Datasets:

farleyknight

/

big_patent_10_percent

like 0

the pesticide or malodorant counteracting composition of this invention includes a catalytic ionic salt and a buffering salt . it may further contain a third component , e . g ., a mixture of a reducing coenzyme and an oxidizing agent , an ionic compound , or a sulfide . the weight ratio of the abovementioned three constituents is 1 : 40 - 4 , 000 : 2 - 200 , and preferably 1 : 1 , 200 - 1 , 500 : 10 - 50 . examples of the catalytic ionic salts include , but are not limited to , nickel chloride , ammonium nickel sulfate , copper chloride , copper sulfate , cuprous chloride , cuprous sulfate , ferric chloride , ferric sulfate , ferrous chloride , ferrous sulfate , manganese chloride , and manganese sulfate . examples of the buffering salts include , but are not limited to , calcium carbonate , lithium carbonate , magnesium carbonate , potassium carbonate , sodium bicarbonate , potassium bicarbonate , magnesium chloride , sodium chloride , potassium phosphate , potassium hydrogen phosphate , potassium dihydrogen phosphate , calcium sulfate , lithium sulfate , and magnesium sulfate . the reducing coenzyme can be reduced flavin mononucleotide , reduced flavin adenine dinucleotide , reduced nicotinamide adenine dinucleotide , or reduced nicotinamide adenine dinucleotide phosphate ; and the oxidizing agent can be hydrogen peroxide or a quinone - based compound . the ionic compound can be that contains a cation of li , na , or k and an anion of chloride , bromide , iodide , sulfite , acetate , succinate , pyrophosphate , perchlorate , gluconate , ascorbate , ethylenediamine tetraacetate , fumarate , or lactate . the sulfide can be rsh , in which r is aryl , alkyl , or aralkyl . alternatively , it can be is cysteine , reduced glutathione , dithiothreitol , or homocysteine . to prepare a composition of this invention , one can mix the desired components at a predetermined ratio . the components can be added in any order . the catalytic ionic salt and buffering salt in the composition react with oxygen molecule in the air and activate it to become oxygen free radial anion . the free radical anion then oxidizes a pesticide or malodorant , thereby converting it to a less toxic or stenchful compound . a mixture of a reducing coenzyme and an oxidizing agent , an ionic compound , or a sulfide can also be included in the composition to re - activate the reacted salts so that the salts are recycled . examples of chemicals that can be decomposed by the above - described compositions include , but are not limited to , health hazardous pesticides and malodorants , including smoke constituents , shown below : a composition of this invention can be used to counteract pesticides adhered to crops or fruits . it can also be used to eliminate underarm odor , perspiration odor , sole odor , bad breath , hair odor , or menstrual odor . further , it can be used to clean contaminated clothes , respirators , masks , gloves , protective equipments , and medical devices . the active time of the composition ranges from 1 - 100 hours , depending on the concentration and dosage . the composition can be applied by various methods to a human being or to an object contaminated with a pesticide or malodorant . for example , an aerosol spray can be used to spray the composition onto the target area . as another example , a washing solution containing the composition can be used to immerse a contaminated object . when an aerosol solution is used , it is preferred to have a concentration of 10 − 4 ˜ 10 − 6 wt %. when a washing solution is used , it is preferred to have a concentration of 10 − 1 ˜ 10 − 4 wt %. the six examples below are to be construed as merely illustrative , and not limitative of the remainder of the disclosure in any way whatsoever . without further elaboration , it is believed that one skilled in the art can , based on the description herein , utilize the present invention to its fullest extent . 0 . 50 g of ammonium nickel sulfate was added to 500 ml of reverse osmosis ( r . o .) water . the solution was stirred for 15 min at ambient temperature to afford clear solution ( a ). 15 g of sodium hydrogen phosphate and 15 g of sodium dihydrogen phosphate were added to 9 . 0 l of r . o . water . the mixture was thoroughly stirred . 120 g of sodium chloride , 40 g of potassium hydrogen carbonate , 5 . 0 g of calcium sulfate , and 5 . 0 g of magnesium chloride were sequentially added . the resulting mixture was stirred for 60 min at ambient temperature to give clear solution ( b ). 10 ml of 3 . 0 % hydrogen peroxide was diluted with 500 ml of r . o . water . to this was added 5 . 0 g of 1 , 4 - benzoquinone . the solution was stirred for 30 min at ambient temperature . 2 . 0 g of coenzyme nadph was added . the resulting solution was stirred for 20 min . combined solutions ( a ) and ( c ) were stirred for 15 min at ambient temperature . to this was added solution ( b ). the mixture was thoroughly stirred to provide the desired composition . 0 . 50 g of ammonium nickel sulfate was added to 500 ml of r . o . water . the solution was stirred for 15 min at ambient temperature to afford clear solution ( a ). 15 g of sodium hydrogen phosphate and 15 g of sodium dihydrogen phosphate were added to 9 . 0 l of r . o . water . the mixture was thoroughly stirred . 120 g of sodium chloride , 40 g of potassium hydrogen carbonate , 5 . 0 g of calcium sulfate , and 5 . 0 g of magnesium chloride were sequentially added . the resulting mixture was stirred for 60 min at ambient temperature to give clear solution ( b ). 50 g of sodium lactate was added into 500 ml of r . o . water . the mixture was stirred for 30 min at ambient temperature to provide clear solution ( c ). solution ( a ) was added to solution ( c ), and the mixture was stirred for 15 min at ambient temperature . solution ( b ) was then added . the resulting mixture was stirred for 20 min to obtain a composition of this invention . 0 . 50 g of ammonium nickel sulfate was added to 500 ml of r . o . water . the solution was stirred for 15 min at ambient temperature to afford clear solution ( a ). 15 g of sodium hydrogen phosphate and 15 g of sodium dihydrogen phosphate were added to 9 . 0 l of r . o . water . the mixture was thoroughly stirred . 120 g of sodium chloride , 40 g of potassium hydrogen carbonate , and 5 . 0 g of calcium sulfate were sequentially added . the resulting mixture was stirred for 60 min at ambient temperature to give clear solution ( b ). 50 g of cysteine was added into 500 ml of r . o . water . the mixture was stirred for 30 min at ambient temperature to provide clear solution ( c ). solution ( a ) was added to solution ( c ), and the mixture was stirred for 15 min at ambient temperature . solution ( b ) was then added . the resulting mixture was stirred for 20 min to obtain a composition of this invention . the above - prepared composition was tested to decompose 17 pesticides , i . e ., diazinon , terbufos , acephate , glyphosate , phosmet , mevinphos , benomyl , metalaxyl , pyrnetrozine , methomyl , fenobucard , carbendazim , pencycuron , hexaconazole , thiophanate - methyl , cartap , and thiabendazole . the decomposition rates were measured as follows : each pesticide was dissolved in tap water at a concentration of 10 ppm . 10 ml pesticide solution was mixed with 10 ml of the composition prepared in example 1 for 5 min . 10 ml pesticide solution was also mixed with 10 ml tap water or 10 ml 10 % brine solution to prepare control solution . the pesticide concentration of each tested reaction solution was measured by high performance liquid chromatography . it showed that in the presence of the composition prepared in example 1 , the pesticide decomposition rate was 2 , 300 ˜ 14 , 000 times higher than that when tap water was used . also , when the composition of this invention was used , the pesticide decomposition rate was 1 , 900 ˜ 11 , 000 times higher than that when 10 % brine solution was used . among these seventeen pesticides , terbufos , acephate , and hexaconazole were decomposed at higher rates than the others . 7 . 5 ml of a pesticide solution , containing 10 ppm terbufos , diazinon , hexaconazole , or fenobucard , was allowed to react with 2 . 5 ml of the composition prepared in example 1 for 1 . 0 min , 3 . 0 min , and 5 . 0 min , respectively . hplc was used to determine the concentrations of the pesticide . all of terbufos , diazinon , hexaconazole , and fenobucard decomposed within 1 . 0 min , 3 . 0 min , and 5 . 0 min , respectively . after 5 . 0 min of the reaction time , 91 % terbufos decomposed , 87 % diazinon decomposed , 85 % hexaconazole decomposed , and 76 % fenobucard decomposed . seven smoke constituents , i . e ., nicotine , acrylamide , imidazole , quinoline , indene , naphthalene , and phenanthrene , were tested for their decomposition in the presence of the composition prepared in example 1 . 9 . 9 ml of 100 ppm aqueous solution of a smoke constituent was allowed to react for 3 . 0 min with 0 . 10 ml of the 20 × and 100 × compositions , respectively . gas chromatography was used to determine the concentrations of the remaining smoke constituents . it showed that more than 90 % of smoke constituents decomposed after treated with either of the 20 × and 100 × compositions . all of the features disclosed in this specification may be combined in any combination . each feature disclosed in this specification may be replaced by an alternative feature serving the same , equivalent , or similar purpose . thus , unless expressly stated otherwise , each feature disclosed is only an example of a generic series of equivalent or similar features . from the above description , one skilled in the art can easily ascertain the essential characteristics of the present invention , and without departing from the spirit and scope thereof , can make various changes and modifications of the invention to adapt it to various usages and conditions . thus , other embodiments are also within the scope of the following claims

this invention relates to compositions that counteract chemicals such as pesticides and malodorants . also disclosed are a method for preparing such compositions and a method for applying such compositions to counteract pesticides or malordorants .

