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referring now to the drawings in detail and in particular to fig1 , a typical trochar assembly 50 , and reference character 10 of fig2 which generally designates a safety - stop device constructed in accordance with a preferred embodiment thereof . the trochar assembly 50 has a set of blades 58 attached to a knob 62 which , after the trochar assembly 50 is used , is removable from the cannula 54 [ trochar tube ]. the cannula 54 , having a width w , is attached to a head assembly 60 with its components [ reference characters 64 , 66 , 68 ] thereon . a blade shield 56 with an shield opening 52 at its far end covers the blades 58 to facilitate safe handling of the trochar assembly 50 and to prevent accidental cuttings . typically once the trochar assembly 50 has been used to execute the surgical procedure , the surgeon grasps the knob 62 and pulls the blades 58 with blade shield 56 out from the cannula 54 . the cannula 54 remains and is in communication with the body cavity into which the trochar assembly 50 penetrated . suitable hoses [ not shown ], for example , are connected to the inlet / outlet 66 on valve 64 , and the valve lever 66 is positioned on / off [ arrows a , b ] to , for example , force air or gas into the patient as , and if , necessary to the procedure . the safety - stop device 10 has a base component 12 , an insert component 40 , and a cap component 30 . the base 12 has a stem 13 [ upstanding member ] attached thereto and a base channel 14 which is bore completely therethrough from the bottom ( point z 1 ] of the base to and out of the top of the upstanding member 13 [ point z 3 ]. the width of the channel 14 at the bottom of the base is x 3 - y 3 . the width at the opening on the top of the upstanding member 13 is x 5 - y 5 . width x 5 - y 5 is greater than width x 3 - y 3 in that the channel 14 initiates an outward angling 14 ′ above the bottom of the base 14 at approximately point z 2 which bears a width x 7 - y 7 and terminates at the top [ point z 3 ] of the upstanding member 13 defining an opening thereat having width x 5 - y 5 wherein width x 5 - y 5 is greater than width x 7 - y 7 and wherein width x 7 - y 7 could be equal to or greater than width x 3 - y 3 . the width of the base 12 [ x 9 - y 9 ] is substantially greater than the width of the upstanding member 13 [ x 8 - y 8 ]. it is this base width [ x 9 - y 9 ] which functions as a stop . the external surface of upstanding member 13 is threaded . the insert 40 , a collet - like component , is configured to fit and seat into the base channel 14 , 14 ′ at approximately point z 2 with its exterior surface 44 ′ bearing an angle approximately equal to angle 14 ′. in this regard , the insert 40 has a height [ z 2 ′ to z 3 ′] which is slightly larger than the distance from point z 2 to point z 3 . the insert 40 has a bore 44 vertically disposed therethrough [ insert channel ]. the width of the insert channel 44 is x 2 - y 2 . the width of the top of the insert 40 is x 4 - y 4 and the width at the bottom of the insert 40 is x 6 - y 6 . as the insert 40 is structured to seat into the base channel 14 , width x 4 - y 4 is slightly greater than width x 5 - y 5 , and width x 6 - y 6 is slightly greater than width x 7 - y 7 . as illustrated in fig2 and 4 , the insert 40 may have one or more vertical slots 46 a on the bottom [ fig2 ] or one or more vertical slots 46 b on the top or any combinations thereof . the slots may be extend upward or downward , respectively , partially or , as illustrated in fig5 , vertically extend the full distance from top to bottom [ reference character 46 c ]. the cap 30 has a hollow interior with threading 38 on the interior surface thereof . the interior threading [ female threading ] 38 of the cap 30 corresponds with the exterior threading 18 [ male threading ] of the upstanding member 13 . once the insert 40 is seated into the upstanding member 13 and the cap 30 threaded over the upstanding member 13 a sealing , retaining , and registering unit is formed . on the top of the cap 30 is a cap aperture 34 which has a width x 1 - y 1 . in this embodiment widths x 1 - y 1 , x 2 - y 2 , x 3 - y 3 are approximately equal and each are approximately equal to or slightly greater than the trochar tube 56 , width w . in operation , there are many methods of attaching the safety - stop device 10 to the trochar assembly 50 ; i . e ., whether the trochar assembly 50 is inserted into the safety - stop device 10 after the safety - stop device 10 has been assembled as a unit or before such assembly as a unit , or whether the assembled or unassembled safety - stop device 10 is inserted onto the trochar assembly 50 , or any combinations there . the final configuration will have the cap 30 distal from the shield opening 52 with the threaded interior 38 facing the shield opening 52 . next is the insert 40 , wider end first , followed by the base 12 with its bottom facing the shield opening 52 . the insert 40 is seated into the upstanding member 13 and the cap 30 and the upstanding member 13 are connected . in view of the larger size of the insert 40 , this connection causes the insert 40 to press against the cannula 54 and tighten and secure around it . the slots 46 a , 46 b , 46 c , depending on which configuration of insert 40 is being used , are squeezed and close or pinch in the process . the tighter the connection between cap 30 and base / upstanding member unit 12 , 13 , the more securely the safety - stop device 10 is contained on the cannula 54 . loosening the connection between the base / upstanding member unit 12 , 13 , loosens the connection between the safety - stop device 10 and the cannula 54 to thereby permit the safety - stop device 10 to translate back and forth on the cannula 54 to any desired point for a pre - determined depth in execution . once that pre - determined point is established , the safety - stop device 10 is secured to the cannula 54 , the trochar assembly is ready to use , and the base 12 acts as a stop once it contacts the skin of the patient to prevent further penetration into the patient &# 39 ; s body cavity . fig6 - 8 illustrate a slightly different safety - stop device 10 configuration without an insert 40 . here the base 12 and upstanding member 13 unit are configured externally basically as described above . in this embodiment the upstanding member 13 has one or more vertically disposed slots 16 , no internally angled walls 14 ′, and a width w 3 - w 4 at the top . the cap 30 is basically identical except that is has one or more vertically disposed fins 32 on its exterior surface to aid the user in tightening the cap 30 onto the base / upstanding member unit 12 , 13 . the threading 38 on the inside surface is somewhat tapered in that the width w 1 - w 2 at the top is less than width w 3 - w 4 at the top of the upstanding member 13 . the cap aperture 34 has a width x 1 - y 1 and the channel aperture 14 at the bottom of the base 12 has a width x 3 - y 3 . each of these widths [ x 1 - y 1 and x 3 - y 3 ] are equal to or slightly greater than the trochar tube 54 width w . as before , once the safety - stop device 10 and the trochar assembly 50 are attached , tightening the cap 34 over the upstanding member 13 , with its smaller width w 1 - w 2 , squeezes the upstanding member 13 tightly [ in the directions of arrows d ] over the trochar tube 54 . loosening the cap 34 permits the user to slide the safety - stop device 10 to any desired location on the trochar tube 54 , re - tighten the cap , and use the trochar assembly 50 . a third embodiment of the safety - stop - device 110 is illustrated i fig9 . here the upstanding member 13 on the base 13 is not threaded . it has one or more vertically disposed slots 16 and may , but need not , have a collar 22 at the top of the upstanding member 13 to aid in retaining the clamp 20 . in operation , the clamp 20 generally is first placed on the trochar tube 54 followed by the base / upstanding member unit 12 , 13 through the base channel 14 . once the unit 12 , 13 is slid on the trochar tube 54 where desired , the clamp 20 is placed over the upstanding member 13 and secured thereover . any suitable clamping device will suffice . as illustrated in fig9 , an over - center clamp 20 , with lever 24 , is utilized because of its ease of use to lock and unlock the clamp 20 . simply moving the lever 24 in the direction of arrow c tightens the clamp 20 over the upstanding member 13 , and squeezes the upstanding member 13 tightly on the trochar tube 54 . the slots 16 in the upstanding member 13 cause the upstanding member 13 to be more flexible and , with the pressure of the clamp 20 , cause the upstanding member 13 , as with the slots described in the previous embodiment , to tightly hold the trochar tube 54 . the base 12 in any embodiment may be round , as illustrated in fig9 , or may have one or more side wings , as illustrated in fig8 , or may bear any geometric shape suitable for the intended purpose ; i . e ., to be a stop member . the safety - stop device 10 may be made of any suitable materials , including , but not limited to plastics . the present disclosure includes that contained in the present claims as well as that of the foregoing description . although this safety - stop device has been described in its preferred forms with a certain degree of particularity , it is understood that the present disclosure of the preferred forms has been made only by way of example and numerous changes in the details of construction and combination and arrangement of parts and method steps may be resorted to without departing from the spirit and scope of the safety - stop device . accordingly , the scope of the safety - stop device should be determined not by the embodiments illustrated , but by the appended claims and their legal equivalents .

a safety - stop device for use with a trochar which is adjustably attachable to the trochar tube to prevent inadvertent cuts being made to a patient . the safety - stop device has retention component for retaining it onto the trochar tube ; a registration component for registering a pre - determined insertion point of the trochar ; and a stop component for preventing additional insertion of the trochar after the pre - determined insertion point has been attained .

in a preferred embodiment , the nose guard of the present invention is constructed of three flexible , light , and durable layers : an outer first layer of fabric having a sun protective factor , an intermediate second layer of open cell foam material , and a third layer of micro suede or brushed nylon material that contacts the skin . the outer first layer is such that it can be embossed , debossed , or sublimated with a desired image or print logo / design . the outer layer may be composed of spandex ( e . g . polyurethane - polyurea copolymer ). the intermediate layer can be breathable foam such as open - cell foam or perforated closed - cell foam ( e . g . airprene ). the third layer of micro - suede has a breathable , wicking effect that allows greater air exchange and acts against the discomfort and eyewear fogging caused by moisture buildup . the layers can be joined via a thermoforming process and preferably cut via laser cutting or comparable method to provide well - sealed edges that are resistant to de - lamination . as known in the art , thermoforming involves heating , sealing / fusing of layers by compression in a mold , and trimmed . the resulting nose guard material can be repeatedly used and washed . for example , the micro - suede layer can first be flame - bonded to the spandex layer , with the foam layer sandwiched in between , followed by thermoforming . the result is a light , flexible , durable and more breathable nose guard that is superior to those existing in the market ( e . g . plastic , metal , or neoprene ). however , the nose guard of the present invention could be comprised of only one , two , or any number of material layers while keeping with the teachings of the invention . for example , in an alternate embodiment , the nose guard could be comprised of a single layer of neoprene , vinyl webbing or silicone . although , certain materials and manufacturing processes are disclosed herein , other comparable or suitable materials and methods may be employed , as known in the art , to carry out the invention . it should also be understood that the nose guard disclosed herein can be made in different sizes to suit various users , and the dimensions of the nose guard can be modified while keeping with the spirit of the invention . fig1 illustrates the layers of the nose guard of the present invention as described above . in an exemplary embodiment , the nose guard is preferably constructed of three flexible , light , and durable layers : an outer first layer 110 having a sun protective factor , an intermediate second layer 120 of open cell foam material , and a third layer 130 of micro suede or brushed nylon material that contacts the skin . the outer first layer 110 is such that it can be embossed , debossed , or sublimated with a desired image or print logo / design , for example , as shown in fig2 b . the outer layer 110 may be composed of spandex ( e . g . polyurethane - polyurea copolymer ). the intermediate layer 120 can be breathable foam such as open - cell foam or perforated closed - cell foam ( e . g . airprene ). the third layer 130 can be a micro - suede with a breathable , wicking effect that allows for greater air exchange and acts against the discomfort caused by perspiration . the layers can be joined via a thermoforming process and preferably cut via laser cutting or comparable method to provide well - sealed edges that are resistant to de - lamination . for example , the micro - suede layer can first be flame - bonded to the spandex layer , with the foam layer sandwiched in between , followed by thermoforming . fig2 a - b illustrate flat , front views of the nose guard of the present invention , which comprises a pair of nose pad cuts 210 , hook patch 220 , loop patch 230 , fastening slits 240 , and fastening strap 260 . fig2 a and 2b each provide a different means of attaching the nose guard to the user &# 39 ; s eyewear . also shown are the triangular extensions from the bottom of the nose guard , i . e . nostril extensions 280 and 290 that connect with each other via the reversible connection of connector tab 255 and slit 275 to form a larger triangular surface , i . e . “ nostril cover ” that provides coverage for the user &# 39 ; s nostrils ( as shown in fig1 and 14 ). connector tab 255 enters slit 275 while flap 295 slides under nostril extension 290 to form a secure connection with adequate coverage . thus , as used herein , the term “ nostril cover ” refers to the nose guard surface that covers both the user &# 39 ; s nostrils . when the nose guard is bent along its vertical axis ( to conform to shape of the user &# 39 ; s nose as shown in fig3 and 14 ) the nostril extensions are bent along dotted line 250 , and then brought into contact and connected as shown in fig1 . once connected , the nose guard remains in a three - dimensional shape configured to receive the user &# 39 ; s nose and provide complete nose protection ( as shown in fig1 ). thus , the bottom of the nose and nostrils are also protected from the elements such as sun / heat , wind and cold . the connection between the nostril extensions is reversible so that if the user wishes to return the nose guard to its flat configured as shown in fig2 b , this can be quickly and easily done . the nostril extensions 280 and 290 have nostril holes 285 that allow the user to breathe through the nostril cover while protecting the nose from the elements . in particular , the nostril cover helps keep the user &# 39 ; s nose warm in cold conditions by trapping and re - circulating the warm air from the user &# 39 ; s nose . in the embodiment shown in fig2 , the nose pad cuts are “ c ”- shaped . however , the nose pad cuts may take other shapes to receive the nose pads of a user &# 39 ; s eyeglasses , such as the “ s ”- shaped nose pad cuts shown in fig1 ( fig1 b shows the nose guard being bent about the vertical axis , which opens the “ s ”- shaped nose pad cuts 1010 to receive eyeglass nose pads ). the nose guard of fig2 a features a flat , plain surface while the embodiment shown in fig2 b contain surface embossments 270 . the benefit of surface embossments and ridges is that the nose guard can be given more or less flexibility in certain directions to provide for a better fit to the user &# 39 ; s nose . also , the raised ridges provide padding for additional protection from outdoor elements as well as physical impact . loop patch 230 contains an adhesive backing for attachment to various surfaces . hook patch 220 is composed of “ hook ” fabric that is configured to attach with the “ loop ” fabric of loop patch 230 . the hook and loop strap 260 contains a portion of hook fabric at one end , with the remaining length of the strap being loop fabric . the hook and loop materials are preferably a low - profile , micro - velcro fabric such as that produced by 3m . to further secure the nose guard to the user &# 39 ; s face , three mechanisms allow the user to optionally secure the nose guard to their eyewear . first , if wearing ski - type goggles or eyeglasses , the user can affix loop patch 230 to the underside of the eyewear nose bridge and then bring hook patch 220 in contact with loop patch 230 as shown in fig4 and 5 . alternatively , the goggle liner itself may be composed of essentially loop - like material such that it can attach to hook patch 220 without the need for applying loop patch 230 . second , when wearing eyeglasses with nose pads , the user can insert the nose pads through the nose pad cuts 210 as shown in fig7 and 11 . third , if wearing eyeglasses without nose pads , or as an alternative to using the nose pad cuts 210 , the fastening strap 260 can be put through the fastening slits 240 and around the bridge of the eyeglasses as shown in fig3 and 6 . any of these three methods secures the nose guard to the user &# 39 ; s eyewear . fig9 , discussed below , shows a preferred embodiment of the nose guard that also gives the user the option of wearing the nose guard without attachment to any eyewear . however , the two attachment methods of fig2 a ( hook and loop patches ) and 2 b ( fastening strap ) could be utilized in the same nose guard . in such as embodiment , the fastening slits would be place immediately above and below the hook patch such that the user could elect to use the hook patch or the fastening strap , depending on their preference and the type of eyewear being used . fig3 a - b illustrate side views of two embodiments of the nose guard of the present invention that each utilize a different means of eyewear attachment . the nose guard of fig3 a utilizes hook and loop patches , to attached to a user &# 39 ; s eyewear as shown in fig4 - 5 . the nose guard of fig3 b utilizes a fastening slit and strap to attach to a user &# 39 ; s eyeglasses as shown in fig6 . as shown , fastening strip 260 ( side view shown as 265 ) is inserted through the fastening slits . fig8 shows a preferred embodiment of the present invention , which features a thin reinforcing strip affixed to the third layer ( skin - facing side ) of the nose guard . the nose guard of fig8 a and 8b each show exemplary shapes for the reinforcing strip 810 and 820 . while the reinforcing strip can take various shapes , it should run laterally ( horizontally ) from one side the nose guard to the other in order to provide structural support to the nose guard and allow the nose guard to be contoured to the user &# 39 ; s nose . in an alternate embodiment , the reinforcing strip can be embedded within the nose guard and not visible to the user , i . e . between the first and second , or second and third , layers . the reinforcing strip is made of a flexible material that can be bent or creased to keep the nose guard portion of the mask contoured to the shape of the user &# 39 ; s nose . the reinforcing strip is preferably made of a polymeric film such as polyester . examples of suitable polyester films known in the art include mylar ( polyethylene terephthalate ), duralar , and silicone . alternatively , the reinforcing strip can be made of a thin strip of metal ( e . g . aluminum ). the reinforcing strip should be thin enough to be flexible , light , and have a low profile , but thick enough to provide some structure to the nose guard . for example , the thickness of the reinforcing strip can be approximately 0 . 005 inches . for additional comfort and insulation , the reinforcing strip can feature a fleece lining . another benefit of the reinforcing strip is that it prevents warm air from the user &# 39 ; s nose from bouncing off the nostril cover and traveling upwards between the nose guard and the user &# 39 ; s nose where it could fog the user &# 39 ; s eyewear and impair vision in cold conditions . thus , the reinforcing strip can act as a fog barrier . in one embodiment , the reinforcing strip can be lined with an adhesive film that sticks to the user &# 39 ; s nose . this allows the nose guard to be worn without attachment to eyewear as shown in fig9 . moreover , the combination of the adhesive and the natural restoring force of the bent nose guard causes the user &# 39 ; s nostrils to be pulled outward , which opens the nostril passage and allows the user to breathe easier . the improved breathing is particularly advantageous during physical activities such as running , hiking , biking , manual labor , or other strenuous outdoor activities . alternatively , an adhesive strip that is separate from the reinforcing strip can be utilized as shown in fig1 ( showing reinforcing strip 1205 and adhesive strip 1215 ). the advantage of using a separate adhesive strip is that the adhesive can take on any shape as opposed to being limited to the surface of the reinforcing strip . as described above , the adhesive strip would also act as a fog barrier in cold conditions . fig1 and 11 illustrate the nose guard of the present invention with “ s ”- shaped nose pad cuts with hook and loop patches for eyewear attachment . the “ s ”- shaped cuts are alternatives to the “ c ”- shaped cuts shown in fig2 and 7 , but operate in the same way . the “ s ”- cuts , like the “ c ”- cuts , are configured to fit around the eyewear nose pads and thereby secure the nose guard to the eyewear . because the “ s ”- shaped cuts are not fully enclosed within the nose guard material , they may provide as quicker and easier means of attachment . fig1 shows the embodiment with hook and loop patch for eyewear attachment , while fig1 illustrates the fastening strap embodiment for eyewear attachment . fig1 a and 13b show the nostril extensions before and after connection with each other to form the nostril cover , respectively . fig1 illustrates the nose guard of the present invention from a bottom view showing the nostril coverage . as described above , the nostril cover helps keep the user &# 39 ; s nose warm in cold conditions by trapping and re - circulating the warm air from the user &# 39 ; s nose . for hot or sunny conditions in which sun protection is important , the nostril cover protects the nostrils from sun - burn and heat . this protection is particularly beneficial in situations where intense sunlight is being reflected upwards towards the user , such as when sun is reflected off snow during skiing or when sun is reflected off the water during fishing . finally , fig1 illustrates the nose guard of the present invention with an alternative embodiment of the nose cover . in this embodiment , the nostril cover is one continuous piece as opposed to two reversibly interlocking pieces ( i . e . interlocking nostril extensions ). the nose guard of fig1 a has a reinforcing strip and has two nostril holes in the nostril cover , whereas the nose guard of fig1 b does not . as described above , the nostril holes allow the user to breathe through the nostril cover while protecting the nose from the elements . while there have been described herein what are considered to be preferred and exemplary embodiments of the present invention , other modifications of the invention shall be apparent to those skilled in the art from the teachings herein . it is therefore desired to be secured , in the appended claims all such modifications as fall within the spirit and scope of the invention .

a flexible nose guard is provided for protecting the entire nose from sunlight , cold , and other outdoor elements . in a preferred embodiment , the nose guard has a pentagonal body that covers the bridge and sides of a user &# 39 ; s nose , resembling an upside - down pentagon with rounded corners . the top portion of the nose guard is substantially flat and conforms to the bridge of the nose . the bottom portion of the nose guard is rounded and configured to rest on top of the bridge of the nose . the bottom portion has two perforated triangular extensions that connect to form a nostril covers that provide protection from the elements while allowing the user to breath . alternatively , a nostril cover can be provided by a single piece of triangular fabric that is connected with the bottom of the nose guard . the nose guard offers numerous means of attachment to the user &# 39 ; s face .

the compound in accordance with the invention is a photosensitizer ( ps ), linked by essentially any structure that does not have detrimental radiation emittance or absorbing characteristics , to a fluorophore , usually a cyanine dye ( cd ). the photosensitizer in accordance the invention is a metallized analog of porphyrins , chlorins , purpurinimides , bacterio purpurinimides , phthalocyanines , expanded porphyrins , benzoporphyrin derivatives and purpurins . structures , photophysical , tumor - imaging characteristics and in vivo efficacy of the metallated analogs of the hpph - cyanine dye conjugates : insertion of metal ( in , ga and pd ) in hpph - cd conjugate enhances pdt effects . among the metallated analogs , the corresponding in ( iii ) analog produced the best efficacy and was almost 8 - fold more effective than the non metallated derivative . see fig1 and 2 . stat - 3 dimerization can be used as biomarker to monitor the pdt response . as seen in fig3 , photoreactions mediated by hpph - cd and metallated derivatives . bcc1 cells were used for determining the level of photoreaction resulting in the oxidative crosslinking of stat3 . the uptake of the compounds was carried out under two conditions . the hpph derivatives were diluted to 400 nm in culture medium containing 10 % fetal calf serum and added to subconfluent monolayer cultures of human basal cell carcinoma ( bcc - 1 ) cells . the cells were incubated for 2 . 5 hours at 37 ° c . alternatively , the hpph - derivatives were diluted to 20 nm in serum - free medium and added to bcc - 1 cells that had been preincubated for 1 . 5 hours in serum - free medium . the cells were incubated for 1 hour at 37 ° c . following uptake , the cells were washed 3 times with serum - free medium and exposed at 37 ° c . for 9 min to light at the indicated wavelength . in each case , the total fluence was 3 j / cm 2 . cells were immediately extracted with ripa buffer . aliquots of the lysates containing 20 μg protein were analyzed by western blotting for the level of stat3 proteins ( one representative exposure of the immunoblots is reproduced ). the enhanced chemiluminescence signals for stat3 monomeric and crosslinked stat3 were quantified and the relative amount of crosslinked dimeric stat3 was expressed as percentage of the total stat3 signal ( indicated above each lane in the figure ). as seen in fig4 , in contrast to hpph - cd where the therapeutic dose was almost 10 - fold higher than the tumor - imaging dose . the metallated analogs showed a great potential for pdt and tumor - imaging at the same dose , which was almost 8 - fold lower than the therapeutic dose of hpph - cyanine dye . hpph - cyanine dye conjugate ( 100 mg ), indium chloride ( 300 mg ) and sodium bicarbonate ( 600 mg ) were put in the solvent mixture of toluene ( 60 ml ) and ethanol ( 20 ml ). the reaction mixture was refluxed for 1 hour . after evaporation , the residue was purified by chromatography using meoh / ch 2 cl 2 ( 1 : 4 ) as the elute solvent and the title compound was obtained in ˜ 80 % yield . uv - vis in meoh : 835 nm ( ε = 159430 ), 646 nm ( ε = 56500 ), 602 nm ( ε = 12425 ), 563 nm ( ε = 8762 ), 416 nm ( ε = 75074 ). nmr ( chcl 3 ), δ ( ppm ) for compound 762 : 9 . 87 ( ss looks like a doublet , 1h , meso - h in hpph part ), 9 . 70 ( s , 1h , meso - h in hpph part ), 8 . 39 ( s , 1h , meso - h in hpph part ), 7 . 98 ( m , 4h , aromatic - h of cyanine dye ), 7 . 84 ( br s , 4h , aromatic - h of cyanine dye ), 7 . 50 ( br s , 4h , aromatic - h of cyanine dye ), 7 . 37 ( br s , 4h , ═ ch — of cyanine dye ), 7 . 07 ( m , 4h , 4h of the linker phenyl group ), 5 . 78 ( m , 1h , h - 3 1 ), 5 . 17 ( m , 1h , h - 17 ), 5 . 03 ( m , 1h , h - 18 ), 4 . 60 ( m , 2h , h - 13 2 ), 4 . 40 ( m , 2h , n + — ch 2 ), 4 . 01 ( br , 10h , 2h for n — ch 2 , 2h for h - 17 1 , 4h for — ch 2 so 3 , 2h for — oc * h 2 ( ch 2 ) 4 ch 3 ), 3 . 78 ( s , 3h , 7 - ch 3 ), 3 . 59 ( s , 3h , 12 - ch 3 ), 3 . 68 - 3 . 45 ( m , 6h , 4h for so 3 — ch 2 c * h 2 —( ch 2 ) 2 , 2h for 8 - c * h 2 ch 3 ), 3 . 34 , ( m , 2h , h - 17 2 ), 3 . 31 ( s , 3h , 2 - ch 3 ), 3 . 12 ( m , 4h , so 3 —( ch 2 ) 2 c * h 2 — ch 2 ), 2 . 04 ( m , 11h , 3h for 3 - ch 3 , 2h for — och 2 c * h 2 ( ch 2 ) 3 ch 3 ), 1 . 73 ( s , 12h , 4x — ch 3 of cyanine dye ), 1 . 33 ( m , 3h , 18 - ch 3 ), 1 . 26 ( m , 3h , 8 - ch 2 c * h 3 ), 1 . 15 ( m , 6h , — o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 ), 0 . 71 ( m , 3h , — o ( ch 2 ) 5 c * h 3 ). ms for 762 : calculated for c 91 h 102 n 7 o 9 s 3 incl : 1682 . 6 . found : 1682 . 5 . hpph - cd ( 100 mg ), gallium chloride ( 400 mg ) and sodium bicarbonate ( 400 mg ) were put in the solvent mixture of toluene ( 65 ml ) and ethanol ( 25 ml ). the reaction mixture was refluxed for 30 minutes . after evaporation , the residue was purified by chromatography using meoh / ch 2 cl 2 ( 1 : 4 ) as the elute solvent and the title compound was obtained in ˜ 45 % yield . uv - vis in meoh : 839 nm ( ε = 159183 ), 649 nm ( ε = 55102 ), 606 nm ( ε = 12505 ), 563 nm ( ε = 8767 ), 419 nm ( ε = 144002 ). nmr ( chcl 3 ), δ ( ppm ) for compound 776 : 9 . 70 ( s , 1h , meso - h in hpph part ), 9 . 22 ( s , 1h , meso - h in hpph part ), 8 . 64 ( s , 1h , meso - h in hpph part ), 8 . 12 ( m , 4h , aromatic - h of cyanine dye ), 8 . 02 ( br s , 4h , aromatic - h of cyanine dye ), 7 . 73 ( br s , 4h , aromatic - h of cyanine dye ), 7 . 46 ( br s , 4h , ═ ch — of cyanine dye ), 7 . 18 ( m , 4h , 4h of the linker phenyl group ), 5 . 79 ( m , 1h , h - 3 1 ), 5 . 19 ( m , 1h , h - 17 ), 5 . 01 ( m , 1h , h - 18 ), 4 . 63 ( m , 2h , h - 13 2 ), 4 . 45 ( m , 2h , n + — ch 2 ), 4 . 07 ( br , 10h , 2h for n — ch 2 , 2h for h - 17 1 , 4h for — ch 2 so 3 , 2h for — oc * h 2 ( ch 2 ) 4 ch 3 ), 3 . 79 ( s , 3h , 7 - ch 3 ), 3 . 55 ( s , 3h , 12 - ch 3 ), 3 . 69 - 3 . 44 ( m , 6h , 4h for so 3 — ch 2 c * h 2 —( ch 2 ) 2 , 2h for 8 - c * h 2 ch 3 ), 3 . 32 , ( m , 2h , h - 17 2 ), 3 . 36 ( s , 3h , 2 - ch 3 ), 3 . 12 ( m , 4h , so 3 —( ch 2 ) 2 c * h 2 — ch 2 ), 2 . 02 ( m , 11h , 3h for 3 - ch 3 , 2h for — och 2 c * h 2 ( ch 2 ) 3 ch 3 ), 1 . 75 ( s , 12h , 4x — ch 3 of cyanine dye ), 1 . 31 ( m , 3h , 18 - ch 3 ), 1 . 24 ( m , 3h , 8 - ch 2 c * h 3 ), 1 . 17 ( m , 6h , — o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 ), 0 . 73 ( m , 3h , — o ( ch 2 ) 5 c * h 3 ). ms for 776 : calculated for c 91 h 102 n 7 o 9 s 3 gacl : 1636 . 6 . found : 1636 . 1 . hpph - cyanine dye ( 100 mg ), l - ascorbic acid 6 - palmitate ( 220 mg ), and palladium acetate ( 160 mg ) were put into the solvent mixture of methanol ( 80 ml ) and chloroform ( 80 ml ). under argon the reaction mixture was stirred overnight at room temperature . after work - up and evaporation , the residue was purified by chromatography using meoh / ch 2 cl 2 ( 1 : 5 ) as the elute solvent and the title compound was obtained in ˜ 85 % yield . uv - vis in meoh : 839 nm ( ε = 132340 ), 635 nm ( ε = 65069 ), 589 nm ( ε = 11949 ), 536 nm ( ε = 9091 ), 415 nm ( ε = 59484 ), 389 . 9 nm ( ε = 62212 ). nmr ( chcl 3 ), δ ( ppm ) for compound 777 : 9 . 75 ( s , 1h , meso - h in hpph part ), 9 . 61 ( s , 1h , meso - h in hpph part ), 8 . 45 ( s , 1h , meso - h in hpph part ), 7 . 72 ( m , 4h , aromatic - h of cyanine dye ), 7 . 53 ( br s , 4h , aromatic - h of cyanine dye ), 7 . 12 ( br s , 4h , aromatic - h of cyanine dye ), 6 . 93 ( br s , 4h , ═ ch — of cyanine dye ), 6 . 80 ( m , 4h , 4h of the linker phenyl group ), 5 . 64 ( m , 1h , h - 3 1 ), 5 . 32 ( m , 1h , h - 17 ), 5 . 02 ( m , 1h , h - 18 ), 4 . 64 ( m , 2h , h - 13 2 ), 4 . 47 ( m , 2h , n + — ch 2 ), 4 . 09 ( br , 10h , 2h for n — ch 2 , 2h for h - 17 1 , 4h for — ch 2 so 3 , 2h for — oc * h 2 ( ch 2 ) 4 ch 3 ), 3 . 76 ( s , 3h , 7 - ch 3 ), 3 . 57 ( s , 3h , 12 - ch 3 ), 3 . 67 - 3 . 46 ( m , 6h , 4h for so 3 — ch 2 c * h 2 —( ch 2 ) 2 , 2h for 8 - c * h 2 ch 3 ), 3 . 35 , ( m , 2h , h - 17 2 ), 3 . 31 ( s , 3h , 2 - ch 3 ), 3 . 16 ( m , 4h , so 3 —( ch 2 ) 2 c * h 2 — ch 2 ), 2 . 05 ( m , 11h , 3h for 3 - ch 3 , 2h for — och 2 c * h 2 ( ch 2 ) 3 ch 3 ), 1 . 73 ( s , 12h , 4x — ch 3 of cyanine dye ), 1 . 34 ( m , 3h , 18 - ch 3 ), 1 . 21 ( m , 3h , 8 - ch 2 c * h 3 ), 1 . 15 ( m , 6h , — o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 ), 0 . 71 ( m , 3h , — o ( ch 2 ) 5 c * h 3 ). ms for 777 : calculated for c 91 h 102 n 7 o 9 s 3 pd : 1638 . 6 . found : 1638 . 5 . hpph ( 100 . 0 mg , 0 . 157 mmol ) was taken in a dry rbf ( 50 . 0 ml ) and dissolved in dry dichloromethane ( 30 . 0 ml ). to this , n — boc - ethylenediamine ( 50 . 3 mg , 0 . 314 mmol ), n - ethyl - n ′-( 3 - dimethylaminopropyl ) carbodiimide hydrochloride ( 60 . 2 mg , 0 . 314 mmol ) and 4 - dimethylamino pyridine ( 38 . 36 mg , 0 . 314 mmol ) were added and the resultant mixture was stirred for 12 hr at room temperature under n 2 atmosphere . reaction mixture was then diluted with dichloromethane ( 50 . 0 ml ) and washed with brine ( 50 ml ). organic layer separated , dried over sodium sulfate and concentrated . product was purified over silica gel column using 1 - 3 % methanol - dichloromethane as mobile phase . yield : 105 . 0 mg ( 85 . 9 %). uv - vis λ max ( in ch 2 cl 2 ): 661 nm ( ε 5 . 0 × 10 4 ), 604 nm ( ε 0 . 8 × 10 4 ), 537 nm ( ε 0 . 9 × 10 4 ), 505 nm ( ε 0 . 9 × 10 4 ), and 410 nm ( ε 10 . 5 × 10 4 ). 1 hnmr ( 400 mhz , cdcl 3 ): δ 9 . 76 ( singlet , 1h , meso - h ), 9 . 21 ( singlet , 1h , meso - h ), 8 . 52 ( singlet , 1h , meso - h ), 6 . 12 ( brs , 1h , nh ), 5 . 92 ( m , 1h , ch 3 c h ohexyl ), 5 . 29 ( d , 1h , 15 1 - c * hh , j = 19 . 6 hz ), 5 . 09 ( d , 1h , 15 1 - ch * h , j = 20 . 0 hz ), 4 . 85 ( brs , 1h , nh ), 4 . 52 ( q , 1h , 17 - h , j = 7 . 6 hz ), 4 . 30 ( d , 1h , h - 18 , j = 5 . 2 hz ), 3 . 62 - 3 . 61 ( m , 4h , 8 - c * h 2 ch 3 & amp ; — oc * h 2 - hexyl ), 3 . 38 ( singlet , 3h , ring - ch 3 ), 3 . 28 ( singlet , 3h , ring - ch 3 ), 3 . 28 ( singlet , 3h , ring - ch 3 ), 3 . 18 ( m , 2h , —( nhch 2 ) 2 —), 3 . 08 ( m , 2h , —( nhch 2 ) 2 —), 2 . 65 ( m , 1h , 17 2 - c * hh ), 2 . 45 ( m , 1h , 17 2 - ch * h ), 2 . 30 ( m , 1h , 17 1 - c h h ), 2 . 13 ( d , 3h , c * h 3 ch — ohexyl , j = 7 . 2 hz ), 2 . 05 ( m , 1h , 17 1 - c * hh ), 1 . 80 ( d , 3h , 18 - ch 3 , j = 7 . 2 hz ), 1 . 75 ( m , 2h , — ch 2 - hexyl ), 1 . 63 ( t , 3h , 8 - ch 2 c * h 3 , j = 7 . 2 hz ), 1 . 43 ( m , 2h , — ch 2 - hexyl ), 1 . 24 ( m , 4h , - 2ch 2 - hexyl ), 1 . 21 ( s , 9h , nh - boc ), 0 . 80 ( t , 3h , ch 3 - hexyl , j = 6 . 8 hz ), 0 . 45 ( brs , 1h , nh ), − 1 . 65 ( brs , 1h , nh ). ms calculated for c 46 h 62 n 6 o 5 779 . 02 . eims : 779 . 3 ( m + ). hpph ( 100 . 0 mg , 0 . 157 mmol ) was taken in a dry rbf ( 50 . 0 ml ) and dissolved in dry dichloromethane ( 30 . 0 ml ). to this , n — boc - 1 , 6 diaminohexane ( 60 . 0 mg , 0 . 31 mmol ), n - ethyl - n ′-( 3 - dimethylaminopropyl ) carbodiimide hydrochloride ( 70 . 0 mg , 0 . 31 mmol ) and 4 - dimethylamino pyridine ( 38 . 36 mg , 0 . 314 mmol ) were added and the resultant mixture was stirred for 12 hr at room temperature under n 2 atmosphere . reaction mixture was then diluted with dichloromethane ( 50 . 0 ml ) and washed with brine ( 50 ml ). organic layer separated , dried over sodium sulfate and concentrated . product was purified over silica gel column using 1 - 3 % methanol - dichloromethane as mobile phase . yield : 105 . 0 mg ( 85 . 9 %). uv - vis λ max ( in ch 2 cl 2 ): 661 nm ( ε 5 . 0 × 10 4 ), 604 nm ( ε 0 . 8 × 10 4 ), 537 nm ( ε 0 . 9 × 10 4 ), 505 nm ( ε 0 . 9 × 10 4 ), and 410 nm ( ε 10 . 5 × 10 4 ). 1 hnmr ( 400 mhz , cdcl 3 ): δ 9 . 76 ( singlet , 1h , meso - h ), 9 . 15 ( singlet , 1h , meso - h ), 8 . 50 ( singlet , 1h , meso - h ), 5 . 92 ( m , 1h , ch 3 c * hohexyl ), 5 . 20 ( d , 1h , 15 1 - c * hh , j = 19 . 6 hz ), 5 . 09 ( d , 1h , 15 1 - ch * h , j = 20 . 0 hz ), 4 . 52 ( q , 1h , 17 - h , j = 7 . 6 hz ), 4 . 30 ( d , 1h , h - 18 , j = 5 . 2 hz ), 3 . 62 - 3 . 61 ( m , 4h , 8 - c * h 2 ch 3 & amp ; — oc * h 2 - hexyl ), 3 . 38 ( singlet , 3h , ring - ch 3 ), 3 . 28 ( singlet , 3h , ring - ch 3 ), 3 . 28 ( singlet , 3h , ring - ch 3 ), 3 . 18 ( m , 2h , —( nhch 2 ) 2 —), 3 . 08 ( m , 2h , —( nhch 2 ) 2 —), 2 . 65 ( m , 1h , 17 2 - c h h ), 2 . 45 ( m , 1h , 17 2 - ch * h ), 2 . 30 ( m , 1h , 17 ′- c * hh ), 2 . 13 ( d , 3h , c * h 3 ch — ohexyl , j = 7 . 2 hz ), 1 . 95 ( m , 1h , 17 ′- c * hh ), 1 . 80 ( d , 3h , 18 - ch 3 , j = 7 . 2 hz ), 1 . 75 ( m , 2h , — ch 2 - hexyl ), 1 . 63 ( t , 3h , 8 - ch 2 c h 3 , j = 7 . 2 hz ), 1 . 43 ( m , 2h , — ch 2 - hexyl ), 1 . 40 - 1 . 31 ( m , 8h , —( nhch 2 ch 2 ch 2 ch 2 ch 2 ch 2 nh ), 1 . 24 ( m , 4h , − 2ch 2 - hexyl ), 1 . 21 ( s , 9h , nh - boc ), 0 . 80 ( t , 3h , ch 3 - hexyl , j = 6 . 8 hz ), 0 . 45 ( brs , 1h , nh ), − 1 . 65 ( brs , 1h , nh ). ms calculated for c 50 h 70 n 6 o 5 835 . 13 eims : 835 . 8 ( m + ). hpph — n - boc ethylenediamine ( 35 . 0 mg , 0 . 052 mmol ) was taken in a dry rbf ( 50 . 0 ml ) and stirred with 50 % tfa / dcm ( 5 . 0 ml ) at rt for 3 hr . resultant mixture was concentrated and dried under high vacuum to remove trace of tfa . the crude thus obtained was dissolved in anhy . dmf ( 25 ml ) and cyanine dye ( 50 . 0 mg , 0 . 052 mmol ), bop ( 30 . 0 mg , 0 . 067 mmol ) and triethyl amine ( 3 - 4 drops ) were added and the resultant mixture was stirred for 12 hr at room temperature under n 2 atmosphere . solvent was removed under vacuum and the product was purified over preparative plates using 15 % methanol - dichloromethane to yield the compound in 35 % yield . uv - vis λ max ( in meoh ): 838 . 9 nm ( ε 2 . 04 × 10 5 ), 659 . 9 nm ( ε 5 . 13 × 10 4 ), 607 . 0 nm ( ε 1 . 16 × 10 4 ), 538 nm ( ε 1 . 0 × 10 4 ), 408 nm ( ε 8 . 1 × 10 4 ) 1 hnmr ( 400 mhz , cd 3 od ): 9 . 73 ( s , 1h , h - 5 of hpph part ), 9 . 35 ( s , 1h , h - 10 of hpph part ), 8 . 50 - 8 . 45 ( m , 2h , aromatic protons of cyanine dye part ), 8 . 40 ( s , 1h , h - 20 of hpph part ,), 7 . 73 - 7 . 67 ( m , 4h , aromatic protons of cyanine dye part ), 7 . 65 - 7 . 62 ( m , 2h ), 7 . 44 - 7 . 42 ( m , 2h ), 7 . 37 - 7 . 21 ( m , 6h ), 7 . 14 - 7 . 11 ( m , 2h ), 6 . 76 - 6 . 74 ( d , 2h ), 5 . 91 - 5 . 90 ( m , 1h , 3 1 - h of hpph part ), 5 . 07 - 5 . 07 ( m , 18 - h of hpph part ), 5 . 02 - 4 . 99 ( m , 17 - h of hpph part ), 4 . 26 ( d , 1h , 13 c * hh of hpph part ), 3 . 92 ( d , 2h , 13 ch * h of hpph part ), 3 . 62 - 3 . 54 ( m , 6h , 2h for — nc * h 2 ( ch 2 ) 3 so 3 − , and 2h for — nc * h 2 ( ch 2 ) 3 so 3 − and 2h for 8 - c * h 2 ch 3 , 3 . 45 - 3 . 44 ( overlapped , 6h , 2h for 3 1 - oc * h 2 ( ch 2 ) 4 ch 3 of hpph part , 4h for 2x — n ( ch 2 ) 3 c * h 2 so 3 − ), 3 . 33 ( s , 3h , 7 - ch 3 of hpph ), 3 . 31 ( s , 3h , 2 - ch 3 ), 3 . 19 ( s , 3h , 12 - ch 3 ), 2 . 83 - 2 . 81 ( m , 2h for 17 - ch 2 c * h 2 co —), 2 . 68 - 2 . 63 ( m , 12h , 8h for 2x — nch 2 ( c * h 2 ) 2 ch 2 so 3 − of cyanine dye part , 4h for — conhc * h 2 c * h 2 nhco —), 2 . 43 - 2 . 63 ( m , 2h for 17 - c * h 2 ch 2 co —), 2 . 10 - 2 . 10 ( overlapped with other peaks , 3h , 3 2 - ch 3 of hpph part ), 1 . 65 - 1 . 57 ( m , 6h , cyclohexene -( ch 2 ) 3 — of cyanine dye part ), 1 . 53 - 1 . 50 ( m , 3h for 18 - ch 3 ), 1 . 29 - 1 . 12 ( overlapped , 17h , 12h for 4x — ch 3 of cyanine dye part , 2h for 3 1 - och 2 c * h 2 ( ch 2 ) 3 ch 3 of hpph part , 3h for 8 - ch 2 c * h 3 of hpph part ), 1 . 17 - 1 . 14 ( m , 6h for 3 1 — o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 ), 0 . 66 ( m , 3h for 3 1 - och 2 ( ch 2 ) 4 c * h 3 ). ms calculated for c 94 h 108 n 8 o 10 s 3 1628 eims ( m / z ): 1650 ( m + + na ). hpph — n - boc hexyldiamine ( 38 . 0 mg , 0 . 052 mmol ) was taken in a dry rbf ( 50 . 0 ml ) and stirred with 50 % tfa / dcm ( 5 . 0 ml ) at rt for 3 hr . resultant mixture was concentrated and dried under high vacuum to remove trace of tfa . the crude thus obtained was dissolved in anhy . dmf ( 25 ml ) and cyanine dye ( 50 . 0 mg , 0 . 052 mmol ), bop ( 30 . 0 mg , 0 . 067 mmol ) and triethyl amine ( 3 - 4 drops ) were added and the resultant mixture was stirred for 12 hr at room temperature under n 2 atmosphere . solvent was removed under vacuum and the product was purified over preparative plates using 15 % methanol - dichloromethane to yield the compound in 35 % yield . uv - vis λ max ( in meoh ): 838 . 1 nm ( ε 2 . 23 × 10 5 ), 661 . 0 nm ( ε 5 . 34 × 10 4 ), 609 . 0 nm ( ε 1 . 02 × 10 4 ), 538 nm ( ε 8 . 79 × 10 4 ), 408 nm ( ε 9 . 07 × 10 5 ) 1 hnmr ( 400 mhz , cd 3 od ): 9 . 65 ( s , 1h , h - 5 of hpph part ), 8 . 93 ( s , 1h , h - 10 of hpph part ), 8 . 75 - 8 . 72 ( m , 3h , 1h , h - 20 of hpph part , 2h , aromatic protons of cyanine dye part ), 7 . 76 ( m , 2h , aromatic protons of cyanine dye part ), 7 . 70 - 7 . 67 ( m , 4h , aromatic protons of cyanine dye part ), 7 . 46 - 7 . 43 ( m , 2h ,), 7 . 30 - 7 . 29 ( m , 2h ), 7 . 20 - 7 . 19 ( m , 4h ,) 6 . 87 - 6 . 83 ( m , 2h ), 5 . 98 ( d , 2h ), 5 . 84 - 5 . 86 ( m , 1h , 3 1 - h of hpph part ), 5 . 01 - 4 . 99 ( m , 18 - h of hpph part ), 4 . 80 - 4 . 77 ( m , 17 - h of hpph part ), 4 . 38 ( d , 1h , 13 c * hh of hpph part ), 4 . 05 ( d , 1h , 13 ch * h of hpph part ), 3 . 70 - 3 . 60 ( m , 2h , — nc * h 2 ( ch 2 ) 3 so 3 − ), 3 . 50 - 3 . 45 ( m , 2h , — nc * h 2 ( ch 2 ) 3 so 3 − ), 3 . 38 - 3 . 35 ( overlapped , 5h , 3h of 7 - ch 3 of hpph and 2h of 8 - c * h 2 ch 3 ), 3 . 33 - 3 . 45 ( overlapped , 8h , 2h for 3 1 - oc * h 2 ( ch 2 ) 4 ch 3 of hpph part , 3h of 2 - ch 3 and 3h of 12 - ch 3 ), 3 . 25 - 3 . 15 ( m , 6h , 2h for 17 - ch 2 c * h 2 co — and 4h for 2x — n ( ch 2 ) 3 c * h 2 so 3 ), 2 . 80 - 2 . 65 ( m , 12h , 8h for 2x —- nch 2 ( c * h 2 ) 2 ch 2 so 3 − of cyanine dye part , 4h for — conhc * h 2 ( ch 2 ) 4 ch 2 nhco —), 2 . 30 - 2 . 22 ( 2h for 17 - c * h 2 ch 2 co ), 2 . 13 - 2 . 08 ( overlapped with other peaks , 3h , 3 2 - ch 3 of hpph part ), 1 . 75 - 1 . 60 ( m , 9h , 6h for cyclohexene -( c * h 2 ) 3 — of cyanine dye part , and 3h for 18 - ch 3 ), 1 . 49 - 1 . 36 ( overlapped , 17h , 12h for 4x — ch 3 of cyanine dye part , 3h for 8 - ch 2 c * h 3 of hpph part ), 2h for 3 1 - och 2 c * h 2 ( ch 2 ) 3 ch 3 of hpph part ), 1 . 35 - 1 . 15 ( m , 14h , 6h for 3 1 - o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 , 8h for — conhch 2 ( c * h 2 ) 4 ch 2 nhco —), 0 . 65 ( m , 3h for 3 1 - och 2 ( ch 2 ) 4 c * h 3 ). ms calculated for c 98 h 116 n 8 o 10 s 3 1684 eims ( m / z ): 1706 ( m + + na ). to a round bottom flask the foregoing conjugate ( 25 mg ) in toluene ( 50 ml ) and dmf ( 1 - 2 ml ) was added indium chloride ( 75 mg ) and sodium bicarbonate ( 150 mg ). mixture was refluxed for 3 hours under argon . the solvent was removed under vacuum and the product was purified over preparative plates using 15 % methanol - dichloromethane to yield the compound in 65 % yield . uv - vis λ max ( in meoh ): 836 . 0 nm ( ε 1 . 91 × 10 5 ), 646 . 0 nm ( ε 7 . 55 × 10 4 ), 602 . 0 nm ( ε 1 . 20 × 10 4 ), 564 nm ( ε 6 . 79 × 10 4 ), 417 nm ( ε 9 . 30 × 10 5 ) 1 hnmr ( 400 mhz , ch 3 od ): 10 . 07 ( s , 1h , h - 5 of hpph part ), 9 . 90 ( s , 1h , h - 10 of hpph part ), 8 . 75 - 8 . 72 ( m , 3h , 1h , h - 20 of hpph part , 2h , aromatic protons of cyanine dye part ), 8 . 07 ( m , 2h , aromatic protons of cyanine dye part ), 7 . 93 - 7 . 89 ( m , 4h , aromatic protons of cyanine dye part ), 7 . 55 - 7 . 40 ( m , 8h ), 7 . 18 - 7 . 17 ( m , 2h ), 6 . 29 ( d , 2h ), 5 . 83 - 5 . 80 ( m , 1h , 3 1 - h of hpph part ), 5 . 33 - 5 . 28 ( m , 18 - h of hpph part ), 5 . 09 - 5 . 05 ( m , 17 - h of hpph part ), 4 . 25 - 4 . 15 ( m , 2h , 13 2 - h of hpph part ), 3 . 90 - 3 . 88 ( m , 2h , — nc * h 2 ( ch 2 ) 3 so 3 ), 3 . 73 - 3 . 70 ( bs , 5h , 2h for — nc * h 2 ( ch 2 ) 3 so 3 − , 3h and 7 - ch 3 of hpph ), 3 . 61 - 3 . 57 ( m , 2h , 8 - c * h 2 ch 3 ), 3 . 38 - 3 . 35 ( overlapped , 6h , 2h for 3 1 - oc * h 2 ( ch 2 ) 4 ch 3 of hpph part , 4h for 2x — n ( ch 2 ) 3 c * h 2 so 3 − ), 3 . 40 ( s , 6h , 2 - ch 3 and 12 - ch 3 ), 3 . 34 - 3 . 11 ( m , 4h for 17 - c * h 2 c * h 2 co —), 2 . 85 - 2 . 44 ( m , 12h , 8h for 2x — nch 2 ( c * h 2 ) 2 ch 2 so 3 − of cyanine dye part , 4h for — conhc * h 2 c * h 2 nhco —), 2 . 12 - 2 . 10 ( overlapped with other peaks , 3h , 3 2 - ch 3 of hpph part ), 1 . 90 ( m , 6h , cyclohexene -( c * h 2 ) 3 — of cyanine dye part ), 1 . 82 ( d , 3h for 18 - ch 3 ), 1 . 79 - 1 . 72 ( overlapped , 17h , 12h for 4x — ch 3 of cyanine dye part , 3h for 8 - ch 2 c * h 3 of hpph part , 2h for 3 1 - och 2 c * h 2 ( ch 2 ) 3 ch 3 of hpph part ), 1 . 33 - 1 . 11 ( m , 6h for 3 1 - o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 , 0 . 71 ( t , 3h for 3 1 - och 2 ( ch 2 ) 4 c * h 3 ) ms calculated for c 94 h 106 c1inn 8 o 10 s 3 1754 . 36 eims ( m / z ): 1754 . 7 ( m + ). synthesis of in ( iii ) complex of hpph - cd linked with a long linker 771 : to a round bottom flask containing hpph - cd linked with a long carbon chain ( 25 mg ) in toluene ( 50 ml ) and dmf ( 1 - 2 ml ) was added indium chloride ( 75 mg ) and sodium bicarbonate ( 150 mg ). ture was refluxed for 3 hours under argon . the solvent was removed under vacuum and the product was purified over preparative plates using 15 % methanol - dichloromethane to yield the compound in 70 % yield . uv - vis λ max ( in meoh ): 836 . 0 nm ( ε 1 . 98 × 10 5 ), 646 . 0 nm ( ε 7 . 33 × 10 4 ), 602 . 0 nm ( ε 1 . 24 × 10 4 ), 565 nm ( ε 6 . 79 × 10 4 ), 418 . 1 nm ( ε 9 . 57 × 10 5 ) 1 hnmr ( 400 mhz , ch 3 od ): 10 . 08 ( s , 1h , h - 5 of hpph part ), 9 . 91 ( s , 1h , h - 10 of hpph part ), 8 . 83 - 8 . 75 ( m , 3h , 1h , h - 20 of hpph part , 2h , aromatic protons of cyanine dye part ), 8 . 09 ( m , 2h , aromatic protons of cyanine dye part ), 7 . 94 - 7 . 91 ( m , 4h , aromatic protons of cyanine dye part ), 7 . 71 - 7 . 66 ( 2h , protons of cyanine dye part ), 7 . 58 - 7 . 50 ( m , 4h ), 7 . 43 ( t , 2h ), 7 . 35 - 7 . 32 ( m , 2h ), 6 . 32 ( d , 2h ), 5 . 85 ( m , 1h , 3 1 - h of hpph part ), 5 . 29 - 5 . 34 ( m , 18 - h of hpph part ), 5 . 03 ( m , 17 - h of hpph part ), 4 . 26 - 4 . 22 ( m , 2h , 13 2 - h of hpph part ), 3 . 92 - 3 . 90 ( m , 2h , — nc * h 2 ( ch 2 ) 3 so 3 ), 3 . 75 - 3 . 73 ( m , 2h , — nc * h 2 ( ch 2 ) 3 so 3 − ), 3 . 69 ( s , 3h , 7 - ch 3 of hpph ), 3 . 63 - 3 . 58 ( m , 2h , 8 - c * h 2 ch 3 ), 3 . 33 - 3 . 40 ( overlapped , 6h , 2h for 3 1 - oc * h 2 ( ch 2 ) 4 ch 3 of hpph part , 4h for 2x — n ( ch 2 ) 3 c * h 2 so 3 ), 3 . 40 ( s , 3h , 2 - ch 3 ), 3 . 34 ( s , 3h , 12 - ch 3 ), 3 . 20 - 3 . 18 ( m , 2h for 17 - c * h 2 ch 2 co —), 2 . 94 - 2 . 66 ( m , 14h , 8h for 2x — nch 2 ( c * h 2 ) 2 ch 2 so 3 − of cyanine dye part , 2h for 17 - ch 2 c * h 2 co —, 4h for — conhc * h 2 ( ch 2 ) 4 c * h 2 nhco —), 2 . 13 - 2 . 08 ( overlapped with other peaks , 3h , 3 2 - ch 3 of hpph part ), 1 . 97 - 1 . 96 ( m , 6h , cyclohexene -( c * h 2 ) 3 — of cyanine dye part ), 1 . 88 ( d , 3h for 18 - ch 3 ), 1 . 80 - 1 . 76 ( overlapped , 17h , 12h for 3 1 - 4x — ch 3 of cyanine dye part , 3h for 8 - ch 2 c * h 3 of hpph part ), 2h for och 2 c * h 2 ( ch 2 ) 3 ch 3 of hpph part ), 1 . 33 - 1 . 11 ( m , 14h , 6h for 3 1 - o ( ch 2 ) 2 ( c * h 2 ) 3 ch 3 , 8h for — conhch 2 ( c * h 2 ) 4 ch 2 nhco —), 0 . 75 - 0 . 70 ( m , 3h for 3 1 - och 2 ( ch 2 ) 4 c * h 3 . ms calculated for c 98 h 114 clinn 8 o 10 s 3 1810 . 4 eims ( m / z ): 1775 . 5 ( m + − cl ).

a compound in the form of a metallized tetrapyrollic photosensitizer linked to a fluorescent dye where the photosensitizer , is linked by a structure that does not have detrimental radiation emittance or absorbing characteristics , to a fluorophore , usually a cyanine dye . the photosensitizer in accordance the invention is a metallized analog of porphyrins , chlorins , purpurinimides , bacterio pupurinimides , phthalocyanines , expanded porphyrins , benzoporphyrin derivatives and purpurins . the fluorophore is usually a cyanine dye with variable substituents . and , a method for determining effectiveness of pdt by comparing proportion of stat - 3 monomer with crosslinked stat - 3 dimer after pdt where the relative proportion of stat - 3 monomer to crosslinked stat - 3 directly correlates to efficacy of the pdt .

electrodes used for spinal cord stimulation are typically implanted in the epidural space 23 between the vertebra 24 and the dura 22 , shown in fig1 . this is done for various reasons , including reduced complexity of the surgery , reduced potential complications , an increased stability of the implant . however , implantation in the epidural space requires a significant amount of additional stimulation power since the signal must be transmitted through the dura 22 and epidural space 23 and cerebrospinal fluid in order to reach its desired neural targets in the spinal cord 20 . anterior roots 25 and posterior roots 26 of the spinal cord 20 and rami communicantes 27 are also shown . there were early stimulator leads 28 which were utilized in the intrathecal space 21 between the spinal cord 20 and the dura 22 without success . typically , these leads resulted in inconsistent stimulation , overstimulation and , generally , ineffective therapy . however , they utilized technology approximately thirty years old . due to development and implementation of better epidural leads , as well as the lack of a concern for energy requirements ( since they were using an external battery pack ), this methodology was quickly abandoned . more recently , intrathecal catheters have been utilized extensively for administration of drugs including morphine and baclofen via implantable drug pumps . catheter complications were so prevalent thirty years ago ( csf leakage , migration , etc .) are no longer a significant problem . of course , administration of a drug does not require a precise electrode placement . this new intrathecal neurostimulation electrode would uses for example four millimeter electrode contacts ( more forgiving when it comes to precise electrode placement ) and yet would require dramatically less power ( less than 20 % of the power required for current epidural electrodes ) because the electrodes would be in direct contact with the csf and much closer to the desired neural targets . the primary insulating factor resulting in higher power requirements for epidural leads is the lack of conductivity of the dura 22 . the shunting effect of electrical current within the csf is a much less significant factor . therefore , an electrode designed with a stabilization means or fixing elements for use in the intrathecal space 21 utilizing materials generally accepted in the art for intrathecal drug administration would provide a unique , novel and advantageous method of stimulation of the spinal cord . fixation methods could include one or more of the following : inflatable balloons , tines which are either retractable with a stilet or simply pliable enough to fit through a specially designed introducer or a novel shape ( d shape ) or the use of nitinol . any of these fixation methods , singly or in combination , can be used to provide stable electrode placement on a long term basis . the advantages of an intrathecal electrode are dramatically reduced size and / or increased life of a neurostimulator implant . in addition , implantation in the intrathecal space allows the use of a larger diameter electrode catheter and , therefore , more electrodes can be placed , providing a wider selection of stimulation sites and stimulation paradigms . these stimulation paradigms could include sophisticated programs that switch stimulation between a number of electrodes slowly ( over seconds or minutes , hours or days ) to avoid accommodation of the stimulation or could be fast ( approximately the same speed of the electrical activity of neurons in the spinal cord ) artificially generating neural signals along the spinal cord 20 which could be perceived as any other sensory function with signals that travel through the spinal cord . for instance , a signal could be generated that would correspond to heat being applied to a patient &# 39 ; s big toe , or pressure being applied to a patient &# 39 ; s foot , or the sensation of a limb in a different orientation than it actually is . theoretically , tastes , smells , sights or even thoughts could be created in this manner allowing various artificial prosthesis ( visual , auditory , etc .) to interface with the human body . a first embodiment is illustrated in fig2 . a catheter lead 30 includes a sheath 32 having a plurality of electrodes 34 at a distal end 36 of the catheter 30 . a proximal end 38 of the catheter 30 have contacts 39 to be connected to a stimulator , not shown . there is one contact 39 for each electrode 34 . the length of the electrodes l1 are generally two to four millimeters . the distance d 1 between the electrodes is typically six millimeters , for example . the electrodes are shown to extend 270 degrees about the circumference of the catheter . in order to achieve further increases in battery life , the surface area of the active electrode contact can be reduced . an electrode with a specific orientation adjacent to the spinal cord would allow a 30 °- 270 ° electrode as opposed to the 360 ° electrodes used in all current catheter electrodes . this would also enable the electrodes to remain at the preferred three or four millimeters in length making it easier for physicians to hit the desired target and requiring fewer electrode contacts in the lead ( also allowing a smaller lead ). different means could be used to stabilize the electrode in place , including ( 1 ) inflatable balloons , ( 2 ) nitinol , ( 3 ) novel shape electrodes , ( 4 ) mechanical system whereby tines are deployed upon removal of the stilet , ( 5 ) mechanical system of flexible tines . a 270 ° electrode is illustrated in fig2 a 90 ° electrode is illustrated in fig3 a and a 60 ° electrode is illustrated in fig4 a . the small radius electrode , for example , 90 ° or less , allows a focused electrical stimulation field along the physiological midline pml of the spinal cord 20 and reduces the effective stimulation field in the area of the bending fibers . as illustrated in fig3 the electrode 34 may also be placed at the nerve root midline nrml . it is well known that bending fibers are preferentially stimulated when compared to longitudinal fibers . thus , by positioning the lead adjacent to the desired longitudinal fibers , a focused stimulation of the longitudinal fibers will take place . the small electrodes in the range of 30 °- 60 ° also allows selective activation of the fibers . this is particularly useful where the nerve enters the cord . such placement is illustrated in fig4 where the 60 ° electrode 34 is adjacent to the nerve roots 25 , 26 . for any of the above lead designs , an additional method of decreasing power requirements is to use monopolar stimulation . a large surface area common anode electrode is used in conjunction with a single electrode in the desired stimulation area on the electrode contact array . monopolar stimulation is not new , but does provide the opportunity to decrease the power requirements for effective stimulation . the incorporation of a large surface area anode electrode some distance away from the other active electrodes on the same catheter or along the length of an intrathecal catheter has never been performed or attempted . in the prior systems , the casing of the stimulator acted as the anode in a monopolar mode . its distance from the distal electrodes created a long current path . this new and novel approach reduces the current path , creates a different field and also allows a unitary electrode system so that the stimulator device itself does not have to be made in two different configurations ( one with an active case anode and one without ). therefore , a choice between bipolar and monopolar stimulation can be made after implantation using a stimulator ( pulse generator ) which could normally only provide bipolar stimulation . as illustrated in fig5 an additional electrode 35 is provided at the distal end 36 displaced from the other electrodes 34 . the electrodes 34 are shown as 360 ° electrodes . as illustrated in fig6 catheter electrode 40 includes a sheath 42 with having a plurality of inline electrodes 44 and an additional electrode 45 on the wire or sheath extension 47 extending from the distal end or paddle 46 . the proximal end 48 has contacts 49 connected to each electrode and to a stimulator . the electrodes 34 , 44 all have a length l1 and the additional electrode 35 , 45 has a length l2 . length l2 is greater than l1 , at least twice its length . thus , for example , if length l1 is two millimeters , the length l2 is four millimeters . the length l2 may be anywhere between 2 - 4 times that of the length l1 . also , it should be noted that the additional electrode 35 , 45 is spaced by a distance d 2 from the nearest electrode 34 , 44 . where d 1 is approximately six millimeters , the distance d 2 is at least 10 millimeters and can be as much as 20 millimeters . with this distance , the electrode acts as a point source when used in conjunction with a second electrode . the electrodes 34 , 44 act as a point source when used in conjunction with the additional electrode 35 , 45 of the increased area . alternatively , a common anode or additional electrode 35 may be the same length as the other electrodes 34 , but have a greater circumferential dimension than that of the electrode 34 . this would increase the surface area of the additional electrode 35 relative to the other electrodes 34 . therefore , the electrodes 34 may be in the 30 ° to 270 ° configuration previously described . the separation difference between the electrodes 34 and that of 35 will allow operation as described with respect to fig5 and 6 . such an electrode is illustrated in fig1 to be discussed below . a catheter lead capable of stimulation electrically as well as dispensing drugs is illustrated in fig7 - 11 . the catheter lead 50 has a sheath 52 with in - line electrodes 54 spaced along the distal end 56 . at the proximal end 58 , terminal contacts 59 are connected internally to each of the electrodes shown . a passage 60 is provided in the sheath 50 . in fig7 an outlet 62 is provided in the tip of the distal end 56 and a balloon fixation device 63 is shown . provision is also made for an optional stilet which is removable and may be used to assist in placement of the catheter . various stilets 61 of different shapes and characteristics may be used with these leads . in fig8 the outlet 64 is shown in the space between the electrodes 54 and a nitinol fixation device 65 is shown in the deployed condition . in fig8 a , nitinol fixation device 65 is shown prior to the deployment through opening 53 in sheath 52 . in fig9 the outlet 64 is shown in or on the electrode 54 and a tine fixation device 67 is shown . although one fixation is illustrated on a specific figure , any fixation device may be used with any of the catheters . fixation methods may also include devices that are actively deployed and / or retracted ( for instance by a stilet ) in addition to the methods shown herein . also , the fixation device may be located at any or more than one location or position along the catheter . a fixation device should be used where the catheter electrode is installed in the intrathecal space . while fig7 - 9 show the passage 60 internal to the sheath 52 , an external delivery 68 may be used as shown in fig1 . the electrode catheter 50 may also include a single or pair of optical channels 70 and 72 having outlets or ports in the distal end . the fiberoptic channels and light energy delivered through a clear translucent area in the catheter is illustrated in fig1 . one of the channels can provide a source of light to be used as a further source of stimulation . the other channel will form a lens for a camera or other monitoring devices . the camera can be used in positioning the electrode or distal end . channel 60 with outlet 64 is also shown for a drug delivery . it should be noted that only a single optical path can be used to provide a source of light for a photon stimulation without the passage 60 or the outlet 64 . it should also be noted that the passage 60 or external passage 68 for drug delivery may be used in combination with the light channel 70 without the electrodes 54 . although two channels 70 , 72 are shown , any number of channels could be used and could include a combination of different types of channels — working channels for instruments , optical channels for light or camera , stilets etc . the catheter of fig7 - 11 may be used in a percutaneous drug treatment method . the drug is administered to the patient and the stimulation cathode is positioned adjacent the tissue to be treated by the drug . the tissue is then stimulated using the catheter . this allows selective and localized drug treatment . certain compounds change chemically when stimulated . compounds can also be delivered via electropheretic means . the intrathecal location of this catheter places it past the blood / brain barrier and therefore offers numerous unique opportunities for combination stimulation / drug treatment regimes . in addition , application of various forms of energy ( heat , cold , etc .) independently or with stimulation allow indirect alteration of brain chemistry . also the production of heat in a tissue may make the tissue more susceptible to absorption of a drug . the drug may be administered through the passage 60 or 68 . the source of stimulation and / or the drugs may be external to the body or totally implantable . the implantable system could include a microprocessor , pump , port and an external port for refilling the pump or selection of a different drug or fluid . the drug may be stimulated by electrical energy using the electrodes 54 or by photonic energy using the optic channel 70 . heat may be produced by either the electrodes 54 or the optical channel 70 . cold may be produced by a peltier effect chip or other means , for example gas or liquids . if the drug is responsive to light energy of a specific wavelength , the stimulation uses light energy of that specific wavelength . finally , intrathecal stimulation by light energy may be administered via the catheter — with or without drugs or electrical stimulation — to activate certain tissues . these tissues may , in some cases , be treated in some manner to increase their sensitivity to this method of activation and maybe used in combination with electrical stimulation . the lead 50 as illustrated in fig1 is curved at its distal end 56 which includes the electrodes 54 . sheath 52 includes a wire extension 57 which includes the additional anode electrode 55 and the electrical contact 59 . the curved distal end 56 wraps around the spinal cord or the nerves . this is another form of a fixing device . the stilet 61 can be inserted through passage 60 to maintain the distal end 56 linear until it is adjacent to the nerve or the spinal cord . the passage 60 may then be used for fluid delivery . different shape stilets may be used ( bent tips for example ) to improve steerability during positioning of the catheter , as illustrated in fig1 . additional electrode 55 has the same length l1 along the sheath 52 or wire 57 as does the electrodes 54 . the difference is that electrodes 54 are illustrated as 270 ° electrodes , whereas additional electrode 55 is a 180 ° electrode . this difference in circumferential dimension provides the difference in surface area . this provides the minimum 2 to 1 surface area as previously discussed . obviously , the distance d 1 between electrodes 54 is substantially less than the distance d 2 between electrodes 54 and 55 . a modified 90 ° electrode is illustrated in cross - section in fig1 . electrode 54 has a smaller radius or diameter a than sheath &# 39 ; s 52 radius or diameter b . for example , the diameter a may be 0 . 0045 inches and diameter b may be 0 . 065 inches . the shape of the sheath and electrode allows introduction through a standard introducer needle . it still offers a reduced area electrode 54 and a stabilizing shape which may be used with or without tines or other fixation means . although the invention has been described for use with an implanted stimulator system ( externally or internally powered ), it should be noted that the same type of regime can be delivered by a non - implantable device . applications for such non - implantable systems could include intra - operative testing of a stimulator system prior to implantation . an external stimulator system is connected to an implantable electrode for a period of trial stimulation prior to determining whether an implantation should be performed . although the present invention has been described and illustrated in detail , it is to be clearly understood that the same is by way of illustration and example only , and is not to be taken by way of limitation . the spirit and scope of the present invention are to be limited only by the terms of the appended claims .

various stimulation catheters are disclosed to lie along and stimulate tissue in the intrathecal space . the electrodes on the leads are various sizes to conserve the battery as well as allowing a more defined area of stimulation . it may also include multiple channels or passages for delivery of drugs , thermal or photonic energy . the sheath includes a fixing element configured to fix the electrode in place along the tissue .

the following detailed description is of the best currently contemplated modes of carrying out the invention . the description is not to be taken in a limiting sense , but is made merely for the purpose of illustrating the general principles of the invention , since the scope of the invention is best defined by the appended claims . referring to fig1 to 4 , a nail polish bottle according to the present invention includes a bottle body 10 . a cylindrical cap 20 is fastened to a bottleneck portion 11 of the bottle body 10 , and includes a disc portion 23 in the cap 20 , with a center hole 21 and a plurality of air holes 22 formed in the disc portion 23 . a pressure opening and closing valve 30 is mounted to the disc portion 23 , and serves to open or close the center hole 21 and the air hole 22 of the disc portion 23 . an inner cap member 40 is mounted to the cap 20 , with a discharge passage 41 and an enlarged groove 42 formed in the inner cap member 40 . an outer cap member 50 is mounted to the cap 20 , with a plurality of external - air introduction grooves 56 formed on the outer cap member 50 . thereby , the inner cap member 40 is covered by the outer cap member 50 that comes into contact with an inner circumference of an upper end of the cap 20 , and the enlarged groove 42 of the inner cap member 40 coupled to the discharge passage 41 is disposed above the center hole 21 of the disc portion 23 . the bottle body 10 is made of a flexible nylon material by injection molding , and a side portion of the bottle body 10 is compressed by external force and then is restored to its original state , with a helical fastening portion 12 formed on the bottleneck portion 11 . referring to fig5 , the cap 20 includes an upper cylindrical portion 24 and a lower cylindrical portion 25 , with the upper cylindrical portion 24 being integrally formed on an upper end of the lower cylindrical portion 25 in a stepped configuration . a helical fastening portion 26 is formed on an inner circumference of the lower cylindrical portion 25 . a stopper protrusion 27 is formed above the helical fastening portion 26 . the disc portion 23 is formed above the stopper protrusion 27 , and the center hole 21 and the plurality of air holes 22 are formed in the disc portion 23 , with a locking protrusion 29 formed on an upper end of an inner circumference of the upper cylindrical portion 24 . thus , as shown in fig3 and 4 , when the helical fastening portion 26 of the cap 20 is fastened to the helical fastening portion 12 formed on the bottleneck portion 11 of the bottle body 10 , the upper end of the bottleneck portion 11 is stopped by the stopper protrusion 27 , thus preventing the cap 20 from being excessively fastened to the bottleneck portion 11 of the bottle body 10 . the nail polish liquid contained in the bottle body 10 is discharged through the center hole 21 that is formed in the disc portion 23 of the cap 20 , and external air is introduced into the bottle body 10 through the air holes 22 of the cylindrical portion 23 . referring to fig6 , the pressure opening and closing valve 30 is made of a silicone material by injection molding . a skirt portion 33 is provided on a lower end of a cylindrical portion 32 in which a hollow portion 31 is formed . a protruding step 34 is provided on an upper end of an outer circumference of the cylindrical portion 32 , and a pair of rectangular pieces 35 and 36 is integrally provided on a top of the cylindrical portion 32 . the rectangular pieces 35 and 36 come into contact with each other to keep an upper end of the hollow portion 31 closed . if pressure is exerted through the hollow portion 31 , the rectangular pieces 35 and 36 move away from each other . hence , as shown in fig4 , the cylindrical portion 32 of the pressure opening and closing valve 30 is placed around the center hole 21 of the disc portion 23 formed in the cap 20 , so that the skirt portion 33 covers a lower surface of the disc portion 23 . the protruding step 34 is stopped by an upper surface of the disc portion 23 , so that the cylindrical portion 32 of the pressure opening and closing valve 30 is mounted around the center hole 21 of the disc portion 23 , and the skirt portion 33 blocks the air holes 22 formed in the disc portion 23 , from the lower surface of the disc portion 23 , thus preventing the nail polish liquid in the bottle body 10 from being introduced into the air holes 22 . in contrast , if the internal pressure of the bottle body 10 is reduced , the skirt portion 33 moves away from the lower surface of the disc portion 23 , so that the air hole 22 is opened . referring to fig7 , the inner cap member 40 includes a body 43 having a truncated cone shape . a cylindrical portion 44 is integrally formed on an upper end of the body 43 in such a way as to extend upwards therefrom . an enlarged groove 42 is defined in the body 43 . a discharge passage 41 extends from an upper end of the enlarged groove 42 in such a way as to pass through the cylindrical portion 44 . a pocket 46 is formed in an upper portion of the body 43 in such a way as to accommodate a brush 47 therein and to be around a lower end of the cylindrical portion 44 . the cylindrical portion 44 is disposed in the brush 47 , with the discharge passage 41 defined in the cylindrical portion 44 . referring to fig8 , the outer cap member 50 includes a cylindrical portion 51 , with an elliptical hollow portion 52 formed in the cylindrical portion 51 . an extended inclined portion 53 is integrally formed on a lower end of the cylindrical portion 51 . an enlarged cylindrical portion 54 is provided on a lower end of the extended inclined portion 53 . an enlarged inclined hole 55 is formed in a lower end of the hollow portion 52 corresponding to the extended inclined portion 53 in such a way as to extend downwards therefrom . an inner inclined surface 57 is formed around the enlarged inclined hole 55 . a plurality of external - air introduction grooves 56 is formed on the extended inclined portion 53 and an outer circumference of the enlarged cylindrical portion 54 . thereby , as shown in fig4 , the circumference of the upper end of the extended inclined portion 53 of the outer cap member 50 is locked by the locking protrusion 29 of the cap 20 so as to prevent unexpected removal . the body 43 of the inner cap member 40 is fitted into the enlarged inclined hole 55 of the outer cap member 50 , so that the body 43 of the inner cap member 40 comes into close contact with the inner inclined surface 57 of the outer cap member 50 , and thereby the brush 47 of the inner cap member 40 is exposed to the outside through the hollow portion 52 of the outer cap member 50 . an operation of the nail polish bottle according to the present invention configured as described above will be described in detail with reference to fig9 and 10 . first , as shown in fig9 , if the bottle body 10 is pushed in a direction of arrow 65 in a state in which the nail polish bottle is turned upside down for the purpose of a manicure , the rectangular pieces 35 and 36 of the pressure opening and closing valve 30 are moved away from each other by pressure . simultaneously , the nail polish liquid 70 contained in the bottle body 10 is discharged through a gap between the rectangular pieces 35 and 36 of the pressure opening and closing valve 30 , the enlarged groove 42 and the discharge passage 41 of the inner cap member 40 . the nail polish liquid discharged from the discharge passage 41 of the inner cap member 40 permeates the brush 47 , thus allowing a user to apply the nail polish liquid . in this regard , the skirt portion 33 of the pressure opening and closing valve 30 blocks the air holes 22 formed in the disc portion 23 , from the lower surface of the disc portion 23 , so that the nail polish liquid of the bottle body 10 is not introduced into the air holes 22 , thus preventing the nail polish liquid from leaking to the outside through the external - air introduction grooves 56 of the outer cap member 50 . further , as shown in fig1 , if a pushing force is removed from the bottle body 10 after a user finishes using the nail polish , the bottle body 10 is restored to its original state in the direction of arrow 66 , and the rectangular pieces 35 and 36 of the pressure opening and closing valve 30 are closed by their own elastic force ( restoring force ), thus preventing the nail polish liquid in the bottle body 10 from leaking to the brush 47 . as such , according to the present invention , even if the bottle body 10 is laid down or turned upside down , the rectangular pieces 35 and 36 of the pressure opening and closing valve 30 are closed , thus preventing the nail polish liquid 70 from unexpectedly leaking from the bottle body 10 . further , if the pushing force is eliminated from the bottle body 10 , the bottle body 10 is restored to its original state by its own elasticity . here , the skirt portion 33 of the pressure opening and closing valve 30 moves away from the lower surface of the disc portion 23 , so that the air holes 22 of the disc portion 23 are opened , and thereby air introduced through the external - air introduction grooves 56 of the outer cap member 50 is fed through the air holes 22 of the disc portion 23 into the bottle body 10 . as described above , the present invention provides a nail polish bottle , which is configured so that , if a bottle body is pushed , the internal pressure of the bottle body is increased and thus the pressure opening and closing valve is opened , thereby discharging nail polish liquid contained in the bottle body through a discharge passage to a brush and allowing a user to apply to polish to his or her nails , and , if force is eliminated from the bottle body , the internal pressure of the bottle body is restored to its original state and thus the pressure opening and closing valve is closed , thereby automatically preventing the nail polish liquid from leaking . while the invention has been described with respect to a limited number of embodiments , it will be appreciated that many variations , modifications and other applications of the invention may be made . therefore , the claimed invention as recited in the claims that follow is not limited to the embodiments described herein .

a nail polish bottle comprises a bottle body , a cap including a disc portion having a center hole and one or more air holes and including a discharge passage and one or more external - air introduction grooves in flow contact with the air holes . a pressure opening and closing valve is mounted to the disc portion such that a skirt portion of the valve may sit below the disc portion and a top of the valve may be above the disc portion . the skirt portion may press against the disc portion to close the air holes . when internal pressure in the bottle body opens the top of the valve , nail polish may flow through the discharge passage if the bottle is upside - down . when the internal pressure is released , the top of the valve may close and the skirt portion may move away from the disc to open the air holes .

referring first to fig1 there is shown a graphical illustration of an “ r - wave ” portion of an electrocardiogram ( ecg ) waveform ( designated “ r ”) and the related plethysmographic waveform ( designated “ p ”). as will be appreciated by one having ordinary skill in the art , the ecg waveform comprises a complex waveform having several components that correspond to electrical heart activity . the qrs component relates to ventricular heart contraction . the r - wave portion of the qrs component is typically the steepest wave therein , having the largest amplitude and slope , and may be used for indicating the onset of cardiovascular activity . the arterial blood pulse flows mechanically and its appearance in any part of the body typically follows the r wave of the electrical heart activity ( i . e ., r - wave event , designated r 1 , r 2 , r 3 , etc . in fig2 ) by a determinable period of time that remains essentially constant for a given patient . see , e . g ., goodlin et al ., systolic time intervals in the fetus and neonate , obstetrics and gynecology , vol . 39 , no . 2 , ( february 1972 ) and u . s . pat . no . 3 , 734 , 086 . correlating the occurrence of cardiovascular activity with the detection of arterial pulses typically occurs by measuring an ecg signal , detecting the occurrence of the r - wave portion of the ecg signal , determining the time delay by which an optical pulse in the detected optical signal follows the r - wave , and using the determined time delay between an r - wave and the following optical pulse to evaluate the waveform . referring now to fig2 there is shown a graphical illustration of the arterial blood pressure ( designated “ p a ”) which is similarly follows the r - wave event by a determinable period of time . the venous blood pressure ( designated “ p v ”), in the absence of extraneous forces or events ( e . g ., restricting venous blood flow ), is typically relatively constant . referring now to fig3 there is shown a schematic illustration of one embodiment of a pulse oximeter apparatus 5 that can be employed within the scope of the invention . as discussed above , conventional pulse oximetry methods and apparatus typically employ two lights ; a first light having a discrete frequently in the range of ˜ 650 - 670 nanometers in the red range and a second light having a discrete frequency in the range of ˜ 800 - 1000 nanometers . the lights are typically directed through a finger 4 via emitters 12 , 14 and detected by a photo detector 16 . emitters 12 and 14 are driven by drive circuitry 18 , which is in turn governed by control signal circuitry 20 . detector 16 is in communication with amplifier 22 . the photo detector 16 provides an output signal s 1 that is transmitted to an amplifier 22 . the amplified signal s 1 from amplifier 22 is then transmitted to demodulator 24 , which is also synched to control signal circuitry 20 . as will be appreciated by one having skill in the art , the output signal from the demodulator 24 would be a time multiplexed signal comprising ( i ) a background signal , ( ii ) the red light range signal and ( iii ) the infrared light range signal . the demodulator 24 , which is employed in most pulse oximeter systems , removes any common mode signals present and splits the time multiplexed signal ( s 1 ) into two ( 2 ) channels , one representing the red voltage ( or optical ) signals ( designated s 3 ) and the other representing the infrared voltage ( or optical ) signals ( designated s 4 ). as illustrated in fig3 the signal from the demodulator 24 is transmitted to analog - digital converter 26 . the desired computations are performed on the output from the converter 26 by signal processor 28 and the results transmitted to display 30 . further details of the conventional pulse oximeter components , and related functions , are set forth in u . s . pat . no . 4 , 934 , 372 , which is incorporated by reference herein . referring now to fig4 the red signal s 3 includes motion artifacts or noise and the base red signal s , which comprises arterial blood ( a b ) and venous blood ( v b ) components . the infrared signal s 4 similarly includes noise and the base infrared signal s . it should be noted that if the pulse oximeter apparatus 5 is designed correctly , such that the red and the infrared light pass through substantially the same tissue , the pulses in the plethysmographic waveform in the red channel , i . e ., red voltage signal ( s ) s 3 , will be shaped identically to those in the infrared channel , i . e ., infrared voltage signal ( s ) s 4 . only their size and the slowly - varying voltage on which they sit will be different . ( see fig5 ) according to the invention , the venous blood component v b can be distinguished from the arterial blood component v a in the following manner : referring to fig6 a and 6b , in a first embodiment of the invention , the pulse oximeter 5 is operatively connected to a patient &# 39 ; s finger 4 . the patient &# 39 ; s hand 3 ( and , hence , finger 4 ) is then raised and held in a first position above the heart level ( designated h ) until substantially all of the venous ( i . e ., non - pulsating ) blood is dissipated from or flows out of the finger 4 . in a preferred embodiment , the hand 3 is held in the raised position for a first time period greater than 3 sec ., more preferably , in the range of approximately 4 . 0 to 6 . 0 sec . during this first period of time , the red and infrared optical ( or oximetry ) signals are obtained . the patient &# 39 ; s hand 3 is then lowered to a second position below the heart level ( h ) for a substantially equal time period ( see fig6 b ). during this second period of time , the red and infrared optical ( or oximetry ) signals are also obtained . referring now to fig7 there is shown a graphical illustration of the venous blood flow during the above described test cycle . as illustrated in fig7 when the finger 4 is in the second position , i . e ., below the heart level ( h ), venous blood flows into the finger 4 , designated v b ( in ) . when the finger is raised to the second position , venus blood dissipates from the finger 4 , designated v b ( out ) . after the oximetry signals are acquired , the ratios of the low frequency ( i . e ., 0 . 08 to 0 . 12 hz ) and high frequency ( i . e ., 0 . 8 - 1 . 2 hz ) signals of s 3 ′ ( red ) and s 4 ′ ( infrared ) are then computed and compared ( see fig8 ). according to the invention , the ratio of the extended time period ( e . g ., 10 sec ) reflects the venous blood component ( v b ). indeed , as will be appreciated by one having ordinary skill in the art , the ratio of the extended time period can only be attributed to the venous blood component ( v b ), since a period of 10 sec . could not be attributed to the heart rate . the following is an illustrative example : an oximeter sensor arrangement is coupled to a finger on patients a &# 39 ; s left hand . the hand is raised over patient a &# 39 ; s head and held for 4 sec . the hand is then lowered to patient &# 39 ; s a &# 39 ; s side and held for 4 sec . referring now to fig9 there is shown a representative modulation of red r and infrared i light for patient a when both the venous concentration and arterial concentration are varying with time . as illustrated in fig9 the arterial blood concentration is varying at approximately 1 cycle / sec . and the venous blood concentration is varying at approximately 1 cycle / 10 sec . as will be appreciated by one having ordinary skill in the art , the 1 cycle / sec . variation is due to the periodic changes in blood pressure attendant with each heart beat . the 1 cycle / 10 sec . variation corresponds to the raising and lowering of the hand 3 above and below the heart level h within a 10 . 0 sec . period . as illustrated in fig9 the 1 cycle / sec . modulation has different amplitudes for red r and infrared i signals ( i . e ., “ saw - tooth ” shaped waveform ). the 1 cycle / 10 sec . modulation has the same amplitude for the red r and infrared i signals . according to the invention , the same ratio variations at low frequencies , designated generally f 1 , is indicative of a venous blood saturation of approximately 81 %. the 2 : 1 amplitude variations ( of the infrared to red signals ) at 1 cycle / sec . is indicative of an arterial blood saturation of approximately 97 %. according to the invention , the arterial and venous blood components of the noted oximetry signals can be determined as follows : v a = ln r max / r min / ln i max / i min = 0 . 52 eq . 1 v b = ln r ′ max / r ′ min / ln i ′ max / i ′ min = 1 . 0 eq . 2 the arterial blood component , v a , would thus correspond to a saturation level of approx . 97 %. the venous blood component , v b , would thus correspond to a saturation level of approx . 80 %. in an additional embodiment of the invention , the red ( r ) and infrared ( i ) signals are achieved by sequentially blocking and releasing the blood flow to the tissue ( e . g ., finger ) coupled to the pulse oximeter . various means may be employed to block and release the blood flow , such as a cuff disposed on the finger . ( see , e . g ., u . s . pat . no . 4 , 883 , 055 ) as will be appreciated by one having ordinary skill in the art , the noted method can be employed with virtually all pulse oximeter methods and apparatus to enhance the accuracy of the output data ( i . e ., plethysmographic waveform ). the method can similarly be employed in the method and apparatus described in co - pending application ser . no . _____ , filed mar . 23 , 2001 , entitled “ method and apparatus for determining physiological characteristics .” the method of the invention is also particularly advantageous when employed in any device where venous saturation could interfere with the accuracy of the output data . without departing from the spirit and scope of this invention , one of ordinary skill can make various changes and modifications to the invention to adapt it to various usages and conditions . as such , these changes and modifications are properly , equitably , and intended to be , within the full range of equivalence of the following claims .

a method for determining the blood constituents of a patient comprising coupling an oximeter sensor arrangement to a tissue region of the patient ; passing first and second lights through the patient &# 39 ; s tissue region for a first period of time while the venous blood in the tissue region has a first volume and for a second period of time while the venous blood in the tissue region has a second volume , the first light being substantially in a red light range and the second light being substantially in an infrared light range ; detecting a red light signal and an infrared light signal , the red and infrared signals having at least first and second frequencies ; computing a first ratio of the red and infrared signals at the first frequency ; computing a second ratio of the red and infrared signals at the second frequency ; comparing the first and second ratios to determine a first blood constituent .

referring to the drawings in detail , and initially to fig1 thereof , a conventional toddler bed 10 is shown which includes a headboard 12 having two downwardly extending headboard support legs 14 at opposite sides thereof . only one such headboard support leg 14 is shown in fig1 . toddler bed 10 further includes a footboard 16 having two downwardly extending footboard support legs 18 at opposite sides thereof . the spacing between headboard support legs 14 and the spacing between footboard support legs 18 are the same , and a mattress support frame 20 is connected between headboard support legs 14 and footboard support legs 18 for supporting a mattress 22 thereon . optionally , two side rail panels 24 may be connected to opposite sides , respectively , of headboard 12 and extend along the side of toddler bed 10 , but only for part of the way along the length of the bed , for example , one - half the length of the bed . this provides safety for the child so as to prevent the child from falling out of the bed , while also providing opening areas 26 between the free ends of side rail panels 24 and footboard 16 to allow the child to easily get out of bed 10 . side rail panels 24 preferably each have a side rail supporting leg 28 at the free end thereof . however , as discussed above , when the child gets older , for example , four to five years old , and is ready for a conventional twin or full size bed , the toddler bed must be discarded and replaced by a conventional twin or full size bed , resulting in additional costs , including the purchase of a new headboard and / or footboard . referring now to fig2 - 8 , a bed frame system 30 according to the present invention for a toddler bed is shown in an unfolded view in fig2 - 4 and in an assembled view in fig5 - 8 . bed frame system 30 includes , starting from the left side in fig2 , a toddler footboard 32 , a toddler side wall 34 and a toddler headboard 36 . an opposite toddler side rail panel or front fence 38 may optionally also be provided , but is not required with the present invention . side wall 34 is formed in three sections , namely , a first outer section 40 , a second outer section 42 and a center section 44 interposed between and which connects together first outer section 40 and second outer section 42 . in this regard , as shown best in fig4 , the inner side edge of first outer section 40 can overlap one side edge of center section 44 , and removable bolts 46 can be inserted in overlapping openings thereof . in like manner , the inner side edge of second outer section 42 can overlap the opposite side edge of center section 44 , and removable bolts 46 can be inserted in overlapping openings thereof . first and second outer sections 40 and 42 and center section 44 each include a relatively flat , generally rectangular panel 40 a , 42 a and 44 a , respectively , with the upper surfaces 40 b and 42 b of panels 40 a and 42 a sloping upwardly in a curved arc toward center section 44 . a first outer section supporting leg 48 is connected to the free outer side edge of first outer section 40 , and a second outer section supporting leg 50 is connected to the free outer side edge of second outer section 42 , for providing support on a floor surface . in this regard , the free outer side edge of first outer section 40 and second outer section 42 each include a recess 39 . the upper wall section defining the recess 39 of first outer section 40 and second outer section 42 each includes an opening 41 for receiving the upper end of each supporting leg 48 and 50 , respectively , and each supporting leg 48 and 50 is removably connected to the lower wall section defining the recess 39 by a removable bolt 43 . a center section supporting leg 52 extends down from the lower edge of center section 44 , at the center thereof , for providing additional support on a floor surface . in addition , a mattress support rail 54 is connected at one end by rivets , bolts or the like 56 to first outer section supporting leg 48 in a cantilevered manner below and parallel to the lower edge of first outer section 40 . the free end of mattress support rail 54 is also connected by a bracket 58 to the lower edge of first outer section 40 . in like manner , a mattress support rail 60 is connected at one end by rivets , bolts or the like 62 to second outer section supporting leg 50 in a cantilevered manner below and parallel to the lower edge of second outer section 42 . the free end of mattress support rail 60 is also connected by a bracket 64 to the lower edge of second outer section 42 . a mattress support rail 66 is connected at its center by rivets , bolts or the like 68 to center section supporting leg 52 below and parallel to the lower edge of center section 44 . in this manner , when first outer section 40 , second outer section 42 and center section 44 are connected together , mattress support rails 54 and 60 engage with mattress support rail 66 to provide continuity thereof , in order to support a crib mattress thereon . in order to provide different decorative effects , each panel 40 a , 42 a and 44 a is provided with a large central opening 40 c , 42 c and 44 c , respectively , and a respective decorative insert panel 70 , 72 and 74 is removably inserted in the respective large central opening . in this manner , the aesthetic appearance of each panel 40 a , 42 a and 44 a can be easily changed . preferably , each decorative insert panel 70 , 72 and 74 is formed by a flat decorative section 76 having a surrounding side wall 78 extending perpendicular to decorative section 76 so that side wall 78 is friction fit within the respective large central opening 40 c , 42 c and 44 c , and a flat circumferential section 80 is connected to the opposite end of side wall 78 for fitting in an outer recess 82 in surrounding relation to each large central opening 40 c , 42 c and 44 c . of course , any other means of securing each decorative insert 70 , 72 and 74 in the respective large central opening 40 c , 42 c and 44 c , can be provided . each flat decorative section 76 is preferably formed as a padded insert on a medium density fiberboard ( mdf ), although the present invention is not limited thereby . footboard 32 includes a flat , generally rectangular panel 84 with a lower edge generally at the same height as mattress support rails 54 , 60 and 66 , and with an upper edge generally at the same height as the upper end of first outer section supporting leg 48 . preferably , as shown , the upper surface 84 a of panel 84 has a gentle slope upwardly toward first outer section 40 . in order to provide different decorative effects , panel 84 is provided with a large central opening 86 and a decorative insert panel 88 is removably inserted in large central opening 86 . in this manner , the aesthetic appearance of panel 88 can be easily changed . preferably , decorative insert panel 88 is formed by a flat decorative section 90 having a surrounding side wall 92 extending perpendicular to decorative section 90 so that side wall 92 can be friction fit within large central opening 86 , and a flat circumferential section 94 is connected to the opposite end of side wall 92 for fitting in an outer recess 96 in surrounding relation to large central opening 86 . of course , any other means of securing decorative insert panel 88 in large central opening 86 can be provided . flat decorative section 90 is preferably formed as a padded insert on a medium density fiberboard ( mdf ), although the present invention is not limited thereby . footboard 32 further includes a cylindrical bushing 98 at the side thereof corresponding to its greater height and which is mounted about first outer section supporting leg 48 to provide rotatable motion , and thereby to permit footboard 32 to pivot thereabout between the coplanar orientation with respect to first outer section 40 , as shown in fig2 - 4 , and a perpendicular orientation with respect to first outer section 40 , as shown in fig5 - 8 . bushing 98 can be inserted over first outer section supporting leg 48 when supporting leg 48 is removed from first outer section 40 by removing bolt 43 . when first outer section supporting leg 48 is secured again to first outer section 40 , bushing 98 is positioned in recess 39 thereof . a footboard supporting leg 100 is connected to the free outer side edge of panel 84 of footboard 32 for providing further support on a floor surface . headboard 36 , in like manner , includes a flat , generally rectangular panel 104 with a lower edge generally at the same height as mattress support rails 54 , 60 and 66 , and with an upper edge generally at the same height as the upper end of second outer section supporting leg 50 . preferably , as shown , the upper surface 104 a of panel 104 has a gentle slope upwardly toward second outer section 42 . in order to provide different decorative effects , panel 104 is provided with a large central opening 106 and a decorative insert panel 108 is removably inserted in large central opening 106 . in this manner , the aesthetic appearance of panel 108 can be easily changed . preferably , decorative insert panel 108 is formed by a flat decorative section 110 having a surrounding side wall 112 extending perpendicular to decorative section 110 so that side wall 112 can be friction fit within large central opening 106 , and a flat circumferential section 114 is connected to the opposite end of side wall 112 for fitting in an outer recess 116 in surrounding relation to large central opening 106 . of course , any other means of securing decorative insert panel 108 in large central opening 106 can be provided . flat decorative section 110 is preferably formed as a padded insert on a medium density fiberboard ( mdf ), although the present invention is not limited thereby . headboard 36 further includes a cylindrical bushing 118 at the side thereof corresponding to its greater height and which is mounted about second outer section supporting leg 50 to provide rotatable motion , and thereby to permit headboard 36 to pivot thereabout between the coplanar orientation with respect to second outer section 42 , as shown in fig2 - 4 , and a perpendicular orientation with respect to second outer section 42 , as shown in fig5 - 8 . bushing 118 can be inserted over second outer section supporting leg 50 when supporting leg 50 is removed from second outer section 42 by removing bolt 43 . when second outer section supporting leg 50 is secured again to second outer section 40 , bushing 118 is positioned in recess 39 thereof . a headboard supporting leg 120 is connected to the free outer side edge of panel 104 of headboard 36 for providing support on a floor surface . in this regard , the free outer side edge of headboard 36 includes a recess 105 . the upper wall section defining the recess 105 of headboard 36 includes an opening 107 for receiving the upper end of headboard supporting leg 120 , and headboard supporting leg 120 is removably connected to the lower wall section defining the recess 105 of headboard 36 by a removable bolt 109 . side rail panel 38 is a rectangular panel having an upper edge at the same height as the upper edge of headboard 36 at the lower height end thereof , and a lower edge which is at the same height as the lower edge of headboard 36 . side rail panel 38 includes two cylindrical bushing grips 122 which are mounted about headboard supporting leg 120 to provide rotatable motion , and thereby to permit side rail panel 38 to pivot thereabout between the coplanar orientation with respect to headboard 36 , as shown in fig2 - 4 , and a perpendicular orientation with respect to headboard 36 , as shown in fig5 - 8 . bushing grips 122 can be inserted over headboard supporting leg 120 when supporting leg 120 is removed from headboard 36 by removing bolt 109 . when headboard supporting leg 120 is secured again to headboard 36 , bushing grips 122 are positioned in recess 105 thereof . a side rail supporting leg 124 is connected to the free outer side edge of side rail panel 38 for providing support on a floor surface . side rail supporting leg 124 corresponds to a standard toddler bed center leg support . in addition , a mattress support rail 126 is connected at one end by rivets , bolts or the like 128 to headboard supporting leg 120 below and parallel to the lower edge of headboard 36 and side rail panel 38 . mattress support rail 126 has a length equal to the connected lengths of mattress support rails 54 , 60 and 66 . the midpoint of mattress support rail 126 is connected by rivets , bolts or the like 130 to side rail supporting leg 124 . the free end of mattress support rail 126 is connected by rivets , bolts or the like 132 to a further supporting leg 133 that is adapted to be secured to footboard supporting leg 100 in order to provide a closed rectangular bed structure , as shown in fig5 - 8 . it will be appreciated that mattress support rails 54 , 60 , 66 and 126 each have an l - shaped cross - sectional profile , as shown in fig4 , so as to include a first segment 134 oriented in a vertical plane and a second segment 136 connected to the lower edge of first segment 134 and which extends inwardly of assembled bed frame system 30 in a horizontal orientation for holding a mattress support 138 ( fig5 - 8 ) thereon . mattress support 138 includes a rectangular frame 140 that seats on second segments 136 and is confined within first segments 134 , and a plurality of slats 142 on which a crib mattress can be supported . referring now to fig9 , there is shown a conventional twin / full bed frame 150 comprising a pair of spaced parallel elongated side frame members 152 spanned by a pair of spaced parallel cross frame members 154 extending generally perpendicular with respect to side frame members 152 . cross frame members 154 may be of a conventional telescoping type . side frame members 152 are each an elongated sheet metal or angle - iron member having an l - shaped cross - section with a horizontal inwardly facing coplanar leg portion 156 adapted to support a box spring and mattress on the upper surface thereof , and a generally vertically extending leg portion 158 adapted to confine the box spring and mattress on the coplanar leg portion 156 . cross frame members 154 are also preferably each a sheet steel or angle - iron member having an l - shaped cross - section with a horizontal coplanar leg portion 160 and a downwardly extending vertical leg portion 162 . cross frame members 154 extend generally perpendicular with respect to side frame members 152 , with horizontal coplanar portions 160 positioned immediately below horizontal leg portions 156 of frame members 152 when the frame is assembled . side frame members 152 are detachably secured to cross frame members 154 by connecting means in a manner well known in the art and a detailed description thereof is omitted from the present application . frame 150 is supported above a floor surface by two pairs of leg assemblies 164 which are positioned at the ends of cross frame members 154 and which extend downwardly with respect to the longitudinal extent of side frame members 152 . each leg assembly 164 preferably includes a lockable wheel or roller 166 at the lower end thereof for support on a floor surface . as shown in fig9 a and 10 , toddler bed frame system 30 is adapted to be used with bed frame 150 of a twin bed size . specifically , bed frame 150 is shown in fig9 a and 10 with a box spring 168 and a mattress 170 thereon . in order to convert bed frame system 30 for use with conventional twin size bed frame 150 , first outer section 40 and second outer section 42 of side wall 34 are detached from center section 44 thereof , by removing bolts 46 . in addition , first outer section 40 is detached from footboard 32 by removing first outer section supporting leg 48 from first outer section 40 by removing the respective bolt 43 , and then reattaching first outer section supporting leg 48 to first outer section 40 after bushing 98 has been removed therefrom . in like manner , second outer section 42 is detached from headboard 36 by removing second outer section supporting leg 50 from second outer section 42 by removing the respective bolt 43 , and then reattaching second outer section supporting leg 50 to second outer section 42 after bushing 118 has been removed therefrom . thereafter , the inner side edge of first outer section 40 is made to overlap the inner side edge of second outer section 42 , and removable bolts 46 can be inserted in overlapping openings thereof to secure first outer section 40 and second outer section 42 together . the connected structure forms a new twin size headboard 172 for twin size bed frame 150 . it will be appreciated that , with new twin size headboard 172 , mattress support rails 54 and 60 are engaged with each other . in order to secure twin size headboard 172 to twin size bed frame 150 , hollow cylindrical extension legs 174 are connected to one end of each side frame member 52 by mounting plates or brackets 176 , and supporting legs 48 and 50 are removably inserted in hollow cylindrical extension legs 174 . with this arrangement , there is no need to purchase a separate twin size headboard when the child moves from a toddler bed to a twin size bed . in like manner , as shown in fig1 - 13 , toddler bed frame system 30 is adapted to be used with bed frame 150 of a full bed size . specifically , full size bed frame 150 is shown in fig1 - 13 with a box spring 178 and a mattress 180 thereon . in order to convert bed frame system 30 for use with conventional full size bed frame 150 , first outer section 40 is detached from footboard 32 by removing first outer section supporting leg 48 from first outer section 40 by removing the respective bolt 43 , and then reattaching first outer section supporting leg 48 to first outer section 40 after bushing 98 has been removed therefrom . in like manner , second outer section 42 is detached from headboard 36 by removing second outer section supporting leg 50 from second outer section 42 by removing the respective bolt 43 , and then reattaching second outer section supporting leg 50 to second outer section 42 after bushing 118 has been removed therefrom . thereafter , side wall 34 forms a new full size headboard 182 for full size bed frame 150 . in order to secure full size headboard 182 to full size bed frame 150 , hollow cylindrical extension legs 184 are connected to one end of each side frame member 52 by mounting plates or brackets 186 , and supporting legs 48 and 50 are removably inserted in hollow cylindrical extension legs 184 . further , side rail panel 38 and side rail 126 are then detached from headboard 36 . specifically , side rail 126 is detached from headboard 36 by removing bolts 128 . side rail panel 38 is detached from headboard 36 by removing headboard supporting leg 120 from headboard 36 by removing the respective bolt 109 , and then reattaching headboard supporting leg 120 to headboard 36 after cylindrical bushing grips 122 have been removed therefrom . thereafter , the inner side edge of footboard 32 is made to overlap the inner side edge of headboard 36 , and a locator pin 188 can be inserted in respective openings thereof for holding footboard 32 and headboard 36 in a fixed relation . in addition , the removed side rail 126 is connected by bolts 190 to supporting legs 100 and 120 in order to retain footboard 32 and headboard 36 in a fixed relation . locator screws 191 can be inserted through side rail 126 into footboard 32 and headboard 36 to further retain side rail 126 in position . the connected structure forms a new footboard 192 for full size bed frame 150 . in this regard , as shown in fig1 - 13 , hollow cylindrical extension legs 194 are connected to the opposite end of each side - frame member 52 by mounting plates or brackets 196 , and supporting legs 100 and 120 are removably inserted in hollow cylindrical extension legs 194 . with this arrangement , there is no need to purchase a separate footboard when the child moves from a toddler bed to a full size bed . it will be appreciated that various modifications can be made to the present invention within the scope of the claims . for example , the dimensions of first outer section 40 and second outer section 42 can be increased to eliminate center section 44 . in such case , bed frame system 30 would be convertible only to a full size bed . also , in such case , first outer section 40 and second outer section 42 can be formed as a single integral section . having described specific preferred embodiments of the invention with reference to the accompanying drawings , it will be appreciated that the present invention is not limited to those precise embodiments and that various changes and modifications can be effected therein by one of ordinary skill in the art without departing from the scope or spirit of the invention as defined by the appended claims .

a toddler bed frame system is convertible for use with either a twin or full size bed , and includes a toddler side wall having detachable components for this purpose . a first supporting leg is connected to one end of the toddler side wall , and a toddler headboard is detachably and pivotally mounted about the first supporting leg a second supporting leg is connected to the opposite end of the toddler side wall , and a toddler footboard is detachably and pivotally mounted about the second supporting leg . a third supporting leg is connected to the opposite end of the toddler headboard , and a side rail panel is detachably and pivotally mounted about the third supporting leg . a fourth supporting leg is connected at a free end of the side rail panel . a fifth supporting leg is connected at a free end of the toddler footboard .

