablation or electroporation . the exemplary estress can be controlled through an exemplary user interface 2340 , and can further include an exemplary safety and emergency shutdown unit 2345 to shut off the exemplary estress apparatus during an emergency . for example , the electrical impedance measurements can be performed across electrodes deployed in the target region using test pulses delivered prior to therapy . the test pulse can be used to perform a frequency sweep of the target region , and coupled with tissue specific information , can be used to estimate the energy levels at which estress can be applied to achieve only desired outcomes . during treatment delivery , the same circuitry can be used to track the generation of estress specific effects . this can manifest as two sets of current measurements , one during the active portion of the waveform and the other during the passive portion of the waveform . the current drawn from the circuit during the active portion of the waveform can be mathematically described as a decreasing exponential curve in shape , and can be analyzed accordingly . the current in the circuit during the passive portion of the waveform can be a non - linear curve that can be based upon the polarity of the active waveform and type of cell being treated . however , the magnitude of the passive portion current recorded can be , for example , 2 - 3 orders of magnitude smaller than the one measured during the active portion . if sufficient quantity of cells in the target region can be killed , then the current measured during the passive portion of the treatment can decrease significantly . this can be used as an added estimate of tissue ablation progress . the exemplary equipment used to generate and deliver estress can also be coupled with a neural and / or cardiac sensor apparatus to enhance safety of delivery . the neural sensors can be coupled to nerves in regions adjacent to estress delivery to monitor undesired nerve activation , and to regulate the waveform amplitude or frequency to reduce such effects . a cardiac sensor , such as , for example , electrocardiogram (“ ecg ”) systems , can be coupled with the generator to facilitate estress treatment close to the heart , or other such sensitive tissues without causing atrial fibrillation or otherwise impacting the cardiac rhythm . the delivery system can also incorporate electrical circuitry , such as current measurement systems , to estimate the magnitude of charge delivered to the target tissue , and also to follow the graph of power drawn to determine normal delivery of therapy . ( see , e . g ., fig2 ). as shown in fig2 , the exemplary estress ablation delivery ( e . g ., through needle electrode 2400 ) can be monitored and synchronized with sensors to achieve optimal treatment outcomes . for example , a nerve monitor 2405 can be used to identify any neuoromuscular activation during energy delivery to target tissue 2410 and a sensor gating unit 2415 can adjust energy parameters to minimize such effects . ecg sensors 2420 can be used to minimize unwanted cardiac effects . the electrode delivery of estress can include a multitude of sensors 2425 , which can include a current monitor ( e . g ., for tracking ablation progress ), temperature probe ( e . g ., for adjusting treatment in the event of excessive temperature rise ) and / or a physiologic function monitor . the above configuration and / or procedure can be controlled through a connection to and / or via a computer / power unit 2430 ( or a plurality thereof ). in addition to the generator , the estress delivery system can include a computer driven graphical or control interface that can facilitate the user to select parameters specific to target tissue biology for specific estress mediated outcomes . the control interface can also feature switches that can be used to commence and stop delivery of therapy , and a kill switch that can be used to safely shut down of the system in case of adverse events . the system can feature exemplary modules that can facilitate rapid connection and disconnection of wires and electrodes used for treatment delivery . the graphical interface can facilitate treatment planning using one or multiple previously described mathematical models , and facilitates the user to use computed tomography (“ ct ”), magnetic resonance imaging (“ mri ”), ultrasound or other imaging modalities to plan relative electrode location . additionally , the graphical interface can provide the operator with useful feedback regarding the progress of estress in the target tissue . various imaging modalities can be used for the planning , treatment delivery and post - treatment confirmation following estress in in - vivo tissue . for example , ct , ultrasound , positron emission tomography (“ pet ”), mri , optical imaging , endoscopy , fluorescent imaging , fluoroscopic techniques and other modalities can be used for identifying tissue and performing calculations used for the delivery of estress . cells that can be lysed by effects of estress can undergo acute necrosis which can immediately be identified using contrast enhanced ct imaging . additionally , the loss viability can alter the diffusion and perfusion properties in the treated region , facilitating the use of multi - parametric magnetic resonance (“ mr ”) imaging for confirmation of treatment . compared to baseline values , estress can induce brief spikes in the metabolic activity of target cells , and this can be captured using exemplary pet imaging techniques . the volume of current passed through tissue during estress can be readily monitored using redox or potentiometric chemical sensors , and can subsequently be imaged using exemplary optical or fluorescent techniques . estress can cause transient erythmeia and hyperemia when treating luminal targets . such changes which can typically be indicative of treatment can be monitored using simple endoscopic techniques . fig2 illustrates a flow diagram of an exemplary ablation procedure . for example , at procedure 2505 , the exemplary ablation procedure can begin . at procedure 2510 , an exemplary imaging modality can be chosen to be used at procedure 2515 ( e . g ., ct 2530 , ultrasound 2535 , fluoroscopy 2540 , pet 2545 , visual / optical / microscopy 2550 , chemical probes / voltage sensors 2555 and / or mri 2560 ). at procedure 2520 , a condition can be detected ( e . g ., hypodense region 2565 , contrast change edema 2570 , contrast extravation 2375 , absence of enhancement 2380 , hemorrhage / hyperemia 2385 , change in fluorescence 2390 and / or dwi or t1 / t2 properties 2395 ). disease , malignancy , quality of life or aesthetics can cause removal or destruction of undesired tissue from the body . two exemplary approaches can be used to achieve this , ( e . g ., surgical techniques and minimally invasive ablations ). a significant difference between the two approaches lies in whether the tissue can be removed in its entirety from the body , as can be done in surgical techniques , or destroyed in - situ as can be done during minimally invasive ablation . the minimally invasive ablation techniques can typically be less invasive than surgical techniques , and can provide increased quality of life benefits to the patients undergoing treatment . as an effect , recovery times can be shorter , and the procedure itself can be better tolerated in a broader spectrum of patients . commonly , during minimally invasive ablation , some form of energy can be delivered through multiple means to induce physical changes that can in turn cause unrecoverable damage to the target tissue ; killing it within the body . physiological processes , such as immune response or scar formation , can facilitate recovery of the tissue to a more desirable state . estress offers all the benefits of currently used minimally invasive image guided ablation techniques as compared to surgical therapy , for the removal undesirable tissue . estress can be or can include a biology mediated ablation technique . for example , estress can ablate only the tissue or structures that have a transmembrane potential . therefore , estress can have no effect on extra cellular matrix , adventitia or other collagenous structures that cannot support , nor have , a transmembrane potential . therefore , it can be possible to use estress to selectively destroy cells in a region while leaving the extra cellular matrix largely intact . this can facilitate application of estress for deep ablations within a lumen or adjacent to such structures . this exemplary feature can also minimize scar formation within the tissue . additionally , vascular supply and nerves within the target region can be largely preserved thereby promoting rapid recovery following ablation . another benefit of being a biology mediated technique can be the ability to target or affect one type of cells more than the other within the ablated region . ( see , e . g ., fig2 a and 27b which illustrates lumen wall 2705 , lethal temperature zone 2710 and estress treatment zone 2715 ). different cells within a region , such as smooth muscle and epithelial mucosal tissue , can present different response to estress that can be contingent on their ability to alter the transmembrane potential , the time taken to recover to baseline values , metabolic rates and the presence or absence of certain ion channels and pumps . estress can utilize such differences in biology of cells through alterations in the applied waveform as defined by the parameters described above . for example , it can be possible to use estress to target nerves surrounding the renal artery or bronchus while completely sparing the cells in the lumen itself . such advantages are unavailable in the known thermal ablation techniques . estress can injure or damage one or more cells through a combination of ion and atp depletion , ros damage , osmotic imbalance and electromechanical stress . these exemplary processes can rely on the alteration of the transmembrane potential of a cell . while the induction of the transmembrane voltage can be enhanced or made easier through an increase in local tissue temperature , it can be largely unaffected by thermal gradients such as large vessels or perfusion related cooling . therefore , it can be possible to use estress to injure or destroy tissue adjacent to large vessels where thermal ablation techniques can be ineffective . the exemplary waveform used to induce estress can be modified to function equally well in both well perfused tissue such as the kidney and liver , or poorly perfused tissue such as the lung parenchyma and adipose tissue , without affecting the overall quality or volume of the ablation . estress parameters are currently described for use with physiological temperature values . as noted above , any increase in local temperature can accelerate the process , and therefore , the voltage of the exemplary waveform can be reduced in magnitude to accommodate these variations . similarly , cooling can also be employed to deliberately reduce the effectiveness or slow down the speed at which the ablation progresses . these exemplary features can increase the indication where estress can be applied for ablation of tissue beyond the capabilities of known thermal ablation techniques . electroporation can be a known phenomenon where high voltage square pulses can be applied to cells to create transient pores in the cell membranes . the creation of pores can facilitate transport of materials , such as small molecules or genes , into the otherwise intact cells . electroporation can be designed in such a way that the trauma induced to the cell can be minimal , and it can survive following introduction of the foreign bodies . the theory behind electroporation can be that repeated application of high voltage pulses can facilitate induction of transmembrane voltage in the range of about 350 mv or higher . this high transmembrane voltage can cause molecular changes to the bilipid plasma membrane with the creation , of transient pores . upon removal of the external electric field , the cell can repair these pores and reseal its plasma membrane , maintaining the cell &# 39 ; s viability . the pores can be a few nanometers in size , and have been demonstrated through computer simulations , in vitro experiments on bilipid layers and in limited but unverified cell culture studies . typically , the success of pore creation , and permeation of the cell , can be demonstrated or detected in two ways . first , the creation of the pores can alter the electrical conduction properties of the cell or the tissue being exposed to the electric field . compared to baseline values , this can be manifested by a transient but significant increase in the current drawn through the tissue or cell as the pulse can be applied . it can also be manifested by an overall increase in current pulled through the tissue . the former increase in current drawn can be attributed to the pores reducing the overall impedance to passage of current through the cell . the latter increase in current can be attributed to leakage of cytoplasm into the surrounding extra cellular region , which can alter the overall electrical conductivity properties of the tissue . another exemplary method of detecting electropermeabilization can be through the use of tissue vitality stains and fluorescent dyes that cannot permeate an intact cell membrane . for example , propidium iodide stains cannot permeate an intact cell , but can readily permeate an electroporated cell and can stain the dna . likewise , fluorescent chemical sensors specific to na + , k + or ca 2 + ions can be used to monitor change in transport of ions due to the electroporation process . electroporation by itself can be a largely benign process and may not be intended to injure or kill cells . however , a number of ablation techniques derived from electroporation can be commonly used for injuring or destroying undesirable tissue . ( see , e . g ., fig2 and 29 ). fig2 and 29 illustrate the exemplary pulse duration — field strength relation when pulsed electric fields can be used to manipulate or ablate cells . nanoporation can be characterized by very short pulse length that can be combined with a very high field strength . electroporation and other related procedures can utilize s longer pulse length ( e . g ., about 10 microseconds or longer ) where cell viability can largely be determined by field strength . field strength in excess of about 1000 v / cm can cause irreversible cell injury while lower field strengths can facilitate the survival of the cell . field strength , and the number of exposures , can also be used in combination when using pulsed electric fields . electroporation can utilize very low energy , and therefore , the associated temperature rise in target tissue can be limited . cells can typically be exposed to fewer than about 500 pulses ( e . g ., to maintain non - thermal benefit ), and differences in various exemplary procedures can be determined by increasing field strength . electroporation can use the least field strength , while irreversible electroporation and nanoporation can employ stronger field strengths . a large number of exposures can cause thermal effects similar to what can be reported during thermal irreversible electroporation . the exemplary estress can cause some temperature change in the tissue and can be characterized by electric fields of low field strength and exposures greater than 250 pulses to achieve ablation . the pores created during the electropermeabilization or electroporation process can be made to endure using a modified set of exemplary treatment parameters . these enduring pores can cause permanent injury to the cell through loss of homeostasis , which can lead to eventual cell death . here , this pore creation and cell injury can lead to cell death as compared to electroporation where typically the cell survives and recovers from the permeabilization process . the process of permanent pore creation during ire can be achieved by using electric field strengths which can be at least two to three times higher than what can be used for electroporation . the higher field strength can be coupled with larger number of square pulse repetition that facilitates creation of transmembrane voltages in the range of about 700 mv — about 1v or higher . the pores resultant at these very high transmembrane voltages can induce pores of a size and number that can be larger than the typical electroporation process , and as a consequence , the cell can be unable to repair the pores even following the removal of the external electric field . similar to electroporation , pores created during ire cannot be detected directly . however , the success of pore creation and ire can be determined by measuring the electrical conductivity of tissue , and through the use of plasma membrane impermeable vitality stains . the pore creation process during ire can cause permanent alteration of tissue conductivity , increasing it by a substantial value . in fact , the success of ire can be directly correlated to the increase in magnitude of conductivity and therefore , the corresponding rise in current driven through the tissue . while there are two studies reporting direct evidence of pore formation through evaluation of treated tissue using electron microscopes , such evidence has been limited and unverifiable . in fact , it may be difficult to clearly distinguish pore formation following ire from permanent cell permeabilization because of cell death processes , such as necrosis . estress can provide certain benefits , and can also differ in comparison to irreversible electroporation and derivative techniques . first , for example , the exemplary working mechanism of estress can use permeabilization of the target tissue . if estress can be delivered successfully , the cells can undergo stress , and can typically die due to necrosis , but the plasma membrane can remain intact through the duration of the treatment . compared to other ire derived techniques , this can result in limited to no edema of tissue , which can be attributed to confounding results on imaging used for follow up of the ablation . as estress can operate through charging and discharging of cells , power drawn during treatment can remain largely constant . due to lack of membrane permeabilization and concomitant electrical conductivity changes , unlike ire and related techniques , there can be no increase in current drawn during estress mediated ablation . ( see , e . g ., fig3 ). fig3 illustrates an exemplary graph that shows differences in current measured during electroporation and estress . the exemplary current graph of estress can be characterized by a sharp peak 3005 , which can stem from charging of the cell membrane and can be fairly stable current from that point onwards . the impedance of the tissue can be stable or can increase slightly . during irreversible or reversible electroporation , there can be a dramatic increase in intrapulse current due to falling tissue impedance . additionally , decreasing impedance can lead to higher current drawn as treatment delivery progresses . this can simplify the design of instruments and generators for delivery of estress . overall , the energy consumption for estress can be a few times larger than ire , but the intensity at which the energy can be consumed can be less . the lower energy density used during delivery of estress can reduce the inadvertent activation of neuro - muscular tissue , which can be electrically sensitive , and can reduce the chances of sparking between electrode gaps , can avoid formation of gaseous bubble formation common to high current densities impingent on the electrodes and can minimize the risk of current induced cardiac arrhythmia . estress can function through cycling a cell through multiple transmembrane charge - discharge cycles . this can be different from ire and related techniques where the repetition of pulses or exposures can be used to build up a transmembrane charge to a critical value , reported to be between about 0 . 7 - 1 . 0v , which can be the threshold used for unrecoverable disruption of the plasma membrane . during estress , the transmembrane voltage can exceed a value of about 0 . 3 - 0 . 5v , which can typically be the lower threshold of reversible electroporation . therefore , when compared to ire and related techniques , a different set of treatment parameters can be used to achieve estress of cells . first , the pulse length for estress can be a few times longer than the charging time of the cell . compared to ire derived techniques , the pulse length can be shorter than that of the transmembrane charging time of other techniques . ( see , e . g ., references 3 and 4 ). the estress pulse length can be magnitudes shorter than the length of other techniques for achieving non - thermal ire . ( see , e . g ., reference 1 ). second , the inter - pulse spacing reported for all electroporation related techniques can be significantly shorter than that of the discharge time for a given cell . for achieving optimal estress effects , the passive portion or the inter - pulse timing can be at least as long as the discharge time for a given cell . finally , the electric field strength used to induce estress effects can be significantly smaller than typical values reported for non - thermal ire or temperature enhanced ire ( e . g ., about 500 - 800v / cm ), supraporation ( e . g ., about 1 kv or higher ) or high frequency electroporation ( e . g ., about 500 - 2500v / cm for ire and about 1 kv or higher for supraporation ). the threshold for inducing estress can have an upper bound where the early effects of electroporation begin manifesting ( e . g ., about 350 - 500v / cm ). ire can be an electric field strength driven threshold phenomenon , while estress can be based on the total charge driven through a given tissue . ( see , e . g ., fig3 ). this can be a fundamental difference between these two techniques with radically different mechanisms of action , and techniques used to plan , deliver or monitor the treatment . high field strengths can be used for achieving ire in tissue , where the strong electric fields can facilitate the charging of cell membranes , which can be analogous to capacitors in an electric circuit . ire , or even electroporation , may not occur unless certain electric field strength values can be achieved ; these values have been reported to be in excess of about 500v / cm . ( see , e . g ., references 1 , 2 and 4 ). while an electric field can be used to induce a transmembrane charge for performing estress , the stress on the cell can be induced through repeated charge — discharge cycles . therefore , effects of estress can be predicated on the total charge moved through a given cell , which in turn can be directly related to the temporal integration of current density induced in a tissue . therefore , it can be possible to achieve effects of estress at external field strengths typically too low to induce any electroporation . fig3 a and 31b illustrate the contrast evolution of a tissue injury over the course of two treatments . the exemplary estress is illustrated in fig3 a and electroporation based modalities are illustrated in fig3 b . the treatment can be centered around a single electrode 3105 and a distal ground pad . boundary 3110 demonstrates the maximum extent of cell injury at the end of treatment delivery . shaded region 3115 represents locations of complete cell death ( e . g ., ablation ). the time evolution of treatment occurs from the top to the bottom of fig3 a . during the exemplary estress , a repeated exposure can cause radially increasing volume of cell death with respect to the electrode center . during the electroporation - based therapies , the extent of cell death can be established even with the first pulses , the completeness of cell death can be achieved with an increased number of pulses . estress can be and / or include a biologically modulated ablation technique . there can be biological and morphological differences of cells in a region that can be used to target one type of cell while sparing others . conversely , ire can be a treatment parameter modulated technique where , if satisfactory thresholds are achieved , most or all cells within a target region can be destroyed . as an added benefit , treatment parameters of estress can be adjusted to achieve varying degree of cell injury or stress levels . therefore , using estress , the molecular transport can be transiently increased , the , metabolic activity can be increased , moderate injury can be caused or cells can be damaged beyond recovery . such controlled injury of cells cannot be achieved using ire . ire can either achieve complete and irreversible damage to cells , or cause reversible electroporation where the cell recovers . additionally , effects of estress can be enhanced or blocked completely through use of simple pharmacological agents such as ion channel blockers or inhibitors , or ion channel promoters , to selectively target certain cells while inhibiting effects on other cells within treatment zone . in addition , commonly used non - pharmacological agents such as dextrose , physiological saline etc ., can be used to alter loco - regional tissue conductivity properties and ion availability can be used to alter the progress of estress in a heterogeneous tissue target . estress can provide safety benefits when compared with ire and derivative techniques . estress can be delivered at field strengths and voltage values that are magnitudes less than what can be commonly used to achieve ire . this brings increased safety when applying estress adjacent to electrically sensitive tissue such as the heart , muscle and nerves . as a non - targeted treatment technique , ire can ablate muscularis layers of lumen structures . this can typically result in stricture formation and affects function of the lumen . estress can be programmed to target mucosal layers while largely sparing the muscularis layers of a lumen , thus being a better candidate for performing mucosal resections . there exist few other non - thermal electrically mediated ablation techniques . electrochemotherapy (“ ect ”) and electrogenetherapy (“ egt ”) are examples of electroporation mediated therapies that do not involve ire , but work through electroporation to introduce chemicals or genes into target cells for purposes that can include ablation . in addition to previously described benefits , estress does not rely on additional pharmacological agents or genes for performing ablations . any such agents can be merely adjuncts to the effects achieved by electrochemical therapy derived method for performing ablations are known . ( see , e . g ., reference 5 ). they can be achieved by inducing localized electrolysis through delivery of dc current into target tissue , and the use of electroporation as an adjunct to enhance the cytotoxic effect of the radicals generated during the electrolysis process . compared to this technique , estress can cause little to no electrochemical change in the treated tissue . electrochemical denaturation of tissue can cause unwanted effects including destruction of protein structures , which can be the cause of venous embolism . additionally , the application of steady dc currents cannot be performed close to cardiac tissue . as estress does not induce tissue electrolysis , it is beneficial over previously known procedures ( see , e . g ., references 5 , 6 , 7 ) where sinusoidal waves at different frequencies can be applied to limit tumor growth . these techniques are not meant to ablate tissue , but are meant to arrest the continued growth of cells by interfering with the cell division process . three examples are presented where estress can be evaluated , in - vivo , using different application modalities . in the first exemplary case , estress delivery can be planned in healthy swine liver using pair of needle electrodes . needle spacing of about 1 . 5 cm and electrode dimension of about 1 . 