the invention relates to a compact platform with no moving parts that possesses resilient qualities such that gentle resistance is encountered by a user applying his or her feet to the platform . generally , the preferred embodiment is a wedge - like shaped platform of resilient material such as polyurethane foam . more specifically , the preferred device possesses resiliency ( i . e . compression / restitution ) characteristics that enable a user to perform mild resistance training while in a seated or prostrate position , which tends to promote circulation and other health benefits . preferably , the resilient means allows compressibility to approximately 30 %- 60 % of the height of the device while returning to the uncompressed state quickly . this provides an optimal energy return or bounce to the feet of the user during exercising , which provides a soothing , toning lower body workout . as illustrated in fig1 a first embodiment of the inventive exerciser is a three - dimensional rectangular platform 2 . the platform 2 possesses two sets of vertical , parallel sidewalls 4 and 6 connected to a top face 8 and a bottom face 9 . preferably , the resilient means of the platform 2 is provided by polyurethane foam having a density of 3 . 0 lbs / cubic ft , also known as “ code 3031 ” foam ( the density is calculated as the mass of a substance divided by the volume , with foam density being expressed in either lbs / cubic ft or kg / cubic meter ). the first two digits of the code number 3031 define the density of the foam . thus , the number 30 refers to 3 . 0 lbs / cuft . the last 2 digits of the code number ( i . e . 31 ) represent the indentation load deflection ( ild ) number as defined by the foam industry . simply stated , the ild is a resilience factor and is calculated by the load that is needed to compress or deflect a foam sample with an area of 50 square inches by 25 %. accordingly , the higher the ild number , the less compressible is the foam . fig2 shows a preferred exerciser , platform 10 . the platform 10 includes a top surface 12 and a bottom surface 14 connected by a first pair of parallel sidewalls , 16 a and 16 b , and a second pair of parallel sides walls 18 . while sidewalls 18 are identical in shape and size , sidewall 16 a is shorter than sidewall 16 b , causing platform 10 to assume a wedge - like shape . the slope of top surface 12 is ideally about 15 - 17 °. however , the slope may be varied during construction or be increased or decreased through the placement of shims or similar devices ( not shown ) underneath the exerciser to adjust the resistance encountered by a user . the resiliency of the foam , or equivalent material , enables the feet to be pushed into the device and be supported by the restitution or rebound pressure . one can therefore move the feet up and down and maintain contact with the surface . moreover , the slope or inclination of the platform enables the difficulty and range of movements to be varied , thus allowing for a greater or lesser amount of work or exercise to be accomplished in a limited space . accordingly , the invention promotes significant lower body exercise even in the confinements of a seated position . the shape of the exerciser may be varied in accordance with the user &# 39 ; s taste and decorative requirements . turning to fig3 a , a rounded platform 20 is shown . platform 20 includes a sloping top surface 22 , a circumferential sidewall 24 , and a bottom surface 26 . similarly , fig3 b shows a rounded heart - shaped platform 28 . the foam embodiments of the invention preferably are compressible by approximately 30 %- 60 % as measured from the original height of the device . through testing and feedback , the inventor has found that this range gives an ideal amount of resistance for most users . for example , if the rear elevation is 7 . 75 inches high , the height may be reduced or compressed by 4 . 41inches ( 57 %) to 3 . 33 inches . the compressibility of the device can be varied by changing the dimensions or density of the device to accommodate user specifications of age ( children and adults ), weight , gender , height and foot size so as to keep them within the preferred compressibility range described above . the material of the invention may be extruded or molded to produce the device shape and bounce characteristics described herein . of course , the invention may be constructed with resilient materials other than polyurethane foam . such resilient means for providing resistance may include gels , particles or particulates , springs or other equivalent material to provide the necessary compression and restitution . for example , fig4 illustrates a platform 30 having a sloped top surface 32 , a bottom surface 34 , and parallel sidewalls 36 and 38 . in this case , the resilient means for providing resistance to a force exerted by a user are springs 40 ( as seen through cut - away section 42 ). alternatively , as shown in fig5 platform 50 may contain an inflated bladder 52 as the resilient means for resisting force applied by a user . such bladders may be inflated with air , other gases , liquids , fibers , or any other medium that provides resiliency . a variety of optional features may be added to the invention . for example , the inventive exerciser may have a textured surface ( including shapes such as footprints ) as pictured in fig6 . in this embodiment , platform 44 simply has a top surface 48 with ridges 46 . the ridges 46 provide a means for massaging the feet of a user , and may be arrayed in practically any fashion . obviously , bumps , studs , and other projections may be used to provide a desired texture to the platforms surfaces . also optionally , as shown in fig7 the exerciser 54 may be encased by a fabric lining 56 ( or by removable cover ) constructed from fabric upholstery or other materials such as fleece - like materials , swede or leather . preferably , the cover is constructed of a machine - washable material so as to facilitate cleaning . obviously , the exerciser and its liner or cover can be made in a variety of sizes and colors . a thermal layer may also be added either to the surface of the exerciser or to its cover to provide for soothing heat . the fact that the preferred material for this device is disclosed to be polyurethane foam is based on in - house testing showing it possessed the most satisfactory restitution characteristics . in other words , a novel range of restitution ( defined in the following test data ) was found to be most satisfying to users based on the amount of resistance and rebound energy provided . in order to quantify the restitution characteristics of the invention , energy impact criterion were measured as follows . the exercise platform was constructed from four different foam densities provided by the two local suppliers , foam and fabric ( ff ) and whitmark ( w ). six individual samples were used in the test . an olympus d460 zoom digital camera , a camera tripod , a 20 inches × 30 inches square cardboard grid , a standard lacrosse ball 2 . 5 inches in diameter , and a cylindrical cardboard chute attached vertically to camera standard were used to provide a drop zone and photographic recordation of the test results . the cylindrical cardboard chute was attached to the camera stand by tape and wires . the uppermost edge of the chute measured 65 inches to the floor . the drop height was measured by holding the ball at about its center point inside the chute ( 1 inch approximately from the upper edge of chute ) and allowing it to drop freely through the chute onto the center of the inclined face of the device on the floor surface ( 6 inches high from the ground ), over a distance of 58 inches ( 65 −{ 6 + 1 }) the ball was dropped several times in order to record a full bounce cycle and at each bounce the ball position was photographed with the cardboard grid in the background . the x and y coordinates of each position of the captured ball images were read off from the grid on the digital photograph and recorded . this procedure was repeated for each of the 6 samples . an algorithm defining the mechanical properties of the bounce of the ball off of the exercise device was developed by a consultant engineer for computer analysis of the data . thus , the bounce of the ball was quantified , with the energy impact defining the relative energy absorption and the rebound of the ball defined as the “ relative energy return ” after numerous test runs and evaluation of the equipment and algorithm , an experiment was performed from which the results are shown in table 1 . the device constructed from foam 3031 ( ff ) and 3031 ( w ) had the highest relative energy return fractions ( 0 . 587633 and 0 . 584656 ) and least relative energy absorption fractions ( 0 . 412367 and 0 . 415344 ), producing what was objectively determined by users to provide the best combination of resistance and restitution energy to the feet and legs . also preferred was foam 1826 , with a relative energy return fraction of 0 . 581310 and relative energy absorption fraction of 0 . 418690 . foam samples 2511 and 1833 had higher than 0 . 42 energy absorption fractions and were not as preferred in this instance . the results of this test indicate that the preferred restitution ( relative energy return ) ranges between 0 . 53 to 0 . 59 because these values correspond to the level of resistance / restitution preferred by test users . while one will find that many methods of use will result in exercise benefits , the preferred method will now be described . turning to fig8 a , the exerciser is placed in position near the legs so that the feet of the user can be placed comfortably on the top surface as shown . both feet are placed parallel , comfortably apart , resting on this upper , inclined surface . there are a variety of movements which can promote exercise of the lower body parts : 1 . each foot can be gently pressed in an alternating fashion in a “ toe - ball - heel ” movement into the spongy surface , compressing the device with a treading - like rhythm the knees are maintained at approximately right angles to the thighs and the back is maintained supported and upright for maximum thrust into the device . these movements are produced by contraction and relaxation of muscles in the lower hips , thighs , lower abdomen , calves including other leg muscles , which produce toning of the muscles . contraction and relaxation of the calf muscles and other leg muscles activate the skeletal pump mechanism enhancing circulation in the lower limbs . these and the other movements described below can be maintained for a number of repetitions or length of time , for example , 1 - 3 minutes , according to the needs and capability of the user . 2 . sitting upright with back supported , knees at approximately right angles to the thighs , both feet are gently pressed simultaneously down and up in a pumping - like motion . a fast or slow rhythm can be maintained , according to the needs of the user . this movement enables strong contraction and relaxation of the thighs and buttocks , promoting toning and circulation . 3 . sitting upright with back supported , knees bent , alternate feet are pressed into the surface , pointing the toes forward and down and extending the foot , followed by pressing of the heel into the surface and flexing the foot with the toes pointing upwards . rhythmic movement can be produced by alternating the feet which result in a pedaling - like motion . alternatively , both feet can be moved simultaneously , producing a back and forth rocking movement . these movements massage the feet and promote contraction and relaxation of the leg muscles , energizing the legs and ankles and stimulating circulation . 4 . sitting upright with back supported , knees bent the feet are pressed into the device alternately . these movements contract and relax the thigh , calf , gluteal , and lower hip muscles , promoting toning and circulation of the lower limbs . 5 . sitting upright with back supported , both feet on the surface , the toes are gently moved to grip the fabric with gentle manipulation of the bouncy surface . repetitions of these movements promote strengthening of the muscles and ligaments of the ankles and arches . 6 . the exerciser may be turned around ( 180 °) so that the feet are placed pointing downwards on the declining slope . exercises as preferred may be repeated in this position so as to work the muscles in an opposite fashion thus reducing muscle stress and producing relaxation . as would be understood by those skilled in the art , any number of functional equivalents may exist in lieu of the preferred embodiments described above . thus , as will be apparent to those skilled in the art , changes in the details and materials that have been described may be within the principles and scope of the invention illustrated herein and defined in the appended claims . accordingly , while the present invention has been shown and described in what is believed to be the most practical and preferred embodiments , it is recognized that departures can be made therefrom within the scope of the invention , which is therefore not to be limited to the details disclosed herein but is to be accorded the full scope of the claims so as to embrace any and all equivalent products and methods . for example , there is a range of sizes designed for office and home use and for air travel . there are soft and firm consistencies . an extra small size is designed for convenient carrying and use on an airplane and may include an attached vinyl slipcover for optional use with shoes . most sizes can be conveniently stuffed in a specifically designed stuff sack for travel . the exerciser can also be used to work the upper limbs and chest areas by compressing the foam with the hands in a pumping or press - up motion when the device is on a table or on the floor . further upper body exercises can be performed with the device placed on the knees while sitting and pushing the sides of the device simultaneously in and out with the hands . modifications of the rectangular prism on a trapezoidal base shape to a small rectangular prism shape can produce a device specifically for exercising the upper and lower arm , upper chest and back areas while sitting . this is particularly useful when traveling long distance in an airplane . the confined space is unsuitable for working out by means of conventional flex stretching devices . by holding the opposite sides of the rectangular prism shape with both hands placed in front of the body , and pushing in and out simultaneously with both hands to compress and decompress the foam laterally , resistance exercise of the upper limbs , chest and back can be achieved , improving muscle tone and circulation while sitting in a confined space .

abstract a lower - body exercising device and method including a three - dimensional platform with a resilient means for providing a resistance - based workout while sitting at work , home or traveling is disclosed . preferably , the invention is manufactured from a single piece of material , is designed to be wedge - like in shape , is compact in size so as to fit under a desk or table or airplane seat , and is constructed from polyurethane foam that provides resistance to a pushing force by the user during manipulation . the invention can be manipulated by pressing the soles of the feet alternately into the device , or together in a “ pumping ” motion . optionally , the device is covered it in a plush , washable upholstery material , has textured s , and / or includes heating elements .