in the present application the various examples , drawings , apparatuses , systems and processes referring to the extraction of milk from mammals having four teats are brought forth for illustrative purposes only and should be understood as applicable to any mammal having two or more teats . referring now to fig1 , which is a simplified block diagram of a quarter milking system 100 designed for a conventional milking parlor in accordance with an example . four teat cups 102 of a milking cluster 104 are attached to four corresponding teats 140 of an udder 160 of a milking animal . the milk obtained from each individual teat flows via a corresponding short tube 106 into a chamberless ( i . e ., does not include a milk chamber ) separate streams claw ( ssc ) 108 where two or more milk streams 124 are maintained separate from each other and do not come in contact with one another . the milk streams exit ssc 108 separately via corresponding long tubes 110 and flow into a sensing and diverting unit ( sdu ) 112 via distinct nipples 128 ( fig8 ). each of the milk streams is individually analyzed by a dedicated plurality of sensors 114 in sdu 112 and selectively diverted by a changeover valve 116 via a determined collecting line such as a grade a milk line 118 , grade b milk line 120 and scrap milk line 122 into a corresponding collection vat 118 ′, 120 ′ and 122 ′. in the example of quarter milking system 100 illustrated in fig1 , the milk streams obtained from teats 140 are maintained separate throughout the course of their flow from teats 140 to changeover valves 116 . reference is now made to fig2 a and 3b , which are simplified cross - section view illustrations of a conventional or semi - automatic ( fig2 ) and a robotic ( fig3 a and 3b ) milking systems . as shown in fig2 , a conventional or semi - automatic milking system 200 milking cluster 104 . milking cluster 250 includes a milk claw 204 , two or four teat cups 102 connected to two or four short tubes 206 and pulsating vacuum tubes 212 . short tubes 206 could be connected to a milk collecting chamber 208 . milk cluster 104 teat cups 102 are manually attached to each corresponding teat 140 . milk obtained from teats 140 flows via short tubes 206 to single common milk collecting chamber 208 which is commonly an integral part of milk claw 204 . the composite milk accumulated in chamber 208 exits via a single long composite milk tube 210 . cluster 104 pulsating vacuum tubes 212 , fed from one or more common pulsating vacuum tubes 214 ( depicted in fig2 a , 3b and 4 as broken lines ) apply pulsating pressure to each corresponding teat cup 102 to initiate the milking process . the pulsating pressure to the teats is controlled ( i . e ., on / off command ) to all teats collectively and does not to provide individual teat milking control . fig3 a and 3b illustrate robotic milking systems . the robotic system is a quarter milking system in which each teat cup 102 is attached to a corresponding teat 140 and connected to a quarter milk long tube 310 . commonly , and as shown in fig3 a , robotic systems do not include milking claws such as milking claw 204 and each quarter milking long tube 310 carries the milk within directly to a collection vat or a diverting unit . each teat cup 102 is individually supplied by a corresponding pulsating vacuum tube 314 . the pulsating pressure to teat 140 is individually controlled . another robotic system such as the system depicted in fig3 b , could be a semi - quarter milking system having a milk claw including , for example , four separate milk collecting chambers 208 . this is could be considered a semi - quarter milking system as compared to a quarter milking system in that the milk in the milking claw flows into a common collecting basin 316 and exits the milking claw via a single outlet and into a single long composite milk tube 210 , whereas in quarter milking the milk steams remain separate from the teat cup to the milk collection vat . referring now to fig4 , which is a cross - section view simplified illustration of a milking cluster in accordance with an example . a quarter milking system 100 cluster 450 includes two or more teat cups 102 each attached to a corresponding teat 140 , and sealingly connected to a corresponding short tube 106 . tubes 106 could be sealingly connected to a separate streams claw ( ssc ) 108 . ssc 108 could include two or more distinct milk conduits 402 in which milk received from each individual teat 140 via short tubes 106 is maintained separate from milk obtained from the other teats or quarters . conduits 402 are sealingly connected to a multi - conduit tube ( mct ) 404 including corresponding two or more milk conduits 406 . the milk obtained from each gland could be weighed separately , analyzed separately , and kept separate from milk obtained from other glands . in milking of animals with four milk glands , a milking system in which each gland is milked independently could be referred to as “ a quarter milking system ”. one advantage of a quarter milking system is in that contaminated milk obtained from one of an animal &# 39 ; s teats could be prevented from contaminating milk obtained from the animal &# 39 ; s other teats . another advantage is that milk obtained from one teat does not come in contact with milk obtained from another teat thus cross - contamination between glands is avoided . to date , conventional milking , which is the most common way of milking in the world , does not include quarter milking . a milking system for quarter milking in conventional milking parlors requires an operator to handle each teat cup separately which is more time intensive and labor intensive . the cost of current sensor / diverting systems is high and the amount of tubes required to transport the quarter milk from each animal make this option not cost effective . consequently , quarter milking in conventional milking parlors is very expensive , unfriendly to operator and complicated . the solutions currently available on the market that attempt to provide the benefits of quarter milking in conventional milking parlors , while avoiding the costly investment in robots and without changing parlor design and architecture are insufficient . in a quarter milking system , such as system 100 , could provide a low - cost quarter milking chamberless system to a conventional milking parlor in that the number of milk stream entering ssc 108 is identical to the number of milk streams streaming out of ssc 108 . the separate streams streaming out of ssc 108 could be drained by mct 404 thus remaining separate until reaching sdu 112 . ssc 108 could also include vacuum supply conduits or channels 408 ( represented by a broken line ) which could be connected at one end thereof to a corresponding cluster 104 pulsating vacuum tube 212 supplying each individual teat cup 102 and at the other end to a corresponding pulsating vacuum tube 314 . one or more vacuum tubes 314 could be an integral part of mct 404 as will be described in greater detail below . the pulsating pressure to each teat 140 could be individually controlled . unlike in the conventional milk cluster , the vacuum applied to each teat , i . e . quarter , could be controlled individually by a dedicated vacuum supply line including a vacuum tube 314 , ssc 108 vacuum supply conduit 408 and cluster 104 pulsating vacuum tube 212 so that a single quarter could be turned on or off independently of the other quarters . reference is now made to fig5 a , 5b , 5c , and 5d , which are oblique and cross - section views of a separate stream claw ( ssc ) 108 in accordance with an example . fig5 b is a cross - section view of ssc 108 of fig5 a taken along axis w - w . fig5 c and 5d are cross - section views of ssc 108 of fig5 a taken along axis q - q . ssc 108 could have 2 , 4 , or any other number of individual milk stream inlet nipples or tubes 502 ( in fig5 a , nipples 502 - 1 , 502 - 2 , 502 - 3 and 502 - 4 ), individual milk stream conduits 402 , and individual milk stream outlet nipples or tubes 504 . each inlet nipple or tube 502 could be sealingly connected to a single channel or conduit 402 and each channel or conduit 402 could be sealingly connected to a single outlet nipple or tube 504 to provide each milk stream a dedicated sealed pathway and prevent contact between milk streams inside ssc 108 . ssc 108 could be handled similarly to conventional claw 204 from an operator &# 39 ; s standpoint . once milking cluster 104 is attached to an animal , ssc 108 could provide a plurality of individual distinct milk streams , one from each teat or quarter of the animal udder . each inlet nipple or tube 502 could be sealingly connected to a different teat cup so that milk from a teat or quarter of an animal could flow through each short tube 106 into inlet nipple or tube 502 . additionally , ssc 108 negates the use of a milk collecting chamber 208 ( i . e ., it is chamberless ) making cluster 104 much lighter in weight and shorter in length ( measured from the teat cup to the bottom of the milking claw ). the configuration of ssc 108 conduits 402 ( fig5 b ) could be in a form of a tube protected by a molded capsule 510 ( fig5 c ) or a lumen , which is part of a multi - luminal potted enclosure 540 ( fig5 d ) enclosing several conduits 402 as will be explained in greater detail below . conduits 402 could be comprised of or lined with metal , plastic , rubber , glass , composite or a combination thereof . nipples 502 / 504 are configured for ease of sealed connection with teat cups 102 ( fig1 ) short tubes 106 and with long tubes or mct 404 downstream ssc 108 . ssc 108 could also include two or more pulsating vacuum conduits 408 . each of pulsating vacuum conduits 408 could also be sealingly connected at a vacuum outlet nipple 506 at one end hereof to a corresponding teat cup 102 via a pulsating vacuum tube 212 , so that each teat cup 102 is sealingly attached to one milk short tube 106 and one vacuum tube 212 , and at an vacuum inlet nipple 508 located at the other end of pulsating vacuum conduits 408 to a dedicated vacuum source ( not shown ) via vacuum tube 314 ( fig3 a ). pulsating vacuum conduits 408 and pulsating vacuum tubes 212 , as well as nipples 506 / 508 could have a diameter different in size than the diameter of milk stream inlet nipples or tubes 502 , milk stream conduits 402 , milk stream outlet nipples or tubes 504 and / or milk short tubes 106 . commonly , the diameter of vacuum conduits is smaller than that of milk channels , conduits or tubes . referring now to fig5 c and 5d , which are cross - section views of ssc 108 of fig5 a taken along axis q - q at an imaginary level of convergence of conduits 402 / 408 with corresponding milk stream outlet nipples or tubes 504 and vacuum inlet nipples 508 . fig5 c depicts a capsule 510 housing conduits 402 / 408 . a void 560 could be defined between capsule 510 and conduits 402 / 408 and may be filled with a suitable material , air or vacuum as will be explained in greater detail below . alternatively , capsule 510 could tightly envelope conduits 402 / 408 in a spaceless manner , i . e ., without void 560 . as shown in fig5 d , conduits 402 / 408 could be formed by a multi - luminal potted enclosure 540 . conduits 402 / 408 could be made of a same as or a different material than enclosure 540 . in an example , conduits 402 / 408 and enclosure 540 could be produced in the same mold as a unitary structure . alternatively and optionally , conduits 402 / 408 formed by multi - luminal potted enclosure 540 could be coated with a material different than that of enclosure 540 . as shown in fig6 , which is an oblique - view simplified illustration of an arrangement of conduits 402 / 408 inside ssc 108 in accordance with an example , conduits 402 and 408 could be arranged and stacked inside ssc 108 in a manifold configuration 602 prior to encapsulation or formed in a manifold configuration by a potting process . this configuration could improve rigidity and durability as well as good control of conduits 402 and 408 geometry and position . molded capsule 510 and / or enclosure 540 could comprise a polymer such as a thermosetting or thermoplastic polymer . in one example , the thermosetting polymer could be polyurethane , epoxy , unsaturated polyester , vinyl ester polymer , amino resin , phenol resin or silicone - containing polymer . the polymer could be filled with filler or fibers . in another example , molded capsule 510 and / or enclosure 540 could be made of thermoplastic polymer such as acetal , polyurethane , polyamide , polyolefine , polyester , polycarbonate , poly vinyl chloride , acrylic , styrenic and thermoplastic elastomer . in yet another example the capsule could be manufactured by forming , machining and molding of polymer , metal , wood , ceramic or glass , forming or assembled or bonded on conduits 402 / 408 . molded capsule 510 and / or enclosure 540 molding material may be solid or foamed . inner voids or spaces such as void 560 could be left in the capsule to achieve a desired capsule weight . nipples 502 / 504 / 506 / 508 could be made of the same material as , or different materials than , conduits 402 / 408 . ssc 108 could have a weight of 100 - 1000 grams . this weight could include internal conduits 402 / 408 and capsule 510 or potting 540 . the weight of cluster 140 according the current example , which includes ssc 108 , short tubes 106 and teat cups 102 could vary between 0 . 5 to 5 kilograms . the dimensions and weight of ssc 108 could be optimized to be ergonomically suitable for a comfortable grip by the human hand , providing comfort handling for both small size and large size hands . the weight is also optimized to provide a counterbalance to the pulsation stroke . as described above , quarter milking system 100 could also include sdu 112 , which is a mechanism for analyzing and separating milk streams 124 ( fig1 ) based upon characteristics of the milk in each of the streams . typical characteristics could be fat and protein content , electrical conductivity , turbidity , density , flow rate , accumulated volume , presence of blood or blood cells in milk and other similar data . sdu 112 could be compact and configured to be mounted in a conventional milking parlor space without need to change the parlor architecture and design . a plurality of independent milk streams 124 flow downstream from ssc 108 to sdu 112 via long tubes 110 or mct 404 . reference is now made to fig7 a , 7b , 7c and 7d , which are cross section view simplified illustrations of multi - conduit tube ( mct ) 404 in accordance with several examples . in example shown in fig7 a - 7d , mct 404 relatively large diameter conduits 406 commonly convey milk whereas relatively smaller diameter conduits 704 commonly supply vacuum to pulsating tubes 212 via ssc 108 . multi - conduit tube 404 could be a molded flexible block 706 or an extruded flexible block 708 containing two or more milk conduits 406 . mct 404 may include two or more blocks 706 / 708 as shown in fig7 a and 7b , or alternatively and optionally , form a single block as shown in fig7 c and 7d . blocks 706 / 708 could be made of a polymeric material , such as an elastomeric material for example , rubber , thermoplastic elastomer or plastomer . in an example , mct 404 could be made of silicone rubber . the average diameter of conduits 406 may be from about 6 to about 20 mm . when the cross - section of the conduits has a geometrical shape other than a circle , the “ diameter ” refers to the maximum measurement that could be taken across the cross - section of the conduit . mct 404 , as shown in fig7 a - d , could also include conduits 710 in addition to milk conduits 406 and vacuum conduits 704 . conduits 710 could carry , for example , system washing cleaning fluid . mct 404 could also be made of a stack of molded or extruded tubes which are welded , bonded , or mechanically interwoven or joined by means of a mechanical connector . joined mct 404 could provide flexibility for easy maintenance and installation while avoiding issues associated with using a plurality of separate individual conduits . reference is now made to fig8 , which is a simplified milk flow diagram through sdu 112 in accordance with an example . sdu 112 is capable of detecting various attributes of the milk and milk flow of each milk stream 124 separately and provide data to a computerized system that could , based on a pre - defined protocol , activate changeover valves to separate the milk into different output streams 126 based on pre - defined criteria as will be explained in greater detail below . for example , separation of milk from an infected and / or sick quarter from other healthy quarters , separation of fat rich milk from fat thin milk and separating protein rich milk from low protein milk . additionally or alternatively , sdu 112 could detect flow rate and total milk volume from each quarter providing important data regarding animal health and productivity . alternatively and optionally , sdu 112 could only sense each quarter milk separately and provide alerts to the user without automatically diverting the milk . this configuration is lower in cost than sdu 112 with diverting valves , and provides the dairyman or user warning of potential infection in specific quarters . for some users , the separate milking of each quarter , followed by separate sensing and the provision of an alert when necessary could be sufficient . referring back to fig1 , sdu 112 sensors 114 could be of or include , but not be limited to , the type of sensor described in u . s . pat . nos . 5 , 116 , 119 and 5 , 581 , 086 . sensors 114 could be positioned in separate channels , each sensor 114 dedicated to a corresponding milk stream 124 so different streams 124 do not come in contact within sdu 112 . sdu 112 could also be configured to provide a hermetic seal against leaks and the penetration of dirt and / or other contaminants while being easy to service and disassemble . sdu 112 could include a single - piece , two - piece or multi - piece shell made of plastic , glass , ceramic , composite , metal or combinations thereof and sealed by a seal or gasket and be manufactured by injection molding or compression molding or thermoforming of a thermoplastic material such as a polyamide , polysulfone , polyester , an acetal polymer , a polycarbonate , a polypropylene , styrenic , polyvinyl chloride and the like . in one example , sdu 112 could have a height of 280 mm , a width of 200 mm , and a depth of 200 mm . typically , each stream of milk 124 flows through a distinct nipple 128 sealingly attached to mct 404 and into sdu 112 . each milk sensor 114 collects data specific to a corresponding distinct milk stream 124 obtained from a specific teat or quarter . the data from each sensor 114 could be then processed and optionally stored by a microprocessor or computer 802 in sdu 112 . alternatively , the data from each sensor 114 could be transferred to a central computer ( not shown ) where data is processed and further registered , analyzed , and stored . the data is useful for diverting the different milk streams 124 according to a pre - defined protocol , as well as to provide indication of the specific animal health and status . the analysis of the milk could be used to determine to where the milk from each gland is to be diverted . in particular , sdu 112 could include changeover valves 116 , which are configured to allow each milk stream 124 to independently flow to one of a plurality of pathways while restricting each stream from flowing to a pathway other than the determined pathway . changeover valves 116 could be controlled and manipulated pneumatically , automatically or manually , usually with compressed air or a vacuum , electrically or magnetically or by any known method in the art . in the current example depicted in fig8 , changeover valves 116 could be two - way , three - way or four - way valves . the pathways commonly include a high quality grade a milk line 118 , for example high protein or high fat content milk , a lower quality grade b milk line 120 and a scrap milk line ( not shown ), for example milk contaminated by bacteria , blood or inflammatory by - products . milk lines 118 , 120 and 122 could be sealingly connected to sda 112 via a plurality of outlet nipples 130 . additionally to diverting the milk , the information of each milk stream of a specific animal and / or animal udder quarter obtained by sensors 114 could be recorded on a computerized data system and be statistically analyzed . analyzed parameters could include for example , fat content , protein content , blood present in milk , flow , volume , turbidity , density etc . the analyzed data is a useful indicator for animal health , fertility , estrus , feeding deficits and potential disease . processing and analysis may be performed inside sdu 112 by a microprocessor or computer 802 ( fig8 ) or by a remote computer 804 . remote computer 804 may be wired to sdu 112 or be connected through a wireless interface . computer or microprocessor 802 could produce commands to changeover valves 116 to divert milk streams 124 as will be explained in greater detail below . referring now to fig9 a , 9b and 9c , which are cross - section view simplified illustrations of changeover valve 116 in accordance with an example . changeover valve 116 could be a three - way , single membrane , binary controlled valve and include a housing 902 , having a milk inlet 904 , a milk outlet 906 and a scrap milk outlet 908 . housing 902 could be made of any rigid material such as metal , plastic or a composite material , and could be made as a mold or of molded parts . milk outlet 906 and a scrap milk outlet 908 could communicate with milk inlet 904 via corresponding milk conveying channels 910 inside housing 902 . milk conveying channels 910 converge at changeover junction 950 ( encircled in fig9 a by a broken line ), the milk flow therethrough controlled by a resilient plunger head 912 having a milk side 930 and a dry side 940 as will be described in greater detail below . changeover valve 116 could also include resilient sealing membrane 950 having a resilient plunger head 912 , a resilient hollow stem 914 and a resilient base 916 . resilient plunger head 912 could be integrally or adhesively attached to a resilient hollow stem 914 and resilient base 916 together forming a single resilient sealing membrane 950 . a rigid or semi - rigid shaft 918 could be accommodated inside and in parallel to longitudinal axis x of hollow stem 914 , abut or be integrally or adhesively attached at one end thereof to dry side 940 of plunger head 912 . the other end of shaft 918 could be adhesively or integrally attached to a bias retention ring 920 slidingly movable against bias 922 within a piston - like portion 924 of an atmospheric pressure air cavity 926 . housing 902 atmospheric pressure air cavity 926 is maintained isolated from milk inlet 904 , milk outlet 906 and scrap milk outlet 908 by resilient sealing membrane 950 and communicates with atmospheric air via air inlet 960 . fig9 b and 9c illustrate the mode of operation of changeover valve 116 . changeover valve 116 located inside sdu 112 could receive milk through milk inlet 904 streaming from an individual quarter or teat cup 102 , via short tube 106 , ssc 108 , mct 404 conduit 406 and sdu 112 sensors 114 . depending on a signal received from sdu 112 , changeover valve 116 could alternate a selected path of flow of a received milk stream 928 via changeover junction 950 to milk outlet 906 or scrap milk outlet 908 . under normal operating conditions , milk paths 910 are under sub - atmospheric pressure induced by one or more vacuum pumps ( not shown ) operating via milk outlet 906 or scrap milk outlet 908 . at this point in time , atmospheric air inlet 960 is maintained closed by a single binary ( on / off type ) valve 970 . pressure on resilient plunger head 912 milk side 930 exerted by milk being suctioned via milk conveying channel 910 - 1 ( fig9 b ) and milk outlet 906 to one end of shaft 918 assisted by pressure exerted by bias 922 on the other end of shaft 918 bring about stem 914 of membrane 950 to slide in a direction indicated by arrow 980 opening a passageway 952 in junction 950 allowing the milk stream to flow towards milk outlet 906 . under conditions in which milk is determined by sdu 112 to be scrap milk , sdu 112 opens valve 970 allowing atmospheric air to enter in a direction indicated by arrow 985 into atmospheric pressure air cavity 926 . the sub - atmospheric pressure in milk conveying channel 910 - 1 applies negative pressure to plunger head 912 milk side 930 pulling plunger head 912 as well as shaft 918 in a direction indicated by arrow 990 against bias 922 thereby spring - loading bias 922 . the movement of plunger head 912 milk side 930 brings about the sealing of passageway 952 and the opening of passageway 954 in junction 950 allowing the milk stream to flow towards milk outlet 908 as indicated by a broken line and into milk conveying channel 910 - 2 ( fig9 c ). it will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove . rather , the scope of the invention includes both combinations and sub - combinations of various features described hereinabove as well as modifications and variations thereof which would occur to a person skilled in the art upon reading the foregoing description and which are not in the prior art .

a compact milking system for conventional milking parlors . the system supports individual milking of each of the milk glands . the system possesses a compact form and weight providing conventional milking parlors with capabilities currently supported only by costly robotic milking systems . the system comprises at least two teat cups attachable to an animal &# 39 ; s udder ; at least one multi - conduit tube having at least two milk conduits ; at least one separate streams claw wherein each milk stream communicates with only one teat cup and one mct milk conduit ; and one sensing and diverting unit communicating with the mct and operative to separately receive and analyze milk from each mct milk conduit .

referring now in detail to the drawings wherein like reference numerals identify similar structural features of the several embodiments of the subject invention , there is illustrated in fig1 an isometric view of a preferred embodiment of the present invention . mask portion 2 is operatively connected to handle portion 1 . mask portion 2 includes ventilation structure 3 disposed generally in the lower portion of exterior surface 20 , and includes ventilation holes 31 in the form of perforations contained in raised surface 30 . flange 21 extends around the periphery of mask portion 2 . handle portion 1 includes front portion 11 and rear portion 12 operatively connected to one another by hinge assembly 5 and maintained in closed orientation by latch assembly 4 . latch assembly 4 includes concave portion 43 formed in front handle portion 11 . concave portion 43 contains aperture 42 , through which hook 41 extends . hook 41 is permanently affixed to rear handle portion 12 , preferably integrally molded with rear handle portion 12 , and is upwardly biased so as to maintain tight contact with surface 44 , thereby maintaining handle portion 1 in a closed orientation . hook 41 may be pressed downward so as to disengage from surface 44 and move through aperture 42 , thereby permitting handle portion 1 to transition to an open orientation . [ 0032 ] fig2 shows a front plan view of a preferred embodiment of the present invention . mask portion 2 is operatively connected to handle portion 1 . mask portion 2 includes ventilation structure 3 disposed generally in the lower front portion of exterior surface 20 , and includes ventilation holes 31 in the form of perforations contained in raised surface 30 . flange 21 extends around the periphery of mask portion 2 at the trailing edge 27 of mask portion 2 . tab 22 extends downwardly from mask portion 2 , where it is engaged between front handle portion 11 and the rear handle portion ( not shown ). when tab 22 is placed between front handle portion 11 and rear handle portion 12 and handle portion is placed into its closed orientation , front handle portion 11 and rear handle portion 12 actively clamp tab 22 , effectively securing mask portion 2 to handle portion 1 . bottom support surface 24 of mask portion 2 is shaped so as to conform substantially with curved top portion 14 of handle portion 1 . front handle portion 11 includes concave portion 43 , which forms part of the latch assembly . hook 41 extends through aperture 42 and abuts surface 44 , maintaining the handle portion in a closed orientation . inner hinge element 51 is located in the bottom portion of handle portion 1 and extends from front handle portion 11 . inner hinge element 51 is operatively received between outer hinge elements 52 , which define an interstitial space dimensioned so as to maintain inner hinge element 51 between outer hinge elements 52 . inner hinge element 51 and outer hinge elements 52 allow rotational movement of front handle portion 11 relative to rear handle portion 12 about the hinge assembly . [ 0035 ] fig3 shows a side plan view of a preferred embodiment of the present invention . mask portion 2 is operatively coupled to handle portion 1 , which is comprised of front portion 11 and rear portion 12 . hook 41 of the latch assembly extends through the aperture of the latch assembly ( not shown ). bottom support surface 24 of mask portion 2 is supported on handle portion 1 on support surface 15 formed in the top of front handle portion 11 . [ 0036 ] fig4 shows a rear plan view of mask portion 2 of a preferred embodiment of the present invention . ventilation structure 3 is disposed generally in the lower portion of interior surface 25 , and includes ventilation holes 31 in the form of perforations contained in raised surface 30 . interior surface 25 is generally concave in shape , thus defining a cavity 26 . flange 21 extends around the periphery of mask portion 2 . tab 22 extends downwardly from mask portion 2 . [ 0037 ] fig5 shows an isometric view of the handle portion of a preferred embodiment of the present invention . front handle portion 11 includes concave portion 43 , which in turn contains aperture 42 , through which hook 41 extends , as described in greater detail above . handle portion 1 includes curved top portion 14 formed in the top of both the front and rear handle portion . support surface 15 is formed in the top of front handle portion 11 . together , curved top portion 14 and support surface 15 help to support a mask portion ( not shown ) that is operatively connected to handle portion 1 . [ 0038 ] fig6 and 7 are side plan views of the handle portions of a preferred embodiment of the present invention shown in closed and open orientations respectively . front portion 11 is maintained abutted to rear portion 12 by hook 41 when in the closed position and is allowed to pivot about the hinge assembly ( not shown ) when hook 41 is pressed downward , thereby being allowed to move through the aperture ( not shown ) of the latch assembly and permitting the handle to transition to an open orientation . support surface 15 is disposed at the top of front portion 11 . [ 0039 ] fig8 a shows a section of rear handle portion 12 , at the bottom of which are disposed outer hinge elements 52 . the space between outer hinge elements 52 is dimensioned to accept inner hinge element 51 , shown in fig8 b in side view extending from front handle portion 11 . [ 0040 ] fig9 a shows a section of front handle portion 11 . concave portion 43 contains aperture 42 and surface 44 . hook 41 , shown in fig9 b in side view extending from a section of rear handle portion 12 , is permanently affixed to rear handle portion 12 , and is preferably integrally molded with rear handle portion 12 . while particular embodiments of the present invention have been shown and described , it will be apparent to those skilled in the pertinent art that changes and modifications may be made without departing from the invention in its broader aspects .

a protective face shield comprising a mask portion and a handle portion , the mask portion having an exterior surface and an interior surface . the mask portion is readily operatively attachable to and removable from the handle portion , and the interior surface definines a cavity adapted to accept a substantial portion of a users face .

illustrative embodiments of the invention are described below . in the interest of clarity , not all features of an actual implementation are described in this specification . it will of course be appreciated that in the development of any such actual embodiment , numerous implementation - specific decisions must be made to achieve the developers &# 39 ; specific goals , such as compliance with system - related and business - related constraints , which will vary from one implementation to another . moreover , it will be appreciated that such a development effort might be complex and time - consuming , but would nevertheless be a routine undertaking for those of ordinary skill in the art having the benefit of this disclosure . the spinal implants disclosed herein boast a variety of inventive features and components that warrant patent protection , both individually and in combination . fig1 - 6 illustrate an example of a surgical fixation system , according to an exemplary embodiment . the surgical fixation system comprises a surgical fixation plate 10 , a plurality of screws 38 ( only two of four shown ), and a plurality of anti - backout elements 20 . as will be explained in greater detail below , the surgical fixation system may be used to provide temporary or permanent fixation along an orthopedic target site , including but not limited to adjacent vertebral levels within the spine ( e . g . cervical spine during anterior fusion surgery , lumbar spine for anterior fusion surgery , etc . . . . ). to do so , the plate 10 is first positioned over the target site such that the screws and anti - backout elements 20 may thereafter be employed to couple the plate 10 to the target site . according to one aspect of the present invention , the screws 38 are prevented from backing out of the target site after placement through the use of the anti - backout elements 20 installed within the plate 10 . the surgical fixation plate 10 includes a first surface 12 , a second surface 14 , and a plurality of bone screw apertures 30 extending between the first and second surfaces 12 , 14 . each bone screw aperture 30 has a corresponding anti - backout element 20 for preventing back - out of only one screw 38 . the anti - backout element 20 resides in a recess 40 in first surface 12 of the plate 10 adjacent to the bone screw aperture 30 . the plate 10 may be provided having any number of different peripheral profiles , including but not limited to the generally rectangular peripheral profile set forth by way of example in the figures . the plate 10 may also be provided with or without a viewing aperture 40 formed between the first and second surfaces 12 , 14 and positioned generally in the central portion of plate 10 . the viewing aperture 40 functions to provide the ability to see or visualize the spinal target site after the plate 10 has been secured to the patient &# 39 ; s vertebrae . it will be appreciated that the viewing aperture 40 may be provided in any number of suitable shapes or configurations without departing from the scope of the invention . insertion tool recesses 32 may be provided on the lateral sides of the plate 10 for receiving at least a portion of an insertion instrument . by way of example only , the plate 10 shown in fig1 - 6 includes a pair of insertion tool recesses 32 , with one located at each side of the plate 10 . fig1 - 6 illustrate a plate 10 having an anti - backout element 20 according to an exemplary embodiment . the anti - backout element 20 includes a locking slide 22 and a biasing member 24 . the biasing member 24 is coupled to the plate 10 medial to the locking slide 22 , and urges the locking slide 22 toward the screw aperture 30 . the biasing member 24 is elastically deformable , such that when a bone screw 38 is inserted into the screw aperture 30 , the head of the screw will urge the locking slide 22 away from the screw aperture 30 against the biasing member 24 , thereby deforming the biasing member 24 . upon passage of the screw head past the locking slide 22 , into the screw aperture 30 , the biasing member 24 will urge the locking slide 22 back toward the screw aperture 30 . at least a portion of the locking slide 22 will project into the screw aperture 30 ( as best shown in fig3 ), and over the proximal edge of the screw head , thereby preventing the screw from backing out of the screw aperture 30 of the plate 10 after insertion . the locking slide 22 has a medial face 36 for engaging the biasing member 24 and a lateral face 34 for engaging the head of a bone screw 38 . according to the exemplary embodiment shown in fig1 - 6 , the lateral face 34 that engages the head of a bone screw has a chamfered surface 28 , such that during insertion of a bone screw 38 into a bone screw aperture 30 of the plate 10 , when the head of the bone screw contacts the chamfered surface 28 of the locking slide 22 , the medial surface 36 of the locking slide 22 will be urged against the biasing member 24 as discussed above . the locking slides may engage with the spinal fixation plate 10 within a recess 40 in the spinal fixation plate 10 , wherein said recess 40 is located medially to a pair of screw apertures 30 ( as best shown in fig5 ). according to an exemplary embodiment , the locking slides 22 have a recess 44 that corresponds to a track 42 in the recess 40 in superior surface 12 of the plate 10 . the track 42 engages the locking slide 22 via the recess 44 in the locking slide 22 and maintains the locking slide 22 within the plate 10 . as such , the locking slide 22 is capable of sliding in a first direction toward its corresponding screw aperture 30 and in second direction , opposite the first direction , away from a corresponding screw aperture 30 and toward the biasing member 24 . fig7 - 8 illustrate a spinal fusion implant assembly 100 according to an exemplary embodiment . the spinal fusion implant assembly 100 is a two - piece assembly including a plate 110 having locking elements 220 , a plurality of bone screws 306 and a generally u - shaped body 120 . the assembled two - piece implant 100 is dimensioned to be contained entirely within the intervertebral space when implanted . according to the exemplary embodiments , the plate 110 and body 120 are constructed of different materials . for example , the plate 110 may be constructed of any biocompatible metal , such as titanium . the body 120 may be constructed of any suitable non - bone composition having suitable radiolucent characteristics , including but not limited to polymer compositions ( e . g . poly - ether - ether - ketone ( peek ) and / or poly - ether - ketone - ketone ( pekk )) or any combination of peek and pekk . according to an exemplary embodiment shown if fig1 , the arms of the u - shaped body may have chamfered surfaces where the body 120 engages the plate . the spinal fusion implant assembly 100 includes a top surface 90 , a bottom surface 95 , two lateral sides , an anterior side 80 , and a posterior side 85 ( each defined relative to the regions of the target disc space when implanted ). according to a preferred method of implantation the spinal fusion implant 100 may be implanted from an anterior approach such that anterior side 80 is the trailing side and posterior side 85 is the leading side during insertion . the plate 110 defines the anterior side 80 of the implant and includes a plurality of bone screw apertures 302 , 304 each for receiving a bone screw therethrough . according to the exemplary embodiments , the screw apertures 302 , 304 are positioned such that there is a lateral upper screw hole , a medial upper screw aperture , a lateral lower screw aperture , and a medial lower screw aperture . the upper screw apertures 302 pass through the plate 110 at an angle such that when the bone screws 306 are inserted into the upper screw apertures 302 , they extend from the plate 110 at an angle and penetrate into the vertebral body inferior to the implant assembly 100 . by way of example only , the upper screw apertures 302 may be angled such that the bone screws penetrate into the vertebral body at an angle between 35 and 55 degrees , and preferably 45 degrees . lower screw apertures 304 also pass through the plate 110 at an angle , but in the opposite direction of the upper screw apertures 302 . thus , when the bone screw 306 is inserted into the lower screw apertures 304 , it extends from the plate 110 at an angle and penetrates the vertebral body superior to the implant assembly 100 . by way of example , the lower screw apertures 304 may be angled such that the lower bone screws 306 penetrate into the vertebral body at an angle between 35 and 55 degrees , and preferably 45 degrees . the screw apertures 302 , 304 may also be angled such that the distal end of the bone screws 306 converge towards each other . by way of example , the screw apertures 302 , 304 may be oriented such that the bone screws 306 are angled medially between 5 and 15 degrees . according to the exemplary embodiment illustrated in fig7 - 8 , the plate 110 further includes an anti - backout element 220 that corresponds to each individual screw aperture 300 . the anti - backout element 220 includes a locking slide 222 and a biasing member 224 . the anti - backout element 220 functions in a way that is similar to the anti - backout element 20 described with respect to the spinal fixation plate 10 discussed above . a pair of locking elements 220 resides in a recess in the anterior surface of the plate 110 between a pair of screw apertures 300 . the biasing member 224 is elastically deformable , such that when a bone screw 306 is inserted into the screw aperture 300 , the head 308 of the screw will urge the locking slide 222 away from the screw aperture 300 against the biasing member 224 , thereby deforming the biasing member 224 . upon passage of the screw head 308 past the locking slide 222 , into the screw aperture 30 , the biasing member 224 will urge the locking slide 222 back toward the screw aperture 300 . at least a portion of the locking slide 222 will project into the screw aperture 300 , and over proximal end of the screw head 308 , thereby preventing the screw 306 from backing out of the screw aperture 300 of the plate 110 after insertion . according to one embodiment , the body 120 includes at least one radiopaque marker 126 . further , the body 120 may also include anti - migration elements . anti - migration features are designed to increase the friction between the spinal fusion implant assembly 100 and the adjacent contacting surfaces of the vertebral bodies so as to further prohibit migration of the spinal fusion implant 100 after placement and during the propagation of natural bony fusion . such anti - migration features may include ridges ( or teeth ) provided along at least a portion of the top surface 90 and / or bottom surface 95 . fig9 - 11 illustrate an alternative embodiment of the spinal fusion implant assembly 100 . this embodiment includes all of the same features as the exemplary embodiment of fig7 - 8 . according to this embodiment , the plate 110 is generally u - shaped and the body 120 is generally u - shaped . the screw apertures 300 extend through the plate 110 from the anterior surface 80 through the top surface 90 ( for lower screw apertures ) of the plate 110 or the bottom surface 95 ( for upper screw apertures ) of the plate 110 . with regard to the embodiment shown in fig7 - 11 , it is contemplated that the spinal fusion implant assembly 100 can be assembled prior to insertion into the intervertebral space and implanted as a single complete implant , or the implant assembly 100 can be assembled within the intervertebral disc space in a multi - step process including inserting the body 120 into the intervertebral space , packing the body 120 and / or disc space adjacent the body 120 with bone growth enhancing material , then inserting the plate 110 and coupling the plate 110 to the body 120 , thereby enclosing bone growth material in the interior space of the implant assembly 100 . both methods of implantation are preferably achieved through a standard anterior approach . in order to facilitate assembly of the implant 100 within the intervertebral space , the body 120 includes an insertion tool aperture 124 to enable the body 120 of the assembly to be implanted in the intervertebral space before the plate 110 . according to the embodiments shown in fig7 - 11 , the body further includes apertures 122 dimensioned to receive a guide element , such as a pin or wire ( not shown ). by way of example only , the guide element apertures 122 may be threaded to receive a guide element with a threaded distal end . accordingly , the plate 110 also includes apertures 112 dimensioned to allow passage of a guide element therethough . the guide apertures 122 in the body align with the guide apertures 112 in the plate , such that after the body 120 is implanted in the intervertebral space with guide elements attached , the plate 110 can be inserted to align with the body 120 . the plate 110 further includes engagement features 140 that correspond to engagement features 150 on the body to facilitate coupling of the plate 110 to the body 120 upon insertion of the plate 110 into the intervertebral space . once the plate 110 is coupled to the body 120 within the disc space , the guide elements may be removed from the implant assembly 100 . the spinal fusion implant assembly 100 may be used to provide temporary or permanent fixation along an orthopedic target site . once deposited in the intervertebral disc space , the spinal implant assembly 100 effects spinal fusion over time as the natural healing process integrates and binds the implant 100 within the intervertebral space by allowing a bony bridge to form through the implant 100 and between the adjacent vertebral bodies . top surface 90 and opposed bottom surface 90 are both adapted for contact with the upper and lower vertebra adjacent the disc space . bone screws may be introduced through the screw apertures 300 and into the adjacent vertebral bodies to fix the implant assembly 100 in the desired position within the disc space . according to an additional embodiment , the top and bottom surfaces 90 , 95 may be angled between the anterior side 80 and posterior side 85 . in lumbar and cervical applications , the posterior side 85 will preferably be shorter in height than the anterior side 80 such that the implant 100 tapers down from anterior side 80 to posterior side 85 . for example , the posterior - to - anterior angle of the tapered top and bottom surfaces 80 , 85 may range from 5 ° and 15 ° relative to a horizontal axis , and preferably 8 ° to 12 °. in this manner , the implant 100 helps maintain the adjacent vertebral bodies in lordosis , which is the natural curvature found in the lumbar and cervical regions of the spine . the top and bottom surfaces 80 , 85 may be configured in any number of suitable shapes to better match the natural contours of the vertebral end plates , such as , for example , concave , convex , or a combination of concave and convex . fusion may be facilitated or augmented by introducing or positioning various osteoinductive materials within cavity between the plate 110 and the body 120 and / or adjacent to the spinal fusion implant assembly 100 within the intervertebral space . such osteoinductive materials may be introduced before , during , or after insertion of the exemplary spinal fusion implant assembly 100 , and may include ( but are not necessarily limited to ) autologous bone harvested from the patient receiving the spinal fusion implant assembly 100 , bone allograft , bone xenograft , any number of non - bone implants ( e . g . ceramic , metallic , polymer ), bone morphogenic protein , and bio - resorbable compositions , including but not limited to , any of a variety of poly ( d , l - lactice - co - glycolide ) based polymers .

the present invention relates generally to medical devices and methods for use in spinal surgery . in particular , the disclosed devices relate to a spinal fixation system and an intervertebral spinal implant assembly sized and dimensioned for the lumbar spine implantable via an anterior or anterolateral approach . the devices include an implant , bone screws , and an improved locking mechanism to prevent the back out of screws .

in preferred embodiments of the present invention illustrated in the drawings , specific terminology is employed for the sake of clarity . however , the invention is not intended to be limited to the specific terminology so selected , and it is to be understood that each specific element includes all technical equivalents which operate in a similar manner to accomplish a similar purpose . in contrast to known furniture , preferred embodiments of the present invention comprise a lattice of interlocking slats of wood laminate . the slats have indentations allowing the slats to fit across one another securely in an interlocking arrangement , thus forming furniture of structural soundness . wood provides a material that is light in weight , easy to finish , and low in cost . the same may be said with regard to aluminum . according to the present invention , the wood laminate slats alone may form both the supporting structure and the visible surfaces of the furniture . this is in contrast to known furniture of comparable weight , in which either thicker , heavier slats are employed ( such as in u . s . pat . nos . des . 296 , 628 and des . 266 , 545 ); or a support structure of thicker beams supports a surfacing of a lighter material supported between the beams ( such as in u . s . pat . nos . des . 151 , 967 and des . 12 , 144 ). fig1 and 3 illustrate exemplary embodiments of chairs according to the present invention . fig1 and 1a illustrate a chair comprising seat 102 , left and right side portions 106 , front portion 104 flanked by front edge slats 110 and 112 and chair back 108 . seat 102 is a planar utilization area made up of an interlocking lattice of six longitudinal slats and five lateral ( or transverse ) slats , the lattice manufactured according to the present invention . support for the seat is provided by left and right side portions 106 , front edge slats 110 and 112 , front portion 104 , and rear portion 124 . the back portion 108 , has six pairs of parallel slats , each pair comprising a frontwardly facing back slat 105 , ending at the top of the chair back 108 , and a rearwardly facing back slat 107 also ending at the top of the chair back 108 . only frontwardly facing back slats 108a through 108f are specifically numbered in fig1 but it is understood that the slats 108a through 108f are paired with rearwardly facing back slats 107 collectively illustrated in fig1 a as 108rf . side portion 106 comprises five vertically oriented slats 106a through 106e which are continuous extensions of the slats which comprise the five lateral slats of the seat 102 . they first extend downwardly , then curving inwardly to meet the ground , providing support for the seat portion . front portion 104 comprises four slats 104b through 104e which are continuous extensions of the four center longitudinal slats that are part of seat portion 102 . slats 104b through 104e extend downward from the seat portion 102 at an angle of approximately 45 ° with respect to the horizontal seat 102 . slats 104b through 104e extend downward to reach the ground , thus providing further support to the seat portion . slats 104b through 104e continue along the ground horizontally for approximately 1 / 4 the distance of the longitudinal depth of the seat portion 102 , and are interwoven with slat 106e which extends the entire transverse width of the chair . after being interwoven with slat 106e , the slats 104b through 104e curve upward in a substantially vertical rear portion 124 , shown most clearly in fig1 a . rear portion 124 extends from the ground to back portion 108 , forming the rear middle four slats 107 thereof . front edge slats 110 and 112 are continuous extensions of the two outermost longitudinal slats of seat 102 . front edge slats extend downwardly at an angle of approximately 82 ° with respect to the horizontal seat portion , extending to run rearwardly along the ground in a woven relationship with slats 106a through 106e for a distance slightly less than the longitudinal depth of the seat portion 102 . the two opposite segments of the edge slats which run along the ground are illustrated in fig1 as base portions 120l and 120r . the base slats 120l and 120r have consecutive alternate indentations for receiving the ends of side slats 106a through 106d and the continuation of slat 106e , thus securing the bottom of the side portion to an extension of the edge of the front portion . curving upwardly from the rear end of base portions 120l and 120r are rear edge slats 114 which in turn continuously extend upwardly to comprise two of the rearwardly facing outermost back slats 107 of back portion 108 . as shown in fig1 a , the two rear edge slats 114 project rearwardly from the bases 120l and 120r ( fig1 ) by a different amount than do the four inner slats of rear portion 124 . the more localized front portion 104 and rear portion 124 enable greater central support for the individual sitting on the center of the chair . the edge slats comprising front edge slats 110 , 112 , bases 120l and 120r , and rear edge slats 114 are further from the center of the chair so as to provide a broader base of support , which is important for the stability of the chair . as these structures extend further from the center of gravity of the chair , the individual may shift his or her weight forward , backward , or laterally with a reduced possibility of the chair tipping over . as already mentioned , back portion 108 has six parallel paired slats 108a through 108f . one slat 105 of the pair extending continuously upward from the longitudinal slats of seat portion 102 , and the second slat 107 of the pair ( collectively indicated by reference numeral 108rf ) projecting continuously upward from rear edge slats 114 and back portion 124 . in this manner , the six slats comprising frontwardly facing back slats 108a through 108f ; the longitudinal slats of seat portion 102 ; the front edge slats 110 and 112 and the front portion slats 104b through 104e and the portions of the slats running along the ground ; rear portion slats 124 and rear edge slats 114 ; and rearwardly facing back slats 108rf comprise a set of six continuous slats , curved so as to interlock with the five transverse slats 106a through 106e to form the chair described above . in the embodiment of fig1 the two outermost slats 110 and 112 are nearly identical , differing only in their complementary indentations for receiving lateral slats 106a through 106e . the inner four longitudinal slats 104b through 104e are nearly identical ; the second ( 104b ) and fourth ( 104d ), and the third ( 104c ) and fifth slats ( 104e ), are identical . similarly , side slats 106a and 106c may be identical , as may side slats 106b and 106d , because they all traverse a path from the ground upward , then laterally through the seat 102 , downward along the opposite side portion , and terminating in the other longitudinal edge slat on the ground . in this arrangement , therefore , the number of types of components is minimized , thus simplifying manufacturing and reducing manufacturing cost . transverse slat 106e is continuous laterally through base portions 120l and 120r , as well as front slats 104b through 104e . in the embodiment shown in fig1 and 1a , cross - supports 116a and 116b are employed as horizontal braces to the vertical slats of back portion 108 . the cross - supports are affixed between corresponding pairs of frontwardly facing back slats 108a through 108f , and rearwardly facing back slats 108rf . cross - support 116a is disposed approximately 80 % of the way from the seat portion 102 to the top edge of back slats 108a through 108f . cross - support 116b , which may be identical in construction to cross - support 116a , is disposed approximately 15 % of the way from the seat portion to the top edge of back slats 108a through 108f . cross - supports 116a and 116b are flat segments of wood laminate , not possessing any indentations . cross - supports 116a and 116b maintain the back slats 108a through 108f in alignment by being glued at cross - points to back slats 108a through 108f and 108rf . cross - support 116a is a bent lamination conforming to a segment of a 36 &# 34 ; radius arc , whereas cross - support 116b is a straight member . insertion of cross - support 116a at the upper part of the chair back introduces a concave reformation of the back slats 108a through 108f from a flat plane at the base of the chair back formed by cross - support 116b to that of a curved arc . this adds physical comfort and security to the user . in the chair illustrated in fig1 and 1a , therefore , only four distinct components are needed to construct an entire chair ; specifically , two longitudinal edge slats , four inner longitudinal slats , five transverse slats , and two cross - supports . in this manner , the number of components and the number of types of components are reduced . fig2 illustrates a second embodiment of a chair fabricated in accordance with the present invention . most components of the fig2 chair correspond to those in the fig1 embodiment , such as seat portion 202 , side portions 206 , front edge slats 210 and 212 , rear edge slats 214 , back portion 208 , and receding front portion 204 . additionally , however , arm rest 220 and arm rest support 224 are provided . arm rest 220 is a slat of laminated wood having a single bend between a longer , horizontal portion 220a and a shorter vertical portion 220b extending from the front end of the horizontal portion . arm rest support 224 comprises a lattice of interlocking slats of the same type as seat portion 202 . in the illustrated embodiment , the lattice comprises two horizontal slats 224a and 224b which extend continuously from one arm rest from portion 220b to the other while being interwoven with back portion 208 . the fig2 embodiment thus replaces the straight cross - supports 116 of fig1 with an interlocking - slat lattice structure 215 including slats 216 . slats 216 advantageously comprise continuations of horizontal slats from arm rest supports 224 so as to provide additional structural cohesion between the back and sides of the chair . each arm rest 224 has five vertical slats 224c through 224g which overlap with the two horizontal slats 224a and 224b to form an interlocking lattice structure 217 . the top ends of the vertical slats 224c through 224g bend inwardly and horizontally to be affixed to the underside of correspond arm rest 220 . the bottom ends of the five vertical slats are affixed as by an adhesive to the outer surfaces of the five corresponding slats 206a through 206e of side portion 206 . the two horizontal slats such as slat 216 occupy only approximately the bottom one - third of the back portion 208 , so that only one - third of the back portion is a lattice . the upper two - thirds of the back portion are six pairs of parallel slats which project upwardly as continuations of the longitudinal slats which project from the lattice in the lower one - third . no cross - supports are present , as they are in the fig1 embodiment . in the fig2 configuration , the upper two - thirds of the chair is allowed to more fully conform to the back of an individual who sits in the chair . advantageously , the total number of types of parts in the chair is kept small by repeated use of identically - shaped , or nearly identically - shaped slats of wood . in addition to the slats which are repeated in the same manner of the fig1 embodiment , the arm rests are identical , and the horizontal and vertical slats which comprise the arm rest supports are nearly identical , varying only in their alternation of indentations for securing the lattice structure . fig3 through 5 illustrate a third embodiment of a chair 310 fabricated in accordance with the present invention . the third embodiment further illustrates application of the interlocking slat structure of the invention . both seat portion 302 and back portion 308 comprise lattices of interlocking slats . unlike the embodiments of fig1 and 2 , the fig3 embodiment provides that the five transverse slats , and the six frontwardly projecting longitudinal slats curve downwardly and then inwardly in a 180 ° arc . at the ends of their respective arcs , the slats are joined by a slat running transverse to them . specifically , on the underside of chair 310 there is a support brace 320 made up of four flat slats 320f , 320l , 320r and 320b that are arranged in a square . the longitudinal slats 330a through 330f terminate in an alternating arrangement and are glued to the upper surface of slat 320f as viewed in fig3 and to slat 320b . similarly , the leftmost of slats 302a through 302e are glued to slat 320l . the rightmost part of slats 302a through 302e are glued to slat 320r . arm rest portions 328 comprise five vertically oriented slats 328a through 328e which first extend upward , and then curve back downward , to interlock at two points with a horizontal slat 326 which curves back around on itself in an analogous fashion . thereafter , the five arm rest slats continue downward to comprise the five vertically oriented slats 306a through 306e of side portion 306 . finally , the vertically oriented slats 306a through 306e curve gently inward and upward in a 180 ° arc , and are secured to the underside of slats 320l and 320r . at the bottom of the arc , 90 ° into the 180 ° arc , the chair touches the ground . horizontal slat 326 extends from the rear outside portion of one arm rest forward to the front of the arm rest , curving inward and backward in a 180 ° arc 326a , then extending rearwardly to join in an interlocking fashion the vertical slats of the arm rest along both its forward and rearward extensions . thereafter , slat 326 curves inwardly 90 ° to traverse the back portion 308 in an interlocking arrangement with the slats in the rear part 309 of chair back 308 . on the opposite side of the back portion , slat 326 traverses a path which is a mirror image of its path on the first arm rest . in this manner , slat 326 joins and provides mutual structural stability to the back portion , arm rests and side portions . front portions 104 and 204 ( from fig1 and 2 ) have been replaced with an interlocking support structure in which longitudinal seat portion slats 330a through 330f curve 180 ° to interlock with the slats making up support structure 320 . slats from side portion 306 curve upward from the ground to support the interlocking areas of the seat portion &# 39 ; s longitudinal and lateral slats 330 and 332 . in this arrangement , a substantial cushioning effect is achieved . as the individual sits on the seat portion 302 of the chair , the curved arcs of the longitudinal and transverse slats which are extensions of the seat portion &# 39 ; s lattice are bent slightly by the weight of the individual . similarly , the weight causes the bottom arc of side portion slats 306a through 306e to bent , cushioning shock which would otherwise be transmitted from the ground through the side portions . in back portion 308 , the top ends of the six longitudinal slats 308a through 308f , and both ends of the five transverse slats 318a through 318e of the back portion curve rearwardly and then inwardly in 180 ° arcs so as to form a woven lattice 309 that matches the woven lattice 307 defined on the chair back 308 . such a back portion structure provides a shock absorbing and cushioning effect as the individual leans back against the back portion of the chair . fig6 a illustrates in side view a short section of a wood laminate slat ( generally illustrated as element 402 ) which may comprise the basic building element of the interlocking slat lattice according to the present invention . the slat comprises two major faces which are bent in the following manner . a central imaginary plane 404 ( perpendicular to the plane of the drawing figure ) defines the location of alternating contact surfaces 414 , 416 , 414 , 416 . . . these alternating contact surfaces 414 and 416 are faces of corresponding parallel segments 408 and 412 , which are located on opposite sides of the central plane 404 . consecutive parallel segments 408 and 412 are joined by connecting segments 406 and 410 which pass through the central plane 404 at an angle so as to join consecutive parallel segments . fig6 b illustrates the manner in which slats overlap and interlock so as to form the lattice structure which provides the aesthetic and structural advantages of furniture according to the present invention . fig6 b illustrates the slat 402 of fig6 a in conjunction with perpendicular slats 420 , 422 , 424 and 426 ( shown in cross section , as they are perpendicular to the plane of the drawing figure ). the perpendicular slats contact the original slat 402 at contact surfaces 414 and 416 . because the thickness of slats 420 , 422 , 424 and 426 is substantially the same as slat 402 , and because the perpendicular slats intersect the original in the central plane 400 , two surface planes 430 and 432 are defined by the outer surfaces of the interlocking slats . the choice of slats having substantially identical thickness allows a smooth surface to be presented to the user of the furniture . that is , when considering a surface of the furniture which is large compared to the slats , a substantially smooth surface is experienced . this implies that , when a person sits in the chair , he or she does not experience an irregular surface which may cause discomfort . advantageously , the angles of interconnecting segments 406 and 410 on the main slat ( fig6 a ) prevent adjacent parallel slats 420 through 426 from shifting laterally on slat 402 . the intersecting slats are preferably affixed to one another using adhesive at the contact surfaces so as to enhance the structural strength provided by their interlocking configuration . by securely affixing the perpendicular slats , any stress placed upon one slat is passed on more efficiently to adjacent slats , in both the longitudinal and lateral directions , so that the overall configuration is capable of withstanding increased stresses from weight bearing . in a preferred embodiment , the slats shown in fig6 b may be fabricated thin in width w ( such as 2 &# 34 ;) with narrow spaces s between adjacent parallel slats ( such as 0 . 75 &# 34 ;), so that an individual sitting on or feeling the furniture is presented with a substantially smooth and continuous planar surface 430 or 432 . individual slat thickness t of 3 / 16 &# 34 ; allows a total lattice thickness 2t of only 3 / 8 &# 34 ;, rendering the furniture light in weight and appearance . of course , the slats may be of dimensions other than the specific dimensions provided here . typical slat widths w may range from 1 / 2 &# 34 ; to 5 &# 34 ;, with corresponding separation s of 3 / 8 &# 34 ; to 1 &# 34 ;, and thickness t of 1 / 8 &# 34 ; to 3 / 8 &# 34 ;. more generally , slat thickness , width and separation should be chosen in light of considerations of strength , aesthetics and interlocking characteristics . for example , a widening of the separation may lighten the chair , but strength and the interlocking nature of the slats may be compromised as well as some of the ergonomic comfort . that is , a greater separation of longitudinal slats causes the interconnecting segments of transverse slats to be longer , and thus more oblique in angle . this obliqueness of angle reduces the interlocking strength of the lattice , so that the strength of the structure is more dependent on any adhesive which joins overlapping slats . the reduction in strength and interlocking nature may be compensated , for example , by increasing the thickness of the slats . the slat thickness increases the strength of the lattice both directly ( by providing more load - bearing capability ) as well as indirectly ( by causing the interconnecting segments to be of a less oblique angle , thus enhancing the interlocking nature ). extra slat thickness may create a too flat and unyielding feel to the surface of the chair . retaining a certain amount of flexibility to the overall surface of the chair is essential for physical comfort . exemplary pieces of furniture and the structure of the preferred interlocking lattice having been described above , the following is a disclosure of preferred methods of fabricating the furniture according to the present invention . the invention provides a method of manufacturing a piece of furniture , comprising the steps which are described below . in step 1 , strips of material to be laminated are placed on a primary form . alternatively , sheets of material may be placed on a primary form , and later cut into strips for assembly into furniture . the primary form is advantageously comprised of a material , such as particle board , plywood , steel , epoxy resin or any other material which possesses the properties of ease of shaping with resistance to deformation from constant use and high pressures . the primary form is shaped to define with a secondary form a mold for shaping wood strips into a pre - formed slat . the face of the primary form thus has a series of parallel segments and non - parallel connecting segments which are the negative of the slat illustrated in side view in fig6 a . during step 2 , an adhesive substance 431 is spread between adjacent strips to be laminated . this step may be performed before the set of strips or sheets is placed on the primary form . adhesive substances which may be used include any permanent resin or glue , such as plastic resin or epoxy glue . as part of step 3 , a caul strip is placed over the stack of strips to be laminated . the purpose of a caul strip is to distribute pressure evenly . the caul strip may advantageously comprise a material such as a piece of veneer wrapped in masking tape or neoprene rubber that is 1 / 16 &# 34 ; to 1 / 4 &# 34 ; thick . in step 4 , a sheet of rigid material is placed over the caul strip . the rigid material may be galvanized steel or other sheet metal , or any other material which will not deform under pressure . for step 5 , blocks are placed over certain portions of the sheet of rigid material . the blocks may comprise wood or any other material such as aluminum or steel having the advantageous properties of ease of machining while not deforming from use under pressure . during step 6 , a secondary form is placed over other certain points of the sheet of rigid material . the secondary form may comprise particle board , or any other material such as plywood or steel which has the advantageous properties of ease of machining while not deforming from use under pressure . the secondary form should be used at points where weave indentations will occur and the blocks should be used where straight flat areas are desired . in step 7 , pressure is applied to the blocks and secondary form . this may be accomplished using clamps or hydraulic pressure , as known to those skilled in the art . during step 8 , the adhesive substance is allowed to adhere the strips securely together , thereby forming laminated strips . normally , this step comprises waiting until the glue cures , or applying heat or pressure to activate glues which are heat - or pressure - activated . in step 9 , the blocks , secondary form , sheet of rigid material and caul are removed . then , in step 10 , the laminated strips are removed from the primary form . if the laminate is in sheet form , it may now be cut into slats of appropriate length and width . the laminated sheet or should be substantially in the form in which they are to be assembled into the finished product . of course , appropriate finishing and sealing steps may be performed at this stage . finally , in step 11 , the laminated slats are woven into a piece of furniture . this may be accomplished by either leaving the interlocking features of the lattice to act alone , or in concert with glue , other fixative substances , or fastening devices at the contact point of slats which cross at , for example , perpendicular angles . in the above - described method , the primary and secondary particle board forms comprise one or more linear segments in which opposing faces of the forms form in the laminated slats , a series of indentations facilitating fitting of slats of laminate across one another at an angle so as to form an interlocking lattice of laminated strips . modifications and variations of the above - described embodiments of the present invention are possible , as appreciated by those skilled in the art in light of the above teachings . for example , the slats may be fabricated of varying thickness , width , separation , and angle of intersection . also , different portions of any given piece of furniture may comprise the interlocking lattice provided by the invention , either alone or in combination with other structural and aesthetic elements of the furniture . further , the process of placing the un - laminated sheets on the forms and assembly of accompanying pressing means may be performed in an order other than that described specifically above . it is therefore to be understood that , within the scope of the appended claims and their equivalents , the invention may be practiced otherwise than as specifically described .

furniture comprises a strong , aesthetically appealing , woven lattice of interlocking slats made of wood laminate having indentations allowing fitting of the slats across one another so as to form a lattice . advantageously , the furniture is manufactured of a single type of material , such as bent wood laminate slats . no other supporting structural material is needed to make the furniture simultaneously possess the advantages of being sturdy , aesthetically appealing , economical to manufacture , and light in structure and appearance .

typically , in filled pasta both the dough and filling need to be acidified if their water activities are higher than 0 . 85 . acidification of both the dough and the filling , however , produces unacceptable sensory attributes due to a strong acidic taste . most of the acidic taste is contributed by the acid in the filling . to eliminate the acidification of the filling while retaining shelf stability , i have found that it is necessary to reduce the filling &# 39 ; s water activity to 0 . 85 or lower . in a preferred embodiment , the shelf - stable pasta is made by first providing pasta ingredients . any suitable material from wheat can be used to make the pasta , such as semolina , farina and flours derived from hard or soft wheat , durum wheat and the like . other flours can also be used , such as those derived from rice , buckwheat and similar grain sources . other ingredients such as flavorants , colorants and texture improving substances such as egg albumen , alginates , gums and cellulose derivatives may be added to the flour . to reduce microbial load , the water used in the pasta is preferably purified by deionization or reverse osmosis water treatment systems , followed by uv light exposure . the optimum amount of water depends on the type of flour used and can be determined by one skilled in the art . edible food acids that are generally recognized as safe ( gras ) are then added to either the water or the ingredients . preferably , the acids are added to the water before mixture with the ingredients . ( alternatively , the formed pasta dough could be immersed in the acids .) the ph of the acids ranges from about 1 . 5 to about 3 . 5 depending on their concentrations . next , the ingredients are mixed with the acidified water to obtain dough ranging in moisture between 29 percent and 36 percent and having an equilibrium ph of about 3 . 8 to 4 . 6 , preferably about 4 . 6 . the dough is sheeted , i . e ., laminated three times by passing it through sheeting rolls to obtain the desired dough thickness . alternatively , the dough may be shaped by extrusion . fillable pasta , such as tortellini or ravioli pieces , are then formed and filled with the filling . the filling is prepared by mixing the filling base ( meat , cheese , vegetable seafood or other fillings ) with flavoring ingredients and seasonings , and water activity depressants such as salts , sugars , gums , alcohol , alginates and humectants such as glycerol or propylene glycol . preservatives may also be added to inhibit the growth of yeast and mold . ( yeast and molds grow at much lower water activity levels than microbes .) the filled pasta pieces are then pasteurized , preferably with superheated steam , to set the pasta shell surface in order to maintain structural integrity during subsequent processing . steam treatment typically occurs in a food grade steamer at atmospheric pressure for about 0 . 5 to about 6 . 0 minutes . the filling within the pasta pieces is then exposed to microwave or radio frequency waves to reduce the water activity of the preferably non - acidified filling to 0 . 85 or lower , more preferably to about 0 . 50 to 0 . 85 , most preferably to about 0 . 80 to 0 . 85 . water activity is the measure of the unbound free water available to support biological and chemical reactions . low values of water activity are known to reduce the growth of microorganisms . one measure of water activity is a w = p / p o , where p is the vapor pressure of water in the food item and p o is the vapor pressure of pure water at the same temperature . lowering a w restricts the growth of bacteria and is accomplished by lowering p , the vapor pressure of water in the food item . p may be depressed by adding solutes to the food item . most bacteria of concern require a w values of 0 . 90 or greater to grow . exposing the pasta to radiation drives water out of the filling , thereby increasing the filling &# 39 ; s solute to water ratio . it is significant that this step entails an initial inside - to - outside movement of water , whereas conventional drying first removes water from the outside of the pasta shell and then , eventually , from the filling inside the shell . conventional drying hardens the pasta shell , preventing rapid moisture removal from the filling . thus , with conventional drying , prolonged drying time is needed to remove the desired amount of water from the filling , and this longer drying time causes excessive drying of the shell while the filling moisture remains high . if the radiation treatment is very short , preferably 5 to 150 seconds , more preferably 15 to 70 seconds , it flushes some moisture out of the filling without changing the state of the enveloping dough from the rubber viscoelastic state that characterizes freshly made pasta . indeed , microwave treatment of only 15 to 70 seconds with a 50 kw batch microwave generator has the effect of moistening the exterior of the pasta shell because moisture that escapes from the inner filling is deposited there . ( preferably , the moisture content of the final pasta shell is around 22 percent .) 50 kw batch microwave generators of the type available from microdry inc . and radio frequency generators of the type used by radio frequency company inc . are preferred . after exposure to radiation , the filled pasta pieces are preferably sealed in modified atmosphere packaging by pulling vacuum and flushing with nitrogen ( n 2 ) or a gas mixture of carbon dioxide ( co 2 ) and nitrogen ( n 2 ). packaging under partial vacuum is preferred because removing excess air improves shelf stability by minimizing oxidative flavor changes . the package can be any food grade , high temperature stable packaging system having good gas and moisture barrier properties . suitable packages include pouches made of a multi - layered film having a liner of low density polyethylene , a layer of standard polyethylene and a polypropylene sealant . finally , the sealed pasta pieces may be pasteurized by , for example , boil - in - bag processing , steaming or microwave pasteurization . in any event , it is essential that the filling in the center of the pasta reach the minimum pasteurization temperature . the temperature at the coldest spot should be in the range of from about 80 ° c . to 110 ° c . for about 5 to 60 minutes , and preferably from about 95 ° c . to 100 ° c . for about 10 to 20 minutes . pasteurization of the filled pasta pieces may be completed before packaging , especially insofar as the purpose of the heat treatment of the packaged filled pasta is to render the package itself non - microbial . the surface appearance and consistency of the radiation - treated filled pasta are very similar to that of freshly produced filled pasta . it does not require refrigeration or freezing , cooks in short time , and has an extended shelf life on the order of nine months . in other embodiments , an uncooked or partially cooked moist pasta dough is extruded and treated with steam . the dough is then immersed in an aqueous solution containing edible acids ( gras ) to reduce the ph to levels that inhibit microbial growth . the solution may also contain water activity depressants . the immersion time will vary with the thickness of the pasta and the concentration of the acid or water depressant . sufficient immersion times generally range from about 1 minute to about 4 minutes . following the immersion step , the pasta is partially surface dried to improve handling properties during subsequent processing . it should be understood that the foregoing summary and detailed description of the invention are not intended to be limiting , but are only exemplary of the inventive features that are defined in the claims .

a shelf - stable filled pasta and a method of making same , the method comprising providing an acid - treated or acid - containing tillable pasta piece having a ph of about 4 . 6 or less ; inserting filling into the tillable pasta piece ; exposing the filling in the filled pasta piece to microwave or radio frequency radiation to reduce the water activity in the filling to about 0 . 85 or less ; sealing the filled pasta piece in a package ; and pasteurizing the filled pasta piece at any point in the process after the filling has been inserted into the fillable pasta piece . the shelf - stable filled pasta is a pasta made by the foregoing method .

an electric toy comprises a source of electrical power , motive means to move various moving parts , and integrated circuit means to control various functions . referring to fig1 a toy fig1 such as an action figure , is mounted atop a rotating table 4 on a base 5 permitting the fig1 to rotate back and forth in a circular motion about a vertical axis passing through the center of the rotating table 4 . in addition , within the figure are located multiple electric motors 8 adapted to move specific moving parts of the figures in specific ranges of motion , as illustrated in fig1 . when the multiple motors are made to simultaneously create movement of different moving parts , complex movements can be created . an integrated circuit ( not shown ) located within the base 5 of the toy is pre - programmed to generate , by controlling the various electric motors , a number of different sets of movements appropriate to different circumstances . for example , a first set of motions may be appropriate to the figure acting on its own . a second set of motions may be appropriate to the figure interacting with a second figure adapted to be linked to one side of the first figure . a third set of motions may be appropriate for interaction of the first figure with a third figure adapted to be linked to the base of the first figure on the opposite side . yet a fourth set of movements may be appropriate when the first figure is linked to both the second and third figure at the same time , as will be discussed more fully below . the base 5 of each toy is provided with connecting means to link one toy to another . typically , these means will be an electrical socket 7 or other suitable connector . additionally , the link between toys may be formed by non - contact electromagnetic signals such as infra red or radio wave spectrum signals ( not shown ). in the particular embodiment illustrated , each of action fig1 and 3 is provided with a sword 15 . each action figure is individually programmed to perform an action and to speak words with appropriate sounds in order to create a unique individual performance . one or more audio speakers ( not shown ) reproduce these sounds under the control of integrated circuits in co - ordination with synchronized corresponding movements of the character or action figure . each figure may represent a different character with a particular persona . in the case of characters taken from a motion picture or television program , portions of the sound track from such productions may be recorded onto the integrated circuits . the actions performed by the figures may be life - like or robotic . one of the remarkable features of the illustrated invention is the ability of the individual toys to interact . each character is programmed to interact with one or more other characters . in the embodiments illustrated , character 1 may interact either with character 2 , as illustrated in fig3 a , or character 3 , as illustrated in fig3 c . when a connection is made allowing signals to pass from one toy to another , each is able to generate a set of sounds and activities appropriate to the particular interaction in question . for example , if character 2 and character 3 are intended to be allies , their interaction with swords , as illustrated in fig3 b , could be a training exercise . yet if either interacts with character 1 , an enemy , their interaction will be a battle . since each toy may be provided with electrical connections on either side of the toy , choices as to where to place electrical connectors appropriate to the combination can be made . for example , the allies , characters 2 and 3 , need only face each other in one direction , so oppositely facing connectors would be appropriate for such toys . if each of characters 2 and 3 is provided with only a single connector , then character 1 will have a connector in each side of the base , to be able to interact with each of characters 2 and 3 individually . with this arrangement of connectors , character 1 can be placed between characters 2 and 3 to do battle with both simultaneously . in this scenario , the provision of a double bladed sword to character 1 facilitates such a battle . thus , as illustrated in fig2 a , 3 b , 3 c , 4 a , 4 b and 5 , character 1 sits atop base 5 - 1 , while characters 2 and 3 sit atop bases 5 - 2 and 5 - 3 respectively . each unit may be individually powered by a set of batteries 17 , or may be adapted to be plugged into a wall electrical outlet . if two or more such toys are intended to interact together , then it is essential that their movements be synchronized . accordingly , it is an advantage that the power source for all linked units be constant . this can be accomplished using electricity from wall outlets . in a further development , if each unit contains a pack of batteries , the batteries of linked toys can be connected in series . this provides a large steady current for both units at the voltage of the battery pack which has the higher voltage . as toys are used , and the voltage drops , the highest voltage of linked toys will always govern . this is a major advantage since these toys can be used separately , thus placing different loads on their individual battery packs , yet when they are linked together , a single voltage and current will be generated to allow them to function in a synchronous manner . the manner in which the toys may be triggered to commence actions along with sound , if desired , may be diverse . for example , if the toy can also function as a coin bank , the deposit of a coin into a coin slot 9 can be used to trigger an action through vibration , changes in electric or magnetic fields , or other known methods . alternatively , a button 11 to activate a switch , or a touch sensitive surface on the toy can be used to trigger the toy to commence action or sound . in the toy of the present invention , additionally , the action may be triggered by motion . use of a short range cds motion detector 13 permits the toy to be stimulated into action by a hand motion close to the toy . extraneous distant motions will not affect the toy . such hand motions can be tailored to the character of the action figure in question . alternatively , if more distant motion is intended to trigger action in the figure , an appropriate form of motion detector can be used . a longer range motion detector might be useful when the toy is to act , for example , as a room guard such as for a child &# 39 ; s room . the short range motion detector would be more appropriate when the toy is to respond to a particular hand signal from the child . the motion detector may have pre - selected characteristics , or may be tuneable for direction , height and range . although a preferred embodiment of the invention has been described , the invention is not to be taken as so limited . modifications and variations to the invention described will be apparent to persons skilled in the art .

an electronic toy with at least one moving part , comprising a pre - programmed integrated circuit and at least one electric motor , is adapted to perform actions . multiple such toys may be inter - connected in different combinations and programmed to interact in groups of two or more .

this object is achieved , according to the invention , by the bite device defined in claim 1 . advantageous embodiments of the invention are subject matter of the sub - claims . the invention improves on the prior art in that a bite device includes a holding member held in a directionally fixed position relative to the x - ray device , and a plate which is pivoted relative to the holding member and which has a bite piece on which the patient bites . the bite device also includes means for measuring the angle of deflection α between the plate and the holding member , which means for measuring the angle of deflection α are located in a zone of the bite device which is free from radiation during x - ray imaging . the zone involving x - ray irradiation can therefore be kept substantially free from metal . the invention is thus based on the idea of measuring the position of the occlusal plane of the patient relative to the device by determining the position of a plate disposed in the occlusal plane . for this purpose , the angle is measured between the plate and a holding member , which can be positioned relative to the x - ray device in fixed alignment . from this angle a signal can be derived which indicates the degree of inclination of the occlusal plane . it is advantageous for the means for measuring the angle of deflection a to contain one or more sensors located in the holding member . for example , the sensors might be in the form of a photoelectric sensor located in the holding member and adapted to register the position of an opening that is moved upwardly and downwardly in accordance with the pivotal motion of the plate . the bite device of the invention can conveniently include means for displaying the angular position of the pivoted plate . in a preferred development of the bite device , there are further provided driving means for vertical adjustment of the holding member and thus for pivoting the plate into a predetermined angular position . this makes it possible to adapt to the patient &# 39 ; s body size , and the patient can be constrained to adjust the inclination of his head to the inclination of the plate , so that a desired angular position of the patient &# 39 ; s occlusal plane relative to the x - ray device will be achieved . it is advantageous for the plate - swinging means to move the plate to the predetermined angular position automatically and to stop when the predetermined angular position has been reached . alternatively or additionally , provision may be made for said means to indicate that the predetermined angular position of the plate has been reached by emitting optical and / or acoustic signals . in a preferred embodiment of the bite device of the invention , the pivoted plate is connected to a rail within the holding member , which rail can be moved upwardly and down - wardly and has an opening for indicating the position of the rail in the holding member . the bite piece of the bite device is preferably equipped with a replaceable protective sheath for hygienic reasons . alternatively , the bite piece can be in the form of a replaceable bite piece . the bite piece is preferably composed of a soft material , particularly a substantially radiolucent material . it has proved to be particularly suitable to fabricate the bite piece from closed - cell ethylene foam . the bite piece preferably occupies an angular range β of the mandibular arch , which is between 20 ° and 40 °, particularly 30 °. this substantially prevents any sideways tipping or tilting of the patient &# 39 ; s head . in an advantageous embodiment , the bite piece has on its upper surface and on its undersurface a bite groove to accommodate part of the dental arch of the patient &# 39 ; s upper and lower jaw respectively . the bite piece is preferably a unitary piece foldable about a folding edge . it preferably has on opposite sides a wedge - shaped projection and a complementary depression for the accommodation of said projection , to enable the bite piece to be removably attached to the pivoted plate . further advantageous embodiments , features , and details of the invention are given in the dependent claims , the description of embodiments , and the drawings . the invention will now be explained in more detail with reference to an embodiment and the drawings . only those elements are shown which are significant for comprehension of the invention . fig1 is a diagrammatic illustration of a panoramic x - ray system ; fig2 is a diagrammatic representation of the system for aligning the tomography zone of the x - ray device to the alveolar arch of a patient ; fig3 shows a perspective view of a bite device according to one embodiment of the invention , shown diagrammatically ; fig4 is a cross - section through the bite device of fig3 ; fig5 shows perspective views of an bite piece for a bite device according to one embodiment of the invention , shown ( unfolded ) diagonally from below in fig5 ( a ) and diagonally from above in fig5 ( b ); fig6 is a cross - section through the bite piece of fig5 , taken along line vi - vi ; and fig7 shows the bite piece of fig5 in the folded position , as attached to the bite device of fig3 . fig1 is a diagrammatic representation of a panoramic x - ray system 10 , in which a rotary unit 12 carries a radiation source 14 equipped with a shutter 16 , and a diametrically opposed detector camera 18 equipped with a shutter 20 . the beam of x - rays 22 emitted from the radiation source 14 transilluminates the jaw region of the head 24 of a patient and produces an image signal in detector camera 18 . this is directed to a control unit 26 for evaluation and display in the usual manner . rotary unit 12 is pivotally or hingedly mounted on an arm 11 which is mounted on a column 13 for vertical adjustable thereon . a drive 15 is provided to perform the vertical adjustment . in this way , the position of x - ray emitter 14 and detector camera 18 can be adjusted to the stature of the patient . it is essential , for obtaining a faultless , high - quality panoramic radiograph , for the tomography zone 30 ( fig2 ) to be in line with the alveolar arch 32 of the patient . fig2 depicts perfect spatial alignment of these two elements , this ensuring the production of a qualitatively good image . insufficient alignment can necessitate a repeat radiograph , resulting in increased x - irradiation of the patient and additional expense in terms of material and time . fig3 is a perspective view of a bite device referenced as 40 , according to one embodiment of the invention , shown diagrammatically , and fig4 is a cross - section through the bite device 40 of fig3 . bite device 40 has a holder 42 which is hinged to a thin plate 46 by means of a pivot 44 . the thin plate 46 is adjoined , at its end remote from pivot 44 , by an imaging zone 48 parallel to said thin plate . the imaging zone 48 has an opening 62 by means of which , in a manner to be described in more detail below , a replaceable bite piece 50 can be quickly and easily attached to the thin plate . on its upper surface and on its undersurface , bite piece 50 has occlusal grooves 64 and 66 respectively , which accommodate the dental arches of the patient &# 39 ; s upper and lower jaw respectively . this arrangement ensures that the thin plate 46 runs parallel to the occlusal plane of the patient when he bites on the bite piece 50 for taking the radiograph . the angle of deflection a of thin plate 46 is measured using a rail 54 capable of being moved upwardly and down - wardly and connected to thin plate 46 in a region 56 , and adapted to extend vertically down the inside 52 of the holding member 42 . in its lower section , rail 54 is provided with a hole 58 . the vertical position of hole 58 is detected by two photodetectors indicated by arrows 60 . the angle of deflection of plate 46 can be deduced from said vertical position . by transferring the inclination of plate 46 to the movable rail , measurement of the angle of deflection a is carried out in a region of holder 42 which is far below plate 46 and is free from radiation . the x - irradiated region can thus be kept substantially free from metal . the bite device cooperates with a driving system 15 shown in fig1 such that rail 54 moves upwardly or downwardly and the thin plate 46 can thus be brought into any desired position . the deflection of thin plate 46 accompanying such vertical adjustment makes it possible to gently guide the patient &# 39 ; s head until it assumes the correct degree of inclination for the panoramic radiograph . vertical adjustment of plate 46 can be performed interactively by the operator . for example , the operator can press an adjustment button until the desired degree of inclination is attained . when a previously defined angular position , for example α = 105 °, which corresponds to an angle between plate 46 and the horizontal of 15 °, is attained , this can be indicated by means of optical and / or acoustic signals . alternatively , the drive can automatically move plate 46 into the predetermined angular position and stop when the desired position is reached . additionally , the angular position of the plate can be displayed for checking by the operator . the bite piece 50 shown in fig3 and 4 will now be described in more detail with reference to fig5 through 7 . fig5 shows , in fig5 ( a ) and fig5 ( b ), a per - spective view of the unfolded insert , shown diagonally from below in fig5 ( a ) and diagonally from above in fig5 ( b ). fig6 shows a cross - section through the bite piece taken along line vi - vi of fig5 ( b ), and fig7 represents the bite piece in the folded position , as attached to the bite device of fig3 . in the present embodiment , bite piece 50 is fabricated as a single piece of closed - cell ethylene foam , a soft and substantially radiolucent material . on its upper surface , bite piece 50 has occlusal grooves 64 and 66 adapted to accommodate part of the dental arch of the upper and lower jaws of the patient . bite piece 50 can be folded along a central folding edge 70 , defined by notches 72 on the undersurface and a central groove 74 on the upper surface of the insert . on its underside , bite piece 50 has a wedge - like tapered projection 76 which , when the insert is folded , slides into a complementary depression 78 located on the opposite side of the insert , this making for a stable but easily releasable connection . the flat imaging zone 48 of the bite device contains an opening 62 ( fig4 ) through which the projection 76 projects when the bite insert is attached , so that insert 50 is firmly attached to the thin plate 46 of the bite device once it has been folded together . after use , however , the insert can be unfolded with no great effort and thrown away for hygienic reasons . the insert shown in the embodiment illustrated in fig5 through 7 , has a width of 40 mm , occupies an angular region β of the dental arch of about 30 °. in order to accommodate for different jaw sizes of patients , bite pieces are also fabricated and used in other widths . the different widths can be easily distinguished by the user on the basis of different color markings or other labels . with this kind of bite piece , the position of the patient can be fixed with great accuracy but without discomfort for the patient .

a bite device for the correct positioning of a patient when a panoramic x - ray is taken , comprising a holder part which can be placed in a fixed direction in relation to the x - ray device , a plate which can pivot against the holder and which is provided with a bite part into which a patient bites , and means for detecting the pivoting angle a between the plate and the holder part .

fig1 is an overall perspective view illustrating a conventional nail clipper 10 having a nail clippings catcher 12 in accordance with the present invention inserted into an open space 14 between an upper jaw 16 and a lower jaw 18 of the nail clipper 10 . the jaws 16 and 18 are similarly - shaped and are secured to each other at first ends 22 by an eyelet 24 . the jaws 16 and 18 diverge away from each other along their length extending away from the first ends 22 at which they are fastened together . each of the jaws 16 and 18 includes matable cutting edges 26 formed at the ends of the jaws 16 and 18 furthest from their juncture at the eyelet 24 . without the nail clippings catcher 12 inserted between the jaws 16 and 18 , the open space 14 between the diverging jaws 16 and 18 permits nail clippings to escape from either side of the nail clipper 10 . this conventional type of nail clipper 10 also includes a cylindrically - shaped rivet 32 having a longitudinal axis 34 that extends through apertures 36 ( only one of which is illustrated in fig1 ) piercing each of the jaws 16 and 18 adjacent to their opposed cutting edges 26 . an enlarged head ( not illustrated in fig1 ), formed at one end of the rivet 32 , engages an outer surface of the lower jaw 18 furthest from the upper jaw 16 . an opposite end 38 of the rivet 32 projecting away from its head extends upward above the upper jaw 16 . a notch 42 formed in the length of the rivet 32 that projects upward above the upper jaw 16 receives one end of an elongated , angled lever 44 . if the lever 44 is properly disposed with respect to the rivet 32 and to the upper jaw 16 as illustrated in fig1 an end 46 of the lever 44 furthest from the rivet 32 is spaced a short distance apart from an outer surface of the upper jaw 16 . disposing the lever in this position opens the opposed cutting edges 26 to permit insertion of an item to be cut , such as a finger nail or a toe nail , between the cutting edges 26 . a force then applied to the end 46 of the lever 44 furthest from the rivet 32 that urges the end 46 toward the upper jaw 16 pulls the rivet 32 through the upper jaw 16 . pulling the rivet 32 through the upper jaw 16 draws the enlarged head of the rivet together with the lower jaw 18 toward the upper jaw 16 . drawing the two jaws 16 and 18 together in this way closes and mates the opposed cutting edges 26 together for severing whatever may be located therebetween . this conventional type of nail clipper 10 is widely available in various different sizes adapted for cutting finger nails and toe nails of different sizes . fig2 is a plan view of a sheet 52 adapted for being folded along a fold - line 54 to form the nail clippings catcher 12 . the particular sheet 52 illustrated in fig2 is pre - cut so that upon being folded into the nail clippings catcher 12 it forms a shape resembling that of a butterfly . upon folding the sheet 52 along the fold - line 54 , a star - shaped aperture 56 punched through the sheet 52 at a location in which the fold - line 54 passes through the aperture 56 provides a channel 58 , depicted in fig4 a and 6 , through the folded sheet 52 for the rivet 32 . fig3 and 3a , cross - sectional views taken along the line 3 -- 3 of fig2 illustrates various layers of material included in the preferred embodiment of the pre - cut sheet 52 depicted in fig2 . the sheet 52 preferably includes a layer 62 of paper which is bonded to a 0 . 002 inch thick layer 64 of polyester material by a first layer 66 of adhesive . a decoration , e . g ., a pattern appearing on the wings of a butterfly , or a text message , e . g ., an advertisement , may be fixed on the surface of the layer 62 adjacent to the layer 64 before the layers 62 and 64 are joined together . a second layer 68 of adhesive , coated on a surface of the paper layer 62 opposite to that on which the layer 64 is bonded , secures a layer 72 of paper liner material to the layer 62 of paper . before the sheet 52 is folded to form the nail clippings catcher 12 , the layer 72 of paper liner material is removed to expose the layer 68 of adhesive . after the layer 68 has been exposed , as depicted in fig3 a a 1 . 4 inch diameter , 0 . 005 inch thick , stiffening disk 74 of polyester or other springy material , through which an aperture 76 shaped identically to that of the aperture 56 has been formed , is secured to the layer 68 with the apertures 56 and 76 aligned . after the disk 74 has been secured to the layer 68 , the sheet 52 together with the disk 74 is folded along the fold - line 54 to juxtapose with itself the layer 68 located on opposite sides of the fold - line 54 . juxtaposing the adhesive layer 68 together , fastens the sheet 52 to itself to form the nail clippings catcher 12 depicted in fig4 and 5 . upon folding both the sheet 52 and the disk 74 along the fold - line 54 , the sheet 52 and the disk 74 establish a pocket 78 within the sheet 52 , illustrated in fig4 a and 5 , that is adapted for receiving nail clippings through the aperture 56 after the nail clippings catcher 12 has been inserted into the open space 14 between the jaws 16 and 18 . as illustrated in fig2 the sheet 52 of material is pre - cut symmetrically with respect to the fold - line 54 so edges 82 of the sheet 52 juxtapose with each other upon folding sheet 52 along the fold - line 54 . during forming of the nail clippings catcher 12 , two registration holes 84 , punched through the sheet 52 symmetrically with respect to the fold - line 54 , mate with a folding fixture ( not illustrated in any of the figs .) to ensure that the sheet 52 folds along the fold - line 54 and that the edges 82 of the formed nail clippings catcher 12 juxtapose with each other . the pre - cut sheet 52 includes tabs 88 which in fig2 project symmetrically outward along the edges 82 of the sheet 52 furthest from the aperture 56 . after the sheet 52 has been formed into the nail clippings catcher 12 depicted in fig4 the tabs 88 , now bonded together into a single tab by the adhesive of layer 68 , may be trimmed to one of various different lengths whereby the nail clippings catcher 12 may be readily adapted for use with one of various different sizes of nail clipper 10 . trimming the tabs 88 adapts the nail clippings catcher 12 for use with a particular size of nail clipper 10 . the edges 82 of the sheet 52 are preferable pre - cut so that after folding the sheet 52 along the fold - line 54 the edges 82 do not extend beyond a circular arc 92 having a radius r lying in a plane that includes the fold - line 54 and that has a center 94 which lies within the aperture 56 . the circular arc 92 extends through an angle α preferably on both sides of a reference line 96 that is disposed normal to the fold - line 54 and that passes through the center 94 . the reference line 96 extends from the aperture 56 toward the edges 82 of the sheet 52 furthest from the aperture 56 . the angle α is preferably no greater than sixty ( 60 ) degrees . to avoid removal of the rivet 32 from the nail clipper 10 in installing the nail clippings catcher 12 , the radius r must be less than the distance from the longitudinal axis 34 of the rivet 32 to the juncture of the jaws 16 and 18 adjacent to their first ends 22 for the smallest nail clipper 10 with which the nail clippings catcher 12 may be used . furthermore , to avoid removal of the rivet 32 in installing the nail clippings catcher 12 , a line 97 which extends between the juncture of the apertures 56 and 76 with the fold - line 54 and the edges 82 of the sheet 52 must have a length 1 less than the distance from the longitudinal axis 34 of the rivet 32 to the juncture of the jaws 16 and 18 adjacent to their first ends 22 for the smallest nail clipper 10 with which the nail clippings catcher 12 may be used . the formed nail clippings catcher 12 depicted in fig4 may be inserted into the open space 14 between the jaws 16 and 18 of the nail clipper 10 as depicted in fig6 and 7 by first sliding the nail clipper 10 obliquely onto the nail clippings catcher 12 with the jaws 16 and 18 disposed respectively on opposite sides of the nail clippings catcher 12 until the channel 58 formed through the folded sheet 52 by the aperture 56 engages the rivet 32 . after the channel 58 engages the rivet 32 , the nail clipper 10 is then rotated about the rivet 32 until the tabs 88 are disposed between the jaws 16 and 18 as depicted in fig7 . rotating the nail clippings catcher 12 about the rivet 32 of the nail clipper 10 until the tabs 88 are disposed between the jaws 16 and 18 disposes the fold - line 54 symmetrically with respect to the cutting edges 26 of the jaws 16 and 18 . the nail clippings catcher 12 may be removed from the nail clipper 10 by reversing the preceding procedure . thus , the nail clippings catcher 12 may be inserted into or removed from the open space 14 between the jaws 16 and 18 of the nail clipper 10 without loosening the rivet 32 from the jaws 16 and 18 . as illustrated in fig2 , 6 and 7 , the sheet 52 included pre - cut slits 98 formed through the sheet 52 immediately adjacent to the tabs 88 . after the tabs 88 are disposed between the jaws 16 and 18 , as illustrated in fig8 the material of the sheet 52 is bent upward and / or downward to engage side surfaces of the jaws 16 and 18 immediately adjacent to where the jaws 16 and 18 join together . engagement of the material of the sheet 52 with side surfaces of the jaws 16 and 18 at the slits 98 and the juncture of the jaws 16 and 18 prevents rotation of the nail clippings catcher 12 about the rivet 32 of the nail clipper 10 . as illustrated in fig2 and 6 ; both of the star shaped apertures 56 and 76 formed respectively through the sheet 52 and the disk 74 include v - shaped notches 102 formed symmetrically on both sides of the fold - line 54 in fig2 . to adapt the nail clippings catcher 12 for use with various different sizes of nail clippers 10 , the width of the apertures 56 and 76 as measured along the fold - line 54 must be wide enough to fit around the rivet 32 of the largest size of nail clipper 10 . when the nail clippings catcher 12 is installed in the nail clipper 10 with the tabs 88 properly trimmed to fit that particular size of nail clipper 10 , the v - shaped notches 102 bear against the rivet 32 thereby centering the nail clippings catcher 12 side - to - side within the nail clipper 10 regardless of the size of the rivet 32 included in the nail clipper 10 . although the present invention has been described in terms of the presently preferred embodiment , it is to be understood that such disclosure is purely illustrative and is not to be interpreted as limiting . for example , the sheet 52 may be pre - cut into various different shapes which upon folding to form the nail clippings catcher 12 resemble something other than a butterfly . similarly , a surface of the sheet 52 that becomes juxtaposed with itself by folding along the fold - line 54 may be fastened to itself in various different ways other than by the adhesive layer 68 . for example the surface of a suitable sheet material may be bonded together by ultrasonic or thermo - compression bonding . while the preferred embodiment of the nail clippings catcher 12 is adapted for insertion into and removal from the open space 14 between the jaws 16 and 18 without removing the rivet 32 from the jaws 16 and 18 , it is readily apparent that a nail clippings catcher 12 in accordance with the present invention may be inserted into or removed from the open space 14 by first removing the rivet 32 from the jaws 16 and 18 prior to insertion or removal of the nail clippings catcher 12 and then reinserting the rivet 32 through the jaws 16 and 18 after the nail clippings catcher 12 has been inserted into or removed from the open space 14 . consequently , without departing from the spirit and scope of the invention , various alterations , modifications , and / or alternative applications of the invention will , no doubt , be suggested to those skilled in the art after having read the preceding disclosure . accordingly , it is intended that the following claims be interpreted as encompassing all alterations , modifications , or alternative applications as fall within the true spirit and scope of the invention .

a nail clippings catcher formed from a pre - cut sheet of material having a hole punched through it . this pre - cut sheet preferably extends for some distance on either side of the hole along a fold - line passing through the hole . folding this pre - cut sheet of material along a fold - line juxtaposes a surface of the sheet with itself . the juxtaposed surface of the sheet is then fastened together while a pocket for receiving nail clippings is concurrently established within the folded sheet . the nail clippings catcher is inserted between the jaws of a conventional nail clipper with the fold - line disposed adjacent to the jaws &# 39 ; cutting edges with the aperture formed through the sheet providing a channel through the folded sheet for the nail clipper &# 39 ; s rivet , and an opening for nail clippings to enter and exit the pocket .

referring to fig1 - 3 , a preferred medical lead and catheter fixation device is depicted . the preferred lead fixation device 10 may be used in conjunction with a standard cranial burr ring or as a stand - alone device implanted in a cranial burr hole . whether or not a separate burr ring is used with a particular patient will depend on the specific circumstances involved in that patient &# 39 ; s case . in addition , the lead fixation device 10 may also be used with the rotatable disc 50 , described more fully below , which is mounted to a standard burr hole ring . the lead fixation device 10 of the present invention defines a sleeve 12 , preferably cylindrical in shape , and a lead - interactive member , preferably a plurality of springs 14 . the lead fixation device 10 is designed to fit within a conventional burr hole ring , or the burr hole ring 52 more fully discussed below , which is then implanted in the cranium . a lead , or cannula if used , is then inserted into the lead fixation device 10 . the lead is anchored within the fixation device with the end of the lead situated within the brain and positioned at the targeted stimulation area . as used herein , the term “ lead ” may refer to any elongated medical apparatus having an electrode providing electrical stimulation , or a parenchymal catheter for infusing pharmaceutical agents . with regard to the burr rings , as one might imagine , there are many possible sizes and shapes . the selection of one burr ring over another will depend on numerous factors such as the size or shape of the burr hole . thus , it should be understood that the following description , by way of example , shows exemplary burr ring configurations which may be used in connection with the present invention . the lead fixation device 10 may be formed as a part of a separate member selectively attachable to the burr hole ring , or it may be formed as an integral portion of the burr hole ring . again , the burr hole ring would typically be pre - placed within the pre - drilled burr hole , with the lead fixation device insertable into the pre - placed burr hole ring . the sleeve 12 , as depicted in fig1 and 2 as a cylindrical member , further defines inwardly extending circular shoulders 16 , 18 , a pair of opposing apertures 20 , 22 at each end of the sleeve 12 , and an inner wall 23 . the sleeve 10 is preferably about 0 . 15 - 0 . 20 inches at its maximum outside diameter and has a preferable length of 0 . 20 - 0 . 30 inches . the sleeve may be made from a biocompatible material , such as , metal or plastic . those skilled in the art will appreciate that the sleeve may incorporate a variety of other dimensions , depending on the chosen lead , burr hole ring and the desired application . the inward circular shoulders 16 , 18 are curved or angled at 21 to permit and control the bending of the lead . the curved shoulders allow the lead to be directed radially outward from the sleeve 12 and parallel to the cranium . a small flexible plug , not shown , may be inserted to engage the sleeve 12 and to close off either of the apertures 20 , 22 . significantly , with the use of the lead - interactive members 14 , the lead is stabilized prior to the placement of the flexible plug . seated between the shoulders 16 , 18 of the sleeve 12 are the lead - interactive members 14 , preferably springs . it is contemplated that other lead - interactive members may be used to fix the lead relative to the sleeve , and still be considered within the spirit and scope of the present invention . as most preferred , two pairs of opposing springs 14 are positioned within the sleeve 12 . these four springs are positioned equidistant around the inner wall 23 of the sleeve 12 resulting in the two pairs of opposing spring sets . the number of springs and their configuration are dictated by the desired amount of radial force to be exerted on the lead . thus , one should understand that other numbers , arrangements , shapes and sizes of springs may be used with the present invention , depending on the desired amount of radial force on the lead body . the springs 14 may be made of any biocompatible material that exhibits resiliency , such as , metal , plastic or rubber . the selection of the material is dictated , at least in part , by the desired spring force to be applied to the lead body . the springs 14 are formed as thin , elongated members defining a curve 24 located near its longitudinal center . the curve 24 creates the resiliency of the spring 14 . the overall length of the spring , in its unsprung state , is slightly less than the distance between the shoulders 16 and 18 . as most preferred , the spring 14 is fixed at one end to the inner wall 23 and is free at its opposing end . that is , for example , the spring 14 is fixed to the inner wall 23 near the shoulder 16 and is free at the opposite spring end near the shoulder 18 . space is provided between the end of the spring 14 and the shoulder 18 to accommodate longitudinal movement of the spring end when the lead is inserted into the sleeve , compressing the spring 14 . as preferred , the installed springs 14 create an opening through the sleeve 12 which has an unsprung diameter of 0 . 040 - 0 . 045 inches to accommodate a standard lead with an outer diameter of 0 . 050 inches . the unsprung diameter is selected to provide a certain radial force on the lead body . accordingly , it will be appreciated by one skilled in the art that other unsprung diameters may be designed depending on the desired radial force to be exerted on the lead body . referring to fig3 insertable within the sleeve 12 and between the springs 14 is the lead 31 , or cannula if used . once the lead 31 is inserted , the resilient springs 14 apply a radial force on the exterior surface of the lead body and , through friction forces between the springs and lead body , the lead is held in place in the desired location . if a cannula is used , the springs depress to accommodate the passage of the cannula through the sleeve 12 . a lead is then inserted into the cannula . once the cannula is removed leaving the lead in the desired position , the springs 14 snap back to engage the lead , thereby fixing it in place . as conventional , the burr hole ring preferably has one or more lead guides to accept the lead once it has been inserted in the brain . these lead guides direct the lead radially outward from the center of the burr ring and substantially parallel to the cranium . a burr ring cap may then be placed over the burr hole ring and installed sleeve 12 . thus , the present invention fixes the lead in the desired position prior to the placement of the burr ring cap , thereby removing the possibility of lead movement during such cap placement . referring to fig4 an alternative embodiment of the sleeve 12 is depicted . as preferred , the sleeve 30 is a stand - alone fixation device which is insertable directly into smaller cranial burr holes , for example , burr holes having a diameter of 3 to 4 millimeters . the sleeve 30 defines a cylindrical sleeve body 32 having either external serrations , threads or knurls 34 , which stabilizes the sleeve 30 in the cranial burr hole . the sleeve 30 also has , at one end , a collar 36 defining an outwardly extending circular shoulder 38 and a tool engaging head 40 . the remaining features of the sleeve 30 are the same as the sleeve 12 , as depicted in fig1 . that is , the sleeve 30 also includes an inner cylindrical wall 23 , apertures 20 , 22 , and inwardly extending shoulders 16 , 18 , which receive the lead - interactive members 14 . upon the insertion of the sleeve 30 into the burr hole in the cranium , the outwardly extending circular shoulder 38 serves to set the depth of the sleeve into the cranium and also serves as a stop to prevent the sleeve from passing through the cranium into the brain . the tool engaging head 40 is preferably hexagonal in shape for engaging a wrench which rotatably positions the sleeve 30 in the burr hole . it should be understood that other tool engaging heads may be used , such as , a round head having either a slot or an internal hexagon , for receiving other types of tools . referring to fig5 - 7 , there is shown another embodiment of the present invention that allows the functional positioning of the lead within a cranium burr hole . this embodiment enhances the placement of the lead relative to the targeted stimulation area . as most preferred , a rotatable disc 50 is mounted within a burr hole ring 52 . the rotatable disc 50 defines a slot 54 through the disc body which extends radially from the center of the disc to its periphery . positioned within the slot 54 is the sleeve 30 or , preferrably , the lead fixation member 56 . the lead fixation member 56 defines a cylindrical sleeve 58 having an integral circular shoulder 60 , and a slot 62 for capturing and fixing the lead body . in use , the sleeve 58 is inserted through the slot 54 with the shoulder 60 seated against the rotatable disc 50 . the sleeve 58 has an external diameter that permits the slidable engagement with the slot 54 . significantly , the lead fixation member 56 may be located at any position along the slot 54 . further , with the disc 50 being rotatable within the burr hole ring 52 , the fixation member 56 may be located at any position within the burr hole ring . that is , the lead fixation member 56 may slide within the slot 54 and be rotated within the burr hole ring 52 , permitting full degree of motion of the fixation member 56 within the burr hole . the preferred embodiments of the invention are now described as to enable a person of ordinary skill in the art to make and use the same . variations of the preferred embodiment are possible without being outside the scope of the present invention . therefore , to particularly point out and distinctly claim the subject matter regarded as the invention , the following claims conclude the specification .

there is disclosed a medical apparatus for positioning and anchoring a lead to a cranium burr hole . the apparatus comprises generally a sleeve and a plurality of springs positioned within the sleeve . the apparatus may be inserted within a conventional burr hole ring or serve as a stand - alone anchoring device that fits within a burr hole . once a lead is inserted into the sleeve between the plurality of springs , the springs exert a radial force on the lead body , thereby holding the lead in the desired position . the apparatus may also include a circular disc , defining a slot , mountable within the burr hole ring . the circular disc permits the selective positioning of the lead within the burr hole .