5 cm can be assumed for delivery of treatment . external electric fields of about 500 , 700 and 1000v / cm . for the given needle electrode geometry and configuration , these field strengths can typically be considered insufficient for causing ire . current drawn during delivery of estress can be monitored , and no change in the magnitude of current drawn can be observed , which can indicate a lack of electroporation or related effects . the cells in the treatment region can be charged and discharged about 450 times ( e . g ., for about 500 v / cm ) or about 900 times ( e . g ., about 700 and 1000v / cm ), with treatment fractionated into groups of about 90 charge - discharge cycles . the anticipated treatment zones can be computed using numerical simulation by solving the laplace distribution of electric potential and the peleg - fermi formulation . entire treatments were concluded between about 8 - 16 minutes based on a number of cycles used . the animals were sacrificed within about 4 hours following delivery of estress to their liver , and the ablated regions can be extracted for histopathology analysis . unaffected blood vessels were found well within the region of ablation , and did affect progression of treatment . gall bladder close to the treatment zone was found to be ablated but be structurally intact without perforation . these can be interpreted as evidence that estress therapy delivery can cause temperature rises insufficient for protein denaturation . ablated regions presented as areas where cells underwent a mixture of coagulative necrosis and apoptosis . histological analysis and measurements can provide evidence that lesion size can be contingent on induced current densities and number of charge - discharge cycles . the ablation can grow with increasing charge - discharge cycles providing evidence for estress being a function of threshold charge moved through given tissue type . ( see , e . g ., fig3 a - 32c ). fig3 a illustrates a photograph of a gross liver tissue specimen treated with estress using needle electrodes . the treated regions 3205 appear darker when compared to surrounding normal untreated tissue 3210 . fig3 b illustrates a low magnification hematoxylin & amp ; eosin (“ h & amp ; e ”) stained tissue slice where the needle tract 3215 can be seen in the corner of the image . the tissue appears hyperemic and darker when compared to surrounding untreated tissue . a blood vessel 3220 can be seen in the vicinity of the ablation zone and has not affected progression of treatment . fig3 c illustrates the contrast enhanced ct scans corresponding to the location of treatment from where the gross tissue specimens were recovered . in a second example of application estress , this exemplary ablation technique can be used for the focal mucosal resection of the swine rectal wall . a specially constructed endo - rectal probe in monopolar configuration in conjunction with a grounding pad was used for performing estress directed mucosal ablation using two charge - discharge cycle settings in six animals . the endo - rectal electrode facilitated ablation of about 90 ° arc of the rectum , with about a 2 cm × 1 cm cross section . estress treatment was delivered at a voltage of about 500v for about 450 or 900 charge — discharge cycles . current drawn during estress was monitored to confirm explicit charge — discharge patterns . compared to a control group of ire directed ablations performed using the same electrode , estress samples demonstrated less tissue edema , hemorrhage and were limited to the mucosal tissue . in addition , during ire , increases in current drawn by the tissue can be observed , a classical indication of electroporation of tissue . such increases can be absent during delivery of estress . the animals were sacrificed within about 4 hours following delivery of estress to their rectum , and the ablated regions was extracted for histopathology analysis . the estress ablation performed at the lower cycle setting indicated evidence of patchy and incomplete ablation , with some regions of viable tissue interleaved with ablated tissue . the mucosa was largely ablated with little to no penetration to the muscle layers . in the higher cycle setting the mucosal layer was found to be uniformly and completely ablated with minor penetration of ablation into the muscularis layers . however , compared with the ire ablations performed with similar setting , the lesions was found to be more superficial and controlled with minimal edema . ( see , e . g ., 34 a and 34 b ). an exemplary comparison of an irreversible electroporation is illustrated in fig3 a , and the exemplary estress is illustrated in fig3 b , for a treated swine rectum . the ire treated rectum can be characterized by tissue edema ( e . g ., from the release of cytosol from electroporation ), with hemorrhage and collagen separation . changes in estress ablated rectum can be milder , with limited tissue edema , and the injury can largely be limited to the mucosa . in the third exemplary demonstration of estress , catheter directed ablation of the bronchial mucosa was attempted in a healthy swine model . two different exemplary approaches were used for the delivery of estress . in the first exemplary approach the lung was isolated and filled with normal saline , following which estress was delivered using a catheter with a coil electrode at its tip to achieve circumferential ablation of the bronchial mucosa . in the second approach , a catheter was made with a sponge like material at its tip . ( see , e . g ., fig3 and 35 ). fig3 illustrates an exemplary procedure where a balloon catheter 3405 can be used to occlude a bronchi to fill a segment of the lung with a conductive fluid . the exemplary estress ablation can then be performed in a target segment . fig3 illustrates an exemplary procedure where the catheter tip is wetted with a conductive fluid 3505 to perform more targeted ablations . the catheter was introduced into the bronchus , and saline was passed through the distal end to complete the electrical pathway . current was delivered through this “ wet electrode ” and a grounding pad to perform ablation of the bronchial mucosa . previously described treatment parameters were used in both catheter directed treatment experiments , and ablation was achieved successfully . for both cases treatment was completed successfully without incident and desired mucosal ablation can be achieved . ( see , e . g ., fig3 a - 36c ). fig3 a and 36b illustrate treated ( arrows 3605 ) and untreated ( arrows 3610 ) segments of swine bronchus . fig3 c illustrates low magnification images of h & amp ; e stained bronchial tissue . treated tissue can be characterized by loss of epithelium , and necrosis of glands . fig3 illustrates an exemplary image of an exemplary catheter 3700 . such exemplary catheter 3700 can be used to ablate an exemplary tissue ( e . g ., esophageal mucosa in a normal swine model ). fig3 shows a set of exemplary images of an exemplary placement of the exemplary catheter 3700 of fig3 . the exemplary images illustrate the placement of catheter electrode 3800 at various exemplary locations within the esophagus ( e . g ., within the peri - cardiac region ). the exemplary catheter 3700 can be used to ablate tissue without significant cardiac adverse events . post - treatment the patency of the lumen can be demonstrated by the absence of extravasation of the injected contrast . fig3 illustrates an exemplary image of an exemplary swine esophagus . a gross examination of the swine esophagus illustrates circumferential regions of discoloration and hyperemia consistent with estress mediated ablation . there can be a small amount , or zero , tissue edema , which can normally be observed during electroporation . element 3905 provides the locations of exemplary lumen that can receive treatment , element 3910 provides a location of sham balloon placement without delivery of the exemplary estress . fig4 shows a set of exemplary images of an exemplary cross - section of photomicrograph of an h & amp ; e stained swine esophagus treated with the exemplary estress . various layers of the swine esophagus can be seen including : mucosa 4010 , depth of treatment effect 4015 , submucosa 4020 and smooth muscle layer 4025 . elements 4005 indicate the extent of penetration of the ablation . the exemplary estress parameters were chosen to target the epithelial type cells in the mucosa while the underlying smooth muscle cells in the muscularis were spared . fig4 shows a set of exemplary images of normal and treated epithelium . high magnification image of the mucosa is illustrated , which shows morphological differences between viable and necrotic epithelial cells in the mucosa . fig4 illustrates an exemplary flow diagram illustrating an exemplary method 4200 for injuring or killing cells and / or tissue . for example , at procedure 4205 , parameters for electric pulses can be established or determined based on one or more characteristics on the tissue to be injured or killed . at procedure 4210 , the location of the placement of the electrode ( e . g ., at or near the tissue ) can be determined , and the electrode can be placed at or near the tissue in procedure 4215 . in procedure 4220 , electrical pulses can be generated for which an application of the electrical pulses can be controlled at procedure 4225 . at procedure 4230 , the cells and / or tissue can be injured or killed . in a further exemplary embodiment , the exemplary catheter of the exemplary estress device / apparatus can include at least one fixed electrode ( a first electrode ), and at least one electrode ( a second electrode ) that can move relative to the fixed electrode . this facilitates the ability to control for the length of lesions without having to perform multiple repositions between ablations . the second electrode can be made of material that can be impedance matched to the target tissue being ablated , and can be surrounded by a conductive fluid that can also be impedance matched to achieve specific ablation effects . the conductive fluid can serve as a conductor for electrical connectivity , but can also be used as a heat sink to reduce or enhance the thermal effects of ablation , and can serve as a reservoir for delivery of chemicals and therapeutic agents to the target regions . the exemplary device can have both temperature and electrical sensors to monitor the course of the ablation . ablations that can be performed using this exemplary device can include , but is not limited , to radiofrequency ablation , irreversible electroporation , electroporation , electrochemical therapy , electrochemotherapy , electrogenetherapy , induced endocytosis , high frequency electroporation , nanoporation and finally , estress . the exemplary device can also perform transmural ablation penetrating into surrounding tissue without causing perforation or heat induced stricture of the lumen . fig4 shows a block diagram of an exemplary embodiment of a system according to the present disclosure . for example , exemplary procedures in accordance with the present disclosure described herein can be performed by a processing arrangement and / or a computing arrangement 4302 . such processing / computing arrangement 4302 can be , for example , entirely or a part of , or include , but not limited to , a computer / processor 4304 that can include , e . g ., one or more microprocessors , and use instructions stored on a computer - accessible medium ( e . g ., ram , rom , hard drive , or other storage device ). as shown in fig4 , e . g ., a computer - accessible medium 4306 ( e . g ., as described herein above , a storage device such as a hard disk , floppy disk , memory stick , cd - rom , ram , rom , etc ., or a collection thereof ) can be provided ( e . g ., in communication with the processing arrangement 4302 ). the computer - accessible medium 4306 can contain executable instructions 4308 thereon . in addition or alternatively , a storage arrangement 4310 can be provided separately from the computer - accessible medium 4306 , which can provide the instructions to the processing arrangement 4302 so as to configure the processing arrangement to execute certain exemplary procedures , processes and methods , as described herein above , for example . further , the exemplary processing arrangement 4302 can be provided with or include an input / output arrangement 4314 , which can include , for example , a wired net - work , a wireless network , the internet , an intranet , a data collection probe , a sensor , etc . as shown in fig4 , the exemplary processing arrangement 4302 can be in communication with an exemplary display arrangement 4312 , which , according to certain exemplary embodiments of the present disclosure , can be a touch - screen configured for inputting information to the processing arrangement in addition to outputting information from the processing arrangement , for example . further , the exemplary display 4312 and / or a storage arrangement 4310 can be used to display and / or store data in a user - accessible format and / or user - readable format . the foregoing merely illustrates the principles of the disclosure . various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein . it will thus be appreciated that those skilled in the art will be able to devise numerous systems , arrangements , and procedures which , although not explicitly shown or described herein , embody the principles of the disclosure and can be thus within the spirit and scope of the disclosure . various different exemplary embodiments can be used together with one another , as well as interchangeably therewith , as should be understood by those having ordinary skill in the art . in addition , certain terms used in the present disclosure , including the specification , drawings and claims thereof , can be used synonymously in certain instances , including , but not limited to , e . g ., data and information . it should be understood that , while these words , and / or other words that can be synonymous to one another , can be used synonymously herein , that there can be instances when such words can be intended to not be used synonymously . further , to the extent that the prior art knowledge has not been explicitly incorporated by reference herein above , it is explicitly incorporated herein in its entirety . all publications referenced are incorporated herein by reference in their entireties . the following references are hereby incorporated by reference in their entirety . [ 14 ] u . s . pat . nos . 7 , 680 , 543 , 7 , 722 , 606 ; u . s . patent publication no . 2009 / 0076502 , 2011 / 0060393 to azure et al . | US-201414910600-A |
methods for producing intraocular lenses which can be non - surgically repositioned after being placed in an eye . such methods include providing a lens blank at least a portion of which is a polymeric material having a glass transition temperature of at least about 40 ° c ., and forming from the lens blank an intraocular lens including an optic and a fixation member so that at least a portion of the fixation member is made of the polymeric material . the position of the optic in the eye can be changed by heating the fixation member to a temperature above the glass transition temperature . | fig1 illustrates a lens blank , shown generally at 10 , which is provided and from which an iol 40 ( fig3 ) is derived . lens blank 10 includes a core 12 and an outer layer 14 which surrounds the core along the length l of the lens blank . lens blank 10 is prepared by casting an optically clear polymer material into the shape of core 12 . a particularly useful material for core 12 is pmma . the optic 46 and the proximal portions of fixation members 42 and 44 of iol 40 ( fig3 ) are derived from core 12 . a polymeric material having a tg of about 45 ° c ., such as poly ( 3 , 3 - dimethylbutyl methacrylate ) is cast in the shape of outer layer 14 around core 12 . the distal portions of fixation members 42 and 44 of iol 40 are made from outer layer 14 . it should be noted that lens blank 10 can be provided in any suitable manner . for example , individual lens blanks , such as lens blank 10 , can be produced by separately forming the core 12 and then forming the outer layer 14 around the pre - formed core 12 . the forming of core 12 can be achieved by polymerizing a polymerizable component , that is one or more monomeric components and , possibly , other components to produce the core . once the core is formed , it can be placed in a mold and surrounded by another polymerizable component or polymer precursor , that is one or more monomeric components , and , possibly , additional materials . this polymer precursor surrounding the pre - formed core is polymerized to produce the outer layer 14 . as an alternate for providing lens blank 10 , an elongated composite rod can be produced . this elongated rod contains an elongated core surrounded along its length by an elongated outer layer . this elongated core and elongated outer layer can be produced in a manner similar to the manner described above for producing the core 12 and outer layer 14 of lens blank 10 . once the elongated rod is produced , it can be cut in a direction transverse to the longitudinal axis of the elongated rod to produce a multiplicity of lens blanks , such as lens blank 10 . the polymerization of the various polymerizable components noted above and the selection of the individual polymerizable components can be accomplished using conventional techniques . therefore , such techniques are not described in detail herein . one important aspect of the present invention is that the outer layer of the lens blank be formed , at least in part , from a polymeric material having a tg of at least about 40 ° c . or about 45 ° c ., more preferably in the range of about 45 ° c . to about 60 ° c . of course , the polymeric material ( as well as the material from which the optic is derived ) used should be compatible with the eye so that implantation of the final iol does not cause any significant harm or damage to the eye . in addition , the core 12 of the lens blank 10 should be made of an optically clear material which is suitable in iol optics . again , such material should be compatible with the eye in which the iol produced in part from the core 12 is implanted . once lens blank 10 is provided , it is machined into an iol precursor , such as shown in fig2 a and 2b or directly into an iol , such as shown in fig3 . this machining can occur using conventional automated lens forming machinery , for example , an automatic lathe . the iol precursors shown in fig2 a and 2b are configured to be unacceptable for implantation into a human eye . thus , the iol precursor 20 shown in fig2 a includes diametrically opposed fixation members 22 and 24 the distal ends of which are located too close to the optic 26 to be acceptable for use in a human eye . the iol precursor 30 shown in fig2 b includes fixation members 32 and 34 the distal ends of which extend too far away from the optic 36 to be acceptable for use in a human eye . both optics 26 and 36 are derived substantially completely from core 12 , while the distal portions of fixation members 22 , 24 , 32 and 34 are derived from outer layer 14 . if desired , the fixation members can be made substantially completely out of the material of outer layer 14 . the fixation members 22 , 24 , 32 and 34 comprise a polymeric material having a glass transition temperature of about 45 ° c . after these &# 34 ; unacceptably configured &# 34 ; iol precursors are produced , the fixation members are heated to above the glass transition temperature and the configuration of the fixation members are altered so as to be acceptable for use in a human eye . such a configuration is shown in fig3 with iol 40 . after the heated iol precursors are altered so that the fixation members are configured to be acceptable , the fixation members are cooled below the glass transition temperature while maintaining the fixation members in the altered configuration . at this point , after cooling below tg , the iol precursors are configured as shown in fig3 . thus , iol 40 includes acceptably configured fixation members 42 and 44 and optic 46 . iol 40 made from either iol precursor 20 or iol precursor 30 has a &# 34 ; memory &# 34 ; based on its manufacturing history . such a &# 34 ; memory &# 34 ; iol 40 can be effectively used as follows : referring now to fig4 and 5 , &# 34 ; memory &# 34 ; iol 40 can be implanted into a mammalian eye , for example , a human eye , using conventional and well - known surgical techniques , such as techniques which are commonly used to implant conventional iols . in general , an incision is made in the eye and a natural lens is removed , for example , using a conventional phacoemulsification procedure . with the lens capsule vacated , the &# 34 ; memory &# 34 ; iol 40 is introduced into the eye , such as into the posterior chamber of the eye , and is positioned and fixed within the eye . the incision is then repaired . after healing , the &# 34 ; memory &# 34 ; iol 40 implanted in the eye is effective to provide vision correction to the recipient of the iol . the present invention is also applicable to iols structured for placement within the anterior chamber of the eye . such anterior chamber iols for the production and use of such anterior chamber iols are within the scope of the present invention . the &# 34 ; memory &# 34 ; iol 40 can be , or over a period of time can become , decentered relative to the pupil of the eye 50 as shown in fig4 . if this condition is left as is , &# 34 ; memory &# 34 ; iol 40 becomes substantially less effective to provide proper vision to the recipient . optical distortion , glare , and / or other possible problems exist when &# 34 ; memory &# 34 ; iol 40 is decentered as in fig3 . in general , with a &# 34 ; memory &# 34 ; iol 40 , the fixation member ( or part thereof ) is heated , for example , by passing radiant energy through the pupil of the eye to heat the fixation member ( or part thereof ) to a temperature above the tg to recenter the optic 46 . for example , with specific reference to fig2 a , fixation members 22 and 24 are originally manufactured in a highly curved configuration . by heating fixation member 42 to above its glass transition temperature , to about 50 ° c . ( by passing radiant energy , for example , from a thin probe tip packed into the eye through a &# 34 ; pin - sized &# 34 ; incision having a size of no more than about 0 . 2 mm and positioned immediately adjacent or in contact with this part ) fixation member 42 moves toward its highly curved configuration , thereby causing optic 46 to move left and to be centered relative to the pupil 50 of the eye . in the case where &# 34 ; memory &# 34 ; iol 40 is derived from iol precursor 30 , &# 34 ; memory &# 34 ; iol is repositioned , for example , in the coronal plain as follows . a pin - sized probe is introduced into the eye adjacent to fixation member 44 . the pin - sized probe causes fixation member 44 to be heated to a temperature above the tg . this causes fixation member 44 to begin to move toward its original configuration as shown in fig2 b . this movement of fixation member 44 causes optic 46 to move to the left so that optic 46 is centered around pupil 50 , as shown in fig5 . once this repositioning has occurred , the heating is stopped and the pin - sized probe is removed from the eye . in another embodiment , the fixation members 42 and 44 are made of tg material which has no specific &# 34 ; memory &# 34 ; based on its manufacturing history ( such as the tg material described in the two immediately preceding paragraphs ). in this embodiment , the iol 40 is made directly from lens blank 10 without any heating and cooling steps as described above . by heating such a fixation member 42 while it is under compression in the eye to a temperature above tg , the fixation member ( or part thereof ) temporarily softens so that the fixation member is further bent or compressed moving the optic 46 of the iol 40 to the left in the eye . for example , with specific reference to fig4 fixation member 42 is made of such a tg material . by heating this part to above its glass transition temperature , to about 50 ° c . ( for example , as described above ), fixation member 42 temporarily softens thereby causing the fixation member to further bend or compress . this , in turn , causes optic 46 to move left and be centered relative to the pupil 50 of the eye . while this invention has been described with respect to various specific examples and embodiments , it is to be understood that the invention is not limited thereto and that it can be variously practiced within the scope of the following claims . | US-24940294-A |
a novel gene defining a novel human udp - glcnac : galβ1 - 3galnacα β1 , 6glcnac - transferase , termed c2gnt3 , with unique enzymatic properties is disclosed . the enzymatic activity of c2gnt3 is shown to be distinct from that of previously identified enzymes of this gene family . the invention discloses isolated dna molecules and dna constructs encoding c2gnt3 and derivatives thereof by way of amino acid deletion , substitution or insertion exhibiting c2gnt3 activity , as well as cloning and expression vectors including such dna , cells transfected with the vectors , and recombinant methods for providing c2gnt3 . the enzyme c2gnt3 and c2gnt3 - active derivatives thereof are disclosed , in particular soluble derivatives comprising the catalytically active domain of c2gnt3 . further , the invention discloses methods of obtaining 1 , 6 - n - acetylglucosaminyl glycosylated saccharides , glycopeptides or glycoproteins by use of an enzymically active c2gnt3 protein or fusion protein thereof or by using cells stably transfected with a vector including dna encoding an enzymatically active c2gnt3 protein as an expression system for recombinant production of such glycopeptides or glycoproteins . methods are disclosed for the identification of agents with the ability to inhibit or stimulate the biological activity of c2gnt3 . furthermore , methods of using c2gnt3 in the structure - based design of inhibitors or stimulators thereof are also disclosed in the invention . also a method for the identification of dna sequence variations in the c2gnt3 gene by isolating dna from a patient , amplifying c2gnt3 - coding exons by pcr , and detecting the presence of dna sequence variation , are disclosed . | all patent applications , patents , and literature references cited in this specification are hereby incorporated by reference in their entirety . in the case of conflict , the present description , including definitions , is intended to control . 1 . “ nucleic acid ” or “ polynucleotide ” as used herein refers to purine - and pyrimidine - containing polymers of any length , either polyribonucleotides or polydeoxyribonucleotides or mixed polyribo - polydeoxyribo nucleotides . this includes single - and double - stranded molecules , i . e ., dna - dna , dna - rna and rna - rna hybrids , as well as “ protein nucleic acids ” ( pna ) formed by conjugating bases to an amino acid backbone . this also includes nucleic acids containing modified bases ( see below ). 2 . “ complementary dna or cdna ” as used herein refers to a dna molecule or sequence that has been enzymatically synthesized from the sequences present in a mrna template , or a clone of such a dna molecule . a “ dna construct ” is a dna molecule or a clone of such a molecule , either single - or double - stranded , which has been modified to contain segments of dna that are combined and juxtaposed in a manner that would not otherwise exist in nature . by way of non - limiting example , a cdna or dna which has no introns , i . e ., is free from non - coding sequences , is inserted adjacent to , or within , exogenous ( e . g ., heterologous ) dna sequences . 3 . a plasmid or , more generally , a vector or “ expression vector ”, is a dna construct containing genetic information that may provide for its replication when inserted into a host cell . a plasmid generally contains at least one gene sequence to be expressed in the host cell , as well as sequences that facilitate such gene expression , including promoters and transcription initiation sites . it may be a linear or closed circular molecule . inserted coding sequences do not occur naturally in the organism from which the vector is derived . 4 . nucleic acids are “ hybridizable ” to each other when at least one strand of one nucleic acid can anneal to another nucleic acid under defined stringency conditions . stringency of hybridization is determined , e . g ., by a ) the temperature at which hybridization and / or washing is performed , and b ) the ionic strength and polarity ( e . g ., formamide ) of the hybridization and washing solutions , as well as other parameters . hybridization requires that the two nucleic acids contain substantially complementary sequences ; depending on the stringency of hybridization , however , mismatches may be tolerated . typically , hybridization of two sequences at high stringency ( such as , for example , in an aqueous solution of 0 . 5 × ssc , at 65 ° c .) requires that the sequences exhibit some high degree of complementarity over their entire sequence . conditions of intermediate stringency ( such as , for example , an aqueous solution of 2 × ssc at 65 ° c .) and low stringency ( such as , for example , an aqueous solution of 2 × ssc at 55 ° c . ), require correspondingly less overall complementarily between the hybridizing sequences . ( 1 × ssc is 0 . 15 m nacl , 0 . 015 m na citrate ). 5 . an “ isolated ” nucleic acid or polypeptide as used herein refers to a component that is removed from its original environment ( for example , its natural environment if it is naturally occurring ). an isolated nucleic acid or polypeptide contains less than about 50 %, preferably less than about 75 %, and most preferably less than about 90 %, of the cellular components with which it was originally associated . 6 . a “ probe ” refers to a nucleic acid that forms a hybrid structure with a sequence in a target region due to complementarily of at least one sequence in the probe with a sequence in the target region . 7 . a nucleic acid that is “ derived from ” a designated sequence refers to a nucleic acid sequence that corresponds to a region of the designated sequence . this encompasses sequences that are homologous or complementary to the sequence , as well as “ sequence - conservative variants ” and “ function - conservative variants ”. sequence - conservative variants are those in which a change of one or more nucleotides in a given codon position results in no alteration in the amino acid encoded at that position . function - conservative variants of c2gnt3 are those in which a given amino acid residue in the polypeptide has been changed without altering the overall conformation and enzymatic activity ( including substrate specificity ) of the native polypeptide ; these changes include , but are not limited to , replacement of an amino acid with one having similar physico - chemical properties ( such as , for example , acidic , basic , hydrophobic , and the like ). 8 . a “ donor substrate ” is a molecule recognized by , e . g ., a core - β1 , 6 - n - acetylglucosaminyltransferase and that contributes an n - acetylglucosaminyl moiety for the transferase reaction . for c2gnt3 , a donor substrate is udp - n - acetylglucosamine . an “ acceptor substrate ” is a molecule , preferably a saccharide or oligosaccharide , that is recognized by , e . g ., an n - acetylglucosaminyltransferase and that is the target for the modification catalyzed by the transferase , i . e ., receives the n - acetylglucosaminyl moiety . for c2gnt3 , acceptor substrates include without limitation oligosaccharides , glycoproteins , o - linked core 1 - glycopeptides , and glycosphingolipids comprising the sequences galβ1 – 3galnac , or glcnacβ1 – 3galnac . 9 . in accordance with the present invention there may be employed conventional molecular biology , microbiology , and recombinant dna techniques within the skill of the art . such techniques are explained fully in the literature . see for example , sambrook , fritsch , maniatis , molecular cloning : a laboratory manual , second edition ( 1989 ) cold spring harbor laboratory press , cold spring harbor , n . y ); dna cloning : a practical approach , volumes i and ii ( d . n . glover ed . 1985 ); oligonucleotide synthesis ( m . j . gait ed . 1984 ); nucleic acid hybridization b . d . hames & amp ; s . j . higgins eds . ( 1985 ); transcription and translation b . d . hames & amp ; s . j . higgins eds ( 1984 ); animal cell culture r . i . freshney , ed . ( 1986 ); immobilized cells and enzymes irl press , ( 1986 ); and b . perbal , a practical guide to molecular cloning ( 1984 ). 10 . the terms “ sequence similarity ” or “ sequence identity ” refer to the relationship between two or more amino acid or nucleic acid sequences , determined by comparing the sequences , which relationship is generally known as “ homology ”. identity in the art also means the degree of sequence relatedness between amino acid or nucleic acid sequences , as the case may be , as determined by the match between strings of such sequences . both identity and similarity can be readily calculated ( computational molecular biology , lesk , a . m ., ed ., oxford university press new york , 1988 ; biocomputing : informatics and genome projects , smith , d . w . ed ., academic press , new york , 1993 ; computer analysis of sequence data , part i , griffin , a . m ., and griffin , h . g . eds . humana press , new jersey , 1994 ; sequence analysis in molecular biology , von heinje , g ., academic press , new york , 1987 ; and sequence analysis primer , gribskov , m . and devereux , s ., eds . m . stockton press , new york , 1991 ). while there are a number of existing methods to measure identity and similarity between two amino acid sequences or two nucleic acid sequences , both terms are well known to the skilled artisan ( sequence analysis in molecular biology , von hinge , g ., academic press , new york , 1987 ; sequence analysis primer , gribskov , m . and devereux , j ., eds . m . stockton press , new york , 1991 ; and carillo , h ., and lipman , d . siam j . applied math ., 48 . 