[ 0030 ] fig1 shows an electronic frying pan 10 constructed according to the invention with ( a ) a thermally conductive pan 12 and ( b ) a handle 14 . one or more temperature sensors 11 coupled with pan 12 connect to an electronics module 16 in handle 14 . electronics module 16 preferably includes display 18 to show a user of pan 10 characteristics associated with pan 12 or food ( in the form of an egg ) 20 within pan 12 . electronics module 16 includes a processor such as a microprocessor and preferably includes memory to store food doneness options and user selections . a user interface 22 provides for user input to select various characteristics and functions of electronics module 16 . display 18 may show digital temperature 18 a , a bar graph representation 18 b of temperature or doneness , or other information . as described below , electronics module 16 preferably detaches from pan 10 so that pan 10 is washable without module 16 attached thereto . teflon wires preferably seal the remaining portions of handle 14 to prevent liquids from entering electronics remaining after removal of module 16 . temperature sensors 11 include , for example , a thermistor or thermocouple . thermocouple 11 couples to electronics module 16 via electronic or thermal conductive path 24 ; path 24 is chosen as a matter of design choice as a medium to transfer data or signals from sensor 11 to module 16 . preferably , stainless steel is used to provide contact between module 16 , path 24 and sensors 11 . fig1 shows one temperature thermocouple 11 coupled with conductive pan 12 , though additional sensors 11 may be placed about pan 12 as a matter of design choice . for example , one or more additional temperature sensors may be placed at different locations 11 a ; sensors at locations 1 a also connect to module 16 and may provide more representative temperature data for food 20 . any temperature sensor 11 may be calibrated to correspond to a temperature profile experienced by food 20 , even though sensor 11 is not directly adjacent food 20 . typical pan calibrations are for pans that are eight , ten or twelve inches in diameter . in operation , a user of pan 10 selects pre - programmed temperature settings or programs personal settings to cook food 20 in a desired manner . for example , such a user may select 300 degrees f . for eggs , 340 degrees f . for bacon , 360 degrees f . for burgers and pork chops , 380 degrees f . for pancakes , and 400 - 420 degrees f . for steak . other options are of course available without departing from the scope of the invention . in the preferred embodiment , display 18 displays the temperature of pan 12 in centigrade or fahrenheit . various cooking levels are preferably selectable at handle 14 . when a cooking level is selected , a microprocessor in module 16 provides a signal converted to display 18 that informs the user that the temperature is at his desired chosen cooking level . [ 0033 ] fig2 shows a partial cross - sectional view of pan 10 of fig1 . those skilled in the art should appreciate that the mechanical design of pan 10 is a matter of design choice and that other configurations may be functionally arranged without departing from the scope of the invention . [ 0034 ] fig3 schematically illustrates circuitry 50 suitable for use with frying pan 10 of fig1 . an lcd display 52 may for example be used as display 18 ; an lcd controller 53 generally controls display 52 as known in the art . dotted line 54 indicates one practical partitioning of components of circuitry 50 that may be conveniently contained within one package . a thermocouple or thermistor 56 may serve in function as one of the sensors 11 to generate signals concerning characteristics of the pan and / or food within pan 12 . a voltage amplifier 57 may be used to boost sensor signals , as desired or needed . an a - d converter 59 is generally used when sensor 56 drives an analog signal . in one embodiment , the handle electronics module can include voice synthesis electronics 58 used to capture human voice commands for pan or food characteristics made by a user of pan 10 . normally , however , users input instructions to circuitry 50 via input buttons 60 ( e . g ., for user interface buttons 22 , fig1 ) so as to select desired food or doneness characteristics . a microcontroller 64 provides for overall function and command intelligence of circuitry 50 ; for example microcontroller 64 adjusts cooking time based on surface temperature of pan 12 , fig1 . a crystal 66 provides for timing in circuitry 50 . [ 0035 ] fig4 a , 4 b show one handle 70 constructed according to the invention and suitable for use an electronic frying pan 71 ( shown only partially , for purposes of illustratinon ) such as pan 10 , fig1 . a display 72 shows food or pan characteristics . preferably the handle electronics are in the form of a removable control module 74 , as shown ; a module alignment nub 75 , ball shap 77 , and lip 79 may be used to facilitate removing from , and alternatively replacing module 74 within , handle 70 . a battery 76 , e . g ., a 2450 lithium battery , fits within handle 74 ; battery 76 may be removed from module 74 via access door 81 . user interface buttons 78 a , 78 b provide for “ advance ” and “ set ” menu options , respectively . a hang hole 80 permits hanging of handle 70 on a hook . a warning buzzer 82 provides an audible warning of programmed food doneness sensed by temperature sensors coupled with module 74 via communications lines 84 . the invention thus provides several advantages . by way of example , eggs are one food difficult to cook with certainty as to whether they are well done , over easy or medium . the invention provides for recalling temperature for desired egg doneness ; and a user need not rely on stove temperature settings . the microcontroller of the preferred embodiment automatically signals the user ( e . g ., via buzzer 82 , fig4 ) when the desired egg doneness is reached . since the display can include an analog representation of doneness , e . g ., via a bar graph or tachagraphic display , then the user may also watch food approach the desired doneness , so as not to be surprised . user selections at the user interface ( e . g ., by pressing button 22 , fig1 ) provide for selecting doneness options ( e . g ., over easy ) and food types ( e . g ., eggs ); or a user can select custom temperatures . in a further advantage , the replaceable module ( e . g ., module 16 , fig1 ) may be used in an array of pans of different size — but with a common electronics module . when the module is coupled with a certain pan size , the user preferably sets pan size through the same user interface so as to adjust any calibrations to temperature sensors with the particular pan . [ 0037 ] fig5 shows a remote food doneness system 100 constructed according to the invention . system 100 is constructed and arranged to attach to surfaces 102 near to cooking food 104 , such as food on stove 106 and within frying pan 108 . by way of example , system 100 attaches to surface 102 via magnets 110 coupled with system 100 ; surfaces 102 are typically metallic surfaces that are part of stove 106 . in operation , system 100 views food 104 through a field of view 105 ; system 100 then monitors food doneness and / or temperature of food 104 to provide an indication 112 of doneness and / or temperature to a user . typically , indication 112 is an audible sound or light made , respectively , from a speaker or led 114 . system 100 thus provides operation similar to the digital frying pans of fig1 - 4 ; however system 100 functions remotely from food 104 . [ 0038 ] fig6 shows a block schematic of system 100 ; those skilled in the art should appreciate that elements of system 100 , as shown in fig6 may be arranged in different ways , or through different components , without departing from the scope of the invention . an infrared optically powered element ( e . g ., a mirror or germanium lens ) 122 images food 104 onto a thermal detector 124 ( e . g ., a bolometer ), as shown by optical imaging lines 125 . a visible optically powered element ( e . g ., a quartz lens ) 126 images food 104 onto a ccd array 128 , as shown by optical imaging lines 129 . a pcb and processing section 130 converts signals from ccd array 128 to data for lcd 130 ; pcb and processing section 130 converts signals from thermal detector 124 to temperature data indicating a temperature of food 104 ; a user may view lcd 132 to view what food 104 system 100 monitors ; specifically , by reviewing lcd 132 a user may position system 100 appropriately on surface 102 so as to appropriately image food 104 to thermal detector 124 . a user interface provides for inputting selections for temperature and food doneness to system 100 ; preferably pcb and processing section 130 includes memory to store food doneness options and food types , similar to system described above in fig1 - 4 . once a selected temperature or food doneness is reached , for food 104 , system 100 informs the user of this through indicator 114 ( e . g ., a buzzer or led ). in this way , a user of system 100 can monitor food doneness and temperature for a food remotely and conveniently . as those skilled in the art understand , determining temperature of food 104 via thermal detectors works best when a reference temperature is available ; thus preferably thermal detector 124 includes at least two detectors , one to receive thermal energy from food 104 and one to receive thermal energy from a reference temperature such as the inside of system 100 , which is generally at room temperature . data from the two detectors 124 may then be compared ( in pcb and processing section 130 ) to determine temperature of food 104 . other calibration techniques for determining absolute temperature may also be used . those skilled in the art should appreciate that system 100 can utilize a single infrared ccd to provide both imaging for lcd display 130 and temperature monitoring of food 104 . in such an embodiment , separate lens 126 and ccd array 128 are not necessary . the invention thus attains the objects set forth above , among those apparent from the preceding description . since certain changes may . be made in the above methods and systems without departing from the scope of the invention , it is intended that all matter contained in the above description or shown in the accompanying drawing be interpreted as illustrative and not in a limiting sense . it is also to be understood that the following claims are to cover all generic and specific features of the invention described herein , and all statements of the scope of the invention which , as a matter of language , might be said to fall there between .

a digital frying pan provides temperature and / or food doneness information associated with food cooked within the pan . a thermal sensor coupled with the pan senses temperature and generates corresponding signals , and processing electronics coupled with the sensor convert the signals to data for display on a lcd . a warning buzzer or led warns the user of completed cooking . the frying pan may be programmed to desired food types or personal temperatures or food doneness options . the invention also provides a remote sensing food doneness system for remotely viewing and then determining food temperature and / or food doneness . the remote system uses thermal imaging optics and thermal sensing techniques to remotely sense food temperature . preferably a second optical element images the food onto a ccd to display an image of the food to a user . the system is mounted by a user who views the ccd to ensure appropriate placement in line of sight from the food . a warning is generated by the system to indicate food doneness or desired temperature .

a harvesting machine 10 in the form of a self - propelled forage harvester is built on a frame 12 that is carried by front and rear pairs of transversely spaced wheels 14 and 16 , respectively . the harvesting machine 10 is controlled from an operator &# 39 ; s cab 18 from which a harvested crop take - up arrangement 20 can be viewed . crop , such as corn , grass or the like , taken up from the ground by means of the harvested crop take - up arrangement 20 , is conducted to a chopper drum 22 which chops it into small pieces and delivers it to a conveyor or blower arrangement 24 . the crop leaves the harvesting machine 10 to a transport vehicle operating alongside through a discharge spout or duct arrangement 26 mounted to the harvesting machine for swinging about a vertical axis . between the chopper drum 22 and the conveyor arrangement 24 , there extends a post - chopper reduction or kernel processor arrangement 28 through which the crop to be conveyed is conducted tangentially to the conveyor arrangement 24 . the positions of the components of the discharge spout arrangement 26 can be varied by means of actuators 30 , 34 , 38 , and 40 . a first actuator 30 , in the form of a hydraulic motor , is used to rotate the discharge spout arrangement 26 , supported in bearings on the frame 12 on a slewing rim 50 , about the vertical axis . the actuator 30 makes it possible to rotate the discharge spout arrangement 26 to the rear into the transport position shown in fig1 or to bring it to the left or the right alongside the harvesting machine 10 . a second actuator 34 , in the form of a hydraulic cylinder , is arranged to pivot the discharge spout arrangement 26 about a horizontal axis 32 located at its upstream or inner end . thereby , the second actuator 34 defines the height of the downstream end of the discharge spout arrangement 26 . a third actuator 38 , in the form of a hydraulic cylinder , is used to pivot an ejection flap 36 at the outlet end of a second spout element 44 of the discharge spout arrangement 26 . the ejection flap 36 , that can be repositioned , makes it possible to adjust the angle at which the harvested crop leaves the discharge spout arrangement 26 . the actuators 34 and 38 are single - acting or double - acting hydraulic cylinders , where , in the case of single - acting hydraulic cylinders , the return movement is performed by the force of gravity on the weight of the discharge spout arrangement 26 or the ejection flap 36 . in the embodiment shown , the actuator 34 is single - acting and the actuator 38 is double - acting . the actuator 30 can selectively rotate the discharge spout arrangement 26 either in the clockwise direction or in the counterclockwise direction about the vertical axis of the slewing rim 50 . the actuator 40 is a double - acting hydraulic cylinder . the actuators 30 , 34 , 38 , and 40 can be remotely controlled by means of an input arrangement 31 attached to an operating control lever , that is located in the operator &# 39 ; s cab 18 . the discharge spout arrangement 26 is composed of a first spout element 42 and the second spout element 44 . the first spout element 42 has an inlet or first end mounted to the frame 12 at the horizontal slewing rim 50 such that the first spout element 42 , and hence the spout arrangement 26 , is rotatable about the vertical axis of the slewing rim 50 . the second spout element 44 is mounted for sliding upon the first spout element 42 at a downstream section containing a second or discharge end of the first spout element 42 . the second spout element 44 telescopically receives , and is mounted for sliding in the axial direction relative to , the first spout element 42 . the actuator 40 is selectively extendable and retractable in order to be able to vary the distance between the outlet or discharge end of the second spout element 44 and the vertical axis of rotation of the discharge spout arrangement 26 during the operation of the harvesting machine 10 , as is indicated by the double - headed arrow in fig1 . the cylinder of the actuator 40 is connected with the first spout element 42 and its piston rod is connected over a connecting pin or element 48 with the second spout element 44 . bearing elements 46 , in the form of elongate , flat rails or strips , constructed of ultra - high molecular weight polyurethane ( uhmw - pe ), are fixed to a top surface of the first spout element 42 in a region immediately preceding the discharge end of the first spout element and are received within a region of the second spout element 44 . the perspective view of the discharge spout arrangement 26 , rendered in fig2 , permits a better view of the structure attaching the second spout element 44 to the first spout element 42 . the first spout element 42 is provided on its side wall with an outwardly or transversely projecting channel element 52 having a rectangular cross section . in the interior of the channel element 52 , a channel is located through which an electrical wire or cable ( not shown ) is routed that leads to a lamp , also not shown , arranged at the outer end of the second spout element 44 . above the channel element 52 , another relatively thin , elongate bearing element 46 , made of uhmw - pe , is provided and is connected with the first spout element 42 , in particular , by means of adhesive . the bearing element 46 can also extend around the channel element 52 or it may include three separate strips that are respectively arranged along the under , outer , and top sides of the channel element 52 . on the basis of fig2 , it cannot be discerned that an identical channel element 52 and an identical bearing element 46 are also arranged on the other side of the first spout element 42 . the bearing elements 46 extend up to the outer end of the first spout element 42 . the second spout element 44 is provided with an inner cross section that is slightly larger than the outer cross section of the first spout element 42 . each of opposite side walls of the second spout element 44 is provided with a rectangular channel 54 that encloses the adjacent channel element 52 of the first spout element 42 . at its end that is slid upon the first spout element 42 , the second spout element 44 is provided with four support bearings , each of which includes an arm 56 rigidly connected with the second spout element 44 , and a roll 58 arranged at the outer end of the arm 56 which can rotate about its axis . two arms 56 with rolls 58 are arranged alongside each other on the upper side of the first spout element 42 and are respectively located to engage the first spout element 42 at locations on opposite sides of the bearing element 46 , but the use of a wider bearing element 46 would be conceivable upon which the rolls 58 can roll along . the arms 56 of the other two support bearings are respectively attached to the undersides of the pair of channels 54 at the opposite sides of the second spout element 44 , and their rolls 58 are respectively in contact with the undersides of the channel elements 52 at the opposite sides of the first spout element 42 . the rolls 58 are attached to the arms 56 so as to be free to rotate about their longitudinal axes that are oriented transverse to the direction of sliding of the second spout element 44 . although the arms 56 are rigidly attached to the second spout element 44 , it would be conceivable to connect them in joints , free to pivot on it , and to preload them with the force of a spring against the first spout element 42 . the first spout element 42 and the second spout element 44 are in the form of channels that open downward , since the chopped harvested crop slides along the upper side of each of the elements 42 , 44 of the discharge spout arrangement 26 due to the inertia imparted to the crop by the conveyor arrangement 24 . however , embodiments partially closed downward would also be conceivable . having described the preferred embodiment , it will become apparent that various modifications can be made without departing from the scope of the invention as defined in the accompanying claims .

a discharge spout arrangement of an agricultural harvesting machine through which harvested crop processed by the harvesting machine can be transported to a transport vehicle . the discharge spout arrangement includes a first spout element connected with the harvesting machine . a second spout element is mounted to and defines an extension the first spout element . the second spout element is slidably movable between fully retracted and extended positions respectively wherein a discharge end of the second spout element is spaced a minimum and a maximum distance from a discharge end of said first spout element .