[ 0023 ] fig1 is a schematic illustration of a magnetic resonance tomography installation for generating a magnetic resonance image of a subject wherein the inventive method is executed . the structure of this magnetic resonance tomography installation corresponds to that of a conventional nuclear magnetic resonance tomography installation , with the additional features described below . a basic field magnet 1 generates a strong , optimally uniformly fashioned magnetic field for the polarization of the nuclear spins in a measurement volume in the inside of the basic field magnet 1 . the high homogeneity of the basic magnetic field required for the magnetic resonance measurement is defined in a spherical measurement volume m into which the parts of the human body to be examined are introduced . this occurs with a displaceable bearing mechanism 5 . for the correction of time - invariable influences , shim plates of ferromagnetic material are applied at suitable locations on the basic field magnet 1 . further influences which disturb the uniformity of the basic field magnet are corrected by shim coils 2 . a system of cylindrical gradient coils 3 introduced into the basic field magnet 1 serves the purpose of generating linear gradient fields in the three spatial directions or in a cartesian coordinate system , or some other coordinate system . each of the three gradient coil systems 3 is supplied with current for generating the gradient magnetic field by an amplifier 8 . in the embodiment of a magnetic resonance tomography apparatus shown here , a gradient field is generated in each of the x - direction , y - direction and z - direction . the gradient fields make it possible to topically code the volume to be measured with one of the known pulse sequences . a radio - frequency antenna 4 is arranged within the gradient coils 3 , which converts the radio - frequency pulses emitted by a radio - frequency power amplifier 9 via a transmission / reception diplexer 6 into a magnetic alternating field . nuclei in the subject are excited by this magnetic alternating field , and the nuclear spins of the subject to be examined or of the region of the subject to be examined are aligned in a rotational motion perpendicular to the basic magnetic field . likewise , the radio - frequency antenna 4 converts the alternating field emanating from the precessing nuclear spins , i . e . the magnetic resonance signals influenced as a rule by a pulse sequence composed of one or more radio frequency pulses and one or more gradient pulses , into a voltage . this voltage is supplied via the transmission / reception diplexer 6 as well as via a pre - amplifier 7 to a radio frequency unit 10 . a narrowly bounded region can be selected with a surface coil 4 a , the resonant signals thereof being received and being supplied to the radio frequency reception unit 10 via a preamplifier 7 a . such a surface coil 4 a usually serves the purpose of obtaining images with especially high resolution and with a good signal - to - noise ratio from a specific organ . a surface coil 4 a is thereby usually applied to or on the body of the person to be examined . a control computer 11 controls the executive sequence of individual measurement sequences ; an image computer 12 generates an image from the acquired measured data by means of fast fourier transformation . the generated image is optically presented to the user at a console 13 that has a keyboard as well as one or more picture screens . the drive of the surface coil 4 a also ensues by means of the control computer 11 . in a flowchart , fig2 schematically shows an embodiment of the present , inventive method . first , overview exposures ( localizers ) having a short measurement on time are registered in a first step s 1 by the control computer 11 in fig2 using the radio - frequency antenna 4 and are visibly presented to the user on the console 13 by the image computer 12 . usually , three tomograms residing on one another are measured as localizers . when planning the next series , a calculation for a field of view indicated by an operator is then made in a further step s 2 in the control computer 11 as to whether an over - convolution signal su ( if present ) is smaller then a reference signal sr for the over - convolution . a reference signal having a magnitude of 3 % of the average signal in the field of view is , for example , beneficial . when this is the case , the selected measurement sequence is implemented for the field of view in a step s 6 , this sequence being implemented by the control computer via the radio frequency antenna 4 or the surface coil 4 a . if , however , the reference signal sr is exceeded , then the operator at the magnetic resonance tomography installation is offered a selection in a next step s 3 at the console 13 controlled by the image computer 12 , having three decision possibilities . the operator can select changing nothing ( represented by the branch m as “ no ”) and can thus have the measurements undertaken immediately in step s 6 . it must then be expected that artifacts or mispresentations will occur ; however , the operator of the magnetic resonance tomography installation at least was informed thereof in advance . as a second selection possibility ( referenced with the branch y for “ yes ”), an offer is made to suitably adapt the parameters . this means that the step width is reduced in the phase coding direction , as indicated as step 4 in fig2 that sequences in the control computer 11 . as a result of such a reduction of the intervals of the individual phase coding gradients , the correctly analyzed field of view is automatically enlarged in the phase coding direction and the resolution is reduced . the measurement can then again follow in step s 6 . in step s 3 ( represented by the branch m for “ modify ”) the inventive method offers the third alternative of selecting a new , smaller region of the field of view wherein disturbing over - convolutions can be avoided . in a step s 5 , a user at the console 13 can more precisely define the smaller region and may undertake even more settings . the method is then iteratively implemented for such a new field of view beginning with the calculation step as to whether an over - convolution signal above a reference value is present . in the exemplary embodiment described herein , the operator of the magnetic resonance tomography installation thus can select whether the resolution should be reduced to such an extent that over - convolution no longer occurs . this is represented in the flowchart with the branch y in the step s 3 . alternatively , the operator can select that the resolution should be only slightly reduced , and the region free of over - convolution is selected somewhat smaller than the selected field of view . this is represented by the branch m for modify . in particular , it is advantageous that the modifications and parameter settings to be undertaken ensue automated . it is thus also possible for an inexperienced person to produce registrations without disturbing over - convolution artifacts . although modifications and changes may be suggested by those skilled in the art , it is in the intention of the inventor to embody within the patent warranted hereon all changes and modifications as reasonably and properly come within the scope of his contribution to the art .

in a method and magnetic tomography apparatus wherein over - convolutions in the phase coding direction in magnetic resonance tomography are avoided , orthogonal slices are measured as overview presentations in a first step and slices for the following measurement series are then determined . overlapping phases and the magnitude of the appertaining signal are calculated and a warning is emitted when this over - convoluted signal exceeds a reference value . a selection possibility is then offered for reducing the phase coding steps and enlarging the field of view and , if selected , the phase coding step width is automatically reduced .

the scientific name of flax is linum usitatissimum of the family linaceae . flax and its parts have been widely used to make edible oil , as a nutritional supplement , and as an ingredient in many other products . although the composition of flax seeds may vary with genetic background , most flax seeds contain substantial amount of fat ( lipid ), protein and fiber , along with significant amount of other ingredients , such as plant hormones , antioxidants , among others . dietary fiber may act as a bulking agent in the digestive system and has a number of health benefits . based on their relative solubility in water , the dietary fibers in flax seeds can be classified into two categories : soluble fiber and insoluble fiber . existing processes for extracting flax seed are mainly focused on achieving higher protein yields . as a result , the majority of the dietary fiber is lost in the process . u . s . pat . no . 5 , 925 , 401 issued to kankaanpaa - anttila et al . ( the &# 39 ; 401 patent hereinafter ) disclosed a process for producing a product containing flax proteins and flax mucilage . according to the &# 39 ; 401 patent , flax seeds are cold and / or hot pressed and are extracted with an alkali solution . the alkali extract is then treated with acid and a lower alkanol for producing a precipitate containing proteins and mucilage . according to this process , although relatively high level of protein is obtained , substantial amount of dietary fiber , especially the portion containing soluble fiber , is lost . rather than using alkali solution , acids and lower alkanols , the present disclosure employs a different solvent , namely , water , to extract flax seed . it is found that substantial amount of soluble fiber is recovered in water after cooking the flax seed under a temperature as high as 100 ° c ., 110 ° c ., 120 ° c . or higher under pressure that is about 15 psi higher than normal atmospheric pressure . flax seed also contain significant amount of phenolics . phenolics are plant compounds that perform different functions in plants . many of these plant compounds have antioxidant effects when used in humans . at least three types of phenolics exist in flax , these include , for example , phenolic acids , flavonoids , and lignans . lignans are bioactive , non - nutrient , non - caloric phenolic compounds that are rich in a number of plants . see e . g ., peterson , j . et al ., dietary lignans : physiology and potential for cardiovascular disease risk reduction . nutr rev . october 2010 ; 68 ( 10 ): 571 - 603 . the various components , such as fiber and phenolics , may have anti - inflammatory effects , and may help reduce the risk of heart disease , diabetes , cancer , obesity , among other diseases . in one aspect , the instant disclosure provides a composition containing lignan in a dispersible form , e . g ., as a liquid . taken together , the instant disclosure provides an improved process for preparing flax seed extract enriched in soluble fiber , phenolics , among others . in one embodiment , the extract may be used as an ingredient in food or beverage products . in another embodiment , the disclosed extract may be used as a binding agent in a meat or poultry product formulations . in another embodiment , the disclosed extract may be used as a binding agent or thickener in canned and extruded pet foods and treats . in another embodiment , the disclosed extract may be used as a thickener in food or feed materials . in another embodiment , the disclosed extract may be used as flavors or in flavor reactions . in another embodiment , the disclosed extract may be used in baked goods as emulsifier , dough improver , texture improver , or staling preventer . in another embodiment , the disclosed extract may be used to aid in particulate affixation on baked goods . in another embodiment , the disclosed extract may be used to preserve healthful lipids of value such as omega - 3 polyunsaturated and monounsaturated fatty acids , as well as to prevent development of rancidity or off flavors , and to preserve flavor integrity . in another embodiment , the disclosed extract may be used to prepare granola , protein , energy , and other nutritional bars as well as nutritional beverages . in another embodiment , the disclosed extract may be used as a lecithin replacer . in another embodiment , the disclosed extract may be used in salad dressings as an emulsifier , thickener , or for flavoring . in another embodiment , the disclosed extract may be used in gravies , sauces , stews , and chili products to prevent fat separation . in another embodiment , the disclosed extract may be used as a plasma replacer in canned pet foods . in another embodiment , the disclosed extract may be used as a viscosity enhancer , gelling agent , gluten replacer , foam stabilizer , emulsion stabilizer , or natural volumetric bulking agent . in another embodiment , the disclosed extract may be used as a fixative agent to adhere compounds , flavors , or mixtures to the surface of dry food products and pet food kibbles . in another embodiment , the disclosed extract may be used as a humectant . in another embodiment , the disclosed extract may be used for inclusion in egg replacement formulations . in another embodiment , the disclosed extract may be used in products containing collagen proteins , poultry broths , and other ingredients in compositions for health applications . in another embodiment , the disclosed extract may be used as a nutritional emulsifier in human or animal diets to improve fat digestibility and thus improve energy efficiency , or as a nutritional emulsifier for flax seed lipids . it is to be noted that , as used in this specification and the claims , the singular forms “ a ,” “ an ,” and “ the ” include plural referents unless the context clearly dictates otherwise . thus , for example , reference to “ a device ” may include reference to one device , as well as two or more devices , unless the context clearly limits the reference to one device . the terms “ between ” and “ at least ” as used herein are inclusive . for example , a range of “ between 5 and 10 ” means any amount equal to or greater than 5 but equal to or smaller than 10 . the terms “ flax seed ” and “ flaxseed ” may be used interchangeably in this disclosure and both refer to the seed ( s ) of flax . unless otherwise specified , the percentage of certain component in a composition is by weight of total solid . various commercially available products may have been described or used in this disclosure . it is to be recognized that these products are cited for purpose of illustration only . certain physical and / or chemical properties and composition of the products may be modified without departing from the spirit of the present disclosure . one of ordinary skill in the art may appreciate that under certain circumstances , it may be more desirable or more convenient to alter the physical and / or chemical characteristics or composition of one or more of these products in order to achieve the same or similar objectives as taught by this disclosure . the following examples are provided to illustrate the present invention , but are not intended to be limiting . the reagents , materials and instruments are presented as typical components , and various substitutions or modifications may be made in view of the foregoing disclosure by one of skills in the art without departing from the principle and spirit of the present invention . whole flax seeds were milled to a coarse flour or meal . 9 parts of water was then added to one part of this flax seed meal , and the mixture was cooked for 6 hours at about 250 ° f . ( about 121 ° c .) in a stove top pressure cooker set at 15 psi . thus , the absolute pressure inside the cooker was atmospheric pressure plus 15 psi . the suspension was cooled to about 180 ° f . ( about 82 ° c . ), and was passed successively through 16 , 25 , and 30 mesh sieves to separate off solid pieces . the liquid thus obtained was strained through fine nylon mesh cloth . the liquid that passed through the fine nylon mesh was concentrated on stove top in a sauce pan . a top layer of fat was skimmed off . as the liquid began thickening , the product was chilled at 11 % solids and stored for later use . the flax seed extract prepared according to this high temperature water extraction process was subject to a chemical analysis , and the results showed that it contained less than 35 % ( w / w ) protein by weight of total solid . further analysis also showed that the flax seed extract contained about 19 . 5 % ( w / w ) of soluble fiber and only about 0 . 3 % ( w / w ) of insoluble fiber by weight of total solid . by contrast , parallel analysis of a commercial flax seed product that was not prepared with the high temperature water extraction process as disclosed herein contained about 11 . 5 % ( w / w ) of soluble fiber and about 21 . 3 % ( w / w ) of insoluble fiber by weight of total solid . a portion of the flax seed extract was dried on a drum dryer making a powdered flax seed extract product that was used in the following examples . the disclosed compositions may be prepared and / or distributed in a concentrated form or a diluted form . a concentrate may be dissolved or dispersed in a solvent to form a reconstituted solution . a portion of the extract ( 11 % solids ) was used to make a dried beef fat ingredient as described below . 267 grams of flax seed extract was heated to 160 ° f . and mixed in a silverson model l5m - a mixer . while mixing , 70 grams of melted , warm beef fat was added . the mixture was then blended for 10 minutes at 10 , 000 rpm , which results in a very stable emulsion . this emulsion contained approximately 30 % solids . this emulsion was dried in a convection oven at 200 ° f . to dryness . this dry beef fat with flax seed extract product was approximately 70 percent fat and 30 percent flax seed extract . another portion of the flax seed extract was used to make a similar dried beef fat product at 80 % fat and 20 % flax seed extract as described below : 20 grams of dried flax seed extract was mixed in 150 grams of water , and then 80 grams of beef fat was mixed in and emulsified in the silverson mixer for 10 minutes at 10 , 000 rpm resulting in a stable liquid emulsion with 40 % solids content . this was dried in a convection oven as above resulting in a dried beef fat product usable as an ingredient in food product applications . following the process described in the previous examples , except canola oil instead of beef fat was used . canola oil emulsified very well with the flax seed extract . dried flax seed extract was blended into raw mechanically separated chicken ( msc ) at level of 2 %, 5 %, and 10 %. the msc with flax seed extract was cooked for 10 minutes to a temperature of 210 ° f . the cooked product was analyzed in the laboratory for oxidative stability against control msc that did not receive the flax seed extract . fat from the msc samples was analyzed for oxidative stability index ( osi ). the data in table 1 show that the flax seed extract had an antioxidant effect on the product . all references listed below and those publications , patents , patent applications cited throughout this disclosure are hereby incorporated expressly into this disclosure as if fully reproduced herein . peterson , j . et al ., dietary lignans : physiology and potential for cardiovascular disease risk reduction . nutr rev . october 2010 ; 68 ( 10 ): 571 - 603 .

this disclosure relates to a process to make a water soluble extract of ground or milled flax seed and / or related by - products that is useful in numerous applications in a wide range of food or beverage products . the flax extract generated from the disclosed process has significant positive functional characteristics , including , for example , emulsion capacity , water binding , cohesive and adhesive properties , antioxidant capacity , and excipient capability .

following multiple oral doses ( 0 . 6 mg twice daily ), the mean elimination half - life of colchicine in young healthy volunteers ( mean age 25 to 28 years of age ) is 26 . 6 to 31 . 2 hours . pharmacy management systems are computer - based systems that are widely used by commercial pharmacies to manage prescriptions and to provide pharmacy and medical personnel with warnings and guidance regarding drugs being administered to patients . such systems typically provide alerts warning either or both of health care providers and patients when a drug that may be harmful to the particular patient is prescribed . for example , such systems can provide alerts warning that a patient has an allergy to a prescribed drug , or is receiving concomitant administration of a drug that can have a dangerous interaction with a prescribed drug . u . s . pat . nos . 5 , 758 , 095 , 5 , 833 , 599 , 5 , 845 , 255 , 6 , 014 , 631 , 6 , 067 , 524 , 6 , 112 , 182 , 6 , 317 , 719 , 6 , 356 , 873 , and 7 , 072 , 840 , each of which is incorporated herein by reference , disclose various pharmacy management systems and aspects thereof . many pharmacy management systems are now commercially available , e . g ., centricity pharmacy from bdm information systems ltd ., general electric healthcare , waukesha , wis ., rx30 pharmacy systems from transaction data systems , inc ., ocoee , fla ., speed script from digital simplistics , inc ., lenexa , kans ., and various pharmacy management systems from opus - ism , hauppauge , n . y . in the specification and claims that follow , references will be made to a number of terms which shall be defined to have the following meaning . the terms “ a ” and “ an ” do not denote a limitation of quantity , but rather denote the presence of at least one of the referenced item . the term “ or ” means “ and / or ”. the terms “ comprising ”, “ having ”, “ including ”, and “ containing ” are to be construed as open - ended terms ( i . e ., meaning “ including , but not limited to ”). “ concomitant ” and “ concomitantly ” as used herein refer to the administration of at least two drugs to a patient either simultaneously or within a time period during which the effects of the first administered drug are still operative in the patient . thus , if the first drug is , e . g ., clarithromycin and the second drug is colchicine , the concomitant administration of the second drug can occur as much as one to two weeks , preferably within one to seven days , after the administration of the first drug . this is because clarithromycin can exert a long - lasting inhibition of cyp3a isozymes so that cyp3a activity in the patient may not return to pre - clarithromycin - administration levels for as much as two weeks after the cessation of clarithromycin administration . if colchicine is the first drug , administration of a second drug would be concomitant if done within 1 to 2 days , preferably 12 to 24 hours . “ dosage amount ” means an amount of a drug suitable to be taken during a fixed period , usually during one day ( i . e ., daily ). “ dosage amount adapted for oral administration ” means a dosage amount that is of an amount deemed safe and effective for the particular patient under the conditions specified . as used herein and in the claims , this dosage amount is determined by following the recommendations of the drug manufacturer &# 39 ; s prescribing information as approved by the us food and drug administration . “ dosing regimen ” means the dose of a drug taken at a first time by a patient and the interval ( time or symptomatic ) and dosage amounts at which any subsequent doses of the drug are taken by the patient . each dose may be of the same or a different dosage amount . a “ dose ” means the measured quantity of a drug to be taken at one time by a patient . a “ patient ” means a human or non - human animal in need of medical treatment . medical treatment can include treatment of an existing condition , such as a disease or disorder , prophylactic or preventative treatment , or diagnostic treatment . in preferred embodiments the patient is human . “ providing ” means giving , administering , selling , distributing , transferring ( for profit or not ), manufacturing , compounding , or dispensing . “ risk ” means the probability or chance of adverse reaction , injury , or other undesirable outcome arising from a medical treatment . an “ acceptable risk ” means a measure of the risk of harm , injury , or disease arising from a medical treatment that will be tolerated by an individual or group . whether a risk is “ acceptable ” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk , whether they accept whatever scientific and other advice is offered about the magnitude of the risk , and numerous other factors , both political and social . an “ acceptable risk ” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small , or whose consequences are so slight , or the benefits ( perceived or real ) of the active agent are so great . an “ unacceptable risk ” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction , the consequences of the adverse reaction , and the benefits ( perceived or real ) of the active agent . “ at risk ” means in a state or condition marked by a high level of risk or susceptibility . pharmacokinetic parameters referred to herein describe the in vivo characteristics of drug ( or a metabolite or a surrogate marker for the drug ) over time . these include plasma concentration ( c ), as well as c max , c n , c 24 , t max , and auc . “ c max ” is the measured plasma concentration of the active agent at the point of maximum , or peak , concentration . “ c min ” is the measured plasma concentration of the active agent at the point of minimum concentration . “ c n ” is the measured plasma concentration of the active agent at about n hours after administration . “ c 24 ” is the measured plasma concentration of the active agent at about 24 hours after administration . the term “ t max ” refers to the time from drug administration until c max is reached . “ auc ” is the area under the curve of a graph of the measured plasma concentration of an active agent vs . time , measured from one time point to another time point . for example auc 0 - t is the area under the curve of plasma concentration versus time from time 0 to time t , where time 0 is the time of initial administration of the drug . time t can be the last time point with measurable plasma concentration for an individual formulation . the auc 0 -∞ or auc 0 - inf is the calculated area under the curve of plasma concentration versus time from time 0 to time infinity . in steady - state studies , auc 0 - τ is the area under the curve of plasma concentration over the dosing interval ( i . e ., from time 0 to time τ ( tau ), where tau is the length of the dosing interval . other pharmacokinetic parameters are the parameter k e or k el , the terminal elimination rate constant calculated from a semi - log plot of the plasma concentration versus time curve ; t 1 / 2 the terminal elimination half - life , calculated as 0 . 693 / k el . cl / f denotes the apparent total body clearance after administration , calculated as total dose / total auc ∞ ; and v area / f denotes the apparent total volume of distribution after administration , calculated as total dose /( total auc ∞ × k el ). “ side effect ” means a secondary effect resulting from taking a drug . the secondary effect can be a negative ( unfavorable ) effect ( i . e ., an adverse side effect ) or a positive ( favorable ) effect . the most frequently reported adverse side effects to colchicine therapy are gastrointestinal , specifically abdominal pain with cramps , diarrhea , nausea , and vomiting . less frequently or rarely reported adverse side effects associated with colchicine therapy include anorexia , agranulocytosis , allergic dermatitis , allergic reactions , alopecia , angioedema , aplastic anemia , bone marrow depression , myopathy , neuropathy , skin rash , thrombocytopenic disorder , and urticaria . whether a patient experiences an adverse side effect can be determined by obtaining information from the patient regarding onset of certain symptoms which may be indicative of the adverse side effect , results of diagnostic tests indicative of the adverse side effect , and the like . the following examples further illustrate aspects of this disclosure but should not be construed as in any way limiting its scope . in particular , the conditions are merely exemplary and can be readily varied by one of ordinary skill in the art . pharmacokinetic study in healthy adults of single vs . multiple oral doses of colchicine tablets this study was a single - center , open - label , single - sequence , two - period study to evaluate the pharmacokinetic profile of colchicine following single and multiple oral doses of colchicine tablets , 0 . 6 mg , in healthy volunteers . in period 1 , study subjects received a 0 . 6 - mg dose of colchicine after an overnight fast of at least 10 hours . in period 2 , subjects received a 0 . 6 - mg dose of colchicine in the morning and the evening ( approximately 12 hours later ) for 10 days ( steady state regimen ). subjects received a light breakfast served 60 minutes following dose administration in the morning and the evening dose was administered 90 minutes after an evening meal on days 15 through 24 only . on day 25 , the colchicine dose was administered after an overnight fast of at least 10 hours and lunch was served 4 hours post - dose . study periods were separated by a 14 - day washout . following the single dose and the last dose of the multiple dose regimen ( beginning on the mornings of day 1 and day 25 , respectively ), blood samples were collected ( 6 ml each ) from each subject within 1 hour prior to dosing and after dose administration at study hours 0 . 5 , 1 , 1 . 5 , 2 , 3 , 4 , 6 , 8 , 10 , 12 , and 24 ( while confined ) and 36 , 48 , 72 , and 96 ( on an outpatient basis ). plasma concentrations of colchicine and its metabolites were determined using validated lc / ms - ms methods . thirteen healthy , non - smoking subjects with a mean age of 25 . 5 years ( range 19 to 38 years ) and within 15 % of ideal body weight were enrolled in this study . all subjects completed both dosing periods according to protocol . after a single dose , plasma concentrations are no longer quantifiable 24 hours post - dose in all but 1 subject . after the last dose of the steady state regimen , concentrations remained quantifiable for 48 to 72 hours . review of individual subject data shows that no subject experienced a secondary colchicine peak , either following a single dose or upon multiple dosing . all 2 - o - demethylcolchicine ( 2 - dmc ) concentrations were below the level of quantitation ( loq , 0 . 2 ng / ml ) and only one sample from 1 subject ( of 13 subjects ) had a detectable 3 - o - demethylcolchciine ( 3 - dmc ) concentration , which was near the level of quantitation . therefore , metabolites are not discussed further . in healthy adults , colchicine appears to be readily absorbed when given orally , reaching a mean maximum plasma concentration of 2 . 5 ng / ml in 1 . 5 hours after a single dose . the drug is distributed widely , with an apparent volume of distribution of 540 l , greatly exceeding total body water . the elimination half - life as calculated following a single oral dose is approximately 5 hours . levels were not detectable by 24 hours post - dose and this is therefore not an accurate estimate . pharmacokinetic parameter values are summarized in the table below . review of trough plasma concentrations indicates that steady state was attained by approximately the eighth day of dosing for most subjects . colchicine may have a diurnal variation reflected in the observed cmin concentrations at steady state . cmin concentrations prior to the morning dose are approximately 12 % higher than the cmin concentrations prior to the evening dose ( day 23 and day 24 ). the mean cmin concentration observed on day 25 was 0 . 907 ng / ml . colchicine accumulated following administration of multiple doses to an extent greater than expected . exposure was nearly two - fold higher ( approximately 1 . 7 based on auc [ day 25 auc o - τ / day 1 auc 0 -∞ ] and approximately 1 . 5 based on cmax [ day 25 c max / day 1 c max ]). this observation could be attributable to an underestimation of auc ∞ following a single dose . with the higher plasma levels that occur with repeated dosing , a longer terminal elimination half life is apparent , 26 . 6 hours . pharmacokinetic parameter values are summarized in the tables below . in the above table , the parameter cl / f denotes the apparent total body clearance after administration , calculated as total dose / total auc0 - tau ; and v d / f denotes the apparent total volume of distribution after administration , calculated as total dose /( total auc ∞ × k el ). a single - center , open - label , one sequence , two - period study was carried out in 23 healthy subjects . on day 1 , a single 0 . 6 - mg dose of colchicine was administered . after completing a 21 - day washout period , all subjects received 250 mg of clarithromycin administered twice daily for 7 days ( days 22 through 29 ), a sufficient dose and duration to inhibit cyp3a4 and pgp . on the final day ( day 29 ), a single dose of colchicine was co - administered with the clarithromycin dose . when combined with steady - state clarithromycin , there is a significant increase in exposure to colchicine as compared to when colchicine is given alone : the mean c max and auc 0 - t concentrations increased 167 % and 250 %, respectively . in addition , co - administration of clarithromycin and colchicine resulted in an increase of 233 % in the plasma elimination half - life ( t½ ) of colchicine and a 75 % decrease in apparent clearance ( cl / f ). a summary of the mean (% cv ) colchicine pharmacokinetic parameters for day 1 ( colchicine administered alone ) and day 29 ( colchicine co - administered with steady - state clarithromycin ) are given in the table below and illustrated in the table that follows . recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range , unless otherwise indicated herein , and each separate value is incorporated into the specification as if it were individually recited herein . the endpoints of all ranges directed to the same component or property are inclusive and independently combinable . all methods described herein can be performed in a suitable order unless otherwise indicated or clearly contradicted by context . the use of any and all examples , or exemplary language ( e . g ., “ such as ”) herein is intended to better illuminate the disclosure and is non - limiting unless otherwise specified . no language in the specification should be construed as indicating that any non - claimed element as essential to the practice of the claimed embodiments . unless defined otherwise , technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs . the terms wt %, weight percent , percent by weight , etc . are equivalent and interchangeable embodiments are described herein , including the best modes known to the inventors . variations of such embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description . the skilled artisan is expected to employ such variations as appropriate , and the disclosed methods are expected to be practiced otherwise than as specifically described herein . accordingly , all modifications and equivalents of the subject matter recited in the claims appended hereto are included to the extent permitted by applicable law . moreover , any combination of the above - described elements in all possible variations thereof is encompassed unless otherwise indicated herein or otherwise clearly contradicted by context .

methods for concomitant administration of colchicine together with one or more macrolide antibiotics , e . g ., clarithromycin , are disclosed . such methods reduce the dangers commonly associated with such concomitant administration and provide additional benefits .

as required , detailed embodiments are disclosed herein ; however , it is to be understood that the disclosed embodiments are merely examples and that the devices , systems and methods described herein can be embodied in various forms . therefore , specific structural and functional 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 of ordinary skill in the art to variously employ the disclosed subject matter in virtually any appropriately detailed structure and function . further , the terms and phrases used herein are not intended to be limiting , but rather , to provide an understandable description . additionally , unless otherwise specifically expressed or clearly understood from the context of use , a term as used herein describes the singular and / or the plural of that term . the terms “ a ” or “ an ”, as used herein , are defined as one or more than one . the term “ plurality ”, as used herein , is defined as two or more than two . the term “ another ”, as used herein , is defined as at least a second or more . the terms “ including ” and “ having ,” as used herein , are defined as comprising i . e ., open language . the term “ coupled ,” as used herein , is defined as “ connected ,” although not necessarily directly , and not necessarily mechanically . “ communicatively coupled ” refers to coupling of components such that these components are able to communicate with one another through , for example , wired , wireless or other communications media . the term “ communicatively coupled ” or “ communicatively coupling ” includes , but is not limited to , communicating electronic control signals by which one element may direct or control another . the term “ configured to ” describes hardware , software or a combination of hardware and software that is adapted to , set up , arranged , commanded , altered , modified , built , composed , constructed , designed , or that has any combination of these characteristics to carry out a given function . the term “ adapted to ” describes hardware , software or a combination of hardware and software that is capable of , able to accommodate , to make , or that is suitable to carry out a given function . the apparatus comprises amplifiers 1 that are connected to recording electrodes 2 within the heart 3 and electronics and associated software 4 . a pacing and recording program 5 issues signals to a pacing signal generator 6 that is switched onto one selected electrode 2 by multiplexer 7 to stimulate the heart 3 . the signals sensed by the other electrodes 2 are amplified and digitized by an adc 8 and stored in memory 9 . subsequently the data is retrieved and analyzed by analysis program 10 . all subsequent analysis is with sampled signals , care having been taken to conform to the nyquist sampling theorem . the use of the multiplexer 7 allows the heart to be stimulated at different sites 3 . the functions and arrangement described above can be derived , in conjunction with the teaching within this document by the person skilled in the art . fig2 illustrates a pacing sequence applied at one electrode 2 , showing the constant rate stimuli s 1 and extra - stimuli s 2 . the intervals between s 1 - s 1 stimuli and the s 2 - s 1 stimuli remain constant , in this example with an interval of 500 ms . the interval between the s 1 and s 2 stimuli varies , and typically reduces by one 1 ms on each occasion . fig3 illustrates the regions 11 preceding s 1 stimuli that are used for evaluating noise on the premise that no physiological signals occur in these regions 11 . also shown are regions 12 that are analyzed to identify physiological signals resulting from s 2 stimuli . as illustrated in fig4 , the noise regions 11 are extracted from the recorded signal and correlated with templates 13 , generated by the analysis program 10 , to create a model 14 with independent eigenvectors . the templates 13 are representations of potentials of varying widths that are likely to be the result of a physiological event . subsequently , the portions 12 of the recorded signal are correlated to templates 13 and projected into model 14 that provides an output 15 that is indicative of whether the sample being analyzed is signal or noise . fig5 illustrates the fifteen templates 13 that are correlated with the signals 11 12 . template number one 13 a has the longest time duration while template number fifteen 13 b has the shortest . the intermediate template numbers 13 c shorten progressively . in practice the templates are always used in their frequency domain representations , i . e . their discrete fourier transform , for computational efficiency . the correlation between templates 13 is shown as a correlation matrix , see fig6 , in which each element is the correlation between template n and template m where n and m are the template numbers . this shows that the templates 13 are not independent since if they were all non - diagonal elements would be equal to zero . referring to fig7 , the templates 13 are computed in the frequency domain 20 . a record of each noise region 11 is transformed into the frequency domain by fast fourier transform 21 and correlated 22 with each template by multiplication . the result is summed to form the mean cross - correlation spectrum 23 . a mean noise co - variance matrix is derived 24 from the cross - correlation spectrum . the co - variance matrix is decomposed 25 into its eigenvectors and eigenvalues , thus forming a noise model 14 . fig8 illustrates a noise model for three templates only ( because of the difficulties of showing high dimensional models ). the three eigenvectors a 1 , a 2 , a 3 are at rights angles , i . e . orthogonal . the limits of the noise model is shown by the shaded area 40 as defined by the eigenvalues . referring to fig9 , every signal identification region 12 is processed individually . the individual signal portion 26 is transformed into the frequency domain 27 and correlated 28 with templates 13 and the result expressed 29 in the time domain . the resultant signal template correlation records are projected 30 into the eigenvector space of the noise model 14 as a trajectory . fig1 is an illustration of the trajectory 41 of a signal within region 11 illustrating that it remains within the limits 40 of the model 14 as defined by the eigenvectors / eigenvalues . fig1 illustrates the trajectory 42 of a signal within the region 12 showing that it exceeds the limits 40 of the noise model 14 and thus is likely to be attributed to a physiological origin . a convenient method of determining whether the signal exceeds the noise is to reduce the trajectory to a single time domain signal . to achieve this , the resultant trajectory is normalized by division of each eigenvector by its eigenvalue so that the noise model becomes a spheroid 43 as illustrated in fig1 . the norm 45 of the trajectory vector in this space 44 is computed to give the one - dimensional time domain signal . any peak in the time domain signal that is above of the noise is considered to be physiologically significant . fig1 shows a portion of a simulated electrogram 50 , corresponding to a single s 1 - s 2 interval . noise has been added to the electrogram together with small potentials expected from a physiological response . the small potentials have the same peak - to - peak amplitude of the noise ; the positions of the small potentials are indicated by arrows 51 . fig1 shows the electrogram of fig1 with a time domain signal output 52 derived using the method described above superimposed . the time domain signal output shows clear peaks that exceed the noise threshold 53 corresponding to the limit of the noise model , at the positions that the small potentials were inserted into the signal with a significant increase in signal to noise ratio . the present subject matter can be embedded in a computer program product , which comprises all the features enabling the implementation of the methods described herein , and which — when loaded in a computer system — is able to carry out these methods . computer program in the present context means any expression , in any language , code or notation , of a set of instructions intended to cause a system having an information processing capability to perform a particular function either directly or after either or both of the following a conversion to another language , code or , notation ; and b reproduction in a different material form . each computer system may include , inter alia , one or more computers and at least a computer readable medium allowing a computer to read data , instructions , messages or message packets , and other computer readable information from the computer readable medium . the computer readable medium may include computer readable storage medium embodying non - volatile memory , such as read - only memory rom , flash memory , disk drive memory , cd - rom , and other permanent storage . additionally , a computer medium may include volatile storage such as ram , buffers , cache memory , and network circuits . furthermore , in certain embodiments of the computer readable medium , other than a computer readable storage medium as discussed above , the computer readable medium may comprise computer readable information in a transitory state medium such as a network link and / or a network interface , including a wired network or a wireless network , that allow a computer to read such computer readable information . the abstract is provided with the understanding that it is not intended be used to interpret or limit the scope or meaning of the claims . in addition , in the foregoing detailed description , various features are grouped together in a single embodiment for the purpose of streamlining the disclosure . this method of disclosure is not to be interpreted as reflecting an intention that the claimed embodiments require more features than are expressly recited in each claim . rather , as the following claims reflect , inventive subject matter lies in less than all features of a single disclosed embodiment . thus the following claims are hereby incorporated into the detailed description , with each claim standing on its own as a separately claimed subject matter . the corresponding structures , materials , acts , and equivalents of all means or step plus function elements in the claims below are intended to include any structure , material , or act for performing the function in combination with other claimed elements as specifically claimed . the description herein has been presented for purposes of illustration and description , but is not intended to be exhaustive or limited to the examples in the form disclosed . many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope of the examples presented or claimed . the disclosed embodiments were chosen and described in order to explain the principles of the embodiments and the practical application , and to enable others of ordinary skill in the art to understand the various embodiments with various modifications as are suited to the particular use contemplated . it is intended that the appended claims below cover any and all such applications , modifications , and variations within the scope of the embodiments . although specific embodiments of the subject matter have been disclosed , those having ordinary skill in the art will understand that changes can be made to the specific embodiments without departing from the scope of the disclosed subject matter . the scope of the disclosure is not to be restricted , therefore , to the specific embodiments , and it is intended that the appended claims cover any and all such applications , modifications , and embodiments within the scope of the present disclosure .

previous research has shown that the risk of sudden death due to cardiac arrhythmias can be predicted by observing the shape of recorded endocardial electrograms in response to pacing , and in particularly detecting certain small deflections in the recorded electrogram following early stimulation of the heart . a long standing problem has been the reliable detection of these small individual potentials because of the presence of noise in the recorded electrical signals created by other electrical equipment within a typical catheter laboratory . the solution described involves deriving a model of noise from a first portion of the electrogram in which a physiological signal is presumed to be absent , and transforming a second portion of the electrogram , presumed to contain a physiological signal , into the model of noise . the physiological signal can then be identified by identifying portions of signal within the second portion of the electrogram that do not conform to the model of noise .

automatic sequencing : the process of automatically downloading a group of fields or segments from the v & amp ; r to the control of the linear accelerator sequentially , without user intervention . control console : the interface and controller of a linear accelerator . the control console interfaces to the v & amp ; r . effective penumbra : the effective penumbra for any combination of high and low isodose lines measures the distance between the points on the higher isodose that comes closest to the target and the points on the lower isodose that come closest to the critical structure . field group : an arbitrary grouping mechanism used to relate several fields together . this relationship is usually based on the desire to autosequence them the fields together . hdi : high definition intensity . creating high - resolution mlc fields through the use of an mlc , software algorithms , and automatic table motion . intensity map : a 3d representation of desired or delivered radiation intensity distribution from a particular port . intensity modulation : the process of shaping , modifying , and moving the beam around a target in order to maximize the dose at the target and minimize the dose to all normal structures . monitor units : the unit of measurement for delivery of radiation on a linear accelerator . monitor units are related to dose by an algebraic formula using dose coefficients . port : used to describe the port of entry for an external beam treatment . a subset of the information contained in a field . port film : a film image acquired at the linear accelerator created from the exit dose radiation from the patient . portal imaging : capturing an image from the radiation exiting from the patient either on film or as an electronic image . segment : a piece of a treatment field . multiple segments are usually used to create an intensity modulated field or a complex dynamic field . segments are sequenced together to create a field . static field : a treatment field or segment defined with no moving parameters such as leaves or gantry angles . static segments can be built up to create an intensity modulated field . step and shoot : a method of intensity modulation of sequentially delivering static fields . treatment record : the record of what was delivered to the patient on the linear accelerator includes all the machine settings and parameters . v & amp ; r : verify and record , the interface to a linear accelerator for downloading fields , verifying the fields before delivery , and recording the delivered field parameters . v & amp ; r software : software utilized to control the position of the leaves in the multileaf collimator . the present invention relates to modulation of radiation delivery to achieve finer resolution and control . the following description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements . various modifications to the preferred embodiment will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments . in the following , the invention is described with primary reference to a system for delivering x - ray radiation to a field of a patient , and for delimiting the field using at least one movable leaf in the beam path from a radiation source . this is by way of example . thus , the present invention is not intended to be limited to the embodiment shown but is to be accorded the widest scope consistent with the principles and features described herein . fig1 illustrates a radiation treatment device 2 of common design , which utilizes a multileaf collimator ( mlc ) 4 and a control unit in a housing 9 along with a treatment processing unit 100 constructed in accordance with the present invention . the radiation treatment device 2 comprises a gantry 6 which can be swiveled around a horizontal axis of rotation 8 in the course of therapeutic treatment . mlc 4 are fastened to a projection of gantry 6 . to generate the high - powered radiation required for the therapy , a linear accelerator is located in gantry 6 . the axis of the radiation bundle emitted from the linear accelerator and gantry 6 is designated 10 . electron , photon , or any other detectable radiation can be used for the therapy . during the treatment , the radiation beam is trained on a zone 12 of an object 13 , for example , a patient who is to be treated , and who lies at the isocenter of the gantry rotation . the rotational axis 8 of the gantry 6 , the rotational axis 14 of a treatment table 16 , and the beam axis 10 all preferably intersect in the isocenter . the construction of such a radiation treatment device is described in general in a brochure “ digital systems for radiation oncology ”, siemens medical laboratories , inc . a91004 - m2630 - b358 - 01 - 4a00 , september 1991 . fig2 shows a portion of an illustrative radiation treatment device 2 and portions of treatment processing unit 100 in more detail . an electron beam 1 is generated in an electron accelerator 20 . accelerator 20 comprises an electron gun 21 , a wave guide 22 , and an evacuated envelope or guide magnet 23 . a trigger system 3 generates injector trigger signals and supplies them to injector 5 . based on these injector trigger signals , injector 5 generates injector pulses which are fed to electron gun 21 in accelerator 20 for generating electron beam 1 . electron beam 1 is accelerated and guided by wave guide 22 . for this purpose , a high frequency ( hf ) source ( not shown ) is provided which supplies radio frequency ( rf ) signals for the generation of an electromagnetic field supplied to wave guide 22 . the electrons injected by injector 5 and emitted by electron gun 21 are accelerated by this electromagnetic field in wave guide 22 and exit at the end opposite to electron gun 21 as electron beam 1 . electron beam 1 then enters a guide magnet 23 , and from there is guided through a window 7 along axis 10 . after passing through a first scattering foil 15 , the beam goes through a passageway 51 of a shield block 50 and encounters a second scattering foil 17 . next , the beam is sent through a measuring chamber 60 , in which the dose is ascertained . if the scattering foils are replaced by a target , the radiation beam is an x - ray beam . finally , mlc 4 includes a plurality of leaves 41 and 42 . of course , this is just one example of a beam - shielding arrangement that can be used in the invention . the invention is suitable in other arrangements , as is well appreciated by those skilled in the art . the mlc 4 comprises a plurality of leaves 41 and 42 and an additional pair of aperture plates ( not shown ) arranged perpendicular to the plurality of leaves 41 and 42 . in order to change the size of the irradiated field , the plurality of leaves can be moved with respect to axis 10 by a drive unit 43 which is indicated in fig2 only with respect to leaf 41 . drive unit 43 comprises an electric motor which is coupled to leaves 41 and 42 and which is controlled by a motor controller 40 . position sensors 44 and 45 are also coupled to leaves 41 and 42 , respectively , for sensing their positions . the area of a patient that is irradiated is known as the field . as is well known , leaves 4 are substantially impervious to the emitted radiation . they are mounted between the radiation source and patient in order to delimit the field . areas of the body , for example , healthy tissue , are therefore subjected to as little radiation as possible , and preferably to none at all . preferably , with at least one of the leaves movable , the distribution of radiation over the field need not be uniform ( one region can be given a higher dose than another ); further , with the gantry able to be rotated , different beam angles and radiation distributions are allowed without having to move the patient around . the central treatment processing or control unit 100 ( fig1 ) is usually located apart from radiation treatment device 2 in a different room to protect the therapist from radiation . treatment processing unit 100 includes an output device , such as at least one visual display unit or monitor 70 , and an input device , such as a keyboard 19 , although data can be input also through data carriers , such as data storage devices . the treatment processing unit 100 is typically operated by the therapist who administers actual delivery of a radiation treatment as prescribed by an oncologist . by utilizing keyboard 19 , or other input device , the therapist enters into a control unit 76 of the treatment processing unit 100 the data that defines the radiation to be delivered to the patient , for example , according to the prescription of the oncologist . the program can also be input via another input device , such as a data storage device , through data transmission . on the screen of a monitor 70 , various data can be displayed before and during the treatment . central processing unit 18 , included in treatment processing unit 100 , is connected with the input device , e . g ., keyboard 19 , for inputting the prescribed delivery of the radiation treatment and with a dose control unit 61 that generates the desired values of radiation for the controlling trigger system 3 . trigger system 3 suitably adapts the pulse repetition frequency or other parameters to change the radiation output . a digital dosimetry system is particularly advantageous in order to more easily control the digital output of central processing unit 18 . central processing unit 18 suitably includes a control unit 76 for controlling execution of the treatment program in conjunction with memory 77 and a combination circuit 78 which suitably receives signals from the control unit 76 and memory 77 . to address the problems associated with lead alloy block and conventional mlc systems , a high definition intensity mlc system is provided which allows for increased dosages with improved conformal radiation therapy . in addition , a system and method in accordance with the present invention provides for minimal leakage . fig3 illustrates a block diagram of a system 300 for treating a patient . the system 300 is divided into two phases , a planning phase 302 and a treatment phase 304 . the planning phase 302 comprises a database 303 which receives treatment fields from treatment planning system 306 , beam shaper 308 and local area therapy information system ( lantis ) 310 . the treatment planning system 306 is typically a very sophisticated system used by a doctor or the like to provide certain information about a particular manner of treating a tumor or the like . one of the functions of the treatment planning system 306 would be to provide a translation of the table as well as the information to the positioning of the leafs on the multileaf collimator . the beam shaper 308 and the lantis 310 similarly provide field information to the database 303 to provide the information related to table position and leaf position information . verification and recording ( v & amp ; r ) software 312 and lantis 310 are utilized to provide segments to , and receive information , from the database 303 related to the control of the multileaf collimator 318 as well as the positioning of the table 320 along with the control of the linear accelerator of the treatment system 316 . a typical v & amp ; r software package is for example primeview , a software package sold by siemens corporation . the v & amp ; r software 312 in the treatment phase 304 receives and provides the information to control console 314 . the control console in turn controls the linear accelerator 316 , the mlc 318 and the table 320 . accordingly , the present invention could be located in the planning phase or the treatment phase as well as in the treatment system to provide the appropriate radiation therapy . specifically , a high definition intensity mlc system could be provided in the v & amp ; r software , such as primeview , to provide the appropriate radiation therapy . to describe the operation of the present invention in more detail , refer now to fig4 . fig4 is a flow chart of a hdi mlc system in accordance with the present invention in this embodiment . first , the treatment port dose is divided into segments , via step 402 . next , the beam associated with the radiotherapy is translated between doses , via step 404 . in a preferred embodiment the beam is translated a subincrement of the leaf width perpendicular to the leaf motion axis . another possibility is to rotate the mlc in varying degrees . finally , the leaf positions of the mlc are adjusted to maintain the shape , via step 406 . in one embodiment , if a port is treated with a standard 1 cm width mlc leaf and the field was divided into two , then each of the two fields would be treated with half of the dose . between fields one and two a translation by 5 mm of the field perpendicular to the leaf motion axis would occur and the leaf positions would be altered to maintain the correct port shape . producing a conformal field by this manner produces a 5 mm resolution of the beam edge and reduces the original leakage by one half . the hdi mlc system allows for a much more conformal shape than the original 1 cm mlc leaf widths . this translation of the field and the repositioning of the leaves can be accomplished through an automated control and the treatment overhead would be minimal as compared to a standard block shaped treatment . it is important when using the hdi to move the table in a precise fashion in three dimensions to insure that the multiple doses are administered accurately . fig5 illustrates the parameters and tables that could be used to determine the incremental table movement when utilizing a system and method in accordance with the present invention . interleaf leakage is a problem with conventional multileaf collimator systems as the dosage amount increases . each time another field division occurs the amount of interleaf leakage drops by one half . for example , a 5 mm shift has interleaf leakage of approximately 0 . 7 % and for a 3 mm shift a leakage of approximately 0 . 3 %. when implementing this clinically , a geometric algorithm is needed to calculate the amount of translation in any of the three planes ( x , y , and z vector ), as well as the leaf movements that are required . a system and method in accordance with the present invention is particularly useful for clinical application delivering a much more conformal field at a significant reduction in x - ray leakage to that of a custom block and a mlc leaf design of smaller leaf width . the following will discuss in more detail a preferred embodiment of the present invention . a hdi method and system , in a preferred embodiment , will be integrated with automatic table motion and mlc support . hdi functionality will allow the user to select an mlc field to be converted to a hdi field . during the conversion , the user will be able to select the desired resolution of the hdi field . a hdi field is a group of fields that are to be auto - sequenced together to create the hdi field definition . hdi functionality can exist completely within the planning phase or the treatment phase . this will allow the new functionality to take advantage of existing interfaces to the database for creating fields and autosequenced groups . hdi functionality is an automated method of creating new fields with new mlc shapes , new table parameters , and new grouping arrangements , which are all done manually today . in a preferred embodiment , the core functionality of hdi will be contained within a hdi dialog for visualizing target shape and hdi definition . the ability to create hdi fields and groups from one mlc field . each field will have new field shapes and new table parameters . the ability to visualize the results of the hdi fields and resolution sections . a new auto - sequence group type for hdi fields with special group rules . the ability to deliver , verify and record the hdi group and fields . an hdi dialog illustrates the mlc shape dependent upon the fields generated . this information is then provided to the control console which in turn controls the position of the leafs of the mlc . fig6 illustrates a dialog in which a portion of the pelvis is to be treated . the preferred embodiment of the operation of the hdi dialog is described below . 1 . the hdi dialog will provide a hdi display of the mlc shape and a projection of the logical mlc leaf edges . 2 . the hdi dialog will provide a control for setting the desired resolution of the logical leaf boundaries . 3 . the hdi display will be dynamically controlled by the resolution control . 4 . the hdi display comprises a grayscale image showing the overlapping hdi field shapes . this will be similar to the txvisualization tab display . 5 . the hdi display will take into account the derived table positions for each hdi field when displaying the overlapping fields . 6 . the hdi dialog will provide a save button and a cancel button . 7 . when the user selects save , the hdi dialog will create new fields corresponding to the original field and the selected resolution . 9 . the save button shall be disabled when none is selected on the resolution control . 10 . based on a defined algorithm , one new field shall be created when the save button is clicked and 5 . 0 mm is selected on the resolution control . 11 . based on a defined algorithm , 2 new fields shall be created when the save button is clicked and 3 . 3 mm is selected on the resolution control . 12 . based on a defined algorithm , 3 new fields shall be created when the save button is clicked and 2 . 5 mm is selected on the resolution control . 13 . based on a defined algorithm , 4 new fields shall be created when the save button is clicked and 2 . 0 mm is selected on the resolution control . fig7 illustrates a first dialog with field being created around a body ( i . e ., tumor ). note the stairstep effect created by the field . fig8 illustrates a second dialog with three new fields being created . as shown , the three new fields match the contour of the body image more conformally . accordingly , a system and method in accordance with the present invention provides for better defined edges around target and critical surfaces than a conventional multileaf collimator ( i . e ., effective penumbra ). it provides for the same clearance as conventional mlc . it provides for the same maximum field size as a conventional mlc . finally , a system and method in accordance with the present invention minimizes leakage between the leafs thereby minimizing leakage to the patient . although the present invention has been described in accordance with the embodiments shown , one of ordinary skill in the art will readily recognize that there could be variations to the embodiments and those variations would be within the spirit and scope of the present invention . accordingly , many modifications may be made by one of ordinary skill in the art without departing from the spirit and scope of the present invention .

a method and system in accordance with the present invention uses the existing hardware and divides the treatment port dose into segments . in between each segment the field , with respect to the beam , would be translated , and the leaf positions would be adjusted to maintain the tumor contour . by integrating the above - identified methodology with a hardware system , accurate conformal radiation therapy is provided while minimizing leakage . in addition , through the present invention , higher dose rates can be provided while not appreciably affecting treatment time .

the basic garment , ie , the brief portion , is illustrated by fig1 and 2 . the brief portion of the present invention is preferably constructed of elastic material such as is use in swim wear or athletic wear ( 10 - 36 % spandex ). the preferred fabric is four - way spandex of 15 - 20 % spandex in all 5 panels , that is the front , back , left and right sides , and crotch panels . however , the crotch panel may be two - way spandex oriented front - to - back . generally , the brief is made by sewing the five panels together , but two or more of the panels may be fashioned from a single continuous piece of spandex comprising two or more panels . the description “ panels ” then refers to the position and function of sections of the single swatch of fabric . because there is no need for providing room for the male external organs , the pattern for cutting can be essentially the same as for women &# 39 ; s swimwear with modifications to adapt to the male torso such as thicker waist , male abdominal shapes , etc . the pubic and perineal panels should fit snugly against the body . in conventional brief style underwear with the penis and scrotum being inside the garment , the crotch panel cannot stretch snugly over the perineum surface , nor can the pubic panel be snugged against the pubes . an elastic waistband ( 6 ) is sewn to the top terminus of the torso surrounding panels , but unlike conventional briefs or even swimwear , the waistband is not worn essentially horizontal , but sloped downward from a high back fitted to pass over the small of the back and a low front passing under the abdomen . the primary function of the waistband is to anchor the briefs in one position , especially in the presence of an enlarged abdomen . the high back / low front cut places the brief &# 39 ; s waistband in the natural position where there is no tendency to creep as is the case with ordinary straight across waistbands on conventional brief type underwear . when the conventional brief type underwear waistband creeps down the front panel becomes loose and blouses . this is unacceptable in a spandex garment . it is essential for a spandex brief to keep the front panel flat and produce even pressure on the pubic area . while creeping and loosening is not a problem in conventional knit underwear , utilizing “ pre - crept ” waistband ( 6 ) like the present waistband would improve conventional style underwear . referring to fig2 , 3 , 4 , and 7 , the preferred characteristics of the waistband ( 6 ) is for it to be made in a continuous unbroken loop of two way spandex sewn all around , to the front , back , and side panels of the shorts . the dimensions are : 1 to 3 inches wide , and the back 2 to 5 inches higher ( 10 ) than the front so that the waistband fits into the small of the back and around the waist under the abdomen . alternatively the waistband may be formed by sewing a hem constructed of two or more layers the spandex panels folded over . the high - low waistband will function in exactly the same manner when worn by a thin man . another advantage of the high back / under - the - abdomen waist band is that the position shown in fig4 is a smaller circumference than the ordinary more horizontal position approximately in the position of the belly band ( 8 ). in fact the high / low position is the smallest circumference of any waist measurement of a portly person . this means that an elastic in position of ( 6 ) will have less hoop tension than other positions of wearing , and that the propensity of an elastic waist band or belt to slip down is greatly reduced as it is already “ slipped down ”. the preferred penis / scrotum hole ( 2 ) is a vertically oriented ovoid ( egg ) shape with the upper arc ( 3 ) having a radius of approximately ¾ inch and the lower arc 4 having a radius of approximately ½ inch . the vertical length of the preferred hole is approximately 2½ to 3½ inches with the variation being at the lower end of the hole . like any garment , the positioning and the specific size of the hole and other garment parts is fitted to match the body size of the wearer . in no case should the hole be so small or misplaced as to pinch the sides or top of the penis , or to bind at the underside of the scrotum . a front covering ( 12 ) is optional , but valued when the garment is used as a hernia brace or as general underwear . the covering 12 is made of knit cotton or any other material and weave suitable for the application . it is fastened to or near the lower edge of the waist band ( 6 ) and to the perineal ( crotch ) panel . covering ( 12 ) is loose enough to form a pocket for the organs without significant binding . the fastening may be by any convenient method such as , tack sewing , buttons , snaps , ties , velcro , etc , and may include attachment along the sides of cover panel ( 12 ). other purposes for the cover panel ( 12 ) are for modesty , to prevent abrasion , for hygiene , and for comfort . the second hernia relief element of the invention is an optional elastic belly band ( 8 ) 2 to 4 inches wide . the belly band is spot sewn to the briefs portion of the invention basic garment waist band ( 6 ) at the back by either of the methods shown in fig8 . fig8 a illustrates preferred method of joining the belly band ( 8 ) to the waistband ( 6 ) being sewn edge to edge . a small overlap to facilitate machine stitching is deemed to be edge - to - edge . this preferred attachment allows the belly band ( 8 ) to pivot at the back while the front is adjusted up and down . fig8 b illustrates the bands being heavily overlapped and sewn together in the overlapping zone . this configuration has less pivot ability than the embodiment shown in fig8 a , and may introduce unbalanced elastic forces tending to cause the belly band to slip down away from its set position . the elastic belly band ( 8 ) is generally placed over or near the navel and is adjusted to cover , flatten , and hold abdominal hernias . pads may be inserted as needed under the front or side pressure panels , waistband , or the belly band . referring to fig6 and 7 , the third part of the invention is the addition of a shirt portion in the general form of an undershirt . the undershirt portion ( 13 ) of the garment is of cotton knit or other suitable materials and weaves . the shoulder straps ( 16 ) convey additional lift to the waist bands and lower abdominal portion , especially if there is a hanging pouch of fat . some spandex may be included in some locations for a conforming fit and support . the undershirt portion is sewn to the elastic waistband ( 6 ) at least at the front half , and preferably all around . the belly band ( 8 ) is left unattached to the undershirt to be free for adjusting up or down . among other things , the attached undershirt prevents the waistband from folding , which would result in pinching and binding . obviously , the undershirt &# 39 ; s attachment to the brief portion also prevents the undershirt from creeping upward on the torso . upper band ( 8 ) is omitted in some embodiments . the undershirt is cut lower under the arms than most tank - top undershirts to give additional length to the shoulder straps so they may be more easily pulled over the shoulders . the top of the torso portion under the arms should end approximately 14 to 16 inches below the top of the shoulder . the front and back undershirt panels may be extended higher than shown in fig6 and 7 . referring again to fig6 and 7 , the fourth part of the invention is the addition of a legging or hose portion in the general form of an long - john type legwear sewn to the leg openings of the brief portion , and extending to the ankle , terminating in stirrup straps passing under the insteps of the feet . the purpose of the hose portion is primarily for warmth when used as an undergarment in cold weather and as sleepwear . the garment is pulled on over the buttocks and pelvis , and the penis and scrotum is pulled through the hole , and the belly band ( 8 ), if used , is adjusted to cover any abdominal hernias . the brief design ( described as the basic garment ) shown in fig1 can be modified by adding short legs ( 11 ) as shown in fig5 for both the preferred usage , and the comfort - sleep wear described below . the garment can be modified for enhancing comfort while sleeping , and in particular will provide a cooling effect on the testes during hot , humid nights , although the comfort feature is useful even on cool nights . for sleepwear and athletic wear , slight modifications of the described invention is desired . the modifications are to have short legs ( 11 ) as shown in fig5 , and a covering panel made of cotton or similar absorbent fabric . this embodiment puts a layer of cloth between the penis and scrotum and the leg during sleeping . thereby reducing sweating and absorbing whatever sweat does occur at the contact area . the fabric not only controls sweating , but because of the contact area being dryer , the growth of fungus and bacteria is inhibited or eliminated . the cooling effect should also be healthier for the testes , which are sensitive to heat .

a brief style elastic undergarment designed for the particular needs of a portly person having an enlarged abdomen . the undergarment is constructed of elastic spandex material and has a high cut back and a low cut front so the waistband traverses the torso passing across the small of the back thence under the abdomen . the undergarment further comprising an auxiliary elastic waistband specifically intended to hold abdominal hernias in , and an attached supporting undershirt . thus the elastic in the briefs and the auxiliary band press small hernias back into the abdominal cavity . for use by males , there is a hole through which the penis and scrotum project to avoid being compressed and allowing a snug , pressure fit across the front . the garment may be used as sleepwear and athletic wear .

a deep diving fishing lure embodying the present invention has a diving lip extending from an elongate lure body . within the diving lip is situated a latch with a catch and a pivotable lure positioning arm . in the latched position , the lure positioning arm facilitates the lure diving downward in the water upon trolling ; in the released position , the lure positioning arm positions the lure to negate the tendency to dive thereby facilitating retrieval of the lure from the water . referring to the drawings and particularly to fig1 , an elongate lure body 10 is depicted having a first end portion or head portion 12 , a second end portion or tail portion 14 , a top side 16 , and a bottom side 18 . a diving lip 20 extends from the first end portion 12 of the lure body 10 . diving lip 20 has a top surface 22 , a convex bottom surface 24 , a front portion 26 , and rear portion 28 . a latch located within diving lip 20 includes lure positioning arm 36 which is pivotably mounted to the front portion 26 of diving lip 20 for fore - and - aft movement , and is adapted for attachment to a fishing line at the proximal end portion 37 . when in the latched position , lure positioning arm 36 facilitates the lure diving downward in the water upon trolling . a fin 30 protruding from the bottom surface 24 of the diving lip 20 extends longitudinally along the centerline of the lure from approximately the midpoint of the underside of the diving lip 20 to the rear portion 28 of the diving lip . eyelets 40 and 42 extend from the underside of the lure body 10 for respective attachment of fish hooks 41 , 43 or the like . referring to fig2 , lure positioning arm 36 is depicted released from the aft position . in the preferred embodiment , lure positioning arm 36 is provided with an offset portion 39 . this offset is desirable to avoid a change in the profile of the diving lip and thus its diving characteristics . referring to fig3 and 4 , top views of fishing lure 10 are depicted . catch 34 is located in groove 32 within the body of diving lip 20 and includes a pair of upstanding , tapered cusps 35 and 37 spaced from one another to receive lure positioning arm 36 therebetween . cusps 35 and 37 are configured for back - and - forth movement relative to one another . as shown in fig3 , catch 34 is made of a flexible material and releasably holds lure positioning arm 36 in the aft position during trolling . in the latched aft position , lure positioning arm 36 facilitates the downward diving motion of lure 10 . in response to the strike of a fish , catch 34 releases lure positioning arm 36 , permitting the arm to move to the fore position , thereby facilitating retrieval of the lure and , if the fish is caught , prompt setting of the hook and landing the hooked fish . fig4 depicts lure positioning arm 36 in the released , fore position . preferably , catch 34 does not project above the top surface 22 of diving lip 20 but is flush with top surface 20 when in the latched aft position . cross - sectional views of lure 10 are depicted in fig5 and 6 . referring to fig5 , in the preferred embodiment catch 34 is located entirely within groove 32 thereby reducing drag through the water . the pivot axis about which lure positioning arm 36 pivots is defined by pin 38 , also located within groove 32 and at or near the front portion 26 of diving lip 20 , preferably about one - tenth of the length of the diving lip away from the leading edge 27 of the lip . all or nearly all of lure positioning arm 36 is located within groove 32 further reducing drag as the lure moves through the water . referring to fig6 , a cross - sectional view of the diving lip 20 is depicted . catch 34 releasably holds lure positioning arm 36 in the aft position . in the preferred embodiment , catch 34 is responsive to the strike of a fish and releases lure positioning arm 36 so that arm 36 can move to the fore position , facilitating removal of the lure from the water . the tapered cusps of the catch releasably holding the lure positioning arm can be situated at a fixed spacing from one another , as shown in fig3 - 6 , or the spacing thereof can be adjustable as shown in fig7 . in particular , cusps 35 and 37 of catch 34 are spaced from one another and the spacing therebetween can be adjusted by a fastener connecting cusps 35 and 37 and passing through the cusps , such as socket cap screw 40 threadedly received in nut 42 which , in turn , is embedded in cusp 35 . socket head 44 of socket cap screw 40 abuts outboard side 46 of cusp 37 . as socket head 44 is turned clockwise , socket cap screw 40 is threaded into nut 42 , cusps 35 and 37 are drawn toward one another , reducing the spacing therebetween , and thereby tightening the grip on lure positioning arm 36 situated between cusps 35 and 37 . similarly , as socket head 44 is turned counterclockwise , cusps 35 and 37 seek to return to their original positions , the space therebetween is increased , and grip on lure positioning arm 36 is loosened . socket head 44 is situated in channel 48 defined in diving lip 20 and is provided with a socket adapted to receive a drive such as an allen drive . if desired , the socket can be chosen to receive other drive types such as slotted , phillips (“ crosshead ”), robertson (“ square ”), and the like . the contour of diving lip 20 preferably is such that the width of lip 20 gradually increases in a direction from leading edge 27 of front portion 26 to a maximum at a point intermediate the length of diving lip 20 and then decreases as the rear portion 28 approaches and ultimately adjoins lure body 10 at the head portion 12 thereof . the foregoing specification and the drawings are intended as illustrative but are not to be taken as limiting of the present invention . still other variations and rearrangements of parts are possible without a departure from the spirit and scope of the present invention .

a deep diving fishing lure having a forwardly - extending diving lip is provided with a fore - and - aft pivotable lure positioning arm mounted to the diving lip . the lure positioning arm , when locked in aft position , maintains the lure in a diving position when pulled through a body of water but negates the lure &# 39 ; s tendency to dive when released from the aft position .

in fig1 - 5 , a multiple chamber fluid container 10 and 10 a comprises a multiple fluid container body 30 and 30 a having plural separate fluid chambers 34 a and 34 b , and a cap 20 and 20 a with fluid access openings 26 , 26 a and 26 b . the multiple fluid container body 30 and 30 a comprises a plurality of separate fluid chambers 34 a and 34 b , with at least two as shown in the drawings . each fluid chamber 34 a and 34 b comprising surrounding walls 38 a and 38 b and a connected bottom 39 a and 39 b , enclosing an interior space 37 a and 37 b for containing fluids , and a top chamber opening 31 a and 31 b for accessing the interior space , as best seen in fig4 . a first fluid chamber 34 a is spaced apart from the second fluid chamber 34 b by an air space 36 between adjacent wall portions 35 a and 35 b . the separate fluid chambers 34 a and 34 b are interconnected at the top chamber opening by an interconnecting ridge 32 between the adjacent wall portions 35 a and 35 b and a common top lip 33 at a top edge of non adjacent wall portions to form a larger shared fluid container body opening defined by the top lip 33 accessing the top chamber openings 31 a and 31 b of each of the separate fluid chambers 34 a and 34 b respectively . each of the separate fluid chambers 34 a and 34 b is configured with tapering wall surfaces narrower at the bottom to allow the multiple chamber bodies 30 to be stacked in a nested array for storing or shipping empty containers , is seen in fig5 . the cap 20 and 20 a comprises a top surface 29 and 29 a and a surrounding downwardly facing channel 23 , in the embodiment of fig1 and 2 , or a threaded connector 18 , in the embodiment of fig3 , around an outer edge of the top surface . the channel 23 or threaded connector 18 removably mating with the shared top lip 33 to seal the multiple fluid container opening . in fig4 , a means for sealing each of the at least two fluid chambers 34 a and 34 b to retain a fluid therein separately from a fluid in any other fluid chamber comprises a portion of the cap top surface 29 contacting the interconnecting ridge 32 between the adjacent wall portions to separate the top chamber openings 31 a and 31 b of the fluid chambers . the top surface 29 and 29 a of the cap 20 and 20 a has a least one , fluid access opening 26 , 26 a and 26 b formed in the top surface for accessing the interior spaces 37 a and 37 b each of the separated fluid chambers . means are provided for accessing one of the access openings 26 , 26 a and 26 b at a time to access one of the separated fluid chambers while maintaining the other of the separated fluid chambers sealed closed to retain a fluid therein . in fig1 and 2 , showing a disposable cup embodiment of the multiple chamber fluid container 10 , the cap 20 has a separate fluid access opening 26 a and 26 b for each of the separate fluid chambers 34 a and 34 b , and the means for accessing one of the at least one fluid access opening at a time comprises a sealing tab 22 a and 22 b over each of the separate fluid access openings . in fig3 , showing a bottle embodiment of the multiple chamber fluid container 10 a , the cap 20 a has a single fluid access opening 26 and the means for accessing one of the at least one fluid access opening at a time over a fluid chamber comprises a rotatable cap surface top 29 a to rotate the single fluid access opening 26 over each of the separate fluid access openings one at a time and the cap further comprises a sealable fluid access spout 19 over the fluid 19 access opening . in the disposable cup embodiment of the multiple chamber fluid container 10 of fig1 and 2 , the multiple fluid container body 30 is fabricated of a thermally insulating disposable synthetic material , such as styrofoam and the cap 20 is fabricated of molded plastic , and the sealing tabs 22 a and 22 b are molded into the cap with living hinges 28 a and 28 b to open and close the sealing tabs 22 a and 22 b . a flat portion 27 a and 27 b of each of the sealing tabs covers the fluid access opening 26 a and 26 b and the sealing tab hooks over the outer channel 23 with a bottom hook tab 21 a and 21 b hooked under the outer channel 23 and an outer face 24 a and 24 b resting against an outer face of the outer channel 23 and a top surface 25 a and 25 b resting on top of the outer channel 23 , as seen in fig1 and 2 . in fig3 , a reusable bottle embodiment he multiple chamber fluid container 10 a the multiple fluid container body 20 a is preferably fabricated of at least one material taken from the list of materials comprising glass , metal , plastic , synthetic foam or other fluid containing materials having durable waterproof qualities , which may have thermally insulated wall surfaces 35 a , 35 b , 38 a and 38 b fabricated with double layer wall surfaces having a thermally insulating substance between two surfaces of the double layer wall surfaces or fabricated of a thermally insulating material . in use , the cap 20 and 20 a may be removed to fill each of the separate fluid chambers 34 a and 34 b with a different fluid . the cap 20 and 20 a seals each of the chambers separately to prevent mixing the fluids together . to access the fluids , a fluid access opening 26 , 26 a or 26 b is opened over the desired chamber containing the desired fluid . the multiple chamber container 10 and 10 a of the present invention may be used for a variety of types of fluids which could include , but not limited to , different beverages including hot and cold beverages , consumer products such as a shampoo and a conditioner or liquid soap and hand lotion , a mixable adhesive requiring two separate liquid or gel components mixed together at the moment of application , or any other type of fluids including powders or granular substances , such as salt and pepper , as well as liquids where having multiple chambers to retain them in a single container . it is understood that the preceding description is given merely by way of illustration and not in limitation of the invention and that various modifications may be made thereto without departing from the spirit of the invention as claimed .

a multiple chamber stackable cup or bottle has an air space separation between the chambers . a rotatable cap with a single sealable spout pivots to access each chamber individually . alternately , a stationary cap has multiple sealable openings , one for each chamber , which communicate one chamber at a time . tapered bodies enable the multiple chamber bodies to be stacked in a nested array .

i turn now to a detailed description of the preferred embodiment , after first describing the drawings . fig1 a and 1b are side views of an earring with an ear clip of the preferred embodiment , showing a clip arm in different positions ; fig2 is a perspective view of a connector of the preferred embodiment prior to assembly ; fig3 is a perspective view of a clip arm of the preferred embodiment prior to assembly ; and fig4 is a perspective view of the assembled connector and clip arm of the preferred embodiment of the invention . referring to fig1 a and 1b , an earring incorporating the invention is shown at 10 . the earring 10 generally comprises an ornamental piece 12 having a back 14 and an ear clip 20 . the earring 10 , however , is just illustrative , and other types of jewelry articles may be used with the clip 20 . referring to fig4 the ear clip 20 generally comprises a connector 22 and a clip arm 40 . the connector 22 is best shown in fig2 . it has a foot 24 , which is attached to the back 14 of the ornamental piece 12 of the earring 10 when the ear clip 20 is in place . the foot 24 may be attached to the back 14 by soldering , gluing or other means . the foot 24 of the preferred embodiment is trapezoidal in shape , but other shapes are possible . the connector 22 has a neck 26 which extends from one end of the foot 24 at approximately a right angle . the end of the neck 26 opposite the foot 24 is attached to a hollow , cylindrical cup 28 having a rounded outer surface 30 bounded by a lip 35 having a surface 34 opposite the cup 28 . the connector 22 is made of a single piece of copper , although other materials may be used . the cup 28 , which is sometimes referred to as a blind hole in the metal fabrication industry , is formed by striking or by coining it into the metal . other methods of making the cup 28 are also possible . the unassembled clip arm 40 is best shown in fig3 . clip arm 40 comprises an engagement paddle 42 , which is integral with a shank 44 . in the preferred embodiment , engagement paddle 42 has the shape of a loop , although other shapes are possible . two cups 46 , 48 are disposed opposite each other on the end of the shank 44 away from the engagement paddle 42 . the paddle 42 , the shank 44 and the cups 46 , 48 are made of a single , thin piece of metal , which is stamped from strip stock using common metal stamping operations including punching , notching , parting , bending or coining . the cups 46 , 48 have rounded outer surfaces 50 , 52 , recesses 54 , 56 and lips 58 , 60 which bound the recesses 54 , 56 . the cups 46 , 48 are made in the same manner as the cup 28 of the connector 20 . however , the cups 46 , 48 are larger than cup 28 , and cup 28 is designed to fit inside the recesses 54 , 56 of cups 46 , 48 . the assembled ear clip 20 is best shown in fig4 . the cup 28 of the connector 20 fits inside recess 56 of cup 48 of the clip arm 40 , and the cups 46 , 48 are pressed together so that lip 58 of cup 46 contacts surface 34 of cup 28 . this is accomplished by use of a press , which pinches the cups 46 , 48 together when the cup 28 is in place in the recess 56 . the cups 46 , 48 are then struck on their top 49 so as to remove any inherent resiliency of the cups 46 , 48 , which might tend to separate them . this forms a joint 70 , wherein both cups 46 , 48 effectively press on the captured portioned of the connector 20 so that the lips 58 , 60 on the cups 46 , 48 respectively press on the surface 34 and the lip 35 of the cup 28 forming a friction fit therewith . it should be noted that cup 46 is not actually needed and can be replaced by a flat surface . however , the appearance of the ear clip 20 is made symmetrical by the addition of cup 46 . of course , it is also possible to have a pair of cups disposed on the connector 22 , which capture a single cup disposed on the clip arm shank . when assembled , the foot 24 is attached to the back 14 of the ornamental piece 12 , as shown in fig1 a and 1b . in operation , the earlobe of the wearer fits between the engagement paddle 42 and the back 14 of the ornamental piece 12 . because of the friction fit at the joint 70 , however , the engagement paddle 42 can be positioned at any angle desired , and it will remain in that position until physically moved by the wearer . thus , any wearer discomfort is avoided , as the amount of pressure exerted by the engagement paddle 42 on the earlobe is controlled by the wearer , while still providing a suitably tight fit to prevent loss of the earring . other embodiments and advantages of the invention will be apparent to those skilled in the art .

an ear clip for an earring comprising a connector and a clip arm , the connector being adapted to attach to an ornamental piece and having a first cup , the clip arm having a second cup which receives the first cup to form a pivot , the pivot creating a friction fit between the cups so as to allow the clip arm to be positioned as desired with respect to an earlobe .

in the following , an embodiment of the invention is described with reference to a reinforcing element for a goalkeeper glove . it is to be understood , however , that the present invention can also be used as a reinforcing element for other types of clothing , namely , sports equipment . for example , the invention is particularly well - suited for use in gloves for snowboarding , football , or other activities , where there exists a high risk of hyperextension of fingers and / or the thumb . the invention may also be utilized in work gloves , particularly those employed in industries where injuries to the hands are common , such as construction or heavy industry . moreover , the reinforcing elements according to the invention may be used for protection of other parts of the body , for example as an active support element in other articles of sports equipment . the articles of sports equipment where such a reinforcing element can be used include but are not limited to sports shoes , gloves , shin guards , ankle braces , back braces , knee braces , elbow braces , neck braces , shoulder braces , and hip braces . fig1 shows a schematic perspective view of one embodiment of a reinforcing element 10 . the reinforcing element 10 may be made as a one - piece part , the sides of which are two substantially aligned elongate elements 11 , 12 that may be spaced substantially evenly or parallel along their lengths . in certain embodiments , the elongate elements 11 , 12 are elastic strips or rails . a plurality of bodies 20 are substantially in alignment and are arranged between the two elements 11 , 12 and spaced such that a thin slit 21 is provided between adjacent bodies 20 . the number of bodies 20 may vary with the length of the reinforcing element 10 . each body 20 is connected via a projection or ridge 22 to the elements 11 , 12 . in one embodiment , the ridge 22 connects the medial side 13 of a body 20 to an upper side 15 of the first element 11 . similarly , another ridge 22 connects the lateral side 14 of the body 20 to an upper side 16 of the second element 12 . gaps or cut - outs 23 between the bodies 20 and the elongate elements 11 , 12 are arranged on the two sides of the ridge 22 substantially parallel with respect to the elongate elements 11 , 12 . the cut - outs 23 effectively decouple the bodies 20 from the bending of the elongate elements 11 , 12 . this decoupling action allows the elongate elements 11 , 12 to bend nearly uniformly along their entire lengths , thus distributing the associated forces evenly , without concentrating them at discrete points along the elements 11 , 12 , which leads to premature element weakening . moreover , this uniform bending may be more comfortable for the wearer than prior art reinforcing elements that bend at discrete points . the size and shape of the cut - out 23 influences the bending properties of the reinforcing element 10 . for example , larger cut - outs 23 may increase the flexibility of the elongate elements 11 , 12 and , thus , increase the flexibility of the entire reinforcing element 10 . in the depicted embodiment , the attachment of each body 20 to the two elements 11 , 12 is limited to the dimensions of the ridges 22 . as a consequence , the bodies 20 maintain a substantially uniform shape and dimension under a bending of the elements 11 , 12 in the direction of the solid arrows 25 ( fig2 a ) which depict a first , or bending , direction . the resistance of the reinforcing element 10 against such a bending is at least partially determined by the dimensions and the material of the elements 11 , 12 on the sides . therefore , when the one - piece part comprising the bodies 20 and the elongate elements 11 , 12 are folded into gripping direction , it is essentially only the resistance of the elongate elements 11 , 12 that has to be overcome . as a result , distinct unidirectional mechanical properties of the reinforcing element 10 are achieved in spite of its one - piece design , which allow a bending into a first direction and which provide a blocking effect into another direction . the thinner the width of the ridges 22 , the greater the decoupling between the bodies 20 and the elements 11 , 12 , thus allowing greater flexibility of the reinforcing element 10 . in the depicted embodiment , each ridge 22 occupies approximately one third of the side surface of a body 20 and is arranged in its center . other arrangements and sizes are possible , however . the tops of the ridges 22 are inclined to the side ( as depicted in fig4 ), so that the reinforcing element 10 has a profile that can be easily integrated into the backside of the glove behind a finger or into another article of sports equipment . since the reinforcing elements are generally inserted into elongate pocket - shaped openings on sports equipment , it is desirable to reduce the size of projecting lateral edges to allow for easy insertion . also , by reducing the size of the projecting lateral edges , the risk of injuries caused by the edges is reduced . in fig2 a , the dashed arrows 26 indicate the second , or hyperextension , direction . when moved into this direction , the bodies 20 contact each other with their adjacent front sides 29 ( fig6 a and 6b ) and block any further bending in this direction . the bodies 20 may be shaped in a manner that a blocking contact is obtained already before the extended position is reached . another embodiment of the reinforcing element 10 ′ is depicted in fig2 b . in this embodiment , a number of bodies 20 ′ are arranged above a single strip 12 ′. the bodies 20 ′ are spaced in a manner similar to those depicted in the embodiment of the reinforcing element 10 in fig2 a , such that there exists a slit 21 ′ between adjacent bodies 20 ′, and a cut - out 23 ′ between each body 20 ′ and the strip 12 ′. in the depicted reinforcing element 10 ′, each body 20 ′ is joined to the strip 12 ′ by a ridge 22 ′. the ridge 22 ′ may extend the full width of the body 20 ′, or only a part thereof . alternatively , instead of a single ridge 22 ′ connecting each body 20 ′ to the strip 12 ′, a plurality of ridges , arranged in a substantially linear orientation along the width of the strip 12 ′ may connect each body 20 ′ to the strip 12 ′. in another embodiment , the bodies 20 ′ are joined to the side of the strip 12 ′. the reinforcing element 10 ′ depicted in fig2 b also includes an insertion area 30 ′ and a flat region 31 ′. the reinforcing element 10 ′ functions similarly to the embodiment depicted in fig2 a when moved in the directions depicted by arrows 25 , 26 , as described below . the comparison of the enlarged views of two adjacent bodies 20 in fig6 a and 6b shows schematically how their blocking interaction or contact can be further adjusted . it is to be noted that fig6 a and 6b are not to scale , as the width and length of the bodies may vary depending on predetermined factors such as use , weight or size restrictions , costs , etc . the bodies 20 depicted in fig6 a and 6b serve only to illustrate one possible adjustment principle . the blocking angle α determines when the bodies 20 start to limit any further backwards bending or bending in the hyperextension direction 26 . if α = 0 °, the blocking contact starts exactly in the extended orientation of the reinforcing element . if α & gt ; 0 °, the blocking interaction starts in a slightly hyperextended orientation . for manufacturing reasons , it may be preferred to have a slit 21 of a certain thickness ( the fixed distance between the points x and y in fig6 a , 6b ), which leads inevitably to an angle α & gt ; 0 °, as depicted in fig6 a . however , if the height h of the contacting facing surfaces 29 of the blocking bodies 20 is increased by an amount δh , as shown in fig6 b , the value of the blocking angle is reduced ( α ′& lt ; α ), so that blocking contact begins earlier , even though the slit 21 width is the same . the greater height ( h + δh ) of the contacting front surfaces 29 can , for example , be achieved by providing the bodies 20 with a linearly increasing thickness from the center 28 to the facing surface 29 , as shown in the cross - section of fig6 b . by increasing or decreasing the height h of the facing surfaces 29 , the first point of blocking contact between the bodies 20 can be adjusted , thereby determining the extension limit of the reinforcing element 10 in the hyperextension direction 26 . the advantage of this shape is that the overall thickness of the reinforcing element 10 is only locally increased , so a glove that utilizes such a reinforcing element 10 does not become too bulky . other shapes are contemplated , such as bodies 20 with concave top sides or bodies where the tops of the facing sides 29 are pitched or inclined toward or away from each other , instead of substantially parallel as depicted . if the reinforcing element 10 described above is integrated into a glove so that the bending direction of the solid arrows 25 in fig2 a corresponds to the natural gripping direction of the hand , a protection against hyperextension of single fingers , the thumb or — depending on the arrangement and the size of the reinforcing element 10 — the wrist is achieved . for a better adaptation to the backside of a finger or of the thumb , the lower sides 24 of the blocking bodies 20 can be curved , as shown in the cross - section of fig4 . this curvature mimics the natural curve of the finger . apart from the dimensions of the ridges 22 , also the size of the cut - outs 23 on the sides determine the bending properties and the resistance of the reinforcing element 10 against hyperextension . as a consequence of utilizing wider cut - outs 23 , the width of the ridges 14 , 16 and / or lengths of the bodies 20 are decreased . in the first case , narrower ridges 22 reduce the resistance to bending , whereas shorter bodies 20 reduce stability in the hyperextension direction 26 . the wider the cut - outs 23 , the smaller the lateral bending strips 11 , 12 or the central bodies 20 , if the overall width of the reinforcing element 10 is kept constant . in the first case , it is primarily the bending resistance in the gripping direction that is reduced , whereas thinner bodies 20 lead to a reduced stability in the direction of hyperextension 26 . as depicted in fig1 , at one terminal end , the reinforcing element 10 forms an insertion area 30 , which may be flattened and rounded on its side to facilitate the insertion into a receptacle , such as a pocket on a backside of a glove . in the same manner , the last body 20 on the same terminal end forms a flat region 31 , which facilitates the holding of the reinforcing element 10 for insertion into the backside of a glove . furthermore , the flat end section 31 serves to transmit the forces caused by the support of a finger into the backside of the hand . the insertion area 30 , as well as the flat end section 31 , can further be used to receive assembly instructions , for example , the direction of insertion and the number of a reinforcing element 10 , which is to be arranged in a certain position in the glove . this is schematically indicated in fig1 and 3 with the arrow and the numeral “ 1 .” additionally , the user may adjust the support properties of the glove by exchanging individual reinforcing elements 10 or by arranging reinforcing elements 10 only behind desired fingers . all these adaptations are facilitated by information about an individual reinforcing element 10 , which can be provided on the flat end section 31 . the depicted reinforcing element 10 is manufactured in a single mold as a continuous , one - piece , unitary component . the element 10 may be manufactured from thermoplastic materials , which can be cost - efficiently and precisely processed by injection molding . the element 10 may also be molded in discreet parts , then joined or otherwise fused together . other exemplary techniques for forming plastic materials , such as deep drawing , vacuum forming or other techniques that facilitate the manufacture of highly individualized reinforcing elements are contemplated . additionally , 3d - printing or stereolithography may be utilized . in any case , the design of the reinforcing element 10 of the present invention eliminates the need for costly manual assembly of the elements 11 , 12 and the bodies 20 . examples of preferred plastic materials are polypropylene ( pp ) for reinforcing elements 10 , which are only subjected to limited loads ( for example for goalkeeper gloves of children and teenagers ) and polyoximethylene ( pom ) for goalkeeper gloves subjected to high loads , such as those encountered by professionals . in this context , it is conceivable to arrange different reinforcing elements behind different fingers of the hand within the glove , for example , to provide a greater protection for the small finger against hyperextension or to obtain a particularly low resistance in gripping direction ( solid arrows 25 in fig2 a and 2b ) for weaker fingers . this may be achieved , for example , by using a different material or by variations of the thickness of the elements 11 , 12 and the ridges 22 and / or the cut - outs 23 . in any case , the injection molding of the reinforcing element 10 as a single piece facilitates adaptations of the size and / or modifications of the construction . in contrast to the prior art , where any modification of the reinforcing element requires new instructions to the production personnel to ensure a sufficient quality of the manually assembled components , the reinforcing element 10 described in this invention requires only an adaptation of the injection molding tool . the tool for injection molding defines , apart from the already discussed details of the reinforcing element , the initial contoured shape of the element 10 in the absence of any external force ( i . e ., when the reinforcing element 10 is not being bent , or is in an otherwise unloaded position ). this initial contoured shape corresponds to the natural shape of the body part being protected , in this case , the curvature of a finger in a relaxed state . the closing of the hand when catching a ball , for example , leads to a bending of the elements 11 , 12 and , thereby , to an elastic restoring force , which brings the hand back into its natural initial configuration . the reinforcing element 10 therefore actively supports the actual course of movements of the hand . furthermore , the slight curvature in the natural initial configuration of the hand is advantageous when the goalkeeper throws up his arms to deflect a surprise shot , since the hand is already in an almost extended configuration and provides therefore the greatest range for the goalkeeper to deflect the ball . as a result , the reinforcing element 10 of the present invention provides improved functional properties , while substantially reducing burdensome manufacturing considerations . having described certain embodiments of the invention , it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention . the described embodiments are to be considered in all respects as only illustrative and not restrictive .

a reinforcing element for an article of clothing includes at least one elongate element and a plurality of raised bodies aligned substantially longitudinally and integrally formed with the elongate element . the bodies define slits therebetween to allow bending of the reinforcing element in a first direction and prevent bending of the reinforcing element in a second direction by a blocking contact of the bodies .