1073 , 1988 ). preferred methods for determining identity are designed to give the largest match between the sequences tested . methods to determine identity are codified in computer programs . preferred computer program methods for determining identity and similarity between two sequences include but are not limited to the gcg program package ( 20 ), blastp , blastn , and fasta ( 21 ). identity or similarity may also be determined using the alignment algorithm of dayhoff et al . ( methods in enzymology 91 : 524 – 545 ( 1983 )]. preferably the nucleic acids of the present invention have substantial sequence identity using the preferred computer programs cited herein , for example greater than 40 %, 45 %, 50 %, 60 %, 70 %, 75 %, 80 %, 85 %, or 90 % identity ; more preferably at least 95 %, 96 %, 97 %, 98 %, or 99 % sequence identity to the sequence shown in seq id no : 1 and fig1 . 11 . the polypeptides of the invention also include homologs of a c2gnt3 polypeptide and / or truncations thereof as described herein . such homologs include polypeptides whose amino acid sequences are comprised of the amino acid sequences of c2gnt3 polypeptide regions from other species that hybridize under selected hybridization conditions ( see discussion of hybridization conditions in particular stringent hybridization conditions herein ) with a probe used to obtain a c2gnt3 polypeptide or to seq id no : 1 . these homologs will generally have the same regions which are characteristic of a c2gnt3 polypeptide . it is anticipated that a polypeptide comprising an amino acid sequence which has at least 40 % identity , at least 45 %, or at least 60 % similarity , preferably at least 60 – 65 % identity or at least 80 – 85 % similarity , more preferably at least 70 – 80 % identity or at least 90 – 95 % similarity , most preferably at least 95 % identity or at least 99 % similarity with the amino acid sequence shown in seq id no : 2 and fig1 and 2 , will be a homolog of a c2gnt3 polypeptide . a percent amino acid sequence similarity or identity is calculated using the methods described herein , preferably the computer programs described herein . the present invention provides the isolated dna molecules , including genomic dna and cdna , encoding the udp - n - acetylglucosamine : n - acetylgalactosamine β1 , 6 n - acetylglucosaminyl - transferase 3 ( c2gnt3 ). c2gnt3 was identified by analysis of genomic survey sequences ( gss ), and cloned based on a genomic clone obtained from a human foreskin fibroblast library . the cloning strategy may be briefly summarized as follows : 1 ) isolation and sequencing of gss clone cit - hsp - 2288b17 . tf ( gss genbank accession number aq005888 ); 2 ) synthesis of oligonucleotides derived from gss sequence information , designated tshc96 and tshc101 ; 3 ) identification , cloning and sequencing of genomic p1 clone gs22597 # 844 / b1 ; 4 ) identification of a novel cdna sequence corresponding to c2gnt3 ; 5 ) confirmatory sequencing of a cdna clone obtained by reverse - transcription - polymerase chain reaction ( rt - pcr ) using human thymus poly a - mrna ; 6 ) construction of expression constructs ; 7 ) expression of the cdna encoding c2gnt3 in sf9 ( spodoptera frugiperda ) cells . more specifically , the isolation of a representative dna molecule encoding a novel third member of the mammalian udp - n - acetylglucosamine : β - n - actylgalactosamine β1 , 6 - n - acetylglucosaminyltransferase family involved the following procedures described below . database searches were performed with the coding sequence of the human c2 / 4gnt ( c2gnt2 ) sequence ( 13 ) using the blastn and the tblastn algorithm with the gss database at the national center for biotechnology information , usa . the blastn algorithm was used to identify clones representing the query gene ( identities of ≧ 95 %), whereas tblastn was used to identify non - identical , but similar gss sequences . gsss with 50 – 90 % nucleotide sequence identity were regarded as different from the query sequence . two gss clones with several apparent short sequence motifs and cysteine residues arranged with similar spacing were selected for further sequence analysis . gss clone cit - hsp - 2288b17 . tf ( gss genbank accession number aq005888 ), derived from a putative homologue to c2 / 4gnt ( c2gnt2 ), was obtained from research genetics inc ., usa . sequencing of this clone revealed a partial open reading frame with significant sequence similarity to c2 / 4gnt ( c2gnt2 ). the coding region of human c2gnt - l ( c2gnt1 ), c2 / 4gnt ( c2gnt2 ) and a bovine homologue was previously found to be organized in one exon (( 22 ),( 15 )). since the 3 ′ sequence available from the c2gnt3 gss was incomplete but likely to be located in a single exon , the missing 3 ′ portion of the open reading frame was obtained by sequencing a genomic p1 clone . the p1 clone was obtained from a human foreskin genomic p1 library ( dupont merck pharmaceutical co . human foreskin fibroblast p1 library ) by screening with the primer pair : one genomic clone for c2gnt3 , gs22597 # 844 / b1 was obtained from genome systems inc . dna from p1 phage was prepared as recommended by genome systems inc . the entire coding sequence of the c2gnt3 gene was represented in the clone and sequenced in full using automated sequencing ( abi377 , perkin - elmer ). confirmatory sequencing was performed on a cdna clone obtained by pcr ( 30 cycles at 95 ° c . for 10 sec ; 55 ° c . for 15 sec and 68 ° c . for 2 min 30 sec ) on cdna from human thymus poly a - mrna with the sense primer : the composite sequence contained an open reading frame of 1359 base pairs encoding a putative protein of 453 amino acids with type ii domain structure predicted by the tmpred - algorithm at the swiss institute for experimental cancer research ( isrec ). an expression construct designed to encode amino acid residues 39 – 453 of c2gnt3 was prepared by pcr using p1 dna , and the primer pair : tshc100 ( 5 ′- cgaggatccgcaaaaagacatttacttggtt - 3 ′, seq id no : 5 ) and tshc121 ( 5 ′- agcgaattcttactatcatgatgtggtagtg - 3 ′, seq id no : 9 ) with bamhl and ecori restriction sites , respectively ( fig2 ). the pcr product was cloned between the bamhi and ecori sites of pacgp67a ( pharmingen ), and the insert was fully sequenced . pacgp67 - c2gnt3 - sol was co - transfected with baculo - gold ™ dna ( pharmingen ) as described previously ( 23 ). recombinant baculovirus was obtained after two successive amplifications in sf9 cells grown in serum - containing medium , and titers of virus were estimated by titration in 24 - well plates with monitoring of enzyme activities . transfection of sf9 - cells with pacgp67 - c2gnt3 - sol resulted in marked increase in glcnac - transferase activity compared to uninfected cells or cells infected with a control construct . c2gnt3 showed significant activity with disaccharide derivatives of o - linked core 1 ( galβ1 – 3galnacα1 - r ). in contrast , no activity was found with core 3 structures ( glcnacβ1 – 3galnacα1 - r ), lacto - n - neotetraose as well as glcnacβ1 – 3gal - me as acceptor substrates indicating that c2gnt3 has no core4gnt and ignt - activity . additionally , no activity could be detected wih α - d - galnac - 1 - para - nitrophenyl indicating that c2gnt3 does not form core 6 ( glcnacβ1 – 6galnacα1 - r ) ( table i ). no substrate inhibition of enzyme activity was found at high acceptor concentrations up to 20 mm core 1 - para - nitrophenyl . c2gnt3 shows strict donor substrate specificity for udp - glcnac , no activity could be detected with udp - gal or udp - galnac ( data not shown ). a enzyme sources were partially purified media of infected high five ™ cells ( see “ experimental procedures ”). background values obtained with uninfected cells or cells infected with an irrelevant construct were subtracted . controls included the pacgp67 - galnac - t3 - sol ( 24 ). the kinetic properties were determined with partially purified enzymes expressed in high five ™ cells . partial purification was performed by consecutive chromatography on amberlite ira - 95 , deae - sephacryl and sp - sepharose essentially as described ( 25 ; 25 ). a human rna master blot containing mrna from fifty healthy human adult and fetal organs ( clontech ) and a human multiple tissue northern blot ( mtnii from clontech ) were probed with a 32 p - labeled probe corresponding to the soluble fragment of c2gnt3 ( base pairs 115 – 1359 ). the autoradiographic analyses showed expression of c2gnt3 predominantly in lymphoid organs and in organs of the gastrointestinal tract with high transcription levels observed in thymus , and lower levels in pbls , lymph node , stomach , pancreas and small intestine ( fig3 a and 3b ). the size of the single transcript was approximately 5 . 5 kilobases , which correlates to the transcript size of 5 . 4 kilobases of the biggest of three transcripts of human c2gnt1 ( fig3 c ). multiple transcripts of c2gnt1 have been suggested to be caused by differential usage of polyadenylation signals , which affects the length of the 3 ′ utr ( 13 ). the c2gnt3 enzyme of the present invention was shown to exhibit o - glycosylation capacity implying that the c2gnt3 gene is vital for correct / full o - glycosylation in vivo as well . a structural defect in the c2gnt3 gene leading to a deficient enzyme or completely defective enzyme would therefore expose a cell or an organism to protein / peptide sequences which were not covered by o - glycosylation as seen in cells or organisms with intact c2gnt3 gene . described in example 5 below is a method for scanning the coding exon for potential structural defects . similar methods could be used for the characterization of defects in the non - coding region of the c2gnt3 gene including the promoter region . in practicing the present invention , many conventional techniques in molecular biology , microbiology , recombinant dna , and immunology , are used . such techniques are well known and are explained fully in , for example , sambrook et al ., 1989 , molecular cloning a laboratory manual , second edition , cold spring harbor laboratory press , cold spring harbor , n . y . ; dna cloning : a practical approach , volumes i and ii , 1985 ( d . n . glover ed . ); oligonucleotide synthesis , 1984 , ( m . l . gait ed . ); nucleic acid hybridization , 1985 , ( hames and higgins ); transcription and translation , 1984 ( hames and higgins eds . ); animal cell culture , 1986 ( r . i . freshney ed . ); immobilized cells and enzymes , 1986 ( irl press ); perbal , 1984 , a practical guide to molecular cloning ; the series , methods in enzymology ( academic press , inc . ); gene transfer vectors for mammalian cells , 1987 ( j . h . miller and m . p . calos eds ., cold spring harbor laboratory ); methods in enzymology vol . 154 and vol . 155 ( wu and grossman , and wu , eds ., respectively ); immunochemical methods in cell and molecular biology , 1987 ( mayer and waler , eds ; academic press , london ); scopes , 1987 , protein purification : principles and practice , second edition ( springer - verlag , n . y .) and handbook of experimental immunology , 1986 , volumes i – iv ( weir and blackwell eds .). the invention encompasses isolated nucleic acid fragments comprising all or part of the nucleic acid sequence disclosed herein as set forth in fig1 . the fragments are at least about 8 nucleotides in length , preferably at least about 12 nucleotides in length , and most preferably at least about 15 – 20 nucleotides in length . the invention further encompasses isolated nucleic acids comprising sequences that are hybridizable under stringency conditions of 2 × ssc , 55 ° c ., to the sequence set forth in fig1 ; preferably , the nucleic acids are hybridizable at 2 × ssc , 65 ° c . ; and most preferably , are hybridizable at 0 . 5 × ssc , 65 ° c . the nucleic acids may be isolated directly from cells . alternatively , the polymerase chain reaction ( pcr ) method can be used to produce the nucleic acids of the invention , using either chemically synthesized strands or genomic material as templates . primers used for pcr can be synthesized using the sequence information provided herein and can further be designed to introduce appropriate new restriction sites , if desirable , to facilitate incorporation into a given vector for recombinant expression . the nucleic acids of the present invention may be flanked by natural human regulatory sequences , or may be associated with heterologous sequences , including transcriptional control elements such as promoters , enhancers , and response elements , or other sequences such as signal sequences , polyadenylation sequences , introns , 5 ′- and 3 ′- noncoding regions , and the like . preferably , although not necessarily , any two nucleotide sequences to be expressed as a fusion polypeptide are inserted in - frame . the nucleic acids may also be modified by many means known in the art . non - limiting examples of such modifications include methylation , “ caps ”, substitution of one or more of the naturally occurring nucleotides with an analog , internucleotide modifications such as , for example , those with uncharged linkages ( e . g ., methyl phosphonates , phosphotriesters , phosphoroamidates , carbamates , etc .) and with charged linkages ( e . g ., phosphorothioates , phosphorodithioates , etc .). nucleic acids may contain one or more additional covalently linked moieties , such as , for example , proteins ( e . g ., nucleases , toxins , antibodies , signal peptides , poly - l - lysine , etc . ), intercalators ( e . g ., acridine , psoralen , etc . ), chelators ( e . g ., metals , radioactive metals , iron , oxidative metals , etc . ), and alkylators . the nucleic acid may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage . furthermore , the nucleic acid sequences of the present invention may also be modified with a label capable of providing a detectable signal , either directly or indirectly . exemplary labels include radioisotopes , fluorescent molecules , biotin , and the like . according to the present invention , useful probes comprise a probe sequence at least eight nucleotides in length that consists of all or part of the sequence from among the sequences as set forth in fig1 or sequence - conservative or function - conservative variants thereof , or a complement thereof , and that has been labelled as described above . the invention also provides nucleic acid vectors comprising the disclosed sequence or derivatives or fragments thereof . a large number of vectors , including plasmid and fungal vectors , have been described for replication and / or expression in a variety of eukaryotic and prokaryotic hosts , and may be used for gene therapy as well as for simple cloning or protein expression . recombinant cloning vectors will often include one or more replication systems for cloning or expression , one or more markers for selection in the host , e . g . antibiotic resistance , and one or more expression cassettes . the inserted coding sequences may be synthesized by standard methods , isolated from natural sources , or prepared as hybrids , etc . ligation of the coding sequences to transcriptional regulatory elements and / or to other amino acid coding sequences may be achieved by known methods . suitable host cells may be transformed / transfected / infected as appropriate by any suitable method including electroporation , cacl 2 mediated dna uptake , fungal infection , microinjection , microprojectile , or other established methods . appropriate host cells included bacteria , archaebacteria , fungi , especially yeast , and plant and animal cells , especially mammalian cells . also included are avian and insect cells . of particular interest are saccharomyces cerevisiae , schizosaccharomyces pombe , pichia pastoris , hansenula polymorpha , neurospora spec ., sf9 cells , c129 cells , 293 cells , and cho cells , cos cells , hela cells , and immortalized mammalian myeloid and lymphoid cell lines . preferred replication systems include m13 , cole1 , 2μ , ars , sv40 , baculovirus , lambda , adenovirus , and the like . a large number of transcription initiation and termination regulatory regions have been isolated and shown to be effective in the transcription and translation of heterologous proteins in the various hosts . examples of these regions , methods of isolation , manner of manipulation , etc . are known in the art . under appropriate expression conditions , host cells can be used as a source of recombinantly produced c2gnt3 derived peptides and polypeptides . advantageously , vectors may also include a transcription regulatory element ( i . e ., a promoter ) operably linked to the c2gnt3 coding portion . the promoter may optionally contain operator portions and / or ribosome binding sites . non - limiting examples of bacterial promoters compatible with e . coli include : β - lactamase ( penicillinase ) promoter ; lactose promoter ; tryptophan ( trp ) promoter ; arabinose bad operon promoter ; lambda - derived p 1 promoter and n gene ribosome binding site ; and the hybrid tac promoter derived from sequences of the trp and lac uv5 promoters . non - limiting examples of yeast promoters include 3 - phosphoglycerate kinase promoter , glyceraldehyde - 3 phosphate dehydrogenase ( gapdh ) promoter , galactokinase ( gal1 ) promoter , galactoepimerase ( gal10 ) promoter , metallothioneine ( cup ) promoter and alcohol dehydrogenase ( adh ) promoter . suitable promoters for mammalian cells include without limitation viral promoters such as that from simian virus 40 ( sv40 ), rous sarcoma virus ( rsv ), adenovirus ( adv ), and bovine papilloma virus ( bpv ). mammalian cells may also require terminator sequences and poly a addition sequences and enhancer sequences which increase expression may also be included ; sequences which cause amplification of the gene may also be desirable . furthermore , sequences that facilitate secretion of the recombinant product from cells , including , but not limited to , bacteria , yeast , and animal cells , such as secretory signal sequences and / or prohormone pro region sequences , may also be included . these sequences are known in the art . nucleic acids encoding wild type or variant polypeptides may also be introduced into cells by recombination events . for example , such a sequence can be introduced into a cell , and thereby effect homologous recombination at the site of an endogenous gene or a sequence with substantial identity to the gene . other recombination - based methods such as nonhomologous recombinations or deletion of endogenous genes by homologous recombination may also be used . the nucleic acids of the present invention find use , for example , as probes for the detection of c2gnt3 in other species or related organisms and as templates for the recombinant production of peptides or polypeptides . these and other embodiments of the present invention are described in more detail below . the present invention encompasses isolated peptides and polypeptides encoded by the disclosed cdna sequence . peptides are preferably at least five residues in length . nucleic acids comprising protein - coding sequences can be used to direct the recombinant expression of polypeptides in intact cells or in cell - free translation systems . the known genetic code , tailored if desired for more efficient expression in a given host organism , can be used to synthesize oligonucleotides encoding the desired amino acid sequences . the phosphoramidite solid support method of ( 26 ), the method of ( 27 ), or other well known methods can be used for such synthesis . the resulting oligonucleotides can be inserted into an appropriate vector and expressed in a compatible host organism . the polypeptides of the present invention , including function - conservative variants of the disclosed sequence , may be isolated from native or from heterologous organisms or cells ( including , but not limited to , bacteria , fungi , insect , plant , and mammalian cells ) into which a protein - coding sequence has been introduced and expressed . furthermore , the polypeptides may be part of recombinant fusion proteins . methods for polypeptide purification are well known in the art , including , without limitation , preparative discontiuous gel elctrophoresis , isoelectric focusing , hplc , reversed - phase hplc , gel filtration , ion exchange and partition chromatography , and countercurrent distribution . for some purposes , it is preferable to produce the polypeptide in a recombinant system in which the protein contains an additional sequence tag that facilitates purification , such as , but not limited to , an affinity ligand , reactive group , and / or a polyhistidine sequence . the polypeptide can then be purified from a crude lysate of the host cell by chromatography on an appropriate solid - phase matrix . alternatively , antibodies produced against a protein or against peptides derived therefrom can be used as purification reagents . other purification methods are possible . the present invention also encompasses derivatives and homologues of polypeptides . for some purposes , nucleic acid sequences encoding the peptides may be altered by substitutions , additions , or deletions that provide for functionally equivalent molecules , i . e ., function - conservative variants . for example , one or more amino acid residues within the sequence can be substituted by another amino acid of similar properties , such as , for example , positively charged amino acids ( arginine , lysine , and histidine ); negatively charged amino acids ( aspartate and glutamate ); polar neutral amino acids ; and non - polar amino acids . the isolated polypeptides may be modified by , for example , phosphorylation , sulfation , acylation , or other protein modifications . they may also be modified with a label capable of providing a detectable signal , either directly or indirectly , including , but not limited to , radioisotopes and fluorescent compounds . the present invention encompasses antibodies that specifically recognize immunogenic components derived from c2gnt3 . such antibodies can be used as reagents for detection and purification of c2gnt3 . c2gnt3 specific antibodies according to the present invention include polyclonal and monoclonal antibodies . the antibodies may be elicited in an animal host by immunization with c2gnt3 components or may be formed by in vitro immunization of immune cells . the immunogenic components used to elicit the antibodies may be isolated from human cells or produced in recombinant systems . the antibodies may also be produced in recombinant systems programmed with appropriate antibody - encoding dna . alternatively , the antibodies may be constructed by biochemical reconstitution of purified heavy and light chains . the antibodies include hybrid antibodies ( i . e ., containing two sets of heavy chain / light chain combinations , each of which recognizes a different antigen ), chimeric antibodies ( i . e ., in which either the heavy chains , light chains , or both , are fusion proteins ), and univalent antibodies ( i . e ., comprised of a heavy chain / light chain complex bound to the constant region of a second heavy chain ). also included are fab fragments , including fab ′ and f ( ab ) 2 fragments of antibodies . methods for the production of all of the above types of antibodies and derivatives are well known in the art . for example , techniques for producing and processing polyclonal antisera are disclosed in mayer and walker , 1987 , immunochemical methods in cell and molecular biology , ( academic press , london ). the antibodies of this invention can be purified by standard methods , including but not limited to preparative disc - gel elctrophoresis , isoelectric focusing , hplc , reversed - phase hplc , gel filtration , ion exchange and partition chromatography , and countercurrent distribution . purification methods for antibodies are disclosed , e . g ., in the art of antibody purification , 1989 , amicon division , w . r . grace & amp ; co . general protein purification methods are described in protein purification : principles and practice , r . k . scopes , ed ., 1987 , springer - verlag , new york , ny . anti c2gnt3 antibodies , whether unlabeled or labeled by standard methods , can be used as the basis for immunoassays . the particular label used will depend upon the type of immunoassay used . examples of labels that can be used include , but are not limited to , radiolabels such as 32 p , 125 i , 3 h and 14 c ; fluorescent labels such as fluorescein and its derivatives , rhodamine and its derivatives , dansyl and umbelliferone ; chemiluminescers such as luciferia and 2 , 3 - dihydrophthalazinediones ; and enzymes such as horseradish peroxidase , alkaline phosphatase , lysozyme and glucose - 6 - phosphate dehydrogenase . the antibodies can be tagged with such labels by known methods . for example , coupling agents such as aldehydes , carbodiimides , dimaleimide , imidates , succinimides , bisdiazotized benzadine and the like may be used to tag the antibodies with fluorescent , chemiluminescent or enzyme labels . the general methods involved are well known in the art and are described in , e . g ., chan ( ed . ), 1987 , immunoassay : a practical guide , academic press , inc ., orlando , fla . the nucleic acid molecules , c2gnt3 polypeptide , and antibodies of the invention may be used in the prognostic and diagnostic evaluation of conditions associated with altered expression or activity of a polypeptide of the invention or conditions requiring modulation of a nucleic acid or polypeptide of the invention including thymus - related disorders and proliferative disorders ( e . g . cancer ), and the identification of subjects with a predisposition to such conditions ( see below ). methods for detecting nucleic acid molecules and polypeptides of the invention can be used to monitor such conditions by detecting and localizing the polypeptides and nucleic acids . it would also be apparent to one skilled in the art that the methods described herein may be used to study the developmental expression of the polypeptides of the invention and , accordingly , will provide further insight into the role of the polypeptides . the applications of the present invention also include methods for the identification of substances or compounds that modulate the biological activity of a polypeptide of the invention ( see below ). the substances , compounds , antibodies etc ., may be used for the treatment of conditions requiring modulation of polypeptides of the invention ( see below ). a variety of methods can be employed for the diagnostic and prognostic evaluation of conditions requiring modulation of a nucleic acid or polypeptide of the invention ( e . g . thymus - related disorders , and cancer ), and the identification of subjects with a predisposition to such conditions . such methods may , for example , utilize nucleic acids of the invention , and fragments thereof , and antibodies directed against polypeptides of the invention , including peptide fragments . in particular , the nucleic acids and antibodies may be used , for example , for : ( 1 ) the detection of the presence of c2gnt3 mutations , or the detection of either over - or under - expression of c2gnt3 mrna relative to a non - disorder state or the qualitative or quantitative detection of alternatively spliced forms of c2gnt3 transcripts which may correlate with certain conditions or susceptibility toward such conditions ; or ( 2 ) the detection of either an over - or an under - abundance of a polypeptide of the invention relative to a non - disorder state or the presence of a modified ( e . g ., less than full length ) polypeptide of the invention which correlates with a disorder state , or a progression toward a disorder state . the methods described herein may be performed by utilizing pre - packaged diagnostic kits comprising at least one specific nucleic acid or antibody described herein , which may be conveniently used , e . g ., in clinical settings , to screen and diagnose patients and to screen and identify those individuals exhibiting a predisposition to developing a disorder . nucleic acid - based detection techniques and peptide detection techniques are described below . the samples that may be analyzed using the methods of the invention include those that are known or suspected to express c2gnt3 nucleic acids or contain a polypeptide of the invention . the methods may be performed on biological samples including but not limited to cells , lysates of cells which have been incubated in cell culture , chromosomes isolated from a cell ( e . g . a spread of metaphase chromosomes ), genomic dna ( in solutions or bound to a solid support such as for southern analysis ), rna ( in solution or bound to a solid support such as for northern analysis ), cdna ( in solution or bound to a solid support ), an extract from cells or a tissue , and biological fluids such as serum , urine , blood , and csf . the samples may be derived from a patient or a culture . the nucleic acid molecules of the invention allow those skilled in the art to construct nucleotide probes for use in the detection of nucleic acid sequences of the invention in biological materials . suitable probes include nucleic acid molecules based on nucleic acid sequences encoding at least 5 sequential amino acids from regions of the c2gnt3 polypeptide ( see seq id no : 1 ), preferably they comprise 15 to 50 nucleotides , more preferably 15 to 40 nucleotides , most preferably 15 – 30 nucleotides . a nucleotide probe may be labelled with a detectable substance such as a radioactive label that provides for an adequate signal and has sufficient half - life such as 32 p , 3 h , 14 c or the like . other detectable substances that may be used include antigens that are recognized by a specific labelled antibody , fluorescent compounds , enzymes , antibodies specific for a labelled antigen , and luminescent compounds . an appropriate label may be selected having regard to the rate of hybridization and binding of the probe to the nucleotide to be detected and the amount of nucleotide available for hybridization . labelled probes may be hybridized to nucleic acids on solid supports such as nitrocellulose filters or nylon membranes as generally described in sambrook et al , 1989 , molecular cloning , a laboratory manual ( 2nd ed .). the nucleic acid probes may be used to detect c2gnt3 genes , preferably in human cells . the nucleotide probes may also be used for example in the diagnosis or prognosis of conditions such as thymus - related disorders and cancer , and in monitoring the progression of these conditions , or monitoring a therapeutic treatment . the probe may be used in hybridisation techniques to detect a c2gnt3 gene . the technique generally involves contacting and incubating nucleic acids ( e . g . recombinant dna molecules , cloned genes ) obtained from a sample from a patient or other cellular source with a probe of the present invention under conditions favourable for the specific annealing of the probes to complementary sequences in the nucleic acids . alter incubation , the non - annealed nucleic acids are removed , and the presence of nucleic acids that have hybridized to the probe if any are detected . the detection of nucleic acid molecules of the invention may involve the amplification of specific gene sequences using an amplification method ( e . g . pcr ), followed by the analysis of the amplified molecules using techniques known to those skilled in the art . suitable primers can be routinely designed by one of skill in the art . for example , primers may be designed using commercially available software , such as oligo 4 . 