fig1 through 3 illustrate footwear , in this case a shoe 10 having an insole 20 , a midsole 40 , and an outsole 50 . fig1 shows the basic configuration of footwear with an added insert device 30 . some footwear may not include one component such as the midsole 40 . in those cases the insert would be inserted into the outsole 50 , which would include the area displayed as the midsole 40 . the removable insert 30 is shown inserted through the midsole 40 . an alternate design would have the insert 30 inserted through the outsole . in this case , the lower face of the insert 30 would be exposed to the elements . this may require removal or partial removal of the outsole and some type of locking device . the preferred method for simplicity would be insertion through the inside of the shoe 10 . fig2 illustrates a plan view or top view illustrating the interior 60 of the shoe 10 with the insert 30 in place . the insert 30 is located in the midsole 40 , or in some instances the outsole 50 if no or a limited midsole is manufactured into the shoe 10 . the tolerances between the insert and the midsole or outsole are minimal in order to provide a firm placement and retention of the insert into the shoe 10 . fig3 illustrates the insert design . the insert 30 can be a cylinder of specific depth and diameter . in different applications it may be better to manufacture the insert in the form of , but not limited to a square 70 , oval or closed “ u ” shape design , of varying depths . the insert 30 is designed to be made of but not limited to materials such as eva ( ethyl - vinyl - acetate ), rubber , polyurethane , materials the midsole , outsole , insole are typically made from . by doing this a piece of footwear can be configured to the user &# 39 ; s personal preference or use . an example would be an athletic running shoe that has a midsole 40 made of eva , the insert 30 could be made of eva returning the footwear to its original intended shock absorbing parameters each time the insert is replaced . if the insert 30 was made of a softer porous material the advantage of greater shock absorbing and cushioning properties could be obtained without the worry of repeated use . after a single or limited number of uses the insert could be replaced , returning the footwear to its original improved shock absorbing properties . this present invention is not limited to athletic footwear but is applicable to all types of footwear . examples include , but are not limited to , athletic , casual , dress , and specialty footwear . the footwear is manufactured or modified after manufacturing to include a cavity in which the insert is placed . the heel of the footwear provides most of the shock absorbing requirements for the wearer during movement such as walking , running , or while stationary . the preferred location of the cavities in a pair of shoes in which the insert 30 is ideally directly under the impact point of the wearer &# 39 ; s heels . this location may be offset but it is most desirable at the point of impact between the heel of the foot and the center of the insert . for example , insert 30 may be a cylindrical insert with a circular diameter in the range of 0 . 5 inch to 3 . 0 inches and preferably of 2 . 0 inches for a size 12 shoe . the size and shape of the insert may vary depending on the size and application of the footwear . the shape and diameter are not limited to a specific dimension or to the cylindrical design but are the most obvious for discussion purposes . other shapes such as ovals , rectangles , squares , or a closed “ u ” shape , with the closed flat end of the “ u ” facing the toe may be more desirable for manufacturing or coverage . the desired goal of the insert 30 is to provide enough area of impact for shock absorption while maintaining the footwear integrity and comfort . if the cavity area is too big , the footwear may not provide the required support or stability . the insert 30 and cavity in the footwear may vary in depth . the cavity depth and vertical dimension of the insert 30 may range from a fraction of an inch from the outside of the outsole 50 to a percentage of that depth . this would be most desirable if the footwear incorporates other shock absorbing devices or materials layered into the footwear . the insert 30 would only seat a percentage of the way between the insole and outside of the outsole as shown in fig4 . the insert 30 may also be made of materials that do not require the use of an insole . in addition the insert 30 may be designed with holes or notched out areas , may be of a unitary design , or it may be layered or formed of adhered segments . an example of varying designs include a single center hole , or a notched out area on one edge that may be desirable for manufacturing , removal , material performance or air transfer . in addition various shapes of this insert 30 may include but are not limited to a cone , bar or strip of specified depth . the advantage of these shapes includes providing variance in the area of coverage for different applications or reduced manufacturing costs . by being removable , the insert can be replaced when the material begins to break down and the ability to provide shock - absorbing properties decreases . when to replace this insert 30 is dependent on the wearer . the insert can be replaced after each use or multiple uses over an extended time period . the insert can be constructed of the same material as the midsole or other materials that provide better cushioning and shock absorbing properties but less durable than the midsole or outsole construction . the shoe can provide optimum durability in the initial design of the shoe and increased shock absorbing properties with the disposable insert . in this configuration a shoe can last for a greater period of time than a shoe that is trying to provide both durability and shock absorption , sacrificing one and / or the other providing a mediocre performing shoe . alternative footwear such as work shoes or boots would provide an ideal application for an insert 30 . with some manufactured work footwear the outsole incorporates the midsole into its design . for these applications a removable insert 30 is ideal . the cavity can create an insert 30 area in order to provide better shock absorption and comfort characteristics to an otherwise ridged shoe . the design of some work footwear incorporating a one - piece outsole 50 and midsole 40 is for safety , corrosion resistance , traction and durability , an ideal application . other applications include but not limited to all types of athletic footwear running , basketball , tennis , cross training , daily footwear casual , business , and specialty footwear . for medical reasons the insert 30 materials could be made with highly elastic properties that may not last under repeated use , but would provide the best shock absorption for reduced impact to feet , legs , hips and back . the specific dimension of the insert , for example complete depth from insole to a fraction of an inch to the outside could improve range of motion for the foot . with the insert made of a softer material that compresses easily this would allowing the heel to travel with a greater range of motion relative to the front of the foot . stretching and recoiling the calf muscle to greater distances . as will be readily appreciated from the foregoing , the disclosed embodiments of the present invention provide for a replaceable insert that enables users to replace worn - out support in their footwear . in addition , the insert and shoe design of the present invention enables a user to selectively replace the insert to facilitate a particular activity , such as a high - impact insert for running , a low - impact insert for walking , and a medium impact insert for working conditions . in addition , various environmental factors may be accommodated , such as designing water resistance or water - repellant properties in the insert through the use of materials or architecture . the insert can also be constructed to facilitate breathability between the interior of the shoe and the exterior , such as through the midsole and the outsole to the bottom of the shoe . this can include a pumping - type of action in a one - way or two - way direction to draw air in through the top of the shoe and expel it through the bottom of the shoe as the wearer is walking or running or moving up and down while standing in place . more particularly , the disposable insert can be manufactured of a porous or semipermeable material that permits air to pass into and out of the interior of the shoe . this would circulate air in the shoe through repeated compression during movement of the foot . the material that provides circulation for the shoe itself can be manufactured with air passages from the sides , top , or bottom of the shoe or any combination of the foregoing . these passages allow air into and out of the shoe or in only one direction , depending on the design and the incorporation of valves in the insert or the shoe in conjunction with the insert operation . in order to restrict water from entering the shoe , valves or passageways can be designed to restrict water or to channel water away from the interior of the shoe . one design formed in accordance with the present invention ; would enable the insert to be rotated about a longitudinal axis to open up air passages when the environment is dry and to rotate in an opposite direction to close air passages between the insert and the shoe to prevent the passage of air and fluid . thus , passages in the shoe may match up or utilize the insert as a means to control air flow . in another embodiment , the insert , which can be disposable , can incorporate a pump mechanism that utilizes valves or channels of different designs and quantities to force air movement in various flow patterns . this would be an actual pump that operates from the pressure of the foot as it moves in the interior of the shoe , and in particular as it exerts pressure on the outsole of the shoe from the interior . all of the above u . s . patents , u . s . patent application publications , u . s . patent applications , foreign patents , foreign patent applications and non - patent publications referred to in this specification and / or listed in the application data sheet , are incorporated herein by reference , in their entirety . from the foregoing it will be appreciated that , although specific embodiments of the invention have been described herein for purposes of illustration , various modifications may be made without deviating from the spirit and scope of the invention . accordingly , the invention is not limited except as by the appended claims .

a removable , disposable shoe insert that can increase the cushion and shock absorbing properties of a shoe without sacrificing durability or comfort is provided . by using different materials for the insert , the user has the option of when to replace the insert . the insert can be of varying sizes , shapes , hardness , and materials . the insert allows manufactures to make the outsole of more durable materials extending the life of the footwear .

the undergarments shown in the figs . are not drawn to scale , and are only intended to be representative of the approximate shapes of the various pieces of the garments relative to each other . as will be appreciated by one having ordinary skill in the art , the undergarments are intended to be configured in sizes and proportions similar to the various sizes and proportions of conventional undergarments that are commercially available . referring now to fig1 , an example undergarment also referred to as a pair of underwear 10 includes two strap portions 12 and 14 attached via a crotch panel 13 . a set of fasteners 12 a , 12 b , 14 a and 14 b disposed on each of a set of ends 15 , 16 , 17 , 18 of the strap portions are used to fasten the two strap portions 12 , 14 together . referring also to fig2 and 3 , the fasteners 12 a and 12 b are disposed on the top side of the underwear and the fasteners 14 a and 14 b are disposed on the bottom side of the underwear , so that when fastened together , the strap portions , 12 and 14 form a single strip of fabric , also referred to as a waistband , for encircling the waist of a wearer ( not shown in fig1 ). when the underwear are being worn ( see fig4 ), the crotch panel 13 fits between the legs of the wearer to thereby form a protective covering of the wearer &# 39 ; s crotch area . as will be appreciated by one having ordinary skill in the art , the strap portions 12 , 14 and panel 13 can be sized and shaped in any number of ways to accomplish the easily removable underwear of the invention . for example and with reference also to fig5 , the strap portions can be designed to be wider . likewise , the crotch panel 13 may be sized and shaped in an elongate strip thereby causing the undergarment to take the shape of a thong when assembled ( see fig1 ). or , in yet another embodiment ( see fig5 ), the crotch panel 13 may be as wide as needed to form an assembled shape of a brief that fully covers the buttocks of the wearer . additionally , the crotch panel 13 can be designed such that the distance between the two strap portions 12 , 14 is maximized or such that the distance between the two strap portions is minimized . in the former case , the underwear may sit above the waist of the wearer when assembled and in the latter , the underwear may sit below the waist of the wearer . the fasteners 12 a , 12 b , 14 a , 14 b may be implemented using any device capable of connecting the strap portions together including , for example , snaps , buttons , velcro strips or patches , zippers , hooks , etc ., whether currently available or developed in the future . as will be appreciated by one having ordinary skill in the art , the strap portions can be made adjustable by incorporating , for example , a slide and buckle / clip as are commonly used on men &# 39 ; s bowties and ladies &# 39 ; bra straps . in this manner , the underwear can be adjusted to fit the waist / hips of any wearer . further and with reference now to fig6 and 7 , the undergarment 10 need not attach at the sides of the wearer &# 39 ; s waist but may instead fasten at the front ( or rear ) of the underwear 10 . in an example embodiment which fastens at the rear ( not shown ), a set of zippers may be placed at the rear right and at the rear left to ease removal of the undergarment without first requiring removal of any pants being worn . as with all embodiments described herein , the fasteners used to attach the strip portions 12 , 14 may be implemented using any device capable of connecting the strap portions 12 , 14 together including , for example , snaps , buttons , velcro strips or patches , zippers , hooks , etc ., keeping in mind that the placement of the fastening device will likely be dictated at least in part by the type of fastener used . for example , using buttons in an embodiment having strip portions 12 , 14 that attach at the sides of the waist may cause the waist to be bulky such that snaps or velcro might be preferred in such an embodiment . alternatively , the position at which the strip portions attach , i . e ., the sides of the waist , the front of the waist , the back , etc ., can be modified to accommodate any preferred type of fastener . fig8 shows the underwear of fig1 having a fully detachable crotch panel 13 . in this example embodiment , the crotch panel 13 includes a set of velcro strips 13 a , 13 b that attach to a set of corresponding velcro strips 12 c , 14 c disposed on the undersurface of the strip portions 12 , 14 . as described with reference to the earlier figs ., the velcro strips 12 c , 14 c and 13 a , 13 b can be implemented using any fastener capable of connecting the crotch panel 13 to the strip portions 12 , 14 . as will be appreciated by one having ordinary skill in the art , and with reference also to fig9 , the example embodiment shown in fig8 need not be configured with two strip portions . in such an example embodiment , the two strip portions are replaced with a single ring of fabric 20 that encircles the waist of the wearer , also referred to as a waistband 20 , and to which the crotch panel 13 attaches . two velcro strips 20 a and 20 b disposed inside of the waistband 20 fasten to two velcro strips 13 a and 13 b disposed on the undersurface of the crotch panel 13 to thereby attach the crotch panel 13 to the waistband 20 . in this example embodiment , the waistband 20 is preferably made of an elasticized fabric capable of stretching sufficiently to allow the waistband to fit over the hips of the wearer when being placed on the body and being sufficiently tight enough to fit the waist of the wearer snugly . in this way , the waistband 20 can be placed on the body by sliding it over the hips and over any pants being worn without first requiring removal of any such pants , i . e ., eliminating the need for any undressing by the wearer . thus , the crotch panel 13 is removable and replaceable with a fresh panel 13 whenever desired by the wearer . referring now to fig1 , in another example embodiment , the crotch panel 13 is only partially detachable from the waistband 20 . in this embodiment , the crotch panel is non - detachably fastened at the back of the waistband along , for example , a stitched seam 18 , and is detachably fastened to the front of the waistband via a velcro strip 13 a disposed on the crotch panel that attaches to a velcro strip 20 a disposed on the waistband 20 . as will also be appreciated by one having ordinary skill in the art , the fabric of which the underwear is made is comprised of any suitable fabric including , for example , an elastic material for the strap portions and , for example , a weave of stretchable and non - stretchable fibers for the crotch panel . in yet another embodiment ( not shown ), the crotch panel is not detachable from the waistband and is divided into two sections and a set of fasteners , such as , for example , a set of snaps disposed on each of the two sections permits the attachment of the two sections together to form a single crotch panel 13 . in this embodiment , the waistband is pulled over the pants of the wearer with the crotch panel sections being unfastened . after the waistband is in place on the waist of the wearer , the crotch panel sections are fastened to form an assembled pair of underwear . the underwear 10 shown in any of fig1 - 10 , can be worn when performing any of a variety of sports including , for example , hockey , baseball , soccer , lacrosse , cycling , wrestling , basketball , track and field , speed skating , skiing , football , running , etc ., or just plain working out at the gym . the underwear may also be worn during the course of one &# 39 ; s daily working / leisure activities . likewise , the underwear 10 can be designed to be worn under other equipment such as in sports like hockey or as part of the outer garment as in track and field or speed skating . accessories can be attached to the underwear of the present invention , again depending on the sport or activity for which they are intended . for example if designed for hockey , the underwear garment can be provided with clips or other fastening means such as velcro strips to hold up a pair of hockey socks . while example embodiments have been illustrated and described , numerous modifications may be made to the examples when making the underwear . the scope of protection is only intended to be limited by the scope of the accompanying claims , either literally or under the doctrine of equivalents .