the terms below have the following meanings unless indicated otherwise . other terms not specifically defined herein which are used to describe the present invention have the same meaning given to those terms within the context of their use by those skilled in the art . the term “ alkyl ” is used herein to refer to a fully saturated monovalent radical containing carbon and hydrogen , and which may be a straight chain , branched or cyclic . examples of alkyl groups are methyl , ethyl , n - butyl , n - heptyl , isopropyl , 2 - methylpropyl . is used to describe an alkylene group where the junction between the two lines represents a methylene ( ch 2 ) group and n is an integer from 0 to 7 . the integer of n = 0 is used to indicate that the methylene group is non - existent . the term “ cycloalkyl ” is used herein to refer to a fully saturated monovalent radical containing up to 8 carbons and hydrogen in a ring . examples of cycloalkyl groups are cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl and cycloheptyl . the term cycloalkyl , when used in context , may also refer to a cycloalkyl group which contains a heteroatom b group ( heterocycle ). the term “ bicycloalkyl ” is used herein to refer to a fully saturated monovalent radical containing up to 10 carbons and hydrogen in a bicyclic ring . examples of bicycloalkyl groups are bicyclo [ 2 . 2 . 2 ] octyl , bicyclo [ 2 . 2 . 1 ] heptyl , bicyclo [ 2 . 2 . 3 ] nonyl and bicylo [ 3 . 2 . 1 ] octyl . the term “ azabicycloalkyl ” is used herein to refer to a fully saturated monovalent radical containing up to 10 carbons and hydrogen and 1 nitrogen atom in a bicyclic ring . examples of azabicycloalkyl groups a include 1 - azabicyclo [ 2 . 2 . 2 ] octyl , 2 - azabicyclo [ 2 . 2 . 2 ] octyl , 1 - azabicyclo [ 2 . 2 . 1 ] heptyl , 2 - azabicyclo [ 2 . 2 . 1 ] heptyl and 1 - azabicylo [ 3 . 2 . 1 ] octyl . the term “ alkenyl ” is used herein to refer to a monovalent radical containing carbon and hydrogen that contains one or two sites of un - saturation , and which may be a straight chain , branched or cyclic . examples of alkenyl groups are ethenyl , n - butenyl , n - heptenyl , isopropenyl , cyclopentenyl , cyclopentenylethyl and cyclohexenyl . the term “ substituted ” with reference to “ substituted alkyl ” groups ( including cycloalkyl and bicycloalkyl groups ), “ substituted alkenyl ” groups and “ substituted alkynyl ” groups , among other related substituted groups ( e . g ., carboxyalkyl , sulfonylalkyl ), refers to one or more functional groups ( containing from 1 - 8 carbon atoms , 1 - 7 carbon atoms , 1 - 6 carbon atoms , 1 - 3 carbon atoms , 2 - 8 carbon atoms , 2 - 7 carbon atoms , 2 - 6 carbon atoms , 3 - 8 carbon atoms , etc . depending upon the substituent ) which are used as a substitute for h , such as alkyl containing from 1 - 8 carbon atoms including cycloalkyl containing from 3 - 7 carbon atoms , aryl , substituted aryl , acyl , halogen ( i . e ., alkyl halos , e . g ., cf 3 ), amido , thioamido cyano , nitro , alkynyl , azido , hydroxy , alkoxy , alkoxyalkyl , amino , alkyl and dialkyl - amino , acylamino , acyloxy , aryloxy , aryloxyalkyl , carboxyalkyl , carboxamido , thio , thioethers , both saturated and unsaturated cyclic hydrocarbons , heterocycles and the like , or as otherwise described herein ( see the term “ substituted ” hereinbelow ). the term “ aryl ” refers to a substituted or unsubstituted monovalent aromatic radical having a single ring ( e . g ., phenyl ) or multiple condensed rings ( e . g ., naphthyl ). other examples include heterocyclic aromatic ring groups having one or more nitrogen , oxygen , or sulfur atoms in the ring , such as oxazolyl , isoxazolyl , pyrazolyl , thiazolyl , thiadiazolyl , tetrazolyl , pyridazinyl , pyrimidyl , benzofuryl , benzothienyl , benzimidazolyl , benzoxazolyl , benzothiazolyl , quinolyl , isoquinolyl , imidazolyl , furyl , pyrrolyl , pyridyl , thienyl and indolyl . thus , the term “ aryl ” subsumes the term “ heteroaryl ” as such terms are used in context . the term “ substituted ” as used in the term “ substituted aryl , substituted aromatic , substituted heteroaryl , or substituted heteroaromatic ”, herein signifies that one or more substituents may be present , said substituents being selected from atoms and groups , which when present do not prevent the compound from functioning as a potentiator of ampa receptor function . examples of substituents that may be present in a substituted aromatic or heteroaromatic group include , but are not limited to , groups such as ( c 1 - c 7 ) alkyl , ( c 1 - c 7 ) acyl , aryl , heteroaryl , substituted aryl and heteroaryl , halogen , cyano , nitro , amido ( optionally substituted with one or two c 1 - c 7 alkyl groups ), thioamido ( optionally substituted with one or two c 1 - c 7 alkyl groups ), azido , ( c 2 - c 7 ) alkynyl , ( c 1 - c 7 ) alkylhalos ( e . g ., cf 3 ), hydroxy , ( c 1 - c 7 ) alkoxy , ( c 2 - c 8 ) alkoxyalkyl , amino , ( c 1 - c 7 ) alkyl and dialkyl amino , ( c 1 - c 7 ) acylamino , ( c 1 - c 7 ) acyloxy , aryloxy , ( c 1 - c 7 ) aryloxyalkyl , ( c 1 - c 7 ) carboxyalkyl , carboxamido , thio , ( c 1 - c 7 ) thioethers , both saturated and unsaturated ( c 3 - c 8 ) cyclic hydrocarbons , ( c 3 - c 8 ) heterocycles and the like . it is noted that each of the substituents disclosed herein may themselves be substituted . “ heterocycle ” or “ heterocyclic ” refers to a carbocyclic ring wherein one or more carbon atoms have been replaced with one or more heteroatoms ( up to 6 atoms , up to 4 atoms , 1 , 2 or 3 atoms ) such as nitrogen , oxygen or sulfur . examples of heterocycles include , but are not limited to , piperidine , pyrrolidine , morpholine , thiomorpholine , piperazine , tetrahydrofuran , tetrahydropyran , 2 - pyrrolidinone , 8 - valerolactam , 8 - valerolactone and 2 - ketopiperazine . the term “ substituted heterocycle ” refers to a heterocycle as just described that contains one or more functional groups such as lower alkyl , acyl , aryl , cyano , halogen , amido , thioamido , azido , hydroxy , alkoxy , alkoxyalkyl , amino , alkyl and dialkyl - amino , acylamino , acyloxy , aryloxy , aryloxyalkyl , carboxyalkyl , carboxamido , thio , thioethers , both saturated and unsaturated cyclic hydrocarbons , heterocycles and the like , as otherwise described herein . the term “ compound ” is used herein to refer to any specific chemical compound disclosed herein . within its use in context , the term generally refers to a single compound , but in certain instances may also refer to stereoisomers and / or optical isomers ( including enantiopure compounds , enantiomerically enriched compounds and racemic mixtures ) of disclosed compounds . the term “ effective amount ” refers to the amount of a selected compound of formula i that is used within the context of its intended use to effect an intended result , for example , to enhance glutamatergic synaptic response by increasing ampa receptor activity . the precise amount used will vary depending upon the particular compound selected and its intended use , the age and weight of the subject , route of administration , and so forth , including the duration of its use , but may be easily determined by routine experimentation . in the case of the treatment of a condition or disease state , an effective amount is that amount which is used to effectively treat the particular condition or disease state . the term , “ pharmaceutically acceptable carrier ” refers to a carrier or excipient which is not unacceptably toxic to the subject to which it is administered . pharmaceutically acceptable excipients are described at length by e . w . martin , in “ remington &# 39 ; s pharmaceutical sciences .” a “ pharmaceutically acceptable salt ” of an amine compound , such as those contemplated in the current invention , is an ammonium salt having as counter ion an inorganic anion such as chloride , bromide , iodide , sulfate , sulfite , nitrate , nitrite , phosphate , and the like , or an organic anion such as acetate , malonate , pyruvate , propionate , fumarate , cinnamate , tosylate , and the like . the term “ patient ” or “ subject ” is used throughout the specification to describe an animal , generally a mammalian animal , including a human , to whom treatment or use with the compounds or compositions according to the present invention is provided . for treatment or use with / or of those conditions or disease states which are specific for a specific animal ( especially , for example , a human subject or patient ), the term patient or subject refers to that particular animal . the term “ sensory motor problems ” is used to describe a problem which arises in a patient or subject from the inability to integrate external information derived from the five known senses in such a way as to direct appropriate physical responses involving movement and action . the term “ cognitive task ” or “ cognitive function ” is used to describe an endeavor or process by a patient or subject that involves thought or knowing . the diverse functions of the association cortices of the parietal , temporal and frontal lobes , which account for approximately 75 % of all human brain tissue , are responsible for much of the information processing that goes on between sensory input and motor output . the diverse functions of the association cortices are often referred to as cognition , which literally means the process by which we come to know the world . selectively attending to a particular stimulus , recognizing and identifying these relevant stimulus features and planning and experiencing the response are some of the processes or abilities mediated by the human brain which are related to cognition . the term “ brain network ” is used to describe different anatomical regions of the brain that communicate with one another via the synaptic activity of neuronal cells . the term “ ampa receptor ” refers to an aggregate of proteins found in some membranes , which allows positive ions to cross the membrane in response to the binding of glutamate or ampa ( dl - α - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid ), but not nmda . the term “ excitatory synapse ” is used to describe a cell - cell junction at which release of a chemical messenger by one cell causes depolarization of the external membrane of the other cell . an excitatory synapse describes a postsynaptic neuron which has a reversal potential that is more positive than the threshold potential and consequently , in such a synapse , a neurotransmitter increases the probability that an excitatory post synaptic potential will result ( a neuron will fire producing an action potential ). reversal potentials and threshold potentials determine postsynaptic excitation and inhibition . if the reversal potential for a post synaptic potential (“ psp ”) is more positive than the action potential threshold , the effect of a transmitter is excitatory and produces an excitatory post synaptic potential (“ epsp ”) and the firing of an action potential by the neuron . if the reversal potential for a post synaptic potential is more negative than the action potential threshold , the transmitter is inhibitory and may generate inhibitory post synaptic potentials ( ipsp ), thus reducing the likelihood that a synapse will fire an action potential . the general rule for postsynaptic action is : if the reversal potential is more positive than threshold , excitation results ; inhibition occurs if the reversal potential is more negative than threshold . see , for example , chapter 7 , neuroscience , edited by dale purves , sinauer associates , inc ., sunderland , mass . 1997 . the term “ motor task ” is used to describe an endeavor taken by a patient or subject that involves movement or action . the term “ perceptual task ” is used to describe an act by a patient or subject of devoting attention to sensory inputs . the term “ synaptic response ” is used to describe biophysical reactions in one cell as a consequence of the release of chemical messengers by another cell with which it is in close contact . the term “ hypoglutamatergic condition ” is used to describe a state or condition in which transmission mediated by glutamate ( or related excitatory amino acids ) is reduced to below normal levels . transmission consists of the release of glutamate , binding to post synaptic receptors , and the opening of channels integral to those receptors . the end point of the hypoglutamatergic condition is reduced excitatory post synaptic current . it can arise from any of the three above noted phases of transmission . conditions or disease states which are considered hypoglutamatergic conditions and which can be treated using the compounds , compositions and methods according to the present invention include , for example , loss of memory , dementia , depression , attention disorders , sexual dysfunction , movement disorders , including parkinson &# 39 ; s disease , schizophrenia or schizophreniform behavior , memory and learning disorders , including those disorders which result from aging , trauma , stroke and neurodegenerative disorders , such as those associated with drug - induced states , neurotoxic agents , alzheimer &# 39 ; s disease and aging , respiratory depression and sleep apnea . these conditions are readily recognized and diagnosed by those of ordinary skill in the art . the term “ cortico - striatal imbalance ” is used to describe a state in which the balance of neuronal activities in the interconnected cortex and underlying striatal complex deviates from that normally found . ‘ activity ’ can be assessed by electrical recording or molecular biological techniques . imbalance can be established by applying these measures to the two structures or by functional ( behavioral or physiological ) criteria . the term “ affective disorder ” or “ mood disorder ” describes the condition when sadness or elation is overly intense and continues beyond the expected impact of a stressful life event , or arises endogenously . as used herein , the term “ effective disorder ” embraces all types of mood disorders as described in , for example , diagnostic and statistical manual of mental disorders , fourth edition ( dsm iv ), pages 317 - 391 . the term “ schizophrenia ” is used to describe a condition which is a common type of psychosis , characterized by a disorder in the thinking processes , such as delusions and hallucinations , and extensive withdrawal of the individual &# 39 ; s interest from other people and the outside world , and the investment of it in his or her own . schizophrenia is now considered a group of mental disorders rather than a single entity , and distinction is made between reactive and process schizophrenias . as used herein , the term schizophrenia or “ schizophreniform ” embraces all types of schizophrenia , including ambulatory schizophrenia , catatonic schizophrenia , hebephrenic schizophrenia , latent schizophrenia , process schizophrenia , pseudoneurotic schizophrenia , reactive schizophrenia , simple schizophrenia , and related psychotic disorders which are similar to schizophrenia , but which are not necessarily diagnosed as schizophrenia per se . schizophrenia and other psychotic disorders may be diagnosed using guidelines established in , for example , diagnostic and statistical manual of mental disorders , fourth edition ( dsm iv ) sections 293 . 81 , 293 . 82 , 295 . 10 , 295 . 20 , 295 . 30 , 295 . 40 , 295 . 60 , 295 . 70 , 295 . 90 , 297 . 1 , 297 . 3 , 298 . 8 . the term “ brain function ” is used to describe the combined tasks of perceiving , integrating , filtering and responding to external stimuli and internal motivational processes . the term “ impaired ” is used to describe a function working at a level that is less than normal . impaired functions can be significantly impacted such that a function is barely being carried out , is virtually non - existent or is working in a fashion that is significantly less than normal . impaired functions may also be sub - optimal . the impairment of function will vary in severity from patient to patient and the condition to be treated . the term “ respiratory depression ” as used herein refers to a variety of conditions characterized by reduced respiratory frequency and inspiratory drive to cranial and spinal motor neurons . specifically , respiratory depression refers to conditions where the medullary neural network associated with respiratory rhythm generating activity does not respond to accumulating levels of pco 2 ( or decreasing levels of po 2 ) in the blood and subsequently under stimulates motorneurons controlling lung musculature . the term “ sleep apnea ” as used herein refers to breathing - related sleep disorders of which there are two types : central and obstructive . central sleep apnea is defined as a neurological condition causing cessation of all respiratory effort during sleep , usually with decreases in blood oxygen saturation , if the brainstem center controlling breathing shuts down there &# 39 ; s no respiratory effort and no breathing . the person is aroused from sleep by an automatic breathing reflex , so may end up getting very little sleep at all . obstructive sleep apnea is characterized by repetitive pauses in breathing during sleep due to the obstruction and / or collapse of the upper airway and followed by an awakening to breathe . respiratory effort continues during the episodes of apnea . the term “ pro - drug ” as used herein refers to a metabolically labile derivative that is pharmacologically inactive in the parent form but that is rapidly metabolized in human or animal plasma to a pharmacologically active form . examples of pro - drugs as used herein include but in no way are limited to , where applicable , ester derivatives of hydroxyl containing moieties or amide derivatives of amine containing moieties , such esters or amides include , but are not limited to those formed from substituted or un - substituted natural or un - natural amino acids . the term “ co - administration ” or “ combination therapy ” is used to describe a therapy in which at least two active compounds in effective amounts are used to treat a disease state or condition as otherwise described herein at the same time . although the term co - administration preferably includes the administration of two active compounds to the patient at the same time , it is not necessary that the compounds be administered to the patient at the same time , although effective amounts of the individual compounds will be present in the patient at the same time . the present invention is directed , in one aspect , to compounds having the property of enhancing ampa receptor function . these are compounds having the structure i , below : x , y and z are independently selected from the group consisting of — n , or — cr , wherein : r is h , — br , — cl , — f , — cn , — no 2 , — or 1 , — sr 1 , — nr 12 , — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted , r 1 is h , — c 1 - c 6 branched or un - branched alkyl which , may be un - substituted or substituted , f ═ o or s , a is h , or — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted , — c 2 - c 6 branched or un - branched alkenyl , which may be un - substituted or substituted , — c 2 - c 6 branched or un - branched alkynyl , which may be un - substituted or substituted , — c 3 - c 7 cycloalkyl which may be un - substituted or substituted , — c 3 - c 7 alkylcycloalkyl which may be un - substituted or substituted , aryl or heterocycle which may be un - substituted or substituted , alkylaryl which may be un - substituted or substituted , alkylheterocycle which may be un - substituted or substituted is a — c 3 - c 7 cycloalkyl , which may be un - substituted or substituted , a — c 4 - c 7 azacycloalkyl , which may be un - substituted or substituted , a c 7 - c 10 bicycloalkyl which may be un - substituted or substituted , a — c 7 - c 10 azabicycloalkyl which may be un - substituted or substituted , aryl which may be un - substituted or substituted or a heterocycle which may be un - substituted or substituted ; b is — c ═, c — r a , o , n , s , c ═ o , s ═ o or so 2 ; r a is h , a halogen ( preferably f ), oh , o - alkyl , cyano , or a — c 1 - c 6 alkyl group which is un - substituted or substituted and which optionally , forms a c 3 - c 7 cycloalkyl group with d ; and d is absent when b is o , s , s ═ o , c ═ o or so 2 , or if present , is bonded to b when b is — c ═, — c — r a or n , and is h , a halogen ( preferably f ), or b , a — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted and which optionally , forms a c 3 - c 7 cycloalkyl group with r a , a — c 2 - c 6 branched or un - branched alkenyl , which may be un - substituted or substituted , a — c 2 - c 6 branched or un - branched alkynyl , which may be un - substituted or substituted , a — c 3 - c 7 cycloalkyl which may be un - substituted or substituted , an aryl which may be un - substituted or substituted , a heterocycle which may be un - substituted or substituted , a — c 2 - c 7 carboxyalkyl which may be un - substituted or substituted , a carboxyaryl which may be un - substituted or substituted , a carboxyheteroaryl which may be un - substituted or substituted , a — c 1 - c 7 sulfonylalkyl which may be un - substituted or substituted , a sulfonylaryl which may be un - substituted or substituted or a sulfonylheteroaryl which may be un - substituted or substituted , or when b is — c — r a , r a and d optionally form a ═ n — r c or a ═ n — or c group with b , wherein r c is h or an unsubstituted or substituted c 1 - c 7 alkyl group , or when b is — c — r a , r a and d optionally form a ═ n — r c or a ═ n — or c group with b , wherein r c is h or an unsubstituted or substituted c 1 - c 7 alkyl group ; and r b is h , a — c 1 - c 7 alkyl group which may be branched or un - branched , un - substituted or substituted or a — c 2 - c 7 acyl group which may be un - substituted or substituted ; a is — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted , a c 3 - c 7 cycloalkyl which may be un - substituted or substituted ; d is absent ( when b is o ), is h or oh when r a is h or alkyl , or is f when r a is f , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . a is a c 1 - c 6 alkyl which may be substituted or un - substituted ; d is absent ( when b is o ), is h or oh when r a is h or alkyl , or is f when r a is f , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . a further preferred embodiment includes compounds according to formula iv below : a is a c 1 - c 6 alkyl which may be substituted or un - substituted , n is 0 , 1 or 2 , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . a further preferred embodiment includes compounds according to formula v below : a is a c 1 - c 6 alkyl which may be substituted or un - substituted , r 1 is h , f , or c 1 - c 4 alkyl , r 2 is h , f , cn , a heterocycle which may be substituted or un - substituted or or 3 , r 3 is h , c 1 - c 6 alkyl which may be substituted or un - substituted , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . a further preferred embodiment includes compounds according to formula vi below : a is a c 1 - c 6 alkyl which may be substituted or un - substituted , r is h , or c 1 - c 4 alkyl , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . a yet further preferred embodiment includes compounds according to formula vii below : d is absent ( when b is o ), is h or oh when r a is h or alkyl , or is f when r a is f , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . in a yet further preferred embodiment compounds are included according to formula viii below : d is absent ( when b is o ), is h or oh when r a is h or alkyl , or is f when r a is f , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . a yet further preferred embodiment includes compounds according to formula ix below : a is a c 1 - c 6 alkyl which may be substituted or un - substituted , r 2 is h , or a c 1 - c 6 alkyl which may be substituted or un - substituted , r 3 is h , or a c 1 - c 6 alkyl which may be substituted or un - substituted , r 4 is h , or a c 1 - c 6 alkyl which may be substituted or un - substituted , or a pharmaceutically acceptable salt , solvate , or polymorph thereof . in a further aspect , the present invention provides compounds of formulas i - ix selected from : n - cycloheptyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 4 , 4 - dimethylcyclohexyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n - spiro [ 2 . 5 ] oct - 6 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclohexyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclopentyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclobutyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclohexyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclopentyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclobutyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cis - 4 - cyanocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - cyanocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - d 3 - methyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( tetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( tetrahydro - 2h - pyran - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( tetrahydro - 2h - pyran - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - ethyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclohexyl - n - ethyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cyclohexylmethyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - benzyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( tetrahydrofuran - 2 - ylmethyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n - pyridin - 3 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n - phenyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - cyclopropyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - tetrahydro - 2h - pyran - 4 - yl - n -( 2 , 2 , 2 - trifluoroethyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide tert - butyl - 4 -[([ 2 , 1 , 3 ]- benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ] piperidine - 1 - carboxylate n - methyl - n - piperidin - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide hydrochloride n - methyl - n -( 1 - methylpiperidin - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 1 - acetylpiperidin - 4 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 1 - formylpiperidin - 4 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 1 -( methylsulfonyl ) piperidin - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( tetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzothiadiazole - 5 - carboxamide n - methyl - n -( tetrahydro - 2h - thiopyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 1 - oxidotetrahydro - 2h - thiopyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 1 , 1 - dioxidotetrahydro - 2h - thiopyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n - tetrahydro - 2h - pyran - 4 - ylquinoxaline - 6 - carboxamide n - methyl - n -( 4 - oxocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -[ 4 -( hydroxyimino ) cyclohexyl ]- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -[ 4 -( methoxyimino ) cyclohexyl ]- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 4 , 4 - difluorocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 4 - fluorocyclohex - 3 - en - 1 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 4 - trans - hydroxycyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - hydroxy - 4 - methylcyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cis - 4 - hydroxy - 4 - methylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - hydroxy - 4 - methylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cis - 4 - hydroxy - 4 - ethylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - hydroxy - 4 - ethylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cis - 4 - ethynyl - 4 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cis - 4 - but - 3 - en - 1 - yl - 4 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - but - 3 - en - 1 - yl - 4 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 4 - trans - hydroxycyclohexyl )- n - d 3 - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - methoxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - methoxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbothioamide n -( 4 - cis - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - a -[ trans - 4 -( 2h - tetrazol - 2 - yl ) cyclohexyl ]-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - azidocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 4 - aminocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( cis - 3 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( trans - 3 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 3 - oxocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 3 , 3 - difluorocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 2 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 2 - oxocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 2 , 2 - difluorocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 2 - hydroxytetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 2 - oxotetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n -( 2 - oxotetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n -( 2 - hydroxytetrahydro - 2h - pyran - 4 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ] cyclohexyl n , n - dimethyl glycinate hydrochloride trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ] cyclohexyl l - alaninate hydrochloride n —( r )- tetrahydrofuran - 3 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n —( r )- tetrahydrofuran - 3 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ] cyclohexyl glycinate hydrochloride n - 2 -( 4 - morpholinyl ) ethyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide n - methyl - n - 2 -( 4 - morpholinyl ) ethyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide hydrochloride n - methyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbothioamide trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ] cyclohexyl l - valinate hydrochloride trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ]- 1 - methylcyclohexyl n , n - dimethyl glycinate hydrochloride n - methyl - n - tetrahydro - 2h - pyran - 4 - ylmethyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ]- 1 - methylcyclohexyl glycinate hydrochloride the synthesis of the compounds of the invention is preferably carried out by the following scheme . alternative syntheses by analogy relying on methodology that exists in the art also may be used . in the scheme , steps a and b , used to produce the n - methylamines 4 ( a = me ) are carried out using standard conditions , for example , amines 1 are dissolved in a suitable organic solvent , for example dichloromethane , a base ( e . g . net 3 or nahco 3 in water ) is added and then a solution of benzyloxycarbonyl chloride ( cbz - cl ) in an organic solvent e . g . dichloromethane is added , which results in the formation of the benzyl carbamates 2 ( step a ). the carbamates 2 are then reduced with for example lithium aluminium hydride ( lialh 4 ) in a suitable organic solvent for example tetrahydrofuran ( thf ) to give amines 4 ( a = me , step b ). amines 4 , may be alternatively prepared by reductive amination of ketones 3 in the presence of an amine ( anh 2 ), using standard conditions , for example pd / c in an appropriate solvent for example ethanol , as shown in step c . acid chloride 8a is synthesized starting with 4 - amino - 3 - nitrobenzoic acid 5 , by firstly oxidizing using sodium hypochlorite in ethanol in the presence of potassium hydroxide to give intermediate 6 ( step d ) and then reducing 6 with triethyl phosphite ( p ( oet ) 3 ) in a suitable solvent , for example ethanol , to give benzofurazan carboxylic acid 7 as shown in step e . the carboxylic acid 7 was transformed to the acid chloride 8a in step f by refluxing with thionyl chloride in toluene . the benzofurazan carboxylic acid 7 can be transformed into amides 9a and 10a using amines 1 and 4 , respectively , using standard amide coupling conditions for example 1 - ethyl - 3 -( 3 - dimethylaminopropyl ) carbodiimide ( edci ), o - benzotriazole - n , n , n ′, n ′- tetramethyl - uronium - hexafluoro - phosphate ( hbtu ), n - hydroxybenzotriazole ( hobt ), dimethylaminopyridine ( dmap ) and triethyalamine in a suitable solvent e . g . dichloromethane ( step g ). alternatively , acid chloride 8a can be transformed into amides 9a and 10a using standard coupling conditions with amines 1 and 4 , respectively , in the presence of a base for example triethylamine in dichloromethane as solvent or aqueous sodium hydrogen carbonate in water and dichloromethane ( step h ). the benzothiadiazole amides 9b and 10b are prepared from the commercially available benzothiadiazole acid chloride 8b using standard coupling conditions with amines 1 and 4 , respectively , in the presence of a base for example triethylamine in dicholoromethane as solvent , or aqueous sodium hydrogen carbonate in water and dichloromethane ( step h ). the quinoxaline - 6 - carboxylic acid chloride 8c is prepared by condensation of commercially available 3 , 4 - diaminobenzoic acid with glyoxal followed by refluxing with thionyl chloride and a catalytic amount of dmf in toluene using standard procedures . 8c was converted to the amides 9c and 10c by coupling reaction with amines 1 and 4 using the standard procedures described previously ( step h ). alternatively , amides 10a - c can be prepared from amides 9a - c by deprotonation with a suitable base for example sodium hydride in a solvent e . g . n , n - dimethylformamide ( dmf ) followed by treatment with an alkylating agent ( r x ) to yield 10a - c ( step i ). the thioamides 11 can be prepared from amides using standard procedures , for example , by reacting 10 with phosphorous pentoxide in a suitable solvent e . g . toluene ( step j ). according to one aspect of the invention , a method is provided for treating a mammalian subject suffering from a hypoglutamatergic condition , or from deficiencies in the number or strength of excitatory synapses or in the number of ampa receptors . in such a subject , memory or other cognitive functions may be impaired , or cortical / striatal imbalance may occur , leading to loss of memory , dementia , depression , attention disorders , sexual dysfunction , movement disorders , schizophrenia or schizophreniform behavior . memory disorders and learning disorders , which are treatable according to the present invention include those disorders that result from , for example , aging , trauma , stroke and neurodegenerative disorders . examples of neurodegenerative disorders include , but are not limited to , those associated with drug - induced states , neurotoxic agents , alzheimer &# 39 ; s disease , and aging . these conditions are readily recognized and diagnosed by those of ordinary skill in the art and treated by administering to the patient an effective amount of one or more compounds according to the present invention . in another aspect , the invention provides a method for reducing or inhibiting respiratory depression in a subject having such a condition , comprising administering to the subject an amount of a compound of the invention , the amount being sufficient to reduce or inhibit respiratory depression . in a further aspect of the invention , a method is provided for reducing or inhibiting respiratory depression comprising administering to the subject an amount of a compound of the invention in combination with an opiate ; examples of such opiates include but are not limited to , alfentanil and fentanyl . in a further aspect , the invention provides a method for reducing or inhibiting breathing - related sleep disorders or sleep apnea in a subject having sleep apnea , comprising administering to the subject an amount of a compound of the invention , the amount being sufficient to reduce or inhibit the breathing related sleep disorder . in the present invention , the method of treatment comprises administering to the subject in need of treatment , in a pharmaceutically acceptable carrier , an effective amount of a compound having the formula i below : x , y and z are independently selected from the group consisting of — n , or — cr , r is h , — br , — cl , — f , — cn , — no 2 , — or 1 , — sr 1 , — nr 12 , — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted , r 1 is h , — c 1 - c 6 branched or un - branched alkyl which , may be un - substituted or substituted , a is h , or — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted , — c 2 - c 6 branched or un - branched alkenyl , which may be un - substituted or substituted , — c 2 - c 6 branched or un - branched alkynyl , which may be un - substituted or substituted , — c 3 - c 7 cycloalkyl which may be un - substituted or substituted , — c 3 - c 7 alkylcycloalkyl which may be un - substituted or substituted , aryl or heterocycle which may be un - substituted or substituted , alkylaryl which may be un - substituted or substituted , alkylheterocycle which may be un - substituted or substituted is a — c 3 - c 7 cycloalkyl , which may be un - substituted or substituted , a — c 4 - c 7 azacycloalkyl , which may be un - substituted or substituted , a c 7 - c 10 bicycloalkyl which may be un - substituted or substituted , a — c 7 - c 10 azabicycloalkyl , which may be un - substituted or substituted , aryl which may be un - substituted or substituted or a heterocycle which may be un - substituted or substituted ; b is — c ═, c — r a , o , n , s , c ═ o , s ═ o or so 2 ; r a is h , a halogen ( preferably f ), oh , o - alkyl , cyano , or a — c 1 - c 6 alkyl group which is un - substituted or substituted and which optionally , forms a c 3 - c 7 cycloalkyl group with d ; and d is absent when b is o , s , c ═ o , s ═ o or so 2 , or if present , is bonded to b when b is — c ═, c — r ″ or n , and is h , a halogen ( preferably f ), or b , a — c 1 - c 6 branched or un - branched alkyl , which may be un - substituted or substituted , and which optionally , forms a c 3 - c 7 cycloalkyl group with r a , a — c 2 - c 6 branched or un - branched alkenyl , which may be un - substituted or substituted , a — c 2 - c 6 branched or un - branched alkynyl , which may be un - substituted or substituted , a — c 3 - c 7 cycloalkyl which may be un - substituted or substituted , an aryl which may be un - substituted or substituted , a heterocycle which may be un - substituted or substituted , a — c 2 - c 7 carboxyalkyl which may be un - substituted or substituted , a carboxyaryl which may be un - substituted or substituted , a carboxyheteroaryl which may be un - substituted or substituted , a — c 1 - c 7 sulfonylalkyl which may be un - substituted or substituted , a sulfonylaryl which may be un - substituted or substituted or a sulfonylheteroaryl which may be un - substituted or substituted , or when b is — c — r a , r a and d optionally form a ═ n — r c or a ═ n — or c group with b , wherein r c is h or an unsubstituted or substituted c 1 - c 7 alkyl group ; and r b is h , a — c 1 - c 7 alkyl group which may be branched or un - branched , un - substituted or substituted or a — c 2 - c 7 acyl group which may be un - substituted or substituted ; or a pharmaceutically acceptable salt , solvate , pro - drug or polymorph thereof , optionally in combination with a pharmaceutically acceptable carrier , additive or excipient . in the present invention , the method of treatment comprises administering to the subject in need of treatment , in a pharmaceutically acceptable carrier , an effective amount of a compound having the formulas ii - ix as previously defined . compounds according to the present invention exhibit enhanced bioavailability in most instances due , at least in part , to enhanced pharmacokinetics exhibited by the present compounds . accordingly , the present compounds may be favorably formulated into pharmaceutical compositions in a variety of dosage forms , and in particular , oral dosage forms . as noted above , treatment of a subject according to the method of the invention is useful for enhancing ampa receptor activity , and thus may be used to facilitate the learning of behaviors dependent upon ampa receptors , and to treat conditions , such as memory impairment , in which ampa receptors , or synapses utilizing these receptors , are reduced in numbers or efficiency . the method is also useful for enhancing excitatory synaptic activity in order to restore an imbalance between brain sub - regions , which may manifest itself in schizophrenia or schizophreniform behavior , or other behavior as described above . the compounds administered in accordance with the method have been found to be more effective than previously described compounds in enhancing ampa receptor activity , as shown in the in vivo tests described below . synaptic responses mediated by ampa receptors are increased according to the method of the invention , using the compounds described herein . the electrophysiological effects of the invention compounds were tested in vivo in anesthetized animals according to the following procedures . animals are maintained under anesthesia by phenobarbital administered using a hamilton syringe pump . stimulating and recording electrodes are inserted into the perforant path and dentate gyrus of the hippocampus , respectively . once electrodes are implanted , a stable baseline of evoked responses are elicited using single monophasic pulses ( 100 μs pulse duration ) delivered at 3 / min to the stimulating electrode . field epsps are monitored until a stable baseline is achieved ( about 20 - 30 min ), after which a solution of test compound is injected intraperitoneally and evoked field potentials are recorded . evoked potentials were recorded for approximately 2 h following drug administration or until the amplitude of the field epsp returns to baseline . in the latter instance , it is common that an iv administration is also carried out with an appropriate dose of the same test compound . invention compounds were assayed in the in vivo electrophysiology assay described above and data for representative test compounds is shown in column 1 in table 1 . compounds of the invention are significantly more active in increasing the amplitude of the field epsp in the rat dentate gyrus following i . p . dosing than cx516 ( 1 -( quinoxalin - 6 - ylcarbonyl ) piperidine ; u . s . pat . no . 5 , 773 , 434 , us2002 / 0055508 ) which gave a 9 % increase in amplitude of the field epsp at 50 mg / kg i . p . the ability of the invention compounds to inhibit d - amphetamine stimulated locomotor activity was assayed according to the following procedure . male cd1 mice , 25 - 30 gm body weight , were brought into the experimental room and allowed at least 30 min of acclimation . each mouse was placed into the testing enclosure with an infrared beam array that automatically monitors the animal &# 39 ; s activity . mice were habituated in the testing enclosure for 20 min , and then returned to their home cage . mice were dosed intraperitoneally with test compound in appropriate vehicle 5 minutes before d - amphetamine injection ( 2 mpk ). ten minutes after d - amphetamine injection , mice were tested for locomotor activity for a total of minutes . the data was computer collected and expressed as “ arbitrary movement units .” all data were analyzed by comparing the groups treated with the test compound to the vehicle control group . the data for test compounds is shown in table 1 , column 2 . the data shown is the % inhibition of hyperactivity induced by acute administration of 2 mg / kg d - amphetamine in mice . the compounds tested produced a statistically significant inhibition of d - amphetamine stimulated locomotion . as noted above , the compounds and method of the invention increase glutamatergic synaptic responses mediated by ampa receptors , and are useful for the treatment of hypoglutamatergic conditions . they are also useful for treatment of conditions such as impairment of memory or other cognitive functions , brought on by a deficiency in the number or strength of excitatory synapses , or in the number of ampa receptors . they may also be used in the treatment of schizophrenia or schizophreniform behavior resulting from a cortical / striatal imbalance , and in facilitation of learning of behaviorsdependent upon ampa receptors . in subjects treated with the present compounds , pharmaceutical compositions and methods memory or other cognitive functions may be impaired or cortical / striatal imbalance may occur , leading to loss of memory , dementia , depression , attention disorders , sexual dysfunction , movement disorders , schizophrenia or schizophreniform behavior . memory disorders and learning disorders , which are treatable according to the present invention , include those disorders that result from aging , trauma , stroke and neurodegenerative disorders . examples of neurodegenerative disorders include , but are not limited to , those associated with drug - induced states , neurotoxic agents , alzheimer &# 39 ; s disease , and aging . these conditions are readily recognized and diagnosed by those of ordinary skill in the art and treated by administering to the patient an effective amount of one or more compounds according to the present invention . generally , dosages and routes of administration of the compound will be determined according to the size and condition of the subject , according to standard pharmaceutical practices . dose levels employed can vary widely , and can readily be determined by those of skill in the art . typically , amounts in the milligram up to gram quantities are employed . the composition may be administered to a subject by various routes , e . g . orally , transdermally , perineurally or parenterally , that is , by intravenous , subcutaneous , intraperitoneal , or intramuscular injection , among others , including buccal , rectal and transdermal administration . subjects contemplated for treatment according to the method of the invention are animals , especially mammals , including humans , companion animals , domesticated animals , laboratory animals , and the like . formulations containing the compounds according to the present invention may take the form of solid , semi - solid , lyophilized powder , or liquid dosage forms , such as , for example , tablets , capsules , powders , sustained - release formulations , solutions , suspensions , emulsions , suppositories , creams , ointments , lotions , aerosols , patches or the like , preferably in unit dosage forms suitable for simple administration of precise dosages . pharmaceutical compositions according to the present invention comprise an effective amount of one or more compounds according to the present invention and typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents , carriers , adjuvants , additives and the like . preferably , the composition will be about 0 . 5 to 75 % by weight or more of a compound or compounds of the invention , with the remainder consisting essentially of suitable pharmaceutical excipients . for oral administration , such excipients include pharmaceutical grades of mannitol , lactose , starch , magnesium stearate , sodium saccharine , talcum , cellulose , glucose , gelatin , sucrose , magnesium carbonate , and the like . if desired , the composition may also contain minor amounts of non - toxic auxiliary substances such as wetting agents , emulsifying agents , or buffers . liquid compositions can be prepared by dissolving or dispersing the compounds ( about 0 . 5 % to about 20 % by weight or more ), and optional pharmaceutical adjuvants , in a carrier , such as , for example , aqueous saline , aqueous dextrose , glycerol , or ethanol , to form a solution or suspension . for use in oral liquid preparation , the composition may be prepared as a solution , suspension , emulsion , or syrup , being supplied either in liquid form or a dried form suitable for hydration in water or normal saline . when the composition is employed in the form of solid preparations for oral administration , the preparations may be tablets , granules , powders , capsules or the like . in a tablet formulation , the composition is typically formulated with additives , e . g . an excipient such as a saccharide or cellulose preparation , a binder such as starch paste or methyl cellulose , a filler , a disintegrator , and other additives typically used in the manufacture of medical preparations . an injectable composition for parenteral administration will typically contain the compound in a suitable i . v . solution , such as sterile physiological salt solution . the composition may also be formulated as a suspension in a lipid or phospholipid , in a liposomal suspension , or in an aqueous emulsion . methods for preparing such dosage forms are known or will be apparent to those skilled in the art ; for example , see remington &# 39 ; s pharmaceutical sciences ( 17th ed ., mack pub . co ., 1985 ). the composition to be administered will contain a quantity of the selected compound in a pharmaceutically effective amount for effecting increased ampa receptor currents in a subject . the following examples illustrate but are not intended in any way to limit the invention . unless otherwise stated , all temperatures are given in degrees celsius . unless otherwise stated , all nmr spectra are 1 h nmr spectra and were obtained in deuterochloroform or deuterated dmso as solvent using tetramethylsilane as an internal standard . all names of example compounds conform to iupac nomenclature as provided by the computer software chemsketch by acd labs . a 3 l reactor fitted with mechanical stirring , reflux condenser , thermometer and nitrogen inlet , koh ( 72 . 46 g ) was dissolved in ethanol ( 250 ml ) and water ( 250 ml ). 4 - amino - 3 - nitrobenzoic acid ( 100 g ) was added and the orange suspension was heated to 65 - 70 ° c . within 30 minutes . the resulting suspension was stirred at the same temperature for 45 minutes and cooled to 0 ° c .± 5 ° c . within 30 minutes . a commercially available ( 13 % w / w ) solution of sodium hypochlorite ( 448 . 93 g ) was added drop wise within 1 . 5 hours at 0 ° c .± 5 ° c . the reaction mixture was stirred at the same temperature for 2 hours and controlled by tlc ( chcl 3 100 / acetone 2 / acetic acid 1 ). water ( 350 ml ) was added within 15 minutes at 0 ° c .± 5 ° c . to give a fine yellow suspension . the reaction mixture was then acidified with a 6n hcl solution ( 239 ml ) until 0 . 5 & lt ; ph & lt ; 1 was reached . sodium chloride ( 58 . 44 g ) was added and the resulting suspension was stirred at 0 ° c .± 5 ° c . for 1 . 5 hours under nitrogen . the solid was collected by filtration , washed with 3 × 400 ml water and dried ( 40 ° c ., 30 mbars , 12 hours ) to yield 83 . 6 g ( 88 . 8 % yield ) of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid n - oxide . in a 2 l reactor fitted with mechanical stirring , thermometer , addition funnel , reflux condenser and nitrogen inlet , [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid n - oxide ( 80 g ) was dissolved in absolute ethanol ( 800 ml ). to this solution triethyl phosphite ( 114 . 05 g ) was added within 10 minutes at 70 ° c .± 2 ° c . the resulting mixture was heated to reflux ( 76 - 78 ° c .) and maintained for 2 hours . monitoring the reaction by tlc ( chcl 3 100 / acetone 2 / acetic acid 1 ) showed complete reaction . the solvent was removed under vacuum ( 30 mbars , 40 ° c .) which yielded a black oil ( 180 g ). water ( 400 ml ) was added and the mixture was extracted with ethyl acetate ( 400 and 160 ml ). the organic phase was extracted with 850 ml water containing naoh ( 9 . 5 & lt ; ph & lt ; 10 ). the aqueous phase was separated and extracted with ethyl acetate ( 3 × 240 ml ). the aqueous phase was acidified ( 78 ml 6 n hcl ) to 1 & lt ; ph & lt ; 2 at 5 ° c .± 2 ° c . which resulted in the crystallization of the yellow product , which was filtered off and dried ( 40 ° c ., 30 mbars , 12 hours ) to yield 65 . 56 g ( 90 % yield ) [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid : mp = 160 - 161 ° c ., 1 h nmr ( 300 mhz , dmso ) δ 13 . 8 ( s , 1h ); 8 . 57 ( s , 1h ); 8 . 56 ( d , 1h , j = 0 . 6 hz ); 7 . 87 ppm ( d , 1h , j = 0 . 6 hz ). in a 500 ml reactor fitted with mechanical stirring , thermometer , addition funnel , reflux condenser and nitrogen inlet , [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid ( 28 g ) was suspended in toluene ( 245 ml ). to this suspension was added thionyl chloride ( 39 . 4 g ) and dmf ( 0 . 35 ml ). the resulting mixture was heated to reflux and maintained for 3 hours . a short pass column was installed and toluene was distilled ( atmospheric pressure , 124 ml ) off to remove excess reagent . after cooling the remaining toluene was distilled off , which resulted in a thick oil . this oil was distilled ( 90 ° c ., 2 mm hg ) to remove impurities and the product crystallized on standing ( 79 . 8 % yield ), mp : 55 - 58 ° c . to a solution of cycloheptanone ( 1 . 12 g , 10 mmol ) in 40 ml of ethanol was added a methylamine ( 2 . 5 ml of a 33 % solution in ethanol ) and 220 mg of pd on c ( 10 %) were added , and the mixture hydrogenated at 50 psi over night . the solids were filtered off and the mixture concentrated under vacuum to give a pale yellow oil . this material and 1 . 2 ml of triethylamine were dissolved in 10 ml of dichloromethane and a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 730 mg , 4 mmol ) was added slowly . after stirring the mixture for 2 hours , the organic phase was washed with 1n hcl and cone . nahco 3 solution , dried over magnesium sulfate , and then concentrated under vacuum to give a white solid , after trituration with ether ( 405 mg , 37 %). mp : 80 - 81 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( m , 1h ); 7 . 80 ( s , 1h ); 7 . 43 - 7 . 37 ( m , 1h ); 4 . 75 - 4 . 60 and 3 . 70 - 3 . 55 ( m + m , 1h ); 3 . 01 and 2 . 87 ( s + s , 3h ); 2 . 00 - 1 . 20 ppm ( m , 12h ). methylamine , generated by heating a mixture of methylamine hydrochloride ( 10 g ) and sodium hydroxide pellets ( 18 g ), was condensed ( dry ice trap ) into a solution of 4 , 4 - dimethylcyclohexanone ( 1 . 0 g , 7 . 9 mmol ) in 40 ml of methanol and 20 ml of thf . 10 % pd on c ( 400 mg ) was added and the mix was hydrogenated at room temperature over night . the solids were filtered off , and the mixture concentrated under vacuum . this material and triethylamine ( 2 ml ) were dissolved in chloroform ( 50 ml ) and a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 900 mg , 4 . 9 mmol ), in chloroform ( 40 ml ), was added slowly at room temperature . after stirring the mixture for 1 hour , the organic phase was washed with 1n hcl and cone . nahco 3 solution , dried over sodium sulfate , and concentrated under vacuum to yield an oil , which was purified using silica gel chromatography eluting with chloroform / ethyl acetate / hexane ( 10 : 20 : 70 ), to give a white solid , after crystallization from methyl - t - butyl ether ( mtbe )/ hexane ( 38 mg ). mp = 143 - 5 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 91 ( d , 1h , j = 8 . 7 hz ); 7 . 81 ( sb , 1h ); 7 . 45 - 7 . 36 ( m , 1h ); 4 . 52 - 4 . 35 and 3 . 45 - 3 . 30 ( m + m , 1h ); 3 . 04 and 2 . 89 ( s + s , 3h ) and 1 . 95 - 0 . 80 ppm ( m , 14h ). a solution of benzyl spiro [ 2 . 5 ] oct - 6 - yl carbamate ( 1 . 1 g , 3 . 85 mmol ) in thf ( 40 ml ) was slowly added to lialh 4 ( 1 . 0 g ) in thf ( 40 ml ), at room temperature , and the mixture stirred for 2 hours . the mixture was then cooled with ice / water and hexane ( 35 ml ) was added , followed by careful addition of a solution of sodium hydroxide ( 1 g ) in water ( 4 ml ). celite was added , the mixture was filtered and the filtrate concentrated under vacuum . a solution of triethylamine ( 2 ml ) in chloroform ( 60 ml ) was added to the residue followed by a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 704 mg , 6 mmol ), in chloroform ( 10 ml ). after stirring the mixture for 1 hour , the organic phase was washed with 1n sulfuric acid and cone . nahco 3 solution , the aqueous phases were re - extracted with chloroform ( 100 ml ), and the combined organic phases were dried over magnesium sulfate , concentrated under vacuum and chromatographed on silica gel eluting with ethyl acetate / hexane ( 30 : 70 ) to give a white solid ( 410 mg , 37 % yield ), after crystallization from dichloromethane / mtbe : mp = 107 - 109 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 91 ( d , 1h , j = 9 . 3 hz ); 7 . 82 ( s , 1h ); 7 . 47 - 7 . 35 ( m , 1h ); 4 . 66 - 4 . 50 and 3 . 55 - 3 . 40 ( m + m , 1h ); 3 . 05 and 2 . 91 ( s + s , 3h ); 2 . 10 - 1 . 55 and 0 . 99 - 0 . 86 ( m , 8h ) and 0 . 40 - 0 . 20 ppm ( m , 4h ). to a solution of cyclohexylamine ( 4 ml , 17 . 4 mmol ) and triethylamine ( 3 ml ) in 50 ml of dichloromethane was slowly added benzylchloroformate ( 2 . 4 ml , 17 . 4 mmol ) and the mixture stirred at room temperature overnight . the solution was extracted with 1n hcl and cone . nahco 3 solution , the organic phase dried over magnesium sulfate , and concentrated under vacuum to yield 2 . 85 g of white solid . the solid was dissolved in thf ( 50 ml ), slowly added to lialh 4 ( 1 . 09 g ) in diethyl ether ( 50 ml ) and the mixture heated to 70 ° c . for 1 hour . the mixture was then cooled with an ice / water bath , hexane ( 40 ml ) was added , followed by careful addition of a solution of sodium hydroxide ( 5 g ) in 10 ml of water . celite was added and the mixture was filtered , followed by concentration under vacuum . to a solution of the resulting residue in triethylamine ( 3 ml ) and dichloromethane ( 50 ml ) was slowly added [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 1 . 095 g , 6 mmol ). after stirring the mixture for 1 hour , the organic phase was washed with 1n hcl and conc . nahco 3 solution , dried over magnesium sulfate , and concentrated under vacuum to give a white solid ( 1 . 45 g ). the material was chromatographed on a silica gel eluting with chloroform / ethyl acetate ( 4 : 1 ) to give a white solid ( 406 mg , 26 % yield ). mp = 134 - 5 ° c ., lc - ms , mh + = 260 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 91 ( d , 1h , j = 9 . 3 hz ); 7 . 81 ( s , 1h ); 7 . 45 - 7 . 36 ( m , 1h ); 4 . 6 - 4 . 45 and 3 . 5 - 3 . 3 ( m + m , 3h ); 3 . 01 and 2 . 87 ( s + s , 1h ); 1 . 95 - 1 . 00 ppm ( m , 10h ). the title compound was prepared from cyclopentanone and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride using the procedures described for example 2 . mp = 110 - 111 ° c ., lc - ms , mh + = 246 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 91 ( d , 1h , j = 9 . 3 hz ); 7 . 83 ( s , 1h ); 7 . 42 ( d , 1h , j = 9 . 3 hz ); 5 . 1 - 4 . 9 and 4 . 15 - 3 . 95 ( m + m , 1h ); 2 . 995 ( s , 3h ); 2 . 1 - 1 . 40 ppm ( m , 8h ). the title compound was prepared from cyclobutylamine hydrochloride and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride according to the procedures described for example 4 . mp = 51 - 2 ° c ., lc - ms , mh + = 232 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 91 ( d , 1h , j = 9 . 0 hz ); 7 . 81 ( s , 1h ); 7 . 42 ( d , 1h , j = 9 . 0 hz ); 5 . 1 - 4 . 9 and 4 . 35 - 4 . 15 ( m + m , 1h ); 3 . 110 ( s , 3h ); 2 . 40 - 1 . 40 ppm ( m , 6h ). to a solution of cyclohexylamine ( 1 ml ) and triethylamine ( 1 . 7 ml ) in dichloromethane ( 20 ml ) was added a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 730 mg , 4 mmol ) in dichloromethane ( 10 ml ). after stirring the mixture for 1 hour , the organic phase was washed with 1n hcl and conc . nahco 3 solution , dried over magnesium sulfate , and concentrated under vacuum . the residue was triturated with ether to give a white solid ( 265 mg , yield = 27 %). mp = 172 - 173 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 15 ( s , 1h ), 7 . 90 ( d , 1h , j = 9 . 0 hz ); 7 . 82 ( d , j = 9 . 0 hz , 1h ); 6 . 09 (“ s ”, nh , 1h ), 4 . 05 - 3 . 97 ( m , 1h ) and 2 . 09 - 1 . 18 ppm ( m , 10h ). this compound was prepared from cyclopentylamine using the procedure described for example 7 . mp : 169 - 170 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 17 - 8 . 14 ( m , 1h ), 7 . 90 ( dd , 1h , j = 9 . 0 and 0 . 6 hz ); 7 . 81 ( dd , j = 9 . 0 and 0 . 9 hz , 1h ); 6 . 25 (“ s ”, nh , 1h ), 4 . 50 - 4 . 35 ( m , 1h ) and 2 . 16 - 1 . 45 ppm ( m , 8h ). the title compound was prepared from cyclobutylamine using the procedure described for example 7 . mp : 175 - 176 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 20 - 8 . 17 ( m , 1h ), 7 . 90 ( dd , j = 9 . 0 and 0 . 9 hz , 1h ); 7 . 82 ( dd , j = 9 . 0 and 0 . 9 hz , 1h ); 6 . 46 (“ s ”, nh , 1h ), 4 . 70 - 4 . 50 ( m , 1h ) and 2 . 50 - 1 . 60 ppm ( m , 6h ). t - butyl methyl -( 4 - oxocyclohexyl ) carbamate ( 4 . 54 g , 20 mmol ) and toluenesulphonylmethyl isocyanide ( 5 . 07 g , 26 mmol ) were dissolved in dry tetrahydrofuran ( 100 ml ) and cooled to 0 ° c . potassium tert - butoxide ( 5 . 16 g , 46 mmol ) was added slowly and the mixture was allowed to warm to 20 ° c . and stir for 3 hours . the reaction mixture was evaporated to dryness and partitioned between ethyl acetate ( 150 ml ) and water ( 50 ml ). the organic layer was separated , dried over magnesium sulfate and evaporated . the crude product was chromatographed on a silica gel eluting with ethyl acetate / hexane ( 66 : 34 ) to give 1 . 43 g of tert - butyl methyl -( 4 - cyanocyclohexyl ) carbamate . t - butyl methyl -( 4 - cyanocyclohexyl ) carbamate ( 710 mg , 3 mmol ) was dissolved in dichloromethane ( 20 ml ) and trifluoroacetic acid ( 3 ml ) was added . the solvent was evaporated after 2 hours , the residue was re - dissolved in a 4n hcl ( 3 ml ) solution in dioxane and the solvent evaporated . dichloromethane ( 30 ml ) and net 3 ( 2 ml ) were added to the residue followed by a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 548 mg , 3 mmol ) in dichloromethane ( 10 ml ). after stirring the mixture for 1 hour at room temperature , the organic phase was washed with 1n hcl and conc . nahco 3 solution , dried over magnesium sulfate , and concentrated under vacuum . the material was purified on a silica gel column eluting with ethyl acetate / chloroform ( 1 : 1 ) to give 170 mg of n -( cis - 4 - cyanocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as a white solid and as the less polar isomer . mp = 222 - 223 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , 1h , j = 9 . 0 hz ); 7 . 85 ( s , 1h ), 7 . 42 ( d , j = 9 . 0 hz , 1h ); 4 . 65 - 4 . 50 and 3 . 55 - 3 . 40 and 3 . 15 - 2 . 80 ( m , 5h ) and 2 . 20 - 1 . 30 ppm ( m , 8h ). the more polar n -( trans - 4 - cyanocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was obtained as a white solid after crystallization from diethyl ether ( 180 mg ). mp = 180 - 181 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , 1h , j = 8 . 7 hz ); 7 . 83 ( s , 1h ), 7 . 42 ( d , j = 8 . 7 hz , 1h ); 4 . 60 - 4 . 45 and 3 . 60 - 3 . 40 and 3 . 05 - 2 . 80 ( m , 5h ) and 2 . 50 - 1 . 40 ppm ( m , 8h ). methylamine , generated by heating a mixture of methylamine hydrochloride ( 10 g ) and sodium hydroxide pellets ( 18 g ), was condensed ( dry ice trap ) into a solution of tetrahydro - 4h - pyran - 4 - one ( 1 . 0 g , 10 mmol ) in methanol ( 50 ml ). 10 % pd on c ( 350 mg ) was added and the mixture was hydrogenated at room temperature for 7 hours . the solids were filtered off and the filtrate concentrated under vacuum . the residue was dissolved in chloroform ( 70 ml ) and triethylamine ( 2 ml ) and a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 500 mg , 2 . 73 mmol ) in chloroform ( 10 ml ) was added slowly . after stirring the reaction mixture for minutes , the organic phase was extracted with 100 ml of water and sulfuric acid (→ ph 2 ) and the aqueous phase re - extracted with chloroform ( 100 ml ), dried over magnesium sulfate , and concentrated under vacuum to give an oil . the crude product was purified by silica gel chromatography eluting ethyl acetate / hexane ( 75 : 25 ) and chloroform / acetone ( 85 : 15 ) to give the title product as a white solid after crystallization from ethyl acetate . mp = 160 - 2 ° c ., lc - ms , mh + = 262 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 93 ( d , 1h , j = 9 . 0 hz ); 7 . 84 ( s , 1h ); 7 . 42 ( d , 1h , j = 9 . 0 hz ); 4 . 90 - 4 . 70 and 4 . 20 - 3 . 10 ( m + m , 5h ); 2 . 927 ( s , 3h ); 2 . 1 - 1 . 5 ppm ( m , 4h ). the compound was prepared according to the procedure for example 12 from d 3 - methylamine and tetrahydro - 4h - pyran - 4 - one . mp = 165 - 166 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 93 ( d , 1h , j = 9 . 0 hz ); 7 . 84 ( s , 1h ); 7 . 42 ( d , 1h , j = 9 . 0 hz ); 4 . 90 - 4 . 70 and 4 . 20 - 3 . 10 ( m + m , 5h ) and 2 . 1 - 1 . 5 ppm ( m , 4h ). a mixture of hydroxylamine hydrochloride ( 5 . 56 g ), sodium acetate ( 6 . 56 g ) and tetrahydro - 4h - pyran - 4 - one ( 4 g , 40 mmol ) in ethanol ( 100 ml ) was refluxed over night . the solids were filtered off and the solvent evaporated . the remaining material was suspended in 100 ml of dry thf and decanted . lialh 4 ( 6 . 07 g ) was slowly added and the mixture was refluxed for 1 hour . the cooled mixture was quenched with 10 % sodium hydroxide solution , celite was added , and the solids were filtered off . the solvent was evaporated and the residue re - dissolved in dichloromethane ( 10 ml ) and triethylamine ( 1 ml ). this mixture was slowly added to a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 365 mg , 2 . 0 mmol ) in dichloromethane ( 10 ml ) and stirred at room temperature for 0 . 5 h . the mixture was washed with 1n hcl ( 100 ml ) and nahco 3 ( 100 ml ) solution and the aqueous re - extracted with dichloromethane ( 100 ml ). the combined organics were dried over magnesium sulfate , and concentrated under vacuum to give a white solid ( 410 mg ). mp = 204 - 205 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 20 - 8 . 18 ( m , 1h ), 7 . 92 ( dd , 1h , j = 9 . 3 and 1 . 2 hz ); 7 . 82 ( dd , 1h , j = 9 . 3 and 1 . 2 hz ); 6 . 25 - 6 . 10 ( m , nh , 1h ); 4 . 33 - 4 . 17 ( m , 1h ), 4 . 07 - 4 . 00 ( m , 2h ), 3 . 59 - 3 . 51 ( m , 2h ), 2 . 07 - 2 . 03 ( m , 2h ) and 1 . 69 - 1 . 58 ppm ( m , 2h ). n -( tetrahydro - 2h - pyran - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was prepared from 3 - aminotetrahydropyran hydrochloride and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride using the procedure described for example 7 . mp = 204 - 205 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 24 - 8 . 10 ( m , 1h ), 7 . 93 ( dd , 1h , j = 9 . 0 and 0 . 9 hz ); 7 . 84 ( dd , 1h , j = 9 . 0 and 1 . 2 hz ); 6 . 70 - 6 . 60 ( m , nh , 1h ); 4 . 24 - 4 . 22 ( m , 1h ), 3 . 86 - 3 . 60 ( m , 4h ) and 1 . 97 - 1 . 61 ppm ( m , 4h ). n -( tetrahydro - 2h - pyran - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 371 mg , 1 . 5 mmol ) was added to a suspension of sodium hydride ( 216 mg , 9 mmol ) in dry dmf ( 5 ml ), followed by methyl iodide ( 1 . 0 ml ) and the mixture was stirred at 20 ° c . for 1 hour . the solvent was evaporated under vacuum , dichloromethane ( 30 ml ) was added and the organic phase was washed with 1n hcl ( 100 ml ) and nahco 3 solution ( 100 ml ). the aqueous was re - extracted with dichloromethane ( 100 ml ), the organics dried over magnesium sulfate and concentrated under vacuum to give the title compound as a white solid after trituration with diethyl ether ( 186 mg ). mp : 134 - 135 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 93 ( d , 1h , j = 9 . 0 hz ); 7 . 83 ( s , 1h ); 7 . 40 ( d , 1h , j = 9 . 0 hz ); 4 . 70 - 3 . 20 ( m , 4h ), 3 . 01 ( sb , 3h ) and 2 . 10 - 1 . 50 ppm ( m , 4h ). to a solution of tetrahydro - 4h - pyran - 4 - one ( 1 . 0 g , 10 mmol ) in methanol ( 60 ml ) was added ethylamine hydrochloride ( 815 mg , 10 mmol ), 1 ml of net 3 , and 10 % pd on c ( 350 mg ). the mixture was hydrogenated at room temperature over night ( 18 hours ). the solids were filtered , washed with methanol ( 20 ml ) and concentrated under vacuum . the residue was dissolved in chloroform ( 70 ml ) and net 3 ( 2 ml ) and a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 600 mg , 3 . 28 mmol ) in chloroform ( 10 ml ) was added slowly . after stirring for 0 . 5 h , the mixture was washed with water ( 100 ml ) and h 2 so 4 (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 100 ml ) and the combined organics were dried over mgso 4 and concentrated under vacuum to give an oil . chromatography on silica gel eluting with ethyl acetate / hexane ( 75 : 25 ) and chloroform / acetone ( 85 : 15 ), gave white solid after crystallization from diethyl ether ( 470 mg ). mp = 102 - 4 ° c ., lc - ms , mh + = 276 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 93 ( d , 1h , j = 9 . 0 hz ); 7 . 80 ( s , 1h ); 7 . 38 ( d , 1h , j = 9 . 0 hz ); 4 . 75 - 4 . 45 and 4 . 15 - 3 . 90 and 3 . 75 - 3 . 05 ( m + m + m , 7h ); 2 . 04 - 1 . 05 ppm ( m , 7h ). the title compound was prepared from ethylamine hydrochloride and cyclohexanone using the procedures described for example 17 . after silica gel chromatography the product was isolated as a white solid . mp = 51 - 2 ° c ., lc - ms , mh + = 274 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 91 ( d , 1h , j = 9 . 0 hz ); 7 . 78 ( s , 1h ); 7 . 76 ( d , 1h , j = 9 . 0 hz ); 4 . 4 - 4 . 3 and 3 . 55 - 3 . 2 ( m + m , 3h ); 1 . 95 - 0 . 95 ppm ( m , 13h ). the title compound was prepared from cyclohexyl - 4 - methylamine using the methods described for example 4 and was isolated as a white solid . mp = 71 - 2 ° c ., lc - ms , mh + = 274 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 94 - 7 . 78 ( m , 2h ); 7 . 48 - 7 . 38 ( m , 1h ); 3 . 43 + 3 . 16 ( d + d , 2h ); 3 . 10 and 3 . 01 ( s + s , 3h ); 1 . 90 - 1 . 55 and 1 . 47 - 0 . 95 and 0 . 73 - 0 . 57 ppm ( m + m + m , 11h ). prepared from n - benzyl - n - methylamine and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride according to the procedure previously described . n - benzyl - n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a white solid . mp = 105 - 106 ° c ., lc - ms , mh + = 268 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 96 - 7 . 86 ( m , 1h ); 7 . 90 ( d , 1h , j = 9 . 6 hz ); 7 . 43 - 7 . 30 ( m , 5h ); 7 . 19 - 7 . 13 ( m , 1h ); 4 . 78 + 4 . 56 ( s + s , 2h ); 3 . 11 and 2 . 94 ppm ( s + s , 3h ). prepared by n - methylation of the product of the reaction of tetrahydrofuran - 2 - methylamine and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride as described for the preparation of examples 7 and 16 . n - methyl - n -( tetrahydrofuran - 2 - ylmethyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a pale yellow oil . lc - ms , mh + = 262 ; 1 h nmr ( 300 mhz , cdcl 3 , 2 rotamers ) δ 7 . 94 - 7 . 85 ( m , 2h ); 7 . 51 - 7 . 44 ( m , 1h ); 4 . 31 - 3 . 22 ( m , 5h ); 3 . 18 and 3 . 14 ( s + s , 3h ); 2 . 18 - 1 . 25 ppm ( m , 4h ). prepared from 3 - aminopyridine using the experimental procedures described for example 4 . n - methyl - n - pyridin - 3 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a yellow oil . lc - ms , mh + = 255 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 44 ( d , 1h , j = 4 . 8 hz ); 8 . 39 ( d , 1h , j = 2 . 1 hz ); 7 . 74 ( s , 1h ); 7 . 72 ( d , 1h , j = 9 hz ); 7 . 51 ( dd , 1h , j = 8 . 4 and 2 . 1 hz ); 7 . 35 ( d , 1h , j = 9 hz ); 7 . 27 ( dd , 1h , j = 8 . 4 and 4 . 8 hz ); 3 . 56 ppm ( s , 3h ). prepared from n - methylaniline and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride using the procedure described for example 7 . n - methyl - n - phenyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a yellow oil . lc - ms , mh + = 254 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 74 ( s , 1h ); 7 . 64 ( d , 1h , j = 9 . 6 hz ); 7 . 34 ( d , 1h , j = 9 . 6 hz ); 7 . 29 - 7 . 09 ( m , 5h ); 3 . 54 ppm ( s , 3h ). n - cyclopropyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was prepared from tetrahydro - 4h - pyran - 4 - one and cyclopropylamine using the procedures described for example 17 and was isolated as a white solid . mp = 108 - 109 ° c ., lc - ms , mh + = 288 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 91 ( t , 1h , j = 1 . 0 and 1 . 0 hz , 1h ); 7 . 76 ( dd , j = 9 . 2 and 1 . 0 hz , 1h ); 7 . 51 ( dd , j = 9 . 2 and 1 . 0 hz , 1h ); 4 . 50 - 4 . 39 ( m , 1h ); 4 . 11 - 4 . 06 ( m , 2h ); 3 . 58 - 3 . 49 ( m , 2h ); 2 . 70 - 2 . 60 ( m , 1h ); 2 . 28 - 2 . 12 ( m , 2h ); 1 . 90 - 1 . 85 ( m , 2h ); 0 . 75 - 0 . 53 ppm ( m , 4h ). the title compound was prepared from tetrahydro - 4h - pyran - 4 - one and 2 , 2 , 2 - trifluoroethylamine using the procedures described for example 17 and was isolated as a white solid . mp = 134 - 135 ° c ., lc - ms , mh + = 330 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 79 ( dd , j = 9 . 2 and 1 . 0 hz , 1h ); 7 . 91 - 7 . 85 ( m , 1h ); 7 . 40 ( dd , j = 9 . 2 and 1 . 0 hz , 1h ); 4 . 20 - 3 . 85 ( m , 5h ); 3 . 35 - 3 . 15 ( m , 2h ); 2 . 02 - 1 . 65 ppm ( m , 4h ). methylamine ( generated by heating a mixture of 10 g of methylamine hydrochloride and 18 g of sodium hydroxide ) was condensed into a solution of boc - 4 - piperidone ( 3 . 5 g , 17 . 6 mmol ) in methanol ( 30 ml ) and thf ( 30 ml ). 10 % pd on c ( 600 mg ) was added and the mixture was hydrogenated at room temperature for 18 hours . the solids were filtered off , washed with methanol ( 20 ml ) and concentrated under vacuum . the residue was dissolved in chloroform ( 50 ml ) and net 3 ( 4 ml ), and a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 2 . 1 g , 11 . 5 mmol ) in dichloromethane ( 20 ml ) was added slowly . after stirring the mixture for 1 h , the organic phase was washed with water ( 100 ml ) and h 2 so 4 (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 100 ml ), the organics combined , dried ( mgso 4 ) and concentrated under vacuum to give an oil . the crude product was purified by silica gel chromatography eluting with ethyl acetate / hexane ( 40 : 60 )→( 60 : 40 ) to give a white solid after crystallization from mtbe / hexane ( 3 . 14 g ). mp = 98 - 100 ° c ., lc - ms , mh + = 361 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 93 ( d , j = 9 . 0 hz , 1h ); 7 . 84 ( s , 1h ); 7 . 42 ( d , j = 9 . 0 hz , 1h ); 4 . 80 - 3 . 40 ( m , 5h ); 3 . 10 - 2 . 85 ( m , 3h ); 1 . 90 - 1 . 60 ( m , 4h ); 1 . 47 ppm ( s , 9h ). tert - butyl - 4 -[([ 2 , 1 , 3 ]- benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino )] piperidine - 1 - carboxylate ( 1 . 2 g , 3 . 33 mmol ) was dissolved in chloroform ( 30 ml ) and tfa ( 3 ml ) was added and the mixture was stirred at room temperature for 2 hours . the mixture was concentrated under vacuum and the residue was dissolved in chloroform ( 30 ml ) ethanol ( 30 ml ) and conc . hcl ( 1 ml ). the mixture was concentrated under vacuum to give a solid that was washed with a mixture of chloroform , ethanol and thf to yield an off white solid ( 920 mg ). mp & gt ; 260 ° c ., 1 h nmr ( 300 mhz , dmso ) δ 9 . 04 - 8 . 78 ( m , 2h ); 8 . 20 - 8 . 05 ( m , 2h ); 7 . 62 - 7 . 52 ( m , 1h ); 4 . 70 - 4 . 50 and 3 . 88 - 3 . 72 ( m , 1h ); 3 . 30 - 2 . 70 ( m , 7h ) and 2 . 20 - 1 . 80 ppm ( m , 4h ). prepared by n - methylation of n - methyl - n - piperidin - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as described for example 16 and isolated as a beige solid after crystallization from ethyl acetate / dichloromethane . mp & gt ; 260 ° c ., lc - ms , mh + = 275 . 2 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 28 - 7 . 20 ( m , 2h ); 6 . 67 ( d , j = 9 . 6 hz , 1h ); 3 . 70 - 6 . 57 and 2 . 90 - 2 . 70 ( m , 1h ); 3 . 70 - 1 . 95 ppm ( m , 14h ). n - methyl - n - piperidin - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide hydrochloride ( 0 . 58 g , 1 . 9 mmol ) was suspended in chloroform ( 50 ml ), and acetic anhydride ( 2 ml ) and triethylamine ( 4 ml ), were added . after stirring for 1 h , the mixture was washed with water ( 100 ml ) and h 2 so 4 (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 2 × 100 ml ) and the combined organics dried ( mgso 4 ) and concentrated under vacuum . the residue was purified by silica gel chromatography eluting with ethyl acetate / chloroform / methanol ( 50 : 45 : 5 ) to give a white solid after crystallization from ethyl acetate / mtbe / hexane ( 470 mg ). mp = 173 - 175 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 93 ( d , j = 9 . 0 hz , 1h ); 7 . 85 ( s , 1h ); 7 . 42 ( d , j = 9 . 0 hz , 1h ); 4 . 90 - 4 . 70 and 4 . 05 - 3 . 80 ( m , 5h ); 2 . 89 ( sb , 3h ); 2 . 13 ( sb , 3h ), 1 . 95 - 1 . 60 ppm ( m , 4h ). n - methyl - n - piperidin - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide hydrochloride ( 0 . 5 g , 1 . 7 mmol ) was suspended in chloroform ( 20 ml ) and thf ( 20 ml ) and triethylamine ( 6 ml ), was added . a mixture of formic acid ( 1 ml ) and acetic anhydride ( 1 ml ) was stirred for 1 . 5 h at room temperature and then slowly added to the suspension . after stirring the mixture for 1 h , it was washed with water ( 100 ml ) and h 2 so 4 (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 2 × 100 ml ) and the combined organics were dried ( mgso 4 ), concentrated under vacuum , and purified by silica gel chromatography , eluting with ethyl acetate / chloroform / methanol ( 50 : 45 : 5 ) to give a white solid ( 341 mg ). mp = 163 - 165 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 05 ( s , 1h ), 7 . 93 ( d , j = 9 . 3 hz , 1h ); 7 . 86 ( s , 1h ); 7 . 42 ( d , j = 9 . 3 hz , 1h ); 4 . 90 - 4 . 45 and 3 . 85 - 2 . 60 ( m , 5h ); 2 . 88 ( sb , 3h ); and 1 . 95 - 1 . 60 ppm ( m , 4h ). n - methyl - n - piperidin - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide hydrochloride ( 0 . 38 g , 1 . 3 mmol ) was suspended in chloroform ( 70 ml ) and triethylamine ( 2 ml ) was added . a solution of methane sulfonyl chloride ( 0 . 14 g , 1 . 26 mmol ) in chloroform ( 10 ml ) was added and the mixture was stirred at 20 ° c . for 2 h . the mixture was washed with water ( 50 ml ) and h 2 so 4 (→ ph 2 ) and nahco 3 solution ( 50 ml ) and the aqueous re - extracted with dichloromethane ( 2 × 50 ml ). the combined organics were dried ( mgso 4 ), concentrated under vacuum , and the crude product was purified on a silica gel column eluting with dichloromethane / thf ( 85 : 15 ) to give a white crystalline product , after crystallization from mtbe / hexane ( 204 mg ). mp = 177 - 179 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 93 ( d , j = 9 . 3 hz , 1h ); 7 . 85 ( s , 1h ); 7 . 42 ( d , j = 9 . 3 hz , 1h ); 4 . 75 - 4 . 46 and 4 . 10 - 3 . 90 and 3 . 10 - 2 . 40 ( m , 5h ); 2 . 92 ( s , 3h ), 2 . 83 ( s , 3h ) and 2 . 10 - 1 . 70 ppm ( m , 4h ). n - methyltetrahydro - 2h - pyran - 4 - amine ( 0 . 4 g , 3 . 4 mmol ), [ 2 , 1 , 3 ]- benzothiadiazole - 5 - carboxylic acid ( 0 . 23 g , 1 . 4 mmol ), dmap ( 0 . 2 g : 1 . 6 mmol ), hobt ( 0 . 2 g , 1 . 5 mmol ), triethylamine ( 1 . 0 ml ) and edci ( 1 g , 6 . 4 mmol ) were dissolved in dmf ( 30 ml ). the mixture was stirred at room temperature for 18 h and then concentrated under vacuum . chloroform ( 100 ml ) was added and the mixture washed with water ( 100 ml ) and h 2 so 4 (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 100 ml ) and the combined organics were dried ( mgso 4 ), concentrated under vacuum , and the crude product was purified on a silica gel column eluting with chloroform / thf ( 90 : 10 ), to give the product as an oil which crystallized on standing . mp = 106 - 108 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 8 . 06 ( d , j = 9 . 0 hz , 1h ); 8 . 01 ( s , 1h ); 7 . 60 ( d , j = 9 . 0 hz , 1h ); 4 . 92 - 4 . 75 and 4 . 15 - 3 . 10 ( m , 5h ); 3 . 10 - 2 . 80 ( m , 3h ) and 2 . 05 - 1 . 50 ppm ( s , 4h ). tetrahydro - 2h - thiopyran - 4 - one ( 1 . 0 g , 8 . 6 mmol ) was dissolved in methanol ( 40 ml ), and methylamine in ethanol ( 3 . 3 ml of a 33 % solution ) was added and the mixture stirred at room temperature for 1 h . the mixture was cooled to − 78 ° c . and a suspension of libh 4 ( 0 . 34 g ) in thf ( 10 ml ) was added and stirred for 18 h whilst warming up to room temperature . water ( 1 ml ) was added and then evaporated and the residue dissolved in chloroform ( 20 ml ). triethylamine ( 2 ml ) was added and the mixture cooled to 0 ° c . before adding slowly a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 1 . 28 g , 7 mmol ) in chloroform ( 15 ml ). the mixture was stirred for 0 . 5 h and then washed with water ( 100 ml ) and hcl (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 100 ml ) and the combined organics were dried ( mgso 4 ) and concentrated under vacuum to give a white solid after trituration with diethyl ether ( 1 . 6 g ). mp = 155 - 156 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 ( d , j = 9 . 3 hz , 1h ); 7 . 83 ( sb , 1h ); 7 . 40 ( d , j = 9 . 3 hz , 1h ); 4 . 60 - 4 . 45 and 3 . 50 - 3 . 30 ( m , 1h ); 3 . 10 - 2 . 40 ( m , 7h ) and 2 . 20 - 1 . 85 ppm ( s , 4h ). n - methyl - n -( tetrahydro - 2h - thiopyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 83 mg , 3 mmol ) was dissolved in thf ( 30 ml ) and methanol ( 20 ml ). a solution of sodium periodate ( 0 . 71 g ) in water ( 30 ml ) was added and the mixture stirred over night . the solvents were evaporated and the product was purified by silica gel chromatography eluting with chloroform / thf / methanol ( 60 : 20 : 20 ), to give two sulfone isomers . the less polar isomer was isolated as a white solid ( 0 . 35 g ). mp = 172 - 173 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 94 ( d , j = 9 . 3 hz , 1h ); 7 . 87 ( sb , 1h ); 7 . 43 ( d , j = 9 . 3 hz , 1h ); 4 . 80 - 4 . 65 and 3 . 70 - 3 . 50 ( m , 1h ); 3 . 0 ( s , 3h ), 3 . 30 - 1 . 60 ppm ( m , 8h ). the more polar isomer was isolated as a 2 : 1 mixture with the less polar isomer ( 0 . 45 g ). mp = 145 - 146 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 96 - 7 . 85 ( m , 2h ); 7 . 45 - 7 . 39 ( m , 1h ); 4 . 80 - 4 . 65 and 3 . 70 - 3 . 40 ( m , 1h ); 3 . 0 ( s , 3h ), 3 . 30 - 1 . 70 ppm ( m , 8h ). n - methyl - n -( tetrahydro - 2h - thiopyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 5 g , 1 . 8 mmol ) was dissolved in chloroform ( 40 ml ) and m - chloroperbenzoic acid ( 0 . 93 g ) was added and stirred for 1 h . the mixture was washed with na 2 co 3 solution ( 100 ml ), dried over mgso 4 and evaporated and the residue crystallized from dichloromethane / diethyl ether to give a white solid ( 44 mg ). mp = 238 - 239 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 95 ( d , j = 9 . 0 hz , 1h ); 7 . 87 ( sb , 1h ); 7 . 41 ( d , j = 9 . 0 hz , 1h ); 4 . 90 - 4 . 70 ( m , 1h ); 3 . 35 - 3 . 10 ( m , 4h ); 2 . 97 ( s , 3h ); 2 . 60 - 2 . 10 ppm ( m , 4h ). to a suspension of quinoxaline - 6 - carboxylic acid ( 0 . 7 g , 4 mmol ) and n - methyltetrahydro - 2h - pyran - 4 - amine ( 0 . 7 g , 6 mmol ), in dmf ( 6 ml ) and dichloromethane ( 6 ml ), were added dmap ( 0 . 49 g , 4 mmol ), hobt ( 0 . 54 g , 4 mmol ), net 3 ( 1 . 6 ml ) and edci ( 1 . 26 g ). the reaction mixture was stirred at room temperature for 4 h and then concentrated under vacuum . the crude product was purified on a silica gel column eluting with chloroform / methanol / triethylamine ( 95 : 5 : 0 . 5 ) to give an oil ( 1 . 5 g ) which formed a beige solid upon trituration with dichloromethane / diethyl ether . mp = 130 - 131 ° c ., lc - ms , mh + = 272 ; 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 91 ( s , 2h ); 8 . 18 ( d , j = 8 . 4 hz , 1h ); 8 . 11 ( s , 1h ); 7 . 79 ( d , j = 8 . 4 hz , 1h ); 4 . 95 - 3 . 50 ( m , 5h ); 3 . 07 and 2 . 91 ( s + s , 3h ); 2 . 02 - 1 . 65 ppm ( m , 4h ). 1 , 4 - cyclohexanedione mono - ethylene ketal ( 3 . 12 g , 20 mmol ), methylamine hydrochloride ( 1 . 35 g , 20 mmol ) and triethylamine ( 2 . 42 g ) were dissolved in methanol ( 80 ml ) and 10 % pd on c ( ig ) was added and the mix hydrogenated at room temperature at 50 psi for 2 h . the solids were filtered off , washed with methanol ( 40 ml ) and the mixture concentrated under vacuum . the product was dissolved in chloroform ( 75 ml ) and triethylamine ( 4 ml ) was added followed by slow addition of a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 2 . 74 g , 15 mmol ) in chloroform ( 15 ml ). after stirring the mixture for 1 h it was washed with water ( 100 ml ) and hcl (→ ph 2 ) and nahco 3 solution ( 100 ml ). the aqueous was extracted with chloroform ( 100 ml ) and the combined organics were dried ( mgso 4 ) and concentrated under vacuum to give the product as a yellow solid ( 4 . 2 g ). this material was dissolved in thf ( 30 ml ), and 2n hcl ( 40 ml ) was added and the mixture stirred overnight . the thf was evaporated and the remaining aqueous was extracted with dichloromethane ( 100 ml ), washed with water ( 100 ml ) and sat . nahco 3 solution ( 100 ml ), and dried over mgso 4 . the solvent was evaporated under vacuum to give a beige solid ( 3 . 5 g ) which was crystallized from dichloromethane / diethyl ether to give a white solid . mp = 183 - 184 ° c ., lc - ms , mh + = 274 ; 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 95 ( d , j = 9 . 0 hz , 1h ); 7 . 87 ( m , 1h ); 7 . 40 (“ d ”, j = 9 . 0 hz , 1h ); 5 . 10 - 4 . 95 and 4 . 10 - 3 . 90 ( m , 1h ); 2 . 93 (“ s ”, 3h ); 2 . 70 - 1 . 95 ppm ( s , 8h ). n - methyl - n -( 4 - oxocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 41 g , 1 . 5 mmol ) was dissolved in chloroform ( 10 ml ), hydroxylamine hydrochloride ( 0 . 63 g ) and triethylamine ( 1 . 6 ml ) were added , and the mixture stirred overnight . evaporation of the solvent and chromatography of the residue on silica gel , eluting with chloroform / ethyl acetate ( 3 : 2 ), gave a white solid ( 0 . 37 g ). mp = 197 - 198 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 49 ( s , 1h ); 7 . 93 ( d , j = 9 . 0 hz , 1h ); 7 . 86 ( m , 1h ); 7 . 43 ( d , j = 9 . 0 hz , 1h ); 4 . 90 - 4 . 70 and 3 . 80 - 3 . 35 ( m , 1h ); 2 . 99 and 2 . 88 ( s + s , 3h ); 2 . 80 - 1 . 50 ppm ( s , 8h ). n - methyl - n -( 4 - oxocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 41 g , 1 . 5 mmol ) was dissolved in chloroform ( 10 ml ), methoxylamine hydrochloride ( 0 . 75 g ) and triethylamine ( 1 . 6 ml ) were added , and the mixture stirred overnight . evaporation of the solvent and chromatography of the residue on silica gel , eluting with chloroform / ethyl acetate ( 3 : 2 ), gave a white solid ( 0 . 32 g ). mp = 167 - 168 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 93 ( d , j = 9 . 3 hz , 1h ); 7 . 84 ( m , 1h ); 7 . 42 ( d , j = 9 . 3 hz , 1h ); 4 . 85 - 4 . 70 and 3 . 80 - 3 . 30 ( m , 1h ); 3 . 83 ( s , 3h ); 2 . 99 and 2 . 88 ( s + s , 3h ); 2 . 60 - 1 . 60 ppm ( s , 8h ). n - methyl - n -( 4 - oxocyclohexyl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 1 . 5 g , 5 . 5 mmol ) was dissolved in dichloromethane ( 50 ml ) and cooled to 0 ° c . diethylaminosulfur trifluoride , “ dast ” ( 1 . 8 ml , 2 . 4 equivalents ) was added slowly and the mixture stirred at room temperature for 3 h . the solution was diluted with dichloromethane ( 100 ml ) and nahco 3 solution was added slowly until ph 9 was reached . the organic phase was washed with brine , dried over mgso 4 and evaporated . the crude product was chromatographed on a silica gel eluting with hexane / ethyl acetate ( 65 : 35 ) to give n -( 4 , 4 - difluorocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 32 g ) as a white solid after trituration with ether . mp = 137 - 138 ° c ., lc - ms , mh + = 296 ; 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , j = 9 . 0 hz , 1h ); 7 . 84 ( s , 1h ); 7 . 41 ( d , j = 9 . 0 hz , 1h ); 4 . 75 - 4 . 60 and 3 . 65 - 3 . 55 ( m , 1h ); 3 . 01 and 2 . 91 ( s + s , 3h ); 2 . 30 - 1 . 60 ppm ( s , 8h ). a second product was isolated as n -( 4 - fluorocyclohex - 3 - en - 1 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 1 g ) as a white solid after trituration with diethyl ether . mp = 117 - 118 ° c ., lc - ms , mh + = 276 ; 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , j = 9 . 0 hz , 1h ); 7 . 84 ( s , 1h ); 7 . 41 ( d , j = 9 . 0 hz , 1h ); 5 . 30 - 5 . 00 ( m , 1h ); 4 . 90 - 4 . 70 and 3 . 80 - 3 . 65 ( m , 1h ); 3 . 02 and 2 . 92 ( s + s , 3h ); 2 . 60 - 1 . 80 ppm ( s , 6h ). to a mixture of trans 4 - aminocyclohexanol hydrochloride ( 0 . 46 g , 3 . 0 mmol ) and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid ( 0 . 33 g , 2 . 0 mmol ) in chloroform ( 10 ml ), were added dmap ( 0 . 24 g , 2 . 0 mmol ), hobt ( 0 . 27 g , 2 . 0 mmol ) and triethylamine ( 1 . 6 ml ). after stirring for 10 minutes , edci ( 1 . 26 g , 6 . 6 mmol ) in dmf ( 3 ml ) was added and the mixture was heated to 45 ° c . for 2 h . the solvents were removed under vacuum and the crude product was purified by silica gel chromatography eluting with ethyl acetate / chloroform ( 3 : 1 ) to give a white solid after trituration with ethyl acetate ( 0 . 4 g ). mp = 242 - 243 ° c ., 1 h nmr ( 300 mhz , dmso + cdcl 3 ) δ 8 . 41 - 8 . 39 ( m , 1h ), 7 . 95 ( dd , j = 9 . 3 and 1 . 2 hz , 1h ); 7 . 85 ( d , j = 9 . 3 hz , 1h ); 7 . 82 (“ s ”, nh , 1h ), 4 . 00 - 3 . 88 ( m , 1h ), 3 . 70 - 3 . 50 ( m , 2h ); 2 . 15 - 1 . 95 ( m , 4h ); 1 . 55 - 1 . 35 ppm ( m , 4h ). prepared from trans - 4 - amino - 1 - methylcyclohexanol using the method described for example 42 . the product was isolated as a white solid . mp = 208 - 209 ° c ., 1 h nmr ( 300 mhz , dmso + cdcl 3 ) δ 8 . 18 - 8 . 16 ( m , 1h ), 7 . 91 ( d , j = 9 . 6 hz , 1h ); 7 . 82 ( dd , j = 9 . 6 and 0 . 9 hz , 1h ); 6 . 10 (“ s ”, nh , 1h ), 4 . 05 - 3 . 90 ( m , 1h ), 2 . 00 - 1 . 50 ( m , 8h ); 1 . 29 ppm ( s , 3h ). to a mixture of 1 , 4 - cyclohexanedione mono - ethylene ketal ( 5 . 0 g , 32 mmol ), methylamine hydrochloride ( 2 . 16 g , 32 mmol ) and triethylamine ( 6 . 7 ml ), in methanol ( 100 ml ), was added 10 % pd on c ( 1 g ) and the mixture was hydrogenated at room temperature ( 50 psi ) for 2 h . the solids were filtered off , washed with methanol ( 40 ml ) and concentrated under vacuum . the residue was dissolved in methanol ( 10 ml ), thf ( 50 ml ) and 2n hcl ( 65 ml ) and stirred for 18 h . sodium hydroxide solution ( concn ) was added to ph 10 , the aqueous extracted with dichloromethane ( 5 × 100 ml ), the combined organics dried ( mgso 4 ) and concentrated under vacuum to give 4 - n - methylaminocyclohexanone ( 4 . 97 g ). this material was slowly added to a solution of di - tert - butyl dicarbonate ( 8 . 38 g ) in dichloromethane ( 80 ml ) and the mixture stirred for 2 h . the mixture was washed with water , dried over mgso 4 , evaporated under vacuum and the residue chromatographed on silica gel eluting with ethyl acetate / hexane ( 30 : 70 ) to give tert - butyl -( 4 - cyclohexanone ) methylcarbamate as a white solid ( 6 . 14 g ). to a solution of the preceding ketone ( 0 . 91 g , 4 . 0 mmol ) in anhydrous thf ( 100 ml ) at − 70 ° c . was added methyl magnesium bromide ( 6 mmol ) and the mixture stirred for 1 h . the mixture was poured into 2n nh 4 cl solution and the ph was adjusted to 7 using citric acid . the aqueous was extracted with dichloromethane ( 5 × 100 ml ), the combined organics dried ( mgso 4 ) and evaporated to give an oil ( ig ) which was chromatographed on silica gel eluting with ethyl acetate / hexane ( 1 : 1 ) to give tert - butyl ( cis - 4 - hydroxy - 4 - methylcyclohexyl ) methylcarbamate ( 0 . 42 g ) as a colorless oil and as the less polar isomer , and tert - butyl ( trans - 4 - hydroxy - 4 - methylcyclohexyl ) methylcarbamate ( 0 . 4 g ) as a white solid . tert - butyl ( cis - 4 - hydroxy - 4 - methylcyclohexyl ) methylcarbamate ( 0 . 42 g ) was dissolved in dichloromethane ( 10 ml ) and tfa ( 2 ml ) added , and stirred for 3 h . the solvent was evaporated under vacuum and the residue dissolved in dichloromethane ( 10 ml ) and cone . hcl ( 1 ml ). the solvent was evaporated and the material was dried over night under high vacuum . the residue was dissolved in dmf ( 5 ml ) and chloroform ( 3 ml ), and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid ( 0 . 28 g , 1 . 7 mmol ), dmap ( 0 . 21 g 1 . 7 mmol ), hobt ( 0 . 23 g 1 . 7 mmol ) and triethylamine ( 1 . 4 ml ) were added . after 0 . 1 h , edci ( 1 . 07 g , 5 . 6 mmol ) was added and after stirring for 2 h at 45 ° c ., the solvents were evaporated . the residue was chromatographed on silica gel eluting with ethyl acetate / chloroform ( 3 : 1 ) to give n -( cis - 4 - hydroxy - 4 - methylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as a white solid ( 0 . 34 g ) after trituration with diethyl ether . mp = 154 - 155 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 91 ( d , j = 9 . 3 hz , 1h ), 7 . 82 ( sb , 1h ); 7 . 46 - 7 . 37 ( m , 1h ); 4 . 60 - 4 . 45 and 3 . 50 - 3 . 30 ( m , 1h ), 3 . 05 and 2 . 91 ( s + s , 3h ); 2 . 10 - 1 . 00 ( m , 8h ) and 1 . 29 and 1 . 16 ppm ( s + s , 3h ). n -( trans - 4 - hydroxy - 4 - methylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was prepared using the procedures above from tert - butyl ( trans - 4 - hydroxy - 4 - methylcyclohexyl ) methyl carbamate and isolated as a white solid . mp = 175 - 176 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ), 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 4 . 60 - 4 . 45 and 3 . 60 - 3 . 40 ( m , 1h ), 3 . 02 and 2 . 90 ( s + s , 3h ); 1 . 90 - 1 . 20 ( m , 8h ) and 1 . 31 ppm ( s , 3h ). these compounds were prepared using the methods described for examples 44 and 45 using ethyl magnesium bromide . n -( cis - 4 - hydroxy - 4 - ethylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a white solid . mp = 145 - 146 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 91 ( d , j = 9 . 0 hz , 1h ), 7 . 82 ( sb , 1h ); 7 . 46 - 7 . 37 ( m , 1h ); 4 . 60 - 4 . 45 and 3 . 50 - 3 . 30 ( m , 1h ), 3 . 05 and 2 . 91 ( s + s , 3h ) and 2 . 10 - 0 . 80 ppm ( m , 13h ). n -( trans - 4 - hydroxy - 4 - ethylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a white solid . mp = 110 - 111 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ), 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 4 . 60 - 4 . 45 and 3 . 60 - 3 . 40 ( m , 1h ), 3 . 00 and 2 . 89 ( s + s , 3h ) and 1 . 95 - 0 . 90 ppm ( m , 13h ). prepared using the methods described for examples 44 and 45 using ethynyl magnesium bromide and isolated as a white solid . mp = 160 - 161 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ), 7 . 83 ( sb , 1h ); 7 . 46 - 7 . 36 ( m , 1h ); 4 . 65 - 4 . 50 and 3 . 60 - 3 . 40 ( m , 1h ), 3 . 03 and 2 . 90 ( s + s , 3h ); 2 . 60 ( s , 1h ) and 2 . 30 - 1 . 35 ppm ( m , 8h ). title compounds were prepared using the methods described for examples 44 and 45 using but - 3 - en - 1 - yl magnesium bromide . n -( cis - 4 - but - 3 - en - 1 - yl - 4 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a white solid . mp = 143 - 144 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 91 ( d , j = 9 . 3 hz , 1h ), 7 . 82 - 7 . 79 ( m , 1h ); 7 . 46 - 7 . 37 ( m , 1h ); 5 . 95 - 5 . 70 ( m , 1h ); 5 . 15 - 4 . 90 ( m , 2h ); 4 . 60 - 4 . 45 and 3 . 50 - 3 . 30 ( m , 1h ), 3 . 05 and 2 . 91 ( s + s , 3h ) and 2 . 60 - 1 . 10 ppm ( m , 12h ). n -( trans - 4 - but - 3 - en - 1 - yl - 4 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was isolated as a white solid . mp = 145 - 146 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ), 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 5 . 95 - 5 . 80 ( m , 1h ); 5 . 12 - 4 . 98 ( m , 2h ); 4 . 60 - 4 . 45 and 3 . 60 - 3 . 40 ( m , 1h ), 3 . 01 and 2 . 90 ( s + s , 3h ) and 2 . 25 - 1 . 20 ppm ( m , 12h ). trans - 4 - aminocyclohexanol hydrochloride ( 60 . 6 g , 0 . 40 mol ) and nahco 3 ( 140 g ) were dissolved in water ( 700 ml ). ethyl acetate ( 500 ml ) was added and the mixture stirred rapidly using a mechanical stirrer whilst a solution of ethyl chloroformate ( 48 ml ) in ethyl acetate ( 200 ml ) was added slowly . the mixture was stirred overnight and then ethyl acetate ( 1 l ) and water ( 500 ml ) were added to dissolve the precipitate . the aqueous was extracted with ethyl acetate ( 2 × 500 ml ) and the combined organic phases were washed with 2n hcl , dried over na 2 so 4 , and the solvent evaporated , to give a white solid ( 73 . 7 g ). this material was dissolved in dry thf ( 600 ml ) and the solution slowly ( 1 h ) added to a suspension of lialh 4 ( 29 . 6 g ) in thf ( 600 ml ). after stirring overnight at 20 ° c . the mixture was cooled in an ice bath and a solution of sodium hydroxide ( 77 g ) in water ( 50 ml ) was slowly added . after 1 h , some celite was added and the mixture was filtered and washed with dichloromethane . the filtrate was dried ( mgso 4 ) and evaporated under vacuum to give trans - 4 - methylaminocyclohexanol a white solid ( 45 . 9 g ). trans - 4 - methylaminocyclohexanol ( 37 . 1 g , 0 . 28 mol ), [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid ( 42 . 7 g , 0 . 26 mol ), dmap ( 32 g , 0 . 26 mol ), hobt ( 1 g , 0 . 08 mol ) and triethylamine ( 54 ml ) were dissolved in dichloromethane ( 750 ml ) and after 15 minutes , edci ( 100 g , 0 . 52 mol ) was added and the mixture refluxed for 2 h . the mixture was washed with 2n hcl ( 500 ml ) and nahco 3 solution ( 500 ml ), dried over mgso 4 and then concentrated under vacuum . the residue was chromatographed on silica gel using ethyl acetate / chloroform ( 3 : 1 ) as eluant to give the title product as a white solid ( 37 g ) after trituration with ethyl acetate . mp = 170 - 171 ° c ., lc - ms , mh + = 276 ; 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ); 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 4 . 60 - 4 . 40 and 3 . 70 - 3 . 40 ( m , 2h ); 2 . 99 and 2 . 87 ( s + s , 3h ); 2 . 20 - 1 . 05 ppm ( s , 8h ). title compound was prepared using the procedure described for example 51 replacing liald 4 for lialh 4 . mp = 170 - 171 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ); 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 4 . 60 - 4 . 40 and 3 . 70 - 3 . 40 ( m , 2h ) and 2 . 20 - 1 . 05 ppm ( s , 8h ). sodium hydride ( 0 . 12 g , 4 . 8 mmol ) followed by methyl iodide ( 1 . 1 ml ) were added to a solution of n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 55 g , 2 . 0 mmol ), in dmf ( 5 ml ), and the mixture stirred at 40 ° c . for 2 h . the dmf was evaporated and the residue was chromatographed on silica gel eluting with ethyl acetate / chloroform ( 3 : 1 ) to give a white solid ( 0 . 42 g ). mp = 143 - 144 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ); 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 4 . 60 - 4 . 40 and 3 . 60 - 3 . 00 ( m , 2h ); 3 . 37 and 3 . 29 ( s + s , 3h ); 2 . 99 and 2 . 88 ( s + s , 3h ); 2 . 30 - 0 . 95 ppm ( s , 8h ). n -( trans - 4 - methoxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 91 g , 3 . 2 mmol ) and phosphorus pentasulfide ( 1 . 42 g ) were refluxed in toluene ( 40 ml ) for 3 h . the mixture was cooled , filtered through a 2 cm layer of silica gel and washed with dichloromethane . evaporation of the solvent and trituration with diethyl ether gave a yellow solid ( 0 . 1 g ). mp = 137 - 138 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 89 - 7 . 83 ( m , 1h ); 7 . 58 - 7 . 55 ( m , 1h ); 7 . 36 - 7 . 30 ( m , 1h ); 5 . 50 - 5 . 40 and 3 . 90 - 3 . 75 and 3 . 50 - 3 . 00 ( m , 2h ); 3 . 44 and 3 . 38 ( s + s , 3h ); 3 . 27 and 3 . 04 ( s + s , 3h ); 2 . 30 - 0 . 95 ppm ( s , 8h ). n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 1 . 26 g , 4 . 57 mmol ), 4 - nitrobenzoic acid ( 1 . 50 g , 9 mmol ) and triphenyl phosphine ( 2 . 36 g , 9 mmol ) were dissolved in thf ( 60 ml ). a solution of diethylazodicarboxylate ( diad , 1 . 82 g , 9 mmol ) in thf ( 3 ml ) was added slowly and the mixture stirred overnight . the mixture was washed with nahco 3 solution ( 100 ml ), the aqueous extracted with ethyl acetate ( 2 × 100 ml ), dried over na 2 so 4 and concentrated . the residue was purified on a silica gel column using ethyl acetate / hexane ( 3 : 1 → 1 : 1 ) as eluant to give the 4 - nitrobenzoate ester as a white solid ( 1 . 4 g ). this material was suspended in anhydrous methanol ( 150 ml ) and a solution of sodium ( 0 . 4 g ) in anhydrous methanol ( 50 ml ) was added . after stirring at 20 ° c . for 1 h , the mixture was acidified with conc . hcl and evaporated onto silica gel ( 10 g ). the crude product was chromatographed on silica gel eluting with chloroform / thf / methanol ( 80 : 17 : 3 ) to give a white solid after crystallization from dichloromethane / mtbe ( 0 . 67 g ). mp = 177 - 179 ° c ., lc - ms , mh + = 276 ; 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 91 ( d , j = 9 . 6 hz , 1h ); 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 6 hz , 1h ); 4 . 65 - 4 . 48 and 4 . 17 - 3 . 92 and 3 . 55 - 3 . 37 ( m , 2h ); 3 . 05 and 2 . 91 ( s + s , 3h ); 2 . 22 - 1 . 25 ppm ( s , 8h ). n -( 4 - cis - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 28 g , 1 . 0 mmol ), 1h - tetrazole ( 0 . 14 g . 2 mmol ) and triphenyl phosphine ( 0 . 52 g , 2 mmol ) were dissolved in thf ( 25 ml ) and a solution of diad ( 0 . 40 g , 2 mmol ), in thf ( 5 ml ), was added slowly and the mixture stirred for 3 h . the mixture was evaporated under vacuum and the residue was purified on a silica gel column using ethyl acetate / hexane / chloroform ( 35 : 50 : 15 ) as eluant , followed by chromatography eluting with toluene / acetone ( 80 : 20 ), to give a white crystalline product after crystallization from dichloromethane / mtbe / hexane ( 0 . 06 g ). mp = 172 - 175 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 8 . 49 ( sb , 1h ), 7 . 94 ( d , j = 9 . 3 hz , 1h ); 7 . 86 ( s , 1h ); 7 . 43 ( d , j = 9 . 3 hz , 1h ); 4 . 85 - 4 . 60 and 3 . 75 - 3 . 60 ( m , 2h ); 3 . 10 - 2 . 90 ( m , 3h ); 2 . 50 - 1 . 80 ppm ( s , 8h ). to a cooled (− 25 ° c .) solution of n -( 4 - cis - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 55 g , 2 . 0 mmol ), diphenylphosphorylazide ( 2 . 2 ml , 10 mmol ) and triphenyl phosphine ( 2 . 62 g , 10 mmol ), in thf ( 50 ml ), was slowly added a solution of diad ( 2 . 0 ml , 10 mmol ), in thf ( 5 ml ), and the mixture stirred for 2 h at − 25 ° c . and for 3 h at 20 ° c . water ( 40 ml ) was added and extracted with ethyl acetate ( 2 × 100 ml ). the combined organics were dried over mgso 4 , concentrated under vacuum , and the residue chromatographed on silica gel eluting with ethyl acetate / hexane / chloroform ( 2 : 1 : 1 ) to give the product as a white solid after trituration with diethyl ether ( 0 . 29 g ). mp = 149 - 150 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 ( d , j = 9 . 3 hz , 1h ); 7 . 82 ( s , 1h ); 7 . 40 ( d , j = 9 . 3 hz , 1h ); 4 . 60 - 4 . 40 and 3 . 60 - 3 . 10 ( m , 2h ); 2 . 99 and 2 . 88 ( s + s , 3h ); 2 . 20 - 1 . 10 ppm ( s , 8h ). n -( trans - 4 - azidocyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 18 g , 0 . 6 mmol ) was dissolved in pyridine ( 4 ml ), ph 3 p ( 0 . 26 g , 1 . 0 mmol ) was added , and the mixture stirred for 1 hour at room temperature . conc . ammonia solution ( 6 ml ) was slowly added and the mixture stirred for 2 h at 20 ° c . before evaporating under vacuum and purifying the crude product on silica gel , eluting with chloroform / methanol / triethylamine ( 90 : 10 : 1 ), to give a white solid after trituration with diethyl ether ( 0 . 067 g ). mp = 145 - 146 ° c ., 1 h nmr ( 300 mhz , dmso + cdcl 3 , rotamers ) δ 7 . 93 ( d , j = 8 . 7 hz , 1h ); 7 . 82 ( s , 1h ); 7 . 41 ( d , j = 8 . 7 hz , 1h ); 4 . 60 - 4 . 50 and 3 . 55 - 3 . 35 and 2 . 80 - 2 . 55 ( m , 2h ); 3 . 00 and 2 . 88 ( s + s , 3h ); 2 . 10 - 0 . 90 ppm ( s , 8h ). the title compounds were prepared from benzyl ( 3 - oxocyclohexyl ) carbamate using the procedures described for example 51 . the cis - and trans - isomers were separated by silica gel chromatography eluting with ethyl acetate / chloroform ( 3 : 1 ). less polar isomer , mp = 159 - 160 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 90 ( d , j = 9 . 3 hz , 1h ); 7 . 83 ( s , 1h ); 7 . 41 ( d , j = 9 . 3 hz , 1h ); 4 . 95 - 4 . 80 and 4 . 37 - 3 . 95 ( m , 2h ); 2 . 99 and 2 . 87 ( s + s , 3h ); 2 . 20 - 1 . 25 ppm ( s , 8h ). more polar isomer , mp = 131 - 132 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 ( d , j = 9 . 0 hz , 1h ); 7 . 83 ( s , 1h ); 7 . 41 ( d , j = 9 . 0 hz , 1h ); 4 . 65 - 4 . 50 and 3 . 90 - 3 . 37 ( m , 2h ); 3 . 02 and 2 . 89 ( s + s , 3h ); 2 . 20 - 1 . 00 ppm ( s , 8h ). n -( 3 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 38 g , 1 . 38 mmol ) was dissolved in dichloromethane ( 10 ml ) and pcc ( 3 g ) was added and the mixture stirred for 3 h at 20 ° c . the solvent was evaporated onto silica gel and the product chromatographed on silica gel eluting with ethyl acetate / chloroform ( 3 : 1 ) to give the title product as a white solid after trituration with diethyl ether ( 0 . 19 g ). mp = 164 - 165 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , j = 9 . 3 hz , 1h ); 7 . 84 ( s , 1h ); 7 . 40 ( d , j = 9 . 3 hz , 1h ); 4 . 90 - 4 . 67 and 4 . 00 - 3 . 75 ( m , 1h ); 3 . 00 ( sb , 3h ); 2 . 71 - 1 . 30 ppm ( s , 8h ). prepared using the methods described for the preparation of example 40 . mp = 119 - 120 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , j = 9 . 0 hz , 1h ); 7 . 84 ( s , 1h ); 7 . 41 ( d , j = 9 . 0 hz , 1h ); 4 . 80 - 4 . 60 and 3 . 85 - 3 . 70 ( m , 1h ); 2 . 94 ( sb , 3h ); 2 . 40 - 1 . 25 ppm ( s , 8h ). prepared from benzyl ( 2 - oxocyclohexyl ) carbamate using the procedures described for example 51 . only one isomer was observed . mp = 148 - 149 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 92 - 7 . 86 ( m , 2h ); 7 . 51 - 7 . 46 ( m , 1h ); 4 . 50 - 4 . 38 and 3 . 75 - 3 . 35 ( m , 2h ); 3 . 05 and 2 . 94 ( s + s , 3h ); 2 . 42 - 1 . 00 ppm ( s , 8h ). prepared from n -( 2 - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide using the method described fro example 61 . mp = 144 - 145 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 94 - 7 . 74 ( m , 2h ); 7 . 53 - 7 . 30 ( m , 1h ); 5 . 30 - 5 . 20 and 4 . 20 - 4 . 10 ( m , 1h ); 3 . 04 and 2 . 94 ( s + s , 3h ); 2 . 62 - 1 . 50 ppm ( s , 8h ). prepared using the methods described for the preparation of example 40 . mp = 101 - 102 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 95 - 7 . 77 ( m , 2h ); 7 . 48 ( m 1h ); 5 . 10 - 4 . 90 and 3 . 80 - 3 . 60 ( m , 1h ); 3 . 17 and 3 . 03 ( s + s , 3h ); 2 . 30 - 1 . 10 ppm ( s , 8h ). to a solution of 3 - aminopentane - 1 , 5 - diol ( 2 . 38 g , 20 mmol ) ( helv . chim . acta 1964 , 47 ( 8 ), 2145 - 2153 ) and triethylamine ( 4 ml ), in dichloromethane ( 30 ml ), was slowly added , at 0 ° c ., a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid chloride ( 1 . 82 g , 10 mmol ), in dichloromethane ( 20 ml ), and the mixture stirred for 1 h . a mixture of methanol ( 30 ml ) and 4n potassium carbonate solution ( 20 ml ) was added and stirred for 3 h . the mixture was evaporated onto silica gel and purified by silica gel chromatography eluting with ethyl acetate / chloroform / methanol ( 60 : 30 : 10 ) to give , after crystallization from dichloromethane / ethyl acetate / diethyl ether , n -( 1 , 5 - dihydroxypentan - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as a white solid ( mp : 87 - 88 ° c .). n -( 1 , 5 - dihydroxypentan - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 5 g , 1 . 9 mmol ), suspended in chloroform ( 20 ml ), was warmed to 45 ° c . and periodinane ( dess martin reagent ; 1 . 6 g ) added and stirred for 1 h . the reaction mixture was evaporated onto silica gel and purified by chromatography , eluting with ethyl acetate / chloroform ( 60 : 40 ) to give n -( 2 - hydroxytetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 12 g ) as a white solid after trituration with diethyl ether and as the less polar of two components ( rf : 0 . 55 ). mp = 91 - 92 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 22 ( s , 1h ); 7 . 96 - 7 . 81 ( m , 2h ); 7 . 10 - 7 . 00 and 6 . 40 - 6 . 05 ( m , 2h ); 4 . 65 - 4 . 40 ( m , 1h ); 4 . 15 - 3 . 70 ( m , 2h ) and 2 . 15 - 0 . 60 ppm ( m , 4h ). the more polar component ( rf : 0 . 45 ; 0 . 035 g ) was identified as n -( 2 - oxotetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide . mp = 157 - 158 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 42 - 8 . 36 ( m , 1h ); 7 . 95 - 7 . 86 ( m , 2h ); 7 . 74 - 7 . 66 ( m , 1h ); 4 . 77 - 4 . 36 ( m , 3h ); 3 . 02 ( dd , j = 7 . 2 and 17 . 7 hz , 1h ); 2 . 72 ( dd , j = 4 . 5 and 17 . 7 hz , 1h ) and 2 . 38 - 2 . 07 ppm ( m , 2h ). 5 , 6 - dihydro - 2h - pyran - 2 - one ( 1 . 0 g , 10 . 2 mmol ) was dissolved in 3 ml of a 33 % solution of methylamine in ethanol and heated to 55 ° c . overnight . the solvent was evaporated , the residue dissolved in methanol ( 20 ml ) and conc . hcl ( 20 ml ) and the mixture heated at 95 ° c . for 2 . 5 h . the mixture was evaporated to dryness , the residue dissolved in thf ( 20 ml ), dichloromethane ( 20 ml ) and triethylamine ( 3 ml ) and a solution of [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxylic acid chloride ( 2 . 0 g , 11 mmol ), in dichloromethane ( 5 ml ), added . after stirring the mixture for 0 . 75 h , the mixture was washed with 1n hcl and conc . nahco 3 solution , dried over sodium sulfate , and concentrated under vacuum . the residue was purified on a silica gel column using ethyl acetate / hexane / dichloromethane ( 70 : 20 : 10 ), to give n - methyl - n -( 2 - oxotetrahydro - 2h - pyran - 4 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as white solid after crystallization from dichloromethane / methanol ( 0 . 21 g ). mp = 169 - 171 ° c ., 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 97 ( d , j = 9 . 0 hz , 1h ); 7 . 90 ( s , 1h ); 7 . 40 ( d , j = 9 . 0 hz , 1h ); 5 . 10 - 4 . 40 ( m , 3h ); 3 . 01 ( s , 3h ); 3 . 00 - 2 . 74 ( m , 2h ) and 2 . 60 - 2 . 10 ppm ( s , 2h ). to a suspension of n -( 1 , 5 - dihydroxypentan - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( see example 66 ; 0 . 9 g , 3 . 4 mmol ), in chloroform ( 20 ml ), was added a solution of acetic anhydride ( 3 ml ) and pyridine ( 3 ml ), drop wise , at room temperature and the mixture stirred for 2 h . chloroform ( 50 ml ) was added and the mixture washed with 1n hcl and saturated sodium bicarbonate solution , dried ( mgso 4 ) and evaporated . the residue was chromatographed on silica gel , eluting with ethyl acetate / chloroform ( 3 : 2 ), to give n -( 1 , 5 - diacetoxypentan - 3 - yl )-[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as a pale yellow solid . to a solution of preceding di - acetate ( 2 . 4 g , 6 . 8 mmol ), in dmf ( 40 ml ), was added sodium hydride ( 0 . 49 g , 20 mmol ) and the mixture stirred at room temperature for 0 . 25 h . methyl iodide ( 1 . 0 ml ) was added , the mixture heated at 60 ° c . for 0 . 5 h and the solvent evaporated . the residue was dissolved in chloroform ( 100 ml ), washed with 1n hcl and saturated sodium bicarbonate solution , dried ( mgso 4 ) and evaporated . the residue was chromatographed on silica gel to give n -( 1 , 5 - diacetoxypentan - 3 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as a pale brown oil . to a solution of n -( 1 , 5 - diacetoxypentan - 3 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 1 . 37 g , 3 . 8 mmol ), in methanol ( 10 - ml ), was added 10 ml of 3n potassium carbonate solution and the mixture stirred at room temperature for 2 h . the methanol was evaporated under vacuum and the residue dissolved in chloroform ( 100 ml ), washed with 1n hcl and saturated sodium bicarbonate solution , dried ( mgso 4 ) and evaporated . the crude product was chromatographed on silica gel eluting with ethyl acetate / chloroform / methanol ( 1 : 1 : 8 %) to give the diol as a pale yellow solid after trituration with diethyl ether ( 0 . 42 g ). mp = 90 - 91 ° c . n -( 1 , 5 - dihydroxypentan - 3 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide was reacted with periodinane as described for examples 66 and 67 to give n -( 2 - hydroxytetrahydro - 2h - pyran - 4 - yl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as a pale yellow solid . mp =& lt ; 90 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 7 . 92 ( d , j = 9 hz , 1h ); 7 . 85 ( s , 1h ), 7 . 41 ( d , j = 9 hz , 1h ); 6 . 40 - 6 . 05 ( m , 1h ); 5 . 20 - 4 . 75 ( m , 1h ); 4 . 20 - 3 . 60 ( m , 3h ), 3 . 10 - 2 . 80 ( m , 3h ), and 2 . 25 - 1 . 50 ppm ( m , 4h ). to a solution of n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 55 g , 2 . 0 mmol ) in dmf ( 10 ml ) was added n , n - dimethyl glycine ( 0 . 52 g , 5 . 0 mmol ), dmap ( 0 . 244 g , 2 . 0 mmol ), hobt ( 0 . 27 g , 2 . 0 mmol ) and edci ( 1 . 15 g , 6 . 1 mmol ) and the mixture heated at 45 ° c . overnight . the solvent was evaporated under vacuum and the residue dissolved in chloroform ( 100 ml ) washed with water , dried ( mgso 4 ) and evaporated . the crude product was chromatographed on silica gel eluting with ethyl acetate / chloroform / methanol ( 1 : 1 : 10 %) to give as a white solid , mp = 174 - 175 ° c . the product was dissolved in 4n hcl in dioxane and then evaporated to dryness to give the hydrochloride salt . mp = 252 - 253 ° c ., 1 h nmr ( 300 mhz , d 2 o , 2 - rotamers ) δ 8 . 03 - 7 . 99 ( m , 2h ), 7 . 52 - 7 . 49 ( m , 1h ), 4 . 43 - 4 . 34 ( m , 0 . 5h ), 4 . 10 and 4 . 03 ( s , 3h ), 3 . 60 - 3 . 40 ( m , 0 . 5h ), 3 . 02 - 2 . 91 ( m , 9h ), and 2 . 22 - 1 . 20 ppm ( m , 8h ). to a solution of n -( tert - butoxycarbonyl )- l - alanine ( 0 . 38 g , 2 . 0 mmol ) in chloroform ( 20 ml ) was added cdi ( 0 . 32 g , 2 mmol ) and the mixture stirred at room temperature for 1 . 5 h . n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 55 g , 2 . 0 mmol ) was added and the mixture stirred overnight . water ( 50 ml ) was added and sulfuric acid (→ ph 2 ) and extracted with dichloromethane ( 2 × 70 ml ). the combined organics was washed with sodium bicarbonate solution ( 50 ml ), dried ( naso 4 ) and evaporated . the residue was chromatographed on silica gel eluting with ethyl acetate / hexane ( 70 : 30 ) to give the product as a foam ( 0 . 55 g ). this material was dissolved in chloroform ( 20 ml ), tfa ( 3 ml ) added , and the mixture stirred for 1 h . the solvent was evaporated and chloroform ( 30 ml ) and 4n hcl in dioxane ( 3 ml ) were added . the solvent was evaporated to give the title compound as a colorless oil that solidified on standing to give a low melting solid ( 0 . 59 g ). 1 h nmr ( 300 mhz , d 2 o , 2 - rotamers ) δ 8 . 03 - 7 . 98 ( m , 2h ), 7 . 52 - 7 . 49 ( m , 1h ), 4 . 94 - 4 . 64 ( m , 1h ), 4 . 43 - 4 . 34 ( m , 0 . 5h ), 4 . 20 - 4 . 10 and 4 . 10 - 4 . 00 ( q , j = 7 . 2 hz , 1h ), 3 . 60 - 3 . 44 ( m , 0 . 5h ), 3 . 01 and 2 . 90 ( s , 3h ), and 2 . 20 - 1 . 20 ( m , 8h ), 1 . 55 and 1 . 45 ppm ( d , j = 7 . 2 hz , 3h ). prepared from intermediate 2 and ( r )-(+)- tetrahydro - 3 - furylamine p - toluenesulphonate in a similar manner to that described for the preparation of example 1 . the title compound was isolated as a white solid following re - crystallization from diethyl ether / ethyl acetate . mp = 157 - 158 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 20 ( s , 1h ), 7 . 92 ( dd , j = 1 . 2 and 9 . 3 hz , 1h ), 7 . 82 ( dd , j = 1 . 2 and 9 . 3 hz , 1h ), 6 . 48 ( br s , 1h ), 4 . 60 - 4 . 64 ( m , 1h ), 4 . 10 - 3 . 80 ( m , 4h ), 2 . 50 - 2 . 38 ( m , 1h ), 2 . 03 - 1 . 94 ppm ( m , 1h ). prepared from n —( r )- tetrahydrofuran - 3 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide using the method described for example 16 . the title compound was isolated as a pale yellow oil . 1 h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 93 ( d , j = 9 . 3 hz , 1h ), 7 . 84 ( s , 1h ), 7 . 42 ( d , j = 9 . 3 hz , 1h ), 5 . 5 - 5 . 25 ( m , 0 . 5h ), 4 . 56 - 4 . 30 ( m , 0 . 5h ), 4 . 18 - 3 . 5 ( m , 4h ), 3 . 16 - 2 . 90 ( br s , 3h ), 2 . 52 - 1 . 90 ppm ( m , 2h ). the title compound was prepared from n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as described for example 71 and isolated as an off white solid . mp = 245 - 246 ° c . ( dec ), 1 h nmr ( 300 mhz , d 2 o , rotamers ) δ 8 . 05 ( d , j = 9 . 3 hz , 1h ), 8 . 00 ( s , 1h ), 7 . 51 ( dd , j = 2 . 5 and 9 . 3 hz , 1h ), 4 . 98 - 4 . 64 ( m , 1h ), 4 . 48 - 4 . 37 and 3 . 60 - 3 . 44 ( m , total 1h ), 3 . 92 and 3 . 82 ( s , total 2h ), 3 . 02 and 2 . 92 ( s , total 3h ), 2 . 03 - 1 . 20 ppm ( m , 8h ). prepared from intermediate 1 and 4 -( 2 - aminoethyl ) morpholine using the method described for example 1 and isolated as a white crystalline solid . mp = 145 - 148 ° c ., 1 h nmr ( 300 mhz , cdcl 3 ) δ 8 . 19 ( br s , 1h ), 7 . 93 ( dd , j = 1 . 2 and 9 . 3 hz , 1h ), 7 . 85 ( dd , j = 1 . 5 and 9 . 3 hz , 1h ), 6 . 92 ( br s , 1h ), 3 . 77 - 3 . 73 ( m , 4h ), 3 . 62 - 3 . 56 ( m , 2h ), 2 . 64 ( t , j = 5 . 8 hz , 2h ), 2 . 55 - 2 . 51 ppm ( m , 4h ). prepared from n - 2 -( 4 - morpholinyl ) ethyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide using the method described for example 16 . the hydrochloride salt was isolated as an off white solid . mp = 210 - 212 ° c ., 1 h nmr ( 300 mhz , d 2 o ) δ 8 . 12 ( s , 1h ), 8 . 05 ( d , j = 9 . 4 hz , 1h ), 7 . 59 ( d , j = 7 . 4 hz , 1h ), 4 . 57 - 4 . 18 ( m , 2h ), 4 . 03 ( t , j = 6 . 3 hz , 2h ), 4 . 00 - 3 . 40 ( m , 6h ), 3 . 59 ( t , j = 6 . 3 hz , 2h ), 3 . 13 ppm ( s , 3h ). the title compound was prepared from n - methyl - n - tetrahydro - 2h - pyran - 4 - yl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide using the procedure described for example 54 and isolated as a yellow solid . mp = 174 - 175 ° c ., h nmr ( 300 mhz , cdcl 3 , rotamers ) δ 7 . 89 and 7 . 86 ( dd , j = 1 . 2 and 9 . 3 hz , total 1h ), 7 . 58 ( d , j = 1 . 2 hz , 1h ), 7 . 36 and 7 . 33 ( dd , j = 1 . 5 and 9 . 3 hz , total 1h ), 5 . 78 - 5 . 64 ( m , 0 . 5h ), 4 . 20 - 3 . 04 ( m , 2 . 5h ), 3 . 63 - 3 . 55 ( m , 1h ), 3 . 48 and 3 . 08 ( s , total 3h ), 3 . 20 - 3 . 14 ( m , 1h ), 2 . 17 - 1 . 54 ppm ( m , 4h ). the title compound was prepared from n -( 4 - trans - hydroxycyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide as described for example 71 and isolated as a white solid . mp = 257 - 258 ° c . ( dec ), 1 h nmr ( 300 mhz , d 2 o , rotamers ) δ 8 . 06 - 7 . 93 ( m , 2h ), 7 . 53 - 7 . 47 ( m , 1h ), 4 . 94 - 4 . 70 ( m , 1h ), 4 . 43 - 4 . 35 and 3 . 60 - 3 . 46 ( m , total 1h ), 4 . 00 and 3 . 89 ( d , j = 3 . 6 hz , total 1h ), 3 . 02 and 2 . 91 ( s , total 3h ), 2 . 43 - 1 . 62 ( m , 8h ), 1 . 40 - 1 . 20 ( m , 1h ), 1 . 10 - 0 . 92 ppm ( m , 6h ). to a solution of n -( trans - 4 - hydroxy - 4 - methylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 7 g , 2 . 4 mmol ) in chloroform ( 10 ml ), at 0 ° c ., was added dimethylaniline ( 0 . 44 g , 3 . 6 mmol ) and then chloroacetyl chloride ( 0 . 23 ml , 2 . 9 mmol ), and the mixture warmed to room temperature and stirred overnight . the reaction mixture was washed with 1n hcl and sodium bicarbonate solution , dried over mgso 4 and evaporated . the residue was chromatographed on silica gel eluting with ethyl acetate / chloroform ( 5 : 2 ) to give the chloro acetyl adduct . dimethylamine ( 3 ml of a 33 % solution in methanol ) was added to a solution of the preceding product ( 0 . 275 g , 0 . 75 mmol ), in chloroform ( 15 ml ), and the mixture stirred at room temperature overnight . the mixture was evaporated and the residue was partitioned between chloroform and water and the organic layer washed with sodium bicarbonate solution , dried ( mgso 4 ) and evaporated . the residue was purified by chromatography on silica gel eluting with ethyl acetate / chloroform / methanol ( 1 : 1 . 5 : 7 %). the hydrochloride salt was prepared by adding a mixture of 4n hcl in dioxane to a solution of the product in chloroform . the solvents were removed under vacuum and the product re - crystallized from methanol / diethyl ether to give the title compound ( 0 . 13 g ) as an off white solid . mp = 201 - 202 ° c ., 1 h nmr ( 300 mhz , d 2 o , 2 - rotamers ) δ 8 . 07 ( d , j = 9 . 3 hz , 1h ), 8 . 02 ( s , 1h ), 7 . 53 ( d , j = 9 . 3 hz , 1h ), 4 . 45 - 4 . 37 and 3 . 63 - 3 . 50 ( both m , total 1h ), 4 . 09 and 4 . 00 ( both s , total 2h ), 3 . 05 , 3 . 00 , 2 . 95 and 2 . 91 ( all s , total 9h ), 2 . 40 - 1 . 56 ( m , 8h ), 1 . 69 and 1 . 63 ppm ( both s , total 3h ). methyl tetrahydro - 2h - pyran - 4 - carboxylate ( 5 ml , 40 . 0 mmol ) was added to a solution of methylamine ( generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets ) in thf ( 30 ml ) and the mixture heated at 110 ° c . in a bomb reactor overnight . the solvents were evaporated , the residue dissolved in thf ( 100 ml ), and liah 4 ( 4 . 6 g , 121 mmol ) added , and the mixture heated at 70 ° c . for 1 h . the mixture was cooled to 0 ° c ., concentrated naoh solution added and the thf evaporated . chloroform ( 100 ml ) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give n - methyl - n - tetrahydro - 2h - pyran - 4 - ylmethylamine as a pale brown oil . the preceding amine ( ig , 7 . 8 mmol ) was dissolved in dichloromethane ( 50 ml ), and triethylamine ( 4 ml ) and [ 2 , 1 , 3 ]- benzoxadiazole - 5 - carbonylchloride ( 1 . 7 g , 9 . 3 mmol ), as a solution in dichloromethane ( 20 ml ), were added , slowly . the mixture was stirred at room temperature for 1 h , the mixture washed with 1n hcl ( 20 ml ), and saturated sodium bicarbonate solution ( 20 ml ), dried ( mgso 4 ) and evaporated . the residue was purified by silica gel chromatography eluting with ethyl acetate / chloroform ( 3 : 1 ) to give the title compound as a pale brown oil . 1 h nmr ( 300 mhz , cdcl 3 , 2 - rotamers ) δ 7 . 93 ( d , j = 9 . 3 hz , 1h ), 7 . 83 ( br s , 1h ), 7 . 38 - 7 . 45 ( m , 1h ), 4 . 10 - 3 . 90 ( m , 2h ), 3 . 52 - 3 . 20 ( m , 4h ), 3 . 13 and 3 . 05 ( both s , total 3h ), 2 . 18 - 1 . 80 ( m , 1h ), 1 . 73 - 1 . 40 ppm ( m , 4h ). n -( trans - 4 - hydroxy - 4 - methylcyclohexyl )- n - methyl -[ 2 , 1 , 3 ]- benzoxadiazole - 5 - carboxamide ( 0 . 49 g , 2 . 0 mmol ) was suspended in thf ( 40 ml ) and dimethylaniline ( 0 . 3 ml , 2 . 2 mmol )) was added . the mixture was heated at 70 ° c . for 0 . 1 h before adding bromoacetyl bromide ( 0 . 2 ml , 2 . 4 mmol ) and stirring at 70 ° c . for 3 h . the mixture was cooled to room temperature before adding chloroform ( 50 ml ) and washing with water ( 50 ml ), 1 n hcl ( 25 ml ) and saturated sodium bicarbonate solution ( 25 ml ). the organic was dried over mgso 4 , evaporated and the residue purified by chromatography on silica gel eluting with ethyl acetate / chloroform ( 1 : 1 ) to give the bromo acetyl derivative as a white solid ( 0 . 63 g , 76 %; mp = 133 - 134 ° c .). to a solution of the preceding acetyl bromide ( 0 . 61 g , 1 . 5 mmol ) in dmf ( 8 ml ) was added sodium azide ( 0 . 59 g , 9 mmol ) and the mixture heated at 50 ° c . for 3 h . the dmf was removed under vacuum and the residue partitioned between chloroform and water . the chloroform extract was washed with 1n hcl and saturated sodium bicarbonate solution , dried ( mgso 4 ) and evaporated to give the desired azide . to this material ( 0 . 56 g , 1 . 5 mmol ) was added pyridine ( 5 ml ) and triphenyl phosphine ( 0 . 63 g , 2 . 4 mmol ) and the mixture stirred at room temperature for 0 . 5 h ) before adding conc n ammonium hydroxide solution ( 10 ml ) and stirring for a further 2 h at room temperature . the pyridine was removed under vacuum and the o0 residue was purified by chromatography on silica gel eluting with ethyl acetate / hexane ( 1 : 1 ) followed by chloroform / methanol / triethylamine ( 90 : 10 : 3 ) to give trans - 4 -[( 2 , 1 , 3 - benzoxadiazol - 5 - ylcarbonyl )( methyl ) amino ]- 1 - methylcyclohexyl glycinate as a yellow solid ( 0 . 42 g ). the hydrochloride salt was prepared as described previously and was isolated as a white solid . mp = 188 - 189 ° c . 1 h nmr ( 300 mhz , d 2 o , 2 - rotamers ) δ 8 . 05 ( d , j = 9 . 3 hz , 1h ), 7 . 99 ( s , 1h ), 7 . 50 ( d , j = 9 . 3 hz , 1h ), 4 . 45 - 4 . 37 and 3 . 63 - 3 . 50 ( both m , total 1h ), 3 . 84 and 3 . 71 ( both s , total 2h ), 3 . 03 and 2 . 93 ( both s , total 3h ), 2 . 40 - 1 . 56 ( m , 8h ), 1 . 66 and 1 . 59 ppm ( both s , total 3h ). the electrophysiological effects of invention compounds were tested in vivo in anesthetized animals according to the following procedures . animals are maintained under anesthesia by phenobarbital administered using a hamilton syringe pump . stimulating and recording electrodes are inserted into the perforant path and dentate gyrus of the hippocampus , respectively . once electrodes are implanted , a stable baseline of evoked responses are elicited using single monophasic pulses ( 100 μs pulse duration ) delivered at 3 / min to the stimulating electrode . field epsps are monitored until a stable baseline is achieved ( about 20 - 30 min ), after which a solution of test compound is injected intraperitoneally and evoked field potentials are recorded . evoked potentials are recorded for approximately 2 h following drug administration or until the amplitude of the field epsp returns to baseline . in the latter instance , it is common that an iv administration is also carried out with an appropriate dose of the same test compound . male cd1 mice , 25 - 30 gm body weight , were brought into the experimental room and allowed at least 30 min of acclimation . each mouse was placed into the testing enclosure with an infrared beam array that automatically monitors the animal &# 39 ; s activity . mice were habituated in the testing enclosure for 20 min , and then returned to their home cage . mice were dosed intraperitoneally with test compound in appropriate vehicle 5 minutes before d - amphetamine injection . ten minutes after d - amphetamine injection , mice were tested for locomotor activity for a total of 15 minutes . the data was computer collected and expressed as “ arbitrary movement units .” all data were analyzed by comparing the groups treated with the test compound to the vehicle control group . statistical analysis was performed by anova followed by dunnet &# 39 ; s t - test where p less than 0 . 05 were considered to be significantly different . while the invention has been described with reference to specific methods and embodiments , it will be appreciated that various modifications may be made without departing from the invention .

this invention relates to compounds , pharmaceutical compositions and methods for use in the prevention and treatment of cerebral insufficiency , including enhancement of receptor functioning in synapses in brain networks responsible for basic and higher order behaviors . these brain networks , which are involved in regulation of breathing , and cognitive abilities related to memory impairment , such as is observed in a variety of dementias , in imbalances in neuronal activity between different brain regions , as is suggested in disorders such as parkinson &# 39 ; s disease , schizophrenia , respiratory depression , sleep apneas , attention deficit hyperactivity disorder and affective or mood disorders , and in disorders wherein a deficiency in neurotrophic factors is implicated , as well as in disorders of respiration such as overdose of an alcohol , an opiate , an opioid , a barbiturate , an anesthetic , or a nerve toxin , or where the respiratory depression results form a medical condition such as central sleep apnea , stroke - induced central sleep apnea , obstructive sleep apnea , congenital hypoventilation syndrome , obesity hypoventilation syndrome , sudden infant death syndrome , rett syndrome , spinal cord injury , traumatic brain injury , cheney - stokes respiration , ondines curse , prader - willi &# 39 ; s syndrome and drowning . in a particular aspect , the invention relates to compounds useful for treatment of such conditions , and methods of using these compounds for such treatment .