06 primer analysis software ( national biosciences , plymouth , minn .) or another appropriate program , to be about 22 to 30 nucleotides in length , to have a gc content of about 50 % or more , and to anneal to the template at temperatures of about 60 ° c . to 72 ° c . genomic dna may be used in hybridization or amplification assays of biological samples to detect abnormalities involving c2gnt3 nucleic acid structure , including point mutations , insertions , deletions , and chromosomal rearrangements . for example , direct sequencing , single stranded conformational polymorphism analyses , heteroduplex analysis , denaturing gradient gel electrophoresis , chemical mismatch cleavage , and oligonucleotide hybridization may be utilized . genotyping techniques known to one skilled in the art can be used to type polymorphisms that are in close proximity to the mutations in a c2gnt3 gene . the polymorphisms may be used to identify individuals in families that are likely to carry mutations . if a polymorphism exhibits linkage disequalibrium with mutations in the g2gnt3 gene , it can also be used to screen for individuals in the general population likely to carry mutations . polymorphisms which may be used include restriction fragment length polymorphisms ( rflps ), single - nucleotide polymorphisms ( snp ), and simple sequence repeat polymorphisms ( sslps ). a probe or primer of the invention may be used to directly identify rflps . a probe or primer of the invention can additionally be used to isolate genomic clones such as yacs , bacs , pacs , cosmids , phage or plasmids . the dna in the clones can be screened for sslps using hybridization or sequencing procedures . hybridization and amplification techniques described herein may be used to assay qualitative and quantitative aspects of c2gnt3 expression . for example rna may be isolated from a cell type or tissue known to express c2gnt3 and tested utilizing the hybridization ( e . g . standard northern analyses ) or pcr techniques referred to herein . the techniques may be used to detect differences in transcript size that may be doe to normal or abnormal alternative splicing . the techniques may be used to detect quantitative differences between levels of full length and / or alternatively splice transcripts detected in normal individuals relative to those individuals exhibiting symptoms of a disease . the primers and probes may be used in the above described methods in situ i . e directly on tissue sections ( fixed and / or frozen ) of patient tissue obtained from biopsies or resections . oligonucleotides or longer fragments derived from any of the nucleic acid molecules of the invention may be used as targets in a microarray . the microarray can be used to simultaneously monitor the expression levels of large numbers of genes and to identify genetic variants , mutations , and polymorphisms . the information from the microarray may be used to determine gene function , to understand the genetic basis of a disorder , to identify predisposition to a disorder , to treat a disorder , to diagnose a disorder , and to develop and monitor the activities of therapeutic agents . the preparation , use , and analysis of micro arrays are well known to a person skilled in the art . ( see , for example , brennan , t . m ., et al . ( 1995 ), u . s . pat . no . 5 , 474 , 796 ; schena et al . ( 1996 ), proc . natl . acad . sci . 93 : 10614 – 10619 ; baldeschweiler et al . ( 1995 ), pct application wo95 / 251116 ; shalon , d ., et al . ( 1995 ), pct application wo95 / 35505 ; heller , r . a ., et al . ( 1997 ), proc . natl . acad . sci . 94 : 2150 – 2155 ; and heller , m . j ., et al . ( 1997 ), u . s . pat . no . 5 , 605 , 662 .) antibodies specifically reactive with a c2gnt3 polypeptide , or derivatives , such as enzyme conjugates or labeled derivatives , may be used to detect c2gnt3 polypeptides in various biological materials . they may be used as diagnostic or prognostic reagents and they may be used to detect abnormalities in the level of c2gnt3 polypeptides , expression , or abnormalities in the structure , and / or temporal , tissue , cellular , or subcellular location of the polypeptides . antibodies may also be used to screen potentially therapeutic compounds in vitro to determine their effects on a condition such as a thymus - related disorder or cancer . in vitro immunoassays may also be used to assess or monitor the efficacy of particular therapies . preferably , antibodies for use in a detection assay have a dissociation constant lower than 1 μm , even more preferably lower than or about 10 nm . the antibodies of the invention may also be used in vitro to determine the level of c2gnt3 polypeptide expression in cells genetically engineered to produce a c2gnt3 polypeptide . the antibodies may be used to detect and quantify polypeptides of the invention in a sample in order to determine their role in particular cellular events or pathological states , and to diagnose and treat such pathological states . in particular , the antibodies of the invention may be used in immuno - histochemical analyses , for example , at the cellular and sub - subcellular level , to detect a polypeptide of the invention , to localize it to particular cells and tissues , and to specific subcellular locations , and to quantitate the level of expression . the antibodies may be used in any known immunoassays that rely on the binding interaction & gt ;& gt ; between an antigenic determinant of a polypeptide of the invention , and the antibodies . examples of such assays are radio immunoassays , enzyme immunoassays ( e . g . elisa ), immunofluorescence , immunoprecipitation , latex agglutination , hemagglutination , and histochemical tests , cytochemical techniques known in the art for localizing antigens using light and electron microscopy may be used to detect a polypeptide of the invention . generally , an antibody of the invention may be labelled with a detectable substance and a polypeptide may be localised in tissues and cells based upon the presence of the detectable substance . various methods of labelling polypeptides are known in the art and may be used . examples of detectable substances include , but are not limited to , the following : radioisotopes ( e . g ., 3 h , 14 c , 35 s , 125 i , 131i ), fluorescent labels ( e . g ., fitc , rhodamine , lanthanide phosphors ), luminescent labels such as luminol , enzymatic labels ( e . g ., horseradish peroxidase , β - galactosidase , luciferase , alkaline phosphatase , acetylcholinesterase ), biotinyl groups ( which can be detected by marked avidin e . g ., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or calorimetric methods ), predetermined polypeptide epitopes recognized by a secondary reporter ( e . g ., leucine zipper pair sequences , binding sites for secondary antibodies , metal binding domains , epitope tags ). in some embodiments , labels are attached via spacer arms of various lengths to reduce potential steric hindrance . antibodies may also be coupled to electron dense substances , such as ferritin or colloidal gold , which are readily visualised by electron microscopy . the antibody or sample may be immobilized on a carrier or solid support which is capable of immobilizing cells , antibodies , etc . for example , the carrier or support may be nitrocellulose , or glass , polyacrylamides , gabbros , and magnetite . the support material may have any possible configuration including spherical ( e . g . bead ), cylindrical ( e . g . inside surface of a test tube or well , or the external surface of a rod ), or flat ( e . g . sheet , test strip ). indirect methods may also be employed in which the primary antigen - antibody reaction is amplified by the introduction of a second antibody , having specificity for the antibody reactive against a polypeptide of the invention . by way of example , if the antibody having specificity against a polypeptide of the invention is a rabbit igg antibody , the second antibody may be goat anti - rabbit gamma - globulin labelled with a detectable substance as described herein . where a radioactive label is used as a detectable substance , a polypeptide of the invention may be localized by radioautography . the results of radioautography may be quantitated by determining the density of particles in the radioautographs by various optical methods , or by counting the grains . a polypeptide of the invention may also be detected by assaying for c2gnt3 activity as described herein . for example , a sample may be reacted with an acceptor substrate and a donor substrate under conditions where a c2gnt3 polypeptide is capable of transferring the donor substrate to the acceptor substrate to produce a donor substrate - acceptor substrate complex . the methods described herein are designed to identify substances and compounds that modulate the expression or biological activity of a c2gnt3 polypeptide including substances that interfere with or enhance the expression or activity of a c2gnt3 polypeptide . substances and compounds identified using the methods of the invention include but are not limited to peptides such as soluble peptides including ig - tailed fusion peptides , members of random peptide libraries and combinatorial chemistry - derived molecular libraries made of d - and / or l - configuration amino acids , phosphopeptides ( including members of random or partially degenerate , directed phosphopeptide libraries ), antibodies [ e . g . polyclonal , monoclonal , humanized , anti - idiotypic , chimeric , single chain antibodies , fragments , ( e . g . fab , f ( ab ) 2 , and fab expression library fragments , and epitope - binding fragments thereof )], polypeptides , nucleic acids , carbohydrates , and small organic or inorganic molecules . a substance or compound may be an endogenous physiological compound or it may be a natural or synthetic compound . modulation of a c2gnt3 polypeptide can be evaluated , for instance , by evaluating the inhibitory / stimulatory effect of an agent on c2gnt3 biological activity in comparison to a control or reference . the control or reference may be , e . g ., a predetermined reference value , or may be evaluated experimentally . for example , in a cell - based assay where a host cell expressing recombinant c2gnt3 is incubated in a medium containing a potential modulating agent , a control or reference may be , e . g ., a host cell incubated with an agent having a known effect on c2gnt3 expression / activity , a host cell incubated in the same medium without any agent , a host cell transfected with a “ mock ” vector not expressing any c2gnt3 polypeptide , or any other suitable control or reference . in a cell - free assay where c2gnt3 polypeptide is incubated in a medium containing a potential modulating agent , a control or reference may be , for example , medium not containing c2gnt3 polypeptide , medium not containing any agent , medium containing a reference polypeptide or agent , or any other suitable control or reference . substances which modulate a c2gnt3 polypeptide can be identified based on their ability to associate with a c2gnt3 polypeptide . therefore , the invention also provides methods for identifying substances that associate with a c2gnt3 polypeptide . substances identified using the methods of the invention may be isolated , cloned and sequenced using conventional techniques . a substance that associates with a polypeptide of the invention may be an agonist or antagonist of the biological or immunological activity of a polypeptide of the invention . the term “ agonist ” refers to a molecule that increases the amount of , or prolongs the duration of , the activity of the polypeptide . the term “ antagonist ” refers to a molecule which decreases the biological or immunological activity of the polypeptide . agonists and antagonists may include proteins , nucleic acids , carbohydrates , or any other molecules that associate with a polypeptide of the invention . substances which can associate with a c2gnt3 polypeptide may be identified by reacting a c2gnt3 polypeptide with a test substance which potentially associates with a c2gnt3 polypeptide , under conditions which permit the association , and removing and / or detecting the associated c2gnt3 polypeptide and substance . substance - polypeptide complexes , free substance , or non - complexed polypeptides may be assayed . conditions which permit the formation of substance - polypeptide complexes may be selected having regard to factors such as the nature and amounts of the substance and the polypeptide . the substance - polypeptide complex , free substance or non - complexes polypeptides may be isolated by conventional isolation techniques , for example , salting out , chromatography , electrophoresis , gel filtration , fractionation , absorption , polyacrylamide gel electrophoresis , agglutination , or combinations thereof . to facilitate the assay of the components , antibody against a polypeptide of the invention or the substance , or labelled polypeptide , or a labelled substance may be utilized . the antibodies , polypeptides , or substances may be labelled with a detectable substance as described above . a c2gnt3 polypeptide , or the substance used in the method of the invention may be insolubilized . for example , a polypeptide , or substance may be bound to a suitable carrier such as agarose , cellulose , dextran , sephadex , sepharose , carboxymethyl cellulose polystyrene , filter paper , ion - exchange resin , plastic film , plastic tube , glass beads , polyamine - methyl vinyl - ether - maleic acid copolymer , amino acid copolymer , ethylene - maleic acid copolymer , nylon , silk , etc . the carrier may be in the shape of , for example , a tube , test plate , beads , disc , sphere etc . the insolubilized polypeptide or substance may be prepared by reacting the material with a suitable insoluble carrier using known chemical or physical methods , for example , cyanogen bromide coupling . the invention also contemplates a method for evaluating a compound for its ability to modulate the biological activity of a polypeptide of the invention , by assaying for an agonist or antagonist ( i . e . enhancer or inhibitor ) of the association of the polypeptide with a substance which interacts with the polypeptide ( e . g . donor or acceptor substrates or parts thereof ). the basic method for evaluating if a compound is an agonist or antagonist of the association of a polypeptide of the invention and a substance that associates with the polypeptide is to prepare a reaction mixture containing the polypeptide and the substance under conditions which permit the formation of substance - polypeptide complexes , in the presence of a test compound . the test compound may be initially added to the mixture , or may be added subsequent to the addition of the polypeptide and substance . control reaction mixtures without the test compound or with a placebo are also prepared . the formation of complexes is detected and the formation of complexes in the control reaction but not in the reaction mixture indicates that the test compound interferes with the interaction of the polypeptide and substance . the reactions may be carried out in the liquid phase or the polypeptide , substance , or test compound may be immobilized as described herein . the agent can be selected from compounds , compositions , antibodies or antibody fragments , antisense sequences and ribozyme nucleotide sequences for c2gnt3 polypeptide . it will be understood that the agonists and antagonists i . e . inhibitors and enhancers , that can be assayed using the methods of the invention may act on one or more of the interaction sites an the polypeptide or substance including agonist binding sites , competitive antagonist binding cites , non - competitive antagonist binding sites or allosteric sites . the invention also makes it possible to screen for antagonists that inhibit the effects of an agonist of the interaction of a polypeptide of the invention with a substance which is capable of associating with the polypeptide . thus , the invention may be used to assay for a compound that competes for the same interacting site of a polypeptide of the invention . substances that modulate a c2gnt3 polypeptide of the invention can be identified based on their ability to interfere with or enhance the activity of a c2gnt3 polypeptide . therefore , the invention provides a method for evaluating a compound for its ability to modulate the activity of a c2gnt3 polypeptide comprising ( a ) reacting an acceptor substrate and a donor substrate for a c2gnt3 polypeptide in the presence of a test substance ; ( b ) measuring the amount of donor substrate transferred to acceptor substrate , and ( c ) carrying out steps ( a ) and ( b ) in the absence of the test substance to determine if the substance interferes with or enhances transfer of the sugar donor to the acceptor by the c2gnt3 polypeptide . suitable acceptor substrate for use in the methods of the invention are a saccharide , oligosaccharides , polysaccharides , polypeptides , glycopolypeptides , or glycolipids which are either synthetic with linkers at the reducing end or naturally occuring structures , for example , asialo - agalacto - fetuin glycopeptide . acceptors will generally comprise β - d - galactosyl - 1 , 3 - n - acetyl - d - galactosaminyl -. the donor substrate may be a nucleotide sugar , dolichol - phosphate - sugar or dolichol - pyrophosphate - oligosaccharide , for example , uridine diphospho - n - acetylglucosamine ( udp - glcnac ), or derivatives or analogs thereof . the c2gnt3 polypeptide may be obtained from natural sources or produced used recombinant methods as described herein . the acceptor or donor substrates may be labeled with a detectable substance as described herein , and the interaction of the polypeptide of the invention with the acceptor and donor will give rise to a detectable change . the detectable change may be colorimetric , photometric , radiometric , potentiometric , etc . the activity of c2gnt3 polypeptide of the invention may also be determined using methods based on hplc ( koenderman et al ., febs lett . 222 : 42 , 1987 ) or methods employed synthetic oligosaccharide acceptors attached to hydrophobic aglycones ( palcic et al glycoconjugate 5 : 49 , 1988 ; and pierce et al , biochem . biophys . res . comm . 146 : 679 , 1987 ). the c2gnt3 polypeptide is reacted with the acceptor and donor substrates at a ph and temperature effective for the polypeptide to transfer the donor to the acceptor , and where one of the components is labeled , to produce a detectable change . it is preferred to use a buffer with the acceptor and donor to maintain the ph within the ph range effective for the polypeptides . the buffer , acceptor and donor may be used as an assay composition . other compounds such as edta and detergents may be added to the assay composition . the reagents suitable for applying the methods of the invention to evaluate compounds that modulate a c2gnt3 polypeptide may be packaged into convenient kits providing the necessary materials packaged into suitable containers . the kits may also include suitable supports useful in performing the methods of the invention . substances that modulate a c2gnt3 polypeptide can also be identified by treating immortalized cells which express the polypeptide with a test substance , and comparing the morphology of the cells with the morphology of the cells in the absence of the substance and / or with immortalized cells which do not express the polypeptide . examples of immortalized cells that can be used include lung epithelial cell lines such as mvllu or hek293 ( human embryonal kidney ) transfected with a vector containing a nucleic acid of the invention . in the absence of an inhibitor the cells show signs of morphologic transformation ( e . g . fibroblastic morphology , spindle shape and pile up ; the cells are less adhesive to substratum ; there is less cell to cell contact in monolayer culture ; there is reduced growth - factor requirements for survival and proliferation ; the cells grow in soft - agar of other semi - solid medium ; there is a lack of contact inhibition and increased apoptosis in low - serum high density cultures ; there is enhanced cell motility , and there is invasion into extracellular matrix and secretion of proteases ). substances that inhibit one or more phenotypes may be considered an inhibitor . a substance that inhibits a c2gnt3 polypeptide may be identified by treating a cell which expresses the polypeptide with a test substance , and assaying for complex core 2 - based o - linked structures ( e . g . repeating gal [ β ] 1 – 4glcnac [ β ]) associated with the cell . the complex core 2 - based o - linked structures can be assayed using a . substance that binds to the structures ( e . g . antibodies ). cells that have not been treated with the substance or which do not express the polypeptide may be employed as controls . substances which inhibit transcription or translation of a c2gnt3 gene may be identified by transfecting a cell with an expression vector comprising a recombinant molecule of the invention , including a reporter gene , in the presence of a test substance and comparing the level of expression of the c2gnt3 polypeptide , or the expression of the polypeptide encoded by the reporter gene with a control cell transfected with the nucleic acid molecule in the absence of the substance . the method can be used to identify transcription and translation inhibitors of a c2gnt3 gene . the substances or compounds identified by the methods described herein , polypeptides , nucleic acid molecules , and antibodies of the invention may be used for modulating the biological activity of a c2gnt3 polypeptide , and they may be used in the treatment of conditions mediated by a c2gnt3 polypeptide . in particular , they may be used to t - cell development and lymphocyte homing and they may be used in the prevention and treatment of thymus - related disorders . therefore , the present invention may be useful for diagnosis or treatment of various thymus - related disorders in mammals , preferably humans . such disorders include the following : tumors and cancers , hypoactivity , hyperactivity , atrophy , enlargement of the thymus , and the like . other disorders include disregulation of t - lymphocyte selection or activity and would include but not be limited to disorders involving autoimmunity , arthritis , leukemias , lymphomas , immunosuppression , sepsis , wound healing , acute and chronic in action , cell mediated immunity , humor immunity , th1 / th2 imbalance , and the like . the substances or compounds identified by the methods described herein , antibodies , and polypeptides , and nucleic acid molecules of the invention may be useful in the prevention and treatment of tumors . tumor metastasis may be inhibited or prevented by inhibiting the adhesion of circulating cancer cells . the substances , compounds , etc . of the invention may be especially useful in the treatment of various forms of neoplasia such as leukemias , lymphomas , melanomas , adenomas , sarcomas , and carcinomas of solid tissues in patients . in particular the composition may be used for treating malignant melanoma , pancreatic cancer , cervico - uterine cancer , cancer of the liver , kidney , stomach , lung , rectum , breast , bowel , gastric , thyroid , neck , cervix , salivary gland , bile duct , pelvis , mediastinum , urethra , bronchogenic , bladder , esophagus and colon , and kaposi &# 39 ; s sarcoma which is a form of cancer associated with hiv - infected patients with acquired immune deficiency syndrome ( aids ). the substances etc . are particularly useful in the prevention and treatment of tumors of the immune system and thymus and the metastases derived from these tumors . a substance or compound identified in accordance with the methods described herein , antibodies , polypeptides , or nucleic acid molecules of the invention may be used to modulate t - cell activation and immunodeficiency due to the wiskott - aldrich syndrome or aids , or to stimulate hematopoietic progenitor cell growth , and / or confer protection against chemotherapy and radiation therapy in a subject . accordingly , the substances , antibodies , and compounds may be formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo . by biologically compatible form suitable for administration in vivo is meant a form of the substance to be administered in which any toxic effects are outweighed by the therapeutic effects . the substances may be administered to living organisms including humans , and animals . administration of a therapeutically active amount of the pharmaceutical compositions of the present invention is defined as an amount effective , at dosages and for periods of time necessary to achieve the desired result . for example , a therapeutically active amount of a substance may vary according to factors such as the disease state , age , sex , and weight of the individual , and the ability of antibody to elicit a desired response in the individual . dosage regima may be adjusted to provide the optimum therapeutic response . for example , several divided doses may be administeted daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation . the active substance may be administered in a convenient manner such as by injection ( subcutaneous , intravenous , etc . ), oral administration , inhalation , transdermal application , or rectal administration . depending on the route of administration , the active substance may be coated in a material to protect the compound from the action of enzymes , acids and other natural conditions that may inactivate the compound . the compositions described herein can be prepared by methods known per se for the preparation of pharmaceutically acceptable compositions which can be administered to subjects , such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle . suitable vehicles are described , for example , in remington &# 39 ; s pharmaceutical sciences ( remington &# 39 ; s pharmaceutical sciences , mack publishing company , easton , pa ., usa 1985 ). on this basis , the compositions include , albeit not exclusively , solutions of the substances or compounds in association with one or more pharmaceutically acceptable vehicles or diluents , and contained in buffered solutions with a suitable ph and iso - osmotic with the physiological fluids . after pharmaceutical compositions have been prepared , they can be placed in an appropriate container and labeled for treatment of an indicated condition . for administration of an inhibitor of a polypeptide of the invention , such labeling would include amount , frequency , and method of administration . the nucleic acids encoding c2gnt3 polypeptides or any fragment thereof , or antisense sequences may be used for therapeutic purposes . antisense to a nucleic acid molecule encoding a polypeptide of the invention may be med in situations to block the synthesis of the polypeptide . in particular , cells may be transformed with sequences complementary to nucleic acid molecules encoding c2gnt3 polypeptide . thus , antisense sequences may be used to modulate c2gnt3 activity or to achieve regulation of gene function . sense or antisense oligomers or larger fragments , can be designed from various locations along the coding or regulatory regions of sequences encoding a polypeptide of the invention . expression vectors may be derived from retroviruses , adenoviruses , herpes or vaccinia viruses or from various bacterial plasmids for delivery of nucleic acid sequences to the target organ , tissue , or cells . vectors that express antisense nucleic acid sequences of c2gnt3 polypeptide can be constructed using techniques well known to those skilled in the art ( see for example , sambrook , fritsch , maniatis , molecular cloning , a laboratory manual , second edition ( 1989 ) cold spring harbor laboratory press , cold spring harbor , n . y ). genes encoding c2cnt3 polypeptide can be turned off by transforming a cell or tissue with expression vectors that express high levels of a nucleic acid molecule or fragment thereof which encodes a polypeptide of the invention . such constructs may be used to introduce untranslatable sense or antisense sequences into a cell . even if they do not integrate into the dna , the vectors may continue to transcribe rna molecules until all copies are disabled by endogenous nucleases . transient expression may last for extended periods of time ( e . g . a month or more ) with a non - replicating vector or if appropriate replication elements are part of the vector system . modification of gene expression may be achieved by designing antisense molecules , dna , rna , or pna , to the control regions of a c2gnt3 polypeptide gene i . e . the promoters , enhancers , and introns . preferably the antisense molecules are oligonucleotides derived from the transcription initiation site ( e . g . between positions − 10 and + 10 from the start site ). inhibition can also be achieved by using triple - helix base - pairing techniques . triple helix pairing causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases , transcription factors , or regulatory molecules ( see gee j . e . et al ( 1994 ) in : huber , b . e . and b . i . carr , molecular and immunologic approaches , futura publishing co ., mt . kisco , n . y .). ribozymes , enzymatic rna molecules , may be used to catalyze the specific cleavage of rna . ribozyme action involves sequence - specific hybridization of the ribozyme molecule to complementary target rna , followed by endonucleolytic cleavage . for example , hammerhead motif ribozyme molecules may be engineered that can specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding a polypeptide of the invention . specific ribosome cleavage sites within any rna target may be initially identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences : gua , guu , and guc . short rna sequences of between 15 and 20 ribonucleotides corresponding to the region of the cleavage site of the target gene may be evaluated for secondary structural features which may render the oligonucleotide inoperable . the suitability of candidate