an undergarment designed for both men and women includes two strap portions connected by a crotch panel . a set of fasteners disposed on a set of ends of each of the strap portions enable the fastening together of the two strap portions to form a single strip that encircles the waist of a wearer . when being worn , the crotch panel extends between the legs of the wearer to cover the wearer &# 39 ; s crotch . due to the shape of the undergarment and the position of the fasteners , the underwear can be donned and removed without requiring the full removal of outer layers of clothing such as , for example , pants , shorts , etc .

an example of realization of the device according to the invention will now be described with reference to the drawings fig1 - 7 . as regards its software aspects , the present invention can be implemented by an appropriate programming of the control software of a known device , for example , a cardiac pacemaker or a defibrillator / cardioverter , including means for collecting a signal provided by endocardial leads and / or one or more implanted sensors . the present invention may particularly be applied to implantable devices such as those of the reply and paradym device families produced and marketed by sorin crm , clamart france , formerly known as ela medical , montrouge , france . these devices include programmable microprocessor circuitry to receive , format , and process electrical signals collected ( detected ) by implanted electrodes and deliver stimulation pulses to these electrodes . it is possible to transmit by telemetry software that will be stored in a memory of the implantable devices and executed to implement the functions of the present invention that will be described herein . the adaptation of these devices to implement the functions and features of the present invention is believed to be within the abilities of a person of ordinary skill in the art , and therefore will not be described in detail . as the mentioned above , the endocardial acceleration ea signal collected during a cardiac cycle includes two major components , corresponding to the two major heart sounds ( s 1 and s 2 sounds of the phonocardiogram ) that can be recognized in each cardiac cycle : the first component of endocardial acceleration (“ ea 1 ”), whose amplitude variations are closely linked to changes in pressure in the ventricle ( the maximum peak - to - peak amplitude of this component ea 1 , called pea 1 , being specifically correlated to the positive maximum pressure variation dp / dt in the left ventricle ) and may therefore be a parameter representative of the myocardial contractility , itself linked to the level of activity of the sympathetic system ; the second component of endocardial acceleration (“ ea 2 ”) which , in turn , occurs during the phase of isovolumetric ventricular relaxation . this second component is mainly produced by the closure of the aortic and pulmonary valves . the ea signal may contain one or two other components , called ea 3 and ea 4 , corresponding to the known sounds s 3 and s 4 of the phonocardiogram . the ea signal shown in fig1 shows the timings identified in three successive cardiac cycles of an ea endocardial acceleration signal and a corresponding electrocardiogram ecg plot . the preliminary processing of the ea component involves , first , to distinguish the successive cardiac cycles in the continuously collected ea signal , by identifying markers at the beginning of the cycle to separate the cycles and to isolate a series of ea sub - signals bounded in time , each corresponding to a duration of one cardiac cycle . in the case of an endocardial ea signal , the time markers at the beginning of the cycle are provided by the implant itself , which memorizes the moments of stimulation v , as shown in fig1 , or the moment of detection r of the r - wave ( depending on the mode of operation at the time ). further , in the case of an external ea signal , the time markers at the beginning of the cardiac cycle are provided by an algorithm to detect peaks of stimulation or qrs complexes of the ecg signal , which signal is collected by means of external electrodes . the next step is to isolate the ea 1 and / or ea 2 component in each sub - signal bounded in time corresponding to a cardiac cycle . in the description which follows , the present invention is described mainly with respect to the ea 1 component because this is the most distinct characteristic . however , it should be understood that the teachings of the invention are equally transferable to an analysis of the ea 2 component , alternatively or in addition to the ea 1 component . in this regard , each of the ea 1 and ea 2 “ components ” are represented by a set of values describing the continuous variation of the ea signal in a given time window extending around the pea 1 and pea 2 peaks , respectively , for a fraction of the duration of a cardiac cycle . specifically , each component consists of a subset of the matrix of n signal samples obtained after scanning the ea signal for the duration of the cardiac cycle . each component thus represents a fraction of the ea signal for the duration of a cardiac cycle . specifically , each component consists of a subset of the matrix of n samples of the ea signal obtained after scanning it over the duration of the cardiac cycle . each component thus represents a fraction of the ea signal for the duration of a cardiac cycle , and each cardiac cycle is constituted by a plurality of “ components ” that follow , especially the first two ea 1 and ea 2 components , these components also being followed by the secondary ea 3 and ea 4 components . preferably , the ea 1 ( and / or ea 2 ) component of the ea signal is determined after averaging over several cycles , typically from three to five cycles , using a technique such as that described in ep 2092885 a1 and its counterpart us patent publication no . 2009 / 0209875 ( both assigned to sorin crm s . a . s , previously known as ela medical ), the disclosures of which are incorporated herein by reference , to eliminate cycle to cycle variations by temporally readjusting the successive components before averaging them . essentially , this technique performs a pre - processing of the continuously collected ea signal , with : division of the ea signal into sub - signals , each corresponding to the duration of a cardiac cycle and identified by a marker at the beginning of a cycle to achieve this division ; segmentation of each of these sub - signals to individualize one or more of the ea 1 and / or ea 2 components in a given temporal window ; for the current ea 1 or ea 2 component thus isolated on a cycle , finding of a autocorrelation peak compared to the ea 1 ( or ea 2 ) components of the other collected cycles ; application of the calculated time shifting to the current component , so as to align it with the others . averaging and analysis processing can then be performed on these successive ea 1 ( and / or ea 2 ) components , eliminating the bias of the cycle to cycle variability as a result of the pre - processing . this phase of the present invention is to predetermine a distinguishing criterion for recognizing the presence or absence of a capture by defining two corresponding classes that are then used for the capture test itself : depending on whether the current values recorded during a cardiac cycle belong to either of these two classes , it is assumed that there is presence or absence of a capture . these classes are defined by a partition of an n - dimensional space into two subspaces , one corresponding to a situation of capture , the other to a situation of non - capture . each of the n dimensions corresponds to a characteristic indicator of the ea component . for clarity and simplicity of presentation , “ ea component ” is referred to as the component “ ea 1 ”, but what is said about this “ ea 1 ” component should be considered applicable mutatis mutandis to the component ea 2 , and indeed even possibly to ea 3 and / or ea 4 components . the term “ indicator ” should be understood to be a measurable quantity of the ea 1 component , obtained by analyzing the ea signal in a time window corresponding to a limited portion of a cardiac cycle including this ea 1 component . the indicator is expressed as a single measured value , that is to say a scalar . each indicator is chosen to characterize by the value it takes in the absence or presence of a capture . specifically , the analysis of one of these indicators ( e . g ., the pea 1 value of peak to peak amplitude of the ea 1 component ) is not sufficient to reliably discriminate between presence and absence of a capture , and if used alone would lead to an excessive number of erroneous determinations , with both false positive and false negative results . therefore , the present invention proposes to use at least two and more preferably a plurality of different indicators characterizing a same ea 1 component collected during a given heartbeat , and to combine these indicators between them , according to the method presented below , to decide between the presence or the absence of a capture with a higher degree of reliability . the set of values all of these various indicators obtained for a given ea 1 component of a heart beat ( this component being possibly averaged over several successive cycles , as outlined above ) is hereafter called “ vector ”. in the example that follows , the simplest example is taken , a vector of dimension n = 2 , with the two following indicators , which can simply describe the morphology of the ea 1 component in a very different way depending on whether or not there is a capture : the pea 1 value of the peak - to - peak amplitude of the ea 1 component on the analysis window in question , for example , on the window [ 0 - 300 ms ], the origin of time ( 0 ms ) corresponding to the moment of the last ventricular pacing , and the lea 1 value of the “ width ” of the ea 1 component , that is to say the duration thereof . these indicators are illustrated in particular in fig2 a and 2 b , respectively , for an ea 1 component obtained in stimulated rhythm with capture , and for an ea 1 component obtained in spontaneous rhythm . specifically with regard to the lea 1 indicator , it can be obtained by thresholding an nrg envelope of energy obtained by squaring the value of signal samples and then applying a smoothing window of , for example , 100 ms . see e . g ., fig2 a and 2 b . the start time t start and the end time t end of the ea component ( with lea 1 = t end − t start ) correspond to the crossing of a threshold which can be , for example , 10 % of the nrg maximum energy on the window [ 0 - 300 ms ]. this method of determination of the characteristic instants of the ea 1 component is described , as well as others , in ep 2092885 a1 and its counterpart us patent publication no . 2009 / 0209875 cited above , incorporated by reference herein , which can be referred to for more details . each of the pairs of values { pea 1 , lea 1 } is a vector representative of the analyzed ea 1 component that can be graphically represented by a point in the plane ( pea 1 , lea 1 ) as shown in fig4 and 5 . the example that is described with n = 2 and wherein the indicators are pea 1 and lea 1 is in no way limiting , however , and it should be understood that it is possible to perform the analysis on vectors of dimension n & gt ; 2 including other indicators , alternatively or in addition . thus , among the representative indicators , temporal indicators can be used , such as : the moment of occurrence of the ea 1 component peak , counted from the origin of the analysis window [ 0 - 300 ms ]. this moment can notably be calculated such as the average of two timings , the occurrence of the minimum peak t m and the occurrence of the maximum peak t m of the ea signal of the ea 1 component ( see fig2 a and 2 b ); the moments of beginning t start and / or of end t end , respectively , of the ea 1 component ( see above for the method these moments are defined ); the moment of the maximum of the power envelope t maxnrg , and it is also possible to select indicators representative of the morphology of the ea 1 component , such as : the signal to noise ratio snr , which can be defined by : σ_noise being the standard deviation of the signal considered as “ noise ”, that is to say the signal contented in the ea 2 useful signal , with the exception of the segment [ t ea2 — start , t ea2 — end ] corresponding to the ea 2 component itself ; σ ea1 — window being the standard deviation of the signal contained in the [ 0 , 300 ms ] window ; this amount reflects the “ degree of order ” of the signal : if the signal is close to white noise , entropy is high , but if it is “ ordered ”, the entropy is lower ; and the cumulative energy , calculated from the area under the nrg energy envelope curve . other characteristic indicators may also be used in conjunction , such as : values of the characteristic amplitudes of the ea 4 component , including the peak - to - peak on the window [− 200 ms , 0 ms ]. it is known that the ea 4 component happens between the beginning of the atrial activity ( p wave in the case of an ecg , or the detection of the atrial depolarization on the lead in the case of an implantable device ) and the beginning of the ea 1 component . one skilled in the art is referred to ep 2189180 a1 and its counterpart us patent publication no . 2010 / 0125308 ( both assigned to sorin crm s . a . s ., previously known as ela medical ), the disclosures of which are hereby incorporated herein by reference , for details on the method to collect and analyze this ea 4 component . fig3 shows the various steps of the initial phase of the method of the present invention , by defining two classes of references ( presence or absence of a capture ), which are then used for the capture test . first ( block 10 ) the ventricle is stimulated under conditions enabling the capture , with a relatively high energy stimulating pulse for pacing and a short atrioventricular delay avd . to avoid variations of rhythm that could disrupt the collection of the ea component , it is also possible to stabilize the heart rate by stimulating the heart through the atrium with a fixed atrial pacing frequency f stim . the ea 1 ( and / or ea 2 ) component is then collected and averaged over n successive cycles ( block 12 ), typically n = 5 , as explained above . the indicators that were chosen are then extracted from the ea component ( block 14 ). in the example above wherein n = 2 and these indicators are the amplitude of the pea peak and the length of the ea 1 component lea 1 , these indicators extracted from the n = 5 successive cycles are : pea_capt_ref_p and lea_capt_ref_p ( p = 1 . . . 