the finished products of the present invention may be wafers , tablets , granules , powders or liquids . tablets or wafers weighing about 100 to 150 mgs are preferred and may be of any size appropriate for oral administration . the compositions of this method may also be introduced into the body by other routes of administration . the disclosed carrier compositions may range in weight from about 1 / 2 gram to about 1200 mgs or more . the preferred method comprises the following steps : ( 1 ) mix the following ingredients together : about 1 gram of flavored gelatin powder or other gelatin - based equivalent , about 2 grams of maltodextrose , about 0 . 5 gram of gelatin a ; about 2 grams of sucrose , optionally for palatability , and as preferred , about 1 gram , or other desired dosage , of flavoring agents or sweeteners , such as aspartane ®. the quantities may be adjusted as preferred by the formulator . after mixing these components , add coacervate phase water in an amount that will make a final volume of about 100 ml ., ( 2 ) heat while stirring the product of step ( 1 ) to about 60 ° c . or until the product becomes a visually clear solution . next , ( 3 ) cool the product of step 2 to about 37 ° c . or less but preferably short of freezing , ( 4 ) following step 3 , the required quantity of the nutrient , drug or other active component is dispersed in the product of step 3 . as preferred , one or more flavoring agents may be added to the product of step 3 at the same time the drug component has been mixed into the product of step 3 ( 5 ). next , rinse the molds to be used in forming the composition with any pharmaceutically acceptable coating liquid or lubricant , for example a solution of about 10 % of a phospholipid , such as lecithin , in grain alcohol of about 150 - 190 proof . ( 6 ) allow the molds to dry at ambient temperature . ( 7 ) next , fill each compartment of the mold with that quantity of the product of step 4 as will give the desired unit does in each finished wafer or tablet as preferred . ( 8 ) store the product of step 7 at a temperature of 0 ° c . or lower for about 30 - 60 minutes or until the molded product ( e . g . wafer or tablet ) is frozen solid . temperatures of about - 20 ° c . to about - 30 ° c . are preferred . ( 9 ) next , on completion of step 8 , the frozen semi - finished product is removed from the mold . at the option of the formulator , any one step or combination of process steps 1 through 8 and the related optional steps may be repeated to produce a semi finished product comprised of any number of layers as preferred by the formulator . the frozen tablets are removed from the mold and contacted with a suitable anhydrous alcohol , e . g . ethyl alcohol , such as by immersion therein , preferably in an airtight ( hermetically sealed ) container , step ( 10 ), as follows : the weight ratio of alcohol to the product can be approximately at least 10 : 1 alcohol to product , but is preferably about 40 : 1 . this ratio may be adjusted as desired by the formulator . next , place the product of step 8 in a suitable fluid - permeable container , e . g . a plastic container which may be a fine mesh plastic bag or a plastic bottle containing multiple holes of 0 . 5 mm or less or more and immerse in a container of anhydrous ethyl alcohol maintained at a temperature of - 15 ° c . or lower . the water content of the alcohol can be measured before this step . step 10 continues until the water content of the alcohol is about 2 . 5 % or more . the process of step 9 is repeated using a fresh supply of anhydrous alcohol until about 100 % of the water has been removed from the dosage form formulation . next , optionally , place the tablets or wafers resulting from step 10 on blotting paper and transfer quickly to a vacuum chamber . ( 11 ) optionally vacuum dry the product of step 10 at ambient temperature until no odor of the ethyl alcohol remains . ( 12 ) a desired quantity of the drug component then is added by means of a pipette to the surface of each wafer or tablet after vacuum drying . another method is as follows : ( 1 ) mix the following ingredients together : about 1 gram of flavored gelatin powder or other gelatin - based equivalent , about 2 grams of maltodextrose , about 0 . 5 gram of gelatin a ; about 2 grams of sucrose , optionally for palatability , and as preferred , about 1 gram , or other desired dosage , of flavoring agents or sweeteners , such as aspartane ®. the quantities may be adjusted as preferred by the formulator . after mixing these components , add distilled water in an amount that will make a final volume of about 100 ml ., ( 2 ) heat while stirring the product of step 1 to about 60 ° c . or until the product becomes a visually clear solution . next , ( 3 ) cool the product of step 2 to about 37 ° c . or less but preferably short of freezing , ( 4 ) rinse the molds to be used in forming the tablets of this method with any pharmaceutically acceptable coating liquid or lubricant , for example a solution of about 10 % of a phospholipid , such as lecithin , in 190 proof grain alcohol . ( 5 ) allow the molds to dry at ambient temperature . next , ( 6 ) fill each compartment of the mold with about 1 ml of the product of step 3 . ( 7 ) store the product of step 6 at a temperature of 0 ° c . or lower for about 30 minutes or until the molded product ( tablet ) is frozen solid . ( 8 ) remove the product of step 7 from storage and add that quantity of the drug , nutrient or combinations of each , preferably in powder or liquid form , e . g ., as an aqueous solution , as preferred by the formulator , to the surface of each tablet within the mold . during this step , the product should be protected from thawing . it is preferred that the product of step 8 is further processed with step ( 9 ) which comprises the following : remove the product of step 8 from storage and add from about 0 . 5 to about 3 mls of the product of step 1 to the upper surface of each frozen tablet in the mold . ( 10 ) refrigerate the product of step 9 for about 30 minutes or more at 0 ° c . or lower . at the conclusion of step 10 , if preferred , the product is removed from refrigeration and one or more flavoring agents are added to the surface of each frozen tablet in an amount ranging from a trace amount to one drop or more according to the preference of the formulator . at this point , the product comprises a semi - finished frozen tablet comprising of three layers . at the option of the formulator , any one step or combination of process steps 1 through 8 and the related optional steps may be repeated to produce a semi finished product comprised of any number of layers as preferred by the formulator . on completion of step 10 the frozen tablets are removed from the mold and contacted with a suitable liquid organic desiccant , e . g . anhydrous ethyl alcohol , such as by immersion therein , preferably in an airtight container , step ( 11 ), as follows : the weight ratio of alcohol to the product can be approximately at least 10 : 1 alcohol to product , but is preferably about 30 : 1 to about 50 : 1 , e . g . about 40 : 1 . this ratio may be adjusted as desired by the formulator . next , place the product of step 10 in a suitable plastic container which may be a fine mesh plastic bag or a plastic bottle containing multiple holes of 0 . 5 mm or less or more and immerse in a container of anhydrous ethyl alcohol maintained at a temperature of - 15 ° c . or lower . the water content of the alcohol can be measured before this step . step 11 continues until the water content of the alcohol is about 2 . 5 % to about 5 % by weight . the process of step 11 is repeated using a fresh supply of anhydrous alcohol until about 100 % of the water has been removed from the dosage form formulation . next , ( 12 ) place the tablets resulting from step 11 on blotting paper and transfer quickly to a vacuum chamber . ( 13 ) vacuum dry the product of step 11 at ambient temperature until no odor of the ethyl alcohol remains . in accordance with another important embodiment of the present invention , ( 14 ) the desired dose of the drug component is added by means of a pipette to the surface of each tablet after the product has been vacuum dried . in accordance with another important embodiment of the present invention to produce the porous carrier materials , the hydrated composition of gel or foam material and gel or foam material rigidifying agent preferably in a frozen state , are spread on a preformed sheet . the sheet then is placed in a suitable freezer chest , preferably manufactured of porcelain . a container of anhydrous ethyl alcohol also is placed in the freezer chest in a weight ratio of at least 10 : 1 alcohol to wet product , e . g ., 40 : 1 . the temperature of the interior of the chest is maintained at the temperature ranging from about 0 ° c . to about - 15 ° c . or lower . the transfer of water from the starting materials to the alcohol is continued until about 90 % to about 100 % of the solvent is transferred from the starting material to the anhydrous ethyl alcohol . the alcohol is replaced as required to complete the process of water removal . the processed material then is removed from the alcohol and dried by any pharmaceutically acceptable method to remove any alcohol which is present in the composition . the resulting product comprises a porous solid suitable for purposes of oral delivery of drugs , nutrients and the like . the product may be in tablet , powder or granular form , or reconstituted with water or other solvents for a liquid product . the preferred procedure to add the drug or nutrient component to the porous solid delivery compositions described above is as follows : the component to be added is dissolved in any appropriate solvent including organic solvents . the dissolved drug is added dropwise by means of a hypodermic syringe or other similar device to the surface of the delivery compositions in that amount that will give the desired dose to each product unit . the porous solid , its spaces now containing the drug or nutrient , then is dried using any conventional drying method to remove all traces of the solvent used in the formulation step . as preferred , the drug or nutrient component can be added to the interim product during early stages of preparing the porous solids . as preferred by the formulator , any flavoring agent may be added to the product by placing the agent in solution and adding that quantity of the flavoring agent that is preferred to the surface of the product by means by a hypodermic syringe or other similar device . to prepare a granular form of the composition , the finished product is processed with a rotating granulator or other similar grinding equipment . to prepare the powder form of this invention , a fine wire mesh with openings ranging from about 50 to 300 microns is used in place of the blister mold used to form tablets or wafers . the steps described to produce the tablet dosage form then are followed to produce a powder delivery form . the starting materials of this method comprise the following compositions or combinations thereof : any pharmaceutically acceptable gel or foam materials prepared from any surfactant , synthetic or biological , particularly proteinaceous materials such as gelatin , including types a and b fluid gelatin and gelatin derivatives and albumin . other suitable gel or foam forming compounds of biological or synthetic origin , used singly or in combination , include phospholipids , singly or in combination , particularly lecithin and coacervate egg lecithin . suitable rigidifying agents for such gels , hydrogels , and foam - forming materials include dextran and dextran derivatives , such as maltodextran ; carbohydrates including the mono -, di -, and other polysaccharides . the monosaccharides include without limitation , dextrose , fructose and galactose and the sugar alcohols mannitol , xylitol and sorbitol ; the disaccharides include without limitation sucrose , lactose and maltose . oligosaccharides include polymers of the monosaccharide sugars , polysaccharides include dextrans having molecular weights ranging from 40 , 000 to 90 , 000 . the amount of rigidifying agent is an amount sufficient to rigidity the gel or foam material , generally about 0 . 1 to 5 times the weight of the gel or foam forming material ( dry basis ). the liquid , anhydrous organic desiccants used for dehydration include any organic solvent without limitation that will dissolve ice at about 0 ° c . or less , including acetone and the alcohols but especially ethyl alcohol about 150 to 200 proof ; about 200 proof is preferred . as preferred , any pharmaceutically acceptable flavoring agent or combinations of such agents , including natural and synthetic flavoring agents , such as aspartane ® and flavor enhancing agents , such as the commercial product veltol ® ( pfizer ); preservatives such as methyl paraben , propyl paraben and combinations thereof . the oral delivery compositions of the present invention are useful to administer drugs in each of the following categories : drugs acting on the central nervous system ; drugs acting at synaptic and neuroeffector sites ; autacoids , cardiovascular drugs ; drugs affecting renal function and electrolyte metabolism ; drugs effecting uterine motility ; antibiotic drugs ; anti - fungal drugs ; antineoplastic drugs ; drugs acting on blood and blood forming organs and hormones . nutrients that are useful for oral delivery in accordance with the present invention include water - soluble vitamins , such as the b vitamins and vitamin c ; water soluble trace elements such as copper , selenium , calcium , chromium , zinc , magnesium and iron ; electrolytes without limitations including sodium , potassium , magnesium , calcium , lithium , ammonium , phosphorous , chloride , iodide , bromide , fluoride , acetate , sulfate , carbonate , phosphate , lactate , gluconate and lactobionate ; also carbohydrates ; amino acids including leucine , isoleucine , lysine , methione , phenylalanine , threonine , tryptophan , valine , alanine , arginine , histidine , proline , serine , tyrosine , glycine , taurine and carnitine , as the l -, d - and racemic forms but particularly the l - acids and branched chain amino acids ; also keto - analogs of all of the above listed amino acids ; partial hydrolysates of proteins and oligo and poly - peptides of synthetic origin ; also phospholipids without limitation . as an option , antioxidants , preferably a tocopherol , may be included in formulations of this invention which deliver nutrients . to prepare freeze dry compositions of food , the following preferred process is used . ( 1 ) freeze a unit of the food composition , e . g ., whole milk , at 0 ° c . or below until the unit is converted into a frozen solid . ( 2 ) next , dehydrate the frozen milk in an airtight container using anhydrous alcohol preferably in a weight ratio of alcohol to frozen milk of at least about 10 : 1 to achieve fast dehydration , as follows : place the product of step 1 in a suitable fluid - permeable container , e . g . a plastic container which may be a fine mesh plastic bag or a plastic bottle containing multiple holes of 0 . 5 mm or less and immerse in a container of anhydrous ethyl alcohol maintained at a temperature of about - 15 ° c . or below . the water content of the alcohol can be measured before this step . step 2 continues until the water content of the alcohol is about 2 . 5 % or more . the process of step 2 is repeated using a fresh supply of anhydrous alcohol . the process continues until about 100 % of the water ( ice ) has been removed from the frozen milk . ( 3 ) next , optionally , place the dehydrated frozen milk , e . g ., in wafer or tablet form , resulting from step 2 on blotting paper and transfer quickly to a vacuum chamber . ( 4 ) optionally vacuum dry the product of step 3 at ambient temperature until no odor of the ethyl alcohol remains . completion of step 4 produces a finished powdered product of freeze dried milk , a dry foodstuff . this product has the flavor of the natural product but has improved stability and an extended shelf life extending to 1 year or more . to improve the stability and dispersibility of drug formulations , the following process is used . ( 1 ) prepare a slurry of the desired drug using any liquid as the solvent , i . e ., water , glycerin , and the like . water is preferred , particularly coacervate phase water . in the instance of water - insoluble drugs , coacervate phase water or a suspension of the drug in water may be used . ( 2 ) place the composition of step 1 in a suitable fluid - permeable container and follow the procedures of steps 2 , 3 , and 4 described above with reference to the processing of frozen milk . the finished product comprises the desired drug in powdered form which may be placed in liquid or solid form and administered or stored . if packed under vacuum conditions , the shelf life of the drug may extend to 3 years or more . mix the following ingredients together : 1 gram of flavored gelatin powder , 2 grams of maltodextran , 0 . 5 gram of gelatin a ; 2 grams of sucrose and 1 gram of aspartane ®. after mixing these components , add distilled water in an amount that will make a final volume of about 100 ml . stir and heat the product to 60 ° c . ; continue this step until it comprises a clear solution . next cool the product to 37 ° c . prepare blister molds to make the porous tablets by first rinsing the molds with a 10 % solution of lecithin in 190 proof grain alcohol . following the rinsing step , and dry the mold at ambient temperature . fill each compartment in the mold with 3 mls of the solution described immediately above . next , store the product at a temperature of - 10 ° c . or lower for 40 minutes . remove the product from storage and add 300 mgs of powdered acetominophen to the surface of each tablet within the mold . during this step , the product must be protected from thawing . the product is then stored under refrigeration at - 10 ° c . for 40 minutes . next , remove the product from storage and add 3 mls of the gelatin - based solution described above to the upper surface of each frozen tablet in the mold . refrigerate the product for 40 minutes at - 10 ° c . transfer the frozen tablets from the mold to a mesh plastic bag . immerse the bag and its contents in a hermetically sealed container of anhydrous ethyl alcohol maintained at a temperature of - 20 ° c . the immersion step continues until tests reveal that the tablets are completely dehydrated . replace the alcohol with fresh supplies of anydrous alcohol as required to facilitate dehydration . continue this step until no odor or other evidence of alcohol can be detected . on completion of this step , the composition comprises a finished product . example 2 follows the procedure of example 1 except that 250 mgs of powdered erythromycin is used in place of acetominophen . example 3 follows the procedure of example 1 except that aspartane ® is not used and the refrigeration temperatures are - 20 ° c . rather than - 10 ° c . example 4 follows the procedure of example 1 except that all the formulation steps are repeated prior to the immersing the product in anydrous ethyl alcohol . the finished product will comprise a six layer tablet . the method of example 1 is followed except that 300 mgs of acetominophen is mixed into the gelatin based solution after it has cooled . the step of adding acetominophen to the surface of the frozen interin product is omitted . the method of example 1 is followed except that 300 mgs of acetominophen is added to the cooled gelatin - based solution . the finished product of this example contains 600 mgs of acetominophen . the method of example 1 is followed except that two drops of cherry flavoring is added by pipette to the surface of each formed tablet . the method of example 1 is followed except that the finished tablets are processed by a granulator to produce a granular porous solid dosage form . the method of example 1 is followed except that a fine plastic mesh is used in place of the blister mold . the finished product comprises a powder form of the claimed composition . the method of example 1 is followed except that the following minerals are added to the cooled gelatin - based solution : iodine 150 mg ; calcium , 1 mg ; magnesium 400 mg ; manganese 3 mg ; iron 18 mg ; copper 2 mg , zink 15 mg ; and phosphorous , 1 gm . store the product at 33 ° c . to give a slurry - like consistency to the product . following the first freezing step , a composition comprised of 500 mgs of vitamin c , 15 units of vitamin e ; 15 mg of vitamin b 1 ; 17 mg vitamin b 2 ; 100 mg niacin ; 25 mg vitamin b 6 ; 12 mg vitamin b 12 , and 25 mg pantothenic acid is added to the surface of each semi - finished frozen tablet . the remaining processing steps of example 1 are used as given . the step in example 1 in which the drug is added is not used in this example . in addition , this example illustrates a method wherein two groups of compositions which are incompatible from a manufacturing point of view can be prepared in a single tablet . the method of example 1 is followed except that the step in which acetominophen is added is not used . in this example , 3 . 5 grams of vivonex ® ( norwich - eaton ) is mixed into the cooling gelatin based solution and stored under refrigeration at 35 ° c . to give a slurry - like consistency to the product . the blister molds are filled with 25 mls of this composition . ( 1 ) mix the following ingredients together : about 1 gram of flavored gelatin powder or other gelatin - based equivalent , about 2 grams of maltodextrose , about 0 . 5 gram of gelatin a ; about 2 grams of sucrose , optionally for palatability , and as preferred , about 1 gram , or other desired dosage , of flavoring agents or sweeteners , such as aspartane ®. the quantities may be adjusted as preferred by the formulator . after mixing these components , add distilled water in an amount that will make a final volume of about 100 ml ., ( 2 ) heat while stirring the product of step 1 to about 60 ° c . or until the product becomes a visually clear solution . next , ( 3 ) cool the product of step 2 to about 37 ° c . or less but preferably short of freezing , ( 4 ) following step 3 , 300 mgs of acetominophen is dispersed in the product of step 3 . as preferred , one or more flavoring agents may be added to the product of step 3 at the same time the drug component has been mixed into the product of step 3 . ( 5 ) next , rinse the molds to be used in forming the composition with any pharmaceutically acceptable coating liquid or lubricant , for example a solution of about 10 % of a phospholipid , such as lecithin , in grain alcohol of about 150 - 190 proof . ( 6 ) allow the molds to dry at ambient temperature . ( 7 ) next , fill each compartment of the mold with that quantity of the product of step 4 that will give the desired unit dose in each finished wafer or tablet as preferred . ( 8 ) store the product of step 7 at a temperature of 0 ° c . or lower for about 30 - 60 minutes or until the molded product ( e . g . wafer or tablet ) is frozen solid . temperatures of about - 20 ° c . to about - 30 ° c . are preferred . ( 9 ) next , on completion of step 8 , the frozen semi - finished product is removed from the mold . the method of example 12 is followed except that equilibrium phase water ( in the same amount ) from a two - phase coacervate composition is substituted for distilled water . the method of example 12 is followed except that coacervate phase water ( in the same amount ) from a two - phase coacervate composition is substituted for distilled water .

a readily dissolvable carrier material having sufficient rigidity for administration of drugs , nutrients , vitamins , biologically - active materials , foodstuffs and combinations thereof capable of rapid dissolution by saliva , bodily fluids or other liquid comprising an interim skeletal structure of a watersoluble , hydratable gel or foam forming material , preferably a proteinaceous material , such as with maltodextran , in the hydrated state and dehydrated to leave spaces in place of hydration water . on dissolution by saliva , bodily fluids or other liquids , the composition becomes a liquid system . while the oral route is preferred , other routes may be used to administer the compositions of this method .

as described above , the present invention relates to a propulsion device designed to increase the propulsion efficiency of a swimmer . the principles of the present invention are described below in connection with one exemplary version of such a propulsion device . however , from the following description , the manner in which the principles of the present invention can be used to design various types of propulsion devices for swimmers will be apparent to those in the art . initially , it is believed useful to describe some factors that applicant considers important in the design of a propulsion device . for example , as described above , as a swimmer kicks , a propulsion device should provide useful thrust while minimizing drag forces that can cause undesirable resistance . in addition , the propulsion device should exploit the strengths of the swimmer &# 39 ; s body and account for its weaknesses . specifically , the device should account for the forces and moments that are applied to the swimmer &# 39 ; s foot and ankle and also minimize the risk of overworking the hamstring and calf muscles of the swimmer &# 39 ; s legs . thus , it is desirable for the device to not overtax these vulnerable parts of the swimmer &# 39 ; s body , while at the same time exploiting strong muscles like the quadriceps . when a swimmer is essentially horizontal in the water , upward strokes are made using the hamstrings . the muscles producing the energy for the downward strokes , the quadriceps , are more powerful than those providing the upward strokes . therefore , it is desirable to set the angles of attack of the fin so that full advantage is taken of the power of the downstroke and the upstroke is manageable by the less powerful muscles used for that stroke . it is also important to understand that effective use of swimming fins requires that the user &# 39 ; s feet be held in alignment with the legs as much as possible . this alignment is easy on the downstrokes but requires use of the calf muscles on the upstrokes . this is a further reason for providing for up - stroke angles of attack which ease the forces needed and do not require full extension of the feet , while still providing useful propulsion . in addition , it is important to take advantage of the efficiencies of a high aspect ratio fin , but also to control the fin &# 39 ; s angle of attack to ensure that it stays efficient over a broad range of operation . for purposes of this disclosure , the angle of incidence is the angle between the base of the fixture ( which is in contact with the soles of the user &# 39 ; s feet ) and the chordal plane of the fin , and the angle of attack is the angle between the chordal plane and the direction of the fluid flow toward the leading edge of the fin . [ 0019 ] fig1 illustrates a swimmer 10 using a propulsion device 11 according to a preferred embodiment of the present invention . for purposes of this disclosure , the swimmer is illustrated as if horizontal and face down in water and down - strokes move the device in the direction indicated by arrow d ( as depicted in fig3 ) and upstrokes in the direction indicated by arrow u ( as depicted in fig4 ). the propulsion device comprises fixture 12 , fin 13 and means for attaching the fin to the fixture ; the means in this embodiment comprising flexible straps 14 and 15 . [ 0020 ] fig2 illustrates the propulsion device in more detail . straps 14 and 15 are attached to support structures 16 and 17 , respectively , by fasteners , one fastener shown at 18 being typical , and through clips 19 and 20 , which distribute the holding forces of the fasteners over the straps . the straps are similarly attached to the fin 13 by fasteners , of which fastener 21 is typical , and clips 22 and 23 . a user &# 39 ; s feet fit into passages 24 and 25 in the fixture with the soles of the feet against base 26 of the fixture . [ 0021 ] fig3 is a side view of the apparatus taken at 3 - 3 in fig1 . the support structures 16 and 17 , strut 17 being shown in fig3 are configured to hold the fin 13 a distance d 1 from the user &# 39 ; s feet to provide undisturbed water flow to the fin . this view illustrates the apparatus during a down - stroke with the fin forced against stop 33 on strut 17 . angle i is the angle of incidence and angle a is the angle of attack . the direction of water flow relative to the fin 13 , indicated by arrow f , is a function of the flow velocity v f of the swimmer through the water and the stroke velocity of the downward stroke of the feet and apparatus v s . the relationship of v f to v s tends to remain fairly constant over typical swimming ranges because as v s increases , v f is increased . as shown in fig4 the foil section s f has camber . this camber generates a hydrodynamic moment indicated by arrow m . this moment helps to hold the fin against the stop 33 during down - strokes and tends to increase the angle of attack during up - strokes . [ 0022 ] fig4 is similar to fig3 but illustrates the apparatus during an up - stroke . the various flow directions and angles are lettered the same as in fig3 . the angle of attack during up - strokes is a function of the flexibility of the straps coupled with the location of the elastic bending center of the straps in relation to the hydrodynamic center of the fin and the effects of the camber in the foil section , along with the velocity components of the water . the hydrodynamic center of the fin is ¼ of the chord length back from the leading edge of the fin . in the down - stroke the elastic bending center of the strap is moved aft near the hydrodynamic center of the fin by the edge of clips 19 and 20 , clip 20 showing in fig4 . the lifting force of the fin crossed with the moment arm from the location of the center of pressure p to the elastic bending center of the flexible strap provides a positive moment (+ axis into page and − axis out of page ). add that to the negative moment m and the resultant vector is the torque that is balanced by the elastic deformation of the straps 14 and 15 . the hydrodynamic moment m increases with the square of the magnitude of f . therefore , high - speed swimming will make the up - stroke powerful and effective , but low - speed swimming will reduce the load to alleviate the swimmer &# 39 ; s hamstrings to prevent cramps on long swimming excursions . this fin suspension system is self - correcting if the fin begins to stall on up - strokes . this is important because the down - stroke is the dominant power stroke and the fin will likely be optimized for that state , leaving the fin more susceptible to stalling on up - strokes . if the fin stalls , its center of pressure begins to move aft , toward the ½ chord position . this shift increases the lever arm from the center of pressure to the elastic bending center of the flexible straps , which deforms the elastic straps and alleviates the stalled condition . the center of pressure p on the fin ( fig3 and 4 ) is only a short distance from the user &# 39 ; s toes . therefore , the moment applied to the user &# 39 ; s ankles by the forces on the fin is considerably less than that applied by conventional fins in which the distance d 1 is much greater than in the subject apparatus . in addition , the aspect ratio of the fin is in the range of 6 . 0 to 12 . 0 . such a high aspect ratio provides the propulsion device with optimum efficiency . [ 0025 ] fig5 and 6 schematically illustrate the force distribution on a fin in a propulsion device of the invention , during a downstroke ( fig5 ), and during an upstroke ( fig6 ). the manner in which the flexible center of the elastic suspension is forward of the center of pressure of the fin for down - strokes , allowing the fin to rotate with little restraint to the mechanical stop during downstrokes , and the manner in which the flexible center of the fin &# 39 ; s elastic suspension moves back near the center of pressure of the fin for up strokes , allowing the elastic forces of the elastic suspension to balance the forces of the fin to set the fin &# 39 ; s angle of incidence during upstrokes , can be further appreciated from those figures . a preferred fin configuration has a span of 3 . 5 to 4 feet and a fin area of approximately 1 . 6 square feet . the fin is attached laterally to the fixture with the span of the fin perpendicular to the height of , and in the plane of the shoulders of , the user . the means for attaching the fin to the fixture is such that the angle of incidence during a down - stroke is physically set with the fin coming into contact with a mechanical stop to set the angle of incidence . the angle of incidence is such that the resulting angle of attack produces a high lift to drag ratio , providing maximum or near maximum thrust from the fin relative to the effort used to produce the thrust . the means for attaching the fin to the fixture is also such that during up - strokes the angle of incidence is hydro dynamically set against the fin &# 39 ; s elastic suspension system , providing angles of attack , which produce useful thrust , while not over - taxing the muscles used for up - strokes . as described above , the fin has a hydrofoil section on the leading edge that is effective on up - strokes and down - strokes , i . e . positive and negative angles of attack . also , it may be cambered near the trailing edge so that it produces a hydrodynamic moment , which tends to rotate it against the angle of incidence limiting stop during the down - strokes and dynamically sets the angle of attack during up - strokes . the addition of this camber will tend to increase the fins effectiveness on both upstrokes and down - strokes . another advantage to using a cambered fin is that a simple adjustment is attainable by remounting of a cambered fin design , reversing top for bottom . this adjustment can be used to lower the fin &# 39 ; s effectiveness making it easier to kick , which may be desirable for swimmers who are smaller than what the fin was designed for . in the disclosed embodiment , the means for attaching the fin is an elastic suspension system , which comprises two flexible straps spaced five to eight inches apart around the span - wise center of lift of the fin to provide lateral stability to the fin . the flexibility of the straps is such that it allows the fin to move to the mechanical stops , one aligned with each suspension strap , during down - strokes and helps to set the angles of incidence during up - strokes . these straps may incorporate a composite laminate within an elastic matrix for strength . an additional benefit to using a composite within the elastic suspension strap , is that the laminate may be biased toward one bending direction of the strap which allows the suspension to bend more easily in one direction than in the other , such that the elastic forces of the suspension system which balance the forces of the fin to set the fin &# 39 ; s angle of incidence on up - strokes may be changed by reversing the top to bottom mounting of the suspension means . in this way the swimmer may select the suspension &# 39 ; s orientation to adjust the fin for their particular style of swimming . another preferred feature of the fin &# 39 ; s suspension is accomplished by the clips , one on either side of each flexible strap , at different lengths , so that the pivot point of the strap is varied with pivot direction rather than fixed in location . this feature may allow the flexible center of the fin &# 39 ; s elastic suspension to be substantially forward of the chordal center of pressure of the fin for down - strokes allowing the fin to rotate with little restraint to the mechanical stop . also , by allowing the flexible center of the fin &# 39 ; s elastic suspension to move back near the center of pressure of the fin for up - strokes , the elastic forces of the suspension system may sufficiently balance the forces of the fin to set the fin &# 39 ; s angle of incidence for up - strokes . alternately , the same mechanical effect can be accomplished by bonding the flexible strap to the fixture , such that the fixture extends beyond the bond joint , so that in one direction the flexible strap bends from the bonding joint , and in the other direction it bends around the end of the fixture . also , in the preferred embodiment , the leading edge of the fin may be notched where it passes over the flexible straps . this will allow the pivot point of the fin , for rotations against the mechanical stop , to be closer to the center of pressure of the fin , thus minimizing mechanical backlash of the fin when the stroke changes in direction . alternately , if the fin is not notched , it may be easier to manufacture the part as a straight extrusion , which may substantially reduce manufacturing costs . the losses incurred from not notching the wing are small as the backlash is still relatively insignificant . still further , in the preferred embodiment , the means for attaching the fin to a swimmer &# 39 ; s feet would include plastic or rubber straps or pockets . alternately , the straps could be made of other materials , including textiles . in addition , in an alternate embodiment of the invention two fins and two fixtures can be used , one set on each foot . in that embodiment , the spans and aspect ratios of the fin will naturally be lower . the mechanical stops , which limit the fin &# 39 ; s rotation for down - strokes , may be made adjustable to accommodate different fins , and / or swimming styles , with one fixture . moreover , surface features that cause early transition from laminar to turbulent flow on the fin may be beneficial because they can delay flow separation at large angles of attack , given the low reynolds numbers at which the fin operates . flow separation seriously decreases the hydrodynamic efficiency of the fin and must be avoided to realize the benefits of the subject invention . accordingly , from the foregoing description , it will be understood by those in the art that a propulsion device according to the principles of the present invention provides an efficient propulsion device for a swimmer . the apparatus allows for the differences in power available for up - strokes and down - strokes . it will also be understood by those in the art that other embodiments and modifications of those described are possible within the scope of the invention , which is limited only by the attached claims .

a new and useful propulsion apparatus for use by a swimmer is provided . the propulsion apparatus comprises a support structure configured for connection to a swimmer &# 39 ; s foot , and a fin connected with the support structure by a flexible coupling in a manner that enables the fin to be stroked in alternating downstrokes and upstrokes by flexion of a swimmer &# 39 ; s knees . the flexible coupling is configured to enable the fin to rotate in a first direction relative to the support structure during a downstroke , and the propulsion apparatus has a mechanical stop for limiting rotation of the fin in the first direction to physically set the angle of attack on the fin during a downstroke . the flexible coupling comprises an elastic suspension extending between the support structure and the fin , the elastic suspension being configured to allow the fin to rotate in a second direction opposite to the first direction during an upstroke and dynamically set the angle of attack during an upstroke .

fig1 a shows a marker arrangement in a vertebral spreading instrument , wherein a tip includes spreading fingers 10 . various artificial intervertebral discs a , b and c can be attached at the spreading fingers 10 . more particularly , the spreading fingers 10 preferably are designed such that various artificial intervertebral discs a , b or c can be attached so as to enable use of the vertebral spreading instrument with a high degree of flexibility . the spreading fingers 10 are situated at a fixed distance 12 away from a reference star 20 , which includes three marker spheres 20 a , 20 b and 20 c . an additional marker is indicated by 30 and is situated at a variable distance 14 from the reference star 20 . the distance 14 varies with the distance between the spreading fingers 10 . fig1 b and 1 c show an exemplary spreading mechanism according to the invention that operates in accordance with a jack principle ( e . g ., a scissor jack ). fig1 b shows spreading fingers 10 a and 10 b , which can be detachably inserted into corresponding cavities 18 b and 18 a . in this way , different spreading fingers 10 can be used in accordance with the desired requirements . in particular , different spreading fingers 10 can be selected in accordance with the artificial intervertebral disc to be used . as shown in fig1 c , the cavities 18 b and 18 a are respectively connected to two limbs or extensions 40 b and 40 a , which can be moved apart in parallel . a turnstile 42 that includes arms 42 a and 42 b is connected to the limbs 40 a and 40 b . the arm 42 b , for example , is connected to the limb 40 b such that it can rotate and can slide in a longitudinal direction of the instrument in a rail within the limb 40 a . correspondingly , the arm 42 a , for example , is connected to the limb 40 a such that it can rotate and can slide in a rail within the limb 40 b . the arms 42 a and 42 b are connected to each other , such that they can rotate via a rotational joint 43 . one end of the threaded rod 44 is connected to the rotational joint 43 . the threaded rod 44 rotates in an inner thread of the casing 45 and can thus be shifted in the longitudinal direction relative to the casing 45 . the inner thread thus serves as a bearing for the threaded rod . the limbs 40 a and 40 b have a pre - set distance from the casing 45 due to a distance holder ( not shown ) and cannot move in the longitudinal direction but rather only towards and away from each other . if the rotational joint 43 is then moved away from the casing , the limbs 40 a and 40 b are moved apart . if the rotational joint 43 is drawn towards the casing by the threaded rod 44 , the limbs 40 a and 40 b are moved towards each other . the casing is positionally fixed with respect to a geometrical focus of the two spreading fingers and , in particular , does not change its position when the distance between the spreading fingers is changed . the casing serves as the first part of the vertebral spreading instrument . fig2 a - 2 c shows an embodiment that uses the mechanism of fig1 b and 1 c . identical reference numerals in fig2 a - 2 c indicate the same parts as in fig1 . the limbs 40 a and 40 b are indicated in general by 40 , since they are adjacent to each other . the threaded rod 44 protrudes at the proximal end of the casing 45 . the threaded rod 44 can be rotated in the casing 45 using a handle 46 , which is connected and rotationally fixed to the threaded rod 44 , such that the threaded rod 44 travels in the longitudinal direction of the casing . this drives the limbs 40 apart , as explained above with respect to fig1 b and 1 c . an indicator 50 , to which the marker 30 is attached , is connected to the threaded rod 44 . the indicator 50 serves as the second part of the vertebral spreading instrument and can travel in a gap in the casing ( not shown ). the indicator 50 is connected to the threaded rod 44 such that indicator 50 participates in the movement of the threaded rod 44 . the position of the indicator 50 in the gap ( not shown ) thus reflects the distance between the spreading fingers 10 a and 10 b . the reference star 20 , including the markers 20 a , 20 b and 20 c , is situated opposite the indicator 50 with the marker 30 . the reference star 20 is fixedly connected to the casing 45 and thus does not travel with the rotational movement of the threaded rod 44 . fig2 b shows a view from the proximal end of the vertebral spreading instrument . fig2 c shows a lateral view of fig2 a . fig3 shows another vertebral spreading instrument according to the invention . functionally identical parts are again provided with the same reference numerals . an artificial intervertebral disc 60 is held by the spreading fingers 10 a and 10 b . the spreading finger 10 a is inserted into a cavity 18 a of the limb 40 a . the spreading finger 10 b is correspondingly inserted into a cavity 18 b of the limb 40 b . thus , the spreading fingers again can be exchanged according to requirement . in particular , the spreading fingers 10 a and 10 b can comprise different receptacles for artificial intervertebral discs . since the spreading fingers 10 a and 10 b can be exchanged , intervertebral discs having any shape and thickness can thus be used . as in the embodiment in fig1 a - 1 c , the distance between the spreading fingers again results from the relative position between the marker 30 and the reference star 20 . the marker 30 is situated on an arm 70 a , which is rigidly connected to the limb 40 a and rotates together with the limb 40 a about a rotational joint 43 . this applies correspondingly to the arm 70 b , which is rigidly connected to the limb 40 b and rotates about the same rotational joint 43 . the reference star 20 is arranged positionally fixed with respect to the rotational joint 43 . by rotating the arms 70 a and 70 b about the rotational joint 43 , the practitioner can move the limbs 40 a and 40 b and , therefore , the spreading fingers 10 a and 10 b apart . the position of the marker 30 relative to the reference star 20 is changed by moving the arms 70 a and 70 b apart . this change is a function of the distance between the spreading fingers 10 a and 10 b . the distance between the spreading fingers 10 a and 10 b can thus be exactly determined by measuring the markers 20 a , 20 b , 20 c and 30 . the embodiments shown in fig2 a - 2 c and 3 thus allow the distance between the spreading fingers 10 a and 10 b to be determined by determining the position of the reference star 20 relative to the marker 30 . in particular , determining the distance between the spreading fingers 10 a and 10 b by inserting templates into the intermediate space between the vertebrae is thus no longer necessary , and surgery is thus made easier . although the invention has been shown and described with respect to a certain preferred embodiment or embodiments , it is obvious that equivalent alterations and modifications will occur to others skilled in the art upon the reading and understanding of this specification and the annexed drawings . in particular regard to the various functions performed by the above described elements ( components , assemblies , devices , compositions , etc . ), the terms ( including a reference to a “ means ”) used to describe such elements are intended to correspond , unless otherwise indicated , to any element which performs the specified function of the described element ( i . e ., that is functionally equivalent ), even though not structurally equivalent to the disclosed structure which performs the function in the herein illustrated exemplary embodiment or embodiments of the invention . in addition , while a particular feature of the invention may have been described above with respect to only one or more of several illustrated embodiments , such feature may be combined with one or more other features of the other embodiments , as may be desired and advantageous for any given or particular application .

a vertebral spreading instrument for moving apart two vertebrae of a spine includes a plurality of spreading fingers and a spreading mechanism for adjusting a distance between the spreading fingers . the spreading mechanism includes a first and a second part , the first and second parts each including a respective marker trackable by a navigation system . relative positions of the first and second parts change when the distance between the spreading fingers is adjusted , and different relative positions are unequivocally assigned to different distances of the spreading fingers .

applicants have surprisingly discovered that the compounds of formula ( i ) have a therapeutic effect on the ability to tolerate stress and tension in a mammal . accordingly , an object of the present invention is a method for treating stress and / or tension in a mammal by administering to the mammal an effective amount of a compound of formula ( i ) or a pharmaceutically acceptable salt thereof . according to the present invention stress is either an acute or chronic condition associated with a variety of types of symptoms , such as anxiety , nervousness , inner tension , insomnia , concentration difficulties , memory impairment , muscle tension and palpitation . according to the present invention tension is either an acute or chronic condition associated with either muscular tension ( associated with symptoms like twitchings , stiffness , myoclonic jerks , grinding of teeth , unsteady voice or increased muscular tone ) or other tension ( associated with symptoms like feelings of tensions , fatigability , startle response , moving to tears easily , trembling , feelings of restlessness or inability to relax ) or both . stress and tension may also be associated with an affective disorder , such as depression or with an anxiety disorder , such as generalized anxiety disorder ( gad ), social anxiety disorder ( sad ), panic disorder ( pd ), obsessive compulsive disorder ( ocd ), post - traumatic stress disorder ( ptsd ) or agoraphobia . for the purposes of this disclosure and claims the term “ treatment ” means treatment in order to cure or alleviate the disease or its symptoms , and to treatment in order to prevent the development or the exacerbation of the disease or its symptoms . pharmaceutically acceptable salts of the compound of formula ( i ) can be formed with inorganic acids , e . g . hydrohalogenic acid such as hydrochloric acid or hydrobromic acid , sulfuric acid , phosphoric acid or nitric acid , or organic acids e . g ., tartaric acid , succinic acid , malic acid , maleic acid , fumaric acid , citric acid , or lactic acid . salt with fumaric acid is preferred . pharmaceutical compositions containing a compound of formula ( i ) or a pharmaceutically acceptable salt thereof as the active ingredient include the usual oral dosage forms , such as tablets , capsules , and liquid preparations . in oral dosage forms , the active ingredient can be mixed with suitable pharmaceutically acceptable excipients , such as starch , lactose , sucrose and magnesium stearate , in accordance with conventional pharmaceutical practice . the precise amount of the drug to be administered to a mammal for the treatment of stress is dependent on numerous factors known to one skilled in the art , such as the compound to be administered , the general condition of the patient , the condition to be treated etc . for example , the usual recommended oral daily dose of deramciclane would be about 5 - 150 mg / day , or about 10 - 60 mg / day , or about 30 - 60 mg / day , or about 30 mg / day . the invention will be further clarified by the following example , which is intended to be purely exemplary of the invention . the effects of deramciclane were studied in a randomised placebo - controlled double - blind study . the subjects were randomly assigned to four parallel groups to receive one tablet twice daily ( b . i . d ) of a placebo , 5 mg (= 10 mg / day ), 15 mg (= 30 mg / day ), or 30 mg (= 60 mg / day ) deramciclane . the efficacy of deramciclane on the ability to tolerate stress was analysed by the visual analogue scale ( vas ). administration of deramciclane improved the ability to tolerate stress when measured by the vas . the ability to tolerate stress was 29 %, 54 % and 43 % better in patients receiving deramciclane 5 mg b . i . d , 15 mg b . i . d , and 30 mg b . i . d ., respectively , than in patients receiving placebo . the efficacy and safety of deramciclane was studied in the treatment of tension as compared to placebo . a randomised plasebo - controlled double - blind parallel group 8 - week study design was used . patients were asked if they had muscular tension ( twitchings , stiffness , myoclonic jerks , grinding of teeth , unsteady voice or increased muscular tone ) or other tension ( feelings of tension , fatigability , startle response , moving to tears easily , trembling , feelings of restlessness or inability to relax ). this tension was related to be not present , mild , moderate , severe or very severe . in addition , patients &# 39 ; tension was also rated with the tension scale 1 - 6 : moderate / severe or very severe muscular tension was present in patients at baseline in 82 % placebo ), 61 % ( 15 mg deramciclane bid ) and 68 % ( 30 g deramciclane bid ) of patients ; the corresponding figures after 8 weeks of treatment were 38 %, 18 % and 15 %. thus deramciclane improved muscular tension in patients . moderate / severe or very severe other tension was present in patients at baseline in all patients . after 8 weeks of treatment this was present in 43 % ( placebo ), 25 % ( 15 mg bid deramciclane ) and 24 % ( 30 mg bid deramciclane ) patients . thus , deramciclane improved also this kind of tension in patients . 48 %, 35 % and 47 % of patients in the placebo , 15 mg bid deramciclane and 30 mg bid deramciclane groups had tension scale number at least 4 at baseline . after 8 weeks of treatment the corresponding numbers were 12 %, 5 % and 11 %. although the invention has been illustrated by the preceding example , it is not to be construed as being limited to the materials employed therein ; rather , the invention is directed to the generic area as herein disclosed . various modifications and embodiments thereof can be made without departing from the spirit or scope thereof .

a method of treating stress and / or tension in a mammal by administering to the mammal an effective amount of 1 , 7 , 7 - trimethyl - bicycloheptane derivative of formula i wherein r is hydrogen or methyl , or a pharmaceutically acceptable salt thereof .

[ 0038 ] fig1 and 2 show methods of using a pulse sensor and defibrillator to determine the appropriate treatment for a victim who appears to be suffering from cardiac arrest . both methods utilize a pulse sensor , described in further detail below , and an automated defibrillator . the automated defibrillator includes ( a ) a pair of electrodes that are placed on the victim &# 39 ; s chest , ( b ) instrumentation constructed to receive signals from the electrodes , monitor the victim &# 39 ; s ecg based on the received signals , and deliver a shock to the electrodes , and ( c ) a display constructed to display information and recommendations to the caregiver . suitable automated defibrillators are commercially available from zoll medical corp ., burlington , mass ., e . g ., m - series automated external defibrillators . the instrumentation also includes the capability of comparing the r - wave of the heart rhythm monitored by the ecg to the victim &# 39 ; s pulse to determine whether the two signals are synchronized . together , the pulse sensor and defibrillator constitute a treatment system for victims who appear to be suffering from cardiac arrest . [ 0039 ] fig1 illustrates a method according to a first embodiment of the invention . in this method , the pulse sensor and defibrillator are used to control the initiation of ecg analysis and to advise a caregiver whether it is appropriate to administer a shock and / or cpr . referring to fig1 when a victim shows signs of cardiac arrest , e . g ., fainting , a caregiver applies a pulse sensor and the electrodes of a defibrillator to the victim ( 100 ). generally , as shown in fig3 the pulse sensor is applied by fastening an elastic strap 20 carrying the sensor element 22 around the victim &# 39 ; s neck 24 , so that the sensor element 22 is held in close contact with the victim &# 39 ; s carotid artery by the elastic strap 20 . the strap is fastened snugly but not tightly about the neck . generally , to obtain an optimal signal the sensor should be placed on the left side of the neck orthogonal to and centered on the carotid artery . if desired , other locations on the patient &# 39 ; s body where a pulse can normally be detected may be used instead of the neck . the neck is generally preferred since it is the measurement and sustenance of blood flow to the brain which is of ultimate importance and the carotid artery carrying this flow provides a strong signal if a pulse is present . the sensor element 22 is connected , e . g ., by a coaxial cable , to instrumentation 26 , which is preferably incorporated in the instrumentation of the defibrillator . the electrodes of the defibrillator are applied in a conventional manner . referring again to fig1 the victim &# 39 ; s pulse is detected and monitored by the pulse sensor , and the victim &# 39 ; s heart rhythm is monitored by the ecg function of the defibrillator via the defibrillation pads . the instrumentation of the defibrillator determines whether the victim &# 39 ; s pulse is correlated with the r - waves of the victim &# 39 ; s heart rhythm ( 102 ). if the pulse and r - waves are synchronized , then a display on the defibrillator indicates to the caregiver that the victim does not appear to be in cardiac arrest , and that the victim should not be shocked or treated with cpr ( 104 ). in this case , the caregiver puts the victim in a “ rescue ” position , according to standard first aid protocol , and continues to monitor the victim &# 39 ; s pulse and ecg ( 106 ) so as to observe if a change in synchronization , a loss of pulse signal or ventricular fibrillation should occur ( 108 ). if the victim &# 39 ; s pulse is or becomes unsynchronized with the r - waves , the defibrillator then performs an ecg analysis ( 110 ) to determine whether the victim &# 39 ; s heart rhythm should be treated by administering an electrical shock , i . e ., whether the victim is suffering from ventricular fibrillation or wide complex ventricular tachycardia ( 112 ). if a shockable rhythm is detected , the display of the defibrillator advises the caregiver to administer a shock to the victim ( 114 ). the caregiver delivers a shock to the victim , and the defibrillator then performs another ecg analysis to determine whether a shockable rhythm is detected ( 110 ). as long as a shockable rhythm is detected , this process is repeated for three shocks ( 116 ). once three shocks have been administered , the system checks again to see whether the victim &# 39 ; s pulse is synchronized with the r - waves ( 118 ). if synchronization is not detected , then the display advises the caregiver to administer cpr for a specified period of time ( 120 ) and then to discontinue cpr ( 122 ). after cpr is discontinued , the ecg analysis ( 110 ) and following steps are repeated . if synchronization is detected , then a display on the defibrillator indicates to the caregiver that the victim does not appear to be in cardiac arrest , and that the victim should not be shocked or treated with cpr ( 104 ), and treatment proceeds as discussed above with reference to steps 106 - 108 . if a shockable rhythm is not detected , this indicates that either the victim is not suffering from cardiac arrest or that the victim has a condition that is not treatable by defibrillation ( 124 ). the system then checks again to see whether the victim &# 39 ; s pulse is synchronized with the r - waves ( 118 ), and treatment proceeds , based on the results , as discussed above . [ 0045 ] fig2 illustrates an alternative method , in which the pulse sensor is used only to advise the caregiver whether it is appropriate to administer cpr . in this method , the ecg analysis is used alone to advise the caregiver whether it is appropriate to administer a defibrillation shock . this method may be used in cases in which checking the patient &# 39 ; s pulse prior to applying the defibrillator electrodes is deemed to be unnecessary , e . g ., the protocol that is currently recommended by the american heart association for lay caregivers . the other steps of the method shown in fig2 are as described above with reference to fig1 . preferably , the pulse sensor is a piezoelectric polymer sensor . piezoelectric sensors are , in their simplest form , capacitive electromechanical transducers that generate electrical charge in proportion to applied stress . the primary purpose of these sensors in the present invention is to generate an electrical signal that is proportional to the force caused by blood flow ( pulse ) in the area of the carotid artery or other areas of the body where a pulse could be detected . the sensors of the invention are not mechanically clamped at their periphery , and are primarily sensitive to longitudinal stress as opposed to a sound pressure wave front . although the sensor material is somewhat sensitive to stress applied normal to its thickness and width , the sensor is designed to be most sensitive to stresses applied normal to its length ( or “ machine direction ”). as blood flows through the carotid artery , or other area ( either by normal heart action or as a result of cpr ), the artery expands and exerts a small amount of stress on the sensor , which is in close contact with the exterior of the patient &# 39 ; s neck , as discussed above . the stress induced in the sensor thus reflects changes in arterial blood flow . as shown in fig4 the sensor includes a piezoelectric polymer film 30 , a common metalization layer 32 and a signal metalization layer 34 . because piezoelectric sensors are generally of very high impedance , electrical interference is often problematic . to minimize electrical interference at the sensor surface , the sensor may be fabricated in a folded ( self - shielding ) manner , as shown in fig4 b and 4 d , so that the common metalization layer 32 almost completely envelops the exterior of the sensor . the sensor is shown prior to folding in fig4 a and 4c ( top and bottom views , respectively ) in which the dashed line indicates the line about which the sensor is folded . the sensor is held in its folded position by a layer of compliant adhesive 36 ( fig4 ). this shielding technique , in conjunction with coaxial cable connections , greatly minimizes interference created by undesirable stray electrical fields . a data acquisition scan performed using the pulse sensor of fig4 is shown in fig7 . the voltage signal level is approximately 100 mv p - p with most of the energy being spectrally located at about 1 . 2 hz , indicating a pulse rate of 72 beats / minute ( bpm ). suitable piezoelectric polymer films include polyvinylidine fluoride ( pvdf ) and co - polymers thereof . such piezoelectric polymer films are commercially available , e . g ., from measurement specialties , inc . of valley forge , pa . ( e . g ., part no . 1 - 1004347 - 0 ). preferably , the thickness of the polymer film is between about 0 . 001 and 0 . 005 inch . a preferred sensor material is polarized piezoelectric polymer film sheet , about 28 micron (˜ 0 . 001 inch ) thick with a silver conductor printed on both sides for a total thickness of about 40 microns (˜ 0 . 0015 inch ). the sensor material may be approximately 5 inches in length and folded back upon itself with compliant adhesive , as shown in fig4 to create a self - shielded sensor that is approximately 1 . 0 inch in width and 2 . 5 inches in length . an electrical signal is produced ( as measured between the ‘ signal ’ and the ‘ shield ’ electrodes ) when any stress is applied ( especially in the longitudinal axis ) to the sensor . the circuit shown in fig5 consists of a voltage source in series with a capacitor . this circuit is acceptable for visualization and modeling of sensor elements of this type as long as the frequency is below ultrasonic range . the capacitance exhibited by these sensors is approximately 10 nf and loss tangent is less than 0 . 02 . because the leakage is so low , it is generally necessary to eliminate long term buildup of charge ( dc drift ) on the electrodes due to triboelectric , pyroelectric or other phenomena especially when the sensor element is to be connected to a high (& gt ; 10 meg ohm ) impedance instrument . eliminating this undesirable dc drift ( charge buildup ) is accomplished ( at the expense of low frequency response ) by placing a ‘ termination ’ resistor ( 10 meg ohm ) across ( in parallel with ) the sensor , as shown in fig6 . the termination resistor allows charge to bleed off from the sensor thus eliminating long - term voltage drift . the loss of low frequency response does not generally pose a problem , as it is typically preferable to minimize low frequency (& lt ; 1 hz ) response so as to attenuate signals due to breathing or other slow artifacts . [ 0054 ] fig6 also shows the capacitance associated with the cable , which is used to connect the sensor to the instrumentation or other apparatus . the capacitance of the connecting cable appears in parallel with the capacitance of the sensor . this should not significantly impair the operation of the sensor as long as the cable capacitance is not appreciably large as compared to the capacitance of the sensor . if the sensor were operated in the ‘ current ’ mode ( connected to a transimpedance amplifier , as shown in fig1 , or a charge amplifier , as shown in fig1 ) the effect of the cable capacitance on the entire sensor system operation would be eliminated since there would be no appreciable voltage for the cable capacitance to charge to . the sensor electronics shown in fig1 - 15 may be integrated onto the sensor , or may be connected as a remote sensing instrument . in alternative embodiments , a piezoelectric polymer sensor element 22 ′ may be bonded to the surface of a compliant thickness member , e . g ., a foam pad 50 as shown in fig8 and 9 , to form a sensor assembly . a coaxial cable and terminating resistor are affixed to the foam pad and electrically connected to the sensor element . an epoxy 48 is applied to the resistor / cable / sensor area for protection . this sensor is designed to be most sensitive to forces which are normal to the length of the sensor . if desired , a second foam pad ( not shown ) may be adhered over the resistor / cable / sensor area . the foam pad is preferably about 1 to 2 mm thick , more preferably about 1 . 5 mm . as shown in fig9 if desired the foam pad 50 may be contoured in regions 51 to enhance signal sensitivity by allowing more stress to be felt by the sensor element 22 . as shown in fig1 , the piezoelectric sensor may also be bonded to the surface of a neutral plane inducer 52 , i . e ., a compliant but non - stretchable member that converts any flexure in the assembly into a tensile or compressive motion normal to the sensor &# 39 ; s length . piezoelectric polymer sensors may be bonded to both opposing surfaces of a foam pad ( not shown ). because any flexure in this assembly will cause tensile force in one sensor while simultaneously causing compressive force in the other sensor , the combined electrical signal will be differential in nature with advantages in increased sensitivity and improved common mode rejection of unwanted signals such as noise or pyroelectric response due to temperature transients . as shown in fig1 , the sensor element 22 ( shown in fig4 and described above ) and foam pad 50 may be bonded to a defibrillator electrode 53 , so that the sensor element may be attached to the chest as part of the defibrillator electrode . the defibrillator electrode includes a pressure - sensitive adhesive 56 and a conductive hydrogel 58 , as is well known in the defibrillator field . as shown in fig1 , a stiff low mass object 54 may be bonded to the adhesive side of the foam pad to aid in making intimate contact with the carotid artery in cases where there are areas of depression in the neck surface . the pulse sensor assembly may be used anywhere on the human body that a pulse can be detected , e . g ., the neck , chest , wrist , arm or ankle . the unamplified voltage signal level output from the sensor should be in the approximate tenths of a volt range when properly affixed to an area of the body that exhibits a moderate pulse strength . the pulse sensor may be attached in a different manner , e . g ., by a clip , as a patch , or using a suction device . small surface mount type electrical components such as operational amplifiers , resistors and capacitors may be integrated onto the sensor element and used to amplify the signal , provide noise immunity , mitigate the effects of cabling ( parasitic capacitance and / or equivalent series resistance ), filter certain frequencies , integrate the sensor electrical charge over time , double integrate the sensor electrical charge over time , scale and / or offset signal output , or otherwise accomplish signal conditioning functions for the electrical signals produced by the sensor element . while automated defibrillators have been discussed above , the pulse sensor may be used in conjunction with a non - automated defibrillator . in this case the pulse sensor would be used by a trained caregiver as an aid in determining the proper course of treatment . the caregiver would observe displayed pulse and ecg signals and perform an independent analysis to determine the proper mode of treatment . while the step of determining whether the patient &# 39 ; s pulse signal and r - wave are synchronized is used in the methods described above , in many cases this step is not necessary . this step is a signal processing technique that is sometimes used to improve performance when one or both of the signals are contaminated with artifacts . other suitable techniques include autocorrelation processing , matched filter processing , and other pattern recognition schemes . in some cases , e . g ., if the signals are relatively uncontaminated , none of these techniques are required .

external defibrillators are provided that include a pulse sensor . these defibrillators may be used to treat a patient showing signs of possible cardiac arrest . ?

referring to the single figure , there is shown in diagrammatic form apparatus for use in carrying out the process of the present invention . the apparatus includes a vaporizing chamber 10 having any well - known means 12 for injecting into chamber 10 a predetermined amount of a solution of hydrogen peroxide and water . chamber 10 may be controllably heated by any well - known means . chamber 10 has an outlet port 14 through which vapors may be exhausted from chamber 10 by means of a vacuum . port 14 may be opened or closed by valve 16 . chamber 10 also has an outlet port 18 leading through passage 20 to a sterilization chamber 22 . passage 20 may be open or closed by valve 24 . in the practice of the present invention , valve 24 is closed and valve 16 is open ; vacuum is applied to chamber 10 to evacuate air . chamber 10 is heated until the desired temperature within chamber 10 is reached ; that temperature is such that , when taken with the pressure within chamber 10 , water in the form of vapor will be flashed from a solution of liquid hydrogen peroxide and water present in chamber 10 . the process of the present invention then is initiated by the injection into evacuated chamber 10 of predetermined amount of a liquid solution of hydrogen peroxide and water through injection means 12 . conditions within chamber 10 cause the preferential vaporization of water from the solution and the vapor formed thereby is withdrawn from chamber 10 through port 14 . at a point in time when a major portion of the water in the injected solution has been vaporized and withdrawn , but before a significant quantity of hydrogen peroxide has vaporized and been withdrawn , valve 16 is closed . what remains in chamber 10 is a hydrogen peroxide - water solution enriched in hydrogen peroxide , specifically greater than 40 % hydrogen peroxide by weight , preferably 50 to 80 % by weight . vaporization of this enriched solution continues within chamber 10 and then valve 24 is opened to admit the vapors formed thereby to evacuated sterilization chamber 22 . with a substantial amount of the water having been removed , the hydrogen peroxide vapor sterilant is able to disperse itself throughout the sterilizer and penetrate wraps and tubes without encountering a barrier effect that otherwise would have been present by reason of the effects of the present of water discussed above . thus , the effective concentration of hydrogen peroxide vapor at the point of attack on the goods to be sterilized is markedly enhanced by the process of the invention . the equipment used in examples 1 and 2 described below includes a vaporization chamber 10 having a volume of 1 . 7 liters and being heated to provide a temperature of 90 ° c . within the chamber . sterilization chamber 22 is conventional and has a volume of 20 . 6 liters . the pressure and temperature maintained within sterilization chamber 22 are 0 . 01 atmospheres and 55 ° c ., respectively . the injected solution in examples 1 and 2 is 1 ml of a 30 weight percent ( 18 . 5 mole %) solution of hydrogen peroxide and water . the procedure used in examples 1 and 2 is that described above , except that in one instance valve 16 is not opened at all in order to illustrate the adverse effect of the presence of water vapor in the sterilization chamber 22 . the goods to be sterilized are stainless steel tubes , 32 cm in length , an outside diameter of 1 / 4 inch , an inside diameter of 5 mm , and having an enlarged chamber at the center . a spore carrier consisting of bacillus subtilis innoculated on peni cylinders , which are prepared and validated in accordance with aoac operating technique 4 . 017 , is placed in the enlarged chamber of each tube . during the procedure , valve 16 remains open for 5 seconds . the procedure was identical to that of example 1 except that valve 16 was not opened at all . the sterilization data for examples 1 and 2 are presented below in table i . table i______________________________________ weight percent hydrogen peroxideexample no . delivered to sterilizer spore kill______________________________________1 & gt ; 40 8 of 8 sterile2 30 2 of 2 not sterile______________________________________ in examples 3 - 5 described below , the objects to be tested for sterilant penetration are glass tubes having an inside diameter of 2 mm and a length of 32 cm . the extent of penetration of hydrogen peroxide into a tube is measured by colorimetrically assaying the amount of hydrogen peroxide deposited on a strip of filter paper which is placed inside the tube at its center . the assay is accomplished by extracting the absorbed hydrogen peroxide from the strip with water . the extraction proceeds by soaking the strip in one milliliter of water for at least 30 minutes . the peroxide in an aliquot of the extract is determined by reaction with ferrous ammonium sulfate in the presence of acid and the dye xylenol orange . the optical absorbance of the resulting solution is measured at 525 nm and compared to the absorbance of solutions of known hydrogen peroxide content . in examples 3 - 5 reagent grade hydrogen peroxide aqueous solutions of varying concentrations are injected into a vaporizing chamber to permit the liquid to vaporize ; then the vapors are allowed to travel into an evacuated sterilizing chamber containing the sample tubes . in example 3 , 90 % hydrogen peroxide , 10 % water ( by weight ) is injected . example 3 is considered to be a close approximation of the results achieved by the process of the present invention . in example 4 , 30 % hydrogen peroxide , 70 % water is injected . example 4 is considered to be a simulation of moore and forstrom . in example 5 , an injection of water precedes an injection of 90 % hydrogen peroxide solution . the purpose of example 5 is to assure that water vapor reaches the sample tube before the hydrogen peroxide is injected . in each of the three tests , 158 mg . of hydrogen peroxide is injected . the results of the tests are reported below in table ii : table ii______________________________________sterilant penetrationexample total hp hp found atno . injection injected , mg tube center , μg______________________________________3 0 . 125 ml 90 % hp * 158 71 + 124 0 . 47 ml 30 % hp 158 29 + 85 0 . 342 ml water + 158 35 + 11 0 . 125 ml 90 % hp______________________________________ * hydrogen peroxide examples 3 - 5 establish that the phenomenon of preferential vaporization of water before hydrogen peroxide results in water vapor reaching and penetrating the sample tube first , there to form a barrier against penetration by hydrogen peroxide vapor when it arrives at the mouths of the tube . this conclusion is demonstrated by the results of examples 4 and 5 . when , however , as in example 3 , water vapor is substantially removed from the hydrogen peroxide solution in order to concentrate the solution to greater than 40 % by weight hydrogen peroxide before the hydrogen peroxide vapor is introduced into the sterilization chamber , the impediment to penetration of the sterilant into the sample tube is removed , thereby permitting effective sterilization .

a process for concentrating hydrogen peroxide from a relatively dilute solution of hydrogen peroxide and water and supplying the concentrated hydrogen peroxide in vapor form to a sterilization chamber . the process includes vaporizing a major portion of the water from the solution and removing the water vapor thereby produced before injecting the concentrated hydrogen peroxide vapor into the sterilizing chamber .

fig1 is a bottom view of a rotary - type foam distributor in accordance with a preferred embodiment of the present invention . as illustrated in fig1 , the distributor , which is generally designated by reference numeral 10 , has a distributor body 12 ( or housing ) having a foam inlet 14 for receiving foam , such as compressed - air foam ( caf ) or other compressed - gas foam . the incoming foam travels along a foam entry axis 15 from a foam supply which is not shown , but which is known in the art of fixed piping fire - suppression . referring to both fig1 and fig2 ( which is a side cross - sectional view of the distributor ), the distributor 10 includes a radial impeller 16 ( although other equivalent devices include an impingement wheel or a rotor mechanism ) which , in turn , has a plurality of vanes 18 or impingement surfaces against which the foam impinges . the radial impeller 16 is offset from the foam entry axis 15 so that impingement of the foam on the vanes of the impeller causes the impeller to rotate . in other words , the centre of the radial impeller 16 ( as opposed to an axial impeller taught in the aforementioned united states patent ) is spaced apart or offset from the foam entry axis 15 , which is aligned to impinge upon the vanes 18 . this configuration effectively taps the energy of the caf flow , harnessing a small fraction of the available energy but does not significantly reduce the range the caf is projected . as shown in fig1 and 2 , the radial impeller 16 is mounted to an input shaft 20 that is rotationally secured within the distributor . preferably , the input shaft 20 is rotationally secured within bearings set in the upper and lower surfaces of the distributor body to provide smooth and efficient rotation of the input shaft 20 relative to the distributor body 12 . the input shaft 20 is operatively connected to an output shaft . 28 via a gear train . specifically in the preferred embodiment , a spur gear 21 is mounted to the input shaft 20 beneath the radial impeller 16 . the spur gear 21 meshes with a first intermediary gear 22 mounted on an idler shaft 24 . a second intermediary gear 23 mounted on the idler shaft provides a gear reduction and meshing with an output gear 26 mounted on the output shaft 28 . therefore , rotation of the input shaft 20 causes rotation of the output shaft 28 , albeit at a reduced angular velocity due to the reduction gearing therebetween . the idler shaft and output shaft can also be rotationally mounted in bearings to provide smoother and more efficient rotation . for optimal performance , depending on the surface area of the impingement surfaces etc ., the reduction gear ratio should be between 6 : 1 and 30 : 1 . this will generally ensure that the angular velocity of the rotary outlet remains within a desired band of about 60 to 180 rpm , although it will be appreciated that caf flow properties , dimensions and configurations of the impingement surfaces , flow properties in the area of the impeller , and other factors may change the optimal gear ratio and / or angular velocities . loose meshing of the gears , as is well known in the art , permits operation in a wide range of temperatures , accommodating different thermal expansions of the respective components . as shown in fig2 , the output shaft 28 is securely connected to a rotary outlet 30 which is rotatable relative to the distributor body . the rotary outlet 30 has a vent or exit through which foam is projected as indicated by a foam projection vector 32 in fig2 . occasionally , the rotary outlet 30 is referred to as a “ nozzle ” even if the outlet does not have a converging cross - section in the downstream direction . optionally , the rotary outlet can be mounted on a bearing to provide more efficient rotation relative to the distributor body . in operation , when the fire - suppression system incorporating the distributor 10 is triggered , compressed foam is injected into the inlet 14 . the foam impinges on the vanes of the radial impeller , causing the radial impeller to rotate and thereby causing the input shaft to rotate . as the input and output shafts are geared together , rotation of the input shaft causes the output shaft to rotate , albeit at a lesser angular velocity , thus causing the rotary outlet to also rotate relative to the distributor body . substantially simultaneously , the foam injected into the inlet is forced under pressure through the enclosure defined by the distributor body 12 , and is forced upwardly through a plurality of exits 34 into the rotary outlet 30 where it is projected radially outwardly in a circular sweeping pattern as the rotary outlet rotates . in other words , in the preferred embodiment shown in fig2 , the rotary outlet 30 can rotate 360 degrees in an unconstrained manner relative to the distributor body to cover a circular target area fully surrounding the distributor . as shown in fig1 , there are preferably five equidistantly spaced exit holes 34 disposed circumferentially around the output shaft 28 . as will be understood by those of ordinary skill in the art , the number and shape of the exit holes 34 can be varied , and other mechanisms for securing a rotating nozzle to a distributor body that permit driving of the nozzle can be used , subject to the strenuous demands of fire suppression applications . for example , a chain drive can be used . from fig2 it should be apparent that the foam is first diverted ninety degrees from the horizontal to the vertical by the distributor body and then ninety degrees back to the horizontal by the rotary outlet . persons of ordinary skill will thus readily appreciate that various refinements can be made to reduce pressure losses as the foam is forced through the two successive ninety - degree turns . for example , it is known in fluid mechanics to introduce smooth bends or elbows to minimize the pressure drop . as shown in fig2 , the rotary outlet 30 causes the foam to divert ninety degrees so that the foam is projected in a direction initially parallel to the foam inlet . in other words , the projection vector 32 revolves in a horizontal plane that is parallel to a horizontal plane of the foam entry axis 15 . the low - profile design of this distributor is compact enough to be used in a variety of tight spaces such as , for example , in a trench of an aircraft hangar where foam can be projected under wings and vehicle bodies to smother a ground - based fuel fire . the distributor is compact enough to be used in a variety of other applications as well , not only on the ground but also on walls or ceilings . fig3 and 4 illustrate a distributor 10 having an oscillating rotary outlet in accordance with another embodiment of the present invention . in this embodiment , the radial impeller 16 is operatively connected to the output shaft 28 ( and hence to the rotary outlet 30 ) by an oscillating mechanism 40 having a crank gear 42 meshed to the spur gear 21 of the input shaft 20 . the crank gear 42 is pivotally connected ( at a first pivot 43 ) to a reciprocating linkage such as a push rod 44 . the push rod 44 connects at a second pivot 46 to an arm 48 fixed to the output shaft . in operation , when the input shaft 20 is rotated by the foam impinging on the radial impeller 16 , the output shaft 28 ( and hence the rotary outlet 30 ) rotationally oscillates over a limited arc . in this embodiment , the rotary outlet 30 oscillates back and forth through an angle of about 170 degrees . this design is particularly useful when the distributor is positioned near a wall and the foam is delivered only to the target area away from the wall . in a preferred embodiment , as illustrated in fig2 and 4 , the distributor 10 includes a gear chamber isolation member , such as a gear chamber isolation plate 25 , for isolating the gear train from the flow of caf . although this component is not required , as is shown in the embodiments of fig1 and 3 , the gear chamber isolation plate 25 is nevertheless helpful to preclude foam from impeding the smooth movement of the gear train . the gear chamber isolation plate 25 is also useful in situations where rust , or other bodies may be present in the caf . if a large enough body were to become lodged in the gear train , it will be appreciated that the gear train may seize . by providing a gear chamber isolation plate 25 or the like , interference with the gear train is precluded . the input and output shafts may be supported by bearings flush mounted to the upper and lower walls of the distributor housing , bearings may be provided in a recess of either the upper or lower walls of the distributor housing , and / or the shafts may extend through one of the upper and lower walls . preferably , if a shaft extends through a wall of the distributor housing , a shaft cover plate 27 , as shown in fig2 and 4 is provided to prevent corrosion , or mechanical friction with anything below the distributor housing . as will be appreciated by those of ordinary skill in the art , a plurality of shaft cover plates covering individual shafts could also be utilized in lieu of a single shaft cover plate , and numerous other supportive and protecting configurations can be used as a matter of design elective . as further illustrated in fig2 and 4 , the gear chamber isolation plate 25 and the shaft cover plate 27 can be affixed to the distributor body 12 by anchor rivets 29 or , alternatively , by screws , welding , or other fastening means . fig5 illustrates another embodiment of the distributor where the rotary outlet is a diffuser having a diverging cross - section in the downstream direction . the diffuser reduces the exit velocity of the foam but projects the foam in an expanding cone rather than a cylindrical “ rope ” of foam . as will be appreciated by those of ordinary skill in the art , the rotary outlet can be a diffuser , a constant - cross - section chamber , or a nozzle depending on the desired projection characteristics . typically a constant cross - sectional area vent or diffuser is preferable ( and not a nozzle which restricts or converges the foam as it exits ). likewise , where a diffuser is used , its design should not cause undue backpressure in the distributor which would stifle the effective throughput of foam through the device . as will be appreciated by those of ordinary skill in the art , the distributor 10 must be constructed to withstand high temperatures so as to be robust enough to remain operable during a fire . a distributor of this design may be able to withstand at least 600 degrees celsius ( 1100 degrees fahrenheit ) for extended periods of time , while in operation . the distributor 10 harnesses the pressure of the foam to drive the rotary outlet . therefore , the distributor is self - powered , which reduces installation and operating costs and which also enhances the robustness of the device . furthermore , the distributor is highly efficient in that it requires very little volume of water and concentrate to cover a fixed area , relative to comparably performing fire - suppression apparatuses . this distributor requires only approximately one quarter to one tenth of the solution of comparable wide - area prior - art systems . also , as noted above , the distributor is both low - profile and capable of covering 360 degrees , which makes it ideal for trench mounting . persons of ordinary skill in the art will appreciate that variations or modifications may be made to the distributor disclosed in the specification and drawings without departing from the spirit and scope of the invention . furthermore , persons of ordinary skill in the art will appreciate that the distributor described and illustrated merely represents the best mode of implementing the invention known to the applicant ; however , it should be understood that other mechanisms or configurations , using similar or different components , can be used to implement the present invention . therefore , the embodiments of the invention described above are only intended to be exemplary . the scope of the invention is limited solely by the claims .

a self - powered foam ) distributor has a rotor mechanism with impingement surfaces against which foam impinges to rotate the rotor . the rotor is mounted on an inlet shaft geared to an output shaft . a rotary outlet is mounted to the output shaft so that foam entering the distributor rotates the rotary outlet , which in turn projects foam around in a circular sweep . the rotary outlet can rotate over a full 360 degrees , providing superior coverage for a large floor space , such as in hangars or warehouses , with less water and concentrate than in unfoamed conventional systems . having a compact vertical profile this versatile distributor can be installed in a floor trench of a hangar or on a wall or ceiling . since all rotational energy is harnessed from the pressure of the foam itself , no external energy source is required to power the distributor .

the invention described herein relates to a force limiter mechanism intervening between force applied by a user at the proximal end of a tool and the transmission of that force to the distal end of a tool . embodiments of the invention may be applied to non - articulating instruments , but many typical embodiments are applied to the operation of articulating tools . steerable articulating instruments are described in u . s . pat . no . 7 , 090 , 637 ; us 2005 / 0107667 ; us 2005 / 0273084 ; us 2005 / 0273085 ; and us 2006 / 0111210 . the articulating mechanisms of the tools described in those publications use multiple pairs of segments or links controlled , e . g ., by multiple sets of cables . depending upon the specific design of the device , the links can be discrete segments ( as described , e . g ., in u . s . pat . no . 7 , 090 , 637 ) or discrete portions of a flexible segment ( as described , e . g ., in us 2005 / 0173085 ). the instrument may also include steerable or controllable links of various types , e . g ., as described in us 2005 / 0273084 , us 2006 / 0111209 , and us 2006 / 0111210 . some articulating or steerable instruments have an articulating capability provided by minimal numbers of link pairs and cables connecting such links , u . s . pat . no . 5 , 916 , 146 of alotta , for example , has a mechanism comprising a single pair of links controlled by a single cable . when using such articulating instruments , a user may manipulate the proximal end of the instrument , thereby moving one or more proximal links of the articulation mechanism . this movement results in relative movement of the distal link ( s ) corresponding to the proximal link ( s ). it may at times be desirable to lock or otherwise maintain the straight or bent shape of the instrument . in certain embodiments of this invention , the shape of the instrument is maintained by preventing movement of at least one of the proximal links with respect to the rest of the instrument . in other embodiments , a friction - based articulation locking mechanism locks all links , proximal and distal ; these embodiments are disclosed in the concurrently filed and hereby incorporated application “ tool with articulation lock ” of hegeman , danitz , hinman , and alvord . many articulating instruments have end effectors controlled by movable actuators ; a movable end effector actuator maybe , for example , a moveable portion of the handle of an instrument , or a thumbpiece . in some embodiments , the end effector actuator has an operation state in which movement is permitted in only one direction and an operation state in which the actuator is free to move in two or more directions . certain embodiments of this invention provide methods and devices for changing the operational state of an end effector actuator between a state in which movement of the actuator is permitted in only one direction ; a state in which the actuator is permitted to move in two directions in response to continuous user input to a state changer , and a state in which the actuator is permitted to in two directions in the absence of user input to a state changer . fig1 - 20 show embodiments or portions of an articulatable tool 100 with an end effector 102 at its distal end and an end effector actuator 104 within a handle 106 at its proximal end . instrument 100 may be used , e . g ., in a laparoscopic procedure requiring grasping or cutting within a patient . proximal articulation links 108 and 110 extend distally from handle 106 , and distal articulation links 112 and 114 extend proximally from end effector 102 . proximal link 108 is connected to and moves with handle 106 . likewise , distal link 112 is connected to and moves with end effector 102 . a bushing 115 separates links 110 and 112 . bushing 115 has convex surfaces at its proximal and distal ends that engage with corresponding concave surfaces on links 108 and 110 . further details of ball and socket links suitable for use with this invention may be found in us 2005 / 0273084 , us 2006 / 0111209 , and us 2006 / 0111210 . an elongated shaft 116 is disposed between the proximal links and the distal links embodiments of the shaft may either be rigid or flexible , although embodiments shown herein are depicted as being rigid . as seen in fig3 and 4 , a set of control cables 118 is attached to proximal link 108 , extends through proximal link 110 , shaft 116 and distal link 114 , and is attached to distal link 112 . a second set of control cables 120 is attached to proximal link 110 , extends through shaft 116 and is attached to distal link 114 . in this embodiment , there are three control cables 118 in the first set and three control cables 120 in the second set . it should be appreciated , however , that other numbers of control cables may be used to connect corresponding proximal and distal links . in addition , mechanisms other than cables may be used to connect corresponding links . as shown in fig2 , movement of handle 106 and proximal link 108 with respect to proximal link 110 moves end effector 102 and distal link 112 in a relative and corresponding manner . likewise , movement of proximal link 110 with respect to shaft 116 moves distal link 114 with respect to shaft 116 in a relative and corresponding manner , also as shown in fig2 . this relative articulation movement provides a way for a user to remotely manipulate the end effector through movement of the handle . the relative movement of the distal link that corresponds to the proximal link movement may either mirror the movement of the proximal link or be reciprocal to it , depending on whether the cables are strung directly ( for reciprocal movement ), or whether they are rotated 180 degrees ( for mirrored movement ) between the proximal and distal links in order to maintain a particular position of the end effector with respect to the shaft , the articulating tool of this invention may have an articulation lock . in the embodiment shown in fig1 - 6 , the articulation lock includes a movable rigid sleeve 130 . in the unlocked position shown in fig1 - 5 , sleeve 130 is distal to proximal links 108 and 110 . in the locked position shown in fig6 , however , sleeve 130 has been moved proximally to a position adjacent to and covering links 108 and 110 as well as the proximal end of shaft 116 , thereby blocking relative movement between links 108 and 110 and between link 110 and shaft 116 . in this locked position , relative movement between distal links 112 and 114 and between link 114 and shaft 116 is prevented as well . as shown in fig6 , a sleeve support mechanism 132 extends proximally from shaft 116 to provide sliding support for sleeve 130 . a distal stop 134 provides a limit of distal movement of sleeve 130 ; a similar stop ( not shown ) is provided on or within handle 106 to limit proximal movement of sleeve 130 . detents , ridges or other mechanisms may be provided to maintain the sleeve in its proximal or distal positions and to provide tactile feedback to the user regarding the position of the sleeve . further detail on mechanisms that control permissibility of articulation in articulatable instruments is provided in the concurrently filed and hereby incorporated u . s . patent application entitled “ tool with articulation lock ” of hegeman , danitz , hinman , and alvord . the description now turns briefly to features of tools that include embodiments of an inventive force limiter , such features including rotatability of the distal end effector by proximal mechanisms , and mechanisms by which rotatability is allowed or disallowed by a locking mechanism . provided here will be a brief description of some these embodiments ; a full disclosure of such embodiments is provided in concurrently filed and hereby incorporated u . s . patent application entitled “ tool with rotation lock ” by hinman and danitz . the end effector 102 of tool 100 may be rotated with respect to handle 106 and then locked so that further rotation between end effector 102 and handle 106 is prevented . a rotation knob 101 is disposed at least partially around link 108 . in the locked position , teeth 103 formed on the proximal face of knob 101 engage corresponding teeth 105 formed on a distal face of handle 106 , as seen in fig1 . handle 106 may be made in two pieces ; two views of one of the two pieces are shown in fig9 and 10 .) in this embodiment , the rotation lock is self - locking due to the action of a spring 107 biasing knob 101 proximally into engagement with handle 106 , as shown in fig8 . when moved distally against the bias of spring 107 , the teeth 103 of knob 101 disengage from the teeth 105 of handle 106 . this disengagement permits knob 101 , links 108 and 110 , shaft 106 , links 112 and 114 , and end effector 102 to rotate with respect to handle 106 . this action permits the end effector to be rotated in any articulated configuration . when the end effector has been rotated the desired amount , release of knob 101 permits the two sets of teeth to re - engage , thereby locking the device against further rotation . in one embodiment , knob 101 is made in two pieces , an inner member 109 and an outer member 111 , as shown in fig8 . the teeth 103 are formed on the inner member 109 . indentations or knurls 113 ( fig7 ) may be formed on knob 101 to facilitate grasping . description now turns to consideration of a force limiter that intervenes in the transmission of force from a user to an end effector on a tool . in the embodiments illustrated in fig1 - 20 , the end effector 102 is a pair of jaws . other end effectors ( surgical , diagnostic , non - medical mechanical manipulators , etc ) and end effector actuators may be used with the articulating tool of this invention . actuation force is transmitted from movable end effector actuator 104 through a transmission or linkage that includes a rotatable rod actuator 122 , a movable rod terminator 124 , and a tension bearing member , such as rod 125 connected to rod terminator 124 , as shown in fig3 , 4 , 7 , and 8 . rod 125 passes through link 108 , bushing 115 , link 110 ; the shaft ( not shown in fig8 ) and the distal links ( not shown in fig8 ) to reach and actuate the end effector . rod terminator 124 encases a portion of rod 125 within handle 106 to prevent the rod 125 from buckling under a compressive load . similar features may be provided throughout the tool 100 to laterally constrain rod 125 . ( see further detail in concurrently sled patent application “ articulating tool with improved tension member system ” of hegeman , danitz , bertsch , and alvord ). end effector actuator 104 and rod actuator 122 are both rotatably mounted on a common bushing 202 so as to be able to be rotated with respect to each other to move rod 125 and thereby actuate end effector 102 . a force limiter such as a leaf spring 200 attached to end effector actuator 104 extends to a ledge 204 ( shown best in fig1 and 16 ) formed in rod actuator 122 and provides for force transmission from the end effector actuator 104 to rod actuator 122 as actuator 104 is moved toward handle grip 206 . actuator 104 may be moved until a stop element 208 on a surface of actuator 104 engages a stop element 210 on grip 206 , as shown in fig3 and 4 and in fig1 and 12 . in fig4 , the end effector jaws are closed when actuator 104 engages stop element 210 . in fig1 , on the other hand , the jaws have encountered an object 212 . the force limiter of this invention permits the actuator 104 to continue moving toward stop element 210 even if the jaws have stopped closing while limiting the amount of force applied by the end effector on the object , as explained below . spring or force limiter 200 rotationally biases the rod actuator 122 against the end effector actuator 104 such that surface 250 of rod actuator 122 contacts surface 252 of end effector actuator 104 as shown in fig1 . in this embodiment , force limiter 200 is formed from a shape memory material ( such as nitinol ) that is in its superelastic state . force limiter 200 is pre - biased ( to , e . g ., 1 . 5 % strain ) so that it is at a known state along its stress / strain curve . this pre - loading of spring 200 ensures that , until a predetermined threshold force is reached ( as described below ), end effector 104 , spring 200 , bushing 202 , and rod actuator 122 all move together and act as a rigid body . if the jaws of end effector 102 encounter an obstacle ( as shown in fig1 ) and the force applied through actuator 104 exceeds the threshold force , the stress on force limiter 200 reaches the characteristic plateau of the stress / strain curve , and force limiter 200 bends elastically substantially without delivering any further rotational movement to rod actuator 122 , as shown in fig1 . in one embodiment , the instrument has a force limiter 200 that establishes an upper limit on the actuation force that may be delivered to the end effector by the end effector actuator . in one embodiment , spring 200 may be formed from an elastomeric or spring metal material . in other embodiments , the material used to form spring 200 is selected and / or treated to provide a stress - strain relationship with a characteristic plateau region in which stress does not substantially change over a range of strain values . for example , in the instrument shown in fig1 - 19 , spring 200 is formed from a superelastic shape memory material , such as nitinol . the nitinol is selected and treated so that spring 200 is in the austenitic phase at the temperatures at which the instrument will be used . the material properties when so treated provide for substantially no change in stress over a range of strain values , e . g ., 1 . 5 % to 6 % strain . when assembling the instrument , spring 200 may be pre - loaded so that its strain is at or near the beginning of the stress plateau . in the absence of any counterforce resisting closing of the jaws of end effector 102 , movement of end effector actuator 104 toward handle grip 206 transmits an actuation force through spring 200 to rod actuator 122 , rod terminator 124 , rod 125 , and finally to end effector 102 . as shown in fig1 and 12 , if the jaws of end effector 102 encounter an object 212 , actuator 104 will experience a counterforce as it continues its movement toward grip 206 . when the counterforce exceeds the characteristic plateau stress of spring 200 , spring 200 will deform without substantially increasing the strain of spring 200 , thereby maintaining the actuation force transmitted through spring 200 and the remaining components of the actuation linkage . in the illustrated embodiment , the material comprising spring 200 may be selected and / or treated so that the spring remains in the stress plateau throughout its range of motion up to and including the point at which end effector actuator meets the limit stop 210 on grip 206 . description now turns briefly to an actuator movement controller that may be included in embodiments of the invention depicted in fig1 - 20 . embodiments may include a shaft having a proximal end and a distal end , an end effector at the distal end of the shaft , a movable end effector actuator at the proximal end of the shaft and operably connected to the end effector , and an actuator movement controller operably connectable to the end effector actuator . the actuator movement controller includes a user - activated state changer that is changeable among several states . these states include ones in which the movement controller is ( 1 ) enabled and engaged with the end effector actuator to prevent movement of the end effector actuator in at least one of two opposing directions , ( 2 ) enabled and disengaged from the end effector actuator to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction in response to continuous user input via the state changer , and ( 3 ) disabled to permit movement of the end effector actuator in a first direction and a second direction opposite to the first direction in the absence of user input via the state changer . in some embodiments , the first state ( enabled and engaged ) may prevent movement of the end effector actuator in both directions . in some embodiments the end effector includes jaws . in some embodiments the actuator movement controller includes a ratchet . in some embodiments the state changer includes a movable trigger . in some embodiments with a trigger , the state changer further includes a toggle operatively connected to the trigger so as to be movable with the trigger and to be rotatable with respect to the trigger . in some of the embodiments with a toggle , the toggle is operatively connected to the trigger so as to move with the trigger without rotating with respect to the trigger when the movement controller is enabled . embodiments of the multi - state ratchet mechanism that controls the end effector and the end effector actuator are disclosed in detail in the u . s . patent application entitled and hereby incorporated “ tool with multi - state ratcheted end effector ” by hinman . the embodiments described herein , by way of example , provide an actuator motion controller using a ratchet mechanism that , when engaged , permits the end effector actuator to be moved in one direction ( to , e . g ., close a pair of jaws ) while preventing the end effector actuator to move in the other direction ( to , e . g ., maintain the jaws in their closed state ). in fig3 , for example , the ratchet is formed from a rack of teeth 220 extending from end effector actuator 104 . a movable pawl 222 is rotatably mounted within handle 106 . a user may change the operation state of the ratchet by operating a trigger 224 which connects to pawl 222 through a toggle 226 . returning now to the force limiter , fig1 and 18 show alternative embodiments of a force limiter according to this invention . elements common to the embodiment shown in fig1 - 20 have been given the same reference numbers . as before , end effector actuator 104 and a rod actuator 502 independently rotate about a common bushing 202 . this embodiment replaces the spring of the embodiment shown in corresponding fig3 and 4 with a spring 500 attached to rod actuator 502 . spring 500 engages end effector actuator at an engagement surface 504 . as in the embodiment shown in fig1 - 16 , spring 500 may be made from a superelastic shape memory material , such as nitinol , and may be configured by design and / or assembly protocol such that it is pre - loaded to be at or near the plateau in its stress / strain curve . in that way , if a threshold actuation force is met , spring 500 deforms to the shape shown , e . g ., in fig1 without any additional stress being transmitted through the device &# 39 ; s linkage to the end effector . fig1 shows yet another alternative embodiment of a force limiter according to the invention in a view that is similar to those of fig1 and 18 . as before , an end effector actuator 104 a and a rod actuator 602 independently rotate about a common bushing 202 . in this embodiment , a coil spring 600 comprising a superelastic shape memory material such as nitinol is pre - loaded and disposed between end effector actuator 104 a and rod actuator 602 . pre - loading stress into the spring can place it at or near the plateau in its stress / strain curve , as described above . consequently , as a threshold actuation force is applied , spring 602 deforms it without transmitting any additional stress through the device &# 39 ; s linkage to the end effector . fig2 shows still another embodiment of a force limiter . in this embodiment , the proximal end of end effector actuation rod 125 ( optionally formed from nitinol ) is held in rod terminator 705 . the distal end of a force limiter 700 is also held in rod terminator 705 , while the proximal end of force limiter 700 is held in a force limiter housing 710 . rod terminator 705 fits into a distal opening of force limiter housing 710 , but the two parts can be separated , as described below . in this embodiment , force limiter 700 is preloaded with a predetermined amount of stress at about or just below the plateau stress of a super elastic material , by , e . g ., providing 1 . 5 % strain in the position shown in fig2 . the distal portion of force limiter housing 710 is attached to a movable slide member 715 , which fits in a fork 720 extending from end effector actuator 704 . when end effector actuator 704 is rotated with a subthreshold force about bushing 702 , fork 720 moves slide 715 , force limiter housing 710 , rod terminator 705 and rod 125 proximally to actuate the end effector . if the force applied to end effector actuator 704 exceeds the threshold force ( due , e . g ., to an object held in end effector jaws ), force limiter 700 will stretch , separating force limiter housing 710 from rod terminator 705 , so that further movement of end effector actuator 704 will not cause any further movement of rod 125 . this feature limits the force delivered by the end effector actuator to the end effector , and consequently the force exerted by the end effector , to the threshold force . in yet another embodiment ( not shown ) similar to that of fig2 , the rod 125 extends back into the linearly movable force limiter housing 710 . by using nitinol for rod 125 , or another suitable super elastic material , if the force applied to rod 125 by end effector actuator 704 induces a stress equal to the plateau stress of rod 125 , then rod 125 will stretch without increasing the force applied to the end effector . while the inventive surgical instruments and devices have been described in some detail by way of illustration , such illustration is for purposes of clarity of understanding only . it will be readily apparent to those of ordinary skill in the art in light of the teachings herein that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims for example , while the force limiter mechanism described herein typically has been in the context of a tool with an articulating mechanism comprising at least two links , the rotation knobs may be used in an instrument comprising only a single link , a multiplicity of links , with any number of cables or cable sets operably connecting the links , or , alternatively , embodiments of the inventive force limiter may be used with surgical instruments that do not articulate at all . further , while the shaft of depicted instruments including embodiments of the force effector have been depicted as rigid , in some variations it may be desirable to have the handle affixed to a shaft that is flexible . still further , while the inventive force limiter has been described in the context of a tool comprising a multi - state ratchet mechanism , some embodiments of the force limiter include tools without a ratchet mechanism . lastly , while the context of the invention is typically understood to be surgical or medical diagnostic procedures , embodiments of the force limiter or tools having such a mechanism may have utility in other , non - medical contexts as well .

the invention provides surgical or diagnostic tools and associated methods that offer improved user control for operating remotely within regions of the body . in some embodiments these tools include a proximally - located actuator for the operation of a distal end effector , as well as proximally - located actuators for articulational and rotational movements of the end effector . control mechanisms and methods refine operator control of end effector actuation and of these articulational and rotational movements . a force limiter mechanism protects the end effector and manipulated objects from the harm of potentially excessive force applied by the operator . the tool may also include other features . a multi - state ratchet for end effector actuation provides enablement - disablement options with tactile feedback . an articulation lock allows the fixing and releasing of both neutral and articulated configurations of the tool and of consequent placement of the end effector . a rotation lock provides for enablement and disablement of rotatability of the end effector .

in general , the instant invention relates to an ablation catheter assembly 10 comprising an ablation catheter 18 having a unique distal portion 12 for ablating tissue 14 using energy emanating from an electrode 16 contained within the ablation catheter 18 . a conductive fluid medium 20 ( e . g ., hypertonic saline ) contacting the electrode 16 and the tissue 14 to be ablated comprises a virtual electrode , eliminating the need for direct contact between the electrode 16 and the tissue 14 to be ablated . fig1 is an isometric view looking downwardly at an ablation catheter assembly 10 according to the present invention . in this embodiment of the catheter assembly 10 , an ablation catheter 18 comprising a catheter shaft 22 having a proximal portion 24 and a distal portion 12 is used in combination with one or more guiding introducers 26 , 28 to facilitate formation of lesions on tissue 14 , for example , cardiovascular tissue . the catheter shaft 22 may be constructed from a number of different polymers ( e . g ., pellethane , polypropylene , oriented polypropylene , polyethylene , crystallized polyethylene terephthalate , polyethylene terephthalate , polyester , polyvinyl chloride , etc .). as depicted in fig1 , the ablation catheter 18 may be used in combination with an inner guiding introducer 28 and an outer guiding introducer 26 . alternatively , a single guiding introducer may be used or a precurved transseptal sheath may be used instead of one or more guiding introducers . in general , the introducer , introducers , or precurved sheath are shaped to facilitate placement of the ablation catheter 18 at the tissue 14 to be ablated . thus , for example , the introducer or the introducers or the transseptal sheath make it possible to navigate to the heart 30 and through its complex physiology to reach specific tissue 14 to be ablated . when the ablation catheter 18 has a specific configuration like the curved configuration depicted in fig1 - 5 , the shape of the introducers 26 , 28 , if used , may change somewhat when the distal portion 12 of the ablation catheter 18 is retracted into the introducers 26 , 28 . this effect is accounted for by the present design . referring more particularly to fig2 - 5 , further details concerning the first embodiment of the ablation catheter 18 according to the present invention are described next . the distal portion 12 of the catheter shaft 22 includes a first curved section 34 of catheter shaft , a second curved section 36 of catheter shaft , and a third curved section 38 of catheter shaft , which together comprise a single unitary component in this embodiment , but which could comprise separate pieces that have been joined together . in this embodiment , the third curved section defines an active region used to ablate tissue . the catheter shaft 22 , which is typically a braided shaft , includes a “ straight ” section 32 that may follow a circuitous path from the location of the distal portion 12 of the catheter shaft 22 adjacent to the tissue 14 to be ablated back to the proximal portion 24 of the catheter shaft 22 , which is outside of the body containing the tissue 14 to be ablated . the straight section 32 is joined to the distal portion 12 by an rf bond . the third curved section 38 of catheter shaft includes a plurality of portholes through which conductive fluid medium 20 flows while the ablation catheter 18 is in use . the plurality of portholes depicted in fig2 - 5 includes an initial or first porthole 40 , a plurality of intermediate portholes 42 , and a final or last porthole 44 , which are described in more detail below . this third curved section 38 of catheter shaft is shaped in a circular , nearly closed “ c ” configuration , as most clearly shown in fig3 . the first and second curved sections 34 , 36 , respectively , tie the straight section 32 to the third section 38 of catheter shaft , while placing the straight section 32 of catheter shaft in a position where a longitudinal axis 46 ( see fig2 and 3 ) extending through the straight section 32 of catheter shaft as depicted in the figures would pass through roughly the center of the open circle formed by the third curved section 38 of catheter shaft . with the straight section 32 of catheter shaft approximately equally displaced from the outer peripheral wall 48 of the third section 38 of catheter shaft , the straight section 32 of catheter shaft is less likely to press against the wall of , for example , a pulmonary vein that is being ablated during use of the ablation catheter 18 . this may be seen in , for example , fig1 , which depicts the ablation catheter 18 in the left superior pulmonary vein 50 with the straight section 32 of catheter shaft extending along the longitudinal axis of the left superior pulmonary vein 50 . other curved sections could be used in place of the first curved section 34 of catheter shaft and the second curved section 36 of catheter shaft if it were desired to place the straight section 32 of catheter shaft in a different position relative to the third section 38 of catheter shaft , which contains the portholes that facilitate the formation of lesions . as shown to good advantage in fig2 - 5 , the portholes 40 - 44 formed in the radial apex of the outer peripheral wall 48 of the third curved section 38 of catheter shaft are circular and increase in diameter from the initial or first porthole 40 to the final or last porthole 44 . in other words , the porthole with the smallest diameter is the initial porthole 40 and the porthole with the largest diameter is the last porthole 44 . also in this embodiment , the distance 52 ( see fig3 and compare 52 ′ of fig6 a ) between the centers of adjacent portholes remains substantially constant . thus , there is a bridge 54 between adjacent portholes , and the width of the bridges narrows as one moves from the first porthole 40 through the intermediate portholes 42 to the last porthole 44 . the bridge 54 spans the gap between , for example , the distal trailing edge 56 of one porthole 40 - 44 and the proximal leading edge 58 of the next adjacent porthole ( see fig7 ). in the embodiment depicted in fig6 and 6a , the distal portion 12 of the ablation catheter 18 of fig1 - 5 and 7 has essentially been straightened out to form a linear distal portion 12 ′. in other words , the complex curved configuration of the distal portion 12 depicted in fig1 - 5 and 7 is not present in the embodiment depicted in fig6 and 6a . the specific embodiment of a distal portion 12 ′ depicted in fig6 and 6a does , however , similarly have an active region including a first porthole 40 ′, intermediate portholes 42 ′, and a last porthole 44 ′, wherein the relative diameter of the portholes 40 ′- 44 ′ increases and the bridges 54 ′ between adjacent portholes decreases or narrows in size as one moves from the first porthole 40 ′ to the last porthole 44 ′. also as clearly depicted in fig6 and 6a , the circular portholes 40 ′- 44 ′ are centered along a porthole centerline 60 ′, which is a tangent line on the surface of the catheter shaft and extends parallel to the longitudinal axis of the catheter shaft on the outer peripheral wall 48 ′ of the distal portion 12 ′ of the ablation catheter . this is also true for the embodiment depicted in fig1 - 5 and 7 , wherein the distal portion 12 is curved . in other words , the portholes 40 - 44 depicted in fig1 - 5 and 7 are also centered on a porthole centerline 60 ( fig5 ), which is a longitudinally extending tangent line on the radial apex of the outer peripheral wall 48 of the third curved section 38 of catheter shaft . as alluded to above , the portholes permit a conductive fluid medium 20 , which contacts a metal electrode 16 ( e . g ., a platinum flat wire ) embedded in the ablation catheter 18 , to exit the distal portion 12 of the ablation catheter 18 and contact adjacent tissue 14 to be ablated . in the embodiment depicted in fig7 , a metal electrode 16 is connected to an rf generator ( not shown ) by an electrical lead 62 , which extends down the catheter shaft 22 to the proximal portion 24 of the catheter shaft 22 where it is connected to the rf generator in a known manner . in this embodiment , the metal electrode 16 emits rf energy 64 ( see fig1 ), which exits the portholes to the adjacent tissue . the embodiment depicted in fig1 - 5 and 7 also preferably includes a shape memory wire 66 ( e . g ., a flat wire comprising an alloy of nickel and titanium , known commercially as niti wire or nitinol wire ), which helps the distal portion 12 of the ablation catheter 18 maintain a desired configuration . “ shape memory wire ” as used herein means a strip of material ( e . g ., a circular or flat wire ) which has the property that after deformation it will return to its former shape when heated to a certain transition temperature . thus , “ shape memory wire ” is wire that has been deformed to a desired shape and briefly heated to “ fix ” that shape . the wire possesses a “ memory ” causing it to return to its fixed shape after being deformed . in the present invention , the shape memory wire 66 helps a distal portion 12 of the ablation catheter 18 take and hold a desired profile or shape . alternatively , the shape memory wire 66 could comprise a strip of stainless steel or another resilient metal , or it could comprise a plastic material . in the embodiment depicted in fig1 - 5 and 7 , the portholes 40 - 44 are formed through the radial apex of the outer peripheral wall 48 of the third curved section 38 of catheter shaft , and the shape memory wire 66 is located within the ablation catheter 18 adjacent to the inner peripheral wall 68 of the distal portion 12 . a rounded tip 70 may comprise the most distal end of the ablation catheter 18 , and this tip 70 may be a tip electrode . if a tip electrode is present at the most distal end of the ablation catheter 18 , it may receive energy from either the same lead 62 that is connected to the metal electrode 16 , or a second lead ( not shown ) may be inserted along the ablation catheter to separately power the tip electrode . fig8 is a cross - sectional view along line 8 - 8 of fig7 and shows further details concerning the internal configuration of the ablation catheter 18 depicted in fig7 . it is apparent from fig8 that this variant of the ablation catheter 18 includes a bi - lumenal catheter shaft . the bi - lumenal shaft in this variant includes a first lumen 72 , which has a modified keyhole shape comprising a nearly - circular subportion 74 mated with a rounded - rectangular subportion 76 . these subportions 74 , 76 of the first lumen 72 are joined at a necked down area 78 defining a pair of retention ledges 80 , 82 . in this embodiment , these retention ledges 80 , 82 retain the metal electrode 16 in the rounded - rectangular subportion 76 of the first lumen 72 . the nearly - circular subportion 74 of the first lumen 72 carries a conductive fluid medium 20 ( see fig1 ), which , by design , flows past , and in contact with , the metal electrode 16 . a number of portholes 42 are visible in fig8 through the radial apex of the outer peripheral wall 48 of the distal portion 12 . a second lumen 84 depicted in cross - section in fig8 carries the shape memory wire 66 ( e . g ., a niti flat wire ) adjacent to the inner peripheral wall 68 of the distal portion 12 . in this particular embodiment , the shape memory wire 66 does not directly contact the conductive fluid medium 20 flowing into the patient &# 39 ; s bloodstream . thus , it would be possible to use a shape memory wire 66 constructed from any material without regard to that material &# 39 ; s biocompatibility . fig9 depicts another possible cross - sectional configuration for the ablation catheter . in this embodiment , only a first lumen 72 ′ is present . fig9 also depicts a mere slice of the ablation catheter and , thus , only a single intermediate porthole 42 ′ through the radial apex of the outer peripheral wall 48 ′ is visible in fig9 . similar to what is depicted in fig8 , the first lumen 72 ′ depicted in fig9 has a modified keyhole shape , comprising a nearly - circular subportion 74 ′ mated with a rounded - rectangular subportion 76 ′ adjacent to inner peripheral wall 68 ′. in this embodiment , a metal electrode ( not shown in fig9 ) would be retained in the rounded - rectangular subportion 76 ′ of the first lumen 72 ′ by retention ledges 80 ′, 82 ′ at necked down area 78 ′, and would provide both the energy for the ablation procedure as well as the shape stability . for example , a niti flat wire could be placed in the rounded - rectangular subportion 76 ′ of the first lumen 72 ′ to serve as both the electrode and to provide configuration stability . if desired , the niti flat wire could be coated with a more conductive material ( e . g ., platinum , which is biocompatible with blood ). fig1 depicts an alternative embodiment for the distal portion 12 ″ of an ablation catheter according to the present invention . this embodiment is most similar to the embodiment depicted in fig5 , but a third curved section 38 ″ includes two rows 86 of portholes . in this second embodiment , each porthole has a corresponding porthole on the opposite side of the longitudinally - extending , circumferential tangent line 88 shown in this figure as bisecting the two rows 86 of portholes . the portholes could be staggered rather than side - by - side . this two row embodiment would provide a wider lesion than the lesion provided by the distal portion 12 depicted in fig5 , but would require a correspondingly greater amount of energy to produce a sufficient lesion in the tissue being ablated . fig1 - 14 depict the ablation catheter according to the present invention while being used to ablate tissue in a left superior pulmonary vein 50 . fig1 and 12 include a number of primary components of the heart to orient the reader . in particular , starting in the upper left - hand portion of fig1 and 12 , and working around the periphery of the heart 30 in a counterclockwise fashion , the following parts of the heart 30 are depicted : superior vena cava 92 , right atrium 94 , inferior vena cava 96 , right ventricle 98 , left ventricle 100 , left inferior pulmonary vein 102 , left superior pulmonary vein 50 , left atrium 104 , right superior pulmonary vein 106 , right inferior pulmonary vein 108 , left pulmonary artery 110 , arch of aorta 112 , and right pulmonary artery 114 . the distal portion 12 of the ablation catheter 18 is positioned adjacent to the ostium 116 of the left superior pulmonary vein 50 using known procedures like the “ seldinger technique .” for example , to get the distal portion 12 of the ablation catheter 18 in the position shown in fig1 , the right venous system may be first accessed using the “ seldinger technique ,” wherein a peripheral vein ( such as a femoral vein ) is punctured with a needle , the puncture wound is dilated with a dilator to a size sufficient to accommodate an introducer ( e . g ., 28 ). the introducer ( e . g ., 28 ) with at least one hemostasis valve ( see fig1 ) is seated within the dilated puncture wound while maintaining relative hemostasis . with the introducer in place , the ablation catheter 18 is introduced through the hemostasis valve of the introducer and is advanced along the peripheral vein , into the region of the vena cava ( e . g ., the inferior vena cava 96 ), and into the right atrium 94 . from there , the ablation catheter 18 together with the guiding introducer or transseptal sheath is further advanced through a hole in the interatrial septum , which a doctor would make before inserting the ablation catheter 18 into the introducer , and into the left atrium . once the ablation catheter 18 is in the left atrium , it can be advanced to the respective positions depicted in fig1 and 12 . in fig1 , the distal portion 12 of the ablation catheter 18 has been inserted into the left superior pulmonary vein 50 . while the ablation catheter 18 is in the pulmonary vein as depicted in fig1 , the electrode would be activated to create the desired lesion in the left superior pulmonary vein 50 . as shown in fig1 , the rf electric current 64 emanating from the metal electrode 16 passes through the conductive fluid medium 20 contained in the nearly - circular subportion 74 of the first lumen 72 through the portholes 42 and into the adjacent tissue 14 . the conductive fluid medium 20 experiences ohmic heating as it flows along the metal electrode 16 and out the portholes 42 . thus , a lesion is formed in the tissue 14 by the rf energy 64 . lesion formation may also be facilitated by the conductive fluid medium 20 , which may have been heated by ohmic heating to a sufficiently high temperature to facilitate or enhance lesion formation , flowing out the portholes . the rf energy is conducted into the adjacent tissue and the heated conductive fluid medium convectively affects the temperature of the tissue . in order to form a sufficient lesion , it is desirable to raise the temperature of the tissue to at least 50 ° c . for an appropriate length of time ( e . g ., one minute ). thus , sufficient rf energy must be supplied to the metal electrode to produce this lesion - forming temperature in the adjacent tissue for the desired duration . the conductive fluid medium 20 flowing through the portholes 40 - 44 prevents blood from flowing into the ablation catheter 18 and pushes blood from the area adjacent to the portholes 40 - 44 . this helps prevent coagulum , which can have undesirable effects on the patient . the conductive fluid medium is caused to flow at a rate that prevents the electrode from overheating the conductive fluid medium and producing vapor in the first lumen 72 . if the conductive fluid medium were to boil , creating a vapor , the ablation catheter &# 39 ; s ability to form a desired lesion in adjacent tissue 14 would be reduced or destroyed since the rf energy would be unable to reach the tissue in sufficient quantity . thus , the flow of conductive fluid medium through the first lumen and out the portholes is managed or regulated so that there is sufficient flow to prevent vaporization , but not so much flow that the metal electrode is prohibited from sufficiently heating the adjacent tissue to form a desired lesion . also , if too much conductive fluid medium flows out of the portholes , the hemodynamics of the patient may be adversely affected by the excess quantity of conductive fluid medium being mixed with the patient &# 39 ; s blood . the desired flow rate is achieved by , for example , adjusting the pressure driving the conductive fluid medium through the first lumen , changing the diameter or distribution of the portholes , altering the spacing between the portholes , and changing the porthole diameter gradient between the small first porthole and the relatively larger last porthole . another factor that may be taken into account when adjusting the flow rate of the conductive fluid medium is the specific configuration of the distal portion of the ablation catheter since the flow of conductive fluid medium is affected by the curvature of the catheter shaft . in the alternative embodiment of a distal portion 12 ′″ depicted in fig1 , the portholes 40 - 44 depicted in , for example , fig2 have been moved from the longitudinally - extending tangent line 60 ( fig5 ) on the radial apex of the outer peripheral wall 48 of the third curved section 38 of catheter shaft to a distally - facing surface 118 at the distal apex of a third curved section 38 ′″. in this configuration , the longitudinal axes of the portholes extend parallel to the longitudinal axis 46 ( see fig2 , 3 , and 5 ) of the straight section 32 of catheter shaft 22 , rather than extending radially outwardly from that longitudinal axis of the straight section of catheter shaft as is the case with the embodiment of fig2 - 5 and 7 . as with the embodiments described above , the longitudinal axis 46 of the straight section 32 of catheter shaft is substantially aligned with a longitudinal axis of a pulmonary vein ( e . g ., 50 in fig1 ). when the configuration depicted in fig1 is used for pulmonary vein ablation , it is unnecessary to insert the distal portion 12 ′″ of the ablation catheter into the pulmonary vein ( compare fig1 , wherein the distal portion 12 has been inserted into the left superior pulmonary vein 50 ). rather , as shown in fig1 , the distal portion of the ablation catheter is placed at the ostium 116 of the pulmonary vein 50 so that the third curved section 38 ′″ of catheter shaft substantially encircles the extended longitudinal axis ( not shown ) of the pulmonary vein 50 . if rf energy is then applied to the ablation catheter , a circular lesion is formed in the left atrium 104 at the ostium 116 of the pulmonary vein 50 , thereby inhibiting entry of stray electrical signals from the pulmonary vein 50 into the left atrium 104 . although preferred embodiments of this invention have been described above with a certain degree of particularity , those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the spirit or scope of this invention . for example , the portholes 40 - 44 are shown at the radial apex of the outer peripheral wall 48 of the third curved section 38 in the embodiment of fig2 - 5 and 7 , and the portholes 40 ′″- 42 ′″ are shown at the distal apex of the third curved section 38 ′″ in the embodiment of fig1 . the portholes could , however , pass through the outer peripheral wall of the third curved section at a location between the radial apex and the distal apex . further , all directional references ( e . g ., upper , lower , upward , downward , left , right , leftward , rightward , top , bottom , above , below , vertical , horizontal , clockwise , and counterclockwise ) are only used for identification purposes to aid the reader &# 39 ; s understanding of the present invention , and do not create limitations , particularly as to the position , orientation , or use of the invention . it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative only and not limiting . changes in detail or structure may be made without departing from the spirit of the invention as defined in the appended claims .

an ablation catheter having a catheter shaft and a virtual electrode , the virtual electrode comprising portholes through an outer peripheral wall of the catheter shaft and a metal electrode , the catheter being used for treatment of cardiac arrhythmia , for example , atrial fibrillation , by electrically isolating a vessel , such as a pulmonary vein , from a chamber , such as the left atrium . the catheter shaft includes a proximal portion and a distal portion . the distal portion includes an active region , which is either a looped structure transverse to the longitudinal axis of the catheter shaft , or a linear structure that extends parallel to the longitudinal axis of the catheter shaft . during use , the active region is directed into contact with , for example , the wall of a pulmonary vein . upon energization , the virtual electrode creates a continuous lesion on an inner wall of the pulmonary vein , thereby electrically isolating the pulmonary vein from the left atrium .

turning first to fig1 therein illustrated is a swing training device embodying the present invention , and having an elongated handgrip generally designated by the numeral 10 and an elongated shaft generally designated by the numeral 12 which is affixed thereto and extends therefrom . disposed within the shaft 12 as indicated by dotted lines is a weight 14 which provides a balance point for the device at the point &# 34 ; b &# 34 ; which is spaced a distance of 17 inches from the free end of the handgrip 10 . the embodiment shown in fig1 is a relatively lightweight swing training device suitable for women to use in the outdoors . its total weight is approximately 11 / 2 pounds . the embodiment illustrated in fig4 is suitable for use by men in the outdoors . as can be seen , it is similarly comprised of elongated handgrip 10a and elongated tubular shaft 12a which is of substantially larger diameter . as seen in fig5 and 6 , the tubular shaft 12a is of annular configuration , and the free or lower end thereof has a plug 24 seated therein to effect a seal of the passage extending thereinto . in fig6 it can be seen that the weight 14a is tack welded at several points about its periphery as indicated by the numeral 22 . as seen in fig7 the handgrip 10a includes a rod 16 which extends into a bore or recess 13 at the upper end of the weight 14 , the several elements being welded as indicated by the numeral 23 . frictionally engaged about the rod 16 is a tubular sleeve 18 of soft synthetic resinous material , and an end cap 20 is provided at the outer end thereof and secured thereto by adhesive or the like . in fig8 there is illustrated still another embodiment of the present invention suitable for use indoors which is essentially similar to fig4 except that the overall length is shortened , and the weight 14 is moved slightly away from the handgrip 10b to maintain the balance point at approximately the same position . fig2 and 3 illustrate the prior art . in fig2 a conventional club is illustrated having a handgrip 26 , an elongated shaft 28 , and a head 30 . the balance point of this particular device is located much closer to the head 30 than to the handgrip 26 . a typical length is about 43 inches and the resulting balance point will be about 30 inches from the end of the grip . in the prior art swing training device as shown in fig3 there is a handgrip 32 , an elongated shaft 34 , and a weight 36 at the end thereof . this device has an overall length of 29 inches and a length to the balance point of approximately 24 inches . in each of the embodiments of fig1 and 8 , the balance point is located at a distance of approximately 17 inches from the free end of the handgrip 10 . as is well known to those who are engaged in the training of golfers , advancement at any skill level is dependent upon the hand strength or ability to grip the club firmly , the ability to swing through a correct plane angle , the ability to maintain a stable posture , and the ability to keep the hands in front of the club head during the down swing to impact . fig9 a through 9i illustrate the manner in which the swing training device cooperates with the correct posture , swing plane angle and placement of the hands as the golfer moves the club through the stroke . the swing training device of the present invention is weighted to locate the center of balance close to the handgrip so that the user swinging the club will normally have the club balanced in the hands so that the hands will lead the stick during the down swing . as a result and as seen in fig5 this will result in presenting the entire training device at impact and not just the club head . moreover , the balance point adjacent the handle provides a high moment located towards the hands . this will tend to strengthen the hands when swung , keep the motion of the hands powerful through the impact zone , and carry the hands , arms and body to a high powerful finish , all as illustrated in the diagrammatic illustrations of the golfer seen in fig9 a through 9i . although the handgrip rod and the elongated shaft may be fabricated from other materials such as reinforced synthetic resins , tubular metallic stock is preferably employed because of the ease of fabrication , its inherent strength , and the ease of assembling and positioning the weight and other elements by welding or like techniques . moreover , the elongated shaft is of annular configuration to facilitate the placement of the weight in the desired position along the length thereof and thereafter its welding oz engagement in that position . the handgrip desirably uses rod or bar stool to facilitate the assembly of the handgrip within the end of the shaft while providing the desired degree of strength . for example , in the devices of fig4 and 8 , the shaft is conveniently tubing of 1 and 1 / 16 inches outer diameter and 15 / 16 inch inner diameter and the rod is 5 / 8 inch diameter bar stock . although weld metal may fill the spacing between the rod and shaft , a bushing may be placed therebetween . the weight may be fabricated of various metals providing relatively high density including ferrous metals and lead . the length will vary depending upon the diameter of the passage in which seated , and the desired weight . as indicated above , its placement within the length of the shaft will depend upon the total weight of the device since it may be moved in either direction in order to provide a balance point within the range of 16 - 18 inches from the end of the handgrip as previously described . the soft comfortable gripping surface is provided to the handgrip by a molded cylindrical sleeve simulating a leather wrap and generally fabricated from a cellular synthetic resin . the sleeve may be expanded to enable its placement over the grip rod , and it can be adhered thereto with a layer of adhesive or frictional engagement may be relied upon . to provide an attractive end finish for the grip , a synthetic resin end cap is adhesively engaged thereon . the end seal at the lower end of the rod or shaft is conveniently a metallic plug or like element which is welded in place . however , a synthetic resin plug may also be employed to preclude dirt and other materials from entering into the hollow core of the shaft . as will be readily appreciated , the elements described above may be readily assembled and comprise materials which are readily available . depending upon the thickness of the shaft and of the rod of the grip , and the resultant weight of those two elements , the mass desired for the weight to be placed within the tubular shaft can be determined , and a length of solid bar stock cut to provide that weight . the balance point for the device can be readily determined by sliding the weight within the tubular shaft until the desired balance point is reached , and the weight can then be secured in place . alternatively , the placement of the weight can be determined empirically based upon the known weight of the various elements . once determined , swing devices of the same length and weight can readily be fabricated without such adjustment and / or continuing determinations . since most women prefer , and are better able to use , lighter clubs than those utilized by men , the swing training device for men will generally be heavier than that employed for women , although the balance point will be at essentially the same location from the end of the grip . for men , the training device will desirably have a total weight of 3 - 5 pounds , and preferably about 4 pounds . for women , the training device will normally have a weight of about 11 / 4 to 21 / 2 pounds , and preferably about 11 / 2 to 13 / 4 pounds . although the preferred swing training devices will normally have a length of about 40 - 44 inches , a device for use indoors will normally have a length 33 - 35 inches to reduce the likelihood of injury to ceilings and wells . as indicated before , by having the balance point for the swing training device closely adjacent the hand grip , the user swinging the device generally tends to have the hands forwardly of the lower end of the device as the lowest point of the swing is being reached , a condition which is highly desirable when swinging with a regular club . moreover , this balance point location tends to provide the desired follow through in the swing as well as to assist in maintaining proper body posture throughout the swing . thus , it can be seen from the foregoing detailed description and the attached drawings , that the golf swing training device of the present invention is one which may be readily fabricated from available materials to provide a long lived construction . the placement of the balance point adjacent the handgrip tends to force the user into adopting a proper swing relationship of the hands relative to the club during the down swing , and movement into the follow through . thus , it helps to develop good posture and swing techniques .