targets may be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays . therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals , such as by calculating the ed 50 ( the dose therapeutically effective in 50 % of the population ) or ld 50 ( the dose lethal to 50 % of the population ) statistics . the therapeutic index is the dose ratio of therapeutic to toxic effects and it can be expressed as the ed 50 / ld 50 ratio . pharmaceutical compositions which exhibit large therapeutic indices are preferred . the invention also provides methods for studying the function of a c2gnt3 polypeptide . cells , tissues , and non - human animals lacking in c2gnt3 expression or partially lacking in c2gnt3 expression may be developed using recombinant expression vectors of the invention having specific deletion or insertion mutations in a c2gnt3 gene . a recombinant expression vector may be used to inactivate or alter the endogenous gene by homologous recombination , and thereby create a c2gnt3 deficient cell , tissue or animal . null alleles may be generated in cells , such as embryonic stem cells by deletion mutation . a recombinant c2gnt3 gene may also be engineered to contain an insertion mutation which inactivates c2gnt3 . such a construct may then be introduced into a cell , such as an embryonic stem cell , by a technique such as transfection , elcctroporation , injection etc . cells lacking an intact c2gnt3 gene may then be identified , for example by southern blotting , northern blotting or by assaying for expression of a polypeptide of the invention using the methods described herein . such cells may then be used to generate transgenic non - human animals deficient in c2gnt3 . germline transmission of the mutation may be achieved , for example , by aggregating the embryonic stem cells with early stage embryos , such as 8 cell embryos , in vitro ; transferring the resulting blastocysts into recipient females and ; generating germline transmission of the resulting aggregation chimeras . such a mutant animal may be used to define specific cell populations , developmental patterns and in vivo processes , normally dependent on c2gnt3 expression . the invention thus provides a transgenic non - human mammal all of whose germ cells and somatic cells contain a recombinant expression vector that inactivates or alters a gene encoding a c2gnt3 polypeptide . further the invention provides a transgenic non - human mammal , which does not express a c2gnt3 polypeptide of the invention . a transgenic non - human animal includes but is not limited to mouse , rat , rabbit , sheep , hamster , guinea pig , micro - pig , pig , dog , cat , goat , and non - human primate , preferably mouse . the invention also provides a transgenic non - human animal assay system which provides a model system for testing for an agent that reduces or inhibits a pathology associated with a c2gnt3 polypeptide comprising : ( a ) administering the agent to a transgenic non - human animal of the invention ; and ( b ) determining whether said agent reduces or inhibits the pathology in the transgenic non - human animal relative to a transgenic non - human animal of step ( a ) to which the agent has not been administered . the agent may be useful to treat the disorders and conditions discussed herein . the agents may also be incorporated in a pharmaceutical composition as described herein . a polypeptide of the invention may be used to support the survival , growth , migration , and / or differentiation of cells expressing the polypeptide . thus , a polypeptide of the invention may be used as a supplement to support , for example cells in culture . the invention relates to a method for preparing an oligosaccharide comprising contacting a reaction mixture comprising an activated donor substrate e . g . glcnac , and an acceptor substrate in the presence of a polypeptide of the invention . examples of acceptor substrates for use in the method for preparing an oligosaccharide are a saccharide , oligosaccharides , polysaccharides , glycopeptides , glycopolypeptides , or glycolipids which are either synthetic with linkers at the reducing end or naturally occurring structures , for example , asialo - agalacto - fetuin glycopeptide . the activated donor substrate is preferably glcnac which may be part of a nucleotide - sugar , a dolichol - phosphate - sugar , or dolichol - pyrophosphate - oligosaccharide . in an embodiment of the invention , the oligosaccharides are prepared on a carrier that is non - toxic to a mammal , in particular a human such as a lipid isoprenoid or polyisoprenoid alcohol . an example of a suitable carrier is dolichol phosphate . the oligosaccharide may be attached to a carrier via a labile bond allowing for chemical removal of the oligosaccharide from the lipid carrier . in the alternative , the oligosaccharide transferase may be used to transfer the oligosaccharide from a lipid carrier to a polypeptide . the following examples are intended to further illustrate the invention without limiting its scope . a : identification of cdna homologous to c2gnt3 by analysis of gss database sequence information . database searches were performed with the coding sequence of the human c2 / 4gnt ( c2gnt2 ) sequence using the blastn and tblastn algorithms against the gss database at the national center for biotechnology information , usa . the blastn algorithm was used to identify gsss representing the query gene ( identities of ≧ 95 %), whereas tblastn was used to identify non - identical , but similar gss sequences . gsss with 50 – 90 % nucleotide sequence identity were regarded as different from the query sequence . composites of the sequence information for two gsss were compiled and analysed for sequence similarity to human c2 / 4gnt ( c2gnt2 ). a gss clone cit - hsp - 2288b17 . tf ( gss genbank accession number aq005888 ), derived from a putative homologue to c2 / 4gnt ( c2gnt2 ), was obtained from research genetics inc ., usa . sequencing of this clone revealed a partial open reading frame with significant sequence similarity to c2 / 4gnt ( c2gnt2 ). the coding region of human c2gnt - l ( c2gnt1 ), c2 / 4gnt ( c2gnt2 ) and a bovine homologue was previously found to be organized in one exon (( 22 ),( 15 )). since the 3 ′ sequence available from the c2gnt3 gss was incomplete but likely to be located in the single exon , the missing 3 ′ portion of the open reading frame was obtained by sequencing a genomic p1 clone . the p1 clone was obtained from a human foreskin genomic p1 library ( dupont merck pharmaceutical co . human foreskin fibroblast p1 library ) by screening with the primer pair : one genomic clone for c2gnt3 , gs22597 # 844 / b1 was obtained from genome systems inc ., usa . dna from p1 phage was prepared as recommended by genome systems inc . the entire coding sequence of the c2gnt3 gene was represented in the clone and sequenced in full using automated sequencing ( abi377 , perkin - elmer ). confirmatory sequencing was performed on a cdna clone obtained by pcr ( 30 cycles at 95 ° c . for 10 sec ; 55 ° c . for 15 sec and 68 ° c . for 2 min 30 sec ) on cdna from human thymus poly a - mrna with the sense primer : the composite sequence contained an open reading frame of 1359 base pairs encoding a putative protein of 453 amino acids with type ii domain structure predicted by the tmpred - algorithm at the swiss institute for experimental cancer research ( isrec ). ( http :// www . ch . embnet . org / software / tmpred_form . html ). an expression vector construct designed to encode amino acid residues 39 – 453 of c2gnt3 was prepared by pcr using p1 dna , and the primer pair : tshc100 ( 5 ′- cgaggatccgcaaaaagacatttacttggtt - 3 ′, seq id no : 5 ) and tshc121 ( 5 ′- agcgaattcttactatcatgatgtggtagtg - 3 ′, seq id no : 9 ) with bamh1 and ecori restriction sites , respectively ( fig2 ). the pcr product was cloned between the bamhi and ecori sites of pacgp67a ( pharmingen ), and the insert was fully sequenced . pacgp67 - c2gnt3 - sol was co - transfected with baculo - gold ™ dna ( pharmingen ) as described previously ( 23 ). recombinant baculo - viruses were obtained after two successive amplifications in sf9 cells grown in serum - containing medium , and titers of virus were estimated by titration in 24 - well plates with monitoring of enzyme activities . transfection of sf9 - cells with pacgp67 - c2gnt3 - sol resulted in marked increase in glcnac - transferase activity compared to uninfected cells or cells infected with a control construct . standard assays were performed using culture supernatant from infected cells in 50 μl reaction mixtures containing 100 mm mes ( ph 6 . 5 ), 0 . 1 % nonidet p - 40 , 150 μm udp -[ 14 c ]- glcnac ( 2 , 000 cpm / nmol ) ( amersham pharmacia biotech ), and the indicated concentrations of acceptor substrates ( sigma and toronto research laboratories ltd ., see table i for structures ). reaction products were quantified by chromatography on dowex ag1 - x8 . a human rna master blot ( clontech ) was used for expression analysis . the cdna - fragment of soluble c2gnt3 was used as a probe for hybridization . the probe was random primer - labeled using [ α 32 p ] datp and and the strip - ez dna labeling kit ( ambion ). the membrane was probed for 6 h at 65 ° c . following the protocol of the manufacturer ( clontech ) and washed five times for 20 min each at 65 ° c . with 2 × ssc , 1 % sds and twice for 20 min each at 55 ° c . with 0 . 1 × ssc , 0 . 5 % sds . a human multiple tissue northern blot mtn ii ( clontech ), was probed as described ( 24 ), and washed twice for 10 min each at room temperature with 2 × ssc , 0 . 1 % sds ; twice for 10 min each at 55 ° c . with 1 × ssc , 0 . 1 % sds ; and once for 10 min with 0 . 1 × ssc , 0 . 1 % sds at 55 ° c . pcr analysis of c2gnt3 expression in resting and activated human blood cell fractions was performed using the primer pair : pcr amplifications with primers specific for human c2gnt3 ( c2gnt3 ) or gapdh ( g3pdh , supplied by the manufacturer ) were performed on a normalized human blood cell cdna panel ( mtc from clontech ) for 31 cycles . expression of c2gnt3 transcript was detected in all peripheral blood mononuclear cell ( pbmc ) fractions with particularly high levels of expression in cd4 and cd8 positive t - lymphocytes ( fig4 ). tshc123 ( 5 ′- gggcagcatttgcctagtatg - 3 ′, seq id no : 10 ) and tshc119 ( 5 ′- gatctctgatttggctcagtg - 3 ′, seq id no : 8 ) as described in fig5 have been used for pcr amplification of individual sequences of the coding exon . each pcr product was subcloned and the sequence of 10 clones containing the appropriate insert was determined assuring that both alleles of each individual are characterized . polymorphism of the amplified dna can be analyzed using , e . g ., dna sequencing , single - strand conformational polymorphism ( sscp ) or mismatch mutation . from the foregoing it will be evident that , although specific embodiments of the invention have been described herein for purposes of illustration , various modifications may be made without deviating from the spirit and scope of the invention . 1 . clausen , h . and bennett , e . p . a family of udp - galnac : polypeptide n - acetylgalactosaminyltransferases control the initiation of mucin - type o - linked glycosylation . glycobiology 6 : 635 – 646 , 1996 . 2 . piller , f ., piller , v ., fox , r . i ., and fukuda , m . human t - lymphocyte activation is associated with changes in o - glycan biosynthesis . j . biol . chem . 263 : 15146 – 15150 , 1988 . 3 . yang , j . m ., byrd , j . c ., siddiki , b . b ., chung , y . s ., okuno , m ., sowa , m ., kim , y . s ., matta , k . l ., and brockhausen , i . alterations of o - glycan biosynthesis in human colon cancer tissues . glycobiology 4 : 873 – 884 , 1994 . 4 . yousefi , s ., higgins , e ., daoling , z ., pollex - kruger , a ., hindsgaul , o ., and dennis , j . w . increased udp - glcnac : gal beta 1 – 3galnac - r ( glcnac to galnac ) beta - 1 , 6 - n - acetylglucosaminyltransferase activity in metastatic murine tumor cell lines . control of polylactosamine synthesis . j . biol . chem . 266 : 1772 – 1782 , 1991 . 5 . fukuda , m . possible roles of tumor - associated carbohydrate antigens . cancer res . 56 : 2237 – 2244 , 1996 . 6 . brockhausen , i ., yang , j . m ., burchell , j ., whitehouse , c ., and taylor - papadimitriou , j . mechanisms underlying aberrant glycosylation of muc1 mucin in breast cancer cells . eur . j . biochem . 233 : 607 – 617 , 1995 . 7 . brockhausen , i ., kuhns , w ., schachter , h ., matta , k . l ., sutherland , d . r ., and baker , m . a . biosynthesis of o - glycans in leukocytes from normal donors and from patients with leukemia : increase in o - glycan core 2 udp - glcnac : gal beta 3 galnac alpha - r ( glcnac to galnac ) beta ( 1 – 6 )- n - acetylglucosaminyltransferase in leukemic cells . cancer res . 51 : 1257 – 1263 , 1991 . 8 . higgins , e . a ., siminovitch , k . a ., zhuang , d . l ., brockhausen , i ., and dennis , j . w . aberrant o - linked oligosaccharide biosynthesis in lymphocytes and platelets from patients with the wiskott - aldrich syndrome . j . biol . chem . 266 : 6280 – 6290 , 1991 . 9 . saitoh , o ., piller , f ., fox , r . i ., and fukuda , m . t - lymphocytic leukemia expresses complex , branched o - linked oligosaccharides on a major sialoglycoprotein , leukosialin . blood 77 : 1491 – 1499 , 1991 . 10 . springer , g . f . t and tn , general carcinoma autoantigens . science 224 : 1198 – 1206 , 1984 . 11 . kumar , r ., camphausen , r . t ., sullivan , f . x ., and cumming , d . a . core2 beta - 1 , 6 - n - acetylglucosaminyltransferase enzyme activity is critical for p - selectin glycoprotein ligand - 1 binding to p - selectin . blood 88 : 3872 – 3879 , 1996 . 12 . williams , d . and schachter , h . mucin synthesis . i . detection in canine submaxillary glands of an n - acetylglucosaminyltransferase which acts on mucin substrates . j . biol . chem . 255 : 11247 – 11252 , 1980 . 13 . bierhuizen , m . f . and fukuda , m . expression cloning of a cdna encoding udp - glcnac : gal beta 1 – 3 - galnac - r ( glcnac to galnac ) beta 1 – 6glcnac transferase by gene transfer into cho cells expressing polyoma large tumor antigen . proc . natl . acad . sci . u . s . a . 89 : 9326 – 9330 , 1992 . 14 . schwientek , t ., yeh , j . c ., levery , s . b ., keck , b ., merkx , g ., van kessel , a . g ., fukuda , m ., and clausen , h . control of o - glycan branch formation . molecular cloning and characterization of a novel thymus - associated core 2 beta1 , 6 - n - acetylglucosaminyltransferase . j . biol . chem . 275 : 11106 – 11113 , 2000 . 15 . schwientek , t ., nomoto , m ., levery , s . b ., merkx , g ., van kessel , a . g ., bennett , e . p ., hollingsworth , m . a ., and clausen , h . control of o - glycan branch formation . molecular cloning of human cdna encoding a novel betal , 6 - n - acetylglucosaminyl - transferase forming core 2 and core 4 . j . biol . chem . 274 : 4504 – 4512 , 1999 . 16 . yeh , j . c ., ong , e ., and fukuda , m . molecular cloning and expression of a novel beta - 1 , 6 - n - acetylglucosaminyltransferase that forms core 2 , core 4 , and i branches . j . biol . chem . 274 : 3215 – 3221 , 1999 . 17 . baum , l . g ., pang , m ., perillo , n . l ., wu , t ., delegeane , a ., uittenbogaart , c . h ., fukuda , m ., and seilhamer , j . j . human thymic epithelial cells express an endogenous lectin , galectin - 1 , which binds to core 2 o - glycans on thymocytes and t lymphoblastoid cells . j . exp . med . 181 : 877 – 887 , 1995 . 18 . perillo , n . l ., marcus , m . e ., and baum , l . g . galectins : versatile modulators of cell adhesion , cell proliferation , and cell death . j . mol . med . 76 : 402 – 412 , 1998 . 19 . perillo , n . l ., pace , k . e ., seilhamer , j . j ., and baum , l . g . apoptosis of t cells mediated by galectin - 1 . nature 378 : 736 – 739 , 1995 . 20 . devereux , j ., haeberli , p ., and smithies , o . a comprehensive set of sequence analysis programs for the vax . nucleic acids res . 12 : 387 – 395 , 1984 21 . altschul , s . f ., gish , w ., miller , w ., myers , e . w ., and lipman , d . j . basic local alignment search tool . j . mol . biol . oct . 5 , 1990 . 215 : 403 – 410 , 22 . bierhuizen , m . f ., maemura , k ., kudo , s ., and fukuda , m . genomic organization of core 2 and i branching beta - 1 , 6 - n - acetylglucosaminyltransferases . implication for evolution of the beta - 1 , 6 - n - acetylglucosaminyltransferase gene family . glycobiology 5 : 417 – 425 , 1995 . 23 . almeida , r ., amado , m ., david , l ., levery , s . b ., holmes , e . h ., merkx , g ., van kessel , a . g ., rygaard , e ., hassan , h ., bennett , e ., and clausen , h . a family of human beta4 - galactosyltransferases . cloning and expression of two novel udp - galactose : beta - n - acetylglucosamine beta1 , 4 - galactosyltransferases , beta4gal - t2 and beta4gal - t3 . j . biol . chem . 272 : 31979 – 31991 , 1997 . 24 . bennett , e . p ., hassan , h ., and clausen , h . cdna cloning and expression of a novel human udp - n - acetyl - alpha - d - galactosamine . polypeptide n - acetylgalactosaminyltransferase , galnac - t3 . j . biol . chem . 271 : 17006 – 17012 , 1996 . 25 . wandall , h . h ., hassan , h ., mirgorodskaya , e ., kristensen , a . k ., roepstorff , p ., bennett , e . p ., nielsen , p . a ., hollingsworth , m . a ., burchell , j ., taylor - papadimitriou , j ., and clausen , h . substrate specificities of three members of the human udp - n - acetyl - alpha - d - galactosamine : polypeptide n - acetylgalactosaminyltransferase family , galnac - t1 , - t2 , and - t3 . j . biol . chem . 272 : 23503 – 23514 , 1997 . 26 . matteucci , m . d . and caruthers , m . h . j . am . chem . soc . 103 : 3185 – 3191 . 1981 . 27 . yoo , y ., rote , k ., and rechsteiner , m . synthesis of peptides as cloned ubiquitin extensions . j . biol . chem . 264 : 17078 – 17083 , 1989 . | US-84372304-A |
adjustable padding systems for garments , incorporating a pocket and a pad . the pocket is coupled to the garment and has a wide , proximal portion and a narrow , distal portion . the pad has corresponding wide and narrow portions . the narrow portion of the pad is longer than the length of the narrow portion of the pocket , but is adjustable in length . accordingly , the location of the wide portion of the pad along the length of the garment can be adjusted by adjusting the length of the narrow portion of the pad . | the following detailed description is directed toward devices and systems for use in padding an individual &# 39 ; s knee or elbow . more particularly , it is directed toward adjustable devices and systems designed to allow the pad to be positioned properly over the individual &# 39 ; s knee or elbow , regardless of the length of the individual &# 39 ; s arm or leg . fig1 shows a pair of pants 10 that incorporate a padding system 12 according to one possible embodiment of the present invention . the illustrated padding system 12 generally incorporates a pocket 14 and a pad 16 . the pocket 14 can be located on an inside surface of a leg 18 of the pants 10 ; the pad 16 can be removably positioned within the pocket . fig2 better illustrates the pocket 14 of this particular embodiment of the invention . the illustrated pocket 14 has a wide portion 20 and a narrow portion 22 . the narrow portion 22 of the pocket 14 is created due to the lateral offset of one , or in this instance both , of the sides of the narrow portion of the pocket with respect to the wide portion 20 . as shown in fig1 , the wide portion 20 of the pocket 14 is located along the leg 18 at the proximal end of the pocket , closest a body 24 ( fig1 ) of the pants 10 , and the narrow portion 22 of the pocket is located at the distal end , closest a terminal end 26 ( fig1 ) of the leg 18 . a shoulder 28 is positioned between the wide portion 20 and the narrow portion 22 of the pocket 14 . in the illustrated embodiment , a flap 30 overlaps a proximal end 32 of the pocket 14 . stitching 34 can couple the perimeter of the pocket 14 and the flap 30 to the pants 10 . the flap 30 and the proximal end 32 of the pocket 14 overlap each other , but the overlapping portions are not stitched together or to the pants . as a result , an opening 36 is formed , providing access to an interior of the pocket . as shown in fig1 , the pad 16 can be inserted into the pocket 14 . the opening 36 allows the pad 16 to be removed from the pocket 14 and reinserted or replaced . the flap 30 can also retain the pad 16 in the pocket 14 . the narrow portion 22 of the pocket 14 terminates at a distal end 38 . the distal end 38 of the pocket 14 is located a fixed depth d from the shoulder 28 . fig3 better illustrates the pad 16 of this particular invention . the illustrated pad 16 is shaped for use as a combination knee / shin pad . the pad 16 has a wide , knee portion 40 and a narrow , shin portion 42 . as shown in fig1 , the knee portion 40 of the pad 16 corresponds to the wide portion 20 of the pocket 14 and the shin portion 42 of the pad corresponds to the narrow portion 22 of the pocket . accordingly , the illustrated pad is sized and shaped to complement the pocket illustrated in fig2 . thus , the knee portion 40 of the pad 16 is slightly narrower than the wide portion 20 of the pocket 14 and the shin portion 42 of the pad is slightly narrower than the narrow portion 22 of the pocket . the shin portion 42 of the pad 16 terminates at a distal end 44 . the shin portion 42 of the pad 16 extends from the distal end 44 to a lower edge 46 of the knee portion 40 . the pad 16 can be made from any material or combination of materials having sufficient cushion for use as a knee pad , such as foam . in addition , the pad 16 of this particular embodiment should be made from a material sufficiently resilient to return to its general shape after being bent . as a result , the pad 16 , or at least the shin portion 42 of the pad should resist folding or buckling , folding or collapsing , allowing the pad 16 to be adjustable , as discussed below . fig4 a - 4c show the pad 16 in three different adaptations . fig4 a shows the pad 16 unaltered , where the lower edge 46 of the knee portion 40 is a maximum , uncut length l a as measured from the distal end 44 of the shin portion 42 . fig4 b shows the pad 16 shortened from its original length by a first , small amount , where the lower edge 46 of the knee portion 40 is a shortened , second length l b as measured from a first cut edge 48 of the shin portion 42 . fig4 c shows the pad 16 shortened from its original length by a second , larger amount , where the lower edge 46 of the knee portion 40 is a further shortened , third length l c as measured from a second cut edge 50 of the shin portion 42 . because the amount shortened increases from one figure to the next , the uncut length l a is longer than the second length l b and the second length is longer than the third length l c . the pad 16 can be shortened by using scissors 52 or other suitable means . in certain embodiments , the pad 16 can be treated to facilitate easy and / or manual shortening , such as with perforations or other features . fig5 a - 5c show the padding system assembled using the three pads illustrated in fig4 a - 4c , respectively . in fig5 a the pad 16 is inserted in the pocket 14 until the distal end 44 of the shin portion 42 of the pad contacts the distal end 38 of the narrow portion 22 of the pocket . the uncut length l a of the shin portion 42 of the pad 16 is greater than the depth d of the narrow portion 22 of the pocket 14 by a maximum , first offset o a , positioning the knee portion 40 of the pad a maximum distance from the terminal end 26 of the leg 12 of the pants 10 . in fig5 b , the pad is inserted in the pocket 14 until the first cut edge 48 contacts the distal end 38 of the narrow portion 22 of the pocket . the second length l b is greater than the depth d of the narrow portion 22 of the pocket 14 by a second offset o b , which is smaller than the first offset o a , positioning the knee portion 40 of the pad 16 an intermediate distance from the terminal end 26 of the leg 12 of the pants 10 . in fig5 c , the pad is inserted in the pocket 14 until the second cut edge 50 contacts the distal end 38 of the narrow portion 22 of the pocket . the second length l c is equal to the depth d of the narrow portion 22 of the pocket 14 , positioning the knee portion 40 of the pad 16 a minimum distance from the terminal end 26 of the leg 12 of the pants 10 . by adjusting the location of the first cut edge 48 , the intermediate distance can be located anywhere between the maximum distance and the minimum distance . thus , the knee portion 40 of the pad 16 can be positioned in any desired location along the leg 18 of the pants 10 . fig6 illustrates a knee pad 116 according to one particular alternative embodiment of the present invention . the pad 116 incorporates a knee portion 140 and an extension portion 142 . the knee portion 140 can be made from material similar to that described above in connection with the previous embodiment . the extension portion 142 in this particular embodiment is not a shin pad , but can be any resilient or rigid material suitable for spacing the knee portion 140 of the pad 116 along the leg 18 of the pants 10 , as discussed above . the illustrated extension portion 142 has features 154 along its length to facilitate bending or breaking the extension portion to a desired length . as a result , the extension portion can be made from a durable material that may otherwise be difficult to cut or break , providing for both durability and adjustability . from the foregoing it will be appreciated that , although specific embodiments of the invention have been described herein for purposes of illustration , various modifications may be made without deviating from the spirit and scope of the invention . accordingly , the invention is not limited except as by the appended claims . | US-12178405-A |
a rope management device is provided that includes features allowing for transition from a rope clamping position to a rope unclamped position when under load . included is a teeter bar having a pivot axis allowing for application of friction on a section of rope to hold a load in place and then when rope is pulled through the device the load is maintained while allowing the teeter bar to pivot to eliminate friction on the rope . | the present invention provides a different embodiment of the disclosures of u . s . pat . no . 6 , 899 , 203 issued on 31 may 2005 to perry l . everett et al . and of u . s . pat . no . 7 , 533 , 871 issued on 19 may 2009 to perry l . everett et al ., which patents are incorporated herein by reference . fig1 is an exploded perspective diagram illustrating the manner in which the components of the present invention , generally designated 110 , are assembled in relationship to each other . as illustrated , the major components include a base plate 1 , access plate 13 , teeter bar 11 , cam 9 , handle 10 , and bollards 2 and 3 . also included are bollard wear sleeves 4 and 5 , bearing 12 , stops 6 , 7 , and 8 , and pivot axis fasteners 3 c , 14 and 15 . further included are miscellaneous fasteners 2 c , 4 b , 5 b , 10 c , 10 d and 15 a . fig2 is a perspective view of the assembled device of fig1 as viewed looking toward the access plate , fig3 is a perspective view of the opposite side on the assembled device of the invention of fig1 as viewed looking toward the base plate , fig4 is a perspective side view of the assembled device of fig1 , and fig5 is a cross - sectional view of the invention taken along lines 5 - 5 of fig4 . after assembly of the device 110 as indicated in fig1 - 4 , there are three component pivot axis &# 39 ; designated pivot axis 1 , pivot axis 2 and pivot axis 3 . pivot axis 1 is defined by aligned pivot holes 1 b , 11 b and 13 b secured by fastener 15 and nut 15 a , pivot axis 2 defined by pivot hole 11 c and secured by fastener 15 , and pivot axis 3 defined by aligned pivot holes 9 c and 1 d and secured to bollard 3 by fastener 3 c . there are two rope attachment points , attachment point 1 at teeter bar attachment hole 11 a , and attachment point 2 defined by aligned base plate attachment hole 1 a and access plate attachment hole 13 a . as indicated in the drawings the components of the invention and their assembly are described as follows : a base plate 1 having ten holes , an attachment hole 1 a , pivot hole 1 b , and six fastener holes 1 c , 1 d , 1 e , 1 f , 1 g , 1 h , 1 i and 1 j ; hole 1 c for receiving threaded fastener screw 2 c therethrough to permanently fasten bollard 2 to side a of base plate 1 by engagement with threaded hole 2 a ; hole 1 d for receiving fastener bolt 3 c therethrough to fasten bollard 3 to side a of base plate 1 , holes 1 e , 1 g , 1 h , 1 i , and 1 j for selectively affixing stop 8 , and threaded hole 1 f for permanently affixing threaded stop 7 ; bollards 2 and 3 include fastener holes 2 a and 3 a , respectively , for receiving securing fasteners 2 c and 3 c , respectively , to affix bollards 2 and 3 to base plate 1 , and replaceable wear sleeves 4 and 5 secured by screws 4 b and 5 b , respectively , threaded hole 2 a also permanently affixing threaded stop 6 to the bottom of bollard 2 ; a cam 9 having a pivot hole 9 c for receiving threaded fastener 3 c therethrough after which threaded fastener 3 c mates with threaded holes 1 d and 3 a to secure bollard 3 to side a of base plate 1 and thereby define pivot axis 3 , and fastener holes 9 a and 9 b for securing handle 10 to side b of cam 9 by means of fastener bolts 10 c and 10 b , respectively , and fastener hole 9 d for securing spring 9 c by means of fastener screw 9 f ; a teeter bar 11 pivotally mounted between base plate 1 and access plate 13 by threaded fastener 15 which transits pivot holes 1 b , 11 b and 13 b to terminate in nut 15 a to thereby define pivot axis 1 , attachment hole 11 a defining attachment point 1 , a friction brake generally designated 11 d , and a fairlead generally designated 11 e having a fastener hole 11 c ; bearing 12 having hole 12 a for fixedly receiving a first end of fastener 14 , the second end of fastener 14 fixedly received by teeter bar hole 11 c , this arrangement allowing bearing 12 to remain in contact with cam 9 , the combination of bearing 12 , fastener 14 and hole 11 c defining pivot axis 2 ; access plate 13 having rope attachment hole 13 a , pivot hole 13 b for receiving bolt 15 , pivot hole 13 b co - acting with fastener 15 , pivot hole 11 b to rotatably affix teeter bar 11 to side b of access plate 13 , hole 13 a co - acting with hole 1 a to define rope attachment point pivot axis 2 , and catch 13 c configured for co - acting with threaded stop 6 ; handle 10 permanently affixed to cam 9 by threaded fasteners 10 c and 10 d transiting holes 10 a and 10 b , respectively , to engage threaded holes 9 a and 9 b , respectively . fig6 a and 6b illustrate an operational configuration for the invention . fig6 a shows tether line 108 attached at one end to attachment point 1 defined by hole 1 a and the other end to security belt 107 shown to be attached to a fellow climber . rope 105 is shown attached at one end to attachment point 2 defined by hole 13 a and then passed around an anchor 103 and then between base plate 1 a and access plate 13 positioned to pass bollards 2 and 3 and then around fairlead 11 e and out for manual control by the device operator . with this configuration it is possible for the operator , by pulling or letting off on the rope 105 , to control the distance between pivot axis 3 ( hole 1 d of base plate 1 ) and pivot axis 2 ( hole 11 c of teeter bar 11 ) to thereby control the distance between bollard 3 and friction brake 11 d . with this control the device 101 can be operated to go from a rope clamping state to an unclamping state even when under load . as shown in fig1 , teeter bar 11 is pivotally mounted between base plate 1 and access plate 13 on pivot axis 1 , thus allowing teeter bar 11 to teeter about pivot axis 1 . as indicated in fig6 a and 6b , when a load is applied to attachment point 1 teeter bar 11 teeters about pivot axis 1 to move fairlead 11 e toward bollard 3 and thus moving pivot axis 2 and pivot axis closer together to apply clamping pressure and friction on a section of rope 105 between wear sleeve 5 of bollard 3 and friction brake 11 d of teeter bar 11 . as the applied load increases , applied clamping pressure and friction increases and holds the load by preventing movement of rope 105 through the device 101 . as is evident from review of the figures , pivot hole 11 b is in an off center location between attachment hole 11 a and fairlead 11 e of teeter bar 11 which provides a leverage advantage . the distance between fairlead 11 e and pivot axis 1 is greater than the distance between attachment hole 11 a and pivot axis 1 . this leverage advantage makes it possible to more easily pull rope 105 through device 101 . as rope 105 is pulled down against fairlead 11 e teeter bar 11 teeters on pivot axis 1 moving pivot axis 2 and pivot axis 3 further apart thus eliminating clamping pressure and friction on rope 105 between wear sleeve 5 of bollard 3 and friction brake 11 d of teeter bar 11 . this unclamping action allows rope 105 to be pulled through device 101 , down across fairlead 11 e moving device 101 closer to anchor 103 . in operation of the device 101 , co - action between handle 10 , cam 9 and bearing 12 provides a mechanical advantage in that this co - action makes it possible to more easily control the distance between pivot axis 2 and pivot axis 3 . this allows a controlled distance between wear sleeve 5 and friction brake 11 d which makes it possible for rope management device 101 to go from a rope clamping position to a rope unclamping position even when under load . as handle 10 and cam 9 are turned counter clockwise on pivot axis 3 , bearing 12 follows cam 9 to move pivot axis 2 and pivot axis 3 further apart thereby reducing clamping pressure and friction on rope 105 between wear sleeve 5 of bollard 3 and friction brake 11 d of teeter bar 11 . this unclamping action allows rope 105 to slip through device 101 at a controlled speed moving device 101 further from anchor 103 . further , threaded fastener hole 9 d of cam 9 , when receiving threaded governor control screw 9 f through governor spring 9 e together with base plate fastener holes 1 g , 1 h , 1 i , 1 j and governor stop bolt 10 f , provides a variable position stop . this provides means for limiting the descent speed of device 101 by limiting how far handle 10 and cam 9 are allowed to turn counter - clockwise before being stopped by governor stop bolt 10 f and governor control screw 9 f . although the present invention has been described with reference to an illustrated and described embodiment , other modifications and embodiments can be devised by those skilled in the art that would fall within the spirit and scope of the invention . | US-79942510-A |