5 ). then the ventricular stimulation is stopped ( block 16 ), of course , if it is possible ( e . g ., in the absence of a complete atrioventricular block ). the presence of a spontaneous rhythm is then sought ( test 18 ) and , if it is present , according to the same method as before , the collection of the ea component over n = 5 cycles and the extraction of the corresponding pea_spont_ref_p and lea_spont_ref_p indicators ( blocks 20 and 22 , similar to blocks 12 and 14 ) are performed . the p vectors x_capt_ref_p and the p vectors x_spont_ref_p are then formed from the indicators previously extracted ( block 24 ). the next step ( block 26 ) is to find a rule for separating of the vectors x_capt_ref_p and x_spont_ref_p into two distinct classes . these classes then allow for a new current vector x from a new stimulation configuration , to determine the presence or absence of a capture according to the classification assigned to this new current vector . several methods can be applied to define the rule separating the two classes . a first technique is to operate separately on the two indicators ( that is to say , the two coordinates of the vector ), for example , by means of simple threshold detectors , the thresholds for each indicator being selected for a predetermined sensitivity / selectivity compromise ( e . g ., sensitivity & gt ; 90 % and specificity & gt ; 95 %). both tests are then combined together by one vote , for example , an and logical function . another technique , preferably used , is to operate directly on two - dimension vectors ( or more generally n - dimension vectors , in the case of n & gt ; 2 indicators extracted from the ea 1 component ). a given vector can thus be graphically represented by a point in the vector space , including a point in the plane ( lea 1 , pea 1 ) in the example given here , as illustrated in fig4 and 5 . one method used is the method of the “ k - nearest neighbours ” ( knn ), applied on vectors of indicators , and illustrated in fig4 . the various distances between the vector to test ( a or b in fig4 ) and all vectors of the training base are calculated for this purpose . the k nearest vectors of the vector to be tested ( in the example shown , k = 3 ) are then selected and the majority class is assigned to the vector to test , the division occurring between two classes . thus , in the illustrated example , for the vector a wherein two of the three closest neighbours are part of the “ stimulated ” class ( x ), the vector a is considered as belonging to the “ stimulated ” class while the vector b , whose three closest neighbours are all part of the “ spontaneous ” class ( o ), is considered as belonging to the “ spontaneous ” class . a second method used is to implement a neural network , applied to the vector of indicators . after a learning phase to adjust the internal parameters of the neural network , each new test vector processed by the neural network is assigned in output a class of belonging among the two ( in the present example ) possible classes . a perceptron neural network can be used , which is a simple linear classifier network with n inputs and one output . more details regarding the implementation of a suitable neural network can be found in : simon haykin , neural networks : a comprehensive foundation ( 2 nd edition ), prentice hall , 1998 or in : christopher m . bishop , neural networks for pattern recognition , oxford university press , 1995 . a third method is to operate a linear classification by estimation of the pseudo - inverse matrix . the class vector taking the values ( 1 , − 1 ) is defined if x belongs to the class capt_ref and taking the values (− 1 , 1 ) if x belongs to the class spont_ref . learning is to compute the matrix w which minimizes the rmse as follows : the vectors x i of the learning base ( of class i class ) are the vectors x_spont_ref_p and x_capt_ref_p . the matrix w is given by the following expression : [ x ] being the matrix resulting from the concatenation of vectors x i : and [ class ] being the matrix resulting from the concatenation of the class i vectors associated with the x i vectors . calculating the vector s = w × y =( s 1 , s 2 ) is sufficient to determine the class of a vector y to be tested . each component of this output vector is a value ( between − 1 and 1 ) that the classifier gives each class . assigning the class associated with the maximum value to y is sufficient ( if this is s 1 , y belongs to the class capt_ref ). fig6 illustrates the simple case of the space ( lea 1 , pea 1 ) divided into two half - spaces with a boundary f which is a line defining the boundary between the two areas capture / non - capture . but according to the chosen approach , the interzone boundary can also be formed by line segments , a circle , a parabola , or any other geometric shape . this limit may also result in a logical condition , for example , in the case of the knn , the membership condition of a point x to a zone is determined by looking at the majority ownership area of the k points which are the nearest of x . it can also be proposed to a user to manually adjust the limit , by drawing it or by moving it on a graph ( not necessarily a straight line ), or by entering the coordinates of two points belonging to the limit , if this limit is a straight line . advantageously , once the two classes are defined , a step of checking the distance between classes is implemented ( block 28 in fig3 ) in order to assess whether the just established classification is really discriminant . the inter - class distance is defined as the euclidean distance between the centers of gravity of the two zones ( capture / no capture ), and it is verified that this distance is sufficiently large compared to the average distances between the elements of each zone in relation to respective centers of gravity . this is particularly illustrated in fig6 , wherein d is the distance between the center of gravity g stim of the vectors classified in the “ capture ” zone , and the center of gravity g spont of the vectors classified in the “ no capture ” zone . this check can be made simply by setting a threshold for deciding that the two zones are sufficiently separated . another criterion is to calculate a ratio j , based on the discriminant criterion of fisher , formed by the relationship between the “ distance between the barycenters ( m 1 and m 2 ) and the “ compactness of the classes ” ( s 1 2 + s 2 2 ): if the criterion for sufficient inter - classes distance is not satisfied , this means there is little or no difference between the ea signal collected by stimulating the ventricle and the ea signal collected in spontaneous rhythm . this may also be the result of a problem with the lead . in such a case , a capture test would be meaningless , and the process is terminated , possibly with an alarm . otherwise , that is to say if the indicators identified for the ea signals , respectively in stimulated and in spontaneous configurations , are sufficiently different , the capture test can be performed . the different steps of the ventricular capture test phase are illustrated in fig7 . this test of ventricular capture will be described in a search of the threshold ( threshold of ventricular pacing ). this search is to apply a sequence of stimulation pulses v for ventricular pacing at progressively decreasing energy , and monitoring the ea signal for the presence or absence of a ventricular contraction by the method that will be described . if the contraction is actually present , the device considers that the ventricular pacing delivered an effective stimulation pulse ( i . e ., there was a ventricular capture ). the energy applied to the next ventricular stimulation pulse to be delivered is then reduced , typically by a step of fixed amplitude , for example , δv = 0 . 25 v . when loss of capture is detected ( i . e ., no ventricular contraction is detected in response to a delivered stimulation pulse ), the device assumes that the last delivered stimulation is ineffective , and therefore the ventricular pacing threshold is greater than the last applied value . in the latter case , a safety margin of an amount that is greater than the last ( ineffective ) stimulation pulse can be applied to ensure a ventricular contraction . the ventricular pacing threshold so determined may be stored in the device memory , may be transmitted to a data collection central station , or used by the implant to change the amplitude of the stimulation pulse applied to the ventricle . for further details on the algorithms for adjusting the stimulation energy from successive capture tests , one skilled in the art is referred to ep 1080744 a1 and its counterpart u . s . pat . no . 6 , 487 , 451 ( both assigned to sorin crm s . a . s ., previously known as ela medical ), which disclosures are incorporated herein by reference and describe various techniques for measuring the threshold , of controlling consistency of the measures and of adjusting of the width and amplitude of the stimulation pulse . the algorithms described therein may be implemented using the capture test of the present invention , by analysis of the morphology of the ea signal instead of an electrical detection of the ventricular depolarization . more precisely , referring to fig7 , the stimulation energy level is set at an initial value v = v init ( block 32 ), from which the amplitude of stimulation is iteratively reduced by a step δv ( step 34 ). the ea ( ea 1 and / or ea 2 ) component is then collected ( block 36 ) in the manner described above , then the selected indicators corresponding to this component are extracted ( block 38 ), on m cycles , in the example illustrated indicators pea_i and lea_i , with i = 1 . . . m . the corresponding vectors x_i are created from the indicators thus extracted ( block 40 ). these m vectors are then classified ( block 42 ) according to one of the methods described above ( e . g ., knn , neural network , estimation of the pseudo - inverse ) and it is chosen that the value of stimulation amplitude v is affected to the majority class among the m . for m , an odd value is preferably chosen , for example m = 3 , but it can also be considered in a simplified version only a single pair of indicators pea_ 1 and lea_ 1 , thereby reducing the response time of the algorithm . according to the majority class so defined , it is considered that there is or there is no capture ( test 44 ): whether there was loss of capture , the stimulation pulse is then restored to its previous energy level value ( block 46 ) and the process is considered completed , to the extent it is considered that this level of stimulation is the lowest level to ensure the capture ; if capture is present , then a return to step 34 is done , to further decrease the pacing threshold by a further increment δv and to test again if , for this level of stimulation , the capture is still present , and so on to detect loss of capture . note that to avoid the effects of the changes in the rhythm , it is possible to perform the capture test with a fixed stimulation frequency resulting of an atrial controlled stimulation in the same method as that used during the determination of the border between the two classes . biventricular pacing of course implies that a capture test is performed on one or the other of the right and left ventricles . in addition , for the optimization of the resynchronization therapy , biventricular stimulation requires to adjust or readjust the interventricular delay vvd at regular intervals . this readjustment of the vvd is often done by scanning the delay between a minimum vvd and a maximum vvd , to seek the maximum of a hemodynamic parameter during this scan , the maximum corresponding to the optimum of the vvd . the modification can also be achieved by simply changing the value of the vvd . in all cases , the change of vvd may affect capture , for example , if stimulation is done with a large vvd , a spontaneous depolarization of the stimulated second ventricle may occur before delivery of stimulation to this ventricle . the capture test must thus be repeated for each adjustment of vvd . one skilled in the art will appreciate that the present invention can be practiced by other than the embodiments described herein , which are provided for purposes of illustration and not of limitation .

an active implantable medical device such as a cardiac prosthesis , including ventricular capture testing by analysis of an endocardial acceleration signal . the device isolates in an endocardial acceleration signal an ea component , extracts from it , n representative indicators , and forms a vector ea from these indicators . a classifier allows acquiring reference ea signals at a stimulation energy level sufficient to cause a capture , and in spontaneous rhythm in the absence of ventricular pacing and forms a corresponding plurality of first reference ea vectors . the n - dimensional space of the ea vectors is partitioned into two corresponding subspaces . the presence or absence of a capture is discriminated based on the position of the current ea vector in one or other of these two sub - spaces . the representative indicators may be : the value of peak to peak amplitude , the width , the moment of occurrence of the peak , the starting time and the ending time of the ea 1 and / or ea 2 components , the signal to noise ratio , the contrast value , the entropy value , and the cumulative energy of the ea 1 and / or ea 2 component , or the value of the peak - to - peak amplitude of the ea 4 component .