a golf swing training device includes a handgrip which is comfortably gripped by both hands of the user and an elongated tublar member secured to one end of the handgrip and providing a total length of 33 - 44 inches . a weight is fixed in the tubular member and provides a total weight of 1 . 25 - 5 . 0 pounds and a fixed balane point at 16 - 18 inches from the outer end of the handgrip .

referring now to the drawings and in particular to fig1 , 2 , and 3 , these show overall views of the combined wall treatment and bed of the invention ( sometimes “ the unit ” hereafter ) in several positions . specifically , fig1 shows the unit in its raised and stowed position , in which it appears as a wall treatment . in this embodiment , the outer face or façade 20 of the unit , which forms the underside of the unit when lowered for sleeping , is shown as a paneled face . all manner of flat surface treatments may be applied to façade 20 , including , without limitation , wood paneling , artwork , fabrics , bulletin boards , black - or white - boards , and the like . it is also within the invention to provide means for readily replacing one form of surface treatment with another , to enable easy redecoration . fig2 shows the combined wall treatment and bed of the present invention in an intermediate position , as it is being lowered to the sleep position or raised to the stowed position . fig3 shows the combined wall treatment and bed of the present invention in the lowered or sleep position , with the preferred hybrid foam / air mattress 134 in inflated position and optional side tables 16 clipped onto side rails 14 , the structure of which is detailed below . fig1 - 3 show that the unit comprises a fixed portion 22 , comprising a bottom frame 24 and headboard 26 , which are fixed to the wall w , and a movable portion 30 , comprising a platform section 32 , the outer surface of which is façade 20 , legs 34 , and a top frame 36 . movable portion 30 pivots around a horizontal axis defined by a mechanism ( detailed below ) comprised by the bottom frame 24 . as illustrated in fig2 , the legs 34 swing out as the movable portion is lowered , pivoting about longitudinal axes near the sides of the platform section 32 , to support the outer or foot end of the platform section 32 in the lowered position , and retract likewise when it is raised . more specifically , the overall effect as illustrated in fig1 is to completely conceal the mechanical components of the unit of the invention , disguising the legs 34 , which move out of the plane of the façade 20 , and the bottom frame 24 , which remains essentially stationary as the movable portion of the bed is pivoted downwardly into the sleep position , as part of the wall treatment . as illustrated by fig1 , when the platform section 32 is raised to the vertical closed position , legs 34 are aligned with top frame 36 ; preferably the legs have a treatment 35 so that legs 34 and top frame 36 are finished similarly , and so that the legs 34 appear to be part of the top frame 36 , so that together with the bottom frame 36 they form a decorative “ frame ” or “ border ” for the façade . façade 20 may be provided with vertical side members 18 , which cooperate esthetically with the bottom frame 24 , legs 34 and top frame 36 to effectively provide a complete visual frame for the internal portion of façade 20 . the top frame 36 cooperates with the legs 34 when the platform 44 is in its raised position , while the remaining mechanism is concealed in the bottom frame 24 and in the platform 32 , concealed beneath the façade 20 . in this way , the owner is given freedom to choose whatever decorative treatment he or she likes for the façade 20 , with the legs 34 , side members 18 , and top and bottom frames 36 and 24 forming part of the design or framing it , as desired . for example , the façade 20 , legs 34 , side members 18 and top and bottom frames 36 and 24 , respectively , can all be finished identically , e . g ., in wood veneer , giving the appearance of a paneled wall . the clearance necessary to allow movement of the various components can be provided by narrow decorative gaps or “ reveals ” between the members . as illustrated in fig2 and 3 , the legs may be rotated out from behind concealing panels , or , as shown in fig1 , the entire leg assembly may rotate as one . the overall visual effect is that when one looks at the unit in the vertical position there is little to give away that it is also a comfortable bed . fig4 shows an elevational view of the principal components of one embodiment of the mechanism , as if looking at the unit in the vertical position , with the façade removed , and with the slat assembly which supports the sleep system shown partially cut away . fig5 shows a more detailed view , in plan , of the torsion spring system , which counterbalances the weight of the unit , easing the work of raising and lowering it between upright and stowed and sleep positions . in another embodiment , discussed in detail in connection with fig2 below , the torsion spring arrangement shown can be replaced by one or more gas spring ( s ); implementation of the gas spring , or another mechanical device for storing energy as the bed is lowered and releasing it as the bed is raised , is considered to be within the skill of the art . in each case the energy - storing device need simply be connected between the fixed and moving portions of the bed of the invention so as to store mechanical energy , as by compressing a gas , tensioning a spring , lifting a weight , or the like , as the bed is lowered , and releasing the stored energy as the bed is raised , easing this task . all manner of mechanisms for doing so are considered within the claims of this application where not specifically excluded . as illustrated in fig4 , in one embodiment of the invention the movable portion 30 of the unit comprises a frame 40 , comprising side rails 42 , a central rail 44 , and top and bottom members 46 and 48 respectively . typically , and without limiting the invention , these will be fabricated of steel or aluminum angle stock , tubing , an aluminum extrusion or the like , provided ( apart from central rail 44 , which is unseen ) with wood veneer concealing members or the like . the fixed portion 22 of the unit comprises a wall plate 50 , secured to the wall as described below , which supports an axle 52 mounted in pillow blocks 54 . the axle 52 is secured to lower member 48 of frame 40 by brackets ( or additional pillow blocks ) 55 , such that the movable portion 30 of the unit and the axle 52 pivot together with respect to fixed portion 22 about the axis defined by axle 52 . in the embodiment shown , but to which the invention is not to be limited , torsion springs 56 fitting concentrically over axle 52 , and detailed further below , counterbalance the weight of the unit . more specifically ( see fig5 ), one end 56 a of each torsion spring 56 is secured to the wall plate 50 by a bracket 64 and a cone 62 fitting over the axle 52 , allowing the torsion spring 56 to rotate freely around axle 52 . the other end 56 b of the torsion spring 22 is secured to the axle 52 by a second cone 66 , secured to the axle 52 . thus , because one end 56 a of the torsion spring is fixed to the wall plate 50 , and the other end 56 b of the torsion spring 56 rotates with the movable portion of the unit , the torsion spring is twisted tighter , creating resistance ( storing energy ) as the frame is lowered , and the energy is released as the bed is raised , easing the work of doing so . the torsion spring assembly thus effectively counterbalances the weight of the unit . the precise amount of counterbalancing desired can be obtained by adjusting the relative position of the end 56 b of the torsion spring with respect to the axle 52 , effectively adjusting the amount of preload applied to the spring . the adjustment should be such that the unit can be lifted with ease by a slight person , for example , so that about ten total pounds of force are required , and so that the unit is held upright against the wall by the torsion springs . the preload applied by the springs 56 can be adjusted as shown in fig8 , an end view showing axle 52 and cone 66 , to which end 56 b of spring 56 is affixed . the preload is effected by turning cone 66 with respect to axle 52 , e . g ., employing a spanner wrench or like tool 68 fitting into bores 69 in cone 66 to exert torque on cone 66 , and locking cone 66 to axle 52 where desired using setscrews 70 . another possibility would be a ratcheting system , which can be easily adjusted and released . these particular embodiments are not meant to limit the torsion spring adjustment systems useful in implementation of this invention . a damper system 58 mounted to the wall plate 50 and secured to axle 52 limits the rate of rotation of the axle 52 with respect to the wall plate , thus controlling the motion of the unit between the upright and stowed position and the sleep position . fig9 shows the damper system 58 , which controls the rate of descent as the bed is being lowered and also slows its ascent as the bed approaches the upright position . in this embodiment , a known hydraulic rotary damper 80 , typically employed as a door closer , is used ; in order to accommodate the existing hydraulic damper in the space available , the axis of rotation of the axle 52 must be redirected though 90 . degree ., e . g ., using a pair of bevel gears 82 . the damper 80 used in this embodiment has three adjustment screw valves 84 , 86 , 88 which , when the unit is used as a door closer , control the door to prevent slamming while ensuring reasonably rapid opening , and so on . as used herein , valve 84 controls the descent of the unit as it descends to a horizontal position , while valve 86 controls the rate of descent as the unit approaches the floor , beginning about 18 inches from the horizontal . wall approach valve 88 controls rate of rotation of the unit as it is being lifted and approaches the vertical , starting about two feet before it approaches the wall in the upright position ; that is , as the work required to be done by the torsion springs is reduced as the unit approaches the vertical , i . e ., as the springs have less work to do per degree of rotation , the damper prevents the unit from moving too fast , which could lead to , e . g ., fingers getting caught in the mechanism , and might be noisy . thus , wall approach valve 88 controls the movement of the bed as it approaches the wall . provision of the damper 80 thus adds safety and control both when the bed is being lowered , keeping it from dropping too quickly , hitting the floor hard , or slamming up against the wall as it is moving upright . in the preferred embodiment of the invention , legs 34 , which support the foot end of the unit in the sleep position , are deployed automatically as the unit is lowered and are similarly retracted as it is raised . as shown in fig4 , legs 34 are mounted to the top frame member 46 at pivots 59 . their automatic deployment and retraction can be accomplished in a wide variety of ways within the scope of the invention . in one preferred embodiment shown and detailed further below one or more tension cables retract the legs when the unit is raised , while springs urge the legs outwardly as it is lowered . thus , as the unit is raised or lowered , the legs are retracted or deployed accordingly . preferably , the mechanism is over - center in that the legs are moved beyond the vertical when deployed , such that they cannot be retracted without lifting the unit and will not buckle and collapse inwardly when loaded . fig6 and 7 show the preferred method of attaching the bottom frame and headboard to the wall w . in this embodiment , and assuming a standard stud - and - drywall wall construction , one or more wall attachment plates 100 are first secured to the structural elements in the wall w , that is , to wooden or metal studs 106 , and a hinge plate 104 , which carries the pillow blocks and other components discussed above , is then secured to the wall attachment plates 100 . this is preferred for reasons of ease of installation , although it is within the scope of the invention to secure the hinge plate 104 directly to the wall w . the wall attachment plates 100 are attached along a straight line a given dimension , typically one foot , off the floor , such that the head of the bed is parallel to the floor when open . in a further option , the wall attachment plates 100 could comprise first members to be secured to the studs and second members to be attached thereto , to which the hinge plate is in turn attached ; the second members could be made vertically adjustable with respect to the first members , for ease in leveling the hinge plate . likewise , the wall attachment plates 100 should be securable to the hinge plate 104 at any position therealong , to ensure secure mounting even if the studs are not evenly spaced . in the embodiment shown , the lower edge of the hinge plate 104 is lowered into a j - shaped channel 110 formed integrally with or fixed to wall attachment plates 100 . the upper edge of the hinge plate 104 is then secured to the wall plates 100 with screws 108 and clips 112 . a headboard 26 can be provided to conceal the wall attachment plates . fig1 , 10 a , and 11 show the cambered slat sleep suspension system , which provides comfort by absorbing movement and pressure , following the contours of the body . in this embodiment , cambered slats 120 are made of thin ( ⅜ ) inch hardwood plywood laminated over curved forms to have a camber of ⅜ inch over the length of the slat . the slats are about 3 ″ wide in this embodiment . the slats 120 could also be made of other flexible materials such as fiberglass , metals , or plastics , and could be of differing dimensions . as illustrated in fig4 , 10 , and 11 , rubber strips 122 are molded to define receptacles to receive the ends of the slats 120 while allowing the slats to move and flex somewhat , absorbing the shifting pressure when the bed is in use . the molded rubber strips are held in place by screws 124 extending into the side rail 42 ( see fig1 ). as shown in fig1 a , the frame may comprise a metal member 127 for strength , concealed by a wooden molding 129 . fig1 also shows the preferred combined air / foam mattress 134 , in dotted lines in the deflated condition and in full as inflated when in a sleep position . this mattress 134 is made of an airtight bladder filled with a compressible fiber / foam material 135 with a thinner layer ( e . g ., one inch thick ) 136 of foam forming a topper . this creates the feel of a natural foam mattress , without the uncomfortable “ roll ” encountered with conventional air mattresses . preferably the mattress 134 is automatically inflated as the unit is operated to take the sleep position and deflated , by applying a vacuum to the interior of the mattress , as the unit is raised . deflating the mattress by application of vacuum compresses the fiber and foam components within the air bladders of the mattress . thus the mattress , which can be as much as seven inches thick and very comfortable when inflated , is compressed to about 2½ inches thick when deflated , reducing the overall thickness of the bed of the invention , as is critical to its appearance as an attractive wall treatment when in the vertical position . inflation and deflation can be accomplished using a bi - directional air pump 138 , connected to the mattress 134 and arranged to be operated automatically upon motion of the movable portion of the unit with respect to the fixed portion . while this embodiment uses the hybrid fiber / foam inflatable component with a foam topper , one could use a simple air mattress to accomplish the same thing . further , of course , while this embodiment uses an electric air handling system one could use a foot pump or other means of inflation and deflation . fig1 - 15 show one preferred embodiment of a mechanism for automatically lowering the legs 34 as the movable portion of the unit is lowered to the sleep position , and for retracting the legs as it is raised . in this embodiment , the legs are spring - biased toward the deployed position , and are pulled back to the retracted position against the spring bias when the movable portion of the unit is raised . other arrangements for providing similar automatic operation of the legs are within the skill of the art . as noted above , fig1 is a perspective view showing the overall arrangement of one embodiment of the leg actuation mechanism , in which a cam 176 mounted on axle 52 controls a cable 174 which retracts the legs against the spring bias . fig1 , comprising fig1 ( a ) and ( b ), shows a detail of the cam assembly , wherein fig1 ( a ) shows the cam assembly when the unit is in the sleep position , and fig1 ( b ) shows the position of the cam assembly with the unit in the upright and stowed position . fig1 shows the assembly of one of the legs to the frame of the unit , and fig1 is a cross - sectional view taken along line 15 - 15 of fig1 . legs 34 are shown as solid members , for simplicity , but of course the invention is not to be thus limited . the structural loads applied to legs 34 could be carried by extruded aluminum members sheathed in a ornamental treatment to match or complement the treatment of the underside of the bed . for example , the legs could be sheathed in veneered composite material . the sheathing applied could also be made readily removable , so that the appearance of the bed could be conveniently altered as desired . as shown , the legs 34 pivot about axes running generally along the sides 42 of the frame ; a bolt 59 ( one leg assembly being shown in fig1 , 14 , and 15 ; the other being minor - imaged ) secures each leg 34 to the frame 40 , e . g ., being threaded into a block 150 welded to the side frame 42 . a bushing 152 , e . g ., of high - density plastic material , spaces the leg 34 from block 150 , provides low - friction pivoting of the leg , and provides a pivot about which hairpin spring 154 is retained . spring 154 is arranged to exert an outward bias on leg 34 , that is , to rotate it clockwise in fig1 , by exerting bias between a pin 156 fixed to leg 34 and an ear 160 on a bracket 162 fixed to frame 40 , e . g ., by screws 164 extending into block 150 . it is desirable to limit the degree to which the leg 34 pivots outwardly responsive to the bias of spring 154 , to ensure that the leg solidly supports the foot end of the unit when in the sleep position . one way to accomplish this is shown in fig1 and 15 . a first pin 168 extends between mating bores in bushing 152 and block 150 , preventing rotation of bushing 152 , and a second pin 170 extends from a bore in leg 34 into an arcuate recess 172 in bushing 152 , limiting the degree of rotation permitted to leg 34 . as noted , a cable 174 is provided to retract the legs 34 against the bias of spring 154 when the movable portion of the unit is raised to the vertical stowed position . as illustrated , one end of cable 174 is secured with respect to the wall plate 50 , so that as the movable portion is raised , rotating axle 52 , cable 174 is wound upon a cam 176 secured to axle 52 . the opposite end of cable 174 is bifurcated , as indicated at 178 , and passes over sheaves 180 secured to the top member 46 of frame 40 so as to simultaneously control the motion of both legs 34 . a spring 182 , of higher spring value than spring 154 ( after consideration of the various mechanical advantages provided ), but having its travel limited , is disposed along cable 174 to keep positive tension on cable 174 , so that the legs are securely retained when the movable portion of the unit is in its upright position . fig1 - 19 show an alternative mechanism for automatically deploying and retracting the legs as the bed is lowered and raised , respectively . in this case the legs are operated by a rigid rod member 200 . member 200 is driven in push - pull fashion by a mechanism shown in fig1 and 19 . motion of member 200 is communicated to the legs by flexible slide members 202 , which are fabricated of a flexible material capable of exerting force without buckling in both tension and compression , such as strips of fiberglass , and by further rigid members 208 , secured to slide members 202 at 210 . flexible members 202 slide within guides 204 , while rigid members 208 are constrained to back - and - forth movement by headed bolts extending through slots 208 a in members 208 . members 208 are then pivotally secured to legs 34 by bolts 212 . thus , as member 200 is urged back and forth , legs 34 are pivoted in and out ; legs 34 may again be provided with springs biasing them to the deployed position , to ensure that that any slack in the mechanism does not result in the failure of the legs to fully deploy . one method of providing back and forth motion to member 200 as the bed is raised and lowered is shown by fig1 and 19 . the axis about which bed frame pivots as it raised and lowered is defined by axle 52 , located with respect to the wall by a first bearing ( or set of bearings ) 54 and with respect to the bed frame by a second bearing 55 . a bracket 216 secured to the sliding member 200 at 222 pivots with respect to a bolt 218 , fixed with respect to the wall , as the bed frame is raised and lowered . as the pivot point defined by axle 52 is not collinear with the pivot point defined by bolt 218 , as the bed is lowered the sliding member 200 is forced outwardly , away from axle 52 , causing the legs to be deployed ; as the bed is raised the opposite occurs , pulling the legs back into their inactive position . a further mechanism for automatically deploying and withdrawing the legs is shown by fig1 a ; here bevel gears 230 on either end of axle 52 simply drive a mating pair of gears 232 mounted on shafts 234 running along the outer edges of the bed frame , and arranged to operate the legs 34 as desired . fig2 shows schematically a further mechanism for automatically deploying and withdrawing the legs as the bed is lowered and raised . ( the decorative sheathing that would normally be provided on the frame members and legs is omitted from this view for clarity .) in this design , as illustrated , individual leg - lifting cables run from the legs to respective actuating mechanisms on the opposite side of the bed . the actuating mechanisms comprise cams , generally similar to that shown in fig1 a and b , while the energy - storage and damping functions are both provided by one or more gas springs , effecting a further simplification . more specifically , in this embodiment the bed pivots about an axis defined by a continuous axle or two stub axles 252 supported by bearing brackets 258 , which would typically be mounted on a wall plate 248 secured to a wall ( not shown ). left and right legs , 240 and 242 respectively , are pivoted about axes 243 and 247 , and are operated by cables 262 and 274 confined in sheaths 260 and 272 . one end of each cable is fixed to the corresponding leg and the other end is fixed with respect to the wall plate 248 and hence the wall by a bracket 266 . cables 274 and 262 are tensioned by cams 270 and 264 as the bed is raised from its lowered position in fig2 to the vertical position , pulling legs 240 and 242 into the plane of the bed frame comprising side frames 247 , 246 and foot member 244 . if the axles 252 are spaced sufficiently from the wall plate 248 it may be possible to dispense with the cams . conversely , as the bed is lowered , tension in the cables is released , and hairpin springs 241 , 245 ( the complete leg attachment mechanism possibly being as shown in fig1 and 15 ) urge the legs to their deployed position . in the fig2 embodiment , as the bed is lowered energy is stored in one or more gas springs 276 , 250 ( a pair being shown ), connected between crank arms 278 , 254 fixed to pivot axles 252 and brackets 255 , 256 fixed to wall plate 248 ; this energy is released as the bed is raised , easing the work of doing so . gas springs suitable for this application and in which the rate of travel is controlled are commercially available , so that the gas springs can also be used to limit the rate of motion of the bed , eliminating the need for a separate damper as shown in other embodiments discussed above . other suitable mechanisms for thus automatically deploying and withdrawing the legs as the bed is lowered and raised are within the skill of the art and are intended to be included within the scope of this invention . a further improvement that is within the scope of the invention is to provide a further mechanism for lowering the decorative façade covering the portion of the unit that is fixed to the wall as the movable portion is pivoted toward the sleep position , and raising it correspondingly ; this would allow the sections of the decorative façade covering the fixed and movable portions of the unit to fit closely to one another , which would be esthetically desirable . this could be accomplished in the fig2 embodiment by mounting this portion of the façade for vertical sliding motion over a range of up to a few inches , and actuating its motion by a mechanism operated by rotation of axles 252 . it is also within the invention to employ the mechanical design of the unit of the invention into a stowable bed intended for use where space - conservation is important but esthetics are less so , such that the unit need not comprise a decorative façade . for example , the unit of the invention could be incorporated in a hospital - room cabinet , to provide temporary accommodation for patients &# 39 ; visitors and the like . while a preferred embodiment of the invention has been described in detail , this is exemplary only and the invention is not to be limited thereby .

a combined wall treatment and bed , that is , a unit which resembles a decorative wall treatment , such as a painting , when in the upright and stowed position , but which can be lowered to provide a comfortable bed . when the unit is in the upright and stowed position its appearance is that of a thin wall treatment , the thickness of a large painting , and thus consumes practically no living space . a fixed component can be attached to any standard wall construction without modification ; it supports the lower edge of a movable portion and defines an axis about which the movable portion pivots to provide a functional and comfortable bed .

the present invention may be embodied in a number of different forms . the specification and drawings that follow describe and disclose some of the specific forms of the invention . in the attached figures there is depicted an infant oral hygiene device constructed in accordance with preferred embodiments of the invention and noted generally by reference numeral 1 . device 1 is comprised of a sleeve 2 that is releasably receivable over the finger of a user . sleeve 2 is generally in the form of a hollow tubular sleeve having a first end 3 and a second end 4 . the sleeve is sized and dimensioned to fit relatively snugly about the finger of an average sized adult , with the adult &# 39 ; s finger being inserted into first end 3 . the diameter of the sleeve may be consistent along its length or , alternatively , in one of the embodiments of the invention the diameter may decrease slightly when moving from first end 3 to second end 4 . sleeve 2 may also include an enlarged ring member five 5 about first end 3 that allows the sleeve to be grasped and pulled onto the user &# 39 ; s finger , and then subsequently grasped and removed from the finger . it will be appreciated that other physical structures aside from ring 5 may equally be utilized to assist in placing the sleeve over a finger and then later removing it . as shown in the attached drawings , sleeve 2 preferably includes one or more openings 6 in or about the second end 4 . in the embodiment of the invention shown in fig1 opening 6 comprises a completely open end 4 of sleeve 2 . alternately , and for example as shown in fig6 , opening 6 may be comprised of a window portion 7 within second end 4 , with the remainder of second end 4 being enclosed . it will be understood that further variations of the size , nature , placement and number of openings could equally be utilized . for example , a series of windows 7 could be placed about the circumference of second end 4 , or the size and shape of the window or windows could be altered . referring to fig1 through 3 , in operation of the invention a fabric 8 is placed over the finger of a user , after which sleeve 2 is slid over the fabric and the finger . the relatively tight fit between the user &# 39 ; s finger and sleeve 2 will cause the sleeve to stay in place on the finger and will retain fabric 8 in a taut configuration . at least a portion of fabric 8 is exposed through opening ( or openings ) 6 . in this manner the fabric exposed through opening 6 can be used to wipe or massage the teeth and / or gums of an infant when the user &# 39 ; s finger , having sleeve 2 and fabric 8 inserted there over , is inserted into the infant &# 39 ; s mouth and slowly drawn across the teeth and gums . the fit of sleeve 2 over the user &# 39 ; s finger ensures that the fabric exposed though openings 6 remains taut . maintaining the fabric in a taut configuration allows the fabric to efficiently clean and massage the teeth and gums , and also helps to present a consistent surface that is less prone to catching upon partially erupted teeth or irritating inflamed gums . it will be appreciated that sleeve 2 could be formed from a wide variety of different materials . although the sleeve could be rigid or semi - rigid in nature , it is expected that in most instances the sleeve will be formed from a pliable material , such as rubber , silicone or a similar product . if formed from a rubber or silicone type material the sleeve will also have a degree of flexible resiliency which will enable it to be stretched as it is slid over the finger of a user . in that manner the sleeve may be held more securely about the finger of the user and will be less likely to slide off . the pliable nature of the material from which sleeve 2 may be formed will also tend to be more soothing to the gums of an infant , and will provide a degree of protection to the finger of a user should the infant bite down upon the user &# 39 ; s finger . with reference to fig4 and 5 , in one embodiment of the invention sleeve 2 may be fitted with a plurality of small bristles 9 and / or nibs 10 located on its outer surface at or generally adjacent to second end 4 . bristles 9 or nibs 10 provide the user with a slightly more aggressive means to brush the gums of the infant should there be a significant emersion of teeth that may lend themselves to cleaning more readily through the use of bristles 9 or nibs 10 . it will be appreciated that either bristles or nibs could be positioned on the outer surface of sleeve 2 , or that in some instances both bristles and nibs could be utilized . it will also be appreciated that the specific location of the bristles and / or nibs on the sleeve could vary . in the enclosed drawings fabric 8 is shown as comprised of a sheet of gauze . it should , however , be understood that a wide variety of different fabrics or fabric - like materials could equally be used while remaining within the broad scope of the invention . it will also be appreciated by those of ordinary skill in the art and having a thorough knowledge of the invention that although the invention has been described for use as an infant oral hygiene device , it could equally be used by older individuals , particularly those having dentures or having teeth that have been extracted . it is to be understood that what has been described are the preferred embodiments of the invention . the scope of the claims should not be limited by the preferred embodiments set forth above , but should be given the broadest interpretation consistent with the description as a whole .

an infant oral hygiene device comprising a sleeve releasably securable over the finger of a user . the sleeve is generally cylindrical and has first and second ends . the first end receives the finger of the user . the sleeve has one or more openings in its second end . the one or more openings expose a portion of a fabric received over the finger of the user and between the user &# 39 ; s finger and the sleeve thereby permitting the fabric to be drawn across the teeth and gums of an infant .

the present invention has utility in suppression of deleterious gene expression products . production of specific proteins is associated with allergic reactions , transplant organ rejection , cancer , and iga nephropathy , to name but a few of the medical conditions a subject may suffer . additionally , according to the present invention , it is appreciated that specific animal proteins are also suppressed in foodstuffs , such as cow &# 39 ; s milk , through the treatment of the animal . inventive compositions include one of a long or short dsrna , or short hairpin rna ( shrna ) that is bound to a cell surface receptor specific ligand and targeted to a specific tissue and / or cell type upon delivery to a subject . in designing a ligand coupled dsrna or shrna , a target tissue and / or cell is selected , and the targeted cell type is analyzed for receptors that internalize ligands following receptor - ligand binding . it is appreciated that the present invention is also operative in suppressing genes within a cell growing in vitro and particularly well suited for limiting contaminants in recombinant protein manufacture . cell specific antigens which are not naturally internalized are operative herein by incorporating an arginine - rich peptide within the ligand , an arginine - rich peptide attached to the cell surface receptor specific ligand , as detailed in u . s . pat . no . 6 , 692 , 935 b1 or u . s . pat . no . 6 , 294 , 353 b1 . an arginine - rich peptide causes cellular internalization of a coupled molecule upon contact of the arginine - rich peptide with the cell membrane . pentratin and transportan are appreciated to also be operative as vectors to induce cellular internalization of a coupled molecule through attachment to the cell surface receptor specific ligand as detailed in u . s . pat . no . 6 , 692 , 935 b1 or u . s . pat . no . 6 , 294 , 353 b1 . a cell surface receptor specific ligand as used herein is defined as a molecule that binds to a receptor or cell surface antigen . a ligand is then coupled to an appropriate dsrna . the ligand is a natural - or engineered - peptide or - protein , such as is commercially available ( antibodies by design , morphosys , martinsried , germany ) ( u . s . pat . no . 5 , 514 , 548 ; u . s . pat . no . 6 , 653 , 068 b2 ; u . s . pat . no . 6 , 667 , 150 b1 ; u . s . pat . no . 6 , 696 , 245 ; u . s . pat . no . 6 , 753 , 136 b1 ; us 2004 / 017291 a1 ). another specific engineered peptide that is commercially available is the camelid single heavy chain variable domain ( nanobodies , ablynx , n v ; zwijnaarde , belgium ); such a variable domain heavy chain antibody fragment is humanized and the antigen specificity thereof is generated from a phage display library from an immunized animal ( van koningbruggen et al . 2003 ) or a nucleic acid sequence expression library from non - immunized animals , as detailed in ep 0 584 421 a1 or u . s . pat . no . 6 , 399 , 763 . if the engineered ligand is an immunoglobulin , the carboxy terminus of the molecule is at the variable end of the protein , and the amino terminus is available for bonding to dsrna . because of the relatively large size of immunoglobulin molecules , preferably a fab fragment is used as the ligand rather than the entire immunoglobulin . more preferably , a ( fab ′) 2 fragment is provided that allows for divalent binding as would occur with the entire immunoglobulin without the encumbrance of the fc component . bridging of cell surface receptors by a divalent ( fab ′) 2 fragment facilitates activation of the signaling pathway and subsequent internalization of the receptor - ligand combination in some internalization processes . the functional rna interference activity of interfering rna transported into target cells as a cargo molecule attached to hiv - 1 transactivator of transcription ( tat ) peptide 47 - 57 has been demonstrated ( chiu y - l et al . 2004 ). the functional rna interference activity of interfering rna transported into target cells as a cargo molecule attached to pentratin has also been demonstrated ( muratovska and eccles 2004 ). the dsrna or shrna oligonucleotide mediating rna interference is delivered into the cell by internalization of the receptor . in the event a targeted cell receptor is a unique receptor that is not naturally internalized , that receptor is nonetheless suitable as a target by incorporating an internalization moiety such as an arginine - rich membrane permeable peptide within the ligand or attaching to the ligand such as an arginine - rich membrane permeable peptide , pentratin , or transportan as detailed in u . s . pat . no . 6 , 692 , 935 b1 or u . s . pat . no . 6 , 294 , 353 b1 . this is readily accomplished using established plasmid technology ( caron et al . 2004 ; he et al . 2004 ). alternatively , the use of morphosys &# 39 ; commercial trinucleotide mutagenesis technology allows the synthesis of a membrane - permeable arginine - rich peptide at a single position of the variable region , as detailed in u . s . pat . no . 6 , 692 , 935 b1 or u . s . pat . no . 6 , 294 , 353 b1 . the morphosys system joins an antigen - non - specific fab fragment containing a membrane - permeable arginine - rich peptide to an engineered fab fragment with a variable region specific for the cell surface receptor in order to provide for the cell specific targeting of the dsrna . these fab fragments are joined by a helix - turn - helix region . alternatively , the membrane - permeable arginine - rich peptide is incorporated into the antigen - specific fab immunoglobulin fragment to yield a bivalent antigen specific molecule produced ( anderson d c 1993 ). the membrane - permeable arginine - rich peptide is optionally also attached to another portion of the immunoglobulin molecule ( mie m et al . 2003 ; u . s . pat . no . 6 , 692 , 935 b1 ; u . s . pat . no . 6 , 294 , 353 b1 ). similarly , pentratin or transportan is attached to or incorporated within any ligand portion of the molecule with the proviso that ligand - receptor binding is maintained . in each situation , the ligand containing the membrane - permeable arginine - rich peptide , pentratin , or transportan serves to carry the dsrna into the targeted cell . arginine - rich peptides which are internalized after contact with the cell membrane have been shown to transport covalently coupled proteins into cells ( peitz m et al . 2002 , jo et al . 2001 ). examples of such internalization moieties illustratively include : membrane - permeable arginine - rich peptides , pentratin , transportan and its deletion analogs . grkkrrqrrrppq ( tat 48 - 60 ) ( seq id no . 1 ) grrrrrrrrrppq ( r9 - tat ) ( seq id no . 2 ) trqarrnrrrrwrerqr ( hiv - 1 rev 34 - 50 ) ( seq id no . 3 ) rrrrnrtrrnrrrvr ( fhv coat 35 - 49 ) ( seq id no . 4 ) kmtraqrraaarrnrwtar ( bmvgag7 - 25 ) ( seq id no . 5 ) trrqrtrrarrnr ( htlv - ii rex 4 - 16 ) ( seq id no . 6 ) rqikiwfqnrrmkwkk ( atennapedia 43 - 58 - pentratin ) ( seq id no . 7 ) likkalaalaklnikllygasnltwg ( transportan ) ( muratovska and eccles 2004 ) ( seq id no . 8 ). alternative amino acid composition for transportan and its deletion analogs which maintain membrane transduction properties ( soomets et al . 2000 ): gwtlnsagyllgkinlkalaalakkil ( transportan ) ( seq id no . 9 ) lnsagyllgkinlkalaalakkil ( transportan7 ) ( seq id no . 10 ) gwtlnsagyllgklkalaalakkil ( transportan9 ) ( seq id no . 11 ) agyllgkinlkalaalakkil ( transportan10 ) ( seq id no . 12 ) lnsagyllgklkalaalakkil ( transportan12 ) ( seq id no . 13 ) agyllgklkalaalakkil ( transportan14 ) ( seq id no . 14 ) preferably , the internalization moiety is coupled to or incorporated into an immunoglobulin ligand which is bonded to an inventive dsrna , or short hairpin rna serving as a substrates for enzymatic production of sirna . receptor - binding immunoglobulins are obtained using hybridoma technology . fab and ( fab ′) 2 fragments are prepared from such immunoglobulins by papain and pepsin hydrolysis , respectively ( stura et al . 1993 ). the resulting molecules are purified using standard biochemical methods . dsrna with sirna sequences that are complementary to the nucleotide sequence of the target gene are prepared . the sirna nucleotide sequence is obtained from the sirna selection program , whitehead institute for biomedical research , massachusetts institute of technology , cambridge , mass . ( http :// jura . wi . mit . edu ) after supplying the accession number or gi number from the national center for biotechnology information website ( www . ncbi . nlm . nih . gov ). the genome database ( www . gdb . org ) provides the nucleic acid sequence link which is used as the national center for biotechnology information accession number . preparation of rna to order is commercially available ( ambion inc ., austin , tex . ; genomechanix , llc , gainesville , fla . ; and others ). determination of the appropriate sequences would be accomplished using the usphs , nih genetic sequence data bank . alternatively , dsrna containing appropriate sirna sequences is ascertained using the strategy of miyagishi and taira ( 2003 ). dsrna may be up to 800 base pairs long ( diallo m et al . 2003 ). the dsrna optionally has a short hairpin structure ( us patent application publication 2004 / 0058886 ). commercially available rnai designer algorithms also exist ( http :// rnaidesigner . invitrogen . com / rnaiexpress /). the ligand and the dsrna are then coupled with linkages illustratively including phosphoramidate , phosphorothioate , or phosphodiester . modified sirna containing a 3 ′- amino group with a 3 - carbon linker may be utilized for coupling to the ligand via the linker group . the modified sirna conjugation to the ligand via a heterobifunctional cross linker ( sulfo - succinimidyl 4 -( p - maleimidophenyl ))- butyrate is accomplished as previously described ( chiu y - l et al . 2004 ). functional sirna coupled to this linker for transmembrane transport by tat has been demonstrated . phosphoramidate bonding is accomplished as described by ( gryaznov and winter 1999 ). phosphodiester bonding is accomplished using standard biochemical methods . phosphorothioate bonding is accomplished as described by ( stec et al . 1991 ). in another embodiment , the dsrna bonding to the ligand by any of the above described chemical bonds is accomplished via a “ helix - turn - helix ” region as described in u . s . pat . no . 5 , 910 , 573 . this allows maximal flexibility of the dsrna positioning allowing for successful enzymatic hydrolysis . in an additional embodiment , a disulfide linkage of the sirna and ligand is formed ( hermanson 1996 ). the sirna is modified with a cystamine at the 5 ′ phosphate group using a carbodiimide reaction such as reaction with 1 - ethyl - 3 -( 3 - dimethylaminopropyl ) carbodiimide hcl ( hermanson pages 651 - 654 ). reaction with a disulfide reducing agent creates a thiol group . the ligand is modified with a heterobifunctional cross linker illustratively n - succinimidyl 3 -( 2 - pyridyldithio ) propionate ( hermanson pages 230 - 232 ). disulfide linkage between the cystamine - modified sirna and the antibody ligand modified with the heterobifunctional cross linker is accomplished as described for enzyme conjugation to dna ( hermanson pages 662 - 664 ). additionally , sirna ligand conjugation can be via stable hydrazone bonds ( solulink bioconjugation system , solulink , san diego , calif . ; kozlov et al . 2004 ). alternatively , cell surface receptor specific ligands that are rich in arginine and tyrosine residues are constructed such that those residues are positioned to form hydrogen bonds with engineered rna containing appropriately positioned guanine and uracil ( jones 2001 ). additionally , the necessity and performance of an internalization moiety is determined in vitro . the suitability of the resulting ligand - dsrna as a substrate for dicer is first determined in vitro using recombinant dicer ( zhang h 2002 , provost 2002 , myers j w 2003 ). optimal ligand molecule size and dsrna length are thereby identified . in an alternate embodiment , the ligand - dsrna molecule is adsorbed onto a dsrna binding molecule ( s ) illustratively including : a histone ( jacobs and imani 1988 ), rde - 4 ( tabara et al . 2002 ; parrish and fire 2001 ), and protamine ( warrant and kim 1978 ) in order to render the ligand - dsrna hydrophilic . the histone with relatively lower rna - histone binding affinity ( jacobs and imani 1988 ) such as histone h1 ( prepared as described by kratzmeier m et al . 2000 ) is preferred . alternatively , rde - 4 is used as prepared commercially ( qiagen , valencia , calif .) using rde - 4 cdna ( gene bank accession numbers ay07926 and y1l832c2 . 3 ) ( www . ncbi . nlm . nih . gov / ieb / research / acembly ). rde - 4 initiates rna interference by presenting dsrna to dicer ( tabara et al ). protamines are arginine - rich proteins . for example , protamine 1 contains 10 arginine residues between amino acid residue number 21 and residue number 35 ( rsrrrrrrscqtrrr ) ( lee et al . 1987 ) ( seq id no . 15 ). protamine binds to rna ( warrant and kim 1978 ). preparation of the ligand - dsrna - histone complex is accomplished as described by ( yoshikawa et al . 2001 ). complexes of lysine rich histone containing 24 . 7 % ( w / w ) lysine and 1 . 9 % arginine ( w / w ) with dsrna is prepared by gentle dilution from a 2 m nacl solution . histone and dsrna are dissolved in 2 m nacl / 10 mm tris / hcl , ph 7 . 4 , in which the charge ratio of dsrna : histone (−/+) is adjusted to 1 . 0 . then the 2 m nacl solution is slowly dispersed in distilled water in a glass vessel to obtain 0 . 2 m and 50 mm nacl solutions . the final volume is 200 μl and final dsrna concentration is 0 . 75 μm in nucleotide units . binding affinity of histones is further reduced by acetylation of the lysine residues of the histone . this reduces the positive charge of the ε - nh 2 group . acetylation is accomplished by established techniques ( garcea and alberts 1980 ). preparation of the ligand - dsrna - rde - 4 complex is accomplished as described by ( johnston et al . 1992 ), for the conserved double - stranded rna binding domain which rde - 4 contains . rde - 4 binding to dsrna to is accomplished in 50 mm nacl / 10 mm mgcl 2 / 10 mm hepes , ph 8 / 0 . 1 mm edta / 1 mm dithiothreitol / 2 . 5 % ( wt / vol ) non - fat dry milk . preparation of the ligand - dsrna - protamine complex is accomplished as described by ( warrant and kim 1978 ). the protamine ( human recombinant protamine 1 , abnova corporation , taiwan , www . abnova . com . tw ) and ligand - dsrna at a molar ratio of 1 : 4 are placed in a buffered solution containing 40 mm na cacodylate , 40 mm mgcl 2 , 3 mm spermine hcl at ph 6 . 0 ( warrant and kim 1978 ). the solution is incubated at 4 ° c .- 6 ° c . for several days . the constructed ligand - dsrna molecule is then administered parenterally and binds to its target cell via its receptor . the constructed ligand - dsrna molecule is then internalized and the dsrna is hydrolyzed by dicer thereby releasing sirna for gene silencing . rnase iii cleaves phosphorothioate - substituted rna ( nicholson 1988 ). 3 ′- exonucleases may also sever phosphorothioate bonds ( heidenreich 1997 ). the invitrogen corporation ( carlsbad , calif .) cellsensor cre - bla jurkat cell - based assay is used . the detailed protocol is available online and is included in the references ( cellsensor protocol ). jurkat cells express cd38 on their cell surfaces which is internalized following ligand binding to it ( funaro at al . 1998 ). cellsensor cre - bla jurkat cell - based assay contains a beta - lactamase reporter gene under control of a camp response element which has been stably integrated into the cre - bla jurkat cell line ( clone e6 - 1 ). beta - lactamase is expressed following forskolin stimulation . short interfering rna 19 base pairs long is prepared using the invitrogen corporation algorithm based on the dna sequence of the cre - bla beta - lactamase gene : atggacccagaaacgctggtgaaagtaaaagatgctgaagatcagttgggtgcacgagtgggttacatcgaac ( seq id no . 16 ) tggatctcaacagcggtaagatccttgagagttttcgccccgaagaacgttttccaatgatgagcacttttaaagttctgctatg tggcgcggtattatcccgtattgacgccgggcaagagcaactcggtcgccgcatacactattctcagaatgacttggttgag tactcaccagtcacagaaaagcatcttacggatggcatgacagtaagagaattatgcagtgctgccataaccatgagtgata acactgcggccaacttacttctgacaacgatcggaggaccgaaggagctaaccgcttttttgcacaacatgggggatcatg taactcgccttgatcgttgggaaccggagctgaatgaagccataccaaacgacgagcgtgacaccacgatgcctgtagca atggcaacaacgttgcgcaaactattaactggcgaactacttactctagcttcccggcaacaattaatagactggatggagg cggataaagttgcaggaccacttctgcgctcggcccttccggctggctggtttattgctgataaatctggagccggtgagcg tgggtctcgcggtatcattgcagcactggggccagatggtaagccctcccgtatcgtagttatctacacgacggggagtca ggcaactatggatgaacgaaatagacagatcgctgagataggtgcctcactgattaagcattggtaa . the dna nucleotide sequence derived for suppressing beta - lactamase synthesis is : ccacgatgcctgtagcaat ( seq id no . 17 ). the complementary rna oligonucleotide is prepared and modified to contain a 3 ′ amino group with a 3 - carbon linker ( 3 ′ n3 ). modified sirna containing the 3 ′ n3 is formed by annealing it with its complementary strand sequences . this duplex sirna is then incubated with a heterobifunctional crosslinker , sulfosuccinimidyl 4 -( p - maleimidophenyl )- butyrate ( chiu et al . 2004 ). this product is conjugated to anti - cd38 antibody ( serotec , raleigh , n . c .) and to the anti - cd38 ( fab ′) 2 fragment via a cysteine residue added to the amino terminal of the antibody . oligonucleotide - protein conjugation is commercially available ( solulink , san diego , calif .). the sirna - anticd38 conjugate is incubated at 37 ° c . with the jurkat cells for from 4 to 24 hours at concentrations ranging from 100 pm to 200 nm to evaluate efficacy . typical efficacy is at 2 nm . effective knockdown of intracellular synthesis of beta - lactamase is demonstrated in this system by the appearance of green cellular fluorescence . positive control cells which produce beta - lactamase fluoresce blue . multiple myeloma is a fatal incurable disease caused by the production of large amounts of a monoclonal immunoglobulin by malignant plasma cells ( grethlein s , multiple myeloma , emedicine 2003 ). cd38 is a cell surface receptor found on myeloma plasma cells ( almeida j et al . 1999 ). ligation of cd38 with anti - cd38 monoclonal antibodies ( serotec , raleigh , n . c . and others ) results in cd38 internalization ( pfister et al . 2001 ). anti - cd38 monoclonal antibodies are hydrolyzed by pepsin to produce anti - cd38 ( fab ′) 2 fragments . the anti - cd38 ( fab ′) 2 fragments are then conjugated by phosphoramidate linkage to dsrna containing a sirna sequence that is complementary to a portion of the nucleotide sequence of the rearranged heavy chain of igg . in this case the nucleotide sequence link is x98954 and the gi number is 1495616 . the sirna sequences provided by the whitehead institute are : s 5 ′: cgccaagaacuuggucuau uu ( seq id no . 18 ) as 3 ′: uu gcgguucuugaaccagaua . ( seq id no . 19 ) alternatively , the anti - cd38 monoclonal antibodies are conjugated to the dsrna containing a sirna sequence that is complementary to a portion of the nucleotide sequence of the rearranged heavy chain of the igg subclass of the subject &# 39 ; s monoclonal igg , i . e ., igg 1 , igg 2 , igg 3 or igg 4 . the sirna is then incorporated into a long dsrna . varying doses ranging from 0 . 4 to 15 grams of the anti - cd38 ( fab ′) 2 - dsrna are administered depending upon response . effective doses of anti - cd38 ( fab ′) 2 - dsrna need to be administered at intervals ranging from one day to several days in order to maintain suppression of igg production . because the half life of igg is approximately up to 23 days , the circulating concentration of the myeloma igg will decrease gradually over several months . suppression of the igg subclass to which the igg myeloma protein belongs will allow maintenance of igg mediated immunity because the remaining igg subclasses are not reduced . improvement and / or prevention of aspects of the disease which are consequences of high concentrations of the myeloma protein occur gradually as the concentration of the myeloma protein decreases . a direct effect of high concentrations of myeloma protein is hyperviscosity . this morbid effect of multiple myeloma is inhibited . the anti - cd38 ( fab ′) 2 - long dsrna containing the above described sirna then binds to cd38 on the surfaces of the subject &# 39 ; s plasma cells . following internalization , dicer hydrolyzes the long sirna into sirna which then interrupts the malignant plasma cell production of igg myeloma protein . allergic disease is mediated via ige binding to the surfaces of mast cells and basophils . upon bridging of adjacent ige molecules by antigen , the mast cells and basophils are activated and release their mediators ( siraganian 1998 ). ige binding by mast cells and basophils causes the signs and symptoms of allergic rhinitis , asthma , food and drug allergy , and anaphylaxis ( e . g . becker 2004 ). the amino acid sequence of the ch3 region of human ige is available as are many of the codons ( kabat e a 1991 ). the dna nucleotide sequence of the ch3 region of human ige is readily deduced . the deduced ch3 region sequence is then provided to the whitehead institute &# 39 ; s internet site as above to yield the corresponding sirna sequence . the anti - cd38 ( fab ′) 2 - long dsrna containing the anti - ige sirna then binds to cd38 on the surfaces of the subject &# 39 ; s plasma cells . following internalization , dicer hydrolyzes the long dsrna into sirna which then interrupts the plasma cell production of the ige . over several months , the mast cell - bound and basophil - bound ige is released and metabolized . the mast cell and basophil ige receptors decrease markedly and the subject loses allergic reactivity . iga nephropathy is an incurable disease of the kidney caused by deposition of iga in the glomeruli of the kidneys ( brake m 2003 ). iga 1 or iga 2 production is interrupted , depending upon the iga subclass in the glomeruli , as described above for the silencing of igg production . the progressive kidney damage caused by iga is thereby interrupted . almeida j , orfao a , mateo g , ocqueteau m , garcia - sanz r , moro m j , hernandez j , ortega f , borrego d , barez a , mejida m , san miguel j f . immunophenotypic and dna content characteristics of plasma cells in multiple myeloma and monoclonal gammopathy of undetermined significance . path biol 1999 ; 47 : 119 - 127 . anderson d c , nichols e , manger r , woodle d , barry m , fritzberg a r . tumor cell retention of antibody fab fragments is enhanced by an attached hiv tat protein - derived peptide . biochem biophys res commun 1993 ; 194 : 876 - 884 . becker j m . allergic rhinitis , in in emedicine , eds : park c l , mary l windle m l , georgitis j w , pallares d , m d , ballow m . 2004 . brake m , somers d . iga nephropathy in emedicine , eds : sondheimer j h , talavera , f , thomas c , schmidt r j , vecihi batuman v . 2003 . caron n j , quenneville s p , tremblay j p . endosome disruption enhances functional nuclear delivery of tat - fusion proteins . biochem biophys res commun 2004 ; 319 : 12 - 20 . cellsensor cre - bla jurkat cell - based assay protocol , catalogue number k1134 ( k1079 ), invitrogen corporation , carlsbad , calif . chiu y - l , ali a , chu c - y , cao h , rana t m . visualizing a correlation between sirna localization , cellular uptake , and rnai in living cells . chem biol 2004 ; 11 : 1165 - 1175 . diallo m , arenz c , schmitz k , sandhoff k , scheppers u . long endogenous dsrnas can induce complete gene silencing in mammalian cells and primary cultures . oligonucleotides 2003 ; 13 : 381 - 392 . funaro a , reinis m , trubiani o , santi s , di primio r , malavasi f . cd38 functions are regulated through an internalization step . j immunol 1998 ; 160 : 2238 - 2247 . futaki s , goto s , sugiura y . membrane permeability commonly shared among arginine - rich peptides . j mol recognit 2003 ; 16 : 260 - 264 . garcea r l , alberts b m . comparative studies of histone acetylation in nucleosomes , nuclei , and intact cells . evidence for special factors which modify acetylase action . j biol chem . 1980 ; 255 : 11454 - 11463 . grethlein s . multiple myeloma . in emedicine , eds : krishnan k , talavera f , guthrie t h , mckenna rajalaxmi , besa e c 2003 . gryaznov s m , winter h . rna mimetics : oligoribonucleotide n3 ′→ p5 ′ phosphoramidates . nucl acids res 1999 ; 26 : 4160 - 4167 . he d , yang h , lin q , huang h . arg9 - peptide facilitates the internalization of an anti - cea imunotoxin and potentiates its specific cytotoxity to target cells . int j biochem cell biol 2005 ; 37 : 192 - 205 . heidenreich o , gryaznov s , nerenberg m . rnase h - independent antisense activity of oligonucleotide n3 ′→ p5 ′ phosphoramidates . nucl acids res 1997 ; 25 : 776 - 780 . hermanson g t . bioconjugate techniques . academic press , san diego , calif . 1996 . hutvagner g , zamore p d . a microrna in a multiple - turnover rnai enzyme complex . nature 2002 ; 297 : 2056 - 2060 . hutvagner g , zamore p d . rnai : nature abhors a double - strand . curr opinion in genetics and development 2002 ; 12 : 225 - 232 . jacobs b l , imani f . histone proteins inhibit activation of the interferon - induced protein kinase by binding to double - stranded rna . j interferon res 1988 ; 8 : 821 - 830 . jo d , nashabi a , doxee c , lin q , unutmaz d , chen j , ruley h e . epigenetic regulation of gene structure and function with a cell - permeable cre recombinase . nature biotechnology 2001 ; 19 : 929 - 933 . jones s , daley t a , luscombe n m , berman h m , thornton j m . protein - rna interactions : a structural analysis . nucl acids res 2001 ; 29 : 943 - 954 . kabat e a , wu t t , perry h m , gottesman k s , foeller c . sequences of proteins of immunological interest . fifth edition . tabulation and analysis of amino acid and nucleic acid sequences of precursors , v - regions , c - regions , j - chain , t - cell receptors for antigen , t - cell surface antigens , β 2 - microglobulins , major histocompatibility antigens , thy - 1 , complement , c - reactive protein , thymopoietin , integrins , post - gamma globulin , α 2 - macroglobulins , and other related proteins . 1991 . nih publication number 91 - 3242 . kozlov i a , melnyk p c , stromborg k e , chee m s , barker d l , zhao c . efficient strategies for the conjugation of oligonucleotides to antibodies enabling highly sensitive protein detection . biopolymers 2004 ; 73 : 621 - 630 . kratzmeier m , albig w , hanecke k , doenecke d . rapid dephosphorylation of h1 histones after apoptosis induction . j biol chem . 2000 ; 275 : 30478 - 30486 . lee c - h , hoyer - fender s , engel w . the nucleotide sequence of a human protamine 1 cdna . nucleic acids research 1987 ; 15 : 7639 . mie m , takahashi f , funabashi h , yanagida y , aizawa m , kobatake e . intracellular delivery of antibodies using tat fusion protein a . biochem biophys res commun 2003 ; 310 : 730 - 734 . miller v m , xia h , marrs g l , gouvion c m , lee g , davidson b l , paulson h l . allele - specific silencing of dominant disease genes . proc natl acad sci usa 2003 ; 100 : 7195 - 7200 . miyagishi m , taira k . strategies for generation of an sirna expression library directed against the human genome . oligonucleotides 2003 ; 13 : 325 - 333 . muratovska a , eccles m r . conjugate for efficient delivery of short interfering rna ( sirna ) into mammalian cells . febs letters 2004 ; 558 : 63 - 68 . myers j w , jones j t , meyer t , ferrell j e jr . recombinant dicer efficiently converts large dsrnas into sirnas suitable for gene silencing . nature biotechnology 2003 ; 21 : 324 - 328 . nicholson a w , niebling k r , mcosker p l , robertson h d . accurate in vitro cleavage by rnase ii of phosphorothioate - substituted rna processing signals in bacteriophage t7 early rna . nucl acids res 1988 ; 16 : 1577 - 1591 . parrish s , fire a . distinct roles for rde - 1 and rde - 4 during rna interference in caenorhabditis elegans . rna 2001 ; 7 : 1397 - 1402 . peitz m , pfannkuche k , rajewsky k , edenhofer f . ability of the hydrophobic fgf and basic tat peptides to promote cellular uptake of the recombinant cre recombinase : a tool for efficient genetic engineering of mammalian genomes . proc natl acad sci usas 2002 ; 99 : 4489 - 4494 . pfister m , ogilvie a , da silva c p , grahnert a , guse a h , hauschildt s . nad degradation and regulation of cd38 expression by human monocytes / macrophages . eur j biochem 2001 ; 268 : 5601 - 5608 . provost p , dishart d , doucer j , frendewey d , samuelsson b , radmark o . ribonuclease activity and rna binding of recombinant human dicer . embo j 2002 ; 21 : 5864 - 5874 . st . johnston d , brown n h , gall j g , jantsch m . a conserved double - stranded rna - binding domain . proc natl acad sci usa 1992 ; 89 : 10979 - 10983 . siraganian r p . biochemical events in basophil or mast cell activation and mediator release . chapter 16 pp 204 - 227 in allergy principles and practice , 5 th edition , eds e middleton , jr , c e reed , e f ellis , n f adkinson , jr , j w yunginger w w busse . mosby , st . louis , 1998 . soomets u , lindgren m , gallet x , hallbrink m , elmquist a , balaspiri l , zorka m , pooga m , brasseur r , langel u . deletion analogues of transportan . biochem biophys acta 2000 ; 1467 : 165 - 176 . stec w j , grajkowski a , kozioliewiecz m , uznanski b . novel route to oligo ( deoxyribonucleoside phosporothioates ). stereocontrolled synthesis of p - chiral oligo ( deoxyribonucleoside phosporothioates ). nucl acids res 1991 ; 19 : 5883 - 5888 . stura e a , fieser g g , wilson i a . crystallization of antibodies and antibody - antigen complexes . immunomethods 1993 ; 3 : 164 - 179 . tabara h , yigit e , siomi h , mello c c . the dsrna binding protein rde - 4 interacts with rde - 1 , dcr - 1 and a dexh - box helicase to direct rnai in c . elegeans . cell 2002 ; 109 : 861 - 871 . van koningsbruggen s , de haard h , de kievit p , dirks r w , van remoortere a , groot a j , van engelen b g , den dunnen j t , verrips c t , frants r r , van der maarel s m . llama - derived phage display antibodies in the dissection of the human disease oculopharyngeal muscular dystrophy . j immunol methods 2003 ; 279 : 149 - 161 . warrant r w , kim s - h . α - helix - double helix interaction shown in the structure of a protamine - transfer rna complex and a nucleoprotamine model . nature 1978 ; 271 : 130 - 135 . waterhouse p m , wang m - b , lough t . gene silencing as an adaptive defense against viruses . nature 2001 ; 411 : 834 - 842 . yaneva j , leuba s h , van holde k , zlatanova j . the major chromatin protein histone h1 binds preferentially to cis - platinum - damaged dna . proc natl acad sci usa 1997 ; 94 : 13448 - 13451 . yoshikawa y , velichko y s , ichiba y , yoshikawa k . self - assembled pearling structure of long duplex dna with histone h1 . eur j biochem 2001 ; 268 : 2593 - 2599 . zhang h , kolb f a , brondini v , billy e , filipowicz w . human dicer preferentially cleaves dsrnas at their termini without a requirement for atp . embo j 2002 ; 21 : 5875 - 5885 . patent documents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains . these documents and publications are incorporated herein by reference to the same extent as if each individual document or publication was specifically and individually incorporated herein by reference . the foregoing description is illustrative of particular embodiments of the invention , but is not meant to be a limitation upon the practice thereof . the following claims , including all equivalents thereof , are intended to define the scope of the invention .

a composition and method are provided by which double - stranded rna containing small interfering rna nucleotide sequences is introduced into specific cells and tissues for the purpose of inhibiting gene expression and protein production in those cells and tissues . intracellular introduction of the small interfering rna nucleotide sequences is accomplished by the internalization of a target cell specific ligand to which the double - stranded rna containing a small interfering rna nucleotide sequence is conjugated . the ligand is specific to a unique target cell surface antigen . the ligand is either spontaneously internalized after binding to the cell surface antigen . internalization is also facilitated by the binding of an rna binding protein to the double - stranded rna . if the unique cell surface antigen is not naturally internalized after binding to its ligand , internalization is promoted by the incorporation of an arginine - rich peptide , or other membrane permeable peptide , into the structure of the ligand or attachment of such a peptide to the ligand . the composition and method are practiced in whole living mammals , as well as cells living in tissue culture . the dsrna is then hydrolyzed by dicer , an rnase iii - like ribonuclease , thereby releasing sirna which silences the target gene . inhibition is nucleotide sequence specific and depends upon sequence identity of small interfering rna with the target nucleic acid .

referring first to fig1 , it shows a device that includes : a ) a longitudinally elongated probe insertible into the vagina , for a test purpose , b ) a support operatively connected with the probe projecting away from the support , i ) a manually manipulable handle , ii ) and an edge presented generally longitudinally for limiting probe insertion into the vagina . as shown , the probe 10 of the apparatus 100 protrudes lengthwise from the support 12 , which defines a handle 12 a that can be easily gripped between the thumb 13 and forefinger 14 of the user , as seen in fig3 . the probe and support preferably have key - like configuration , as shown . forwardly or longitudinally presented edge 20 of the support limits insertion of the probe , as by engagement with the body 21 , and dual edges may be provided as at 20 a and 20 b , at opposite lateral sides of the probe , for that purpose . the apparatus 100 may for example consist of plastic , metal or compressed fiber ( example paper ). surface irregularities may be provided on one laterally facing side of the support , and such irregularities are shown to extend longitudinally to be grasped by the thumb and prevent lateral slippage , relative to the user &# 39 ; s thumb . the irregularities are shown in the form of protuberances 24 which are laterally spaced apart . the probe and support , or handle may have the following dimensions for best results : probe overall length “ l 1 ” 1½ m to 2½ inches probe width “ w 1 ”= ¼ to ½ inch support width w 2 = ¾ to 1½ inch thickness “ t ”= 3 / 16 to 5 / 16 inch overall length l 2 of probe and support = 3¼ to 3¾ inches . w 1 ≅ ⅜ inch w 2 ≅ 1¼ inch t ≅ ¼ inch l 2 ≅ 3½ inch . also , the probe has an approximately flat , oval cross section , as seen in fig6 . fig1 also shows a test element or indicator 30 at the side of the probe , near its tip 31 , to be pressed toward and against the vaginal wall . element 30 typically comprises an indicator element , as for example one of the following : i ) a ph indicator ii ) an amine indicator iii ) a bacteria indicator iv ) sialidase indicator v ) prolidase indicator . the ph indicator or detector typically takes the form of a nitrazine ® strip or other carrier element adhered to the side of the probe , as for example by double sided adhesive tape . after exposure of the strip to vaginal moisture , its changed color ( according to ph level ) is compared with the series 41 of bands on a sheath 42 , as seen in fig9 . each band has a different color corresponding to a ph level color to which the detector strip may change . see for example the indicated ph levels 4 . 5 , 5 . 0 , 5 . 5 , 6 . 0 , 6 . 5 , 7 . 0 and 7 . 5 adjacent the color bands . the bands may be provided on a support strip 142 adhered to the outer surface of the sleeve or receptacle 42 . see also fig1 showing a manipulable element 145 including a probe 175 and handle 146 received in recesses 144 in a plastic carrier 180 , with support strip 146 adhered to the carrier . a series of bands 185 , like bands 41 , is located on the strip 146 . paper strips providing such elements are known , and sold under the name hydrion papers , by micro essential laboratory inc ., brooklyn , n . y . 11210 . the band for ph 4 . 5 is typically bright yellow ; the band for ph 6 . 0 is olive in color ; and the band for ph 7 . 5 is navy blue . in fig1 a standard comparison zone is provided on the probe , one example being a plastic part 150 aa received in a recess in the probe in proximity to the ph sensitive indicator 130 a . the outer surface of part 150 aa has a color corresponding to a predetermined ph level , at or near neutral ph level , such as 4 . 5 for example , for quick visual color comparison with the color of the indicator , after indicator contact with vaginal moisture . when a nitrazine ® indicator is used , the surface of part 150 aa can be sunflower yellow , to indicate a standard 4 . 5 ph . a corresponding part 150 a is shown in fig1 , 4 and 7 . in use , the user first visually compares the color of the indicator 130 a ( after exposure to vaginal moisture ) and the standard zone ( such as the surface of locality 150 aa ), and any difference in color indicates a possible problem . this consists of a screen test . the color , size , and location of standard zone 150 are such as to provide prominent visual color comparison of zone 150 aa with the indicator . next , the probe 175 and sleeve or receptacle 180 are relatively moved , to bring the detector indicator 130 a ( after its exposure to moisture and color change as referred to above ) into lateral registration with the color comparison bands 185 , enabling ready visual comparison of the color of the detector strip with the closest color of one of the bands , enabling a ph level determination . for this purpose , a window zone of the carrier sleeve adjacent the bands may be transparent to allow visual observation of the detector , through that zone , adjacent the bands . in summary , the probe is inserted into the vagina to collect moisture and withdrawn , and the quick visual screen comparison is made , viewing the probe indictor and the standard comparison zone for quick detection of a possible problem , as for example need for estrogen . thereafter , color comparison may be made with the colored bands , to more definitively determine moisture ph level . the probe is re - inserted into the elongated carrier receptacle 180 . the color changing reactant may consist , for example , of one or more of the following : bromocresol green , bromocresol purple , nitrazine yellow , bromophenol blue , and equivalents . an optional procedure consists of obtaining a visual comparison of the color changed zone on the receiver 130 a with a color ? or different colors , or band color shades , as at 185 , where one color band may indicate presence of putrecine ; another color band may indicate presence of cadaverine ; and a third band may have another color or color shade close to but different from the first two , and so indicating absence of putrecine or cadaverine , or other bacterial producing amine , i . e . an amine test when compared side - by - side with the color on the receiver 130 a . such amine indicates presence of pathogenic bacteria . in fig1 , the indicator 130 a and comparison zone 150 a have substantially the same sizes and shapes , for enhancement of visual accuracy of color comparison . also , the probe 145 has a substantially flat side 175 , the indicator and comparison zones being exposed at that flat side . the local indicator and comparison zones are located in mutually edgewise convex proximity lengthwise of the probe , for rapid digital type color comparison readout ( i . e . problem or no problem , per color visual differentiation ). both are substantially circular , and the exposed surfaces of each extend in substantially the same flat plane . undulant edges 180 a of the carrier and / or edges of 130 a to 150 a allow or facilitate relative travel of moisture along multiple paths 181 to reach the indicator 130 a or zone 150 a . see path arrows 182 . the diameters of 130 a and 150 a may be between 3 / 16 and ⅜ inch , for optimum visual comparison effect . all of these contribute to enhancement of accurate , quick , viewing comparison to quickly detect color differences from a standard level . carrier 180 receives the probe 145 and handle 146 , and carries the ph color comparison chart 177 . fig1 shows reception of an indictor 160 and comparison zone plastic button 161 , in recesses 162 and 163 in a probe 164 , the outward facing surfaces of 160 and 161 being of generally the same size and shape and in the same plane for accuracy of comparison ( equal illumination , light reflections , etc .). additional indicators and standard comparison zones may be provided on the probe , as shown at 160 a and 161 a , in fig1 , for redundancy and color differentiation confirmation . fig1 shows a modification 199 in which elements the same as in fig1 have the same identifying numerals . in addition , an elongated strip 200 is applied to the flat side 175 of the probe 145 . strip 200 includes , or carries , a thin layer of koh , or other equivalent hydroxide reactive with an amine produced by vaginal bacteria , for use in testing for such an amine in the fluid sample from the vagina . see flow path arrow 182 . when contacted with an amine in vaginal moisture the koh reacts to produce a characteristic odor , which is a “ fish ” type odor , from which a doctor can diagnose the presence of amine in the test sample . accordingly , the device 199 provides multiple test sites to enable quick multiple diagnostic tests for vaginal ph as may indicate estrogen deficiency as described , and for presence of amines ( produced by vaginal bacteria ) indicative of bv ( i . e . bacterial vaginosis ). such amines include cadavarine and putrecine . in fig1 and 13 it will be noted that the ph indicator and the local comparison zone are linearly aligned in the direction of the probe , being aligned on a line which extends between two lateral edges of the handle presented toward the test sites , the ph indicator and the comparison zone both having curved edges facing oppositely and convexly away from that line , and protruding at opposite sides of the probe . fig1 shows a further modified device 210 which comprises an elongated thin stem 211 having test site zones 212 and 213 extending endwise oppositely of stem mid - portion 214 . that mid - portion is adapted to be grasped as by the user &# 39 ; s thumb 215 and first finger 216 , during use of the device 210 . there may be concave recesses 217 , and 218 sunk in the edges 214 a and 214 b of stem mid - portion 214 , for grasping and stem manipulation purposes . test sites 130 a and 150 a at zone 212 are the same as provided in fig1 , i . e . have the same utility and relative placement . test site 200 has the same structure and utility as site 200 in fig1 ; however , it is located at zone 213 , remotely from sites 130 a and 150 a . in use the stem or stick is manipulated so that either zone 212 or zone 213 is first inserted into the vagina to receive vaginal moisture , and subsequently the stem is withdrawn and endwise removed so that the other of the zones 212 or 213 can then be separately inserted into the vagina to receive vaginal moisture and then withdrawn . this procedure avoids contact of moisture on site 200 with moisture on sites 130 a and 150 a , while still enabling rapid use and observation of all test sites 130 a , 150 a and 200 . such contact of moisture on site 200 with moisture on either or both of sites 130 a and 150 a could detrimentally change the ph at those latter sites due to the ph of the hydroxide containing moisture at site 200 . as an alternative , the device of fig1 could be modified to place site 200 at the opposite side of the stem 175 , so that moisture on site 200 would be unlikely to be displaced as by smearing to contact moisture at sites 130 a and 150 a , at the opposite sides of the stem . a protective film may be applied to cover site 200 until use , as for example by application to koh or other hydroxide at the site of vaginal discharge , i . e applied for example by a q - tip . fig1 and 16 show a preferred modification 210 in which elements the same as in fig1 have the same identifying numerals . in addition an elongated absorbent strip 211 is attached to the flat opposite side 212 of the probe 145 , where side 212 is opposite side 175 . in use , sides 175 and 212 are exposed to moisture in the vagina , and the probe is then removed . strip 211 constitutes a test site for production of amine or amines , such as cadaverine and putrecine . an hydroxide is then applied to the test site at moistened strip 211 , externally of the vagina so contact of hydroxide with the vagina is avoided . see drops 214 of liquid hydroxide in fig1 , applied to strip 211 , the amount of applied hydroxide being easily controllable , as by manipulation of an ampule 216 . as referred to above , when contacted with an amine in vaginal moisture , the hydroxide reacts to produce a characteristic odor , which is a “ fish ” type odor , from which a user 219 can detect ( as seen at 220 in fig1 ) the presence of amines in the test at the test site . accordingly , the device 210 provides multiple test sites to enable quick multiple diagnostic tests for vaginal ph as may indicate estrogen deficiency as described , and for presence of amine ( produced by vaginal bacteria ) indicative of bacterial vaginosis . by avoiding inclusion of hydroxide on the probe at the time of insertion into the vagina , undesirable application or mixing of hydroxide with the ph test sites seen in fig1 is avoided , whereby erroneous readings of ph are avoided . strip 211 can thus be located at the direct opposite side of the probe from the ph indicators 130 a and 150 a , without risk of hydroxide contamination of those sites . usable hydroxides include : koh , milk of magnesia , baking soda and sea water , as well as others . the strip 211 may consist of a “ super absorbent polymer ” such as “ waste lock ”, from m2 polymer , or the highly moisture absorbent “ lyocell fiber ” referenced in “ medical textiles ”, june 2003 , at page 3 , as well as others , such as filter paper . fig1 shows a kit 230 including a carrier tray 231 ; probe 210 on the tray ; and hydroxide ampules 216 on the tray ; and a ph color comparison chart 177 on the tray . that type chart use also referenced in fig1 . elements of the kit are used as described in fig1 - 17 , after removal from the tray . in the above , the word “ hydroxide ” is intended to include , within its scope , alkaline substances , that may for example be flowable .

the method of quickly screening for vaginal moisture conditions , that includes providing a manually manipulable element including a probe insertible into the vagina ; providing one or more ph indicating first test site or sites on one portion of the probe ; providing a vaginosis test site on another portion of the probe ; manipulating the probe to transfer vaginal moisture to the sites , and , therefore , externally of the vagina , applying an hydroxide to the vaginosis test site , to come in contact with moisture at the vaginosis test site ; and detecting presences of an amine or amines produced at the vaginosis site .

referring first of all to fig1 through 7 the present concept is toothbrush 100 which includes the following major components namely body 102 , brush head 104 , bottom cap 106 , screw 108 and neck 110 . brush head 104 includes a removable back 112 , an extrusion face 114 , an extrusion cavity 116 and bristle apertures 118 . the lower portion of the body 102 of toothbrush 100 defines a reservoir 120 which will house polymer 122 therein . in fig1 toothbrush 100 is shown connected to dock 126 which contains a motor drive 128 and connects to the bottom end 130 of body 102 as schematically depicted in fig1 . dock 126 makes a mechanical connection between the motor drive 128 and the screw 108 thereby both reciprocating and rotating screw 108 when motor drive 128 is activated . fig1 further depicts channel 132 through which the polymer 122 flows as well as heating elements 134 which surround channel 132 to ensure that the polymer 122 remains molten as it flows through channel 132 . fig1 also depicts an extrude button 136 which is depressed in order to initiate the extruding action of toothbrush 100 . now referring to fig2 which shows toothbrush 100 in the inverted position wherein the bottom end 130 is releasably attached to dock 126 and the brush head 104 is also releaseably engaged within extrusion mold 140 . in the inverted position shown in fig2 toothbrush 100 is in a position in which extrusion of new bristles can take place . by depressing extrude button 136 the motor drive 128 as well as connections to the internal heaters is activated thereby heating polymer 122 located within reservoir 120 of body 102 . the action of screw 108 forces molten polymer 148 down the length of the body 102 of toothbrush 100 and through channels 132 and into extrusion cavity 116 . once molten polymer 148 is located in extrusion cavity 116 a plunger 142 forceably urges molten polymer 148 out through bristle apertures 118 thereby forming bristles 146 . an advancement screw 144 or other advancement mechanism within extrusion mold 140 is used to urge plunger 142 into extrusion cavity 116 . extrusion mold 140 is releaseably attached to the neck 110 as well as the brush head 104 . neck heaters 150 as well as screw heaters 152 maintain polymer 122 in its molten state namely molten polymer 148 . fig2 depicts the flow of molten polymer as 156 shown as polymer flow flowing downwardly along body 102 through channels 132 and into extrusion cavity 116 . referring now to fig3 which is an assembly of the removable back 112 , the brush head 104 and the extrusion face 114 . both the removable back and the extrusion face are clipped into position onto brush head 104 and can be removed for cleaning purposes and also for the purpose of removing a bristle extrusion 160 . referring now to fig4 which shows an exploded assembly view of removable back 112 , brush head 104 , extrusion face 114 as well as a bristle extrusion 160 . once bristles 146 have worn to the point where there are no longer usable it is necessary to remove removable back in order to extract the spent bristle extrusion from brush head 104 . in cases where cleaning is necessary it is also possible to remove extrusion face 114 thereby being able to completely clean brush head 104 , removable back 112 and extrusion face 114 separately . fig5 depicts screw 108 and in cut away fashion shows screw heater 152 running through roughly the centre of screw 108 for heating of screw 108 and ultimately the polymer 122 surrounding screw 108 . there is a coupling 162 at the bottom end of screw 108 which couples with motor drive 128 . fig6 depicts body 102 and removable bottom cap 106 . fig7 depicts schematically the direction of flow 156 of molten polymer 148 through the body and out through to the neck . a method of extruding bristles from the head of toothbrush 100 is summarized in fig8 as follows : step 1 requires removing the bottom cap from the body and filling the reservoir with polymer . the polymer can be in the form of pellets , powder or granules or may even be in the form of a liquid . the next step is to connect the bottom end 130 to a dock 126 with the brush head 104 downward and the top end inserted into an extrusion mold 140 . the next step is to push the extrude button 136 to activate the extrusion process . the next step is the activation of screw 108 and the heating elements 134 including the neck heater 150 and the screw heater 152 thereby warming the polymer 122 . this forms a molten polymer 148 which has the ability to flow through channel 132 and into extrusion cavity 116 . the screw 108 is coupled to motor drive 128 which reciprocates and turns thereby urging the polymer along the neck channel 132 and into the extrusion cavity 116 . in the next step with the extrusion mold removeably snapped into place onto the brush head and neck 110 portion of brush 100 , the plunger 142 advances to urge molten polymer 148 through the bristle apertures 118 of extrusion face 114 thereby forming new bristles 146 . in the last step the toothbrush is removed from the dock and the extrusion mold is ready for use . it should be apparent to persons skilled in the arts that various modifications and adaptation of this structure described above are possible without departure from the spirit of the invention the scope of which defined in the appended claim .

the present concept is a bristle extruding toothbrush and the method of the bristle extruding toothbrush replacing its own bristles . polymer is stored in a reservoir in the body of the toothbrush before being heated and urged into an extrusion cavity by a screw housed in the reservoir . molten polymer is extruded through bristle apertures on the extrusion face found on the brush head to form bristles by the action of an extrusion mold plunger .

the reader is directed to the referenced prior patent which will assist in understanding the improvements offered by the present application . for the convenience of the reader , the same instrument assembly as described in the patent is used to illustrate the invention with the improvements of the present invention incorporated therein . the same reference numerals as used in the drawings of the references patent are also used for the convenience of the reader . the reader is directed to that patent for any further details of the overall assembly construction which are omitted here as unnecessary to a complete understanding of the present invention . more particularly , those skilled in the art will recognize that the invention is not limited to the specific construction of the reciprocating mechanism described in the patent , and other well - known reciprocating mechanisms in similar type instruments are deemed within the scope of the present invention . moreover , the invention is not limited to cutter constructions in which the cutter head is removable and disposable . conventional electrosurgical apparatus can be used with instruments of the invention , but it is preferred to use low - power electrosurgical apparatus . such apparatus is available from ellman international of hewlett , n . y . as model iec50 . the latter has the advantage that it generates rf electrosurgical currents in the mhz range , specifically , about 1 . 5 – 4 mhz , which we prefer for their less damaging effect on neighboring tissue . in the preferred embodiment of a reciprocating cutter instrument according to the invention illustrated in fig1 , the instrument 10 comprises a drive housing 12 containing on its interior a power source and a conventional motor section . a switch 44 turns the motor on and off . the disposable , removable cutter head 16 when mounted engages a bayonet type connector to maintain the units assembled with the motor shaft engaging and rotating a cam 80 having a cam surface 82 in the cutter head 16 . the rf cutting device 10 of the present invention contains all the parts such as battery , motor , switch , spring coil 86 , as described in the patent , but certain critical changes are necessary to implement the invention . these changes include the following . the housing of the drive section 12 , which is generally cylindrical , is made of an electrically - insulating material , such as a suitable plastic . also , the body 70 of the cutter head 16 also is made of an electrically - insulating material , such as a suitable plastic . in addition , the cam 80 is similarly made of an electrically - insulating material , such as a suitably hard plastic provided with a smooth inclined cam face 82 which contacts an electrically - conductive metal cam follower assembly 84 held against the cam face by an electrically - conductive coil spring 86 . other changes are also necessary which will be explained below . in this embodiment , the cam follower assembly 84 comprises a periphery which is hexagonal in shape slightly smaller than the hexagonal bore 73 of the body which permits axial movement of the cam follower assembly 84 but which prevents rotation . in this manner , well known in the art , rotary movement of the cam 80 is converted to reciprocating movement of the cam follower 84 . bearing against the reverse side of follower 84 is the metal spring 86 which is seated against an electrically - conductive retaining ring 92 , for example , of metal , mounted in the bore 93 of the body 70 . the electrically - conductive retaining ring 92 has a wire 201 mechanically bound and soldered to the ring 92 on the side of the bore 93 and is thus electrically connected to the wire 201 . the wire 201 , which is insulated wire , extends through a tubular extension 202 to an external small electrical jack 203 , to which it may be connected by , for example , a quick banana connector ( not shown ) to the unipolar outlet of an electrosurgical generator 19 via the usual cable . the generated rf energy from the electrosurgical generator 19 will go through the cable to the wire 201 , the conductive retaining ring 92 , the conductive coil spring 86 , and then the cam follower 84 which has a hollow cutting inner electrically - conductive tube blade 95 , for example , of metal , mounted in the bore 93 in the stem of the cam follower and reciprocates therewith . the inner electrically - conductive tube 95 is positioned within an outer stationary electrically - insulating , for example , of hard plastic , outer tube 94 fixed to the end of the nose body in a plastic cap member 97 . the inner metal cutting tube blade 95 and the outer plastic tube 94 may be of any configuration as long as they are matched for a close telescoping fit in the area where tissue cutting or separation takes place . as in the instrument described in the patent , a tubular extension 76 provides access to the inner bore 71 . the extension 76 in turn is coupled to a conduit 104 which terminates in a suction - generating device 102 . the inner tube 95 is also provided with an aperture 151 which provides access to the hollow inner tube interior . when suction is activated , the bore 71 is emptied as well as the hollow inner tube 95 when the tube is in its retracted position and the tube aperture 151 exposed . at the distal end of the structure , to the left in fig2 , the outer tube end is closed off 99 except for an aperture 98 which provides access for tissue into the distal end of the outer tube 94 . in the patent arrangement , when the inner tube 95 is reciprocated to its forward extended position , the open cutter end 101 of the inner tube 95 traverses the aperture 98 thereby slicing off or separating , and receiving in the hollow inner tube 95 , any tissue drawn by the suction through the aperture 98 into the interior of the hollow outer tube 94 . the suction then suctions away the tissue or any fluids present via the aperture 151 and the tubular extension 76 to the collecting means of the suction generator 102 . in the inventive instrument , however , the tissue excision takes place mainly due to the rf energy supplied by the electrosurgical apparatus 19 which is present at the electrically - conductive end 101 of the inner tube 95 , substantially free of the mechanical pressing force of the prior art device . the return path for the rf energy is the usual large indifferent plate placed in contact with the patient . the aperture 98 in the outer plastic tube 94 may be of any preferred shape or size in the side wall near the end of the outer plastic tube 94 to permit entry of the tissue , especially , vitreous material , when suction is applied . the relative lengths of the inner 95 and outer 94 tubes are such that the open end 101 of the inner tube 95 , which may or may not be sharpened , passes across the aperture 98 with each down stroke of the cam 80 . each upstroke of the cam 80 uncovers the aperture 98 to permit entry of fresh vitreous or other tissue material . the upstroke is accomplished by the action of the conductive coil spring 86 which is sealed on the retaining ring 92 pushing against the force of the cam follower 84 and driving it towards the cam face 82 . the down stroke action of the blade 95 with rf energy at its working end 101 disintegrates the vitreous material between the tube end 101 of the inner tube 95 and the edge of the aperture 98 . it is not necessary to have a sharp cutting surface for the aperture , since the cutting is mainly by the rf energy , and very little , if any , pressing force is required . the cam follower assembly is mounted in the retainer ring 92 which abuts a circular seal 100 to prevent entry of foreign material from cavity 71 into the bore 52 of the cutter head . the reciprocating cutter tube blade 95 is also provided with the aperture 151 which allows the cut vitreous or tissue or fluids to be drawn upward through the inside diameter of the inner cutting tube 95 and out through the opening 151 into the suction chamber 71 and then into the syringe 102 . the external fixed thin wall tube 94 projects from the end of the body 70 with the distal end 99 being formed into a smoothly blended non - conductive enclosure to prevent any unintended scattering of rf energy . the conductive retaining ring 92 and seal 100 are mounted around the cam follower 84 to keep fluids from entering into the cavity housing the coupling means , thus preventing any leakage of vitreous material , fluid , blood or other materials past the shaft . the seal also prevents air from being drawn into the syringe via motor shaft leakage . the cam follower shaft 105 and ring 92 and seal 100 effectively seal off bore 71 to form the fluid receiving chamber 71 . it is important to confine the rf energy in the controlled area adjacent the distal end 101 of the electrically - conductive inner tube 95 . it will be appreciated that , in the preferred embodiment , the outer parts of the structure are electrically insulating to prevent accidental electrical shock to the surgeon or patient and prevent inadvertent tissue damage upon contact . the electrically - conductive parts which carry the rf electrosurgical currents are all buried within the structure . in order to transmit the rf energy from the wire 201 to the inner tube 95 , the wire is electrically connected to the conductive retaining ring 92 which in operation is axially fixed . the electrical path is from the retaining ring 92 to the electrically - conductive spring 86 to the electrically - conductive cam follower 84 and thereby to the electrically - conductive inner tube 95 which is mounted to the cam follower 84 via the shaft 105 . of those parts , only the retaining ring 92 is immovable and thus the preferred wire connecting member . extending the wire 201 to connect to the reciprocating cam follower shaft 105 or directly to the inner tube 95 is also possible , but has the possible disadvantages of constant flexing of the wire end that may reduce its lifetime and exposure of the wire end to the withdrawn body fluids . however , this is less of a problem with a disposable cutter head which undergoes only one use before being thrown out . by also making the cam 80 of electrically - insulating material prevents the rf energy from flowing back to the power source , which may include control circuitry , that may be damaged by the rf energy . the structure 77 at the right end of fig2 is for mounting of the cutter head 16 to the power assembly 12 . the surgical procedure is as follows . only the steps relative to the invention are recited in broad terms . the cutter 10 is connected in the usual way to the electrosurgical apparatus 19 . the surgeon inserts the working end 99 into the tissue to be excised and removed . the surgeon then activates the electrosurgical apparatus 19 choosing operating parameters such that relatively low power , low voltage settings of the apparatus are chosen . for the iec50 instrument , which generates an output power of about 50 watts , a typical power setting of about 3 – 8 can be used . these values can be determined beforehand using test tissue , typically animal , and measuring the temperature due to resistive heating in the tissue surrounding the tip of the needle after a reasonable on time of the instrument , say about 2 – 10 sec . the goal should be a low tissue temperature of about 50ec . the on switch of the cutter is then depressed . the tissue inside the aperture 98 and subject to the rf energy from the reciprocating inner tube end 101 disintegrates and is suctioned out by the applied suction . the procedure is otherwise the same as that used with the electromechanical reciprocating cutter . no heating occurs around the electrically - insulating sections , because they are adequately electrically - insulated and no electrosurgical currents flow into the tissue from those sections . while the invention has been described in connection with preferred embodiments , it will be understood that modifications thereof within the principles outlined above will be evident to those skilled in the art and thus the invention is not limited to the preferred embodiments but is intended to encompass such modifications .

a novel cutter instrument uses radiofrequency electrosurgery and rf energy to achieve the desired cutting action with minimum of mechanical force , thereby reducing the risk of tissue damage due to excessive mechanical cutting action . preferably , a cutter head of the instrument comprises an outer tube of electrically - insulating material with an aperture into which is telescoped an inner electrically - conductive tube . when the working or leading end of the latter is reciprocated across the aperture in the outer tube while rf electrosurgical currents are applied to the inner tube , the cutting action of tissue entering the aperture takes place primarily via the rf electrosurgical currents .

soybean cultivar 942365966149 has superior characteristics and was developed from the cross hp3134 × a3237 × 40 - 3 - 2 . f 1 and f 2 plants were advanced by a modified pedigree selection . f 3 derived f 4 lines were selected in 1996 . in 1997 f 3 derived f 5 plants of 942365966149 were grown and selected . in late 1997 , f 3 derived f 6 was entered in a yield test at 4 locations in the upper midwest , where it placed third of 50 entries . 942365966149 is a late maturity group iii variety with very high yield potential and resistance to roundup ™ herbicide . 942365966149 has superior yields compared to lines of similar maturity and has excellent agronomic characteristics , including excellent lodging resistance and a major gene for phytophthora root rot resistance , rps1c , conferring resistance to most races of phytophthora . 942365966149 is well adapted to the late maturity group iii growing areas of the corn belt , including iowa , illinois , missouri , indiana , nebraska and kansas . some of the criteria used to select in various generations include : seed yield , lodging resistance , emergence , disease tolerance , maturity , late season plant intactness , plant height and shattering resistance . the cultivar has shown uniformity and stability for the traits , as described in the following variety description information . it has been self - pollinated a sufficient number of generations with careful attention to uniformity of plant type . the line has been increased with continued observation for uniformity . soybean cultivar 942365966149 has the following morphologic and other characteristics ( based primarily on data collected at oxford , ind .). ______________________________________phytophthora rot ( phytophthora megasperma var . sojae ): ______________________________________ race 1 resistant race 2 resistant race 3 resistant race 6 resistant race 7 resistant race 8 resistant race 9 resistant race 10 resistant race 11 resistant race 13 resistant race 15 resistant race 17 resistant race 21 resistant race 23 resistant race 24 resistant______________________________________ this invention is also directed to methods for producing a soybean plant by crossing a first parent soybean plant with a second parent soybean plant , wherein the first or second soybean plant is the soybean plant from the line 942365966149 . further , both first and second parent soybean plants may be from the cultivar 942365966149 . therefore , any methods using the cultivar 942365966149 are part of this invention : selfing , backcrosses , hybrid breeding , and crosses to populations . any plants produced using cultivar 942365966149 as a parent are within the scope of this invention . as used herein , the term &# 34 ; plant &# 34 ; includes plant cells , plant protoplasts , plant cells of tissue culture from which soybean plants can be regenerated , plant calli , plant clumps , and plant cells that are intact in plants or parts of plants , such as pollen , flowers , seeds , pods , leaves , stems , and the like . thus , another aspect of this invention is to provide for cells which upon growth and differentiation produce the cultivar 942365966149 . the cultivar 942365966149 is similar to a3404 . while similar to a3404 , there are numerous differences including : 942365966149 is resistant to the roundup ™ herbicides and a3404 does not contain this gene . additionally , 942365966149 has a major gene for tolerance to phytophthora root rot and a3404 is susceptible to phytophthora root rot . in table 1 that follows , the traits and characteristics of soybean cultivar 942365966149 are compared to several competing varieties of commercial soybeans of similar maturity . in the tables , column 1 shows the yield in bushels / acre for the instant invention and the competitor variety . column 2 indicates the days to maturity after september 1 for the instant invention and the competitor variety . column 3 shows the plant height in inches for the instant invention and the competitor variety . column 4 indicates the plant lodging for the instant invention and the competitor variety . column 5 shows the general appearance rating scores for the instant invention and the competitor variety . lodging and general appearance rating scores are rated 1 = best and 5 = worst . table 1______________________________________1997 agronomic data bu / a mat hgt ldg gr______________________________________overall mean 59 . 63 37 . 20 32 . 00 1 . 30 2 . 10 number of locations 3 3 2 3 3 942365966149 66 . 62 38 . 00 31 . 00 1 . 30 1 . 30 asgrow a3244 68 . 45 33 . 00 30 . 50 1 . 00 1 . 30 asgrow a3559 62 . 16 36 . 00 29 . 00 1 . 20 1 . 30 asgrow a3834 59 . 43 40 . 30 29 . 50 1 . 20 1 . 70______________________________________ a deposit of the soybean seed of this invention is maintained by asgrow seed company , 4140 114th street , urbandale , ia 50322 . access to this deposit will be available during the pendency of this application to persons determined by the commissioner of patents and trademarks to be entitled thereto under 37 cfr 1 . 14 and 35 usc 122 . upon allowance of any claims in this application , all restrictions on the availability to the public of the variety will be irrevocably removed by affording access to a deposit of at least 2 , 500 seeds of the same variety with the american type culture collection , manassas , va . although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding , it will be obvious that certain changes and modifications may be practiced within the scope of the invention , as limited only by the scope of the appended claims .

a novel soybean cultivar , designated 942365966149 , is disclosed . the invention relates to the seeds of soybean cultivar 942365966149 , to the plants of soybean 942365966149 and to methods for producing a soybean plant produced by crossing the cultivar 942365966149 with itself or another soybean variety . the invention further relates to hybrid soybean seeds and plants produced by crossing the cultivar 942365966149 with another soybean cultivar .

a baking system 1 according to fig1 to 4 with a baking oven 2 and an upstream means of conveyance 3 is used for the baking of fresh dough pieces . they are provided , on the one hand , as a plurality of dough pieces on the charging side of baking oven 2 in the form of bulk material . these dough pieces of a first basic type are in particular roll dough pieces which may also be partly frozen or deep - frozen . on the other hand , the dough pieces that are to be baked in the baking oven 2 are available as a second basic type , i . e . as a plurality of dough pieces 4 , 5 , for instance in the form of loaves of bread and baguette which are provided and conveyed as individual pieces . the means of conveyance is provided with a driven endless conveyor belt 6 . the latter is attached on both sides centrally between its two deflection pulleys to two lifting columns 7 holding between them the endless conveyor belt 6 . by means of a lifting drive ( not shown ), the endless conveyor belt 6 can be raised and lowered relative to the lifting columns 7 . a separator 8 which is arranged in the direction towards the means of conveyance 3 on the upper side of a baking oven housing 9 of baking oven is in conveyance connection with the endless conveyor belt 6 . in the direction towards the means of conveyance 3 , separator 8 is provided with a semi - circular bent baffle plate 10 which prevents dough pieces of the bulk material from falling back from separator 8 to the means of conveyance 3 . moreover , separator 8 is provided with a round separator bottom 11 around which a slat conveyor belt 12 is arranged . both the separator bottom 11 and the conveyor belt 12 can be driven independently of each other by means of driving motors ( not shown ). the top plan view of fig2 shows that the separator bottom 11 is driven counter - clockwise and that the slat conveyor belt 12 is driven clockwise . almost immediately above separator bottom 11 , a bent guide plate 13 which is shown in fig2 only is rigidly connected to a support ( not shown ) attached to the baking oven housing . the said guide plate extends from a central , vertical rotation axis 14 of separator bottom 11 up to the support arranged between separator bottom 11 and the slat conveyor belt 12 . a portion of the slat conveyor belt 12 adjacent to the support - side end of guide plate 13 is hereinafter referred to as charging portion 15 . downstream of charging portion 15 , a separating deflector 16 is arranged next to the slat conveyor belt 12 on its outside . the said deflector is provided with a deflection flap 17 the position of which can be changed by means of a drive unit 18 from a through position — shown in the fig .— to a deflection position . in the latter position , the deflection flap 17 bars access to the slat conveyor belt 12 . in respect to the conveyance direction of the slat conveyor belt 12 downstream , a separation sensor ( not shown ) which is designed as a light barrier is associated with the separation deflector 16 . the top plan view of fig2 shows that the slat conveyor belt 12 has approximately the form of an inverted letter “ d ”. the straight d leg of the slat conveyor belt 12 is hereinafter referred to as delivery portion 19 . arranged alongside delivery portion 19 , a delivery slider 20 which is adjustable by a driving mechanism is provided . the said slider is guided on a guide rail 21 which is arranged above the slat conveyor belt 12 the guide rail in turn being supported between two opposite support portions 22 attached to the baking oven housing . an upstream means of conveyance 23 is arranged downstream of supply slider 20 in the conveyance direction of the dough pieces conveyed along the slat conveyor belt 12 . the said means of conveyance is provided as an endless upstream conveyor belt . the upstream means of conveyance 23 is provided with a plurality of receiving portions for conveyance 24 which are separated from each other by separating wall portions 25 travelling with the means of conveyance . the downstream means of conveyance 23 is arranged on the baking oven 2 . it is provided between side walls 26 of baking oven housing 9 and can be horizontally moved in such a way that an end 27 — on the left side in the drawing — of the upstream means of conveyance 23 can be associated in a receiving position with separator 8 , in a first delivery position with a first baking oven supply inlet 28 , and in a second delivery position with a second baking oven supply inlet 29 in the baking oven housing 9 . in the drawing , the first baking oven supply inlet 28 is arranged to the left of the second baking oven supply inlet 29 . both supply inlets 28 , 29 are defined in an upper defining wall 30 of baking oven housing 9 and can both be closed by means of a driven pivotal shutter 31 , 32 . a switch flap 33 is arranged downstream of the first baking oven supply inlet 28 in the conveyance direction of the dough pieces . the said flap is pivotally arranged , i . e . hinged , around a swivel axis 34 perpendicular to the drawing plane of fig4 . the switch flap 33 as a switch member is part of a conveyance portion between the first baking oven supply inlet 28 and two baking drums 35 , 36 of a first baking zone 37 of a baking chamber 38 of baking oven 2 . a first conveyance slide 39 which is associated in the drawing with the left baking drum 35 is arranged downstream of the switch flap 33 in the conveyance direction of the dough pieces , as well as a second conveyance slide 40 which in the drawing is associated with the central baking drum 36 . a third conveyance slide 41 is arranged downstream of the second baking oven supply inlet 29 in the conveyance direction and is associated with a baking drum 42 which is shown on the right side in fig4 . all three baking drums 35 , 36 , 42 are of the same design so that it will suffice hereinafter to describe one of the three baking drums 35 , 36 , 42 . baking drum 35 is provided with a plurality of receiving portions for dough pieces — eleven in the present embodiment . these portions are defined outwardly by an external defining wall 44 and inwardly by an internal defining wall 45 of baking drum 35 . both defining walls 44 , 45 may be driven independently of each other around a rotation axis coinciding with the rotation symmetry axis of baking drum 35 by means of a drive unit 46 which is schematically shown in fig2 only . when the two defining walls 44 , 45 are driven in a synchronised manner , the receiving portions 43 are also rotated around this axis of rotation . the outer defining wall 44 is provided with a through opening 47 the width of which corresponds in the circumferential direction to the width of a receiving portion 43 . an endless delivery conveyor belt 48 is arranged below the three baking drums 35 , 36 , 42 which are arranged next to each other . a delivery portion 49 — shown on the right side in the drawing — of the endless delivery conveyor belt 48 is adjacent to a first baking oven outlet opening 50 which can be closed by means of a pivotal sealing cap 51 . baking oven 2 is a circulating air baking oven . two fans 52 which are equipped with relevant heating sources , i . e . heating coils , serve as circulating air source . the fans 52 are fixed to opposite side walls 53 , 54 of the baking oven housing 9 which are shown in the drawing on the left and on the right side . the fans 52 suck in the circulating air centrally from the baking chamber 38 and feed the same radially heated back to the baking chamber 38 . for separating the sucking area and the feedback area in the neighbourhood of the fans 52 , respective rectangular guiding plates are arranged parallel to the side walls 53 , 54 within the baking chamber 38 . for circulating the circulating air generated by the fans 52 within the baking chamber 38 , the baking drums 35 , 36 42 are each provided on their front side with a plurality of vanes 56 , i . e . twelve each . the said vanes are mounted onto the front walls 57 of the baking drums 35 , 36 , 42 and extend radially and straight from the outer circumference of the front walls 57 inwardly up to about half of the radius of the front walls 57 . the baking drums 35 , 36 , 42 and the endless delivery conveyor belt 48 are arranged within the first baking zone 37 of baking chamber 38 which is used for baking the dough pieces which are supplied and conveyed as bulk material . below the first baking zone 37 and freely connected with the same , a second baking zone 58 is located within the baking chamber 38 . within the same , a plurality of endless baking conveyor belts 59 — three in the illustrated embodiment — are arranged in decks on top of each other and below the endless delivery conveyor belt conveyor belt 48 . conveyor belts 48 , 59 are made of an air - permeable steel mesh . the endless delivery conveyor belt 48 as well as the endless baking conveyor belts 59 can be driven independently of each other . on the endless baking conveyor belts 59 individually supplied and conveyed dough pieces are being baked piece by piece in the second baking zone 58 . the uppermost endless baking conveyor belt 59 holds a number of baguette loaves 5 arranged transversely to the conveyance direction . the endless baking conveyor belt 59 at the bottom holds a number of loaves 4 transversely arranged side by side . supply portions 60 of the endless baking conveyor belts 59 which are shown on the left side of the drawing are arranged adjacent to baking oven supply inlets 61 in the left side wall 53 of the baking oven housing 9 . the baking oven supply inlets 61 can be closed by means of pivotal sealing flaps 62 . delivery portions 63 of the endless baking conveyor belts 59 which are shown on the right side of the drawing are arranged adjacent to baking oven delivery outlets 64 . the latter can be closed by means of pivotal sealing caps 65 . the switch flap 33 , the conveyance slides 39 , 40 , 41 , the driven baking drums 35 , 36 , 42 , the endless delivery conveyor belt 48 as well as the endless baking conveyor belts 59 are components of a controlled means of conveyance 66 for conveying the dough pieces of the two basic types , i . e . dough pieces supplied as bulk material through the first baking zone 37 and of the dough pieces supplied as individual pieces through the second baking zone 58 from the supply inlets 28 , 29 and 61 to the delivery outlets 50 , 64 . the baking system 1 is operated as follows , controlled by a control unit ( not shown ): for example , at first it is found out from the customer which basic type of dough pieces is to be baked . if dough pieces which are supplied as bulk material are to be baked , the dough pieces are first placed — in a manner which is not shown — on the endless conveyor belt 6 of the means of conveyance 3 located upstream of baking oven 2 . the endless conveyor belt 6 is then lifted until the conveyance plane of the endless conveyor belt 6 is positioned above separator 8 . by means of a transverse drive — which is not shown — the endless conveyor belt 6 as a whole is then shifted horizontally in the conveyance plane until the delivery outlet of the endless conveyor belt 6 has been positioned above separator bottom 11 of separator 8 . the endless conveyor belt 6 is then driven so that a first batch of dough pieces is delivered onto the separator bottom 11 . for separating the dough pieces , the separator bottom 11 in fig2 rotates anti - clockwise . the dough pieces are then conveyed by means of guiding plate 13 onto the supply portion 15 of the slat conveyor belt 12 . the latter is then driven clockwise in fig2 so that the dough pieces which are lying on the slat conveyor belt 12 are conveyed past the deflector flap 17 of the separation deflector 16 which is initially in a ‘ let through position ’. as soon as the first dough piece has passed the separating sensor after the separation deflector 16 , the deflector flap 17 is changed over to the deflection position so that dough pieces which follow on the slat conveyor belt 12 are conveyed back to separator bottom 11 . for the first dough piece , the supply slider 20 is in the supply position which is farthest away downstream of the delivery portion 19 of the slat conveyor belt 12 . the first dough piece is then conveyed from supply slider 20 under the impact of the movement of the slat conveyor belt 12 and under the influence of gravity up to the receiving portion for conveyance 24 that is closest to separator 8 . while the first dough piece is transferred onto the receiving portion for conveyance 24 , the separation of the next dough piece by means of separation deflector 16 and of the separating sensor can already start , as described above . for transferring the second dough piece onto the receiving portion for conveyance 24 , supply slider 20 travels over a certain distance along supply portion 19 upstream so that the next separated dough piece is placed after the transfer next to the first separated dough piece in the receiving portion for conveyance 24 . this procedure is now being repeated for dough pieces separated thereafter until a batch of for instance six or eight dough pieces is positioned on the receiving portion for conveyance 24 . as soon as such batch is complete , the endless conveyor belt of the upstream means of conveyance 23 is moved in the drawing over a certain distance to the right until the next receiving portion for conveyance 24 is associated with separator 8 on the supply side . thereafter the said next receiving portion for conveyance 24 is charged as explained above . this step is repeated in cycles until a pre - determined number of receiving portions for conveyance 24 have each been charged with a batch of dough pieces . the described embodiment shows that it is possible to charge a total of 11 receiving portions for conveyance 24 . thereafter , the upstream means of conveyance 23 is transferred from the receiving position which is shown for instance in fig1 to the first supply position which is shown in fig5 . thereafter , sealing flap 31 which is associated with the first baking oven supply inlet 28 is opened as is shown in fig5 . thereupon , it is decided via the control unit which of the baking drums 35 , 36 is to be charged , and the switch flap 33 is set accordingly . in the position of the switch flap 33 as shown in fig5 , the central baking drum 36 is charged . the outer defining wall 44 of the said baking drum 36 is rotated so that passage opening 47 is positioned downstream of the second conveyance slide 40 in the direction of conveyance . this position is shown in fig5 . thereafter the first receiving portion 43 of baking drum 36 can be charged . for this purpose , the endless conveyor belt of the upstream means of conveyance 23 is driven and shifted so that the supply - side batch of dough pieces falls from the receiving portion for conveyance 24 through the first baking - oven supply inlet 28 and , guided by switch flap 33 and the second conveyance slide 40 , falls through passage opening 47 onto the associated receiving portion 43 . thereupon , the internal defining wall 45 is rotated over a certain distance so that the next receiving portion 43 is positioned downstream of the second conveyance slide 40 in the direction of conveyance . this charging procedure for the receiving portions 43 is now repeated in cycles for a total of ten times so that ten of the eleven receiving portions 43 of baking drum 36 have been filled . thereafter , the outer defining wall 44 is rotated relative to the inner defining wall 45 in such a way that passage opening 47 is associated with the only unfilled receiving portion 43 . in the same way also baking drum 35 which is shown on the left side in the drawing can be charged . for this purpose , switch flap 33 is pivoted around swivel axis 34 in such a way that it forms together with the first conveyance slide 39 a conveyance connection between the first baking oven supply inlet 28 and passage opening 47 of baking drum 35 . for charging baking drum 42 — shown on the right side in the drawing — the upstream means of conveyance 23 on which batches of dough pieces were placed is transferred into the second supply position according to fig6 . sealing flap 31 of the second baking oven supply inlet 29 is opened . as already described above , ten of the eleven receiving portions 43 of baking drum 42 are now filled in cycles . the dough pieces in the baking drums 35 , 36 , 42 can now be baked in baking oven 2 . for doing so , the rotation of the outer defining walls 44 is synchronised with that of the inner defining walls 45 . upon the completion of baking , the defining walls 44 , 45 are synchronously rotated in respect to each other so that the passage opening 47 reaches its lowest position in which it is closest to the endless delivery conveyor belt 48 . now , the inner defining wall 45 is rotated in cycles while the outer defining wall 44 remains stationary . synchronised with the rotation in cycles of the inner defining wall 44 , the endless delivery conveyor belt 48 is always moved on over a certain distance . this synchronous shifting in cycles of the inner defining wall 45 on the one hand , and of the endless delivery conveyor belt 48 , on the other hand , is continued until the baking drums 35 , 36 , 42 that are to be emptied are completely empty . thereafter , the baked pieces of dough are conveyed on the endless delivery conveyor belt 48 to the baking - oven delivery outlet 50 . the baked dough pieces can then leave the baking - oven delivery outlet 50 through the opened sealing flap 51 . the baked dough pieces are then transferred into a storage bin — which is not shown — from where they can be taken out by the customer . each of the baking drums 35 , 36 , 42 may be associated with a specific type of dough pieces of the first basic type . in baking drum 35 , rolls may , for instance , be baked which require a comparatively short baking time while rolls are baked in baking drum 42 which require a comparatively long baking time . alternatively , it will be appreciated that it is possible not to associate the types of dough pieces with baking drums 35 , 36 , 42 and to pre - set the baking times by means of the central control unit . if , for instance upon the request of a customer , individually supplied and conveyed dough pieces , e . g . loaves of bread 4 or baguette 5 are to be baked , the same are at first placed piece by piece on the endless conveyor belt 6 in a manner which is not shown . thereupon , one of the endless baking conveyor belts 59 in the second baking zone 58 is selected on which the baking is to be done . the endless conveyor belt 6 of the means of conveyance 3 will then be brought to the same height as the selected endless conveyor belt 59 . with the transverse drive , the endless conveyor belt 6 is moved from its position until it is adjacent to the baking oven supply inlet 61 of the selected endless baking conveyor belt 59 . thereafter , the dough pieces on the endless conveyor belt 6 are moved past the opened sealing flap 62 and transferred through the baking - oven supply inlet 61 onto the selected endless baking conveyor belt 59 . this transfer is continued until the endless conveyor belt 6 has been emptied . if necessary , the endless conveyor belt 6 may be charged once again in order to fully charge a selected endless baking conveyor belt 59 or also in order to charge all endless baking conveyor belts 59 of the second baking zone 58 . as soon as the charging is completed , the dough pieces are baked on the endless baking conveyor belts 59 in the second baking zone 58 . owing to the deck - like arrangement of the endless baking conveyor belts 59 below the endless delivery conveyor belt 48 , a temperature stratification is generated in the baking chamber of baking oven 2 . the temperature in the area of the lower endless baking conveyor belt 59 is somewhat lower than that of the endless baking conveyor belt 59 arranged above it . further up , the temperature increases still further . in the first baking zone 37 , the temperature is highest . this temperature stratification can be used in order to bake different types of dough pieces on the different endless baking conveyor belts 59 . upon the completion of baking in the second baking zone 58 , the baked dough pieces are conveyed on the selected endless baking conveyor belt 59 to the respective baking - oven delivery outlet 64 and transferred past the opened sealing flap 65 into a storage bin — which is not shown — from where they may be taken out by the customer . upon request , dough pieces which belong to one of the basic types described above can be baked with baking oven 2 . also within the basic types , dough pieces with different baking requirements as to baking time and baking temperature can be baked . apart from the circulating air source , baking oven 2 is provided with a plurality of radiant heaters 67 — schematically indicated in fig4 only — as additional heating elements which generate radiant heat . the same are shown in cross - section in fig4 . the radiant heaters 67 are provided with an electric resistance heating and are arranged between the upper strand and the lower strand of the endless baking conveyor belts 59 . the radiant heaters 67 in the lowest endless baking conveyor belt 59 are used for generating bottom heat for dough pieces which are arranged on the lowest endless baking conveyor belt 59 . the radiant heaters 67 in the central endless baking conveyor belt 59 are used for generating upper heat for dough pieces which are arranged on the lowest endless baking conveyor belt 59 and bottom heat for dough pieces which are arranged on the central endless baking conveyor belt 59 . the radiant heaters 67 in the uppermost endless baking conveyor belt 59 are used for generating upper heat for dough pieces which are arranged on the central endless baking conveyor belt 59 and bottom heat for dough pieces which are arranged on the uppermost endless baking conveyor belt 59 . additional radiant heaters 68 arranged below the endless delivery conveyor belt 48 — indicated schematically in cross - section in fig4 only — are provided which also serve as sources of radiant heat for baking oven 2 . the radiant heaters 68 generate upper heat for dough pieces which are arranged on the uppermost endless baking conveyor belt 59 . temperature distribution within baking oven 2 , in particular temperature stratification , can be controlled via the heating radiators 67 , 68 . the heating capacity of radiant heaters 67 , 68 can be pre - set by the central control unit independently for each of them .