a post including a back post and leg , together constituting a one - piece member . the member is bent to form the back post and leg , and when it is in upright active position , the back post rests against the wall , and the leg extends forwardly at an acute angle to the back post . a foot is secured to the lower end of the leg , extending transversely and engaging the floor . the back post is provided with holes for receiving brackets . there is no mechanical connection between the post and the wall or floor . | fig1 shows a pair of posts made according to the invention . in this case the posts are provided with brackets 11 and a shelf 12 to be referred to again hereinbelow . in fig1 the two posts 10 are set up in upright or active position , spaced apart and supporting the shelf . the two posts are identical and a description of a single post will apply in all of the illustrations . fig1 shows the posts 10 in a space or room 13 having a wall 14 and a floor 15 , the juncture therebetween being indicated by a line 16 . each post is made up of a back post 17 , a leg 18 , and a foot 20 . in this construction , the back post and leg are made of a single integral , one - piece member , while the foot 20 is a separate member , secured to the leg . the back post / leg 17 / 18 is preferably an extruded tubular metal piece , polygonal in cross section and preferably square . the post in upright active position , is so positioned with the foot 20 on and supported by the floor , and the back post 17 resting against the wall . the leg 18 is disposed at an obique angle 28 ( fig2 ) to the back post , and thus to the floor . the back post 17 engages the wall throughout substantially its own length , minor variations in surface area being accommodated . the post is thus supported mainly by the floor , which receives basically the weight of the post and the load thereon , and the back post has friction engagement with the wall and thus supported by the wall , not only in direction against the wall , but against moving or sliding in transverse directions , i . e . along the surface of the wall . when the post is in upright active position , it may be referred to as having a rear side 30 and a front side 32 . as will be observed , the rear side is directed against the wall while the front side is directed to the interior of the room . the foot 20 is positioned transverse to the leg 18 and when the post is in active position , it engages the floor essentially throughout its length , in one form , but as referred to hereinbelow , it may be constructed so as to engage the floor only at its ends . the member making up the back post and leg is originally a straight piece , taken from an aggregate supply , and cut to the desired length , and then bent at point 34 which thereby constitutes a juncture between the back post and leg . the foot 20 is also preferably of metal , tubular in construction , and may be round in cross section and is provided with a recess 36 ( fig7 ) in one side . the lower end of the leg 18 is fitted in the recess , and is secured therein by means of a screw 38 . any suitable detail structure may be utilized for securing or locking the leg in the foot such as a plug 40 fitted in the leg , and securely anchored therein as by welding or staking . it has a tapped aperture receiving the threaded screw . the wall of the foot has a hole 42 receiving the screw and the screw head is held in engagement with that wall . the outer opening of the recess 36 , at point 44 , constitutes a point of engagement between the leg and the foot , and thus the interengagement between the leg and the foot is at two points , 44 , 42 , and thus spaced apart transversely of the foot at maximum positions , providing secure anchoring of the leg in the foot . the recess 36 is of a shape complementary to the cross - sectional shape of the leg , in this case square . the plug 40 constitutes one of various kinds of inserts for securing and locking the leg in the foot . the foot 20 is essentially straight , and thereby engages the floor throughout its own length , normally , when the floor is even , this engagement including that at the ends of the foot , which with the engagement of the post with the wall , provides 3 - point support . however , due to occasional uneven or non - planar shapes , such as may often happen in wood floors , the foot may be provided with elements at its ends that directly engage the floor , such as shown in fig6 . such elements are indicated at 46 and may be simple inserts or plugs ( fig8 ) snapped into holes in the wall of the foot . these inserts thus constitute floor engaging elements , and in the active position of the post , they are lower than the remaining points of the foot between those inserts . therefore the inserts constitute two points at the end of the foot , for providing solid and stable support totally preventing wobbling of the post . however it is of course to be noted that any variations or unevenness in the floor are accommodated . preferably the foot 20 is cut from aggregate supply and to provide a pleasant appearance , and additional strength , plugs 48 ( fig8 ) are inserted in the otherwise open ends of the body of the foot , preferably by merely snapping them in . these plugs may be of metal or plastic , or other suitable material . the single leg 18 and foot 20 provide a compact arrangement and trim appearance at the bottom of the post , at the juncture of the wall and floor . the back post 17 on its flat front side , is provided with a series of holes , elongated vertically , and vertically spaced throughout its length . these holes receive the brackets 11 , which are of known kind , having hooks inserted in the holes . the shelves 12 are simple boards that rest on the brackets . fig2 also shows a load 50 on a shelf . the mounting of the brackets and shelves , on the post , is similar to that in our prior application identified above , and the details need not be entered into herein . a similar situation exists in connection with the load 50 , and the load will be referred to again hereinbelow in connection with fig9 . while the posts are adapted for use with shelves , a single post can also be used to support an article . such an arrangement is shown in fig4 where a single post 10 is in active position , resting on the floor , and the back post 17 bearing against the wall 14 . a single bracket 11 is mounted on the back post , supporting a load 52 represented by a flower pot . stability of the post exists where a single post is used as in fig4 and it is not necessary to utilize shelves for aiding in the stability . the stability is provided by the engagement of the back post against the wall , and the engagement of the foot 20 with the floor at the ends of the foot . the posts 16 may also be utilized in double , or back - to - back , arrangement , as shown in fig5 . in this figure two posts are positioned back - to - back , with the back posts 17 thereof fitted together , and preferably secured together by bolts 54 to prevent the two individual posts 10 from sliding out of mutual engagement . these two posts 10 then constitute a double post 56 , and a plurality of such double posts can be arranged in a series ( fig5 ). brackets 11 may be mounted in the front sides of the individual posts 10 , i . e ., on opposite sides of the double posts , and shelves 12 placed on the brackets that are mounted in two or more double posts . this feature is also shown in our prior application identified above , and the presentation here exemplifies the stability of the present form of posts put in double - post arrangements . fig9 depicts the stability of the post in use . this is a front view , and on the back post is a point 58 where a load , i . e . 52 , is supported , this point being where the bracket is mounted . any tendency of the post to tip , or to be tipped , is counteracted by the load . in fig9 the full line position is the upright active position , stabilized . assume , for example , that the post were to be tipped in one direction , i . e . to the right ( fig9 )-- as it goes toward the dot - dash line 10 &# 39 ;, it of course pivots about the point 60 on the radius 61 , and the point 58 where the load is suspended follows the arc 62 upwardly to its highest position at point 58 &# 39 ;. the load tends to move the point downwardly , i . e ., along the arc to the left , to its lowermost position , and thereby produces a stabilizing effect . an identical situation exists relative to the left half of the arrangement represented in fig9 . this stabilizing effect exists whether a single post is used , or a number of posts with shelves used . it will be understood of course that this phenomenon intending to retain the post upright , is additive to the resistance provided by the engagement with the wall which maintains the post upright . in the case of the double post , fig5 each single post 10 provides a supporting means , or supporting surface to the other post , and thus functions in the same manner as a supporting wall , and as used herein , and particularly in the claims , each post may be referred to as a supporting wall . | US-32703994-A |
the end of a bronchoalveolar lavage catheter is coupled to an adaptor manifold which has a pressure port that allows communication to occur between the lumen at the center of the bronchoalveolar lavage catheter and an air pressure tube leading to a pressure transducer . air pressure impulses from the air passageways of a patient are then communicated to the pressure transducer and converted into electronic signals capable of providing useful feedback to medical personnel . one form of feedback constitutes real - time pressure waveforms which are monitored to detect the existence at the tip of the bronchoalveolar lavage catheter of significant wedging - related conditions of interest to medical personnel attempting to effect wedging of the distal tip of the bronchoalveolar lavage catheter . the significant wedging - related conditions comprise conditions of correct wedging , ineffectual wedging , precluded wedging and overwedging . the proximal end of the bronchoalveolar lavage catheter is manipulated on the basis of the predetermined wedging related conditions detected in order thereby to verify correct wedging prior to the infusion of sampling fluid . | fig1 illustrates the environment in which the inventive system and method are employed in relation patient 10 intubated with an endotracheal tube 12 . although intubation is not required in order to perform bronchoalveolar lavage with the inventive method and system disclosed herein , intubation may be employed expressly for the purpose of facilitating the procedure of bronchoalveolar lavage . generally , however , intubation is undertaken in order to provide ongoing mechanical ventilation of a patient . as seen in fig1 endotracheal tube 12 extends through mouth 14 and trachea 16 of the upper respiratory system of patient 10 , terminating at a distal end 18 above the point 20 at the first bifurcation of trachea 16 into the right lung 22 through right mainstem bronchus 24 and into left lung 26 through left mainstem bronchus 28 . typical sub - branchings of the bronchia are shown in fig1 for illustrative purposes in relation to the sub - branching of left mainstem bronchus 24 into left lung 26 . distal end 18 of endotracheal tube 12 is provided with a balloon 30 which , when inflated , engages the walls of trachea 16 to facilitate mechanical ventilation of patient 10 through a y - connector 32 coupled to a standard endotracheal tube adapter 34 at proximal end 36 of endotracheal tube 12 . air from the ventilating apparatus for patient 10 enters endotracheal tube 12 through a first leg 38 of y - connector 32 as indicated in fig1 by arrow a 1 . correspondingly , air is returned to the ventilating apparatus from patient 10 through a second leg 40 of y - connector 32 as shown in fig1 by arrow a 2 . an elbow coupling 42 connects endotracheal tube adapter 34 with y - connector 32 and is provided at a point on the outer radius thereof with a bronchoalveolar lavage catheter access port 44 through which a bronchoalveolar lavage catheter can be entered into endotracheal tube 12 and advanced therethrough into a preselected lung of patient 10 without losing the positive end expiratory pressure ( peep ) often required during mechanical ventilation . according to one aspect of the inventive system , bronchoalveolar lavage catheter access port 44 is provided with a locking means for fixing the longitudinal position of a bronchoalveolar lavage catheter entered through bronchoalveolar lavage catheter access port 44 into a lung of patient 10 . the locking means is manually actuatable to prevent movement of the bronchoalveolar lavage catheter relative to endotracheal tube 12 , thereby maintaining correct wedging if such has been effected . it must be emphasized that use of the inventive system and methods disclose herein is not limited to use with patients undergoing mechanical ventilation , or even patients in whom intubation with an endotracheal tube has occurred . indeed , bronchoalveolar lavage can be conducted with the inventive system and method through the nasal passages 45 of a patient , such as patient 10 , rather than through the mouth 14 thereof . typically , as illustrated in fig1 bronchoalveolar lavage is to be performed on a portion of left lung 26 of patient 10 . in the process , a sterile fluid from a reservoir 46 thereof is infused in individual aliquots using a syringe 48 . the fluid of each infusion is then aspirated using either syringe 48 or the wall vacuum in the medical institution in which the bronchoalveolar lavage is conducted . according to another aspect of the present invention , means are provided for monitoring air passageway pressure distal of the tip of a bronchoalveolar lavage catheter . as shown in fig1 by way of example and not limitation , a gas pressure monitor 50 containing a pressure transducer ( not shown ) is so coupled to bronchoalveolar lavage catheter 60 as inform medical personnel of the air pressure patterns arising in the air passageways of patient 10 distal of the distal tip of a bronchoalveolar lavage catheter . accordingly , gas pressure monitor 50 could include a cathode ray tube screen 52 for exhibiting real time pressure waveforms 53 or a printout 54 of continuous paper , if a permanent record of waveforms 53 is desirable . alternatively , or in addition thereto , gas pressure monitor 50 may be provided with indicator lights 55 and mechanisms for creating audible tones 56 as where the evaluation of waveforms 53 is undertaken without substantial operator intervention utilizing microprocessor - based artificial intelligence software . in one aspect of the means for monitoring , means are provided for coupling gas pressure monitor 50 to the lumen inside a bronchoalveolar lavage catheter . as shown in fig1 by way of illustration and not limitation , the means for coupling comprises an adaptor manifold 57 to be coupled at the proximal end of a bronchoalveolar lavage catheter and gas pressure tubing 58 communicating with the pressure transducer in gas pressure monitor 50 . as shown in fig1 adaptor manifold 57 includes a selectively operable pressure stopcock 59 to be described in more detail subsequently . with gas pressure tubing 58 attached to one output of pressure stopcock 59 , the pressure transducer of gas pressure monitor 50 can be selectively coupled to the lumen in the bronchoalveolar lavage catheter with which the means for monitoring is employed . under such conditions , the pressure transducer of gas pressure monitor 50 converts pressure impulses from the tip of a bronchoalveolar lavage catheter into pressure waveforms 53 by which the correct wedging or other disposition of that bronchoalveolar lavage catheter can be effected and verified . the manner in which pressure waveforms 53 contribute to this objective will also be discussed subsequently . illustrated in fig1 is one embodiment of a bronchoalveolar lavage catheter 60 useable in the system and the method of the present invention . basically , bronchoalveolar lavage catheter 60 is an assembly of subcomponents functioning together for the purpose stated . nevertheless , it will be understood from the disclosure which follows that some or all of the components thereof may be eliminated from bronchoalveolar lavage catheter 60 while yet incorporating teachings of the present invention . accordingly , as shown in fig1 bronchoalveolar lavage catheter 60 includes an inner sampling catheter 62 so sized and configured as to extend from a bronchiole in left lung 26 of patient 10 through the upper respiratory system . according to one aspect of the present invention , at proximal end 64 of sampling catheter 62 , means are provided for infusing and aspirating fluid through sampling catheter 62 into the lung of a patient . as shown by way of example and not limitation , a sampling stopcock 66 is coupled to proximal end 64 of sampling catheter 62 . sampling stopcock 62 is capable of connection to reservoir 46 and to syringe 48 in such a manner as to selectively place syringe 48 alternately in communication with reservoir 46 or with proximal end 64 of sampling catheter 62 . in another aspect of the present invention , a pressure stopcock 59 comprising a portion of the inventive means for monitoring airway pressure distal of the tip of a bronchoalveolar lavage catheter is located between proximal end 64 of sampling catheter 62 and sampling stopcock 66 . pressure stopcock 59 is capable of selectively placing proximal end 64 of sampling catheter 62 in communication alternately with air passageway pressure monitor 50 or with sampling stopcock 66 . in the latter condition , it is impossible to infuse and aspirate fluid from reservoir 46 through sampling catheter 62 . when the process of infusion and aspiration is not ongoing , the placement of air passageway pressure monitor 50 in communication with the lumen of sampling catheter 62 by the appropriate manipulation of pressure stopcock 59 enables a medical practitioner to evaluate the air pressure patterns in air passageways of patient 10 distal of the tip of distal end 70 of sampling catheter 62 . the structures are used to effect and verify correct wedging of the tip of distal end 70 of sampling catheter 62 in a bronchiole of patient 10 . bronchoalveolar lavaqe catheter 60 is provided with means for directing distal end 70 of sampling catheter 62 into a preselected lung of patient 10 , while also protecting the outside of sampling catheter 62 from contamination during the advancement of distal end 70 of sampling catheter 62 through the upper respiratory system of patient 10 . as shown by way of example , and not limitation , bronchoalveolar lavage catheter 60 comprises an elongated outer catheter or insertion sheath 72 so sized and configured as to encircle sampling catheter 62 and to be capable of extending from a location below the point 20 at the first bifurcation of trachea 16 through the upper respiratory system of patient 10 . the structure of insertion sheath 72 and interaction thereof with sampling catheter 62 during the process of conducting bronchoalveolar lavage with bronchoalveolar lavage catheter 60 will be more clearly appreciated by reference first to fig2 . there sampling catheter 62 is disposed within insertion sheath 72 with the tip 74 at distal end 70 of sampling catheter 62 at distal end 76 of insertion sheath 72 . the ability of bronchoalveolar lavage catheter 60 to effect bronchoalveolar lavage in a preselected lung of patient 10 is dependent both upon the structure of distal end 76 of insertion sheath 72 and upon the composition of which insertion sheath 72 is formed . as seen in fig2 distal end 76 of insertion sheath 72 is displaced at a predetermined bend angle b to the longitudinal axis of insertion sheath 72 . a direction indicator 78 at proximal end 80 of insertion sheath 72 projects from insertion sheath 72 in the same radial direction as the radial direction at which distal end 76 of insertion sheath 72 departs from the longitudinal axis thereof . insertion sheath 72 is comprised of a relatively rigid material , such as ethyl vinyl acetate . in this manner , insertion sheath 72 will be design possess sufficient structural rigidity as to be capable , when disposed in the warm , upper respiratory system of patient 10 , of exhibiting at distal end 76 one - to - one rotation about the longitudinal axis of insertion sheath 72 relative to proximal end 80 thereof . when insertion sheath 72 is disposed in the upper respiratory system of patient 10 as shown in fig1 the rotation of proximal end 80 of insertion sheath 72 about the longitudinal axis thereof will result in a corresponding identical rotation of distal end 76 of insertion sheath 72 about the longitudinal axis thereof . direction indicator 78 will at all times be oriented in the radial direction at which distal end 76 departs from the longitudinal axis of insertion sheath 72 . by utilizing this feature of bronchoalveolar lavage catheter 60 , sampling catheter 62 can be advanced for the purpose of conducting bronchoalveolar lavage into a preselected one of the lungs 22 , 26 of patient 10 . a position indicator mark 82 is provided on sampling catheter 62 at the location thereupon which is disposed at proximal end 80 of insertion sheath 72 when tip 74 of sampling catheter 62 is located at distal end 76 of insertion sheath 72 . as will be discussed in further detail , in this relative position of sampling catheter 62 and insertion sheath 72 , tip 74 sealingly engages distal end 76 of insertion sheath 72 . as becomes clear by reference to fig3 however , insertion sheath 72 and sampling catheter 62 are relatively sized so that sampling catheter 62 can slide freely within insertion sheath 72 . thus , sampling catheter 62 can be advanced within insertion sheath 72 , so that tip 74 moves a distance d 1 away from distal end 76 of insertion sheath 72 revealing distal end 84 of sampling catheter 62 . correspondingly , position indicator mark 82 is advanced into proximal end 80 of insertion sheath 72 by distance d 2 equal to the distance d 1 . in use , once insertion sheath 72 is disposed in the upper respiratory tract of patient 10 , and insertion sheath 72 is rotated about the axis thereof to orient direction indicator 78 toward a preselected one of lungs 22 , 26 , sampling catheter 62 is advanced within insertion sheath 72 in the manner illustrated in fig3 . doing so necessarily results in distal end 84 of sampling catheter 62 advancing into the preselected one of lungs 22 , 26 . thus , the initial direction in which distal end 84 of sampling catheter 62 advances from insertion sheath 72 is determined by the orientation of the bend at distal end 76 of insertion sheath 72 . thereafter , distal end 84 of sampling catheter 62 advances into the preselected one of lungs 22 , 24 on the basis of its own structure , which desirably is more pliable than that of insertion sheath 72 . according to another aspect of the present system , sampling catheter 62 comprises a first closure means located at distal end 70 thereof for sealing distal end 76 of insertion sheath 72 when insertion sheath 72 is disposed encircling sampling catheter 62 with distal end 70 of sampling catheter 62 at distal end 76 of insertion sheath 72 . this is the relative positioning of sampling catheter 62 and insertion sheath 72 shown in fig2 with position indicator mark 82 being located just at the terminus of proximal end 80 of insertion sheath 72 . tip 74 comprises a radially symmetrical insert secured in distal end 70 of sampling catheter 62 . when insertion sheath 72 and sampling catheter 62 are in the relative positions illustrated in fig2 insertion sheath 72 with sampling catheter 62 disposed therein can be advanced through the upper respiratory system of patient 10 while protecting the outer surface of sampling catheter 62 from contamination by micro - organisms residing within the upper respiratory system . only after distal end 76 of insertion sheath 72 has been rotated so as to be directed into the preselected one of lungs 22 , 24 and has then thereafter been advanced beyond the point 20 at which trachea 16 initially branches , is sampling catheter 62 advanced out of insertion sheath 72 , exposing the outer surface of sampling catheter 62 to ambient contaminations . nevertheless , at this point in the respiratory system of patient 10 the chances that micro - organisms inhabiting the upper respiratory system will attach to the outer surface of sampling catheter 62 are substantially reduced , contributing to more accuracy in the samples recovered through sampling catheter 62 . during the advancement of sampling catheter 62 out of insertion sheath 72 and into the preselected one of lungs 22 , 24 , the size of the air passage through which tip 74 is advanced gradually decreases until the lead surface of tip 74 wedges within the walls of a single bronchiole . the shape of tip 74 assists in the process of initial wedging by continuing to deflect tip 74 away from the walls of the air passageway into which sampling catheter 62 is being advanced , until such time as the walls of that air passageway uniformly surround and close upon the outer circumference of tip 74 . thereafter , the mushroom - shaped cross - section of tip 74 prevents the inadvertent withdrawal of tip 74 from its wedged position . tissue from the wall of the air passageway in which tip 74 is wedged presses against the full outer circumference of tip 74 . this tissue tends to hold tip 74 in a wedging position in a desirable manner . nevertheless , the smooth shape of tip 74 has the effect of minimizing trauma as wedging is actually effected . thereafter , the infusion and aspiration be safely and reliably undertaken . the steps for utilizing bronchoalveolar lavage catheter 60 will be discussed first with reference to fig4 . insertion sheath 72 with sampling catheter 62 disposed therein in the manner shown in fig2 is introduced into endotracheal tube 12 through an appropriate coupling , such as elbow coupling 42 and bronchoalveolar lavage catheter access port 44 . the assembly of insertion sheath 74 with sampling catheter 62 therein is then advanced through the upper respiratory system of patient 10 to distal end 18 of endotracheal tube 12 . thereafter , the assembly of insertion sheath 72 and sampling catheter 62 therewithin is advanced out of distal end 18 of endotracheal tube 12 into trachea 16 of the upper respiratory system of patient 10 . the advancement of the assembly is terminated above a point 20 at the first bifurcation of trachea 16 . as thus shown , the bend at distal end 76 of insertion sheath 72 is oriented toward left mainstem bronchus 28 leading into left lung 26 ( not shown ). when sampling catheter 62 is advanced out of distal end 76 of insertion sheath 72 with insertion sheath 72 disposed in the orientation illustrated in fig4 then tip 74 of sampling catheter 62 advances into left mainstem bronchus 28 and ultimately into left lung 26 ( not shown ) of patient 10 . nevertheless , due to the structure of insertion sheath 72 in particular , it is possible in the alternative , and with a high degree of reliability , to orient tip 74 of sampling catheter 62 into right mainstem bronchus 24 , thereby to cause tip 74 ultimately to wedge into a bronchiole in right lung 22 ( not shown ) of patient 10 . to accomplish this end , it is only necessary to rotate proximal end 80 ( fig2 and 3 ) of insertion sheath 74 outside the body of patient 10 . because of the relative structural rigidity imparted to insertion sheath 72 by the material of which it is comprised , rotation of proximal end 80 thereof results in a one - to - one rotation of distal end 76 as , for example , illustrated by arrow r . rotation of insertion sheath 72 about the longitudinal axis thereof in the manner illustrated by arrow r in fig4 will eventually bring the bend at distal end 76 of insertion sheath 72 into the position shown in fig4 in dashed lines , oriented toward right mainstem bronchus 24 . the advancement of sampling catheter 62 ( not shown ) out of distal end 76 of insertion sheath 72 would then advance tip 74 of sampling catheter 62 into right mainstem bronchus 24 . nevertheless , proceeding from the orientation of distal end 76 of insertion sheath 72 shown in fig4 in solid lines , in order to insure that tip 74 of sampling catheter 62 ( not shown ) enters left lung 26 , it is advisable to further advance the assembly of insertion sheath 72 and sampling catheter 62 into the body of patient 10 . in this manner distal end 76 of insertion sheath 72 actually enters left mainstem bronchus 28 before sampling catheter 62 is advanced from distal end 76 thereof . until this point , tip 74 has effected a sealing engagement with distal end 76 of insertion sheath 72 , whereby the outer surface of sampling catheter 62 has been protected from contamination of the type typically located in the upper respiratory system of a patient . nevertheless , during the advancement process the outer surface of tip 74 of sampling catheter 62 may have become contaminated and aperture 85 communicating therethrough into the lumen ( not shown ) in sampling catheter 62 may have become blocked by a mucus plug . accordingly , after full advancement of insertion sheath 72 into the body of patient 10 , distal end 84 of sampling catheter 62 is advanced a short distance out of distal end 76 of insertion sheath 72 in the manner shown in fig5 and a small quantity of sampling fluid 86 from reservoir 46 ( fig1 ) is used to flush any mucus plug from aperture 85 in tip 74 . in accordance with the inventive method for effecting and verifying correct wedging of tip 74 into a bronchiole 88 of patient 10 , gas pressure monitor 50 is placed in communication through aperture 85 in tip 74 with the air passageways of patient 10 distal of distal end 84 of sampling catheter 62 . this is accomplished , by first moving sampling stopcock 66 ( fig1 ) into a position blocking fluid flow from reservoir 46 . pressure stopcock 59 is then rotated to place the lumen in sampling catheter 62 in communication with gas pressure tubing 58 . in this manner the pressure transducer in gas pressure monitor 50 is coupled to the proximal end of bronchoalveolar lavage catheter 60 . pressure waveforms are generated from the pressure transducer that reflect changes in the air pressure in the body of the patient at the distal end of bronchoalveolar lavage catheter 60 . the result is a baseline pressure waveform which can be used as a point of comparison with pressure waveforms subsequently acquired at distal end 84 of sampling catheter 62 as tip 74 interacts with the walls of bronchiole 88 of patient 10 . as a result of this comparison , the nature of the interaction occurring can be verified with specificity . a typical baseline pressure waveform 132 is shown in fig6 derived from an experimental study conducted using a sheep . the sheep was infected with pneumonia , and bronchoalveolar lavage was conducted thereon through a tracheostomy tube . other pressure waveforms appearing in the present disclosure resulted from the same study . in fig6 and the other graphs included in the present disclosure , the vertical axis represents the air pressure distal of tip 74 of sampling catheter 62 inside the lung . the air pressure scale ranges from zero ( 0 ) to forty ( 40 ) millimeters of mercury . the horizontal axis represents time , so that the waveform illustrated is a real - time depiction of the air pressure variations being observed . the speed of the trace producing base line pressure waveform 132 was adjustable by the operator to accentuate characteristics anticipated to be indicative of distinct wedging - related conditions of interest to the operator . baseline pressure waveform 132 comprises a succession of waves in the form of a repeating sequence of high pressure peaks with intervening low , but positive , pressure troughs . each wave has a high pressure peak 134 at a pressure p 1 and an intervening low pressure trough 136 at a positive pressure p 2 . as shown in fig6 pressure p 1 is in the range of from about twenty - two ( 22 ) to about twenty - eight ( 28 ) millimeters mercury , and more particularly in the range of from about twenty - five ( 25 ) to about twenty - seven ( 27 ) millimeters of mercury . on the other hand , low pressure troughs 136 occur at a pressure p 2 in the range of from about one ( 1 ) to about seven ( 7 ) millimeters of mercury , or more particularly in the range from about two ( 2 ) to about four ( 4 ) millimeters of mercury . baseline pressure waveform 132 exhibits characteristic rapid upstrokes 137 , terminating in rounded peaks 134 and relative steep , but flattening down strokes 138 , terminating in almost flat low pressure troughs 136 . pressure waveforms , such as baseline pressure waveform 132 , are produced in a subject regardless of whether that subject is breathing naturally or is under mechanical ventilation . naturally , in the latter circumstances , the features of baseline pressure waveform 132 should conform substantially to the established ventilating parameters set for the subject involved . it should be understood that baseline pressure waveform 132 is only typical of the type of the baseline pressure waveform that might be derived by monitoring the air pressure in the air passageways of a patient . thus , baseline pressure waveform 132 is not definitive , but should be viewed as illustrative only . in addition , baseline pressure waveforms will vary among individuals . thus a given baseline pressure waveform can only be used for purposes of comparison with subsequently acquired pressure waveforms for the same patient . baseline pressure waveforms should be obtained after flushing aperture 85 with sampling fluid 86 , as shown in fig5 to ensure unobstructed communication between the pressure transducer in of gas pressure monitor 50 and the air passageways of a patient distal of bronchoalveolar lavage catheter tip 74 . once a baseline pressure waveform is obtained , inner sampling catheter 62 is advanced into patient 10 as the operator observes gas pressure monitor 50 . this causes sampling catheter 62 to be advanced further out of insertion sheath 72 and into a bronchiole 88 of patient 10 , until tip 74 of sampling catheter 62 encounters resistance to forward movement by interacting with the walls of bronchiole 88 . such interactions , however , do no alone indicate that correct wedging has occurred . instead , conditions of overwedging or ineffectual and precluded wedge may have been developed . accordingly , as will be discussed below , wedging should be verified through the use of gas pressure monitor 50 prior to the infusion of sampling solution . it is also frequently the case that the medical personnel operating bronchoalveolar lavage catheter 60 conclude without encountering tangible resistance to forward movement of bronchoalveolar lavage catheter 60 that wedging has occurred . under such circumstances , according to the teachings of the present invention , correct wedging should also be verified through the use of gas monitor 50 . once correct wedging has been verified , however , longitudinal movement of sampling catheter 62 is preferably restrained , for example , by the restraining means of bronchoalveolar lavage catheter access port 44 ( fig1 ). thereafter sampling fluid from reservoir 46 is infused and withdrawn using sampling stopcock 66 in combination with syringe 48 . baseline pressure waveform 132 is contrasted with subsequently acquired pressure waveforms to determine whether these acquired pressure waveforms exhibit characteristics corresponding to distinct wedging - related conditions of interest to medical personnel . these distinct wedging conditions include , not only conditions of correct wedging , but conditions of ineffective and precluded wedging in which infusion of sampling fluid would be inappropriate . thus as bronchoalveolar lavage catheter 60 is advanced , inner sampling catheter 62 may encounter physical resistance without causing any concomitant change in pressure waveform being exhibited on air pressure monitor 50 . correct wedging would not exist under such conditions . a second distinct wedging - related condition of interest occurs when the circumference of tip 74 of sampling catheter 62 makes full circumferential contact with the walls of a bronchiole 88 , creating a correct wedging condition . the third distinct wedging - related condition of interest in that of overwedging , wherein the circumference of distal tip 74 of inner sampling catheter 62 may contact with walls of a bronchiole 88 , such that aperture 85 in tip 74 is in close proximity to a wall of bronchiole 88 . in these conditions , normal respiration may result in drawing tissue of the walls of bronchiole 88 into aperture 85 blocking further aspiration . in this overwedged condition sampling fluid 86 may be infused into bronchiole 88 , but will predictably be prevented from removal when the walls of the bronchiole 88 are drawn over aperture 85 by the suction required for aspiration . it is also possible to produce an overwedged condition when tissue from the walls of a bronchiole 88 directly enter aperture 85 due to the orientation of tip 74 as it engages those walls . as indicated in fig7 a , distal end 84 of sampling catheter 62 is advanced out of insertion sheath 72 and along the air passages of patient 10 until tip 74 meets resistance to its advancement . in fig7 a and in the detail associated therewith in fig7 b , correct wedging of tip 74 in a bronchiole 88a is illustrated . there , the tissue of walls 139 of bronchiole 88a achieve secure contact about the full outer circumference 140 of tip 74 . this contact seals the alveolar chamber distal of tip 74 into a closed space allowing sampling fluid 86 to be infused and aspirated into a controlled portion of the lung . the creation of a closed system in this manner , tends to contain sampling fluid 86 in the alveolar chamber distal of tip 74 and enables efficient aspiration . conditions of correct wedging also reduce the likelihood that infused sampling fluid will escape from the air passageways distal of tip 74 , entering other portions of the lung from which the fluid cannot be removed . another manner of effecting correct wedging will be disclosed subsequently in relation to a second embodiment of fig8 a is a graph of a desired pressure waveform 142 obtained under conditions of correct wedging , such as those illustrated in fig7 b . nevertheless , desired pressure waveform 142 is only typical of the type of desired pressure waveforms obtainable by monitoring the air pressure variations in the air passageways of a patient under conditions of correct wedging . accordingly , desired pressure waveform 142 does not define the nature of all desired pressure waveform and should properly be viewed as illustrative only . desired pressure waveform 142 exhibits in a general sense the characteristics of a damped version of baseline waveform 132 . thus , desired pressure waveform 142 is a series of waves comprising a sequence of alternating high pressure peaks 144 at a pressure p 3 alternating with low , but positive , pressure troughs 146 at a pressure p 4 . pressure p 3 as shown in fig8 a is in the range of from about thirty ( 30 ) to about thirty - eight ( 38 ) millimeters of mercury , and more specifically , in the range from about thirty - one ( 31 ) to about thirty - four ( 34 ) millimeters of mercury . pressure p 4 is in the range of from about two ( 2 ) to about eight ( 8 ) millimeters of mercury , and more particularly , in the range from about four ( 4 ) to about six ( 6 ) millimeters of mercury . desired pressure waveform 142 exhibits a more steeply sloped upstroke 147 than does baseline pressure waveform 132 of fig6 . upstrokes 147 culminate at a higher pressure and in more pointed high pressure peaks 144 than the corresponding feature of baseline pressure waveforms 132 . downstroke 148 inclines downwardly following high pressure peak 144 in a less precipitous manner than does downstroke 138 of baseline pressure waveform 132 . compensatingly , however , downstroke 148 never assumes the flatness exhibited in the latter portion of downstroke 138 . low pressure trough 146 , while at a somewhat elevated pressure from that of low pressure trough 136 in baseline pressure waveform 132 , is more pointed than the corresponding feature of baseline pressure waveform 132 . fig8 a is a graph of a second desired pressure waveform 152 obtained under conditions of correct wedging , such as those illustrated in fig7 b . nevertheless , desired pressure waveform 152 is but one example of the type of desired pressure waveform obtainable by monitoring the air pressure variations in the air passageways of a patient under conditions of correct wedging . accordingly , the features of desired pressure waveform 152 are offered by way of example in the present disclosure , and not limitation . desired pressure waveform 152 also exhibits the characteristics of a damped version of baseline waveform 132 . thus , desired pressure waveform 156 is a series of waves comprising alternating high pressure peaks 154 and low pressure troughs 156 at pressures p 5 and p 6 , respectively . pressure p 5 is in the range from about twenty - eight ( 28 ) to about thirty - two ( 32 ) millimeters of mercury , or preferably the range from about twenty - nine ( 29 ) to about thirty - one ( 31 ) millimeters of mercury . pressure p 6 l is in the range from about eight ( 8 ) to about twelve ( 12 ) millimeters mercury , or more preferably , in the range from about nine ( 9 ) to about eleven ( 11 ) millimeters mercury . while desired waveform 152 maintains the periodicity apparent in baseline pressure waveform 132 in fig6 characteristic deviations therefrom indicative of correct wedging are also apparent . the first is the generally elevated pressures p 5 and p 6 relative to pressures p 1 and p 2 , respectively , of baseline pressure waveform 132 . in addition , desired pressure waveform 152 exhibits an upstroke 157 that is steeper than the corresponding feature of baseline pressure waveform 132 . upstrokes 157 terminate in a relatively sharper high pressure peak 154 than high pressure peak 134 of baseline waveform 132 . downstroke 158 is shorter in the vertical direction than the corresponding feature of baseline pressure waveform 132 , resulting in a flatter low pressure trough 156 than low pressure trough 136 thereof . by contrast to the correct wedging illustrated in fig7 b , fig9 a and 9b illustrate conditions under which tip 74 of sampling catheter 62 has been unable to effect correct wedging in a bronchiole 88a of left lung 26 of patient 10 . fig9 a illustrates conditions typical of ineffective wedging . while some portions of outer circumference 140 of tip 74 are engaged by the walls 139 of bronchiole 88a , a gap g remains at some points along outer circumference 140 , so that the air passageways distal of tip 74 are not sealed off from the rest of the air passageways in lung 26 . accordingly , sampling fluid 86 infused through aperture 85 can escape through gap g into other portions of the lung 26 than the air passageways distal of tip 74 . in addition , when aspiration is attempted , the existence of gap g prevents the establishment of the suction required to withdraw the infused sampling fluid 86 in air passageways distal of tip 74 . conditions such as those in fig9 a arise in part due to irregular shaping or branching of bronchiole 88a , or the development therein of so substantial an amount of mucous as to give the operator a sense of physical resistance to advancement of tip 74 when conditions of correct wedging have not been effected . for whatever reason , the infusion of sampling fluid 86 under the conditions illustrated may produce health hazards to patient 10 and provide an inadequate sample volume . fig9 b illustrates conditions typical of precluded wedging . physical resistance may be encountered to advancement of tip 74 , while still failing to result in conditions of correct wedging . as seen in fig9 b , the advancement of sampling catheter 62 into bronchiole 88a has brought tip 74 into proximity of the branching of bronchiole 88a into sub - bronchioles 90a and 90b . instead of entering one of sub - bronchioles 90a or 90b , tip 74 has become lodged against the tissue 92 disposed therebetween . resistance to the advancement of sampling catheter 62 will be felt by the operator , but as seen in fig9 b , the full circumference 194 of tip 74 is not engaged by the walls 139 of bronchiole 88a . neither is aperture 85 in tip 74 blocked by tissue 92 . accordingly , sampling fluid 86 infused through aperture 85 will pass into sub - bronchiole 90b , but because of the gap g between a portion of outer circumference 140 of tip 74 and walls 139 of bronchiole 88a , sampling fluid 86 can escape from the air passageways distal of tip 74 . in addition , when aspiration is attempted , the existence of gap g prevents the development of sufficient suction for removing sampling fluid 86 from sub - bronchiole 90b . the conditions illustrated in fig9 a of ineffective wedging or in fig9 b of precluded wedging do not isolate the air passageways distal of tip 74 from the rest of the air passageways in the lung of the patient . air pressure changes in the air passageways distal of tip 74 correspond to air pressure changes resulting from the ventilation of patient 10 , whether that ventilation is undertaken with or without mechanical assistance . the air pressure waveforms resulting under conditions such as those illustrated in fig9 a and 9b are thus substantially similar to baseline pressure waveform 132 of fig6 . through the use of air pressure monitor 50 , an operator is provided with information indicating that no infusion of sampling fluid 86 should be undertaken , as no correct wedging has been effected . this determination can be made by the operator through a visual inspection of the air pressure waveforms generated . if a comparison of these pressure waveforms with baseline pressure waveform 132 is undertaken on an automated basis , other means , such as the illumination of one of indicator lights 55 ( fig1 ), or the production of an audible tone 56 , can be used to signal the operator that correct wedging has not been effected . fig1 a and 10b illustrate circumstances which can give rise to overwedging of tip 76 in a bronchiole 88a of patient 10 . fig1 a illustrates an overwedged condition which occurs when distal tip 74 of sampling catheter 62 lodges in a bronchiole 88a at such an angle that aperture 85 thereof is not centrally located within bronchiole 88a . rather , aperture 85 is proximate to one wall 139a of bronchiole 88a . being relatively free of structural rigidity , wall 139a of bronchiole 88a can be drawn toward and into aperture 85 by normal respiration of patient 10 . under such conditions , it is predictable that any subsequent aspiration of any infused sampling fluid 86 cannot be effected . such a situation is illustrated in fig1 a in dashed lines . under such conditions , sampling fluid 85 can be infused into the air passageways distal of tip 76 , but because of the relatively flexible structure of the air passageways at the level of branching illustrated , it is highly likely that suction applied through sampling catheter 62 to those air passageways will distort the wall 139a of bronchiole 88a from the position shown in solid to the position shown in dashed lines . then , the tissue of wall 139a will block aperture 85 , precluding further aspiration of sampling fluid 85 from the air passageways distal of tip 76 . this can result in health hazards to patient 10 and provide an inadequate sample volume . one advantage of the present invention is the capacity to detect such an overwedged condition prior to infusing irretrievable sampling fluid 85 . fig1 b illustrates another circumstance in which overwedging of tip 76 can occur . as shown , tip 74 of sampling catheter 62 has advanced into proximity with the branching of bronchiole 88a into sub - bronchioles 90a and 90b . tip 74 has been driven head - on into the tissue 92 between sub - bronchioles 90a and 90b , so that tissue 92 blocks aperture 85 ( not shown ) in tip 74 . under such circumstances , whether or not outer circumference 140 of tip 74 engages walls 139 of bronchiole 88a , sampling fluid 85 can be infused into the air passageways distal of tip 74 . nevertheless , the interposition of tissue 92 into aperture 85 precludes the aspiration of any such infused sampling fluid 85 . fortunately , according to the teachings of the present invention , an overwedged condition , such as that illustrated in fig1 a or 10b , can be detected through the use of gas pressure monitor 150 , before the infusion of any sampling fluid 85 . accordingly , although resistance would be experienced by , an operator to the further advancement of sampling catheter 62 into left lung 26 of patient 10 , the operator could from the pressure waveforms generated determine that tip 74 should be withdrawn slightly with sampling catheter 62 in order to again attempt a correct wedge therewith . the nature of the pressure waveforms generated in overwedged conditions will be explored in relation to the graphs depicted in fig1 a through 11c . when such overwedged pressure waveforms are detected by medical personnel , inner sampling catheter 62 can be slightly retracted , rotated , and then readvanced in order to renew the effort to effect correct wedging . fig1 a is a graph of an overwedged pressure waveform 162 obtained under conditions of overwedging , such as are illustrated in fig1 a and 10b . nevertheless , overwedged pressure waveform 162 is only illustrative of the type of waveform obtained when air pressure variations in the air passageways of a patient are monitored under conditions of overwedging . accordingly , the features of overwedged pressure waveform 162 can properly be viewed only as exemplary , rather than as limitative . overwedged pressure waveform 162 exhibits in a general sense the characteristics of an overly - damped version of baseline waveform 132 shown in fig6 . thus , overwedged pressure waveform 162 is a series of waves comprising a succession of alternating high pressure peaks 164 at a pressure p 7 and low , but positive , pressure troughs 166 at a pressure p 8 . pressure p 7 as shown in fig1 a is in the range of from about twenty - three ( 23 ) to about twenty - eight ( 28 ) millimeters of mercury , or more specifically , in the range from about twenty - four ( 24 ) to about twenty - six ( 26 ) millimeters of mercury . pressure p 8 is in the range of from about twenty ( 20 ) to about twenty - four ( 24 ) millimeters mercury , or more particularly in the range of from about twenty - two ( 22 ) to about twenty - three ( 23 ) millimeters of mercury . overwedged pressure waveform 162 exhibits severe and abrupt flattening in the area of low pressure troughs 166 , which is characteristic of over - damped pressure waveform corresponding to an overwedged condition . the relatively minor pressure differences between pressure p 7 of high pressure peaks 164 and pressure p 8 of low pressure troughs 166 is further indicative of a condition in which virtually no pressure variation is observable between inhalation and exhalation in the air passageways distal of tip 74 . at most , overwedged pressure waveform 162 resembles base line pressure waveform 132 of fig6 only in the periodicity of high pressure peaks 164 . otherwise , the qualities of upstrokes 167 and downstrokes 168 of overwedged pressure waveform 162 are hardly characterizable , given the shortness of the lengths thereof . overwedged pressure waveform 162 is dominated by the flattening of downstroke 168 into lengthy troughs 166 corresponding to low pressures p 8 substantially elevated relative to low pressure p 2 of base line pressure waveform 132 under some circumstances of severe overwedging , the pressure waveform resulting may flatten entirely , so that no periodicity whatsoever is detectable . overwedged waveform 162 might be expected in conditions of overwedging such as those illustrated in fig1 b , where tissue blocks aperture 85 ( not shown ) at all times , rather than intermittently , as shown in fig1 a . illustrated in fig1 b is a second overwedged pressure waveform 172 reflecting overwedged conditions , such as those illustrated in fig1 a or 10b . it should be born in mind that overwedged pressure waveform 172 is only typical of the type of waveform produced when air pressure variations in the air passageways of a patient are monitored under conditions of overwedging . the features of overwedged pressure waveform 172 are accordingly disclosed herein for the purpose of example , rather than limitation . overwedged pressure waveform 172 is a less severely overdamped version of base line pressure waveform 132 than is overwedged pressure waveform 162 of fig1 a . overwedged pressure waveform 172 is a series of waves comprising a succession of alternating high pressure peaks 174 at a pressure p 9 and low , but positive , pressure , troughs 176 at a pressure p 10 . as seen in fig1 b , pressure p 9 is in the range of from about twenty - four ( 24 ) to about thirty ( 30 ) millimeters of mercury , or more preferably , in the range from about twenty - five ( 25 ) to about twenty - eight ( 28 ) millimeters of mercury . overwedged pressure waveform 172 exhibits irregular upstrokes 177 terminating in rounded high pressure peaks 174 . long gradually sloping downstrokes 178 lead to round , almost flat low pressure troughs 176 . minor pressure differential exist between pressure p 9 of high pressure peaks 174 and pressure p 10 of low pressure troughs 176 thus tends to suggest that , for at least a portion of each cycle of inhalation and exhalation , aperture 85 is totally or partially blocked by some structure , such as the tissue of a wall of a bronchiole . illustrated in fig1 c is a third overwedged pressure waveform 182 reflecting conditions such as those illustrated in fig1 a or 10b . overwedged pressure waveform 182 is , however , only exemplary of the type of waveform that is produced when the air pressure variations in air passageways of a patient are monitored in conditions of overwedging . the features of overwedged pressure waveform 182 are , accordingly , offered herein for the purpose of example , rather than limitation . over - damping intermediate that of overwedged pressure waveform 162 of fig1 a and overwedged pressure waveform 172 of fig1 b . overwedged pressure waveform 182 comprises a series of waves taking the form of a succession of alternating high pressure peaks 184 at a pressure p 11 and low , but positive , pressure troughs 186 having a pressure p 12 . as seen in fig1 c , pressure p 11 is in the range of from about nineteen ( 19 ) to about twenty - five ( 25 ) millimeters of mercury , or more specifically , from about twenty - one ( 21 ) to about twenty - three ( 23 ) millimeters of mercury . pressure p 12 is in the range of from about fifteen ( 15 ) to about twenty ( 20 ) millimeters of mercury , or more particularly in the range from about seventeen ( 17 ) to about nineteen ( 19 ) millimeters of mercury . overwedged pressure waveform 182 exhibits rolling high pressure peaks 184 and low pressure troughs 186 , both well rounded and interconnected by relatively linear upstrokes 187 and downstrokes 188 . nevertheless , in an overall sense , when compared to baseline pressure waveform 132 of fig6 overwedged pressure waveform 182 is severely flat in terms of the extremes of its high and low pressures , p 11 and p 12 , respectively . this type of narrowing of the range of value found in a pressure waveform is taken to be indicative of an overwedged condition . in some instances , it may be desirable to conduct bronchoalveolar lavage of a larger portion of a preselected lung of patient 10 than would be possible in the air passageways distal of the point at which tip 74 can effect a condition of correct wedging on a bronchiole . toward this end , modifications can be made at distal end 84 of sampling catheter 62 which will permit the effecting of conditions of correct wedging in bronchioles of patient 10 having a diameter larger than the diameter of tip 74 . accordingly , as seen in fig1 a , distal end 84 of sampling catheter 62 is shown disposed in a larger bronciole 100 of patient 10 . in order to effect correct wedging in larger bronchiole 200 , a flexible cuff 202 is attached to and encircles the outer surface 204 of sampling catheter 62 at a point proximal of tip 74 . as more clearly understood by reference to the cross - sectional view found in fig1 b , sampling catheter 62 comprises a first lumen 206 so sized as to permit the infusion and aspiration of sampling fluid from reservoir 46 . in addition , however , sampling catheter 62 comprises a second lumen 208 having a size relatively smaller than that of first lumen 206 and being capable of transmitting a gas from proximal end 64 of sampling catheter 62 to distal end 84 thereof . tip 74 of sampling catheter 62 is secured in the end of first lumen 106 in such a manner that the proximal surface 210 of tip 74 closes distal end 212 of second lumen 208 . flexible cuff 202 is a generally cylindrical structure which is secured at each periphery 214 thereof to outer surface 204 of sampling catheter 62 , thereby defining between flexible cuff 202 and outer surface 204 an annular inflation space 216 . an inflation aperture 218 communicates between second lumen 208 and inflation space 216 . flexible cuff 202 is thus inflated utilizing pressurized air from second lumen 108 . as illustrated in fig1 , the inflation of flexible cuff 202 brings it into engagement with the walls 220 of larger bronchiole 200 of patient 10 , making a full circumferential seal therewith . larger bronciole 200 has a diameter greater than that of the bronchiole in which tip 74 of sampling catheter 62 could otherwise become lodged directly , as in fig7 b . in this manner , the air passageways of patient 100 distal of flexible cuff 202 and of tip 74 are isolated from the balance of the air passageways in left lung 26 . accordingly , the inflation of flexible cuff 202 has resulted in conditions of correct wedging , and sampling fluid 86 infused through aperture 85 can reliably be aspirated . air pressure monitor 50 ( fig1 ) would , accordingly , exhibit an air pressure waveform such as a desired pressure waveform 152 in fig8 b indicative of correct wedging . a larger section of a preselected one of lungs of patient 10 can be subjected to bronchoalveolar lavage sampling . naturally , as with the earlier described embodiment of sampling catheter 62 which lacked any structure , such as flexible cuff 202 , conditions of ineffective wedging , precluded wedging , and over - wedging can result in the manners as illustrated in fig9 a , 9b , 10a , and 10b . in addition , however , certain specific conditions can develop with a sampling catheter provided with a flexible cuff , such as flexible cuff 202 . as shown in fig1 , for example , the under - inflation of flexible cuff 202 in larger bronchiole 200 may not result in a complete circumferential seal between walls 220 of larger bronchiole 200 and the outer most circumference of inflated flexible cuff 202 . accordingly , a gap g is shown between a portion of the outer circumference of flexible cuff 202 and the wall 220 of larger bronchiole 200 . through gap g sampling fluid 86 can escape from the air passageways distal of the flexible cuff 202 . in addition , gap g precludes the application through aperture 85 of suction by which to recover infused sampling fluid 86 . under conditions illustrated in fig1 , a pressure waveform , such as baseline pressure waveform 132 of fig6 would be observed , and an operator would be well advised to refrain from undertaking any infusion whatsoever . instead , sampling catheter 62 could be advanced further into the air passageways of patient 10 or flexible cuff 202 could be additionally inflated . continued inflation of flexible cuff 202 beyond that required to effect a full circumferential seal against the walls of a given bronchiole , can also produce difficulties . as shown in fig1 , for example , over - inflation of flexible cuff 202 can cause portions of flexible cuff 202 to expand longitudinally along sampling catheter 62 within larger bronchiole 200 . thus , a first portion 222 of flexible cuff 202 has expanded along larger bronchiole 200 in the direction proximal of tip 74 , while a second portion 224 of flexible cuff 202 has expanded longitudinally along larger bronchiole 200 to reach a position distal of tip 74 . under such conditions , an effective wedging seal has been created , and sampling fluid 86 could conceivably be infused . nevertheless , the presence of second portion 224 of flexible cuff 202 distal of tip 74 and of aperture 85 thereof is problematic . as shown in dashed lines in fig1 , the action of normal respiration by patient 10 is likely to draw the second portion of 224 of flexible cuff 202 toward and into aperture 85 , predictably blocking any aspiration of infused sampling fluid 86 . accordingly , a condition of over - wedging would exist . the relationship depicted in fig1 would be reflected , however , in a pressure waveform 53 appearing on air pressure monitor 50 similar to over - wedging pressure waveform 162 , 172 , or 182 of fig1 a , 11b , or 11c , respectively . the characteristics of and condition of over - wedging would then stimulate the operator to reduce the pressure in inflatable cuff 202 to see whether , on the basis of new air pressure waveforms , a condition of correct wedging could be effected . ultimately , it may be necessary to totally deflate flexible cuff 202 and commence inflation again in gradual stages and at a new location in the bronchioles of patient 10 . it will be appreciated that the present invention provides a method and system for conveying to an operator the conditions existing at the distal tip of a bronchoalveolar lavage catheter in a manner that improves the accuracy of diagnostic efforts without resorting to costly bronchoscopic techniques . through the use of the present invention , correct wedging must be confirmed before sampling fluid is infused , thereby alleviating the added burden on a patient of absorbing sampling fluid improperly infused into the lung thereof . the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics . the described embodiments are to be considered in all respects only as illustrative and not restrictive . the scope of the invention is , therefore , indicated by the appended claims rather than by the foregoing description . all changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope . | US-63326690-A |