the invention described herein is founded , in part , on the realization that to maximize the rheologic benefit , a specially selected polymer or combination of polymers needs to be either bound with very high affinity or covalently bound to the rbc surface . a strongly - bound surface coating of a polymer or combination of polymers selected according to the criteria described herein creates a steric barrier which prevents large plasma proteins ( such as fibrinogen and immunoglobulins ) from approaching the surface of the living cell . the data presented herein shows that a peg polymer of appropriate molecular weight , or combination of peg polymers with appropriate , but distinct , molecular weights inhibits rbc - rbc adhesive interactions , leading to a very effective reduction of low - shear blood viscosity are anti - aggregant , and are immunologically masked . however , the bound polymer presents no significant barrier to the free diffusion of small molecules such as dissolved gases ( i . e ., oxygen and carbon dioxide ), electrolytes , sugars , amino acids and water in and out of the cell . this invention includes a peg - modification or coating technique that is inexpensive , rapid and simple to perform . because the technique is designed to be compatible with physiological conditions , the technique causes no damage to the target living cell as demonstrated by the data for rbcs presented herein . this invention also includes optimal peg - derivatives , which , together with the coating technique enable conjugation to the target cell as described below . pursuant to this invention , one or both ends of the peg molecule is modified by the addition of a chemically reactive functional group , which acts as a “ linker ” to bind the otherwise inert peg molecule to the target . although a wide range of different peg derivatives have been synthesized for binding to protein , and many of these are commercially available , most of these derivatives react primarily with available amino groups ( lysine residues ) on the target proteins . ( j . m . harris , poly ( ethylene glycol ) chemistry : biotechnical and biomedical applications ; plenum press , new york 1992 ; s . zalipsky , chemistry of poly ( ethylene glycol ) conjugates with biologically active molecules , adv . drug delivery rev ., 16 ( 1995 ) 157 - 182 ; c . delgado , g . e . francis and d . fisher , the uses and properties of peg - linked proteins , crit . rev . ther . drug carrier syst ., 9 ( 1992 ) 249 - 304 ). these existing peg derivatives vary in terms of their reactivity and their optimal reaction conditions . to peg - modify rbcs without loss of viability , this invention discloses peg derivatives that are capable of modifying living cells existing in aqueous media and under conditions as near to physiological as possible . to verify the utility of the compounds disclosed herein , twenty different monofunctional peg derivatives , each of 5000 daltons molecular weight , were incubated with washed rbc suspended in triethanolamine buffer at ph 8 . 6 for 2 hours at 25 ° c . the rbc were then washed and resuspended in autologous plasma . successful peg - coating of the cell was verified first by measuring inhibition of rbc aggregation , using an automated rbc aggregometer and by visually examining the rate and extent of rouleaux formation after a well - mixed sample was introduced into a chamber between a microscope slide and a cover slip . the results demonstrate that certain peg - derivative formulations are particularly effective for targeting living cells . referring to fig1 a , monomethoxy poly ( ethylene glycol )- 4 , 6 - dichloro - s - triazine ( obtained from sigma chemical co ., st . louis , mo .) is considerably more effective than the others . peg - dichlorotriazine derivatives react rapidly in aqueous media at alkaline ph with the amino groups of lysine residues and may also react with thiol groups . the n - hydroxy - succinimidyl derivatives , mpeg - sc and mpeg - spa ( shearwater polymers , huntsville , ala . ), also showed a tendency to reduce rbc aggregation , but to a much lesser extent . many other peg derivatives tested , including peg - aldehyde , peg - epoxide , peg - hydrazide , peg - tresylate or peg - maleic anhydride , each fail to show significant inhibition of rbc aggregation . referring again to fig1 a , this molecule is a mono - functional derivative prepared from peg with one end capped by an unreactive methyl group ( i . e ., monomethoxy peg , or mpeg ). the derivative is prepared by reacting the hydroxyl - terminated end of the mpeg molecule with an excess of 2 , 4 , 6 - trichloro - s - triazine in a non - aqueous solvent such as benzene ( a . abuchowski , t . van es ., n . c . palczuk and f . f . davis , alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol ., j . biol . chem ., 252 , 3578 - 3581 , 1977 . the trivial name for trichlorotriazine ( c 3 n 3 cl 3 ) is cyanuric chloride ; hence , this derivative is commonly abbreviated as peg - cn . ( note that the — cn suffix denotes the heterocycle c 3 n 3 , and does not refer to cyanide (— c ═ n )). studies were performed using mpeg - cn of 5000 daltons molecular weight obtained from sigma chemical co ., st . louis , mo . referring to fig1 b , two di - functional peg - cn derivatives of 3350 and 18500 daltons molecular weight were also synthesized according to the method of abuchowski et al . ( a . abuchowski , t . van es ., n . c . palczuk and f . f . davis , alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol ., j . biol . chem ., 252 , 3578 - 3581 , 1977 ). using these selected peg derivatives , the peg coating technique was conducted using rbcs as exemplary living cells . peg - coating of rbc was performed by first washing the rbcs and then suspending at 50 % hematocrit in 30 mm triethanolamine buffer at ph 8 . 3 , with 0 . 5 % human serum albumin ( hsa ). the desired concentration of the selected peg - cn derivative was rapidly dissolved in a small volume of buffer and added to the rbc suspension . the rbc - polymer mixture was then rocked gently at room temperature for 30 minutes , after which the rbc was washed twice in buffer . the coated rbc were resuspended at 40 % hematocrit in autologous plasma . after peg - coating , rbc showed normal morphology ( i . e ., biconcave discs ) as evaluated by optical microscopy , except when very high peg concentrations were used , which resulted in echinocytosis ( m . bessis , r . i . weed and p . leblond . red cell shape , springer - verlag , new york , 1973 ). rbc deformability was measured using the cell transit analyzer ( cta , abx , montpellier , france ), which measures the time taken for rbc to deform and pass through 5 micron diameter pores . the deformability of peg - coated rbc was unchanged from control , except at high peg concentrations and only when the morphology was also compromised . oxygen uptake and release , measured using a hemox - analyzer model b ( tcs medical products co ., huntingdon , pa .) was found to be identical to control rbc . referring to fig2 the effect of peg - coating on whole blood viscosity is shown . the viscosity of control rbc and peg - coated rbc were compared over a range of shear rates using a couette viscometer ( contraves ls30 , contraves ag , switzerland ). the control rbc show a typical steep change in viscosity with shear rate . in contrast , the viscosity for the peg - coated rbc ( lower curve ) showed very little shear dependence , i . e ., the blood behaved in a nearly newtonian manner , consistent with the complete elimination of rbc - rbc aggregation . at the higher shear rates ( 10 - 100 sec − 1 ), the curves for control and peg - coated rbc exactly converged . given that the hematocrit and plasma viscosity were identical for the two samples , this confirms that the rbc deformability was not altered by the peg - coating . note that the amount of bound peg required to abolish rbc aggregation and minimize low shear viscosity is much lower than that required for antigen masking ( see example 2 below ), and is therefore less likely to impair the function or compromise the survival of the rbc — an essential requirement for non - transfusion - related applications . referring to fig3 the viscosity of rbc in plasma at 40 % hematocrit as a function of shear rate is shown and compared with rbc hemodiluted with dextran with peg - modified rbc , and with poloxamer 188 ( p188 ). the curve for untreated , control rbc demonstrates the well - established shear - dependent decrease in viscosity : at low shear the viscosity is markedly elevated due to rbc aggregation , while with each stepwise increase in shear , the viscosity decreases due to the disruption of rbc aggregates . rbc treated with mpeg - cn showed a much reduced low shear viscosity ( 75 % less than control ). by comparison , poloxamer 188 at 5 mg / ml was less effective , reducing the low shear viscosity by approximately 30 %. rbc aggregation measured by the myrenne aggregometer ( m mode ) was reduced by 93 ± 8 % after mpeg - cn treatment compared to 33 ± 9 % for 5 mg / ml poloxamer 188 ( mean ± sd ). microscopic examination of rbc in autologous plasma showed that & gt ; 98 % of rbc remained as biconcave discocytes after mpeg - cn treatment . the only observable microscopic difference between mpeg - coated and control rbc was the absence of rouleaux formation . no change in rbc deformability was detected with the cell transit analyzer . referring again to fig3 the potential of peg - coated rbc as a rheological treatment , is demonstrated by comparing the viscosity reduction observed in vitro by either hemodilution or the addition of poloxamer 188 ( basf , parsippany , n . j .) as compared with that for the peg - coated rbc of this invention . as noted above , hemodilution from 40 % to 30 % hematocrit with dextran 40 ( sigma ) resulted in a large drop in viscosity , especially low - shear viscosity . however , the low - shear viscosity was still lower for the peg - coated rbc suspension at 40 % hematocrit , in 100 % plasma , than for the hemodiluted blood at 30 % hematocrit . thus , the peg - coating achieved a greater reduction in viscosity , but without compromising the oxygen - carrying capacity of the blood . in contrast , poloxamer 188 caused only a modest reduction in low shear viscosity at a concentration of 5 mg / ml plasma , which represents the upper limit of the concentration that would be achieved in clinical use ( r . c . jewell , s . p . khor , d . f . kisor , k . a . k . lacroix and w . a . wargin , pharmacokinetics of rheothrx injection in healthy male volunteers , j . pharm . sciences , 86 ( 1997 ) 808 - 812 ). the extent of antigen masking that could be achieved by peg coating was examined using the peg - cn derivatives described above , alone and in combination , over a range of concentrations . standard blood bank serology techniques ( agglutination testing ) were used for the initial screening of antigen masking ; blockade of antibody binding was later quantified directly by flow cytometry , agglutination studies were conducted using a standard tube test , with antisera ( immucor inc ., norcross , ga . and gamma biologicals inc ., houston , tx .) to a selected range of antigens from the rh and other blood groups , many of which are commonly implicated in delayed hemolytic transfusion actions . the standard glass tube was pre - coated with human serum albumin ( hsa ) by rinsing with apes ( sigma chemical co ., st . louis , mo . ), washing with water , soaking in 3 % hsa in pbs for 5 min ., and finally rinsing with water and allowing to dry before use . table 1 compares the direct agglutination observed for control ( untreated ) rbc and rbc incubated with peg - cn 18500 daltons at 20 mg / ml . the striking result was that direct agglutination , which was 3 + or 4 + for the control rbc , could be completely blocked by the peg - cn 18500 for each of the antisera tested . table 1 : direct agglutination tests , using antisera for several clinically important blood group antigens , for control ( untreated ) rbc and rbc incubated with peg - cn 18500 at 20 mg / ml . rh antigens other blood group antigens d c c e e le b jk a jk b fy a n p 1 control 4 + 4 + 4 + 4 + 4 + 3 + 4 + 4 + 3 + 3 + 3 + peg - coated 0 0 0 0 0 0 0 0 0 0 0 rbc the other peg derivatives , mpeg - cn 5000 and peg - cn 3350 , also inhibited agglutination , but were slightly less effective , typically giving a 1 + reaction . in contrast , it proved more difficult to block agglutination by antisera to the a and b antigens . with each of the peg derivatives , agglutination was observed with the full - strength antisera . thus , it was necessary to prepare serial dilutions of the anti - a and anti - b reagents to compare the titers at which agglutination was prevented . table 2 : titers ( reciprocal dilutions ) at which anti - a antisera no longer caused detectable rbc agglutination , for rbc coated with three different molecular weights of peg . a high titer indicates strong reactivity . masking of the a antigen by peg - coating is indicated by a reduction in titer . anti - a titer concentration ( mg / ml ) peg 18500 peg 3350 mpeg 5000 0 512 512 128 10 16 128 64 20 4 64 32 30 2 64 16 40 16 16 again , the peg 18500 proved to be the most effective ; the minimum titer at which detectable agglutination was observed decreased from 512 to 2 with 30 mg / ml peg - cn 18500 . smaller pegs were less effective ; the titer was reduced to 16 at 40 mg / ml for both peg - cn 3350 and mpeg - cn 5000 . higher concentrations of peg were not tried , because between 30 and 40 mg / ml the normal rbc morphology was lost , and all cells became spheroechinocytic when examined in autologous plasma . because the prevention of agglutination does not necessarily indicate that the rbc are “ antigenically silent ,” the blocking of antibody binding by techniques other than agglutination must be demonstrated . thus , flow cytometry was used to precisely quantitate the degree of blockade of antibody binding . an fitc - conjugated goat anti - human igg antibody ( sigma ) was used to quantitate the amount of anti - d antibody bound to rbc after incubation with increasing concentrations of peg - cn 3350 and peg - cn 18500 . the control and treated rbc were incubated with the primary anti - d antibody at a high antibody - to - cell ratio to prevent direct agglutination , washed 4 times , and then incubated with the fitc - conjugated secondary antibody , again at a high antibody - to - cell ratio . the cells were then analyzed by flow cytometry . even with the above precautions , some agglutinates were observed for the control ( non - peg - coated ) rbc , though these were typically less than 50 % of the total number of events . thus , for analysis , a gate was set using the forward and side scatter pattern to include only single rbc , and exclude agglutinates of 2 or more cells . referring to fig4 the effect of coating with peg 3350 on anti - d binding is shown . the first column shows the modal fluorescence ( in arbitrary units ) of d positive ( control ) rbc . the last column shows the background fluorescence of d negative rbc . a progressive decrease in antibody binding was observed with increasing peg concentration , which reached a minimum of about 85 % inhibition at a peg - cn 3350 concentration of 20 mg / ml . no additional effect was observed at higher peg concentrations . [ 0055 ] fig5 shows that peg - cn 18500 alone was less effective at blocking anti - d binding than peg - cn 3350 at the same concentration ( 71 % vs . 85 %). however , when the peg - cn 18500 and 3350 were used in combination , an additive effect was observed which resulted in substantial further decrease in anti - d binding ( to 96 %). this combination of two discrete peg derivatives having a higher and lower molecular weight ( e . g ., 10000 - 50000 , 2000 - 5000 ) has given the best results to date , and typically resulted in a greater degree of masking for antigens other than d , e . g ., 97 . 4 % and 99 . 4 % for the rh antigens c and e , respectively . the larger molecule , peg 18500 , was more effective at blocking agglutination to the a and i antigens , which are carbohydrates , than were the smaller peg molecules . these carbohydrate antigens are present in high copy number on the cell , and may be located throughout the glycocalyx at some distance from the nearest adjacent protein . as the peg derivatives bind exclusively to proteins , the higher molecular weight peg , with its larger zone of steric hindrance , is more likely to mask the carbohydrate antigens than the lower molecular weight peg molecules . in contrast , the flow cytometry results showed that the lower molecular weight peg 3350 was more effective at masking the rh antigens . the rh antigens are located on transmembrane proteins , with their antigenic sites located close to the membrane . thus , the rbc membrane surface is more accessible to the lower molecular weight peg molecules , while the higher molecular weight peg molecules may be excluded by steric interactions with larger rbc surface structures and the rbc glycocalyx . to achieve the best results , two discrete molecular weight ranges are used . a higher molecular weight range has at least a portion of the range above 10 , 000 daltons and a lower range has at least a portion below 10 , 000 . preferably , the molecular weight range of the lower molecular weight peg derivative is between approximately 2 , 000 and 5 , 000 daltons , e . g ., 3350 . the molecular weight range of the higher molecular weight peg derivative is approximately 10 , 000 - 50 , 000 daltons e . g ., 18 , 500 . thus , a preferred rbc formulation according to this invention has rbcs with two species of peg derivatives having discrete molecular weight ranges covalently bound to the surface : this combination has been demonstrated to yield improved results over either species alone . using this technique of selecting a plurality of certain peg derivatives with discrete molecular weight ranges , i . e ., with a combination of peg - cn 18500 and peg - cn 3500 at 20 mg / ml , between 96 and 99 % of anti - d binding can be consistently blocked , with similar or greater inhibition for the other rh antigens . the use of higher concentrations of these simple linear peg - cn derivatives can further reduce antibody binding , but was found to severely compromise the rbc morphology . this was especially noticeable with the mpeg - cn 5000 derivative , with which rbc became severely echinocytic at concentrations above 10 mg / ml . improved peg derivatives can be created by providing linkers other than dichlorotriazine and by using known polymer molecules with a different geometry to create an even more effective steric barrier while maintaining rbc morphology and deformability . in addition to the antigen masking effects described above , the attachment of peg also strongly inhibits the aggregation of rbc . the aggregation of rbc in autologous plasma was measured using a myrenne aggregometer ( myrenne gmbh , roetgen , germany ), an instrument which quantifies rbc aggregation by measuring the rate of change of light transmission through a sheared blood sample r . m . bauersachs , r . b . wenby and h . j . meiselman , determination of specific red blood cell indices via an automated system , clin . hemorheol , 9 ( 1989 ) 1 - 25 ). peg - coated rbc were prepared as described above ( control rbc were incubated in buffer alone ), after which both peg - coated and control rbc were resuspended in autologous plasma at 40 % hematocrit . referring to fig6 the effect of incubating rbc with increasing concentrations of mpeg - cn 5000 is shown . rbc aggregation decreased with increasing peg concentration , and was abolished at a concentration of 5 mg / ml and above . peg - cn 18500 was more effective , and completely inhibited rbc aggregation at 1 mg / ml ( i . e ., nearly 20 times more effective on a molar basis ). furthermore , given that the techniques require ex vivo rbc modification , it would be difficult in practice to treat all of the circulating rbc . the proportion of treated cells required to achieve a significant rheologic effect is shown in fig7 . when half of the rbc were treated , aggregation was reduced by & gt ; 80 %, while replacement of just one tenth of rbc with peg - treated cells reduced aggregation by 20 %. applying the teachings of this invention , one may select several different polymers for covalent binding to a cell surface . poloxamers , as described above , are a well - known class of polymers whose efficacy in certain biological situations has been reported . pursuant to this invention , rbcs may be coated with poloxamers to make an rbc formulation that maintains the antigen masking effects described above while tailoring the viscosity effects as desired by the clinical indication . the covalently bound f68 strongly reduces low shear viscosity at 25 °. however , at 37 ° ( body temperature ), the viscosity is much closer to the control . f98 covalently bound to rbcs is strongly pro - aggregant at both temperatures . thus , where antigen masking is desired without a low viscosity rbc formulation , the invention provides a selection of polymers that may be utilized . the particular examples set forth herein are instructional and should not be interpreted as limitations on the applications to which those of ordinary skill are able to apply this invention . modifications and other uses are available to those skilled in the art which are encompassed within the spirit and scope of the following claims .