a baking oven is provided with a baking oven housing with a baking chamber . the latter is divided into at least two baking zones each of them being provided with at least one own baking oven supply inlet for the feeding of dough pieces . at least one delivery outlet is used for the delivery of the dough pieces . a first one of the at least two baking zones is configured so that a plurality of dough pieces available and conveyed on the supply side as bulk material is being baked there . a second one of the at least two baking zones is configured so that a plurality of dough pieces which are available and conveyed as individual pieces are being baked there . more - over , baking oven is provided with a circulating air source and a means of conveyance for conveying the dough pieces from the supply inlet through the baking chamber to the delivery outlet . a baking system with such a baking oven is furthermore provided with an upstream means of conveyance for conveying dough pieces to the baking oven . the result is a baking oven and a baking system equipped with the same by means of which during baking different requests of the customers can be flexibly complied with .

according to an exemplary embodiment of the invention as shown in fig1 , a nerve cuff stimulation electrode 100 is constructed , using a silicone rubber tube 101 , with at least two exposed pt / ir ( or equivalent material ) ring contacts 102 in its interior wall in contact with the vagus nerve 103 surface , and a closing structure 104 . the cuff stimulation electrode 100 can be self - coiling , or it may include other closing mechanisms , such as a piano hinge with a nylon suture . biocompatible strings 105 are built on the cuff stimulation electrode 100 outer wall to open it for easy implantation around the nerve 103 . electronic circuitry 106 , which may include a pulsation sensor , a triaxial accelerometer , and associated front - end electronic circuitry , is built on the cuff stimulation electrode 100 outer wall and / or associated assembly structures . in an exemplary embodiment , the ring contacts 102 are replaced by multiple contacts around the nerve 103 . local bipolar stimulation between any two of these contacts may increase effectiveness and selectivity for cardiovascular effects . the nerve cuff stimulation electrode 100 is connectable to an implantable pulse generator ( ipg ) 107 located in the patient &# 39 ; s chest area via a subcutaneously implanted wire 108 . such wire 108 provides electrical connection to the contacts 102 , powers the electronic module 106 built on the cuff stimulation electrode 100 , and receives pre - processed pressure and acceleration signals from the vicinity of the cuff stimulation electrode 100 . electronic circuitry in the ipg 107 can drive the ring contacts 102 for delivering low - level electrical stimulation pulses to the nerve 103 , i . e . a stimulation level that may not cause a heart rate drop or any other noticeable effect in the patient . sub - threshold pulses can also be delivered through the ring contacts 102 for impedance measurement to assess potential nerve 103 damage , connective tissue growth , or closing structure 104 failure . the ipg 107 also has the capabilities of recording intrathoracic far - field egms 109 between its can and a contact 102 , or alternatively using a separate lead with contact ( s ) 110 closer to the heart . thus , the ipg 107 acts as a control device for the cuff stimulation electrode 100 . it should be noted that the control device may also be another device different from an ipg . fig2 is a schematic block diagram showing the main electronic components of the nerve cuff stimulation electrode 100 . these may include a pulsation sensor 106 . 2 , which utilizes a displacement - sensitive measurement method ( e . g . a strain gage ), and a triaxial accelerometer 106 . 3 , both connected to the front - end electronic circuitry 106 . 1 . such circuitry 106 . 1 may be connected to stimulation contacts 102 and / or to communication contacts 106 . 4 . these contacts 106 . 4 may serve for galvanic intrabody data communication via modulation of an imposed alternating electric field on the body . they can be part of a data communication interface of the ipg 107 . for the purpose of data communication , the ipg 107 may comprise a data transceiver connected to communication contacts 106 . 4 . in an embodiment , the pulsation sensor is based on electrical impedance plethsymography re - utilizing these contacts 106 . 4 ( multiplexed with communication ) and the ipg 107 circuitry utilized for nerve 103 impedance measurements . in an embodiment , the control device is integrated with the electronic circuitry 106 and powered by a thermoelectric generator ( teg ) module 111 implanted around the external jugular vein ( ejv ) 112 using a ni - based vein cuff , with the teg &# 39 ; s hot plate in thermal contact with the ejv 112 outer wall and the cold plate facing the surrounding tissue beneath the skin 113 , as shown in fig3 . a temperature difference of 2 k can be expected between the two plates of the teg module 111 , and such temperature difference can be converted ( by seebeck effect ) into electrical energy for powering the embedded electronic circuitry 106 . typically 1 . 0 v at 5 . 0 μa or 5 . 0 μw can be harvested with this teg . this is enough power for the particular application given that vns for chf is duty cycled with a few pulses delivered every few seconds or cardiac cycles . a typical stimulation pulse may have a rectangular pulse of 1 . 0 ma with a 200 μs width which requires negligible charge consumption compared with the background power consumption required for operation . most of the power consumption in the present application is required for signal processing from the mentioned sensors . the circuitry 106 in this case includes the necessary low - power management circuitry for power regulation and continuous operation . power supply from the teg module 111 to the control device and electronic circuitry 106 is provided by the power supply wire 114 . fig4 sketches a cross - sectional view of the vagus nerve 103 , the common carotid artery ( cca ) 200 and the internal jugular vein ( ijv ) 201 within the carotid sheath 203 in the neck area . as can be seen , the nerve cuff electrode 100 is implanted so its built - in electronic circuitry 106 faces the cca 200 and ijv 201 for pressure waveform recording . in an embodiment , the nerve cuff electrode 100 may partially or fully wrap at least one of the cca 200 and ijv 201 for improved pressure waveform recording . as can be taken from fig5 , the teg module 111 is instead placed with its hot plate adjacent to the cca 300 and its cold plate facing surrounding tissue away from the blood vessel , for instance the ijv . the teg module 111 anchoring may be part of the cuff 304 , wrapping both the vagus nerve 103 and the cca 300 . as can be seen in fig5 , the cuff 304 is implanted so its embedded electronic circuitry 106 faces the cca 300 . as pointed out above , the signal provided by the pulsation sensor 106 . 2 is representative of arterial and venous pressures in terms of shape and timing with respect to the cardiac cycle and thus can be considered an indirect pressure signal . the cca 200 and ijv 201 pressure waveforms provide relevant information about the patient &# 39 ; s heart condition and hence are very useful for the monitoring of chf status . as shown in fig6 , the ijv pressure waveform can be differentiated from the cca pressure waveform by recording when the triaxial accelerometer indicates a supine and a semi - recumbent or erect position , respectively . the sampled pressure waveform is band - pass filtered to eliminate or minimize respiratory components . in an embodiment , the lower limit of the digital linear phase filter is set to a frequency above the fundamental respiratory rate and below the fundamental heart rate . the upper limit , on the other hand , can be set to reduce electrical noise from the mains . the front - end electronic circuitry 106 . 1 is configured to filter the pressure signal with a lower cutoff frequency between 0 . 75 hz - 1 . 75 hz and an upper cutoff frequency between 20 hz - 30 hz . the pressure signal either represents the ijv or cca pressure based on the patient &# 39 ; s position . an exemplary sampling rate can be 200 hz . the accelerometer signal provided by the triaxial accelerometer 106 . 3 is pre - processed by the front - end electronic circuitry 106 . 1 to determine heart and respiratory signals as follows : also in an embodiment , morphological filters are implemented in the ipg 107 embedded electronic circuitry to track changes in the ijv and cca pressure waveforms . the parameters of these filters may be adjusted following implantation . deviations from the original waveforms with time will indicate heart complications that may occur with the progression of the patient &# 39 ; s condition . in addition , changes in the pulse transit time ( ptt ) 303 , i . e . the delay between the r - wave detection and the peak of the cca pressure waveform , can be used to determine arterial stiffness and to perform monitoring of arterial blood pressure . ptt trending analysis can be used to assess disease progression . the system of the present invention has the signal processing capabilities to identify changes that may occur in the cca and ijv pressure waveforms and alerting , for example , a home monitoring center via a bedside patient messenger . in an embodiment , the system of the present invention has the signal processing capabilities to identify changes that may occur in the cca and ijv pressure waveforms and alert , for example , a home monitoring center accordingly either via a skin patch when applied or by relaying the information to a heart monitor implanted device with wireless communication with the outside world . as mentioned above , the triaxial accelerometer 106 . 3 signal can also be filtered in different ways to extract heart , breathing and snoring signals , which are key elements for the diagnosis of osa . it can also be used to extract sleeping angle patterns . a decrease in the patient &# 39 ; s sleeping angle will indicate an improvement of the patient &# 39 ; s condition , as patients with chf tend to sleep with several pillows due to breathing difficulties associated with the disease . furthermore , the accelerometer can be used to determine the reflected wave transit time ( rwtt ) of the cca pulse wave , which is the temporal difference between the incident and reflected wave at the same position . it has been shown in vivo that the rwtt has high correlation with systolic blood pressure , and hence it can be used as an estimator . going to fig7 , the ipg 107 can be wirelessly programmed by an external programmer 400 via a mics - band link 401 ( or equivalent ). the ipg 107 can also communicate with a bedside patient messenger 402 via a similar link 403 . arrhythmia detection , blood pressure waveform changes , and the other relevant diagnostic parameters described before can be transmitted to the bedside patient messenger 402 who can alert a home monitoring / remote programming center , if medical attention is required . referring to fig8 , the nerve stimulation electrode cuff 304 includes a minimum of two external contacts 600 placed longitudinally across its outer wall that can be used for galvanic communication 601 with an external skin patch 602 applied on the patient &# 39 ; s neck 603 or adjacent upper body location and wired to an external programmer 604 . the external skin patch 602 can also be employed as an ambulatory monitor , if desired , with a low - power wireless link 605 to a bedside patient messenger 606 connected to , for example , a home monitoring / remote programming center . the external contacts 600 can also be used for heart rate determination . in an embodiment , the same communication contacts 600 of fig8 for galvanic intrabody communication via modulation of an imposed alternating electric field can be multiplexed and utilized for impedance plethysmography that indirectly allows measuring the pulsatile blood flow through the cca . the circuitry built - in for nerve impedance measurement can be used for this purpose . the nerve cuff stimulation electrode 304 may also communicate via galvanic intrabody communication 607 with an implantable heart monitor 608 or another implantable device with the capability of mics - communication 609 ( or equivalent ) with the bedside patient messenger 606 . technical advantages of this invention include at least : a nerve cuff stimulation electrode with built - in electronic circuitry that includes a pulsation sensor ( e . g . electrical impedance plethsymography or strain gauge ), a tilt - kinematic sensor ( e . g . a triaxial accelerometer ), and associated front - end electronic circuitry , implanted as a standard vns cuff for chf ; a vns for chf system , capable of recording cca and ijv pressure waveforms , critical parameters for chf monitoring , in addition to other relevant parameters , such as heart rate , osa - related , body posture , etc . ; a vns for chf system , capable of recording intrathoracic far - field egms for arrhythmia detection in particular ; and / or a vns for chf system , suitable for integration into a home monitoring / remote programming regime or another monitoring device . the invention being thus described , it will be obvious that the same may be varied in many ways . such variations are not to be regarded as a departure from the spirit and scope of the invention , and all such modifications as would be obvious to one skilled in the art are to be included within the scope of the following claims .

a nerve cuff stimulation electrode for cervical vns is provided and configured to be arranged so as to at least partially surround or enclose one of the vagus nerves . the cuff stimulation electrode has at least two contacts configured to deliver electric stimulation pulses to a vagus nerve . the cuff stimulation electrode further has or may be attached or connected to a tilt sensor , a kinematic sensor , and / or a pulsation sensor configured to generate a signal representative of arterial and venous pressures . the implantable tilt sensor is configured to output a posture signal indicating a patient &# 39 ; s posture , thus allowing discrimination between supine and semi - recumbent or erect postures .

referring now to fig1 the power unit 10 of the invention is illustrated as it is applied to conventional rope jumping . as there illustrated , the power unit 10 is shown mounted on a pedestal stand 20 having a pedestal 28 and a vertical standard 30 that supports the power unit at a sufficient elevation to provide ground clearance for the jumping element 40 . the jumping element can be a conventional , flexible jump rope , or it can be a semi - rigid element with a preformed bight , e . g ., a plastic tube . at its opposite end , the jumping element 40 is secured to a stationary support such as a vertical post 50 and , for this purpose , the end of the jumping element can have an eyelet 52 through which the jumping element 40 is passed , thereby forming a loop 54 that can be secured about the vertical post 50 . alternatively , a plate with an eyelet can be provided for attachment to any elevated surface . the opposite end of the jumping element 40 is secured to the crank element 60 by releasable attachment 62 . the crank element 60 has a crank arm 65 which is preferably covered with a soft sleeve 64 , such as a sleeve formed of a closed cell , compressible plastic foam . in use , the power unit 10 rotates the crank element 60 about a horizontal axis , thereby twirling jumping element 40 which is shown at its opposite maximum excursions by the solid lines , and by phantom lines 41 . one or several jumpers 70 and 72 can then jump rope in a conventional manner , without the necessity of having other players twirl the jumping element 40 . referring now to fig2 a variant of the conventional rope jumping game is illustrated . in this application , the power unit 10 is mounted in a recess 22 in the pedestal base 28 of the pedestal stand 20 . the vertical standard 30 ( as illustrated in fig1 ) is not used in this embodiment . in this position , the crank element 60 is mounted for rotation about a vertical axis shown at 61 . a short jumping element 41 is secured to the end of the crank element 60 , and this element can be a flexible rope or can be a stiff or flexible wand . preferably a flexible rope is used and a weight 49 , such as a foam ball , is attached to its outer end . in the application shown in fig2 a tether cord 12 is attached to the on / off control 11 of the power unit 10 so that a player , such as 70 , can turn the power unit 10 on and off . when the power unit is turned on , it rotates the crank element 60 about vertical axis 61 as shown by arrowhead line 63 and a jumper such as 72 jumps with each revolution of the rope . many jumpers can participate , forming a circle about the power unit 10 . as apparent from fig2 this application of the invention provides all the fun and excitement of rope jumping and presents entirely new possibilities for the game . also . fig2 illustrates that this application does not require any substantial overhead clearance for the rope , thus permitting indoor use in rooms with conventional ceilings . referring now to fig3 the power unit 10 and pedestal stand 20 of the invention will be described in greater detail . as shown in fig3 the power unit 10 has a housing 14 which contains the drive train 35 ( as illustrated in fig8 and 9 ). unit . the crank element 60 has a crank hub 66 which is supported on a horizontal power shaft ( not shown ) of the drive train 35 . the crank hub 66 has a cross slot 68 which receives the end of the crank arm 65 . preferably , the crank arm 65 is yieldingly restrained in cross slot 68 and , for this purpose , the cross slot 68 is provided with one or more u - shaped brackets 67 ( as shown in fig4 ), which grasp the crank arm 65 . the construction of the crank arm 65 and its restraint in the crank hub 66 is shown ing reater detail by fig4 and 5 . fig4 is a sectional view along line 4 - 4 &# 39 ; of fig3 . the crank arm 65 is shown as restrained by the u - shaped bracket 67 which is mounted in cross slot 68 of the crank hub 66 . as illustrated , the u - shaped bracket 67 has an arcuate bight and extends slightly beyond 180 degrees to provide thereby a yielding detent for the cylindrical crank arm 65 . as illustrated in fig4 the crank hub 66 is formed with a first hub element 76 . the shape and assembly of these hub elements is shown in fig5 . referring now to fig5 the crank hub 66 is shown in exploded view by solid lines and in assembled view in phantom lines . the u - shaped brackets 67 are permanently attached to the second hub element 76 , which has a circular end flange 77 and supports the output shaft 78 of the power unit 10 . the end flange 77 has a semicircular slot 798 which receives the split cylindrical boss 81 of the first hub element 74 . each of the hub elements 74 and 76 has an arcuate groove , 83 and 85 , respectively , which together form the cross slot 68 . the crank hub 66 is shown in assembly by the phantom line illustration of fig5 . this crank hub 66 mounted on the forward face 15 of the housing 14 of the power unit 10 , with the output shaft 78 extending to the drive train 35 ( as shown in fig8 and 9 ) within housing 14 . referring now to fig6 the power unit 10 is provided with operational controls and these controls are mounted on the back panel 16 of the housing 14 . for this purpose , the back panel 16 can have a recessed area 17 for a control panel which includes an on / off switch 18 and a speed control knob 19 . the control panel preferably also has connector 21 for attachment of an electrical cord which supplies electrical power to the unit for operation or for recharging the rechargeable batteries that are preferably contained within housing 14 . the housing 14 is preferably formed of two half shells 23 and 25 which also provide a recess on the undersurface of the housing 14 to permit the housing 14 to be mounted on the vertical standard 30 of the pedestal stand 20 . referring again to fig3 the vertical standard 30 is preferably tubular to provide an interior recess whcih can receive the tether cord 12 of the power unit 10 , thereby storing this cord when the power unit 10 is used in its configuration illustrated in fig3 . the pedestal base 28 for the invention is preferably of hollow form , polygonal shape . the forward portion 24 of the pedestal base 28 has a recess 22 which has the shape of the exterior dimension of housing 14 , thereby providing a recess to receive the housing 14 in its horizontal position , as shown in fig2 . the recess 22 includes means to restrain the housing 14 , which peferably is sized to provide a snug , or frictional , fit for the housing 14 . alternatively , a rib and groove detent , or spring biased detents can be used to restrain the housing 14 in recess 22 . preferably , the pedestal base 28 has a through aperture in one of its horizontal upper surfaces which is closed by a removable cap 27 . ths permits one to fill the pedestal base 28 with sand , water or other weighted material . the pedestal base 28 has a socket 26 or through aperture that removably receives the vertical standard 30 . when the power unit 10 is configured as shown in fig2 the vertical standard 30 is removed from the power unit 10 . as illustrated in fig1 the jumping element 40 , such as a jump rope , is secured to the crank element 60 by a releasable attachment 62 . fig7 illustrates the releasable attachment 62 . for this purpose , the end of the jmmping element 40 is permanently received in a ferrule 42 which is compressed about the end of the jumping element and which has a short shaft 43 and a distal ball 44 . the crank arm 65 distally supports a socket member 45 which has a spherical socket 46 to yieldingly receive the distal ball 44 . the jumping element 40 is retained by crank arm 65 with distal ball 44 freely rotational in socket 46 , thereby permitting the jumping element 40 to swivel in crank arm 65 , thus avoiding twisting of the jumping element 40 . the yielding restraint of the crank arm 65 in crank hub 66 , previously described with reference to fig3 and 4 , and the yielding restraint of the jumping element 40 in the socket member 45 on the crank arm 65 , provide very important safety features for the invention . in the event that the crank arm 65 strikes a jumper or encounters an obstruction , it will be dislodged from the crank hub 66 before any injury or damage can occur . similarly , in the event that the jumping element 40 should become entangled with a jumper or an obstruction , the distal ball 44 carried on the jumping element 40 will pop out of its detenting restraint in the socket member 45 before any injury or damage will result . referring now to fig8 the construction of the power unit 10 is shown in greater detail . as there illustrated , the housing 14 has an interior chamber 33 in which is mounted the drive train 35 and the drive motor 37 . the drive train 35 includes compound gears 34 and 36 which are engaged , respectively , by the drive sprocket gear 38 and the gear 51 on the output shaft 78 of the unit . this use of compound gears in the drive train 35 provides a significant lever advantage to the drive motor 37 and permits use of a drive motor 37 of relatively low power demand . the housing 14 also contains , within the interior chamber 33 , a rechargeable storage batter 53 which can be a conventional battery of long life and rechargeable characteristics . the base 55 of the housing 14 has a recess 57 to receive the upper end of the vertical standard 30 . preferably the recess 57 and vertical standard 30 are indexed together to prevent rotation of the vertical standard 30 in the assembly . various indexing means can be used ; a key 31 on the internal sidewall of recess 57 , whichf its into a slot 32 in the end of the vertical standard 30 , is shown . alternatively , vertical standard 30 and its mating recess 57 could be formed with non - circular cross sections . the vertical standard 30 could also be received in a snug , friction fit in recess 57 to readily permit disassembly of the power unit 10 from the supporting vertical standard 30 . a similar or identical indexing means can be provided between the lower end of vertical standard 30 and the socket 26 in the pedestal base 28 . alternate power sources can be used for the power unit 10 . fig9 illustrates an alternate power means in which the power unit 10 is provided with a standard sleeved hose connector 92 having internal threads for the attachment of a garden hose 94 . the hose connector 92 communicates with a fluid nozzle 96 which is directed to discharge a jet of water against the impeller blades 98 of a water turbine 100 that is rotatably mounted on a support shaft 102 and that is coupled to the output shaft 78 . the housing 14 is provided with a drain 102 to permit the water to drain from the housing . as with the previously described embodiments , the power unit 10 of this embodiment can also be removed from the vertical standard 30 and placed in a horizontal position on the pedestal base 28 to provide the configuration for twirling a jumping element about a vertical axis , such as shown in fig2 . referring now to fig1 , the power unit 10 is shown with an alternate crank element , disk 110 , which is mounted on the output shaft 78 . the disk 110 provides the additional safety feature of avoiding a crank arm 65 . the disk 110 also can be provided with a plurality of bosses 112 which are positioned eccentric to output shaft 78 and which have sockets such as 46 to receive the distal ball 44 of the jumping element 40 . for this purpose , a distal ball and socket attachment means similar to that shown in fig7 can be employed . as shown in fig1 , the power unit 10 can be provided with a suitable remote control means to control the operation of the power unit 10 . for this purpose , a radio signal , or infrared beam control unit 120 can be placed on the power unit 10 with an antenna 122 , if necessary . one or more of the participants can wear a radio signal or infrared beam transmitter 124 . in this application . a simple wrist band 126 can be used to attach the radio signal or infrared beam transmitter 124 , thereby permitting the jumper to control the on / off switch and revoltuion speed of the power unit 10 . the invention has been described with reference to the illustrated and presently preferred embodiments . it is not intended that this invention be unduly limited by this disclosure of the presently preferred embodiment . instead , it is intended that the invention be defined by the means , and their obvious equivalents , set forth in the following claims .

there is disclosed a power unit for twirling a jump rope about a substantially horizontal axis , as in conventional rope jumping , or about a vertical axis to provide an entirely new variation of the game . the power unit includes a stand with a vertical standard which supports a motorized drive with an output shaft on which is mounted a crank element . one end of a jump rope is attached to the crank element , which twirls the jump rope . the opposite end of the jump rope is secured to a stationary support , e . g ., fence post , side of a building , etc . the power unit can also be removed from the vertical standard and seated in a recess in the base of the stand with the drive shaft vertically oriented , whereby the crank element is rotationally driven about a vertical axis . a short rope is secured to the crank element and a weighted element such as a foam plastic ball is secured to its free end . the players jump the rope as it swung around in a horizontal arc of rotation , thereby providing a new variation of the game .

fig1 and 2 show an injection device 28 that , because of its small size , is also referred to as a “ pen injector .” at the rear , i . e . at its end facing away from the patient , it has an adjusting knob 30 for setting a desired injection dose ( by rotating knob 30 ), the dose that is set being displayed in a window 32 . during setting , knob 30 is rotated out of housing 34 , and during an injection the patient pushes on knob 30 in the direction of an arrow 36 , i . e . toward the patient . the result is that a piston rod 38 , which is equipped with an external thread 40 , is moved forward in the direction of an arrow 42 toward the patient ( who is to be thought of as being at the top in fig1 to 12 and 23 to 32 ). external thread 40 is depicted as a left - hand thread . in fig2 and 3 , piston rod 38 is located in a carpule container 44 that is equipped with two oppositely located windows 46 . fig3 shows pen injector 28 with an empty carpule 50 whose shape can best be gathered from fig1 . the injection fluid 52 ( fig2 , 6 , 7 , 8 , 9 , 11 ) is exhausted , and piston rod 38 is in its maximally forward position . before a completely filled carpule 50 can be inserted , as shown by fig1 , piston rod 38 must now be brought into its maximally rearward position . in many pen injectors this is done by unscrewing carpule container 44 and then turning piston rod 38 back by turning a separate component that is referred to as a “ return ring .” in other pen injectors piston rod 38 is simply pushed manually into housing 34 after carpule container 44 is removed . in the case of the injection device depicted , piston rod 38 is screwed back by rotating carpule container 44 , in this case by turning it counterclockwise ( see arrow 58 in fig4 ). ( the rotation direction is indicated from the viewpoint of the front end of injector 28 , i . e . as viewed from above .) when piston rod 38 has reached its maximally rearward position , carpule container 44 can be removed ( fig5 ) and the empty carpule 50 can be replaced by a full one ( see fig6 ). carpule container 44 can then be remounted onto housing 34 ( see fig7 ). piston rod 38 is screwed forward by a rotation opposite to direction 58 ( fig4 ), i . e . in this case by a clockwise rotation ( see arrow 60 of fig8 ). as soon as plate 46 ′ of piston rod 38 reaches piston 48 ( see fig8 ), the system automatically locks , i . e . a further rotation of carpule container 44 in a clockwise direction 60 becomes impossible . an elevated torque must now be exerted in order to rotate the carpule container counterclockwise ( see arrow 58 of fig4 ). this prevents the patient from inadvertently rotating carpule container 44 counterclockwise even though he or she still wishes to withdraw injections from carpule 50 that is presently inserted . the reason is that a gap 62 ( fig9 ) would thereby be produced between plate 46 ′ and piston 48 , so that the distance over which the latter would be moved forward during a subsequent injection , by plate 46 ′ of piston rod 38 , is too small by an amount equal to the size of said gap 62 , so that the fluid quantity injected in the context of the injection would correspondingly be too small . correct “ presetting ” of plate 46 ′ against piston 48 is therefore very important . in the locked state ( fig8 ), carpule container 44 can therefore be rotated counterclockwise only with an elevated torque . this provides protection against inadvertent initiation of a carpule change ( fig4 ), similar in effect to the protection that is usual with comparable pen injectors . once carpule container 44 is locked , as will be described below , the patient can begin with injections without needing to specifically prime the pen injector again . this results in very intuitive and easily understandable operation . fig1 to 12 serve to explain carpule container 44 . the latter has at its end 63 remote from the patient a peg 64 that serves for bayonet connection with a corresponding opening 66 of a first component 68 that is depicted in fig1 to 15 and 23 to 32 . for latching ( as shown in fig2 ), peg 64 is introduced from above along a track 70 into opening 66 , and then brought , by rotation ( to the left ) over a latching lug 74 along a distance 72 , into the latched position depicted in fig2 , 26 , and 27 . lower boundary 78 ( fig2 ) of opening 66 is elastically resilient as a result of an axially extending opening 76 ( fig2 ), in order to enable a latching connection . component 68 has a hollow - cylindrical outer wall 80 , and recessed into said wall are elastically resilient guidance members 82 that have associated with them , in housing 34 , an annular groove 84 ( fig2 , 24 , 28 , 29 ). upon assembly , guidance members 82 latch into this annular groove 84 , and component 68 is then rotatably guided by guidance members 82 in annular groove 84 of housing 34 but cannot be displaced axially relative to housing 34 . component 68 is in turn connected fixedly , but disengageably , to carpule container 44 via bayonet connection 64 , 66 . as fig1 shows , component 68 has , adjacently to the cylindrical outer wall 80 , a base 86 at whose center is located an opening 88 into which projects ( as shown in fig2 , 29 ) a collar 90 of a second component 92 , so that components 68 and 92 are rotatable and also axially displaceable relative to one another . collar 90 has an opening 94 , extending in an axial direction , that serves for axial guidance of piston rod 38 and is therefore adapted to the latter &# 39 ; s cross - sectional shape ( as is shown , for example , by fig1 , 17 , and 19 ) so that piston rod 38 and second component 92 can rotate only together , but can shift axially relative to one another . in contrast thereto , first component 68 can rotate relative to housing 34 but cannot shift axially . the same is then true of carpule container 44 when it is latched in on part 68 . first component 68 and second component 92 together form a linkage 98 whose function will be described below with reference to fig2 to 27 . it serves to convert a relative rotation between components 68 and 92 into an axial motion of second component 92 , which motion has the function of immobilizing second component 92 and piston rod 38 guided therein , for example by positive engagement of component 92 with housing 34 ( see fig2 to 23 and 25 to 27 ) or by generating a strong friction between second component 92 and housing 34 ( as depicted in fig3 to 36 ). as fig1 to 36 show , first component 68 and second component 92 are equipped with ramps 104 and 118 , respectively . fig1 and 15 show , by way of example , three ramps 104 that are arranged on base 86 of first component 68 at equal spacings of 120 °. proceeding , in fig1 , from a point 105 that would correspond on a clock to approximately three o &# 39 ; clock , this is followed clockwise firstly by a ramp - free portion 106 having an angular extent of approximately 50 °. this is followed by a portion 108 ( e . g . 30 °) having a ramp portion 110 that usually rises to a maximum in portion 108 . there then follows a flat portion 112 ( e . g . 40 °) in which the height of ramp 104 does not substantially change further , and at the end 114 of this portion 112 the height of ramp 104 drops abruptly to zero , i . e . point 114 represents a shoulder of ramp 104 . first component 68 thus has a total of three ramps 104 , three shoulders 114 , and three ramp portions 110 . the above - described configuration repeats after shoulder 114 , i . e . the next ramp portion 110 begins to rise at an angular spacing 106 from shoulder 114 , as is clearly evident from fig1 and 15 . second component 92 ( fig1 to 19 ) has a configuration largely complementary thereto , as shown by a comparison of fig1 and 19 . it likewise has three ramps 118 . beginning at a shoulder 120 ( fig1 ) at a location corresponding approximately to four o &# 39 ; clock there comes first ( viewed clockwise ) a flat region 122 ( e . g . 50 °) adjacent to which is a rising region 124 of the lower ( in fig1 ) ramp 118 . this ramp region 124 has in this example an angular extent 126 of approximately 30 °, and it ends in a flat roof region having an angular extent 128 of , for example , 40 °, at the end of which a shoulder 120 is again located . ramps 118 are located around collar 90 , and located inside collar 90 is opening 94 in which piston rod 38 is guided . when second component 92 rotates , piston rod 38 therefore also rotates , and the latter can shift freely in an axial direction in opening 94 as is necessary , for example , when priming . on its side facing away from ramps 118 , second component 92 has a coupling projection 130 that tapers frustoconically at its free end 132 and is equipped with longitudinal grooves 134 for engagement into corresponding longitudinal grooves 136 of housing 34 , so that projection 130 , upon engagement into longitudinal grooves 136 , is prevented by positive engagement from rotating . this effect can optionally also , in accordance with fig3 to 36 , be achieved without the projection by the fact that second component 92 is simply pressed against a surface 140 ( fig3 ) of housing 34 and secured there by friction to prevent rotation . second component 92 is pressed by a spring 142 in a direction toward first component 68 , which latter is guided in the housing rotatably , but ( because of guidance members 82 and annular groove 84 ) axially nondisplaceably . as fig2 shows , upon a clockwise rotation 60 such as that which occurs after insertion of a new carpule 50 ( see fig8 ), ramps 104 of first component 68 are located between ramps 118 of second component 92 , since the latter is pressed by spring 142 ( fig2 ) against first component 68 . as a result , coupling part 130 is out of engagement with coupling part 136 provided in housing 34 , so that when the patient rotates carpule container 44 clockwise ( arrow 60 ), first component 68 with its ramps 104 also rotates along with carpule container 44 , and said ramps 104 engage ( as shown in fig2 ) between ramps 118 of second component 92 and thereby also transfer said rotary motion 60 to second component 92 and to piston rod 38 guided therein . the latter is guided in housing 34 in a threaded part 150 ( fig2 , 29 ) that , for example , can be part of the dosing apparatus of the injector and that does not rotate during a carpule change . piston rod 38 is therefore moved in an upward direction in fig2 , i . e . toward the patient , in the context of a rotation 60 ( fig2 ). as depicted in fig9 , piston rod 38 thereby comes into contact by means of its plate 46 ′ against piston 48 in carpule 50 , i . e . injector 28 is now primed , i . e . correctly prepared for an injection . piston rod 38 therefore cannot move any farther upward , i . e . the torque in the direction of arrow 60 ( fig2 ) continues to act because the patient is continuing to turn carpule container 44 as depicted in fig2 , but the rotation of second component 92 is now blocked because piston rod 38 is abutting against piston 48 ( see fig8 ). oblique surfaces 110 ( fig1 to 16 ) of ramps 104 of first component 68 therefore now produce an axial force on oblique surfaces 124 of ramps 118 of second component 92 and displace the latter , as depicted in fig2 , against the force of spring 142 ( fig2 ) away from first component 68 . this results in a coupling between projection 130 ( fig2 ) and longitudinal grooves 136 in housing 34 ( fig2 ), so that second component 92 cannot rotate any farther in a clockwise direction 60 . injection device 28 is thus now ready to use , i . e . the patient can , in normal fashion , set his or her individual injection dose and give him - or herself injections until the contents of carpule 50 are exhausted . carpule container 44 must then be removed . for this , it is rotated counterclockwise in direction 58 , as shown in fig2 . this causes the previous coupling between first component 68 and second component 92 to disengage ; the latter is displaced upward by spring 142 ; and shoulders 114 of first component 68 come into abutment against shoulders 120 of second component 92 so that the latter is likewise driven in counterclockwise direction 58 . as a result , piston rod 38 is rotated into housing 34 until it comes to a stop , and at the end of this procedure bayonet closure 64 , 66 is disengaged , so that carpule container 44 can be taken off in order to remove the exhausted carpule and insert a new carpule 50 , as has already been described with reference to fig1 to 9 . the above - described procedure is then repeated in order to prime the new carpule 50 again , and once again prepare injection device 28 for reliable use . in order to optimize the present invention , the slope of the ramps was also modified . each of these ramps can be imagined as part of a thread whose ( notional ) flights have a specific pitch . this thread pitch is the spacing from one flight to the next , and in this case is preferably approximately 10 to 20 mm . the inside diameter a and outside diameter b of ramps 124 ′ of part 92 are plotted in fig3 . practical values can be , for example , one ramp 124 ′ extends here over an angle beta that is equal , for example , to 40 °. if parts 68 and 92 rotate during presetting through an angle of 36 ° relative to one another , their spacing h then changes by a value if the thread pitch is equal to 15 mm , h therefore has a value of approximately 1 . 5 mm , which experiments have shown to be a favorable value . ramps 104 on part 68 have the same shape as ramps 124 ′ of part 92 , and are therefore shown only in fig3 to 41 . part 68 and its ramps 104 are shown therein in gray in order to facilitate comprehension . fig3 to 41 are highly schematic depictions of the adjusting procedures . fig3 shows the presetting of plate 46 ′ against piston 48 . ramps 118 are rotated in the direction of arrow 60 so that they initially move plate 46 ′ upward toward piston 48 . in fig4 , plate 46 ′ has reached piston 48 . upper ramps 110 therefore now shift relative to lower ramps 124 ′ and displace part 92 downward , so that the latter is now at a spacing h ′ from part 68 , and part 92 is blocked in terms of rotation in the manner described . the injection device is now primed . fig4 shows the procedure in the context of a cartridge change . carpule container 44 is rotated in the direction of arrow 58 , with the result that ramps 104 disengage from ramps 124 ′ and the spacing between parts 68 and 92 once again becomes h . part 92 is pressed by its spring 142 ( see fig3 ) toward part 68 . ramps 104 now press with their steep flanks 114 against the corresponding flanks 120 ( fig4 ) of ramps 110 . because part 68 is rotating together with part 92 in the direction of arrow 58 , plate 46 ′ is moved downward ; and at the end of this movement , part 68 disengages from dosing part 44 , as depicted in fig5 . operation is therefore very simple and intuitive , and dosing accuracy is correspondingly increased . numerous variants and modifications are , of course , possible within the scope of the present invention .

an injection device has a housing , and a carpule container for receiving a carpule having a fluid to be injected and having a piston displaceable in said carpule . it further has a piston rod with end plate which serves , in the context of an injection , to displace the piston of a carpule inserted into the carpule container and thereby to eject fluid from the carpule . in order to minimize patient error in adjusting the amount of fluid medication to be injected , the mechanism includes a first component and a second component which link and interact with each other , to control when the carpule container can rotate with respect to the housing , and to prevent creation of an axial gap between end plate and piston .

the invention features peptides containing 8 to 20 amino acids ; these peptides include defined portions of the amino acid sequence of the naturally occurring protein histatin 3 ( seq id no : 11 ), which is shown in fig1 . in addition , the peptides of the invention include defined portions of the amino acid sequence of histatin 3 , with amino acid substitutions at particular positions of the peptides . these peptides are referred to herein as “ histatin - related peptides .” histatins ( also referred to in the literature as histidine - rich proteins or hrps ) are salivary proteins that are synthesized in the parotid and submandibular - sublingual secretory glands of humans and old world monkeys and are believed to be part of the extraimmunologic defense system of the oral cavity . the family of naturally occurring human histatins is a group of twelve low molecular weight peptides . the peptides of the present invention can thus be obtained from naturally occurring sources of histatin ; alternatively , they can be obtained by recombinant dna techniques as expression products from cellular sources . the peptides can also be chemically synthesized . for example , cloned dna encoding the histatins or histatin - related peptides may be obtained as described by l . m . sabatini et al ., biochem . biophys . res . comm . 160 : 495 - 502 ( 1989 ) and j . c . vanderspek et al ., arch . oral biol . 35 ( 2 ): 137 - 43 ( 1990 ). cdna encoding the histatin - related peptides can be cloned by recombinant dna techniques , for instance , by using degenerate oligonucleotides based on the amino acid sequence of histatin - related peptides as primers for polymerase chain reaction amplification . alternatively , oligonucleotides encoding histatins or histatin - related peptides can be synthesized chemically using commercially available equipment . they can then be made double - stranded and cloned into vectors for amplification . the histatin - related peptides can be produced in a variety of expression vector / host systems , which are available commercially or can be reproduced according to recombinant dna and cell culture techniques . the vector / host expression systems can be prokaryotic or eukaryotic , and can include bacterial , yeast , insect , mammalian , and viral expression systems . the construction of expression vectors encoding histatin - related peptides , transfer of the vectors into various host cells , and production of peptides from transformed host cells can be accomplished using genetic engineering techniques , as described in manuals such as j . sambrook et al ., molecular cloning ( 2d ed . 1989 ) and current protocols in molecular biology , ( f . m . ausubel et al ., eds .). the histatin - related peptides encoded by expression vectors may be modified by post - translational processing in a particular expression vector / host cell system . in addition , these peptides can be altered by minor chemical modifications , such as by adding small substituents or by modifying one or more of the covalent bonds within or between the amino acid residues . the substituent groups can be bulky and may include one or more natural or modified amino acids . useful modifications include the addition of a substituent to either the amino terminus , the carboxyl terminus , or to both termini of the peptide . particularly useful modifications include acylation or carbamylation of the amino terminus of the peptide , or amidation of the carboxyl terminus of the peptide . these alterations do not significantly diminish the antifungal or antibacterial activities of the peptides and appear to stabilize the peptide in its active form and to aid in the prevention of enzymatic degradation of these peptides . the peptides can also be made by standard solid phase synthetic methods . the peptides described herein can be used in preventive treatment as well . the compositions may contain combinations of histatin - related peptides , in order to obtain maximum activity against all developmental forms of fungi or bacteria that cause pulmonary infections . the ionic strength , presence of various mono - and divalent ions , and ph of the compositions may be adjusted to obtain maximum activity of the histatin - related peptides , as described in t . xu et al ., infect . immun . 59 ( 8 ): 2549 - 54 ( 1991 ). carriers appropriate for administration of pharmaceutical agents to the respiratory system are known and described , for instance , in pollock et al ., u . s . pat . no . 4 , 725 , 576 . compositions for treatment of cystic fibrosis can be administered by various routes ; for example , they may be administered by inhalation . there now follow particular examples that describe the preparation of histatin - related peptides and the antibacterial activity of various histatin - related peptides against strains of p . aeruginosa . these examples are provided for the purpose of illustrating the invention , and should not be construed as limiting . the isolation and amino acid sequence determination of human histatins are performed as described in f . g . oppenheim et al ., j . biol . chem . 263 ( 16 ): 7472 - 7477 ( 1988 ). human parotid secretion from healthy adults is stimulated using sour lemon candies , collected with curby cups in ice - chilled graduated cylinders , pooled , dialyzed and lyophilized . the total protein in the human parotid secretion is subjected to fractionation on bio - gel p - 2 ( bio - rad laboratories , richmond , calif .) developed in 0 . 05 m ammonium formate buffer , ph 4 . 0 . the protein fractionation enriched with histatins is further purified using reverse - phase high - performance liquid chromatography on a c 18 column . purified histatins are evaporated to dryness , dissolved in deionized water , quantified by amino acid analysis , lyophilized , and stored at − 20 ° c . until use . histatin - related peptides are synthesized by the solid phase method of b . merrifield , science 232 : 341 - 47 ( 1986 ). peptides are synthesized on a milligen / bioresearch sam - two peptide synthesizer using fmoc l - amino acid kits ( millipore , bedford , mass . ), and purified on a tsk ods - i2ot c 18 column ( 5μm , 4 . 6 × 250 nm ) using rp - hplc ( pharmacia - lkb ). the purified peptides are quantified by amino acid analysis on a beckman system 6300 amino acid analyzer . antibacterial activity of a histatin - related peptide derivative p - 113 against various strains of p . aeruginosa pseudomonas clinical isolates were gathered from cystic fibrosis patients , ranging in age from 14 to 51 , from different parts of the country . these isolates were exposed to a variety of antibiotics that are commonly used to treat pulmonary infections , including ceftazidime , imipenem , amikacin , piperacillin , aztreonam , tobramycin , ciprofloxacin , gentamicin , ticarcillin , and timentin . all of the isolates were resistant to the majority of these antibiotics , and some were resistant to all of these antibiotics . five of these isolates were resistant to all antibiotics tested , including high doses of tobramycin and gentamicin . the susceptibility of these isolates to these antibiotics is summarized in table 1 . these pseudomonas clinical isolates , as well as a variety of pseudomonas atcc strains , were tested for their susceptibility to the histatin derivative having the sequence ala - lys - arg - his - his - gly - tyr - lys - arg - lys - phe - his - nh 2 ( seq id no : 1 ) ( p - 113 ). p - 113 was used at a concentration of 100 μg / ml to 0 . 75 μ / ml . p . aeruginosa atcc 27853 was used as a control in each assay . the atcc strains were tested using direct antibacterial assay sop 98 - 020 ; the clinical isolates were tested using either the direct antibacterial assay ( d ) or alamar blue antimicrobial / antifungal assay sop 96 - 018 ( a ). the direct assay is an mic test in microtiter plate format in which cells resuspended in lm broth are exposed to two - fold dilutions of p - 113 , and the cell density is determined directly after an overnight incubation . cells are inoculated onto a blood agar plate and incubated for 18 hours at 37 ° c ., and then stored at room temperature for use later in the day . cells are resuspended and diluted based on the optical density to a final concentration of 5 × 10 5 per ml in lm broth containing two - fold dilutions of antibiotics . after 16 - 18 hours at 37 ° c ., the optical density is measured with a molecular devices thermonix plate reader . a reading of ˜ 0 . 3 over background is observed for cells grown in the absence of drug . readings & lt ; 0 . 01 correlated with no visible growth . at least two independent tests were conducted with each strain , and if matching mics were not obtained , at least one additional test was conducted to determine the mic . the composition of lm broth is as follows : 5 % cation - adjusted mueller hinton broth supplemented with 2 . 2 mm sodium phosphate , 0 . 1 mm magnesium sulfate , 1 . 0 mm sodium citrate , all to final concentrations . in addition , 0 . 4 mg zncl 2 , 2 . 0 mg fecl 3 * 10h 2 o , all per liter of medium . also glucose , amino acid mix , and vitamin mix all from life technologies rpmi - 1640 select - amine kit , supplemented as instructed by the vendor ( accumed international , inc ., westlake , ohio . the alamar blue biological assay was used to compare the effects of various antimicrobial and antifungal agents on candida albicans with that of a reference standard . the effect of the antimicrobial agent on the growth of c . albicans was monitored using alamar blue , a growth indicator dye that is based on the detection of metabolic activity . the dye incorporates an oxidation - reduction ( redox ) indicator that changes color in response to chemical reduction of growth medium resulting from cell growth . the redox indicator exhibits a colorimetric change in the appropriate oxidation - reduction range relating to cellular metabolic activity and produces a clear , stable and distinct change which can be quantitated using a spectrophotometric microtiter plate reader . a dose response curve was generated using both the test article and the reference standard ( positive control ). zero % inhibition was defined as the result obtained when buffer without peptide is added to the cells ( negative control ). the 50 % inhibition points ( lc 50 ) were used to calculate the activity of the test article , which was expressed as percent activity relative to the reference standard . the ic 5 o for the reference standard fell within the range of 0 . 60 to 2 . 24 μg / ml under the conditions of this assay . 1 strains from atcc are designated . most of the other strains are clinical cf isolates obtained from dr . lisa saiman at columbia university . four strains ( indicated with an asterisk ) were obtained from dr . gerry pier at harvard university as shown in table 2 , the peptide p - 113 was effective against nearly all of the pseudomonas strains tested . antibacterial activity of a first group of histatin - related peptides against p . aeruginosa histatin derivatives having the following amino acid sequences were tested for activity against p . aeruginosa : ala - lys - arg - his - his - gly - tyr - lys - arg - lys - phe - his - nh 2 ( seq id no : 1 ) ( p - 113 ); ala - lys - arg - his - his - lys - tyr - lys - arg - lys - phe - his - nh 2 ( seq id no : 5 ) ( p - 113 - k6 ); ala - lys - arg - his - his - gly - tyr - his - arg - phe - his - nh 2 ( seq id no : 6 ) ( p - 113 - h8 ); ala - lys - arg - his - his - gly - tyr - his - arg - lys - phe - his - nh 2 ( seq id no : 7 ) ( p - 113 - k6h8 ); ac - ala - lys - arg - his - his - gly - tyr - lys - arg - lys - phe - his - nh 2 ( seq id no : 1 ) ( p - 113 - na ); and ala - lys - arg - phe - phe - gly - tyr - lys - arg - lys - phe - phe nh 2 ( seq id no : 4 ) ( p113 - f4 . 5 . 12 ). the standard procedure used for testing activity was incubation of the bacterial strain with the peptide for one hour at 37 ° c ., followed by plating at two dilutions . the results are shown in fig3 . as shown there , the peptides all showed antimicrobial activity against p . aeruginosa . all of the peptides were capable of killing at least 80 % of the bacteria at peptide concentrations of about 0 . 5 μm and higher . antibacterial activity of a second group of histatin - related peptides against p . aeruginosa peptides having the following amino acid sequences ( including p - 113 , as in example 4 ) were tested for activity against p . aeruginosa under the conditions described above : ala - lys - arg - his - his - gly - tyr - lys - arg - lys - phe - his - nh 2 ( seq id no : 1 ) ( p - 113 ); ala - lys - arg - tyr - tyr - gly - tyr - lys - arg - lys - phe - tyr - nh 2 ( seq id no : 8 ) ( p - 113 - y4 . 5 . 12 ); ala - lys - arg - leu - leu - gly - tyr - lys - arg - lys - phe - leu - nh 2 ( seq id no : 12 ) ( p - 113 - l4 . 5 . 12 ); ala - gln - arg - his - his - gly - tyr - lys - arg - gln - phe - his - nh 2 ( seq id no : 9 ) ( p - 113 - q2 . 10 ); ala - lys - gln - his - his - gly - tyr - lys - gln - lys - phe - his - nh 2 ( seq id no : 13 ) ( p - 113 - q3 . 9 ); and ala - gln - gln - his - his - gly - tyr - lys - gln - gln - phe - his - nh 2 ( seq id no : 14 ) ( p - 113 - q2 . 3 . 9 . 10 ). the results are shown in fig4 . as shown there , p - 113 , p - 113 y4 . 5 . 12 , and p - 113 q2 . 10 were very active against p . aeruginosa ; p - 113 q3 . 9 and p - 113 l4 . 5 . 12 were also active . p - 113 q2 . 3 . 9 . 10 was inactive against p . aeruginosa , even at high peptide concentrations . antibacterial activity of a third group of histatin - related peptides against p . aeruginosa peptides having the following amino acid sequences were tested for antibacterial activity against p . aeruginosa : ala - lys - arg - leu - leu - ser - tyr - lys - arg - lys - phe - leu - nh 2 ( seq id no : 15 ) ( p - 113 - g6s - h4 . 5 . 12l ); ala - orn - arg - tyr - tyr - gly - tyr - lys - arg - orn - phe - tyr - nh 2 ( seq id no : 10 )( p - 113 - k2 . 10o - h4 . 5 . 12y ); ala - lys - lys - his - his - gly - tyr - lys - lys - lys - phe - his - nh 2 ( seq id no : 16 ) ( p113 - r3 . 9k ); his - lys - lys - his - his - lys - tyr - his - lys - lys - phe - his - nh 2 ( seq id no : 17 ) ( p - 113 h - amphipathic ); leu - lys - lys - phe - phe - gly - tyr - leu - lys - lys - phe - phe - nh 2 ( seq id no : 18 ) ( p - 113 amphipathic ); and ala - gln - gln - his - his - gly - tyr - lys - gln - gln - phe - his - nh 2 ( seq id no : 14 ) ( p - 113 - kr2 . 3 . 9 . 10q ). the results for two runs of the same assay are shown in fig5 and 6 . as shown there , all of the peptides tested in this series had activity against p . aeruginosa . all of the peptides killed at least 80 % of the cells at peptide concentrations of about 2 μm . p - 113 and his - 5 were tested against p . aeruginosa under the conditions described in the preceding examples . the dilution values were as follows : expected - 2000 cfu / plate ( in broth ) from dilution a . a = 1 / 2 . 5 × dilution ; plate 50 μl . b = 1 / 2 . 5 × dilution ; plate 25 μl . the results are shown in table 3 . both peptides were effective in killing these bacteria , with p - 113 exhibiting greater efficacy than his - 5 . all publications and patents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference . from the foregoing description , it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions . such embodiments are also within the scope of the following claims .

methods for treating cystic fibrosis in a mammal that include administering to the mammal an effective amount of a histatin , a histatin fragment , or a histatin - related peptide are disclosed .

according to the invention , the sphingomyelinase is preferably extracted from gram - positive bacteria , gram - negative bacteria , lactic bacteria or mixtures thereof lactic bacteria should preferably be chosen from among the following : lactobacillus acidophillus , lactobacillus brevis , lactobacillus buchneri , lactobacillus casei , lactobacillus catenaforme , lactobacillus cellobiosus , lactobacillus crispatus , lactobacillus curvatus , lactobacillus delbrueckii , lactobacillus fermeitum , lactobacillus jeasenii , lactobacillus leichmanii , lactobacillus mintutus , lactobacillus plantarum , lactobacillus rogosae , lactobacillus salivarius , bifidobacterium adolescentis , bifidobacterium anigulatum , bifidobacterium bifidum , bifidobacterium breeve , bifidobacterium catenulatum , bifidobacterium dentium , bifidobacterium eriksonii , bifidobacterium infantis , bifidobacterium loziguw , bifidobacterium plantarum , bifidobacterium pseudocateiulatum , bifidobacterium pseudolongum , steptococcus lactis , streptococcus rafflizwlactis and streptococcus thermophilus . according to a preferred embodiment of the invention , the cells are used in the form of lyophilized or sonicated cells . according to the present invention , the sphingomyelinase can furthermore be used as a cutaneous permeation or absorption enhancer , either alone or in admixture with other enhancers , for preparing pharmaceutical or cosmetic compositions suitable for transdermal administration . a further object of the present invention is to provide dermatological or cosmetic compositions characterized by the fact that they contain an amount of sphingomyelinase effective for producing an increase in the level of ceramides in the skin or mucosa . according to the invention , the sphingomyelinase contained in such compositions is preferably extracted from gram - positive bacteria , gram - negative bacteria , lactic bacteria or mixtures thereof . lactic bacteria should preferably be chosen from among the following : lactobacillus acidophilus , lactobacillus brevis , lactobacillus buchneri , lactobacillus casei , lactobacillus catenaforme , lactobacillus cellobiosus , lactobacillus crispatus , lactobacillus curvatus , lactobacillus delbrueckii , lactobacillus fermentum , lactobacillus jensenii , lactobacillus leichmanii , lactobacillus minutus , lactobacillus plantarum , lactobacillus rogosae , lactobacillus salivarius , bifidobacterium adolescentis , bifidobacterium angulatum , bifidobacterium bifidum , bifidobacterium breve , bifidobacterium catenulatum , bifidobacterium dentiuin , bifidobacterium erik sonii , bifidobacterium infantis , bifidobacterium longum , bifidobacteriumn plantarum , bifidobacterium pseudocatenulatum , bifidobacterium pseudoloigum , steptococcus lactis , streptococcus raffizwlactis and streptococcus thermophilus . according to a preferred embodiment of the invention the cells contained in the compositions are in the form of lyophilized or sonicated cells . the dermatological or cosmetic compositions of the invention shall preferably comprise from 1 × 10 2 to 1 × 10 15 cfu of lactic bacteria per gram of composition . the dermatological or cosmetic composition of the invention may also contain exogenous ceramide or products containing exogenous ceramide , sphingomyelines , fatty acids , cholesterol , ceramidase inhibitors , protease inhibitors , immunomodulators , vitamins , groih factors , surfactants , emulsifiers , stabilizers , lipids , rheological additives , humidifiers , antioxidants , preservatives , colouring agents , lakes , pigments , auxiliary substances ( e . g . acids , bases , propellants ) and functional substances ( astringents , antiseborrhoeic agents , anti - dandruff agents , deodorants , skin purifiers , keratogenous agents , moisturizers , anti - xerosis agents , smoothing agents , screens , sunscreens , pigmenting agents , antidepigmenting agents , emollients , restorers , eutrophic agents , anti - wrinkle agents , antiradicals , stiffeners , anti - stretch - mark agents , vasoprotectors , anti - skin - rash agents , soothing agents , anti - cellulitis agents , tonifying agents , stimulants , hypereluting agents , epilators , nail protectors ) lastly , the dermatological or cosmetic compositions of the invention can be formulated in the form of liquid , semiliquid , semisolid , solid or powder products , e . g . in the form of creams , ointments , lotions , capsules , pearls , ovules , mascara , eyewashes , toothpaste , mouthwashes , lipsticks , liposomes , soap , shaving soap , tonics , douches , enteroclysis solutions , shampoos , anti - dandruff preparations , impregnated and / or medicated bandage or gauze , patches , medicated emulsions , transdermal gels or patches . to confirm the ability of these bacteria to induce the generation of ceramide in the skin , the following experiment was conducted , based on the detection of neutral sphingomyelinase , the enzyme responsible for generating ceramide in human skin . 10 mg of lyophilized streptococcus thermophilus were resuspended in 500 μl of buffer containing hepes 20 mm , ph 7 . 4 , mgcl 2 10 mm , edta 2 mm , dtt 5 mm , na 3 vo 4 0 . 1 mm , na 2 moo 4 0 . 1 mm , p - nitrophenylphosphate 30 mm , β - glycerophosphate 10 mm , atp 750 mm , pmsf 1 μm , leupeptin 10 μm , pepstatin 10 μm ( sigma chemical co .) and 0 . 2 % triton x - 100 ( for the assay of neutral smase activity ) or 500 μl of 0 . 2 % triton x - 100 ( for the assay of acid smase activity ). the samples thus prepared were then submitted to lysis by sonication ( for 1 min and 50 sec , alternating 10 sec of sonication with 10 sec of rest ) using vibracell sonicator ( sonic and materials inc ., danbury , conn .). the sonicated samples were then centrifuged for 30 min at 14 , 000 rpm , at 4 ° c ., the supernatant was removed and the protein concentration determined using the bio - rad laboratories kit ( richmond , calif .). 100 μg of sample were incubated for 2 hours at 37 ° c . in a buffer ( 50 μl final volume ) containing hepes 20 mm , mgcl 2 1 mm , ph 7 . 4 , and 2 . 25 μl of [ n - methyl - 14 c ] sphingomyelin ( sm ) ( 0 . 2 μci / ml , a . s . 56 . 6 mci / mmol , amersham ). to measure the activity of add sphingomyelinase , 100 μg of bacterial lysate were incubated for 2 hours at 37 ° c . in a buffer ( 50 μl final volume ) containing sodium acetate 250 mm , edta 1 mm , ph 5 . 0 , and 2 . 25 μl of [ n - methyl - 14 c ] sm . the reaction was blocked by the addition of 250 μl of chloroform : methanol : acetic acid ( 4 : 2 : 1 ). the phospholipids were extracted , analysed on plates by tlc and hydrolysis of sm quantified by means of autoradiography and liquid scintillation . the smase present in the sonicated bacteria was indicated as units / mg protein . one unit of neutral smase hydrolyses 1 μmole of sphingomyelin per min at ph 7 . 4 at 37 ° c . one unit of acid smase hydrolyzes 1 nmole of sm to n - acetylsphingosine and choline phosphate per hour at ph 5 . 0 at 37 ° c . a cream was prepared ( using a dehydrating base cream ) containing sonicated lactic bacteria [ 2 20 - g tubes of base cream plus 1 vial of sonicated lactic bacteria ( 1 × 10 12 cfu ) in 20 ml of water ] and the effect of daily applications of the cream on the ceramide levels of the horny layer of the epidermis of the forearm was assayed in 8 volunteers as indicated in table 1 here below the subjects were instructed to self - administer the control cream and the experimental cream containing the lactic bacteria twice per day ( approximately 1 ml , morning and evening ). the control cream was applied daily on the right forearm , while the experimental cream was applied on the left forearm . both creams were rubbed in until they were fully absorbed . lipids of the horny layer of the epidermis were collected from the forearm by washing with 250 ml of 99 . 5 % ethanol prior to the start of application of the cream ( t0 ) and one week ( t1 ) after the start of treatment . the ethanol extracts were concentrated with a rotary evaporator and then evaporated dry . the dried samples were dissolved in 2 ml of chloroform , dried with nitrogen and subjected to dag kinase assay for ceramide quantification ( amersham , buckinghamshire , great britain ). after three extraction runs , the lipids were dried again with nitrogen , dissolved in 100 μl of chloroform and subjected to thin layer chromatography ( tlc ), using chloroform : methanol : acetic acid ( 65 : 15 : 5 , v / v / v ) as the run solvent . phosphorylated ceramide was detected by autoradiography . the patches corresponding to ceramide - 1 - phosphate were cut and subjected to a count of the radioactivity present using scintillation liquid in a β - counter . the amount of ceramide present was determined on the basis of a standard curve obtained with authentic ceramide ( type iii ; of bovine brain ; sigma chemical co ., st . louis , mo .). the levels of neutral sphingomyelinase activity in the sonicated lactic bacteria samples were approximately 2 × 10 − 7 units / mg of bacteria . no acid sphingomyelinase activity was detected . the ceramide levels in the ethanol extracts obtained as described in the “ methods ” section are given in table 2 here below and the respective autoradiographs are shown in fig1 . it can be noted , regardless of the substantial subjective basal variability , that the use of both creams gave rise to an increase in ceramide levels in the forearm skin of all the subjects analyzed . however , the increase was much more marked and significant after application of the cream containing latic bacteria . what is more , the effect of the experimental cream on ceramide levels could be detected earlier compared to that induced by the base cream , thus indicating faster action of the former .

the use of sphingomyelinase to increase the levels of skin and mucosal ceramides , as well as dermatolgical and cosmetic compositions containing game which are suitable for topical application are disclosed .

a trocar system is illustrated in fig1 and is designated by reference numeral 10 . this system includes a cannula 12 , defining a working channel 14 , and a valve housing 16 . the system 10 also includes an obturator 18 having a shaft 21 extending along an axis 23 . a handle 25 is disposed at a proximal end of the shaft 21 while a blunt tip 27 is disposed at a distal end of the shaft 21 . the shaft 21 of the obturator 18 is sized and configured for disposition within the working channel 14 of the cannula 12 . with this disposition , the obturator 18 can be placed across a body wall such as the abdominal wall to provide the cannula 12 with access across the wall and into a body cavity , such as the peritoneal or abdominal cavity . the blunt tip 27 serves to direct the obturator 18 through the abdominal wall and the peritoneum , and can be removed with the obturator 18 once the cannula 12 is operatively disposed with the working channel 14 extending into the abdominal cavity . the diameter of the shaft 21 can range from about 3 mm to about 20 mm and is designed to fit within a trocar seal and the cannula 12 . in accordance with the present invention , the tip 27 is provided with a blunt tip configuration . the blunt tip 27 of the invention takes into account the anatomical configuration of the abdominal wall with an improved structural design and method of insertion . to fully appreciate these aspects of the invention , it is helpful to initially discuss the anatomy associated with the abdominal wall . the abdominal wall typically includes a skin layer and a series of muscle layers , in addition to fat and fascia . the muscle layers are each defined by muscle fibers that extend generally parallel to each other in a direction that is different for each of the layers . for example , fibers of a first muscle layer and a second muscle layer may extend in directions that are generally 90 degrees off of each other . having noted the directional nature of the muscle fibers , it can be appreciated that such a structure may be separated or divaricated by an obturator having a blunt tip . the blunt tip may also include a twisted rectangular configuration to facilitate movement between the muscle fibers and layers . that is , the blunt tip is capable of being moved generally parallel to and between the fibers associated with a particular muscle layer . as described earlier , the fibers of the muscle layers may be oriented at different angles to each other such that proper alignment of the tip 27 for separation of one layer may not necessarily result in proper alignment for separation of the next layer . for at least this reason , the obturator 18 has a blunt tip 27 to direct the obturator 18 through the different layers and a rectangular configuration that is twisted slightly so that separation of a first layer begins to rotate the distal end of the blunt tip 27 into proper orientation for separation of the next layer . the twisted configuration of the blunt tip 27 also causes the blunt tip 27 to function , for example , with the mechanical advantage of a screw thread . with this configuration , an exemplary method of placement requires that the user grip the handle 25 of the obturator 18 and twist it about the axis 23 . this twisting motion in combination with the screw configuration of the blunt tip 27 converts radial movement into forward movement along the axis 23 . thus , the user applies both a forwardly directed force as well as a radial force to move the trocar system 10 in a forward direction . the twisted configuration of the blunt tip 27 is most apparent in the side elevation views of fig2 and 3 . in this embodiment , the blunt tip 27 comprises generally of eight surfaces : two opposing surfaces 50 and 52 , separated by two side surfaces 54 and 56 , two end surfaces 58 and 59 , a generally tapered surface 60 formed in surfaces 50 and 52 around axis 23 and extending beyond end surfaces 58 and 59 , and a blunt surface 62 . the surfaces 50 and 52 , side surfaces 54 and 56 , and tapered surface 60 generally define the cross - section of the blunt tip 27 from blunt surface 62 to proximal end 61 . this configuration can best be appreciated with reference to the cross - section views of fig4 - 9 . in fig4 , the distal end of the blunt tip 27 is shown with a circle 64 having the smallest circular area and a rectangle 63 having the greatest length - to - width ratio . the rectangle 63 has a twisted , s - shaped configuration at end surfaces 58 and 59 . as views are taken along progressive proximal cross - sections , it can be seen that the circle 64 becomes larger and the rectangle 63 becomes less twisted , and the width increases relative to the length of the rectangle 63 . the spiral nature of the blunt tip 27 is also apparent as the circle 64 and rectangle 63 move counterclockwise around the axis 23 . this is perhaps best appreciated in a comparison of the circle 64 , the rectangle 63 and the side surfaces 54 and 56 in fig6 relative to that in fig5 . with progressive proximal positions , the circle 64 begins to expand with increasing circular area and the rectangle 63 begins to widen with a reduction in the ratio of length to width . the long sides 63 ′ of the rectangle 63 also tend to become more arcuate as they approach a more rounded configuration most apparent in fig8 and 9 . that is , the circle 64 and the rounded rectangle 63 become more circular with progressive proximal positions . furthermore , the circle 64 expands at a lesser rate than the rectangle 63 , which eventually absorbs the circle 64 as shown in fig8 and 9 . in these figures , it will also be apparent that the rotation of the rectangle 63 reaches a most counterclockwise position and then begins to move clockwise . this is best illustrated in fig7 - 9 . this back and forth rotation results from the configuration of the side surfaces 54 and 56 , which in general are u - shaped as best illustrated in fig2 and 3 . the ratio of the length to width of the rectangle 63 is dependent on the configuration of the side surfaces 54 and 56 , which define the short sides of the rectangle 63 as well as the configuration of the surfaces 50 and 52 , which define the long sides of the rectangle 63 . again with reference to fig2 and 3 , it can be seen that the side surfaces 54 and 56 are most narrow at the end surfaces 58 and 59 . as the side surfaces 54 and 56 extend proximally , they reach a maximum width near the point of the most counterclockwise rotation , shown generally in fig8 , and then reduce in width as they approach the proximal end 61 . along this same distal to proximal path , the surfaces 50 and 52 transition from a generally flat configuration at the end surfaces 58 and 59 to a generally rounded configuration at the proximal end 61 . in the progressive views of fig5 - 7 , the circle 64 is further designated with a lower case letter a , b or c , respectively ; similarly , the rectangle 63 and the side surfaces 54 and 56 are further designated with a lower case letter a , b , c , d or e , respectively , in fig5 - 9 . in fig1 , the circles 64 , 64 a - 64 c , the rectangles 63 , 63 a - 63 e and the side surfaces 54 , 54 a - 54 e and 56 , 56 a - 56 e are superimposed on the axis 23 to show their relative sizes , shapes and angular orientations . with a generally tapered configuration at the distal end and a rectangular configuration at a distal portion of the tip , the tip 27 appears much like a flathead screwdriver having a blunt tip . more particularly , the tip 27 includes a tapered structure extending outward from the end surfaces 58 and 59 that serves to direct the obturator 18 through the tissue fibers . in one aspect , the lengths of the end surfaces 58 and 59 may be aligned parallel with the fibers of each muscle layer . a simple back and forth twisting motion of the blunt tip 27 tends to separate the fibers along natural lines of separation , opening the muscle layer to accept the larger diameter of the cannula 12 . once the first layer is substantially separated , the tapered and twisted configuration of the blunt tip 27 directs and turns the rectangle 63 more into a parallel alignment with fibers in the next layer . again , the blunt tip 27 and the twisting or dithering motion facilitates an easy separation of the fibers requiring a significantly reduced insertion force . the invention facilitates a unique method of separating tissue and can be applied to any object with a blunt tip and generally flat sides . in particular , the device of the invention can be operated by rotating in alternating clockwise and counterclockwise directions while applying a downward force . when rotating in alternating directions , the tissue is moved apart and a larger opening is created for a profile of greater cross - sectional area to follow . this process continues safely as the device enters the peritoneal cavity and moves to its operative position . when the cannula 12 is ultimately removed , the size of the opening left in the tissue is minimal . importantly , this opening is left with a small defect that does not require suturing due to a dilating effect caused by the mere separation of fibers . since there are no sharp blades , sharp edges or piercing points to cut tissue fibers , the healing process is shortened . it is appreciated that in other aspects of the invention , the tip of the bladeless obturator 18 can be formed as a generally tapered shape 27 a with a blunt distal end as illustrated in fig1 , as a pyramidal shape 27 b with a blunt distal end and blunt edges as illustrated in fig1 , and as a fully radiused tip 27 c for insertion through flaccid tissue or an existing body orifice such as the urethra as illustrated in fig1 . the blunt tip 27 can be formed from a translucent or a transparent material . the blunt tip 27 can be formed from a plastic material or a glass material . in one aspect , the shaft 21 and the tip 27 are formed from a transparent polycarbonate material . referring to fig1 and 15 , the bladeless obturator 18 of the invention is designed to accommodate the insertion of a conventional laparoscope 30 . in particular , the shaft 21 of the bladeless obturator 18 is hollow to allow for the insertion of the laparoscope 30 at an opening 32 . the shaft 21 is sized and configured to allow the laparoscope 30 to slide within proximity of the tip 27 thus providing a viewing area through the tip 27 . an endoscopic video camera ( not shown ) is typically connected to the laparoscope 30 and this combination is connected to a video monitor . by enabling the positioning of the conventional laparoscope 30 within the tip 27 of the bladeless obturator 18 , it is possible to visually observe body tissue as it is being separated by the trocar system 10 . visualization of body tissue as it is being separated by the trocar system 10 allows a surgeon to monitor the advancement of the trocar system 10 and to avoid traumatizing vessels or organs . for example , during a laparoscopic cholecystectomy , a trocar is usually placed through the umbilicus of the patient . the placement of this trocar is typically performed in a blind fashion in that the surgeon cannot see where the tip of the trocar is as it is advanced through the abdominal wall and into the abdominal cavity of the patient . this results in a high degree of risk that the trocar may be inadvertently advanced too far into the abdomen of the patient resulting in trauma to vital organs and / or vessels . by providing a trocar system with visualization properties , this risk is diminished as the surgeon is better able to determine when the trocar has traversed the abdominal wall . it is appreciated that the tip 27 may be generally hollow or it may be substantially solid to receive the distal end of the laparoscope 30 . in another aspect , the tip 27 may be a solid tip . the tip 27 may further comprise at least one portion that is marked differently from the rest of the tip to serve as an indicator , for example , of depth as the tip 27 is being inserted into the body tissue . the at least one portion may be opaque or marked with a different color from the rest of the tip 27 . the shaft 21 and the tip 27 of the bladeless obturator 18 can accommodate a laparoscope with a non - angled lens , also known as a 0 ° laparoscope . the shaft 21 and the tip 27 can also accommodate a laparoscope with an angled lens such as a 30 ° laparoscope . the tip 27 is designed such that when either a 0 ° laparoscope or a 30 ° laparoscope is inserted therein , the lens of the laparoscope extends beyond a distal edge 36 of the cannula 12 thereby providing a clear and unobstructed view through the tip 27 . the tip 27 further includes a ledge 39 that properly engages either the 0 ° laparoscope or the 30 ° laparoscope . it should be noted that conventional trocars with visualization properties typically require a 0 ° laparoscope for insertion of the trocars and a 30 ° laparoscope for viewing anatomical structures during the remainder of the laparoscopic procedure . this requires the operating staff to provide two laparoscopes for the laparoscopic procedure , which increases hospital inventory costs and surgical preparation costs relating to cleaning and sterilization of the laparoscopes . in addition , because two laparoscopes are required for the laparoscopic procedure , there is additional operating room time required during the surgical procedure to transfer the endoscopic video camera from the 0 ° laparoscope to the 30 ° laparoscope which results in increased operating room costs for the hospital . the bladeless obturator of the present invention provides a clear unobstructed view of body tissue through either a 0 ° or a 30 ° laparoscope , therefore obviating the need for a hospital to carry the additional inventory required to provide two laparoscopes for each laparoscopic surgical procedure , and obviating the need for a hospital to clean and sterilize a second laparoscope for each laparoscopic surgical procedure , and obviating the need to transfer the endoscopic video equipment from one laparoscope to the other laparoscope during each laparoscopic surgical procedure . referring to fig1 , the shaft 21 may include a tip with a bulbous section 27 d to better accommodate the distal end of the angled lens laparoscope . by adding the bulbous section 27 d , the distal end of the angled lens laparoscope would be closer to the tip of the obturator thereby improving visualization . in yet another aspect of the invention , the bladeless obturator can include integral fiber optic light fiber elements and an integral imaging element within the shaft and the tip of the obturator . the bladeless obturator with integral imaging means can be formed of reusable or disposable materials . the bladeless obturator 18 can be constructed as a single component or as multiple components such as the shaft 21 and the tip 27 . if the obturator 18 is constructed as a single component , then it can be formed from either disposable or reusable materials . if the obturator 18 is constructed as two or more components , then each component can be formed from either disposable or reusable materials as desired for a particular configuration . in one aspect , the obturator 18 is constructed from a single reusable material such as metal ( e . g ., stainless steel ) or an autoclavable polymer to facilitate re - sterilization . in another aspect , the obturator 18 is formed from a transparent steam sterilizable reusable plastic material such as polyphenylsulfone or polyetherimide . the blunt tip 27 can also be coated or otherwise constructed from a soft elastomeric material . in such a case , the material can be a solid elastomer or composite elastomer / polymer . it is further appreciated that the shaft 21 can be formed so as to be partially or fully flexible . with this configuration , the obturator 18 can be inserted through a passageway containing one or more curves of virtually any shape . a partially or fully flexed obturator 18 can then be used with a flexible cannula 12 allowing greater access to an associated body cavity . the obturator 18 can include a separately molded tip 27 and a molded or extruded shaft 21 with the two components , as explained above , comprising of the same material or different materials . the tip 27 can then be attached to the shaft 21 by adhesive bonding , ultrasonic welding , snap - fitting , or with a shrink tube . the tip 27 can also be overmolded over the shaft 21 to mechanically lock the two components together . the tip 27 can be formed from a transparent material such as polycarbonate to enable visualization while the shaft 21 can be formed from either an opaque material or a transparent material . the shaft 21 can also be formed from a metal material . in another aspect , the obturator 18 can include a disposable tip that is releasably attached to a reusable shaft 21 . in this aspect , a new tip 27 can be used for each procedure to provide optimal visualization through the tip 27 of the obturator 18 during each procedure . referring to fig1 , there is shown a shaft 18 e in accordance with another aspect of the invention including a cutout section 100 e in the tip portion 27 e that enables direct visualization of the body tissue as the tip 27 e separates tissue fibers . by providing an obturator with cutout sections , the reflection of light from the laparoscope is minimized and the visibility of the tissue through the laparoscope is improved as compared to a design where visualization occurs through a plastic or glass window . it is appreciated that the shaft 21 e can include a single or a plurality of cutouts 100 e in the tip 27 e or along the shaft of the obturator . referring to fig1 , there is shown a shaft 21 f in accordance with another aspect of the invention having a cutout portion 100 f along the axial axis of the shaft 21 f . the shaft 21 f has a cross - section of about ½ - circle to about ¾ - circle and the cutout portion 100 f has a cross - section of about ½ - circle to about ¼ - circle . an advantage of this aspect of the invention is the wall of the shaft 21 f can be a little thicker as a result of the cutout section , which makes injection molding of the shaft easier . referring to fig1 , there is shown a cover 102 f that can be attached over the cutout portion 100 f of the ½ - circle shaft 21 f as shown in fig1 . in particular , a polycarbonate cover also with a ½ - circle shaped cross - section can be attached to the shaft to form a tubular cross - section . an advantage of molding the tubular shaft 21 f in two pieces is increased manufacturability of the shaft 21 f . the cover 102 f can be attached to the shaft 21 f with an adhesive bond , an ultrasonic weld , a snap - fit , or with a shrink tube . in another aspect , the obturator can be formed from two clam - shell components each including one - half of the shaft and tip configuration along the axial axis of the obturator . the two components can then be affixed together using an adhesive bond , an ultrasonic weld , an outer shrink tube , or a snap fit . referring to fig2 and 21 , another feature of the bladeless obturator 18 of the invention is it is designed to frictionally lock the laparoscope 30 in place using a laparoscope lock 40 , which can be formed within the handle 25 . more specifically , the laparoscope lock 40 prevents the laparoscope 30 from moving axially relative to the shaft 21 of the obturator 18 during handling within the sterile field and during insertion through a body wall but enables the laparoscope 30 to rotate freely relative to the shaft 21 . this rotation of the lock 40 enables the trocar system 10 to be twisted during insertion into and through the abdominal wall while maintaining the laparoscope 30 in a fixed rotational position that provides for a stable viewing image on the video monitor . the conventional obturators with visualization properties include means for locking the laparoscope in place but these obturators lock the laparoscope both axially and rotationally . a drawback of the conventional devices is the viewing image on the video monitor is unstable if the trocar is twisted during insertion . more specifically , with prior art obturator laparoscope locks , if the trocar is twisted back and forth in a clockwise and counter - clockwise fashion , the laparoscope also moves clockwise and counter - clockwise with the trocar resulting in an oscillating and disorienting viewing image on the video monitor . the laparoscope lock 40 of the present invention improves visualization and enables a more precise placement of the trocar within the body tissue and across the body wall as compared to obturators of the prior art while preventing inadvertent axial movement of the laparoscope during handling and use . in another aspect of the invention as illustrated in fig2 and 21 , the bladeless obturator 18 further comprises a cap 42 that can be snap - fitted onto the proximal end of the obturator shaft 21 , after which the laparoscope lock 40 can be snap - fitted onto the end of the cap 42 . both the cap 42 and the lock 40 can be formed of a plastic material such as polycarbonate . the obturator cap 42 can be provided with and without a pistol - grip handle . the handled version of the bladeless obturator provides a pistol - grip to ease insertion of the trocar system as illustrated in fig2 and 23 . the pistol - grip handle is designed to nest into the handle on the trocar seal to prevent excessive flexure of the handle during insertion of the trocar as illustrated in fig2 . more particularly , the handled bladeless obturator includes three components comprising of an obturator shaft 21 b , an obturator cap 42 b having a pistol - grip handle 26 b , and a laparoscope lock 40 b , all of which can be injection molded out of polycarbonate . the pistol - grip handle 26 b can be formed with two components frictionally fitted together with , for example , interference pins . the interference pins can be fitted into holes in the handle 26 b to affect a frictional lock between the two components . referring to fig2 , the bladeless obturator 18 is designed to releasably attach to a trocar seal 17 via two cantilever snap - fits 70 a , 70 b . as the obturator 18 is inserted into the trocar seal 17 and cannula 12 , the snap - fits 70 a , 70 b passively engage the trocar seal 17 and serve to axially lock the obturator 18 to the trocar seal 17 and cannula 12 ( fig2 and 25 ). to release the obturator 18 from the trocar seal 17 and cannula 12 , outboard tabs 72 a , 72 b on the obturator cap 42 are depressed inwardly and the obturator 18 is then free to be slidably removed as illustrated in fig2 and 27 . referring back to fig2 and 21 , the bladeless obturator 18 includes axial key members 74 at its proximal end which are designed to mate with axial keyways on the trocar seal 17 . as the bladeless obturator 18 is inserted into the trocar seal 17 and cannula 12 , the obturator 18 is rotated slightly to align the axial key members 74 with the axial keyways and then advanced until the snap - fits 70 a , 70 b engage the trocar seal 17 . the axial key members 74 serve to rotationally lock the obturator 18 to the trocar seal 17 . referring to fig2 , there is shown another embodiment of the laparoscope lock 40 c comprising a multiple - finger collet 80 c comprising a plurality of fingers 82 c . the multiple - finger collet 80 c has an inner diameter that is smaller than the outer diameter of the laparoscope . the fingers 82 c of the collet 80 c spread open during insertion of the laparoscope providing frictional engagement with the outer diameter of the laparoscope . the laparoscope lock 40 c is free to rotate on an obturator cap 42 c , and allows the laparoscope to freely rotate relative to the shaft of the bladeless obturator . referring back to fig2 and 21 , the obturator shaft 21 of the bladeless obturator 18 can be configured with a barb 76 at its proximal end . the barb 76 is vertically slotted to enable the shaft 21 to flex during assembly . the obturator shaft 21 may also include a plurality of keys ( not shown ) near its proximal end . the obturator cap 42 is configured to axially slide over the barb 76 on the obturator shaft 21 to affect a one - way snap - fit lock between the two components . this snap - fit prevents the removal of the obturator cap 42 from the obturator shaft 21 . the obturator cap 42 may further include keyways ( not shown ) that engage the keys on the obturator shaft 21 to rotationally index the components together . the obturator cap 42 may further include a second barb ( not shown ) at its proximal end . the laparoscope lock 40 may include a plurality of tabs ( not shown ) that are designed to spread and axially slide over the second barb on the obturator cap 42 to affect a one - way snap - fit lock between the obturator cap 42 and the laparoscope lock 40 . this snap - fit prevents the axial removal of the laparoscope lock 40 from the obturator cap 42 . the laparoscope lock 40 is free to rotate relative to the obturator cap 42 . referring to fig2 , there is shown another aspect of the invention of a laparoscope 30 a having a tip 33 a configured similar to that of the tip 27 of the bladeless obturator 18 described above , the tip 33 a being adapted to snap - fit or frictionally engage the end of the laparoscope 30 a . with this configuration , the combination of the tip 33 a and the laparoscope 30 a serve to form an optical obturator having a blunt tip . once the trocar is inserted and the laparoscope removed from the trocar seal and cannula , the bladeless tip 33 a can then be removed from the laparoscope 30 a . the bladeless tip 33 a can be formed from either a disposable or reusable transparent material . the bladeless tip 33 a can be temporarily or permanently affixed to the scope 30 a by any of the known methods of attaching the two components together as explained above . referring to fig3 and 31 , there is shown a laparoscope lock 40 d in accordance with another embodiment of the invention including an active lock comprising a camming member 43 d . with this type of lock , the laparascope would first be inserted into the shaft of the obturator and then the lock 40 d would be activated to lock the laparoscope in an axial position relative to the shaft . the lock 40 d can either rotate freely to enable the laparoscope to rotate freely relative to the shaft or the lock 40 d can be rotationally fixed to prevent the laparoscope from rotating relative to the shaft . in another aspect as illustrated in fig3 and 33 , a lock 40 e can include an active lock comprising a clamping member 45 e . with this type of lock , the laparascope would first be inserted into the shaft of the obturator and then the lock would be activated to lock the laparoscope in an axial position relative to the shaft . the lock 40 e can either rotate freely to enable the laparoscope to rotate freely relative to the shaft or the lock 40 e can be rotationally fixed to prevent the laparoscope from rotating relative to the shaft . referring to fig3 and 35 , there is shown a lock 40 f in accordance with another embodiment of the invention including an active lock comprising a locking collar 46 positioned eccentrically with respect to the axis of the obturator so that as the locking collar 46 is turned , a frictional engagement with the laparoscope is affected . the laparoscope would first be inserted into the locking collar 46 and the shaft of the obturator , the locking collar 46 can then be turned to frictionally engage the laparoscope . the laparoscope lock 40 f can either rotate freely to enable the laparoscope to rotate freely relative to the shaft or the laparoscope lock 40 f can be rotationally fixed to prevent the laparoscope from rotating relative to the shaft . in another aspect of the invention as illustrated in fig3 and 37 , there is shown a laparoscope lock 40 g including an active lock comprising of a locking nut 48 and a thread . the threaded portion of the lock 40 g has flexible elements similar to those on a collet . the laparoscope would first be inserted into the threaded portion of the lock 40 g and the nut then rotated clockwise to collapse the flexible elements to frictionally engage the laparoscope . to release the laparoscope , the nut is rotated counter - clockwise . in another aspect , the laparoscope lock can include a lock that includes an elastomeric element . the addition of the elastomeric element can enhance the frictional engagement with the laparoscope . an example of such an elastomeric element is a silicone o - ring sized with an inside diameter smaller than the outside diameter of the laparoscope . the laparoscope lock can either rotate freely to enable the laparoscope to rotate freely relative to the shaft or the laparoscope lock can be rotationally fixed to prevent the laparoscope from rotating relative to the shaft . in yet another aspect , the obturator 18 can also be used as an insufflation needle having a passageway and valve to administer carbon dioxide or other insufflation gas to the peritoneal cavity . the obturator 18 can also be used with an insufflation needle cannula in which case removal of the obturator 18 upon entry would allow for rapid insufflation of the peritoneal cavity . in another aspect of the invention , the bladeless obturator can be formed with a 2 - 3 mm outer diameter and with a small thru - hole at its distal end . the bladeless obturator can be used in conjunction with a miniaturized laparoscope to provide initial access into a hollow body cavity . once access is obtained , the laparoscope can be removed from the bladeless obturator and an insufflation gas such as carbon dioxide can be dispensed through the obturator into the hollow body cavity . the bladeless obturator can also include holes in the tip portion to enhance the flow of insufflation gases though the obturator . more particularly , the bladeless obturator can be formed with a 2 - 3 mm outer diameter and used in conjunction with a miniaturized laparoscope to provide initial access into a hollow body cavity . after access is obtained , the bladeless obturator can be removed from the trocar cannula and an insufflation gas such as carbon dioxide can be dispensed though the cannula and into the hollow body cavity . it will be understood that many modifications can be made to the disclosed embodiments without departing from the spirit and scope of the invention . for example , various sizes of the surgical device are contemplated as well as various types of constructions and materials . it will also be apparent that many modifications can be made to the configuration of parts as well as their interaction . for these reasons , the above description should not be construed as limiting the invention , but should be interpreted as merely exemplary of preferred embodiments .

a surgical access device comprising a tissue separating obturator suitable for connection with a cannula is disclosed . the obturator includes an elongate shaft having a transparent distal tip . the elongate shaft extends along a longitudinal axis and defines a lumen . the transparent distal tip has a tapered configuration and includes an inner surface and an outer surface adapted for penetrating tissue . the lumen is sized and configured to receive an optical instrument such as a laparoscope . the surgical access device further includes a scope lock at the proximal end of the shaft portion . the lock includes a multi - fingered collet coaxial with the lumen . the inner diameter of the collet is smaller than an outer diameter of the optical instrument and the fingers of the collet provide frictional engagement with the outer diameter of the optical instrument that is inserted into the lumen of the obturator .

animals . all animal procedures were performed under the supervision and approval of the university of miami institutional animal care and use committee ( iacuc ). mice ( 7 - 8 week old balb / c ( h - 2 d ), c57bl / 6 ( b6 ; h - 2 b ) and c3h / hej ( c3h ; h - 2 k )) were purchased from jackson laboratories ( bar harbor , me .). recipient c57bl / 6 mice were used at 9 - 10 weeks of age . all animals were housed in pathogen - free room in sterile microisolator cages with autoclaved feed and autoclaved acidified water . bone marrow transplantation . balb / c mice , 8 - 9 weeks old , used as donors , were sacrificed on the day of the transplant . bmc were prepared according to a previously published regimen . briefly , after removing femura and tibiae , and cleaning them from muscle tissue and cartilage , bmc were flushed with sterile rpmi - 1640 ( mediatech , inc , herndon , va .) supplemented with 0 . 8 mg / ml gentamycin ( gibco , gaithersburg , md . ), using 23g needle . bmc were filtered through a sterile nylon mesh and counted . fully mch - mismatched c57bl / 6 recipients , 9 - 10 weeks of age , were injected intravenously with either 20 × 10 6 or 100 × 10 6 unmanipulated bmcs resuspended in 0 . 5 and 1 . 0 ml of hbss ( mediatech ) respectively , on either day 7 or 14 . tolerance induction protocol consisted of either 150 or 500 μci of 153 sm - edtmp ( berlex laboratories wayne , n . j . ), i . v ., on day − 7 , and 0 . 5 mg hamster anti - murine cd154 mab ( mr - 1 ), purchased from taconic ( germantown , n . y .) administered intraperitoneally ( i . p .) on days − 1 , 0 , 7 , 14 , 21 and 28 . skin grafting . full - thickness skin donor ( balb / c ) and third party ( c3h / hej ) grafts were transplanted onto the lateral thoracic area of the recipients either the day following bmc - tx , or 4 weeks following the last administration of mr - 1 mab , using techniques described previously . briefly , square , full - thickness skin grafts ( 1 cm 2 ) were prepared from the tail skin of donors . graft beds were prepared on the right ( donor - specific ) and left ( third party ) lateral thoracic wall of recipient mice . grafts were fixed to the beds with 4 sutures of 5 . 0 silk at the corners of the graft and covered with a petroleum jelly - coated gauze and a plaster cast . the grafts were first inspected on the eighth - day following grafting , and every third day thereafter . graft rejection was considered complete when no viable graft tissue was detected by visual inspection . recipient mice were considered to be tolerant when donor - specific skin grafts survived in perfect condition for & lt ; 150 days . immunohemotyping of chimeras . engraftment of donor - derived bmcs was ascertained by flow cytometric analysis ( fcm ) of recipient peripheral blood mononuclear cells ( pbmcs ), splenocytes , thymocytes and bone marrow cells after staining with fitc - conjugated anti - mouse h - 2k b or h - 2k d and cy - chrome - conjugated cd3 monoclonal antibodies ( mabs ) purchased from pharmingen ( san diego , calif .) at multiple time points during the experiment as well as at sacrifice . cells were also assessed for non - specific staining using an ig isotype control ( fitc - conjugated mouse igg 2a and cy - chrome - conjugated rat igg 2b ), and the percentage of cells stained with this ab was subtracted from the values obtained from staining with the specific ab to determine the relative number of positive cells . reconstitution of various cell lineages was assessed using fitc - conjugated anti - mouse h - 2k b or h - 2k d and pe - conjugated anti - mouse cd19 / cd22 in the b cell , pe - conjugated anti - mouse ly - 6g in the granulocyte , and pe - conjugated anti - mouse mac - 3 in the macrophage compartments . recipient animals were first tested 1 week after bmc - tx , every 2 weeks up to 6 weeks , and every 4 weeks thereafter . purified anti - mouse cd16 / cd32 ( fcγ iii / ii ) was used to block non - specific binding to the fc receptors . fcm analyses were preformed using cellquest software on a facscan cytometer purchased from becton dickinson & amp ; co . ( mountain view , calif .). analysis of various t cell receptor families . splenocytes were used to analyze the expression of vb3 + , vb5 + , vb11 + and vb14 + families in the chimeras at the time of sacrifice . for two - color analysis , cells were blocked with purified anti - mouse cd16 / cd32 ( fcγ iii / ii ) ( pharmingen ), and then incubated with fitc - conjugated h - 2k d and pe - conjugated anti - vb3 + , vb5 + , vb11 + or vb14 + ( pharmingen ) for 30 minutes on ice . fitc - conjugated mouse igg2a , pe - conjugated armenian hamster igg , group 2 , mouse igg1 , rat igg2b and rat igm antibodies ( pharmingen ) were used as negative controls . mixed lymphocyte reaction . splenocytes depleted of red blood cells were incubated at 37 ° c . in 5 % co 2 for 3 days in quintuplicate wells containing 2 × 10 5 responders with 2 × 10 5 stimulators treated with mytomicin c ( sigma , st . louis , mo .) in iscove &# 39 ; s tissue culture media ( gibco , gaithersburgh , md .) containing 10 % heat - inactivated fcs , 2 mm l - glutamine ( mediatech ), 25 mm hepes ( mediatech ) and 0 . 05 mm β - mercaptoethanol . responder cells from chimeric mice and stimulator splenocytes , bmcs and keratinocytes were incubated for 3 days in a 96 round - bottom tissue culture plates , and then pulsed with 1 μci [ 3 h ] thymidine ; [ 3 h ] thymidine incorporation was assessed after 8 hours . stimulation indices were calculated by dividing mean counts per minute ( c . p . m .) by responses against self . staining for the presence of anti - donor antibodies . 1 × 10 6 splenocytes , isolated from naïve balb / c donors were incubated with several different dilutions ( 1 : 3 ; 1 : 10 ; 1 : 30 ; 1 : 100 ) of plasma from the chimeric recipients at 4 ° c . for 60 minutes . cells were washed with pbs supplemented with 1 % bsa , 0 . 02 % sodium azide , and then incubated with fitc - conjugated goat anti - mouse igg ( h + l ) ( jackson immunoresearch laboratories , west grove , pa .) and pe - conjugated anti - mouse cd22 for 30 minutes on ice . the cells were then washed with pbs and analyzed on a becton dickinson facscan . plasma from a naïve c57bl / 6 incubated with splenocytes from naïve balb / c donors was used as a baseline . recipient animals ( c57bl / 6 , h - 2 b ) were treated with a single iv dose of 153 sm - edtmp , 150 μci or 500 μci , prior to administration of 20 × 10 6 or 100 × 10 6 allogenic donor bone marrow cells ( bmc ) ( balb / c , h - 2 d ), also administered as a single iv dose . bmc transplantation ( bmc - tx ) was performed on day 7 or 14 following the administration of 153 sm in the presence of transient t lymphocyte co - stimulatory blockade by mr - 1 ( hamster anti - murine cd154 mab ) on days - 1 , 0 , 7 , 14 , 21 and 28 , 0 . 5 mg ip . the lower dose of 153 sm , 150 μci , proved to be as effective as the higher dose , 500 μci . treatment with 153 sm - edtmp resulted in transient myelodepression that occurred one week post administration of the compound and was spontaneously resolved by 4 - 6 weeks post - administration , as shown in fig1 . both the 150 μci and 500 μci doses of 153 sm - edtmp have similar effect on hemolymphopoietic elements . although there is a marked myelodepression , as assessed by a decreased white blood cell counts ( wbc ), administration of 153 sm - edtmp does not have significant effect on red blood cell ( rbc ), hemoglobin ( hb ), and platelet ( plt ) counts . similar data were obtained in animals treated with 153 sm - edtmp and not transplanted with allogeneic bmc ( not shown ). thus , 153 sm - edmp leads to a transient myelodepression of the wbc compartment , which is spontaneously reversible either in the presence or absence of an allogeneic bmc - tx . no dramatic alterations of rbc , plt or hb counts were evident . single administration of bmc resulted in bm engraftment in all recipient animals analyzed . fig2 shows percentages of donor - derived cells in the recipients treated with 100 × 10 6 bmc , anti - cd154 mab , and one of 4 conditioning approaches — 153 sm - edtmp 150 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 500 μci , followed by administration of bmc on day 7 , 153 sm - edtmp 150 μci , followed by administration of bmc on day 14 ; and 153 sm - edtmp 500 μci , followed by administration of bmc on day 14 . typing of pbl obtained from the recipient animals starting at 2 weeks following the reconstitution with donor - derived bm allogeneic cells , every two weeks up to 6 weeks post - reconstitution , and every 4 weeks afterwards was performed using anti class i h - 2 b - fitc and h - 2 d - fitc . analysis was performed on the lymphoid gate , and the values were normalized to 100 %. cd3 + t lymphocytes of donor origin were also present , suggesting mixed chimerism of the lymphoid lineage as well . in fig3 is shown the percentage of donor - derived cells in the recipients treated with 20 × 10 6 bmc , anti - cd154 mab , and one of the 4 conditioning approaches : 153 sm - edtmp 150 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 500 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 150 μci , followed by administration of bmc on day 14 ; and 153 sm - edtmp 500 μci , followed by administration of bmc on day 14 . typing of pbl obtained from the recipient animals starting at 2 weeks following the reconstitution with donor - derived bm allogeneic cells , every two weeks up to 6 weeks post - reconstitution , and every 4 weeks afterwards was performed using anti class i h - 2 b - fitc and h - 2 d - fitc . analysis was performed on the lymphoid gate , and the values were normalized to 100 %. cd3 + t lymphocytes of donor origin were also present , suggesting mixed chimerism of the lymphoid lineage as well . therefore , administration of 153 sm - edmp in the presence of costimulatory blockade leads to long - lasting hematopoietic chimerism in the recipients of allogeneic bmc . the dose of 153 sm - edmp ( 150 μci vs . 500 μci ) and the timing of bmc - tx relative to 153 sm - edmp administration do not grossly influence the results . bmc dose , on the other hand , directly correlates with the levels of chimerism achieved . as shown in fig4 the percentage of donor - derived cells in the control animals treated with 100 × 10 6 bmc and one of the 4 conditioning approaches was assessed . the conditioning regimens were 153 sm - edtmp 150 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 500 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 150 μci , followed by administration of bmc on day 14 ; and 153 sm - edtmp 500 μci , followed by administration of bmc on day 14 . this fourth regimen differs from the previous , since no anti - cd154 mab to induce costimulatory blockade was used . typing of pbl obtained from the recipient animals starting at 2 weeks following the reconstitution with donor - derived bmc allogeneic cells , every two weeks up to 6 weeks post - reconstitution , and every 4 weeks afterwards was performed using anti class i h - 2 b - fitc and h - 2 d - fitc . analysis was performed on the lymphoid gate , and the values were normalized to 100 %. [ 0045 ] fig5 shows the percent of donor - derived cells in the control animals treated with 20 × 10 6 bmc , and one of the 4 conditioning approaches : 153 sm - edtmp 150 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 500 μci , followed by administration of bmc on day 7 ; 153 sm - edtmp 150 μci , followed by administration of bmc on day 14 ; and 153 sm - edtmp 500 μci , followed by administration of bmc on day 14 ( this regimen differs from the previous , since no anti - cd154 mab to induce costimulatory blockade was used ). typing of pbl obtained from the recipient animals starting at 2 weeks following the reconstitution with donor - derived bmc allogeneic cells , every two weeks up to 6 weeks post - reconstitution , and every 4 weeks following that was performed using anti class i h - 2 b - fitc and h - 2 d - fitc . analysis was performed on the lymphoid gate , and the values were normalized to 100 %. thus , the data from fig4 - 5 show that in the absence of co - stimulatory blockade , 153 sm - edmp administration followed by bmc - tx only leads to transient chimerism , regardless of the dose of bmc ( 20 × 10 6 or 100 × 10 6 ). the percentage of donor - derived cells in the control animals treated with 20 × 10 6 bmc or 100 × 10 6 bmc along with anti - cd154 mab ( in the absence of 153 sm - edtmp treatment ) is shown in fig6 . typing of pbl obtained from the recipient animals starting at 2 weeks following the reconstitution with donor - derived bmc allogeneic cells , every two weeks up to 6 weeks post - reconstitution , and every 4 weeks following that was performed using anti class i h - 2 b - fitc and h - 2 d - fitc . analysis was performed on the lymphoid gate , and the values to were normalized to 100 %. the results indicate that treatment with bmc - tx and co - stimulatory blockade without administration of 153 sm - edmp , leads to transient chimerism when a low dose ( 20 × 10 6 ) bmc is administered and to low level , stable chimerism when 100 × 10 6 bmc are administered . [ 0048 ] fig7 shows a two - color flow cytometric analysis of the proportion of donor - derived lymphoid ( b cells ), nk , and myeloid ( granulocytes ) lineages in representative mixed chimeras prepared using a non - lethal conditioning regiment of 20 × 10 6 bmc , 153 sm - edtmp , and anti - cd154 mab ( upper panels ) as well as 20 × 10 6 bmc and anti - cd154 mab ( lower panels ). analysis was performed using class i h - 2 d - fitc and either cd22 ( b cells ), nk , or gran1 ( granulocytes ), all pe . analysis was performed on the lymphoid gate , and the values were normalized to 100 %. in fig8 is shown a two - color flow cytometric analysis of the proportion of donor - derived lymphoid ( b cells ), nk , and myeloid ( granulocytes ) lineages in representative mixed chimeras prepared using a non - lethal conditioning regiment of 100 × 10 6 bmc , 153 sm - edtmp , and anti - cd154 mab ( upper panels ) as well as 100 × 10 6 bmc and anti - cd154 mab ( lower panels ). analysis was preformed using class i h - 2 d - fitc and either cd22 ( b cells ), nk , or gran1 ( granulocytes ), all pe . analysis was performed on the lymphoid gate , and the values were normalized to 100 %. as is evident from the data presented in fig7 and 8 , long - term , stable multilineage chimerism is achieved in the group treated with a combination of bmc - tx , 153 sm - edmp , and anti - cd154 mab . the survival of full thickness tail - derived skin grafts placed on the recipients treated with 20 × 10 6 bmc , 153 sm - edtmp , and anti - cd154 mab , or indicated control groups is shown in fig9 . grafts were prepared 30 days following the last administration of anti - cd154 mab in the treated animals . two different donor strain combinations , balb / c ( h - 2 d ) and c3h / j ( h - 2 k ) were used . each recipient received skin grafts from both strains : donor - type , balb / c ( h - 2 d ), as well as third - party , c3h / j ( h - 2 k ). third party grafts were rejected within the same time frame as were donor - specific grafts placed on naive recipients . grafts were followed for a minimum of 128 days and were considered rejected when viable tissue was no longer detected at the transplant site . therefore , tolerance to donor - specific skin grafts is obtained when animals receive a low dose of bmc ( 20 × 10 6 ), only if 153 sm - edmp is part of the treatment , while co - stimulation alone ( along with bmc ) is not sufficient to achieve the same result . the survival of full thickness tail - derived skin grafts placed on the recipients treated with 100 × 10 6 bmc , 153 sm - edtmp , and anti - cd154 mab , or indicated control groups is depicted graphically in fig1 . grafts were prepared 30 days following the last administration of anti - cd154 mab in the treated animals . two different donor strain combinations , balb / c ( h - 2 d ) and c3h / j ( h - 2 k ) were used . each recipient received skin grafts from both strains : donor - type , balb / c ( h - 2 d ), as well as third - party , c3h / j ( h - 2 k ). third party grafts were rejected within the same time frame as were donor - specific grafts placed on naïve recipients . grafts were followed for a minimum of 128 days and were considered rejected when viable tissue was no longer detected at the transplant site . thus , when a high dose of bmc is given ( 100 × 10 6 ), the enhancing effect of 153 sm - edmp administration is still visible on chimerism levels , that are reproducibly higher , but lost on graft survival since co - stimulatory blockade only (+ bmc - tx ) appears similarly efficacious . radionuclide complexes between lanthanides and bone specific carriers may be formulated into any pharmaceutically acceptable dosage form , including liquids , emulsions , suspensions and the like . liquid solutions for injection are particularly preferred . pharmaceutical compositions of the complexes for use according to the invention may also contain suitable diluents , excipients , buffers , stabilizers and carriers . sterile water or sterile isotonic saline solutions are particularly preferred . while the invention has been illustrated via the preferred embodiments described above , it will be understood that the invention may be practiced employing various modifications evident to those skilled in the art without departing from the spirit and scope of the invention as generally described herein , and as further set forth by the appended claims . 1 . saba n , flaig t . bone marrow transplantation for nonmalignant diseases . j hematother stem cell res . 2002 ( 2 ): 377 - 87 . 2 . furst d e . stem cell transplantation for autoimmune disease : progress and problems . curr opin rheumatol . 2002 ; 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45 ( 1 ): 91 - 9 . 27 . serafini a n , houston s j , resche i , quick d p , grund f m , ell p j , bertrand a , ahmann f r , orihuela e , reid r h , lerski r a , collier b d , mckillop j h , purnell g l , pecking a p , thomas f d , harrison k a . palliation of pain associated with metastatic bone cancer using samarium - 153 lexidronam : a double - blind placebo - controlled clinical trial . j clin oncol . 1998 ; 16 ( 4 ): 1574 - 81 . 28 . farhanghi m , holmes r a , volkert w a , logan k w , singh a . samarium - 153 - edtmp : pharmacokinetic , toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer . j nucl med . 1992 ; 33 ( 8 ): 1451 - 8 . 28 . collins c , eary j f , donaldson g , vernon c , bush n e , petersdorf s , livingston r b , gordon e e , chapman c r , appelbaum f r . samarium - 153 - edtmp in bone metastases of hormone refractory prostate carcinoma : a phase i / ii trial . j nucl med . 1993 nov ; 34 ( 11 ): 1839 - 44 .

non - lethal methods of conditioning a recipient prior to bone marrow transplantation to achieve highly enhanced , stable , long - term hematopoietic chimerism in presence of transient immunosuppression are described . in particular , the administration of non - lethal doses of bone - seeking radiopharmaceuticals such as 153 samarium lexidronam , a radioactive compound linked to a tetraphosphonate group , to target bone marrow cells , are disclosed herein .