an injector and method for injecting a dual optic aiol into an eye wherein the aiol is loaded into the injector in an initially loaded condition with the first and second optics in generally coaxial alignment . a lens moving element is provided and operable to move the first optic toward the proximal end of the main body whereupon the first optic becomes located proximally of the second optic . a stop may be provided to prevent the second optic from moving proximally with the first optic . displacing the optics to a non - coaxial position reduces the cross - sectional area of the aiol which allows the aiol to non - destructively compress to the size of the opening of the injector tip which may be as small as about 2 . 8 mm or less , for example . | a prior art aiol 10 is shown in fig1 and includes first and second optics 12 , 14 , respectively , interconnected by three flexible haptics 16 a , b and c . as is well known in the intraocular lens art , aiol 10 may be made of a hydrophilic or hydrophobic material which may be folded and compressed to deliver the aiol through the small tip opening of the injector as explained below . an injector 18 according to an embodiment of the invention is seen in fig2 to include main body portion 20 having a lumen 22 ( see fig4 a - c ) extending between proximal and distal ends 24 , 26 thereof , respectively . a plunger 28 is received in lumen 22 at proximal end 24 of main body portion 20 and operates in the manner of a syringe to express the aiol 10 from injector tip 30 and into an eye . referring to fig3 , an embodiment of the invention is seen to include a lens platform 32 extending from main body portion distal end 26 . lens platform 32 includes a lens mounting surface 34 adapted for placing the aiol 10 thereon in an initially loaded condition seen in fig4 a , i . e ., lens mounting surface 34 is sized to allow placement of aiol 10 thereon with first optic 12 and second optic 14 in spaced , generally coaxial alignment along an optical axis oa - oa which extends substantially perpendicular to the longitudinal axis x - x of injector 18 ( see fig4 a ). a cover 36 may be provided which is configured to close over lens platform 32 capturing aiol 10 therebetween as seen in fig4 a . cover 36 may be pivotally connected to platform 32 via hinge connections 38 , 40 ( see fig3 ). a ramp 42 is provided on lens platform 32 proximally of lens mounting surface 34 . ramp 42 includes an inclined surface which extends proximally and toward longitudinal axis x - x . in the embodiment of fig3 and 4 a - c , tip 30 is a separate component which is adapted to be connected to injector main body portion 20 . tip 30 includes a lumen 44 extending between proximal and distal ends 46 , 48 , respectively , with distal end 46 terminating in a small open tip 48 a wherethrough the aiol 10 is expressed from the injector 18 and into an eye . proximal end 46 is shaped and sized to receive and encase lens platform 32 and cover 36 when in the closed position . a lens moving element 50 is provided within tip lumen 44 in the form of a finger - like projection extending toward proximal end 46 , terminating in a free end 52 which may be tapered . as seen in fig4 a , lens moving element 50 is positioned to align with first optic 12 as platform 32 and cover 36 are located to be received in tip proximal end 46 . as seen in fig4 b , as tip 30 is advanced further toward injector body distal end 26 , lens moving element free end 52 abuts first optic 12 and begins moving first optic 12 proximally up ramp 42 . upon full advancement and attachment of tip 30 on lens platform 32 and cover 36 , first optic 12 becomes positioned at the top of ramp 42 . it will be noticed that as first optic 12 is moved proximally by lens moving element 50 , second optic 14 remains substantially stationary such that first optic 12 becomes positioned proximally of second optic 14 and thus no longer in coaxial alignment with first optic 12 , i . e ., the optical axis oa of first optic 12 becomes off - set from the optical axis oa of second optic 14 . this is considered the delivery position in which the overall height and cross - section of aiol is reduced to allow an optimum compression profile for expression from tip opening 48 a . it is noted that although first and second optics 12 , 14 are shown in fig4 c as slightly overlapping , they may instead become positioned edge to edge or even slightly longitudinally spaced from each other . to ensure second optic 14 does not move proximally as first optic 12 is moved up ramp 42 by element 50 , a stop 54 may be provided in the form of a shoulder provided on the inner surface of cover 36 opposite lens mounting surface 34 . in the initially loaded condition of aiol 10 and closing of cover 36 , stop 54 is positioned proximally of second optic 14 . as such , stop 54 forms a physical barrier against proximal advancement of second optic 14 . other configurations and locations for stop 54 are of course possible to inhibit proximal advancement of second optic 14 . once tip 30 has been fully attached to main body portion 20 as seen in fig4 c , plunger 28 may be advanced within lumen 22 whereupon the plunger tip 28 a engages and pushes against first optic 12 . since second optic 14 is positioned distally of first optic 12 , both optics are advanced together toward and then expressed from open tip 48 a . tip lumen 44 may taper toward open tip 48 a to compress aiol 10 to the size of open tip 48 a . as seen best in fig3 , ramp 42 may be provided in a bifurcated configuration with spaced ramp segments 42 a , 42 b . the spacing between ramp segments 42 a , 42 is such that first optic 12 will span and be supported by both ramp segments 42 a , 42 b as first optic 12 is moved up ramp 42 by lens moving element 50 . lens moving element free end 52 may be positioned and configured to slide and fit between ramp segments 42 a , 42 b as tip 30 is attached to lens platform 32 and cover 36 . in this way , lens moving element 50 and ramp segments 42 a , 42 b form a support surface for first optic 12 when aiol 10 is in the delivery position seen in fig4 c . upon advancing plunger 28 , aiol is moved along the surface of lens moving element 50 which in part defines tip lumen 44 . in another embodiment of the invention shown in fig5 , the lens moving element is provided on the lens platform 32 in the form of a clip 150 which may slide therealong in the proximal direction as indicated by arrow “ a ”. a projection 152 connects to and moves together with clip 150 as indicated by arrow “ b ”. the proximal end 146 of tip 130 is shaped and sized to align with clip 150 such that as tip 130 is attached to lens platform 32 , proximal end 146 moves clip 150 ( and hence also projection 152 ) toward main body portion 120 . projection 152 is operable to move first optic 12 up ramp 142 in the same manner as lens moving element 50 in the embodiment of fig3 and 4 a - c . it is noted no cover similar to cover 36 is shown in fig5 for the sake of clarity . it will be appreciated that while the invention has been shown and described in relation to two possible embodiments thereof , many changes may be made without departing from the fill spirit and scope of the invention as defined by the claims which follow . for example , the injector tip 30 may be integrally formed with the main body portion of the injector rather than a separately attached component . in this instance , the lens moving element could comprise an element which extends radially through the injector body wall into the lumen . the element may be slidable within a groove provided in the injector body wall toward the proximal end of the injector body whereupon the element engages and moves the first optic proximally of the second optic . the ramp may be provided within the main body lumen proximally of the lens loading area . as a further example , the lens may be preloaded into the lumen at manufacture so that the doctor does not need to perform this step . as yet a further example , the lens may be preloaded into a cartridge which is adapted to be received in the injector body . the cartridge may include the lens moving feature such that the lens is moved to its delivery position prior to the cartridge being attached to the injector body . these and other modifications will be apparent to those skilled in the art . | US-13700908-A |
a process for treating periodontitis existing in the mouth of a patient having teeth with roots extending downwardly in the gums by using a scaler including a scraper with a cutting edge and a handle for the scraper . a dentist uses the scraper to remove tartar , concretions and necrotic root element from a tooth by guiding the cutting edge along the tooth root under the gums from the lowest point of the gum pocket and while exerting pressure on the root suddenly moving the cutting edge with a powerful jerk in scraping manner toward the chewing face of the tooth . the scaler is adapted for manual movement by the dentist and also has a mechanism which when actuated initiates and performs the jerk action without manual movement of the scraper by the dentist . | referring now to fig1 a hollow handle is provided with a cover 2 , a rear casing 3 and a front casing 4 . a casing neck 5 is connected to the front case 4 . the rear casing 3 receives a drive means 10 . front 4 and casing neck 5 contains a striking rod 6 , striking body 7 and transmission means 8 . the transmission means 8 are differently constructed in the scalers according to fig1 to 8 , but have the function of converting the movement of drive means 10 into a movement of striking rod 6 . at its end remote from transmission means 8 , striking rod 6 carries a scraper 9 , which is used for cleaning a tooth . however , to enable said cleaning to be carried out , the scraper 9 must be moved relatively slowly away from the handle , whilst the return movement towards the handle must take place in a sudden and jerky manner . in fig1 the transmission means 8 comprises a link disk 15 and a feeler roll 17 mounted in rotary manner on striking rod 6 by means of a pin 18 . the drive means 10 is an electric drive motor provided with an electrical connection 11 passing through cover 2 and which is optionally equipped with a reduction gear . a link disk 15 is mounted in fixed manner by means of a threaded pin 13 on the drive shaft 12 of the motor or gear and from the front face 14 thereof rises a link 16 constructed as a circular rim or edge . link 16 forms a constantly sloping path on which the feeler roll 17 rolls and which at one point has a sudden transition 19 . if , viewed from scraper 9 , the link disk 15 rotates counterclockwise , the striking rod 6 is moved slowly away from the handle by feeler roll 17 and counter to the action of a working spring 20 . at the sudden transition 19 , striking rod 6 and therefore scraper 9 is moved in a sudden or jerky movement about the jump height of transition 19 in the direction of drive means 10 . this movement corresponds to the manual striking movement which the dentist has to perform with a known scaler . in the scaler described in fig1 this sudden or jerky movement is now automatically performed by the apparatus , so that the dentist is relieved of this strenuous activity . the mass of the striking rod 6 moved in sudden manner will produce a reaction on handle 1 , through which the handle is moved in the opposite direction and therefore substantially reduces the sudden return movement of scraper 9 . to overcome this disadvantage , in the front casing 4 the striking body 7 is so coupled by means of a two - arm coupling level 25 to the striking rod 6 , that striking body 7 performs a movement in the opposite direction to that of striking rod 6 . as a result , during the sudden return movement of striking rod 6 , the striking body ensures a mass equilibrium , so that during the return movement of scraper 9 , handle 1 is immovable in the operator &# 39 ; s hand . working spring 20 assists the movement of striking rod 6 and striking body 7 . an insert ring 24 , e . g . made from an elastomer or some other plastics material , damps the movement of striking body 7 at the end of the return movement of scraper 9 . the embodiments according to fig3 to 12 show scaler drives , all of which utilize a striking body 7 for mass compensation purposes . the only differences relate to the arrangement of striking rod 6 , striking body 7 and the transmission means . fig2 shows the mounting of coupling lever 25 , which is rotatably mounted on a shaft 26 with a pivot 27 and has a first arm 28 for driving striking body 7 and a second arm 29 for driving striking rod 6 . the two arms 28 , 29 extend into recesses 30 , 31 in striking body 7 or striking rod 6 . the arrangement of working spring 20 in fig1 to 5 , 7 , 10 and - 1 has the advantage that the drives of striking rod 6 or striking body 7 are kept free from play . the mass equilibrium thereof is not impaired even in the case of wear . in view of the fact that the scrape must exert forces in specific directions , it is necessary to ensure that neither striking rod 6 nor striking body 7 rotate . thus , according to fig2 rollers 32 , 33 are rotatably mounted on shaft 26 . striking body 7 is supported on rollers 32 and striking rod 6 on rollers 33 . in fig1 and 2 the two arms 28 , 29 of coupling lever 25 have unequal lengths , but they can be equally long or have a different length ratio . in fig3 to 8 the same reference numerals designate the same part as in fig1 - 2 . in the embodiment according to fig3 the scaler has the same transmission means 8 , i . e . link disk 15 , link 16 and feeler roll 17 , as in the case of the embodiment of fig1 and 2 . the difference is that feeler roll 17 is mounted in rotary manner on striking body 7 . striking body 7 is located in the interior of a sleeve - like attachment 35 of striking rod 6 . a return spring 37 is placed in the cavity 36 between the end face of striking body 7 and the base of attachment 35 . in the embodiment according to fig3 and when viewed from the scraper , link disk 15 rotates clockwise . on the constantly sloping edge of link 16 , striking body 7 moves in the direction of drive means 10 and striking rod 6 in the opposite direction via coupling lever 25 . for performing the sudden return movement of striking rod 6 , the feeler roll 17 moves suddenly from the base of the sudden transition 19 on to the link rim or edge which is higher by the height of the jump , so that the striking rod 6 is retracted in a sudden or jerky manner . the return spring 37 merely serves to hold the feeler roll 17 on link 16 . as in fig1 drive means 10 is a motor , optionally with a reduction gear , whose drive shaft 12 performs a rotary movement . the electric motor of fig1 and 3 can be replaced by a hydraulic or pneumatic motor . in the scaler embodiment according to fig4 a lifting unit is used and its drive shaft 12 performs a reciprocating movement . a striking ring 40 is secured to the drive shaft 12 . the front edge of ring 40 acts on an edge portion 42 of the striking body 7 . as in the embodiment according to fig3 striking body 7 is located in the interior of a sleeve - like attachment 35 of striking rod 6 . whenever edge 41 of striking ring 40 meets the edge portion 42 of striking body 7 , there is a movement of the latter away from drive means 10 and simultaneously a return movement of striking rod 6 . it is also possible in this way to obtain a sudden return movement of the scraper . in fig4 return spring 37 is also inserted in cavity 36 . if this spring is removed , the function of the scaler is not impaired . in this case the operator assumes responsibility for the slow movement of scraper 9 away from the tooth contact surface in the direction of the tooth root . striking rod 6 and therefore also the sleeve - like attachment 35 is moved in the direction of drive means 10 , so that by means of coupling lever 25 edge portion 42 of striking body 7 is raised from edge 41 of striking ring 40 . if handle 1 is now moved in the direction of the tooth root against the chewing face of the tooth , the scraper remains on the tooth contact surface , the striking rod 6 moves away from drive means 10 and striking body 7 towards said drive means until the edge 41 of the striking ring meets the edge portion 42 , so that the sudden return movement of scraper 9 takes place . here again , the scaler according to fig4 automatically carries out the scraper return movement , which requires a considerable effort . the return movement can also take place in the form of a sequence of small return movements and then optionally a manual return movement is superimposed thereon . the embodiment of the scaler according to fig5 is the same arrangement of the striking rod 6 , striking body 7 and coupling lever 25 as in fig3 . the feeler roll 17 is mounted in rotary manner on striking body 7 as in fig3 . in place of link disk 15 a disk cam 50 is used on fig5 and is fixed to a shaft 51 . on the entire circumference of disk cam 50 is provided a constantly changing radius with a sudden transition ( not shown ). in the same was as in fig3 said transition gives the striking body 7 a sudden movement away from drive means 10 , which brings about a corresponding sudden return movement of striking rod 6 . in the construction according to fig5 the drive means 10 is constituted by a motor performing a rotary movement , whose drive shaft 52 rotates shaft 51 and therefore the crank gear 50 by means of a bevel gear train with a pinion 53 and a bevel gear 54 . in the scaler embodiment according to fig6 the drive means 10 rotates by means of drive shaft 12 a link disk 61 , whose link 62 with the transition 63 is directed against drive means 10 . a feeler ball 64 rolls freely on link 62 and is located in freely movable manner in the free space 67 formed by link 62 and flange 65 of a screw cover 66 screwed on to the striking body 7 . the rotary movement of link disk 61 takes place counterclockwise and when feeler ball 62 drops at the sudden transition 63 a working spring 68 moves the striking body 7 away from drive means 10 , so that the striking rod 6 forms the sudden return movement with scraper 9 . in the scaler embodiment according to fig7 and 8 striking rod 6 and striking body 7 are not coupled to a coupling lever as in the previously described embodiments . in fig7 a link body 70 is mounted in fixed manner on drive shaft 12 of drive means 10 and has two link slots 71 , 72 extending over the circumference , the link slot 71 closer to drive means 10 receiving a feeler roll 73 , which is rotatably mounted on striking body 7 by means of a pin 74 . in the link slot 72 more remote from drive means 10 is guided a feeler roll 75 , which is mounted in rotary manner with a pin 76 on striking rod 6 . the shape of link slots 71 , 72 is such that at the sudden transition 77 of slot 71 striking body 7 is moved suddenly away from the drive means and striking rod 6 in an oppositely directly transition 78 of slot 72 is suddenly moved towards drive means 10 . a working spring 79 aids the sudden movements of striking body 7 and striking rod 6 . in the scaler embodiment according to fig8 a link body 80 is also fixed to the drive shaft 12 of drive means 10 and has two link slots 81 , 82 . a feeler roll 83 mounted in rotary manner on striking rod 6 is supported in slot 81 and a feeler roll 84 mounted in rotary manner on striking body 7 is supported in slot 82 . in this embodiment the sudden transitions 85 of slot 81 and 86 of slot 82 are constructed in such a way that at these points the striking rod 6 performs a sudden movement towards drive means 10 and striking body 7 a movement away from said drive means . in the embodiments according to fig7 and 8 the rotary movement of drive shaft 10 takes place clockwise , viewed from scraper 9 . in both embodiments there are also means for preventing a rotary movement of striking rod 6 and striking body 7 in the form of a shaft 27 ( cf . fig2 ), which is mounted in the front casing part 4 and carries the rotary rolls , on which are supported striking rod 6 and striking body 7 . in the embodiment according to fig8 there is no working spring as in fig7 . the sudden movements are in this case solely ensured by the sudden transitions 85 , 86 . in the embodiment according to fig9 the end of striking rod 6 and striking body 7 are successively arranged and are provided on their facing faces with inclined planes 93 , 94 . a disk cam 90 is fixed to drive shaft 12 and its diameter constantly decreases and has a sudden transition 91 used for producing the sudden return movement of striking rod 6 . a freely movable ball 92 is in operative connection with the disk cam 90 and is supported on the inclined planes 93 , 94 of striking rod 6 or striking body 7 . through the action of in each case one working spring 95 , 96 acting on striking rod 6 or striking body 7 , ball 92 is held in clearance - free manner between the circumference of disk cam 90 and inclined planes 93 , 94 of striking rod 6 or striking body 7 . if drive shaft 12 rotates , ball 92 is slowly forced outwards by disk cam 90 , so that striking rod 6 and striking body 7 are driven apart counter to the tension of springs 95 , 96 , which leads to the slow movement of striking rod 6 . at the sudden transition of disk cam 90 , as a result of the tension of springs 95 , 96 on inclined planes 93 , 94 , the ball moves suddenly on the smaller diameter of the disk cam , which leads to the sudden return movement of striking rod 6 with the scraper . a rotation of striking rod 6 is prevented by an ordinary key 97 inserted in the front casing part 4 . in the case of the partly represented scaler of fig1 , it is shown that coupling means 99 are provided between drive shaft 12 and link disk 16 , said coupling means having a clearance in the circumferential direction . to this end the link disk 16 is rotatably mounted , e . g . with an antifriction bearing 100 and has a slot 101 , into which projects a bolt 102 inserted in drive shaft 12 . the bolt diameter is smaller than the width of slot 101 . thus , on the transition of feeler roll 17 at the sudden transition 19 , it is possible to displace the link disk 16 and consequently the sudden return movement takes place even more rapidly . a further reinforcement of the striking action of striking rod 6 can be achieved by subdividing said rod into two partial rods 6 &# 39 ;, 6 &# 34 ;, which are held together with clearance by a coupling 98 . coupling means 98 comprise a pin 104 mounted in the striking rod portion 6 &# 39 ; and a slot 105 in portion 6 &# 34 ;. if at the transition of feeler roll 17 at the sudden transition 19 the return movement is initiated , then initially only rod portion 6 &# 34 ; moves and then the other rod portion 6 &# 34 ;, which carries the scraper , is suddenly moved backwards . as a result of the coupling means 98 , 99 with a clearance , it is possible to reinforce the striking action of the scraper . it is obviously also possible to use said striking reinforcing coupling means in the other embodiments . in the scaler embodiment according to fig1 to 12 the transition means 8 comprises a disk 115 driven by driven means 10 , a cam follower 116 fixed to the face 114 of said disk , an eccentric pin 113 arranged alongside the cam follower 116 with a greater eccentric spacing than that of follower 116 and a tilting lever 118 , the latter being pivotably mounted in the shaft 26 supported in the front casing part 4 . cam follower 116 and eccentric pin 113 project into a depression of tilting lever 118 , which is constructed as a slot 117 . thus , the depression is only bounded on two sides by walls on which can be supported cam follower 116 and eccentric pin 113 . these conditions are shown on a larger scale in fig1 . in the represented position , cam follower 116 essentially performs no lifting movement , whilst the eccentric pin 113 gives an additional movement to tilting lever 118 , because it lags with respect to the rotation direction of cam follower 116 , preferably by approximately 20 ° to 45 °. thus , the feeler roll 120 of tilting lever 118 located on the opposite side of shaft 26 is moved at a higher speed over the highest protuberance of a conical surface 122 shaped in the bottom of a ball 121 in striking rod 6 . as a result of this additional movement brought about by eccentric pin 113 , it is ensured that the tilting lever 118 , which moves on the conical surface 122 and forces striking rod 6 downwards against the tension of a spring 20 , is instantaneously removed from the conical surface 122 , so that the striking rod 6 is moved in the direction of drive move means 10 in a sudden or jerky manner as a result of the tension of spring 20 . fig1 shows that the coupling lever 25 is located in a recess 119 of tilting lever 118 and on whose lower end is mounted feeler roll 120 . shaft 26 extends through slits 124 , 125 in striking body 7 or striking rod 6 , so that said body and said rod are prevented from rotating in handle 1 . the use of the tilting lever 118 for producing the sudden or jerky return movement of the scaler has the advantage that the drive power is lower than when using a link disk . as a speed increase is obtained with the tilting lever 118 , the power expended by the drive means 10 is correspondingly reduced . the scaler described in the different embodiments can be easily handled by the operator . the speed or striking rate can be varied by correspondingly regulating the drive means 10 . as required , sudden return movements can be achieved on scraper 9 , it being possible to modify the travel of the return movement by using link disks 15 or disk cams 50 , 90 with a different height of the sudden transition 90 , 91 . compared with known scalers , it is possible to achieve a much higher output and this also does not fatigue the operator . it is obvious that during the movements of scraper 9 , the scaler can be moved manually over the tooth surface , only the scraping movements are being performed automatically . while the fundamental novel features of the invention have been shown and described and pointed out , it will be understood that various substitutions and changes in the form of the details of the embodiments shown may be made by those skilled in the art without departing from the concepts of the invention a limited only by the scope of the claims which follow . | US-92700886-A |
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