the overall objective is to create a tool for farmers , researchers and authorities , that enables them to know in real time the position of their animals and the vital signs that they want to monitor ( eg . temperature ) to prevent theft , loss of animals and / or epidemics in their animal population and also to better understand the behavior of the animals in order to improve the various cattle breeding processes within the different establishments . the aim is to create a simple , low cost device , both in its implementation and in its annual maintenance , to be applied to the maximum number of animals , which increases the information on the possible occurrence of fmd or other disease . its wide dispersion will be possible if the conditions of simplicity , reliability and low cost are fulfilled . at first there will be a slow development but there is no doubt that in the future their use of the device will be widespread as more farmers see its advantages , and it could even be that national authorities decide to make it compulsory . moreover , the wide social impact is considered fundamental , since different regional sectors will be involved , and , will receive direct benefit from the invention . it is undeniable that , after several national and regional disasters , there is a notorious perceived necessity of pre - empting epidemic outbursts , and that has defined my vision and my mission in developing this invention . that through the project the whole world can acquire secure , fast and objective information regarding the occurrence of cattle diseases outbreaks . to create a 24 - hour - enabled system that allows the detection of any abnormality at any time and place in order to isolate the anomalies as soon as possible . this project is completely innovative since there are no other current products or processes . it must be stated that this invention is based on the combination of multiple existing technologies , some of them used in a novel way , besides the novelty of the combination itself , with surprising results in its double role of preempting epidemic diseases and cattle rustling : the radiofrequency network such as the cellular network , the general packet radio service ( gprs ) modem , the global positioning system ( gps ) receiver , the subcutaneous radio frequency identification ( rfid ) temperature sensors , and other sensors . this makes it much easier to implement , since in most regions some or all of the components already exist . using bio - thermal technology the device measures the animal &# 39 ; s temperature through a subcutaneous chip . the chip must be implanted in the retro auricular region , which is the best place to take the animal &# 39 ; s temperature [ 6 ]. this chip is also a microtransponder that transmits the information that it contains to an rfid transceiver . therefore , the animal carries a collar that contains an rfid transceiver , which meets the corresponding international standard organization ( iso ) standard , where the temperature measurement can be received and stored . there is also a global positioning system ( gps ) receiver ( or any other system for geographical positioning ) and a general packet radio service ( gprs ) modem ( or any other data system transceiver ). a micro controller controls all these components . the information is sent in a text message , or the type that enables the technology available in the area , to the company &# 39 ; s server and it contains the animal &# 39 ; s identification and the animal &# 39 ; s temperature measurement , which is obtained from the rfid transceiver , and the position coordinates , which are obtained from the gps receiver . the content of the text message goes through a proprietary software program that processes the information and in case the temperature exceeds a certain threshold immediately triggers a visual and sound alarm . in the company &# 39 ; s computers the warning signal is seen in real time on a map specifying the location where the high temperature was detected , enabling the fast decision making by a highly qualified veterinarian team . it is noteworthy that the collar is both animal - friendly and environmentally friendly . in order to power the electronic system there is a lithium polymer battery or a lithium ion battery rechargeable by a solar cell . the same is located in the outside of the collar . this makes the system completely autonomous without having to connect it to the power grid . the device allows sending and receiving information from remote locations without being connected to the power grid and without the need to have personnel to manipulate the devices once placed in animals . a wire is also attached to the whole length of the collar so that if the collar is opened or cut a message is sent to the company &# 39 ; s server and to the ranch administrator &# 39 ; s cell phone so appropriate action can be taken . also , the system can detect if the animal is outside of the ranch premises and alert the ranch administrator . the information is sent as many times as the application requires it . for example , to monitor diseases a message is sent 4 times per day , but if the temperature exceeds a certain threshold the information is sent immediately after the anomaly is detected . the system allows the addition of other sensors to monitor other physiological parameters of the animal . the information recovered from those sensors can be transmitted together with the other information . in addition , through a very easy to use web platform the farmer can monitor his livestock and access statistics , which are generated with all the information collected and stored in the data base , to improve his production . method of monitoring the animal &# 39 ; s temperature ( or other physiological variables ) through a sensor and a transmission collar , and of sending through a data message the temperature and geographical location of the animal ( or object ) and other data to an informatics central to facilitate in real time the health control , thereby creating a proprietary database that can be processed using a proprietary information processing software . device to be used according to the above - noted method , that comprises the following characteristics : tracking systems , radiofrequency networks , informatics systems , measurement sensors , power management , etc . method of detecting animal diseases that manifest through changes in the temperature . method that enables the detection of temperature changes in animals in an automatic , continuous and remote way . system that enables the creation of a database with the animal &# 39 ; s temperature , the environmental conditions , the animal &# 39 ; s identification , the geographical coordinates , etc . low cost method . this is a non - exclusive example of an implementation plan made for the uruguayan case . the idea is to then expand it to the rest of the world . being this device for continuous control at a distance , it will be even more useful the bigger the country is . initially , a 24 - hour a day monitoring office in the south region will be required . the office can be rented , and there will be personnel working 8 hour shifts ( in the beginning no more than one employee per shift will be required , with back up personnel because of the existing law ). the office will have administrative staff and computer technicians who will monitor the devices supported by veterinary technicians . initially , there will be two 4 × 4 trucks that will go around the two regions into which the country will be divided . later , when the scheduled conditions require it , there will be 4 more trucks and a new office in the north region . there will also be a specific maintenance department for repair and replacement of devices , collars , and other supplies . furthermore , the project &# 39 ; s original proprietary device design will be outsourced for manufacturing and will be ordered in quantities according to the need . a device will be placed in three out of every one hundred animals , but this ratio can vary according to the area and the proximity of the animals to each other and according to the application that the customer requires , for example , if what it is wanted is to monitor the position of each animal then every animal must wear a collar . when the customer buys the devices and pays the monthly maintenance fee he also purchases an insurance for breakage of one every three devices per year . this insurance is included in the contract . after the placement of the devices , the rural producers must pay a modest monthly fee to keep the system operational , maintain the contact with the company , and the system maintenance , among other things . it must be taken into account that the device is applied on a living creature , which makes it very dynamic . the animals are sent to slaughter or die because of different circumstances ; therefore , a subcutaneous chip must be implanted in another animal while the collar can be reused . the foregoing process will be possible because the office does not require high implementation costs . regarding the components , support will be sought at the new enterprises sector of the national bank [ 7 ] and at the national corporation for the development ( cnd ) [ 8 ], who is eager to support such projects as mandated in the statutes of the cnd . significantly , this project would have support from international , technical , and financial organizations of the countries that import meat products , since the project fosters transparency in the handling of animal health issues . in terms of the success of the project , the goal is to have the system installed in at least all the developing world ( it should be remembered how fmd dramatically affected uruguay ). obviously , implementation in those countries would be based on the same principles . since this project is based on the utilization of radio frequency networks , at the same time there should be negotiations with the international telecommunications companies , with which mutual beneficial agreements must be reached . the cellular network operator benefits from this business because it generates data traffic where today it does not exist ( as hypothetical case it is posed that only one percent of the head of beef cattle in uruguay , on an estimated at the end of 2012 of approximately eleven million , use this system sending three text messages per day , it generates a new text messaging market to the telephony operator of about three hundred thousand new text messages daily ). finally , this project involves the participation of professional technicians , such as agronomists , veterinarians , financial institutions , public offices , non - governmental organizations , and society as a whole . this project will definitely provide a solution to a very sensitive area . moreover , given the past experiences , it is obvious the need that justifies this invention and gives its reason for being . the target group includes all the agricultural sectors that , in the case of uruguay geographically cover more than three - fourths of the territory [ 9 ]. these rural areas generally form the majority of a developing country &# 39 ; s territory . such countries will buy the device because it is an additional means of protecting animal health . rapid detection of the disease in a region will help curtail its fast expansion in faraway areas with difficult access to information . the unique selling point is very clear : no other product with similar characteristics exists . the costs for the buyer are reduced based on the enormous benefit that the same causes . it is added in this aspect the benefits at political level since it should be part of a good state policy . furthermore , other big beneficiaries are the countries importing meat products . the perceived need , then , is multiple : covers small , medium and large livestock producers , the exporter countries and importing countries . the product should be simple and its entry into the market should focus on its two or three main characteristics and a single direct benefit as the basis of the campaign . the most accessible price is sought , since the objective is its massification . in the event that individual countries do not buy it , it must be accessible to the micro consumer market . since the product is directed to large territorial extensions there is no specific site and its adaptation can be both general and comprehensive . the recommendations for uruguay should be general and basic to place the project at a global level . thus the advertising should be specific to the sectors involved ( health , related professionals , farmers , government offices ) through brochures , personal contact and use of social networks . based on this and alongside , a strategy of easy access to information will be implemented for the annual maintenance stages . for this there will be a team that will prioritize the personalization of the information to be delivered to the users with respect to structural factors , technological and application developments and improvements , general information , etc . given the impact that this activity will produce , it will certainly lead to the presence in mass media through interviews , news reports , and technical reports . from the point of view of the rural producer , the social and economic benefit will be undeniable because it generates more security on its activity . by decreasing the incident of fmd and its widespread transmittal it reduces the apprehension among the small producers and the wage earners , who are directly affected during the months that the epidemic lasts . in the case of the small producer , the benefits of the system are more extreme , since fmd could involve the death of a whole herd . the service sector also benefits , since it drives the micro economy in developing countries . the appearance of fmd decreases the country &# 39 ; s activity , and in prolonged periods it can lead to recessions . from this it can be seen that it hurts the country since it has to do great efforts to balance the macro economy that has been damaged by a casual and accidental fortuitous event . as stated in the executive summary , transparency is the critical factor in all - human activity and the social impact of the project will be enormous , embracing almost every sector within and outside a country &# 39 ; s borders . thus , the perceived necessity of this invention is acutely felt , being this not only in developing countries but also in developed countries that import much of their beef and also have their very important cattle breeding activity . the project &# 39 ; s growth potential is enormous . although the growth will be slow at first , it will be steady . in the medium - term , its growth will be exponential , as more and more producers , as well as government agencies , will be attracted by the advantages that this invention entails . most important , this growth will result in greater social benefit . in this section the uruguayan case is considered as a non - exclusive example . considering the recommended distribution of 3 devices for every one hundred cattle ( in the case that the system will be used to monitor diseases ), approximately 350 , 000 devices will be needed to cover a cattle population of over 11 , 000 , 000 animals . such devices cost approximately us $ 190 ( cost approximately no more than a couple of hundred dollars each , getting cheaper as the purchases increase and as there is worldwide production ). from the beginning of the project the devices will be purchased gradually , according to market requirements . regarding item ( a ) table i shows that funds must be obtained in the year 0 . that is , prior to the market launch of the operational activities . this includes : the presentation before the national authorities , as well as public and private funding institutions ; personnel recruiting ; negotiating several contracts ; and international negotiation efforts . the company will pursue tax exemptions ( reduction in vat rates on imports and sales of products in the domestic market , import tariffs and domestic excise tax ). in item ( b ) the company would already be in the operational development until its normal activity . it was done for a five year period , which is considered sufficient for the project to be operational throughout the whole country , as shown in table ii . given the enormous social interest in the project , the necessary funding will be sought through the national bank ( banco de la republica oriental del uruguay ) and through the national corporation for development ( cnd ). also , the company will pursue the support of international institutions that generally endorse projects of social interest , such as the inter - american development bank and the world bank . furthermore , as illustrated in tables i and ii , the financial needs are limited to years 0 and 1 since the breakeven point will be obtained in year 2 , and the project would be completely self - sustaining from then on . for all the reasons stated above , the funding that will be needed , which is detailed in the implementation plan , would correspond to a figure close to us $ 260 , 000 , with part of the banking services included . as seen in table ii , the breakeven point would be reached in the first semester of year 2 . therefore , the loan will be amortized and completely repaid within 36 months maximum . a credit line of up to us $ 500 , 000 should also be solicited to be exclusively dedicated to the import operations , at least , during years 1 and 2 . as it was previously said , alongside all the above it will be negotiated the respective agreements and conventions with the telecommunications companies ( such agreement is considered in the incomes for monthly maintenance in table ii ) figures are expressed in united states dollars 2012 except for the item “ number of devices ”, which is expressed in physical units . the selling price of each device would be of approximately us $ 210 . * corresponds to a monthly fee of us $ 20 per establishment . this fee will increase in the case of facilities with more than , for example , 500 animals . as stated in the previous section , the development of the project is specified in a clear chronology . thus it can be seen that in year 0 the focus will be on promoting and advertising the activities . at this time , detailed information on the project will be provided to the national authorities in order to obtain the appropriate authorization for the company &# 39 ; s operation . it is also considered the administrative , technical and personnel needs that are required when any investment project . table i show figures in the different items needed for this implementation . the project requires an operational office , two 4 × 4 trucks to go to the country &# 39 ; s key points , accounting staff , a minimal of monitoring staff and a veterinarian . year 1 is particularly laborious because it requires everything needed in year 0 plus effective and efficient implementation and operation . revenues will be negligible in year 1 , because the major activities will be to implement the project administration and to generate stocks . the projects original device design will be outsourced for manufacturing to countries that specialize in this kind of manufacture . therefore , the stocks are to be formed through a permanent import and according to the need of devices . it is important to clarify that uruguay has a very fluid external trade with few obstacles to importing , especially when it is a project with a wide social interest . the unit costs of the devices include the tariffs and import taxes . of course , the project will apply for the appropriate tax exemptions that are allowed based on the high degree of social interest , which would result in a substantial reduction in the cost and consequently , a reduction in the selling price . furthermore , the monitoring staff will be increased and another veterinarian must be hired . in year 2 the administrative component is organized and operational throughout the country . furthermore , the devices imported each year will be sold immediately , and this process will continue from year 3 onward . in this case three more 4 × 4 trucks will be purchased and two additional veterinarians will be hired . then , the country will be divided into four regions , each of them having its own office as an operational base ; therefore , the respective premises will be rented in the most convenient place . it is significant that , since the project is based on technological devices , a primary and basic element for the viability of the entire project is the maintenance and update , which can be seen in the respective item in table ii . the figures in this item increase according to the devices in circulation , and tend to remain constant with the passing of time . in the user contract a period of insurance at the company &# 39 ; s expense will be specified and separate from the maintenance for malfunction , or manufacturing defects . obviously , this cost includes not only the devices but also the personnel that will be in charge of repairing them . throughout this work , the business will be the monthly maintenance , rather than the sale of the devices since the goal is to keep the cost for the farmer as lower as possible to fulfill the planned objectives . with the medium or long - term application of this project — subject to its widespread implementation — the eradication of fmd becomes a realistic outcome . the real - time detection and the immediate location of the outbreak mean that the disease can be researched at an early stage to determine the causes of the outbreak . this research , together with the use of statistics , will enable the company to keep optimal control of the areas where the disease is most likely to become endemic , leading to risk reduction , and even to eradication of the disease . this in no way prejudices the commercial aspect of the project , since its initial investment costs are amortized over a short time , and the earnings are direct in subsequent years . moreover , even in the case of disease eradication , the monitoring should persist . finally it should be taken into account that the country itself might decide to perform the administration , advertisement , and placement of the devices ; in that case the company &# 39 ; s activity would be limited to providing the appropriate devices . only costs and sales would be handled by the company , plus administrative costs . this possibility should be taken into account but it would not be elaborated in this document . the investment cost of year 0 would be the same , while in the following years the same criteria as the one used in table ii would apply . also , the credit line might vary because of the likelihood that the devices will be purchased in bulk . [ 1 ] dias , l ., “ sacrificio y disposición de animales en emergencias sanitarias , ii . la experiencia de fiebre aftosa en uruguay , años 2000 y 2001 ”. available at url : http :// www . mgap . gub . uy / dgsg / capacitaci % c3 % b3n / bienestar / e1 % 20sacrificio % 20sanitario . p df , ( accessed may 2012 ). [ 2 ] álvarez , c ., “ uruguay extrema controles sanitarios ante fiebre aftosa en paraguay ”. available at url : http :// www . biobiochile . c1 / 2011 / 09 / 24 / uruguay - extrema - controles - sanitarios - ante - fiebre - aftosa - en - paraguay . shtml , ( accessed may 2012 ). [ 3 ] global conference on foot and mouth disease control . available at url : http :// www . fmdconference2012 . com / background . html , ( accessed june 2012 ). [ 4 ] campolider . com , “ el argentino dardo chieza preside el foro mercosur de la carne ”. available at url : http :// campolider . com / 2012 / 04 / 27 / el - argentino - dardo - chiesa - preside - el - foro - mercosur - de - la - carne /, ( accessed may 2012 ). [ 5 ] ministerio de ganadería agricultura y pesca de la republica oriental del uruguay , “ anuarios ”. available at url : http :// www . mgap . gub . uy / portal / hgxpp001 . aspx ? 7 , 5 , 583 , o , s , 0 , mnu ; e ; 41 ; 1 ; mnu , ( accessed may 2012 ). [ 6 ] hulu , i ., ionescu , v ., cimponeriu , a ., chilinlan , m ., “ rfid technology used for identification and temperature monitoring of cattle ”, lucr { hacek over ( a )} ri stiinlifice medicin { hacek over ( a )} veterinar { hacek over ( a )} vol . xlii ( 2 ), 2009 . [ 7 ] banco de la republica oriental del uruguay . available at url : http :// www . bancorepublica . com . uy /, ( accessed may 2012 ). [ 8 ] corporación nacional para el desarrollo . available at url : http :// www . cnd . org . uy /, ( accessed may 2012 ). [ 9 ] ministerio de ganadería agricultura y pesca de la republica oriental del uruguay , “ el uruguay en cifras ”. available at url : http :// www . mgap . gub . uy / portal / hgxpp001aspx ? 7 , 5 , 86 , o , s , 0 , mnu ; e ; 2 ; 16 ; 10 ; 8 ; mnu

a device or assortment of devices is provided for measuring temperature and / or other biological parameters , and locating cattle or other types of animals in a remote , continuous and autonomous way . this allows early detection of sickness and other biological states , especially epidemic outbursts or cattle rustling , thus facilitating the early reaction of owners and / or authorities .

as used herein , the term &# 34 ; comprising &# 34 ; means various components can be conjointly employed in the pharmaceutical compositon of this invention . accordingly , the terms &# 34 ; consisting essentially of &# 34 ; and &# 34 ; consisting of &# 34 ; are embodied in the term comprising . as used herein , a &# 34 ; pharmaceutically acceptable &# 34 ; component is one that is suitable for use with humans and / or animals without undue adverse side effects ( such as toxicity , irritation , and allergic response ) commensurate with a reasonable benefit / risk ratio . as used herein , the term &# 34 ; safe and effective amount &# 34 ; refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects ( such as toxicity , irritation , or allergic response ) commensurate with a reasonable benefit / risk ratio when used in the manner of this invention . the specific &# 34 ; safe and effective amount &# 34 ; will , obviously , vary with such factors as the particular condition being treated , the physical condition of the patient , the type of mammal being treated , the duration of the treatment , the nature of concurrent therapy ( if any ), and the specific formulations employed and the structure of the compounds or its derivatives . as used herein , a &# 34 ; pharmaceutical addition salts &# 34 ; is salt of the anti - cancer compound with an organic or inorganic acid . these preferred acid addition salts are chlorides , bromides , sulfates , nitrates , phosphates , sulfonates , formates , tartrates , maleates , malates , citrates , benzoates , salicylates , ascorbates , and the like . as used herein , a &# 34 ; pharmaceutical carrier &# 34 ; is a pharmaceutically acceptable solvent , suspending agent or vehicle for delivering the anti - cancer agent to the animal or human . the carrier may be liquid or solid and is selected with the planned manner of administration in mind . as used herein , &# 34 ; cancer &# 34 ; refers , to all types of cancers or neoplasm or malignant tumors found in mammals . as used herein , the &# 34 ; anticancer compounds &# 34 ; are the benzimidazoles , and their salts . the exact benzimidazoles are described in detail below . the preferred materials are the products sold under the names &# 34 ; thiabendazole ®&# 34 ;, &# 34 ; benomyl ®&# 34 ; and &# 34 ; carbendazim ®&# 34 ; by basf and hoechst , dupont and msd - agvet . as used herein &# 34 ; viruses &# 34 ; includes viruses which infect animals or mammals , including humans . viruses includes hiv , influenza , polio viruses , herpes , rhinoviruses , and the like . the anti - cancer compounds are benzimidazole derivatives which are known for their antifungal activities . they are systemic fungicides used to prevent and eradicate fungi . the compounds have the following structure : ## str3 ## wherein x is hydrogen , halogen , alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms ; n is a positive integer of less than 4 ; y is hydrogen , chlorine , nitro , methyl or ethyl ; and r is hydrogen or an alkyl group having from 1 to 8 carbons , and r 2 is 4 - thiazolyl , nhcoor 1 wherein r 1 is aliphatic hydrocarbon of less than 7 carbon atoms , and preferably and alkyl group of less than 7 carbon atoms . preferably the compositions are : ## str4 ## wherein r is an alkyl of 1 through 8 carbon atoms and r 2 is selected from the group consisting of 4 - thiazolyl , nhcoor 1 , wherein r 1 is methyl , ethyl or isopropyl and the non - toxic , pharmaceutically acceptable acid addition salts with both organic and inorganic acids . the most preferred compounds are 2 -( 4 - thiazolyl ) benzimidazole , methyl -( butylcarbamoyl )- 2 - benzimidazolecarbamate and 2 - methoxycarbonylamino - benzimidazole and the compounds wherein y is chloro and x is hydrogen . these compounds are prepared according to the method described in u . s . pat . no . 3 , 738 , 995 issued to adams et al , jun . 12 , 1973 . the thiazolyl derivatives are prepared according to the method described in brown et al ., j . am . chem . soc ., 83 1764 ( 1961 ) and grenda et al ., j . org . chem ., 30 , 259 ( 1965 ). it is believed that fungicides , particularly systemic fungicides , have the capability of reducing tumors or decreasing their growth significantly . systemic fungicides have the ability to migrate through the plant or animal body . while this is a positive attribute , it is not an essential requirement of the effective compounds for treating viral infections , cancers or tumors . any suitable dosage may be given in the method of the invention . the type of compound and - the carrier and the amount will vary widely depending on the species of the warm blooded animal or human , body weight , and tumor being treated . generally a dosage of between about 2 milligrams ( mg ) per kilogram ( kg ) of body weight and about 400 mg per kg of body weight is suitable . preferably from 15 mg to about 150 mg / kg of body weight is used . generally , the dosage in man is lower than for small warm blooded mammals such as mice . a dosage unit may comprise a single compound or mixtures thereof with other compounds or other cancer inhibiting compounds . the dosage unit can also comprise diluents , extenders , carriers and the like . the unit may be in solid or gel form such as pills , tablets , capsules and the like or in liquid form suitable for oral , rectal , topical , intravenous injection or parenteral administration or injection into or around the tumor . the anti - cancer compounds are typically mixed with a pharmaceutically acceptable carrier . this carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used . the active agent can be coadministered in the form of a tablet or capsule , as an agglomerated powder or in a liquid form . examples of suitable solid carriers include lactose , sucrose , gelatin and agar . capsule or tablets can be easily formulated and can be made easy to swallow or chew ; other solid forms include granules , and bulk powders . tablets may contain suitable binders , lubricants , diluents , disintegrating agents , coloring agents , flavoring agents , flow - inducing agents , and melting agents . examples of suitable liquid dosage forms include solutions or suspensions in water , pharmaceutically acceptable fats and oils , alcohols or other organic solvents , including esters , emulsions , syrups or elixirs , suspensions , solutions and / or suspensions reconstituted from non - effervescent granules and effervescent preparations reconstituted from effervescent granules . such liquid dosage forms may contain , for example , suitable solvents , preservatives , emulsifying agents , suspending agents , diluents , sweeteners , thickeners , and melting agents . oral dosage forms optionally contain flavorants and coloring agents . parenteral and intravenous forms would also include minerals and other materials to make them compatible with the type of injection or delivery system chosen . specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in u . s . pat . no . 3 , 903 , 297 to robert , issued sep . 2 , 1975 . techniques and compositions for making dosage forms useful in the present invention are described in the following references : 7 modern pharmaceutics , chapters 9 and 10 ( banker & amp ; rhodes , editors , 1979 ); lieberman et al ., pharmaceutical dosage forms : tablets ( 1981 ); and ansel , introduction to pharmaceutical dosage forms 2nd edition ( 1976 ). the method of treatment can be any suitable method which is effective in the treatment of the particular virus or tumor type that is being treated . treatment may be oral , rectal , topical , parenteral or intravenous administration or by injection into the tumor and the like . the method of applying an effective amount also varies depending on the tumor being treated . it is believed that parenteral treatment by intravenous , subcutaneous , or intramuscular application of the benzimodale compounds , formulated with an appropriate carrier , additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals . the method of treating viral infections may also be by oral , rectal , topical , parenteral or intravenous administration . the actual time and dosage will depend on the virus being treated and the desired blood levels . the following examples are illustrative and are not meant to be limiting to the invention . the following cell culture tests were performed to test the toxicity of the benzimidazole compounds on colon , breast and lung human tumor cells . the viability of the cells were tested by looking at mtt ( 3 - 4 , 5 - dimethylthiazol - 2 - yl !- 2 , 5 - diphenyltetrazolium bromide ) reduction . mtt assay is a well known measure of cell viability . the colon tumor cells ( ht29 from american type culture collection ( atcc ) ) and the breast cells ( mx1 from cell lines from atcc ) were cultured in eagle &# 39 ; s miminal essential medium with 10 % fetal bovine serum . the lung tumor cells ( a549 from atcc cell lines ) were cultured in ham &# 39 ; s f12 medium with 10 % fetal bovine serum . the tumor cells were passaged and seeded into culture flasks at the desired cell densities . the culture medium was decanted and the cell sheets were washed twice with phosphate buffered saline ( pbs ). the cells were trypsinized and triturated prior to seeding the flasks . unless otherwise indicated the cultures were incubated at 37 °± 1 ° c . in a humidified atmosphere of 5 ± 1 % carbon dioxide in air . the cultures were incubated until they were 50 - 80 % confluent . the cells were subcultured when the flasks were subconfluent . the medium was aspirated from the flasks and the cell sheets rinsed twice with pbs . next , the trypsin solution was added to each flask to cover the cell sheet . the trypsin solution was removed after 30 - 60 seconds and the flasks were incubated at room temperature for two to six minutes . when 90 % of the cells became dislodged , growth medium was added . the cells were removed by trituration and transferred to a sterile centrifuge tube . the concentration of cells in the suspension was determined , and an appropriate dilution was made to obtain a density of 5000 cells / ml . the cells were subcultured into the designated wells of the 96 - well bioassay plates ( 200 microliter cell suspension per well ). pbs was added to all the remaining wells to maintain humidity . the plates were then incubated overnight before test article treatment . each dose of test article was tested by treating quadruplicate wells of cultures with 100 microliter of each dilution . those wells designated as solvent controls received an additional 100 microliter of methanol control ; negative controls wells received an additional 100 microliters of treatment medium . pbs was added to the remaining wells not treated with test article or medium . the plates were then incubated for approximately 5 days . at the end of the 5 day incubation , each dose group was examined microscopically to assess toxicity . a 0 . 5 mg / ml dilution of mtt was made in treatment medium , and the dilution was filtered through a 0 , 45 micrometer filter to remove undissolved crystals . the medium was decanted from the wells of the bioassy plates . immediately thereafter , 2000 microliter of the filtered mtt solution was added to all test wells except for the two untreated blank test wells . the two blank wells received 200 microliters of treatment medium . the plates were returned to the incubator for about 3 hours . after incubation , the mtt containing medium was decanted .. excess medium - was added to each well and the plates were shaken at room temperature for about 2 hours . the absorbance at 550 nm ( od 550 ) of each well was measured with a molecular devices ( menlo park , calif .) vmax plate reader . the mean od 550 of the solvent control wells and that of each test article dilution , and that of each of the blank wells and the positive control were calculated . the mean od 550 of the blank wells was subtracted from the mean of the solvent control wells , and test article wells , respectively to give the corresponding mean od 550 . ## equ1 ## dose response curves were prepared as semi - log plots with % of control on the ordinate ( linear ) and the test article concentration on the abscissa ( logarithmic ). the ec 50 was interpolated from the plots for each test article . for the test articles administered in methanol , separate responses were prepared to correct for the methanol data . adriamycin was used as a positive control . in all cases , it was more toxic than any of the test materials by one or two logs . adriamycin is one of the more potent agents in current use and one with significant side effects . the peak plasma concentration of other , quite effective chemotherapeutic agents may be 10 to 50 times higher than that of adriamycin . the ec 50 is the concentration at which one half of the cells are killed . table 1______________________________________ ec - 50 result ( ppm ) test material ht29 ht29 mx1 mx1 a549 a549______________________________________adriamycin 0 . 03 0 . 006 0 . 02 0 . 001 0 . 03 0 . 009benomyl 0 . 742 0 . 747 1 . 42 2 . 42 0 . 980 1 . 02carbendazim 0 . 621 0 . 662 0 . 829 0 . 856 0 . 856 0 . 836______________________________________ in normal healthy cells , the following results were obtained . as is evident , the benomyl and carbendazim were much less toxic to normal healthy cells than adriamycin . table 2______________________________________ec - 50 broncheal kerotinoyletest material cells cells fibroblasts______________________________________benomyl 0 . 728 0 . 682 3 . 26 2 . 4 3 . 24 2 . 81carbendazin 0 . 320 0 . 506 0 . 752 0 . 822 1 . 52 1 . 42adriamycin 0 . 015 0 . 0020 0 . 0035 0 . 0093 0 . 065 0 . 10______________________________________ in a related study using lung tumor cells ( a - 549 ) breast tumor cells ( mcf - 7 ) and colon tumor cells ( ht - 29 ), thiabendazol , a systemic fungicide , effectively killed these cells . table 3 summarizes the results table 3______________________________________ optical densityconcentration ( ppm ) a - 549 mcf - 7 ht - 29______________________________________0 - control 0 . 600 0 . 245 0 . 398173 0 . 007 0 . 007 0 . 00535 0 . 411 0 . 025 0 . 01117 . 3 0 . 851 0 . 258 0 . 2043 . 46 1 . 12 0 . 466 0 . 7130 . 87 1 . 32 0 . 507 0 . 852______________________________________ these experiments show that these compositions are effective in killing tumor cells . these same systemic fungicides are effective against viruses including hiv , influenza , rhionoviruses and herpes viruses . the fungicides can be used alone or in combination with other fungicides .

a pharmaceutical composition that inhibits the growth of tumors and cancers in mammals and can be used to treat viral infections that comprises a fungicide is disclosed . the particular fungicide used is a benzimidazole derivative .

the present invention may be further understood with reference to the following description and the appended drawings , wherein like elements are referred to with the same reference numerals . the cradle according to embodiments of the present invention may be utilized to hold stacks of materials ( e . g ., sheet - like construction materials ) near the point of use of those materials . the exemplary cradle presents a topmost one of the elements in the stack at a substantially constant height , so that the worker using the materials can reach for the materials at a nearly constant , convenient height above the ground . the worker does not have to reach up to take the elements when the stack is full , and does not have to bend over to pick up the material elements when the stack is nearly used up . thus , the worker may incur fewer injuries due to lifting and may work in a more efficient manner . large stacks can be used , while the top most element in the stack is always presented at a convenient location . [ 0020 ] fig1 a shows an exemplary embodiment of the cradle according to the present invention . cradle 100 includes a base 102 that provides an anchoring point on the ground for the rest of the cradle 100 . a support mechanism 109 is provided to position planar surface 106 relative to the base 102 . planar surface 106 receives the materials 200 ( e . g ., construction materials ), and is movable in the direction shown by arrows “ a ” with respect to base 102 . support mechanism 109 provides a guide to control the movement of planar surface 106 , so that it can move only in a direction substantially perpendicular to base 102 . a system to resist displacement of planar surface 102 from a preferred distance “ d ” from base 102 is also provided by support mechanism 109 . this system applies a restoring force to planar surface 106 , that opposes the weight of construction elements 200 deposited on the planar surface 106 . in the exemplary embodiment shown in fig1 a , the support mechanism 109 includes several support members 104 that are secured to base 102 , and extend substantially perpendicularly therefrom . supports 104 and base 102 form a structural frame for cradle 100 . for example , for a rectangular base 102 , there may be four supports 104 placed at the corners of base 102 . alternatively , a different shape of the base 102 or planar surface 106 may require a different configuration of supports 104 . supports 104 may include guides 108 that are designed to direct the movement of planar surface 106 in a desired direction . guides 108 may have a shape complementary to corners 111 , to permit planar surface 106 to move in a direction along arrows “ a ”, substantially perpendicular to base 102 . [ 0022 ] fig1 b shows another exemplary embodiment of the cradle 100 according to the present invention which is similar to the embodiment shown in fig1 a . the cradle 100 has a plurality ( e . g ., three or four ) moving arrangements , such as wheels 230 , 232 . the moving arrangements allows the worker easily move heavy loads of materials 200 . in addition , the moving arrangements may have a braking mechanism ( not shown ). the braking mechanism allows the worker to fix the cradle 100 at a particular location , thus preventing the cradle 100 from incidentally moving from that fixed location . also , the material 200 may be a different shapes . for example , the material 200 may be a shape of the surface 106 ( as shown in fig2 a ). alternately , the material 200 may be of a smaller shape and placed in the middle of the surface 106 ( as shown in fig1 a ). those skilled in the art would understand that materials 200 may come in different shapes and sizes and that the cradle 100 may be adjusted to accommodate theses shapes and sizes . for example , to accommodate the smaller shape materials 200 ( as a shown in fig1 a ), a frame ( not shown ) may be attached to the surface 106 which would prevent the materials 200 from shifting . as shown in fig1 a , 1 b , 2 a and 2 b , support mechanism 109 may also include resilient / biasing elements such as springs 110 , used to urge the planar surface 106 to a desired height “ d ” from base 102 . springs 110 may be associated with the supports 104 , or alternatively may be separate . in the exemplary embodiment shown , there is a spring 110 for each support 104 . however , the number of springs 110 and supports 104 does not have to be the same . in the exemplary embodiment , springs 110 are located between the base 102 and planar surface 106 . the neutral extension of springs 110 , meaning the extension at which no force is exerted , corresponds to the desired height “ d ”. when a weight such as stack 200 is placed in planar surface 106 , springs 110 are compressed , and tend to resist the displacement of planar surface 106 . since the resisting force exerted by a spring is proportional to its compression , the more planar surface 106 is displaced , the greater the force opposing such displacement is generated by springs 110 . by carefully selecting the size and spring constant of springs 110 , it is possible to control the displacement of planar surface 106 such that topmost element 202 on stack 200 will always be at or near the height “ d ” from base 102 . for example , when the cradle 100 is empty , the weight of planar surface 106 will balance the spring force at height “ d ”. when a full stack is added , the additional weight compresses springs 110 until topmost element 202 is approximately at a height “ d ”, while planar surface 106 is lower . as the elements of construction material are removed from the top of stack 200 , the reduced weight compresses springs 110 less , and planar surface 106 is pushed upwards , such that the new topmost element is now approximately at a height “ d ” above base 102 . it should be apparent to one skilled in the art that the same result may be obtained by using springs under tension rather than under compression , for example simply by connecting the springs to the tops of supports 104 rather than to base 102 . a feed mechanism for the construction elements is thus provided , that places the topmost element of the stack at a constant height . the exemplary embodiment shown provides the advantage that planar surface 106 is to a certain extent self leveling . springs 110 are located at the corners , and if a weight is placed near a corner rather than near the center of planar surface 106 , the spring nearest to the weight will be compressed the most , causing a greater restoring force that opposes further compression of that spring . the corner where the weight was added thus drops only a small distance , before further displacement is stopped by the spring . elements of the exemplary embodiment of the present invention are further described with reference to fig4 . a detail of the support mechanism 109 is shown , as a cross section view taken on line iv - iv of fig2 a and 2 b . one of supports 104 is shown , in this example having a structural portion with an l shaped cross section which resists buckling , and provides stability to the structure . in this example , the four l shaped supports 104 , together with base 102 , form a rigid frame that keeps the movement of planar surface 106 constrained to the desired direction . the support mechanism 109 of the exemplary embodiment includes a spring guide 112 that may be attached to support member 104 . spring guide 112 surrounds a portion of the perimeter of spring 110 , and thus prevents it from buckling or being displaced . in this exemplary embodiment , spring guide 112 forms an internal channel , but does not completely surround spring 110 , so that a connection with planar surface 106 may be made , as will be described below . however , other configurations of spring guide 112 may be devised , which may surround spring 110 to a greater or lesser extent . in the configuration shown in fig4 spring guide 112 has a circular cross section that extends for slightly more than 180 degrees , so that spring 110 cannot fall out through the opening defined by edges 120 . in this configuration , spring 110 is not attached to spring guide 112 , and is retained by gravity within channel 122 defined by the guide 112 . planar surface 106 may have extensions 114 that are shaped to fit in guides 108 of the support mechanism 109 . in the exemplary embodiment shown in fig5 extension 114 is a track interface that fits in the track or channel 122 defined by spring guide 112 , which here also acts as a guide for planar surface 106 . however , different configurations may be designed where extension 114 fits in a separate guide , or is guided by the surfaces of support member 104 . in this exemplary embodiment , extension 114 is circular , and fits in channel 122 on top of spring 110 . thus , the force exerted by spring 110 is transmitted to planar surface 106 through the extensions 114 , which have the dual role of interfacing with springs 110 and keeping the planar surface 106 within the guide portions . extension 114 may enter channel 122 , for example , through the opening defined by edges 120 . the combination of forces applied to a plurality of extensions 114 by corresponding spring guides 112 maintains planar surface 106 in its proper position relative to base 102 , particularly if extensions 114 are spaced around the perimeter of planar surface 106 , as shown in fig3 . according to an exemplary embodiment of the present invention , the frame of cradle 100 is disassembled , so that when not in use the cradle 100 may be stored or transported easily . in the present embodiment , planar surface 106 may be lifted up away from support members 104 , since during use it rests by gravity on springs 110 , within spring guides 112 . springs 110 also can be lifted out of spring guides 112 , which in turn are easily removable from support members 104 . support members 104 may be removed from base 102 , since they are held in place thereon by a friction or locking mechanism . in an alternative embodiment , support members 104 may be hinged to base 102 , so that when not in use they may be folded within the base 102 . [ 0031 ] fig6 shows an exemplary embodiment of the mounting blocks 152 for the support members 104 and springs 110 to base 102 . a single mounting block 152 may be used for both components , or separate attachments may be used . the mounting block 152 may be a solid cylindrical base having a shape , e . g ., of a male pedestal . the support member 104 and the spring 110 may be removably coupled to the mounting block 152 . in alternative exemplary embodiment of the present invention , the support member 104 and the spring 110 may be attached to the base 102 using a female attaching members 240 shown in fig3 a . each of the female attaching members 240 is coupled on the exterior of the base 102 and has a shape of a female coupling . the support member 104 and the spring 110 are removably inserted into the female attaching member 240 . the guide 112 stops at the top of the base 102 , while the spring 110 extends through the base 102 and stops at the bottom of the base 102 . the female attaching members 240 also server buffers to prevent incidental damage to the cradle 100 if it collides with another object . as indicated above , cradle 100 may be folded when not in use . fig7 and 8 show successive steps to disassemble and fold the cradle 100 . in fig7 the springs 110 and support members 104 are removed from mounting blocks 152 of base 102 , and are placed within a box like storage portion formed by bottom surface 150 and side surfaces 154 of base 102 . in a subsequent step illustrated in fig8 the planar surface 106 is placed on top of the springs 110 and support members 104 , forming a lid to the box defined by base 102 . in another embodiment , latches or locks may be used to prevent separation of planar surface 106 from base 102 , so that the components of the support mechanism may be securely held in the box like structure . the entire cradle 100 can be transported between job sites , or may be stored while occupying a minimal amount of space . this dual nature of the cradle 100 is one of its main advantages . the cradle 100 may , on one hand , serve to support materials 200 at a certain height ; on the another hand , the cradle 100 , when in the folded position , may server a dolly to move the materials 200 . another advantage of the present invention is that the cradle 100 does not require any complicated electrical and / or mechanical components . furthermore , the cradle 100 allows to load the materials 200 from the top . in the preceding specification , the present invention has been described with reference to specific exemplary embodiments thereof . it will , however , be evident that various modifications and changes may be made thereto without departing from the broadest spirit and scope of the present invention as set forth in the claims that follow . the specification and drawings are accordingly to be regarded in an illustrative rather than restrictive sense .

described is a portable cradle which includes a removable planar surface , a base and a plurality of vertical support members removably coupled to the base and supporting the planar surface above the base . each vertical support member includes a biasing member urging the planar member upward away from the base with a total biasing force applied to the planar member being selected based on property of materials to be supported on the planar surface so that a position of an upper surface of the supported materials remains substantially constant as a quantity of materials supported on the planar surface is changed .

reference is made to all of the boxes “ a ” with a number thereafter , namely ; 1 a , 2 a , 3 a , etc . these several boxes all list key ingredients , which are all treated in the manner recited in the series of steps that lead to the center of the fig1 for the commencement of the process . natural beet or cane sugar , honey , rice syrup or any sweetener can be employed as the sweetening agent . a brix level of about 27 is considered desirable , in order to properly enable freezing at about 27 ° f ., no matter which type of sweetener is employed . it is within the skill of the art to determine the quantity of the sweetener product for the brix sweetener level . in order to keep the calorie content down , and to appeal to those who want to have a dessert yet avoid the sugar blues or blahs , the process of this invention may utilize non - nutritive sweeteners . thus mention may be made of saccharine , or when combined with malto - dextrose as sweet &# 39 ; n low ™, aspartame such as is sold under the brand names nutra - sweet ™ or equal ™, and sugar derived products , such as splenda ™. it is well known that for the same level of sweetness , for coffee , one utilizes two “ blues ” ( equal ™) to equal one “ pink ” ( sweet &# 39 ; n low ™). the sweetness level of the “ yellows ” ( splenda ™) relative to the “ blues ” and “ pinks ” is well known . suffice it to say that the products of this invention , in many instances , have original sweetness from the fruit or flavorant added , as well as from the added sweetener . as the stabilizer , i can use many ingredients to form a hydrocolloid system . there are many different kinds of pectin that can be used singularly or mixed together to accomplish the desired consistency for the product . also , all sorts of starches , such as corn , tapioca , roots , arrowroot , flours , or modified food starch may be employed . these have different procedures for mixing , some need to be mixed while hot , others can be mixed cool . some need a certain sugar level ( brix ) to be activated , others do not . these can be readily purchased from such sources as danisco , a danish company headquartered in copenhagen , which company has thirteen u . s . a . offices , but there are many others . the melting point and freezing point is very important in making an ice cream - like product . the term “ melts in your mouth ” is commonly used for chocolate , but this concept also very important in the frozen desserts industry . ice cream freezes at approximately 27 degrees fahrenheit ( f .). water freezes at 32 degrees f , and the addition of sugar depresses the freezing point of a frozen dessert . the addition of non - nutritive sweeteners also affects the freezing point of a frozen dessert . plain strawberries freeze at approximately 31 degrees f . thus , to make an ice cream - like product , a freeze inhibitor must be added to drop the freezing point . to use strawberries as an example , strawberries freeze at a lower temperature than water because of the natural sugars that are in the fruit , around 12 brix . sugar is a common freeze inhibitor . if you add sugar to raise the sweetness level to 20 brix , this lowers the freezing temperature to approximately 29 degrees f . if you raise the sweetness level further to 27 brix , the new freezing temperature is approximately 27 degrees f ., the same as ice cream . there are other materials aside from sugar that inhibit freezing . salt , alcohol , and glycerin are some . these items can be used in making lower calorie or diet versions of the product . again using strawberries as an example , the addition of one tablespoon of glycerin to ten ounces of strawberry , the new freezing point is 29 degrees f . if you add two tablespoons of glycerin to ten ounces of strawberry , the freezing point is approximately 27 degrees f . likewise , if you add one tablespoon of glycerin and ¼ teaspoon of salt to ten ounces of strawberry , the new freezing point is approximately 27 degrees f . indeed , if you add sugar to ten ounces of strawberries to make 20 brix and add one tablespoon of glycerin , you can inhibit the freezing temperature to approximately 27 degrees f . this shows that there are many ways to manipulate the freezing temperature , which of course could correspond to calorie count , depending upon the chose freeze inhibitor . glycerin , also known as glycerol , which is non - caloric , and has a sweetness of about 60 % of that of sucrose , serves a similar function to lower the freezing point . care must be taken in the addition of a bulking agent ( sweetener ). frozen desserts with too low a freezing point may become too soft when stored in a conventional home freezer , as the temperature is higher here than in a commercial freezer . conversely , desserts can become too hard if the freezing point is too high . thus , attention must be given to the total recipe of the frozen dessert . reference is made again to fig1 at box 10 , which begins the process of this invention to create the mix . to get to this beginning of the process , one may utilize the key ingredients recited by groups in any of boxes 1 a , 2 a , 3 a , 4 a , or 5 a , and follow the procedural arrows of the box sets 1 - 5 ; namely 1 a through 1 d ; 2 a through 2 e ; 3 a ; 4 a - 4 b ; and 5 a through 5 c , respectively . from the last box of these single digit successions , one arrives at box 10 . note also that flavorants , per box 9 , can be added . once the mix is created , sweetener is optionally added to the desired level . as mentioned earlier herein , non - nutritive sweeteners may be utilized as well as cane or beet sugar . the mix should be sweetened to a level of between 26 and 28 brix , for a wide range of consumer appeal . see box 15 . the next step involves an addition , from box 18 or box 23 . in box 23 , the pectin or other stabilizer is added in a within the skill of the art amount in grams for the batch size , while in box 18 , sufficient glycerin or another freeze inhibitor is added in conjunction to the pectin to stabilize the mix for the batch size . the amount of pectin utilized with or without glycerin or other freeze inhibitor remains the same , depending upon the key ingredient ( s ) employed in the creation of the mix . it is preferred to add the stabilizer after the pasteurization step of box 20 , per fig1 . some pectins require that sugar be the sweetener and perhaps a ph adjustment to carry out the intended addition purpose , others do not . other pectins require the addition of calcium and a ph adjustment . for a no sugar added product , the latter type of pectin may be employed . while pectins are the preferred stabilizer , due to low price and easy availability , other food stabilizers , such as xanthan gum or locust bean gum may be suitably employed in their traditional manner . the created mixture , with the optional sweetener , is heated with the freeze inhibitor of box 18 added , to about 180 degrees fahrenheit , to pasteurize the mix . see box 20 . the time to accomplish this will vary , depending upon the material of the vessel employed , and the surface area in contact with the heat source . it is believed that , for 5 gallons of mix , the pasteurization will take about 5 to 10 minutes in time to reach the temperature minimum for pasteurization . subsequent to the addition , or lack thereof , of the glycerin to the pectin and into the mix , at the elevated temperature , the mix is cooled down per box 30 to about 40 degrees f . this cooling can be carried out by placing the mix into a conventional refrigerator at about 40 degrees fahrenheit , for between about 7 and 10 hours , because freezing at cooler temperatures allows for easier freezing . the next step is to freeze ,— per box 35 —, the stabilized , freeze inhibited mixture . “ quick freezing ”, which prolongs shelf life is recommended ., but is not completely necessary . however quick freezing provides smaller ice crystals , relatively , and the smaller the ice crystals , the better the product . ice crystals are not stationary but rather they grow in time . therefore starting with the smallest possible ice crystals , will provide a longer shelf life both at home and prior to purchase , before a sandy or course mouth feel sets in . care should also be given to the physical shape or configuration of the frozen product such that it can be easily masticated in the chosen masticator machine . it is seen that in fig1 , it is suggested that the brick , which sometimes could be relatively soft yet frozen — based upon key ingredient ( s ), be freeze hardened . after this optional step , the brick is easier to physically handle for the mastication step . of course there is a delicate balance between being overly hard which would require more effort for mastication , versus being “ underly ” hard which contributes to difficult handling prior to the mastication step . such balance handling is within the skill of the art . the frozen bricks or blocks are then subjected to a mastication step per box 45 . to carry out the mastication , the frozen blocks are removed from their containers using a fork or other implement , but without applying heat and placed into the masticator . typical machines that can be used for this process include the champion juicer , among others available in the market place , and the machine of zweben , u . s . pat . no . 7 , 028 , 607 . mastication is carried out for as long as necessary , until the frozen mix has achieved a pudding - like or soft - serve state . the mastication of the frozen stabilized mixture completely scrambles the frozen molecules to create a creamy textured product , similar to ice cream . during the course of the mastication , an overrun of about 10 %- 15 % is achieved , but this can be changed a bit if desired . overrun is a term known to the art as an increase in volume due to entrained air . while the inventor hereof has utilized a modified champion brand juicer for the mastication , any machine having a rotating rotor , with blades thereon , onto which the frozen product is forced may be employed . in essence , the mastication step grinds the frozen bars into the desired pudding like product . once the pudding consistency has been reached , a portion may be put into a bowl or cone and immediately served to a hungry recipient , per box 50 . unused product in the pudding state should be refrigerated to prevent breakdown to a liquid . at this point in time , chunks or pieces of fruit , nuts , candy , chocolate , or coconut can be folded or mixed into the pudding per box 46 , if desired . in the alternative , once the pudding consistency is reached , the pudding can be re - frozen at a temperature of about 10 degrees fahrenheit or colder , and the “ left over ” pudding soft serve from box 50 , and then frozen hard in a home freezer to form an ice cream consistency product . see box 60 . alternatively , the creamy pudding can be pumped into a mold , into which a stick may be placed at a suitable time to form an on - the - stick product , and hardened in an immersion or blast freezer to solidify the random and scattered molecules . the result is a product that is creamy similar to ice cream but which does not employ typical ice cream or sorbet ingredients . it is ready for service in a cone or cup , per box 65 . the reader is advised that “ blast ,” “ immersion ,” “ nitrogen ,” and “ plate ” freezers are well known to skilled artisans in the ice cream and frozen confectionary industry . all of these freezers are readily available in the marketplace . see also u . s . pat . no . 6 , 109 , 056 , of feldpausch issued aug . 29 , 2000 , for discussion of an immersion freezer . prior to discussing specific examples of this process , the 3 tables aforementioned are presented . it is to be noted that ice cream freezes as noted at 27 ° f ., and thus to simulate an ice cream product , the product must have the same freeze point . the three tables below depict temperature in the vertical column and in the horizontal 10 oz . of plain strawberries are shown at its freeze point , at ( a ), while b , c , d , and e each pertain to the free point of on the chart of 10 oz with the recited amounts of the freeze inhibitor and / or stabilizer . in all instances a = 10 oz strawberries at 12 brix , which represents no added sweetener . the same volume of unsweetened strawberries was used in experiments b through n these 3 tables illustrate the role of freeze inhibitors in affecting the freeze point of fruit . while only strawberries have been recited experiments with other fruits yield similar types of results . glycerin has also been replaced by other freeze inhibitors , such as maltodextrin , with similar results . sorbitol and polydextrose can also be added to inhibit the freeze point of the key ingredient to raise or lower the temperature to reach the desired 27 degree freeze point . nota bene that the smaller dots are meant to signify that the freeze point is located between the two degrees where the smaller dot is set out . the following examples utilize various types of the key ingredients as shown in fig1 . these examples are not to be considered as limiting but are only typical of the products that can be prepared according to this process . in all of these examples , the percentages are by weight , not by volume . note the lack of need for added pectin in this example , due to the high naturally occurring pectin content , which pectin acts as a stabilizer . it is to be noted that while example iii utilized flavored non - fat milk , unflavored non - fat milk as well as flavored and unflavored 1 % and 2 % fat milk will give similar results when employed in the formulae of both example iii and example iv . the process of this invention can make an ice cream like product that does not rely on fat for its creaminess and at the same time utilizes non - dairy ingredients . the invention incorporates not just typical non - dairy , but rather whole fruit , including the seeds and skins , but not pits like apricot or peach . the type of seeds intended are seeds the size of raspberry , pomegranate , blackberry , pear , or apple . the process of this invention can also use the skins of the fruit . for instance , blueberries , grapes , and apples need not be peeled . the process can also use vegetables and tubers , such as yam and sweet potato , or even yucca — savored by people from the carribean countries . it is well known that most of the vitamins and minerals are stored in the seeds and skins of the fruit or vegetable . therefore , utilizing the whole fruit achieves a more wholesome , natural , and nutritious product . the most famous of the roots that may be employed as a key ingredient are ginger and ginseng . members of the squash family include pumpkin and spaghetti squash . when one uses a traditional ice cream freezer to make a frozen dessert , something as small as a strawberry seed can be detrimental to the operation of the freezer . for this process , the mixture need not be thin and free flowing . here , even peanut and other nut butters can be used as the key ingredient . thus , not only is a uniquely flavored product made available to kids and adults alike , but meal replacements of a very tasty nature chock full of vitamins and minerals can be had in an easy to eat format . the major difference between this product and sorbet is that sorbet is prepared in an ice cream machine . sorbet starts as a liquid and is slowly frozen and aerated . this series of product \ s are not made on traditional ice cream machinery . for products such as frozen lemonade and other high water content related products that are made in an ice cream machine , the water content turns into small ice crystals which can be felt on the tongue . in contrast , here the ice crystals are virtually gone . by stabilizing the liquid and then freezing the mass in a rapid manner , followed by mastication , the ice crystals that are present are completely broken away from their chains into small groups . by maintaining the cold temperature , before rehardening , the crystals of ice are inhibited from chain reformation , which would yield a very hard product like an ice cube . instead a product of ice cream like consistency is formed . thus i can make a frozen dessert from such diverse fluids as green tea , coffee , koolaid ®, coca cola ®, and sprite ® among others . while any of the key ingredients be they as solids or liquids , can be used in combinations , certain combinations of these are well known . thus strawberries and kiwi and strawberries with banana may be mentioned along with cherry and cola soft drinks , and mint with chocolate and pineapple with coconut may be mentioned . other unique flavor combinations include coconut milk + vanilla , and mango pineapple among others . if desired , subsequent to the mastication step , chunks of edibles may be added to enhance the taste experience . mention may be made of oreo ® bits , m & amp ; m ® candies and chocolate , fruit chunks , such as pieces of cherry and other fruit such as peach , miniature marshmallows and the like , per box 46 . in this era of adult onset diabetes and obesity in people of all ages , the products of this invention offer a nutritionally beneficial , pleasurable to eat product . basically , the two formats of the products of this invention utilize whole fruit or vegetable to which a little sweetener is added , rather than a bit of fruit , and a large amount of sweetener with milk or water fluid , as is the case for traditional ice cream or sorbet . rather than adding the wording “ if necessary ”, to box 15 and to box 23 of fig1 and 2 , it should be readily recognized by those skilled i the art that certain key ingredients inherently contain adequate stabilizer and / or adequate sweetener to not require the addition of a stabilizer or a freeze inhibitor . mention may be made of such key ingredients as cranberries and bananas . it is seen therefore , that there has been disclosed a product that has a smooth mouth feel much like that of fat rich ice cream , and the process for making it , which product may be made with non - fat , reduced fat , or whole milk , or no milk at all , as may be desired . whatever path is taken , the result is a good tasting soft - serve product or as a creamy ice cream replacement product as may be desired . since certain changes may be made in the herein disclosed process and product without departing from the scope of the invention involved , it is intended that all matter contained in the about description and shown in the accompanying drawings shall be interpreted as illustrative only and not in a limiting sense .

the process of this invention involves one or more of at least one or more key ingredients , which can be almost any human consumable food stuff , such as whole fruit ; soda pop of any flavor ; milk and milk replacements with / without a flavorant added ; tubers , roots and squash family products ; and other edibles such as coconut milk , coconut meat which is diced as needed , cooked if not edible raw , mixed with a freeze inhibitor as may be needed , and a stabilizer as may be needed . the mix is then frozen and masticated to yield a soft serve dessert product . the product can then be served for immediate consumption , or frozen again , hard , for serving later in time as an ice cream replacement .

with respect to the embodiments shown in fig1 through 178 , these are directed to improved deformable elements and specific arrangements optimized for the biomechanics of a user &# 39 ; s foot . in particular , fig1 through 168 disclose improved shapes of the elastically deformable elements , and arrangements therefore within airtight casings . for example , fig6 illustrates an arrangement of elastically deformable elements which are substantially oval shaped in cross - section . according to another aspect of the invention , the deformable elements have been cored , wherein a hole has been formed through the center of the deformable element in order to reduce the weight of the element . for example , fig6 illustrates an arrangement of elastically deformable members 110 which are substantially oval in a cross - section . deformable members 110 are provided with holes 112 which reduce their weight . it is also conceived that deformable elements 110 are dimpled or otherwise reduced in order to minimize the weight of elements 110 . preferably , elements 110 are vacuumed sealed in a casing 114 . the edges of elements 110 , are tapered as shown in dashed lines in fig6 and illustrated as recesses 118 in fig5 . fig6 shows an arrangement of deformable elements 110 which are broken down into three deformable element batteries 116 , wherein each battery includes at least two deformable elements 110 which are joined by integral bridging portions 120 . each of the deformable element batteries 116 are joined by battery bridging portion 122 . preferably , bridging portions 122 are integrally formed with casing 114 which is vacuum sealed around elements 110 . the advantage achieved by forming deformable elements 110 with an oval cross - section , is that it is possible to use larger elements which provide a more continuous contact and therefore more evenly distributed energy transfer between the user &# 39 ; s foot and the element , while maintaining the flexibility necessary in an article of footwear sole . for example , it has been found that it is more costly to provide an array of elastic members including a large number of elements 110 , and that the flexibility of the resulting sole is reduced if larger elements are used . it has also been found that deformable elements that are substantially round or barrel shaped do not flex with the sole of the article of footwear during use and therefore do not provide continuous support of the user &# 39 ; s foot during use . in order to provide better support of the user &# 39 ; s foot , the present invention employs the use of oval deformable elements 110 connected by bridging portion 120 . constructed as such , deformable battery 116 , for example , can more easily bend along bridging portion 120 . therefore , an aspect of the invention is to align deformable elements 110 such that bridging portions 120 are aligned with flex lines of a foot . the flex lines referred to are generally known in that when a user is walking or running , the sole of the user &# 39 ; s foot bends throughout each step . therefore an aspect of the invention is to construct deformable elements 110 and batteries 116 such that deformable elements 110 can flex with the bend lines of a foot and thereby better follow and maintain contact with the sole of a user &# 39 ; s foot . another advantage attained by the invention , is that casing or encapsulating bag 114 is formed by a vacuum forming or blow molding which thereby eases and lowers the cost of manufacturing . another aspect of the invention is that the arrangement , stiffness and viscoelastic properties of deformable elements are varied throughout positions in the sole in order to match the biomechanics of the user &# 39 ; s foot , and preferably , according to the particular athletic activity . fig1 - 167 show that a deformable element 110 may comprise a single unitary member having either a plurality of holes 124 or none at all to best suit the effect on the foot of the user and to minimize weight where necessary . fig1 - 178 disclose a variety of arrangements of deformable elements 110 and deformable batteries 116 according to a particular athletic activity . as shown in fig1 , deformable elements 110 are arranged inside deformable batteries 116 such that bridging portions 120 and 122 are aligned with flex lines of the foot . therefore , bridging portions 120 . 122 allow deformable elements 110 and batteries 116 to flex as the sole of the user &# 39 ; s foot flexes during an athletic activity . the arrangement shown in fig1 , is optimized for running . a heel unit is aligned with the first contact area of the sole with the ground during the heel strike phase of running gait . the rearmost battery of the heel unit is hinged to the central battery of the heel unit to reduce the accelerating leverage that results from the heel striking a unitary cushioning element . a separate battery of the heel unit is placed toward the arch of a wearer &# 39 ; s foot and is made more stiff than the other parts of the heel unit . this arrangement reduces the pronation rate of a wearer and thus reduces the risk of chronic stability related injuries . a forefoot section of three parts is provided at least under the first and second metatarsal - phalangeal joints of a wearer . this is an area exposed to great stress during the push off phase of the running gait . a narrowed and hinged segmental arrangement is provided in the forefoot area unit and includes a hinge 122 leading to a battery under the wearer &# 39 ; s great toe . a hinge 120 between the elements may be provided at any point in the structure such that the hinge is in general alignment with the joints of a wearer &# 39 ; s foot or is oriented to match with the rotational distortion of the sole and midsole resulting from their flexion and compression during foot contact with the ground common to running . [ 0208 ] fig1 through 173 show alternative embodiments for arrangements optimized for running . fig1 includes a separate element placed on the medial border of the sole , generally under the wearer &# 39 ; s arch . this has a greater stiffness then the other elements in the heel area of this arrangement to reduce the degree or rate of pronation of a wearer &# 39 ; s foot during running . the forefoot has two separate elements with an area of separation corresponding generally to the metatarsal - phalangeal joints of a wearer . fig1 includes a forefoot pad under the first , second and third metatarsal - phalangeal joints of a wearer . the barrel elements shown therein are ovoid and their longitudinal axis is generally aligned with the flex lines of a wearer &# 39 ; s foot to permit greater ease of flexion . [ 0209 ] fig1 shows a heel element with a hinged portion between the central heel cushioning portion and a lateral cushioning portion positioned to absorb some impact energy upon the heel striking the same . the hinging reduces the tendency of a heel to act as a unitary plate of material and thus reduces the leveraged acceleration of the sole towards the ground . this in turn reduces the rate of pronation of a wearer . [ 0210 ] fig1 shows a heel element with a hinged portion between the central heel cushioning portion and a lateral cushioning portion positioned to absorb some impact energy at heel strike . the rear lateral border of the pad is positioned away from the outside border of the sole and midsole to permit encapsulation of the parts with a foam such as pu or eva . similarly , fig1 through 177 illustrate arrangements optimized for basketball . fig1 shows a sole including two heel and two forefoot elements divided about a generally longitudinal axis . this division reduces the tendency of the cushioning elements to act as a monolithic sheet and thus reduces the leveraged acceleration resulting from forceful ground impacts on the lateral or medial borders of the article of footwear . these impacts may occur during landing on a court surface after jumping in the air . [ 0212 ] fig1 includes cushioning elements at the rear of the heel to protect the wearer from impact shock during running on a court surface . the forefoot includes a laterally placed element . this reduces the tendency of the sole to collapse under the forefoot lateral border during the motion known as cutting , or the application of other rapid lateral shearing forces to the article of footwear . [ 0213 ] fig1 provides a heel cushion for court running actions and a forefoot pad positioned in from the borders of the sole . this permits full encapsulation of the element in foam to reduce manufacturing costs while still permitting a user the extraordinary benefits of the cushioning elements featured in this invention . [ 0214 ] fig1 shows an article of footwear sole including a heel cushioning element provided for comfort during the running phase of basketball game . this is positioned inward from the border of the sole to permit full encapsulation of the part in foam . finally , fig1 illustrates an arrangement optimized for tennis . fig1 shows a sole featuring two aspects of the present invention . the heel provides cushioning under the calcaneus of a wearer during the heel strike motions associated with lunging for a stroke or running on the heels . a separate forefoot section cushions the foot under the first four metatarsal - phalangeal joints of a wearer . this is an area exposed to stress by the motions of service and many movements needed to position a player for optimum return strokes . the disclosure of provisional application serial no . 60 / 073 , 576 upon which this application is based is incorporated herein by reference . obviously , numerous modifications and variations of the present invention are possible in light of the above teachings . it is therefore to be understood that within the scope of the appended claims , the invention may be practiced otherwise than as specifically described herein .

an article of footwear is disclosed which comprises a vamp , a lower support connected to the vamp and at least one insert mounted in the lower support and which includes an airtight casing having a plurality of elements positioned therein which are elastically deformable such that the biomechanics of the foot of the user are optimized .

a diagram of an exemplary embodiment of optical imaging catheter system / apparatus according to the present disclosure is shown in fig1 . this exemplary apparatus can include a microstructural imaging system 110 , a single mode optical fiber 115 , a marking laser for guided biopsy or tissue treatment 120 , a rotary junction 130 , an optical imaging catheter 140 , a data acquisition system 160 and a data processing and storage arrangement 170 ( which include one or more computers and one or more data storage devices ). the exemplary microstructural imaging system ( e . g ., system utilizing at least one of optical frequency domain imaging , optical coherence tomography , etc . modalities ) 110 can detect a back - reflected light ( or other electro - magnetic radiation ) from one or more portions of an anatomical structure , such as the tissue 180 , to acquire signals and / or information regarding the tissue microstructures . for example , the optical signals and / or data from both the microstructural imaging modality and the marking / treatment laser platform are coupled into the single mode fiber 115 that can be connected to the rotary junction 130 . the rotary junction 130 can serve as the interface between the stationary imaging systems to the optical imaging catheter 140 , which can be rotating and / or translating . the imaging probe 150 can be rotated and translated for a helical scanning inside the catheter 140 . the optical imaging probe 150 can focus the optical imaging beam 155 onto the tissue 180 . returning light signals ( or signals associated with the electro - magnetic radiation ) from the tissue 180 can be detected by the microstructural imaging system 110 . the signals can be acquired by the data acquisition system 160 . the data processing and storage arrangement / apparatus 170 can store and / or process the data which is based on the received signals , e . g ., in a real - time , for an appropriate proper operation , and subsequent possible visualization and analysis . fig2 ( a ) is a diagram of a balloon catheter apparatus with the flexible neck during a transnasal placement , according to another exemplary embodiment of the present disclosure . the exemplary apparatus can comprise a long , small diameter drive - shaft 150 within a flexible protective sheath 210 . at the distal end of the catheter / apparatus , a positioning balloon 250 can be placed , which can center the optical probe within esophagus . the air for inflating of the balloon 250 can be delivered through an outer sheath 220 . the length of an imaging window of the inflated balloon , as shown in fig2 ( b ), can define the length of the tissue scanned during imaging . the outer sheath 220 can be connected to the balloon 250 by a short segment of an additional flexible sheath , which can be called a flexible neck 230 . the flexible neck 230 can be also introduced and / or provided in a proximal end of the balloon 250 , e . g ., in the inner protective sheath 210 . as shown at fig3 ( a ), one role of the flexible neck 230 can be to absorb some , most or even all of the bending of the catheter / apparatus . without the flexible neck 230 , e . g ., the imaging part of the inner protective sheath 210 inside the balloon 250 would likely bends . due to the complexity of the luminal organs and patient movement , the bending of the catheter / apparatus can occur often in clinical practice . such bending may cause a decentration of the optical probe , and provide suboptimal imaging of the luminal organs with lower image contrast and resolution . a small diameter of the balloon catheter with flexible neck can facilitate its use and implementation for imaging of human esophagus , e . g ., without sedation . for this purpose , the exemplary catheter can , in another exemplary embodiment of the present disclosure , be introduce through the nose . in order accomplish this mode of delivery of the exemplary device / apparatus , the exemplary catheter can be enclosed in an additional outer tube 240 , as shown in fig2 ( b ). the exemplary outer tube 240 can be dimensionally and mechanically similar and / or identical to a standard nasogastric ng ( feeding ) tube . the deflated balloon - catheter can be enclosed in the outer tube 240 , and advanced to the stomach , e . g ., using standard ng tube placement techniques . following a confirmation that the exemplary device is in the stomach , the exemplary outer tube 240 can be withdrawn . after the retraction of the outer tube 240 , e . g ., for 6 - 7 cm , the balloon 250 can be exposed and inflated , as shown at fig2 ( b ). following the imaging procedure , the balloon 250 can be deflated , the exemplary catheter withdrawn into the tube 240 , and the entire device can be removed from the patient . fig4 ( a ) shows a diagram of a balloon - catheter tethered capsule device during placing inside patient , according to a further exemplary embodiment of the present disclosure . in such exemplary embodiment , the tether can comprise the long , small diameter driveshaft 150 within the flexible sheath 210 . in another exemplary embodiment , the tether can be a thin flexible tube that can contain a wire for transceiving electrical signals , an optical fiber for transceiving optical signals , and / or a hollow conduit for transmitting gas ( i . e . air ) or fluid ( i . e . water ). for example , as shown in fig4 ( a ), a pressure sensing fiber 460 can be contained within or immediately adjacent to the sheath 210 . the sheath 210 can be terminated by a transparent , folded balloon 430 that can extend over a length of 3 . 0 cm in its uninflated state and can reside within rigid end - caps 420 to provide structure to the capsule . the entire device can be encapsulated within a custom - fit , transparent and highly elastic silicone rubber outer sheath 410 . the silicone balloon 410 can keep the capsule portion smooth during swallowing and the imaging balloon can impart a stability when it is fully inflated to an inflated state 450 for imaging at the gej , as shown at fig4 ( b ). an elastic centering wire 440 , which can be fixed to the distal end cap and configured to freely translate within the distal lumen of the driveshaft , facilitates the centering of the drive - shaft in the balloon 410 . such exemplary design can ease the manufacturing of the balloons , reduce or eliminate the astigmatism caused by an inner sheath , and facilitate the folded balloon 410 to expand to 6 cm when inflated . an optical pressure sensor 470 can be incorporated into the proximal end cap , and utilized by the exemplary apparatus . the tethered ofdi capsule can be swallowed while the patient is drinking a fluid , e . g ., water . the exemplary capsule can travel to the stomach by peristalsis . after the capsule enters the stomach , the operator can pull up on the tether until resistance is perceived . at this point , the patient can swallow the exemplary capsule , and the capsule can be moved to the les , e . g ., guided by serial pressure measurements . when at the les , the balloon 430 can be fully inflated to its inflated state 450 , which can facilitate the expansion of the silicone rubber sheath 410 . an helical ofdi procedure can then be conducted over the capsule &# 39 ; s entire imaging window . after imaging , the balloon 430 can be deflated , and the capsule can return to its initial state , this allowing the capsule to be removed from the patient by reeling in the tether . because the silicon rubber 410 encapsulates the entire tethered capsule device , the capsule and the tether can be sterilized and reused , thus possibly further reduce the costs . fig5 ( a ) shows a structured balloon 500 with the one or more spherical protuberances 510 according to yet another exemplary embodiment of the present disclosure . this exemplary balloon 500 can facilitate an elevation of the tissue in respect to the circumference of the balloon 500 used for imaging . the same or similar effect can be achieved by placing one or more rings 520 over the balloon surface 500 , as shown at fig5 ( b ). in one further exemplary embodiment of the present disclosure , the number of protuberances can be minimized or reduced , to increase and / or maximize the imaging surface of the balloon . in yet another exemplary embodiment of the present disclosure , the protuberances should keep the balloon elevated over the tissue . as a result , the tissue surface will not be compressed by the surface of the balloon , thus possibly resulting in improvement of the visualization of the luminal tissue surface topology . the electro - magnetic radiation and / or light can be provided through the balloon 500 . in one exemplary embodiment , the electro - magnetic radiation or light can be prevented from being passed through one or more of the protuberances 510 and / or one or more of the rings 520 . according to another exemplary embodiment , the electro - magnetic radiation or light can also pass through one or more of the protuberances 510 and / or one or more of the rings 520 . 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 . indeed , the arrangements , systems and methods according to the exemplary embodiments of the present disclosure can be used with and / or implement any oct system , ofdi system , sd - oct system or other imaging systems , and for example with those described in international patent application pct / us2004 / 029148 , filed sep . 8 , 2004 which published as international patent publication no . wo 2005 / 047813 on may 26 , 2005 , u . s . patent application ser . no . 11 / 266 , 779 , filed nov . 2 , 2005 which published as u . s . patent publication no . 2006 / 0093276 on may 4 , 2006 , and u . s . patent application ser . no . 10 / 501 , 276 , filed jul . 9 , 2004 which published as u . s . patent publication no . 2005 / 0018201 on jan . 27 , 2005 , and u . s . patent publication no . 2002 / 0122246 , published on may 9 , 2002 , the disclosures of which are incorporated by reference herein in their entireties . it will thus be appreciated that those skilled in the art will be able to devise numerous systems , arrangements and methods which , although not explicitly shown or described herein , embody the principles of the disclosure and are thus within the spirit and scope of the present disclosure . further , the exemplary embodiments described herein can operate together with one another and interchangeably therewith . in addition , to the extent that the prior art knowledge has not been explicitly incorporated by reference herein above , it is explicitly being incorporated herein in its entirety . all publications referenced herein above are incorporated herein by reference in their entireties .

in accordance with exemplary embodiments of the present disclosure , device and method can be provided which can facilitate imaging of biological tissues , e . g ., luminal organs in vivo , using optical techniques . the exemplary device can include different designs an features of one or more catheters , which can illuminate the tissues , and collect signals from the inside of the lumen . in another exemplary embodiment according to the present disclosure , a balloon - catheter can be provided with the flexible neck , which can absorb most of the bending . according to still another exemplary embodiments of the present disclosure , a balloon - catheter tethered capsule can be provided , and according a yet further exemplary embodiment , a structured balloon design can be provided with one or more protuberances , thus enabling imaging of the structures in close contact , e . g ., without compressing of the tissue .

this disclosure describes surgical methods for resurfacing portions of arthritic or diseased bone . the resurfacing techniques include passing a graft into a joint and fixating the graft against an articulating surface of a bone of the joint . the resurfacing techniques may be performed to decrease pain and increase functionality of any joint of a musculoskeletal system . in some non - limiting embodiments , the surgical methods include sizing a graft , arthroscopically positioning the graft against an articulating surface of the bone , and then securing the graft to the bone . in other non - limiting embodiments , the graft is secured to the bone using one or more suture anchors . in still other non - limiting embodiments , the graft is passed into a joint space and positioned relative to the bone using sutures . these and other features are described in detail in the following paragraphs of this detailed description . fig1 illustrates a joint 10 of the human musculoskeletal system . the joint 10 may be any joint found in the musculoskeletal system of the human body . in a non - limiting embodiment , the joint 10 is an ankle joint that includes a tibia 12 and a talus 14 that supports the tibia 12 . other bones may be associated with the ankle joint , including but not limited to , the calcaneus 15 , the cuboid 17 and the fibula 19 . the talus 14 acts as the primary load bearing surface for transferring loads from the tibia 12 through the entire foot . because of this , over time , arthritis may develop on the talus 14 , such as at an articulating surface 16 of the talus 14 . this disclosure describes resurfacing techniques for resurfacing bone , such as the talus , the patella ( see fig1 ) or any other bone , in order to reduce the pain associated with arthritis . the arthritis may be caused by repetitive trauma to the joint 10 , such as may be experienced during sporting activities . although resurfacing of the talus and patella are described throughout this disclosure as example resurfacing techniques , this disclosure is not intended to be limited to such embodiments . in other words , the various techniques and instrumentation described herein may be used to resurface any bone of any joint of the human musculoskeletal system . fig2 - 10 , with continued reference to fig1 , schematically illustrate an exemplary bone resurfacing procedure . in one non - limiting embodiment , the bone resurfacing procedure is an arthroscopic procedure . the exemplary bone resurfacing procedure is one option for treating end stage arthritis in a patient . prior to performing the bone resurfacing procedure , appropriate radiological studies may be conducted to determine the grade of the arthritis that has developed on the bone . excessive arthritis , such as arthritis of grades iv and higher , may require more aggressive procedures than those proposed herein . in one non - limiting embodiment , a replicate of the bone that requires resurfacing may be created to aid in planning and executing the bone resurfacing procedure . as shown in fig2 , a radiographical image 21 may be obtained of the bone that is to be resurfaced , which in this example is the talus 14 . the radiographical image 21 could be obtained using computed tomography ( ct ), magnetic resonance imaging ( mri ) or any other imaging technique . the radiographical image 21 may next be communicated for additional processing . for example , the radiographical image 21 , and its underlying data , could be sent to a computer system 23 equipped with appropriate modeling software for processing the radiographical image 21 . processing may include subtracting non - critical elements and noise from the radiographical image 21 , smoothing or modifying surface features , etc ., to generate a 3d model 25 of the talus 14 . the 3d model 25 can be sent to a rapid prototyping system 27 to create a bone replicate 29 of the talus 14 . the 3d model 25 provides the necessary numerical data for manufacturing the bone replicate 29 . the rapid prototyping system 27 could be a stereolithography ( sla ) system or any other rapid prototyping system . in one non - limiting embodiment , the rapid prototyping system 27 utilizes a powder resin that is selectively sintered by a laser of the rapid prototyping system 27 in a layer - by - layer fashion to generate the bone replicate 29 . the bone replicate 29 can be made from a plastic material or any other suitable material . once created , the bone replicate 29 can be used to plan and execute the bone resurfacing technique . for example , referring now to fig1 and 3 , a graft 18 may be sized and shaped to generally match the articulating surface 16 of the talus 14 using the bone replicate 29 . the bone replicate 29 can also be used to practice drilling and fixation methods by using trial grafts . alternatively , in another non - limiting embodiment , a ct scan or other computerized image of the patient &# 39 ; s joint 10 may be used to estimate the size and shape of the graft 18 . various cutting lines 20 may be marked on the graft 18 using a marker or other writing utensil to outline the desired shape of the graft 18 . the graft 18 may then be cut to the desired size and shape using any known cutting device or cutting methodology . in another non - limiting embodiment , the radiographical image 21 can be used to model and create a patient specific cutting jig / device to precisely cut the graft 18 to a desired shape to enable the surgeon to quickly create the desired shape intraoperatively . the cutting jig / device could be marked circumferentially with reference features or numbers that would correspond to the portions of the graft 18 that require stitching so that marking the graft 18 and anchoring alignment would be facilitated once inserted into the joint . alternatively , in another non - limiting embodiment , a tissue bank could create and send the precise shaped graft 18 , customized to the patient , to the surgical facility for use during surgery . in one non - limiting embodiment , the graft 18 is an acellular dermal extracellular matrix . arthroflex ®, sold by arthrex , inc ., is one type of graft suitable for use in the exemplary bone resurfacing procedures of this disclosure . the articulating surface 16 of the talus 14 is next prepared for receiving the graft 18 . as shown in fig4 , the talus 14 may be prepped by performing bone marrow stimulation . for example , a microfracture procedure or some other technique may be performed to obtain a bleeding bone bed 22 . during the microfracture surgery , multiple perforations 24 are created on the articulating surface 16 of the talus 14 . the bleeding bone bed 22 may be created using a tool 26 , such as arthrex &# 39 ; s powerpick ™, to create the perforations 24 . formation of the perforations 24 creates the bleeding bone bed 22 , which stimulates bone marrow seepage at the repair site . in another non - limiting embodiment , the bleeding bone bed 22 may be created via abrasion arthroplasty or by debriding the bone surface using a mechanized burr . other techniques can also be used to create the bleeding bone bed 22 , including but not limited to , drilling , hammering , curetting , scraping , etc . in another non - limiting embodiment , the talus 14 may optionally be further prepared for receiving the graft 18 by debriding the articulating surface 16 . the debriding procedure may be performed using another tool 28 , such as arthrex &# 39 ; s powerrasp ™. fig5 illustrates the positioning of a drill guide 30 relative to the talus 14 . the drill guide 30 may include a bracket 32 , an arm 34 rotatable relative to the bracket 32 and a cannula guide 36 moveable within a slot 38 of the bracket 32 . a cannula 40 may be received through the cannula guide 36 and a marking hook 42 may extend from the arm 34 . in one non - limiting embodiment , the drill guide 30 is positioned relative to the talus 14 by seating a distal hook 44 of the marking hook 42 on a posterior rim 46 of the talus 14 at a location just below the articulating surface 16 . the cannula 40 may be positioned at a desired location of the medial rim 48 of the talus 14 by moving the cannula guide 36 within the slot 38 of the bracket 32 . referring now to fig5 and 6a , a drill 50 may be inserted through the cannula 40 to prepare tunnels 52 a , 52 b through the talus 14 beneath the articulating surface 16 ( see fig6 a ). although not shown , a depth sleeve may be used in conjunction with the cannula 40 to control the depth of insertion of the drill 50 up to the distal hook 44 of the marking hook 42 . in one non - limiting embodiment , the tunnels 52 a , 52 b are transosseous or crossing drill tunnels . for example , one of the tunnels 52 a , 52 b may exit from the posteriomedial corner of the talus 14 , whereas the other of the tunnels 52 a , 52 b may exit from the posteriolateral corner of the talus 14 . as shown in fig6 b , a shuttling device 54 may be passed through each of the tunnels 52 a , 52 b . in one non - limiting embodiment , the shuttling devices 54 are lassos made of either wire or suture . in another non - limiting embodiment , portions of the shuttling devices 54 are stiffened to simply passage of the shuttling devices 54 through the tunnels 52 a , 52 b . each shuttling device 54 may include looped ends 56 . the shuttling devices 54 may be advanced through a cannulation ( not shown ) of the drill 50 and then fed through the tunnels 52 a , 52 b from the anterior direction toward the posterior direction . other insertion techniques may also be utilized . the looped ends 56 of the shuttling devices 54 that exit the tunnels 52 a , 52 b on the posterior side of the talus 14 may then be retrieved through an arthroscopic portal for subsequent use to position the graft 18 within the joint space . fig7 illustrates preparation of the graft 18 for its passing into the joint space to resurface the articulating surface 16 of the talus 14 . a plurality of flexible strands 58 a , 58 b may be attached to the graft 18 to aid in the placement of the graft 18 over the articulating surface 16 of the talus 14 . in one non - limiting embodiment , the flexible strands 58 a are suture tapes and the flexible strands 58 b are sutures . the flexible stands 58 a may be attached to each corner of the graft 18 , and one or more of the flexible strands 58 b may be attached to the graft between the flexible strands 58 b along a periphery of the graft 18 . the flexible strands 58 a aid in passing the graft 18 into the joint space , and the flexible strands 58 b provide additional fixation options . other suture configurations than shown in fig7 are contemplated within the scope of this disclosure . referring now to fig8 , the graft 18 may be pulled into place within the joint space using the shuttling devices 54 and the flexible strands 58 a . in one non - limiting embodiment , ends of each flexible strand 58 a are looped through one of the looped ends 56 of the shuttling devices 54 . the opposite looped ends 56 from those receiving the flexible strands 58 a are then pulled to shuttle the flexible strands 58 a into the tunnels 52 a , 52 b and thereby pull the graft 18 into place over the talus 14 . prior to pulling the flexible strands 58 a into the place , the graft 18 may be partially folded to ease insertion through a small incision , which may be an anterolateral or anteromedial incision . once the graft 18 is fully seated on the talus 14 , anatomic coverage of the graft 18 may be confirmed arthroscopically . in another non - limiting embodiment , intra - portal atraumatic capsular and soft tissue retraction methods and devices , such as soft cannulas , percutaneous retraction stitches , flexible cannulas , etc ., are used to lift away soft tissue from the work area and create space for graft introduction and manipulation followed by bone preparation and graft anchoring . fig9 illustrates fixation of the graft 18 to the talus 14 using one or more suture anchors 94 . the graft 18 may be affixed to the articulating surface 16 of the talus 14 after confirming proper seating of the graft 18 . the suture anchors 94 may be any suture anchor type or combination of suture anchors types . in one non - limiting embodiment , the suture anchors 94 are knotless suture anchors . holes 96 may optionally be pre - formed around a periphery of the talus 14 and below the edge of the graft 18 for receiving the suture anchors 94 . each hole 96 is configured to receive one of the suture anchors 94 . a drill and other tools may be used to form the holes 96 . next , the flexible strands 58 a are loaded through a portion 98 of the suture anchor 94 . the suture anchors 94 may be passed into the joint space via an arthroscopic portal 99 . in one non - limiting embodiment , the portion 98 of the suture anchor 94 includes an eyelet 97 . after receiving the flexible strand 58 a , the eyelet 97 may be inserted into one of the holes 96 . once the eyelet 97 is positioned at least partially in the hole 96 , the flexible strand 58 a is tensioned in a direction d 1 to approximate the graft 18 to the talus 14 . next , an anchor body 95 of the suture anchor 94 may be moved toward the eyelet 97 to trap the flexible strand 58 a between the talus 14 and the anchor body 95 in order to fixate the graft 18 . the procedure just described can be repeated to implant multiple suture anchors 94 to fully fixate the graft 18 to the talus 14 . although suture anchors are illustrated in this embodiment , it should be understood that fixation of the graft 18 could alternatively or additionally be achieved via the use of trans - osseous tunnels to tie suture or other filament over flush fixation devices such as buttons , staples , screws , etc . in yet another non - limiting embodiment , graft to soft tissue anastomosis could be used for fixating the graft 18 to nearby soft tissue connected to the talus 14 . in another non - limiting embodiment , as shown in fig1 , a bone marrow concentrate 90 that has been previously harvested from the patient may be injected under the graft 18 ( i . e ., between the graft 18 and the articulating surface 16 of the talus 14 ) after the graft 18 has been properly seated . the bone marrow concentrate 90 may be applied using an applicator 92 . alternatively , the graft 18 may be soaked or impregnated with biologic blood components from the patient prior to inserting and attaching the graft 18 to the talus 14 . fig1 illustrates another joint 110 of the human musculoskeletal system . in this non - limiting embodiment , the joint 110 is a knee joint that includes a femur 112 , a tibia 114 and a patella 116 . various tendons 115 ( quadriceps , patellar , etc .) may extend between bones and muscles of the joint 110 . the patella 116 articulates with the femur 112 and covers and protects an anterior articular surface 118 of the femur 112 . because of this , over time , arthritis and associated loss of articular cartilage may develop on the patella 116 , such as at a posterior articulating surface 120 of the patella 116 . this embodiment describes a resurfacing technique for resurfacing the patella 116 in order to reduce the pain associated with arthritic or diseased bone . fig1 - 19 , with continued reference to fig1 , schematically illustrate another exemplary bone resurfacing procedure . in one non - limiting embodiment , the bone resurfacing procedure is an arthroscopic procedure that may be performed through various arthroscopic portals that provide access to an internal joint space . the exemplary bone resurfacing procedure is one option for treating a patient suffering from arthritis . prior to performing the bone resurfacing procedure , appropriate radiological studies may be conducted to determine the grade of arthritis that has developed within a patient &# 39 ; s joint . excessive arthritis , such as arthritis of grades iv and higher , may require more aggressive procedures than those proposed herein . referring first to fig1 , 13a and 13b , the patella 116 may be distracted away from the femur 112 using a surgical system 122 . the patella 116 is distracted away from the femur 112 to gain access to the posterior articulating surface 120 . the posterior articulating surface 120 may need resurfaced because of the development of arthritis . in one non - limiting embodiment , the surgical system 122 includes a limb positioner 124 , a suture anchor 126 , and at least one flexible strand 128 connected between the limb positioner 124 and the suture anchor 126 . the surgical system 122 is configured to apply a vertical force f 1 to the patella 116 to lift it away from the femur 112 . in one non - limiting embodiment , the suture anchor 126 is inserted near a center of an anterior surface 130 of the patella 116 . any type of suture anchor may be used . in addition , although only a single suture anchor is shown in fig1 , a plurality of suture anchors could be utilized during the exemplary distraction procedure . a pilot hole 132 may optionally be pre - drilled into the patella 116 for inserting the suture anchor 126 . once inserted , the suture anchor 126 is fixated within the patella 116 . the flexible strand 128 , which may include one or more sutures , may be attached to the suture anchor 126 either before or after its insertion into the pilot hole 132 . the flexible strand 128 is next looped over an arm 134 of the limb positioner 124 . the arm 134 may be moved , such as by pivoting , between a first position p 1 and a second position p 2 ( shown in phantom in fig1 ) to distract the patella 116 away from the femur 112 . because the suture anchor 126 is fixated inside the patella 116 , movement of the arm 134 tensions the flexible strand 128 to apply the vertical force f 1 to the patella 116 . in another non - limiting embodiment , a holding device 136 of the surgical system 122 may optionally be employed to act as a partial counter force during the distraction procedure ( see fig1 a ). the holding device 136 may be positioned relative to either the femur 112 or the tibia 114 . additional details of the limb positioner 124 of the surgical system 122 are shown in fig1 a and 13b . the limb positioner 124 may include a body 138 , the arm 134 , an adjustment device 140 and a stand 142 . the stand 142 includes an attachment device 144 for attaching the limb positioner 124 to a sturdy surface , such as a bed rail . the body 138 is attached to an opposite end of the stand 142 from the attachment device 144 . the arm 134 may be pivotally connected to the body 138 . the adjustment device 140 , which includes a knob 143 and a threaded portion 146 , may be used to change the positioning of the arm 134 . for example , in one non - limiting embodiment , the knob 143 may be turned to advance the threaded portion 146 relative to the body 138 . the threaded portion 146 is connected to an extension 148 of the arm 134 , and the arm 134 is pivoted as the threaded portion 146 is advanced . the posterior articulating surface 120 of the patella 116 may be prepared for receiving a graft 150 ( see fig1 b ). this may be done any time after distracting the patella 116 from the femur 112 . as shown in fig1 , the patella 116 may be prepared by performing bone marrow stimulation . for example , a microfracture procedure or some other technique may be performed to obtain a bleeding bone bed 125 . during the microfracture surgery , multiple perforations 135 are created on the posterior articulating surface 120 of the patella 116 . the bleeding bone bed 125 may be created using a tool 145 to create the perforations 135 . formation of the perforations 135 creates the bleeding bone bed 125 , which stimulates bone marrow seepage at the repair site . other techniques can also be used to create the bleeding bone bed 125 , including but not limited to , drilling , hammering , curetting , scraping , etc . in another non - limiting embodiment , the patella 116 may be further prepared for undergoing resurfacing by debriding the posterior articulating surface 120 . the debriding procedure may be performed using another tool 155 . referring to fig1 a and 15b , a graft 150 may be sized and shaped to generally match the posterior articulating surface 120 of the patella 116 . in one non - limiting embodiment , the graft 150 is an acellular dermal extracellular matrix . other graft types are also contemplated . in one non - limiting embodiment , the graft 150 is sized and shaped using a bone replicate of the patella 116 that can be manufactured in a manner similar to that shown in fig2 . in another non - limiting embodiment , the size and shape of the patella 116 is visualized by outlining the patella 116 with a plurality of needles 152 . the actual number of needles 152 used during this procedure could vary from patient to patient and therefore is not intended to limit this disclosure . a flexible strand 154 ( shown using dashed lines in fig1 a ) could optionally be wrapped around the outsides of the needles 152 . the length of the flexible strand 154 may then be used to estimate a circumference of the patella 116 . this calculated circumference can then be used to cut the graft 150 to a desired size and shape . in an alternative , non - limiting embodiment , the surface area of the patella 116 ( or any other bone ) could be arthroscopically visualized and measured using an articulating or extending measuring device . as shown in fig1 b , the graft 150 may be placed over the patella 116 ( ex - situ ) between the needles 152 . markings 156 may be made around the periphery of the graft 150 . the markings 156 correspond to the locations of the needles 152 . the markings 156 may be made using a marker or any other writing utensil . flexible strands 158 , such as suture , suture tape , or other strands , may next be passed through the graft 150 at the location of each marking 156 . any known suture passer may be employed to pass and retrieve the flexible strands 158 . the needles 152 and the flexible strands 158 may be left in place for later use to arthroscopically shuttle the graft 150 into the joint space . fig1 schematically depicts arthroscopically shuttling the flexible strands 158 into the joint space . the flexible strands 158 are shuttled into the joint space one by one and are kept separate from one another ex - situ to prevent tangling . in one non - limiting embodiment , the flexible strands 158 are individually passed through an arthroscopic portal 160 to enter the joint space . free ends 164 of the flexible strands 158 may then be extracted through the patient &# 39 ; s skin 162 at a location of the needle 152 that corresponds to the flexible strand 158 being passed . various surgical instruments , including but not limited to graspers , elevators , etc ., may be used to shuttle and extract the flexible strands 158 in the manner previously described . once each flexible strand 158 has been passed , the needles 152 are removed . after each flexible strand 158 has been shuttled into the joint space , the graft 150 may be pulled into place by pulling each flexible strand 158 . this step is schematically shown in fig1 . prior to pulling the flexible strands 158 to position the graft 150 , the graft 150 may be partially folded to ease insertion through a small incision , which may be made laterally or medially . once the graft 150 is fully seated on the posterior articulating surface 120 of the patella 116 , anatomic coverage of the graft 150 may be confirmed arthroscopically . fig1 illustrates fixation of the graft 150 to the patella 116 using one or more suture anchors 166 . the graft 150 may be affixed to the posterior articulating surface 120 of the patella 116 after confirming proper seating of the graft 150 . the suture anchors 166 may be any suture anchor type or combination of suture anchors types . in one non - limiting embodiment , the suture anchors 166 are knotless suture anchors . holes 168 may optionally be pre - formed around a periphery of the patella 116 for receiving the suture anchors 166 . each hole 168 is configured to receive one of the suture anchors 166 . a drill may be used to form the holes 168 in the patella 116 . next , the free ends 164 of one of the flexible strands 158 are pulled back through the skin and are loaded through a portion 170 of the suture anchor 166 . the suture anchors 166 may be passed into the joint space via an arthroscopic portal 165 . in one non - limiting embodiment , the portion 170 of the suture anchor 166 includes an eyelet 172 . after receiving the free ends 164 of the flexible strand 158 , the eyelet 172 may be inserted into one of the holes 168 . once the eyelet 172 is positioned at least partially in the hole 168 , the flexible strand 158 is tensioned in a direction d 1 to approximate the graft 150 to the patella 116 . next , an anchor body 174 of the suture anchor 166 may be moved toward the eyelet 172 to trap the flexible strand 158 between the patella 116 and the anchor body 174 in order to knotlessly fixate the graft 150 . the free ends 164 of the flexible strand 158 may be trimmed flush to the bone . the procedure just described can be repeated to implant multiple suture anchors 166 to fully fixate the graft 150 around the periphery of the patella 116 . in another non - limiting embodiment , shown in fig1 , a bone marrow concentrate 176 that has been previously harvested from the patient may be injected under the graft 150 ( i . e ., between the graft 150 and the posterior articulating surface 120 of the patella 116 ) after the graft 150 has been fixated . the bone marrow concentrate 176 may be applied using an applicator 178 . alternatively , the graft 150 may be soaked or impregnated with biologic blood components from the patient prior to inserting and attaching the graft 150 to the patella 116 . in yet another non - limiting embodiment , initial adhesion of the graft 150 to the patella 116 can be augmented by using a biologic glue , such as fibrin glue mixed with acp or bma , to accelerate adhesion and reduce the initial suture anchor loads . although the different non - limiting embodiments are illustrated as having specific components , the embodiments of this disclosure are not limited to those particular combinations . it is possible to use some of the components or features from any of the non - limiting embodiments in combination with features or components from any of the other non - limiting embodiments . it should be understood that like reference numerals identify corresponding or similar elements throughout the several drawings . it should also be understood that although a particular component arrangement is disclosed and illustrated in these exemplary embodiments , other arrangements could also benefit from the teachings of this disclosure . the foregoing description shall be interpreted as illustrative and not in any limiting sense . a worker of ordinary skill in the art would understand that certain modifications could come within the scope of this disclosure . for these reasons , the following claims should be studied to determine the true scope and content of this disclosure .

this disclosure relates to arthroscopic resurfacing techniques for treating diseased bone . the techniques include passing a graft into a joint and fixating the graft against an articulating surface of a bone of the joint . a method for resurfacing a bone according to an exemplary aspect of the present disclosure includes , among other things , sizing a graft based on a replicate of a bone , arthroscopically positioning the graft against an articulating surface of the bone , and securing the graft to the bone using at least one suture anchor .

as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 40 mg / l of pcb was mixed with 25 g of dmi and 5 g of sodium ethoxide ( naoet , in table 1 ) in a 100 ml flask , and the mixture was then stirred briskly while being maintained at a temperature of 160 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of dmi was removed and the pcb in the oil layer was analyzed by gas chromatography in accordance with the method specified by jis ( japanese industrial standard ) k0093 , and it was confirmed that the pcb content had decreased to 1 . 2 mg / l . as listed in table 1 , a sample consisting of 40 g of reclaimed transformer oil containing 40 mg / l of pcb was mixed with 25 g of suflolane , 0 . 5 g of β - cyclodextrin and 0 . 5 g of sodium ethoxide in a flask , and the mixture was then stirred briskly while being maintained at a temperature of 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the layer of sulfolane was removed and the pcb in the layer was analyzed , whereby it was confirmed that the pcb content had decreased to 2 . 9 mg / l . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 15 mg / l of pcb was mixed with 25 g of sulfolane and 1 . 5 g of caustic soda ( naoh in table 1 ) in a flask , and the mixture was then stirred briskly while being maintained at a temperature of 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of sulfolane was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that pcb content had decreased to 0 . 61 mg / l . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 15 mg / l of pcb was mixed with 25 g of suflolane and 5 g of caustic soda in a flask , and the mixture was then stirred briskly while being maintained at a temperature of 160 ° c . for about 2 . 5 hours . after cooling the mixture to room temperature , the lower layer of sulfolane was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to 1 . 9 mg / l . as listed in table 1 , a sample consisting of 100 g of reclaimed transformer oil containing 40 mg / l of pcb was mixed with 50 g of sulfolane and 2 g of sodium ethoxide in a flask , and the mixture was then stirred briskly while being maintained at a temperature of 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of sulfolane was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to the pcb detection limit of 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 100 g of reclaimed transformer oil containing 40 mg / l of pcb was mixed with 50 g of sulfolane and 3 g of caustic soda in a flask , and the mixture was then stirred briskly while being maintained at a temperature of 160 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of sulfolane was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 40 mg / l of pcb was mixed with 5 g of sulfolane and 1 . 5 g of sodium ethoxide in a flask , and the mixture was then stirred briskly while being maintained at a temperature of 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of sulfolane was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 12 mg / l of pcb was mixed in a flask with 25 g of a mixed solvent consisting of 12 . 5 g of diethylene glycol ( hereinafter &# 34 ; deg &# 34 ;) and 12 . 5 g of dmi , and 0 . 1 g of caustic soda , and the mixture was then stirred briskly while being maintained at a temperature of from 180 ° c . to 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of deg and dmi was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to the pcb detection limit of 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 12 mg / l of pcb was mixed in a flask with 25 g of a mixed solvent consisting of 1 . 25 g of polyethylene glycol ( hereinafter &# 34 ; peg &# 34 ;) having a mean molecular weight of 200 and 23 . 75 g of dmi , and 0 . 1 g of caustic soda , and the mixture was then stirred briskly while being maintained at a temperature of from 180 ° c . to 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of peg and dmi was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to the pcb detection limit of 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 12 mg / l of pcb was mixed in a flask with 25 . 5 g of a mixed solvent consisting of 0 . 5 g of 18 - crown - 6 and 25 g of dmi , and 0 . 1 g of caustic potash ( koh in table 1 ), and the mixture was then stirred briskly while being maintained at a temperature of from 170 ° c . to 180 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of 18 - crown - 5 and dmi was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to the pcb detection limit of 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 12 mg / l of pcb was mixed in a flask with 25 g of dmi and 0 . 05 g of caustic soda , and the mixture was then stirred briskly while being maintained at a temperature of from 200 ° c . to 210 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of dmi was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to the pcb detection limit of 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 12 mg / l of pcb was mixed in a flask with 25 g of sulfolane and 0 . 05 g of caustic soda , and the mixture was then stirred briskly while being maintained at a temperature of from 195 ° c . to 205 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of sulfolane was removed and the pcb in the oil layer was analyzed , whereby it was confirmed that the pcb content had decreased to the pcb detection limit of 0 . 5 mg / l or less . as listed in table 1 , a sample consisting of 200 g of reclaimed transformer oil containing 50 mg / l of pcb was mixed in a flask with 50 g of dmi , and the mixture was then stirred briskly while being maintained at a temperature of 80 ° c . for about 1 hour . after cooling the mixture to room temperature , the lower layer of dmi was removed . on analyzing the pcb in the oil layer , the pcb content was found to be 40 mg / l . as listed in table 1 , a sample consisting of 100 g of reclaimed transformer oil containing 50 mg / l of pcb was mixed in a flask with 50 g of dmi and 0 . 5 g of caustic soda , and the mixture was then stirred briskly while being maintained at a temperature of 80 ° c . for about 1 hour . after cooling the mixture to room temperature , the lower layer of dmi was removed . on analyzing the pcb in the oil layer , the pcb content was found to be 48 mg / l . as listed in table 1 , a sample consisting of 100 g of reclaimed transformer oil containing 100 mg / l of pcb was mixed in a flask with 72 . 5 g of dmi and 0 . 45 g of sodium ethoxide , and the mixture was then stirred briskly while being maintained at a temperature of 80 ° c . for about 1 hour . after cooling the mixture to room temperature , the lower layer of dmi was removed . on analyzing the pcb in the oil layer , the pcb content was found to be 31 mg / l . as listed in table 1 , a sample consisting of 100 g of reclaimed transformer oil containing 100 mg / l of pcb was mixed in a flask was subjected to 0 . 5 hours of ultrasonic agitation at room temperature . analysis showed that the pcb content was 59 mg / l . as listed in table 1 , a sample consisting of 50 g of reclaimed transformer oil containing 40 mg / l of pcb was mixed in a flask with 25 g of dmi and 0 . 5 g of β - cyclodextrin , and the mixture was then stirred briskly while being maintained at a temperature of 200 ° c . for about 2 hours . after cooling the mixture to room temperature , the lower layer of dmi was removed . on analyzing the pcb in the oil layer , the pcb content was found to be 12 mg / l . thus , in each of the inventive examples pcb was removed with good efficiency . however , even using the same conditions the addition of β - cyclodextrin tended somewhat to hinder pcb removal . in both inventive and comparative examples , in accordance with the procedure of jis k0093 analysis of the pcb was done by gas chromatography . table 1 - 1__________________________________________________________________________ sample reclaimed sample extraction alkali processing processing remaining transformer pcb agent ( catalyst ) temperature time pcb contentconditions oil ( g ) ( mg / l ) ( g ) ( g ) (° c .) ( hr ) ( mg / l ) __________________________________________________________________________inventiveexamples1 50 40 dmi 25 naoet 0 . 5 160 2 1 . 22 50 40 sulfolane 25 β - cyclo - 0 . 5 200 2 2 . 9 dextrin naoet 0 . 53 50 15 sulfolane 25 naoh 1 . 5 200 2 0 . 61 beads4 50 15 sulfolane 25 naoh 1 . 5 160 2 . 5 1 . 9 beads5 100 40 sulfolane 50 naoet 2 200 2 0 . 5 or less__________________________________________________________________________ table 1 - 2__________________________________________________________________________ sample reclaimed sample extraction alkali processing processing remaining transformer pcb agent ( catalyst ) temperature time pcb contentconditions oil ( g ) ( mg / l ) ( g ) ( g ) (° c .) ( hr ) ( mg / l ) __________________________________________________________________________inventiveexamples6 100 40 sulfolane 50 naoh 3 160 2 0 . 5 or less beads7 50 40 sulfolane 5 naoet 1 . 5 200 2 0 . 5 or less8 50 12 deg 12 . 5 naoh 0 . 1 180 - 200 2 0 . 5 or less dmi 12 . 59 50 12 peg ( 200 ) naoh 0 . 1 180 - 200 2 0 . 5 or less 1 . 25 dmi 23 . 7510 50 12 18 - crown - 6 koh 0 . 1 170 - 180 2 0 . 5 or less 0 . 5 dmi 25__________________________________________________________________________ table i - 3__________________________________________________________________________ sample reclaimed sample extraction alkali processing processing remaining transformer pcb agent ( catalyst ) temperature time pcb contentconditions oil ( g ) ( mg / l ) ( g ) ( g ) (° c .) ( hr ) ( mg / l ) __________________________________________________________________________inventiveexamples11 50 12 dmi 25 naoh 0 . 05 200 - 210 2 0 . 5 or less12 50 12 sulfolane 25 naoh 0 . 05 195 - 205 2 0 . 5 or lesscomparativeexamples1 200 50 dmi 50 none 80 1 402 100 50 dmi 25 naoh 0 . 5 80 1 483 50 100 dmi 72 . 5 naoet 0 . 45 80 1 314 100 100 none none ; ultrasonic waves at 0 . 5 59 room temperature5 50 40 dmi 25 β - cyclo - 0 . 5 200 2 12 dextrin__________________________________________________________________________ as described in the foregoing , in accordance with the present invention , pcb and other such halogenated aromatic compounds which , even in small quantities , pose environmental problems and are directly hazardous to the human body , can be removed from hydrocarbon oil having non - aromatic hydrocarbon oil as the main constituent , to the extent that the pcb or other such compound is rendered substantially harmless .

a safe and reliable method of removing halogenated aromatic compounds present in small amounts in hydrocarbon oil constituted mainly by non - aromatic hydrocarbon oil . the hydrocarbon oil is contacted with a heat - resistant alkaline polar solvent in the presence of an alkaline at a temperature ranging from about 100 ° c . to 300 ° c ., and the non - aromatic hydrocarbon oil and heat - resistant alkaline polar solvent are then separated , thereby removing the halogenated aromatic compounds from the hydrocarbon oil .

referring now to fig1 , a side elevation of the invention big game dressing tool 10 is illustrated according to the first preferred embodiment . tool 10 is formed substantially symmetrically about axis 14 . tool 10 has a tip 12 that is substantially cylindrical in shape with a hemispherical portion at a first end thereof that is distal from a handle 22 . a series of substantially triangular barbs 16 are formed in angularly dispersed positions around tip 12 to extend radially outwardly from the rear portion of tip 12 . in the illustrated embodiment , tool 10 is formed with four barbs 16 ( see fig3 ), although different numbers of barbs 16 are contemplated within the scope of the invention . tip 12 has a diameter d , and barbs 16 extend on opposite sides of axis 14 to a width w that is greater than diameter d . diameter d is preferably sized for being inserted into the anus of a slain animal , for example a deer . in the preferred embodiments described herein , width w is at least twice as great as diameter d . referring further to fig1 , a shank 18 is substantially a coaxial extension of tip 12 along axis 14 . shank 18 terminates in handle 22 that is formed transverse to axis 14 . in the first preferred embodiment , tip 12 and shank 18 share a hollow , cylindrical bore 24 so as to reduce the weight of tool 10 without significant sacrifice of rigidity . handle 22 may be hollow or solid , depending on the material used . shank 18 is formed sufficiently long to allow insertion of tip 12 and barbs 16 into the anus of the slain animal by at least 3 - 4 inches while the handle is being held by the user outside the body of the animal . it is preferred that tool 10 is manufactured by the process of plastics injection molding , with the choice of plastics resin to be determined by the manufacturer . referring now to fig2 , tool 10 a is formed with a tip portion 12 and barbs 16 similar to that described above in reference to fig1 . shank 26 is connected coaxially to tip 12 at the proximal end thereof . shank 26 is formed as an orthogonal cross of ribs 28 a - 28 d , as seen more clearly in fig4 described below . shank 26 connects at its proximal end to handle 30 , formed in cross section ( not shown ) in the form of the letter “ h .” in a further embodiment of tool 10 , the handle is a linear extension of shank 26 , and may have a transverse hole for gripping or carrying . referring now to fig3 , a cross section of tool 10 is shown in the direction indicated by line 3 - 3 of fig1 . the relation between the diameter d of hollow shank 18 and the width w across the tips of barbs 16 is clearly shown . bore 24 extends through shank 18 and tip 12 ( see fig1 ). in the preferred embodiment , barbs 16 extend radially outward from shank 18 . fig4 illustrates the cross section of tool 10 a as indicated by line 4 - 4 of fig2 with shank 26 having a plurality of ribs 28 a - 28 d formed in orthogonal assembly . as described above with respect to barbs 16 , different numbers of ribs 28 may be employed , preferably not less than 3 for reasons of rigidity . referring now to fig5 , the method of use of big game field dressing tool 10 is illustrated in sequential steps . a side elevation view of the rear portion of a slain large animal , such as a deer , is illustrated in each figure with selected internal organs depicted in dashed lines . the animal &# 39 ; s rectum 40 , being the last section of intestine , connects to the anus 42 at the animal &# 39 ; s rump . the internal end of rectum 40 continues as intestines that ultimately terminate at the stomach ( not shown ). tool 10 is positioned in fig5 in alignment with anus 42 with its tip 12 adjacent to anus 42 . tool 10 is to be pushed in the direction indicated by arrow a until tip 12 and barbs 16 have passed anus 42 and entered rectum 40 to be in the position shown in fig6 . a bladder 46 and a urethra ( 44 a in the case of a buck or 44 b in the case of a doe ) are shown as an additional source of waste contamination , although they are not direct objects of the present invention . as illustrated in fig6 , rectum 40 is stretched radially to accommodate and engage barbs 16 therein . tool 10 is next rotated as indicated by arrow b through an angle of approximately 180 °. since barbs 16 are formed along a series of perpendicular planes that pass through axis 14 of tool 10 ( see fig1 ), rotation of tool 10 can be either clockwise or counterclockwise . in an alternate version of the invention , barbs 16 may be formed along a series of planes that are tangent to the periphery of tip 12 , in which case tool 10 must be rotated in a direction to cause barbs 16 to hook into rectum 40 . with the extended sharp points of barbs 16 stretched over the membrane comprising rectum 40 , rotation of tool 10 causes barbs 16 to dig into and ensnare the wall of rectum 40 . referring now to fig7 , tool 10 is withdrawn in the direction indicated by arrow c from the animal &# 39 ; s anus 42 , drawing a section of rectum 40 ′ outside anus 42 . in order to enable tying or clamping of rectum 40 ′, tool 10 is pulled out of anus 42 by a distance of 10 - 12 inches . tool 10 is removed from the rectum by cutting the intestinal wall either before or after clamping is done , as described below . referring now to fig8 , the extended section of rectum 40 ′ is then tied into a knot 48 . in an alternate method a clamp ( not shown ), for example a cord , is applied and pulled tight enough to prevent solid waste from escaping from rectum 40 ′ during the balance of the process of eviscerating the slain animal . twisting rectum 40 ′ outside the body cavity of the animal prior to clamping serves to further prevent waste leakage . with the intestines tied or clamped to prevent waste leakage , the process of dressing the slain animal proceeds . the extended section of rectum is repositioned in the body cavity either by pushing the extended section through the anus or pulling the extended section from within after the lower abdominal skin has been opened . the intestines and the balance of the digestive tract are then removed through the abdominal opening , together with the bladder and urethra . while the description above discloses preferred embodiments of the present invention , it is contemplated that numerous variations and modifications of the invention are possible and are considered to be within the scope of the claims that follow .

a tool and method of using are disclosed for field dressing big game . the tool has a tip sized for insertion into the anus of the animal and a set of barbs extending a radial distance beyond the tip . the tip and the barbs are mounted to a shank and handle . inserting the tip and barbs into the rectum causes radial stretching of the rectal wall , and rotation of the tool causes ensnarement of the rectum on the barbs . the tool is retracted from the anus , pulling a section of rectum external , to be closed for the prevention of leakage of bodily waste matter .