living cells modified at their surface with specially selected polymers are disclosed . a simple method to covalently attach specially selected peg derivatives to the surface of rbc in aqueous media under mild conditions is a preferred example . the selected peg - modification dramatically reduced aggregation and low shear viscosity of rbc resuspended in autologous plasma , and inhibited rbc agglutination by blood group - specific antibodies . the morphology and deformability of the peg - treated cells were unaltered . the peg coating of the rbc surface is applicable to the treatment of a variety of diseases characterized by vaso - occlusion or impaired blood flow , e . g ., myocardial infarction , shock , and sickle cell disease .

devices , systems , methods and kits provided herewith can obviate the need for a plurality of procedures , including , for example : 1 ) percutaneous cholecystostomy , 2 ) cholecystectomy , 3 ) percutaneous trans - hepatic cholangiography ( pthc ), and 4 ) endoscopic retrograde cholangiopancreatography ( ercp ). additionally , disclosed treatment modalities enable treatment of a distal common bile duct 18 obstruction , e . g . secondary to pancreatic carcinoma , cholangiocarcinoma , and / or ampullary carcinoma . as will be appreciated by those skilled in the art , the conventional standard of care for treating biliary disease has been surgical removal of the gallbladder 14 and closure of the cystic duct 16 . while this has proven to be an effective mechanism for permanently eliminating biliary disease and its recurrence , the present invention seeks to accomplish the same end in a less invasive and less costly way . this may be achieved by treating biliary disease without requiring the removal of the gallbladder 14 . methods and apparatus are described in this application that are intended to effectively treat biliary disease with the gallbladder 14 and cystic duct 16 left in situ by defunctionalizing the gallbladder . by treating the gallbladder in situ in such a way that the biliary disease necessitating treatment is addressed and the likelihood of recurrence is low or altogether eliminated , the need for additional treatment , e . g . cholecystectomy , may be obviated . one method for achieving these goals may be defunctionalization of the gallbladder . a gallbladder that is treated and remains in situ but is otherwise non - functional may lead to the desired result . alternatively , for example , this goal may be achieved by altering the configuration of the gallbladder 14 in such a way that the underlying condition is addressed and prevented from recurring . the gallbladder can be accessed by any suitable mechanism including , percutaneously , endoscopically , laparoscopically , and the like . moreover , any of the materials and substances delivered to the gallbladder can be delivered concurrently or sequentially . delivery of substances can occur sequentially in time or the sequence of delivery can be separated by seconds , minutes , or hours . a method of treating biliary disease involves using an endoscope 310 to access a region in the gastrointestinal ( gi ) tract ( fig3 ) to which the gallbladder 14 is in close proximity 350 , locating the gallbladder 14 , accessing the gallbladder 14 , and then treating the underlying condition that led to the need for intervention ( fig3 ). treatments may also include , but are not limited to : providing for drainage of the gallbladder 14 and / or the biliary tree , delivering suitable substances or materials , such as antibiotics , inflammatory , and / or anti - inflammatory agents ( any of which may be short - term acting , fast acting , or time release ), and / or other substances ( e . g . adhesives , bioadhesives , etc .) to the gallbladder 14 and / or biliary tree , removing gallstones 20 , facilitating the destruction and subsequent removal of gallstones , clearing obstructions , delivering catheters , delivering stents ( drug coated or not drug coated ), temporarily or permanently defunctionalizing the cystic duct 16 , temporarily or permanently defunctionalizing the gallbladder 14 . devices and therapies can be delivered in a single treatment , with minimal likelihood of or necessity for follow - up or repeat procedures . localization of the gallbladder 14 can be performed via endoscopic ultrasound ( eus ) by accessing the wall of the gi tract with an endoscope 310 as shown in fig3 . localization may also be achieved by any other method that visualizes anatomical features , such as fluoroscopy , x - rays , magnetic resonance imaging ( mri ), computed axial tomography ( ct ) scans , ultrasound imaging from outside the body , or any method of anatomical imaging and visualization . once the gallbladder 14 has been located , it may be accessed and / or treated 350 through the wall of the gi tract ( or any lumen in proximity to the gallbladder 14 ) with tools and devices ( e . g . needles , guidewires , guidance catheters , dilators , shunts , etc .) delivered through or by , for example , an endoscope 310 . such tools and devices may be inserted down the length of the endoscope &# 39 ; s working channel 312 , or loaded onto or near the distal end of the endoscope 310 . alternately , tools and other devices may be used that do not require the aid of the endoscope for navigation or delivery . direct visualization may be provided by the endoscope 310 during the procedure , as well as irrigation , suction , and insufflation . though the preferred location for accessing the gallbladder lumen is the duodenum 30 , it may also be readily achieved through the wall of other regions of the gi tract , such as the stomach or the jejunum , for example . thus , any lumen in close proximity to the gallbladder 14 is a candidate for access to and treatment of the gallbladder 14 and other members of the biliary system . in order to defunctionalize the gallbladder 14 , it may be beneficial to sclerose or necrotize the tissue inside the lumen of the gallbladder 14 . this may involve only the tissue within the gallbladder 14 , but it may also include , for example , the tissue comprising the cystic duct 16 , which is the passageway leading into the gallbladder 14 from the common bile duct 18 . sclerosing or necrotizing the tissue within the gallbladder 14 may be achieved by using any ablating technique , such as cryoablation , thermal ablation , chemical ablation , radio frequency ( rf ) ablation , microwave ablation , and ultrasound ablation . in the case of cryoablation , cold fluids ( such as liquids , sprays , mists , and gases ) may be applied to the walls of the lumen of the gallbladder 14 with an applicator 420 having a proximal end 402 and distal end 404 ( fig4 ). any non - solid sclerosing agent may be similarly applied with an applicator . such fluids may be applied evenly so that the effect is consistent throughout the affected areas , or they may be applied selectively or unevenly . the applicator 420 optionally includes a user controllable valve 440 , as illustrated in fig4 e , within its lumen to facilitate control and application of the fluids or gases during the defunctionalization process . the user controllable valve can be positioned proximally from the delivery tip . the applicator 420 can be delivered through a working channel 412 of an endoscope 410 . during defunctionalization part or all of the walls may be treated . in order to have the ability to apply therapy anywhere within the gallbladder , it may be necessary to direct the application of such fluids by the applicator 420 at a variety of depths within the gallbladder 14 , and at any or all angular orientations . the applicator 420 has one or more apertures 422 in communication with a central lumen through which fluid 423 or material is delivered . as discussed above , a controllable valve 440 is positioned within the interior lumen of the applicator 420 to provide control of the amount and timing of delivery . different applicators 420 or nozzles may be useful for achieving this , such as those configurable to direct flow in a 360 ° radial pattern ( fig4 a ), a sharp stream or a cone shape directed forward by the applicator ( fig4 b ), or a sharp stream or a cone shape directed sideways by the applicator ( fig4 c ). the applicator 420 may be capable of articulating so that it may be selectively aimed ( fig4 d ). in order to distinguish treated areas from untreated areas , a pigment may be added to the fluid . alternately , treated tissue may have a different appearance from untreated tissue due to the resulting sclerosis or necrosis . applicators may be guided by one or more of a needle , a guidewire , and / or a guidance catheter , and controlled proximally by a clinician , as illustrated in fig6 . alternately , applicators may navigate freely within the gallbladder . applicators 620 may be delivered to the gallbladder lumen 14 through the tool channel 612 of an endoscope 610 and may remain within the endoscope during their use , or they may be guided into the gallbladder 14 using alternate guidance elements 630 ( e . g . a needle , a guidewire , and / or a guidance catheter ). in some instances , directly visualizing the devices and navigational devices used may also be desirable , and may facilitate control and treatment . visualization may be achieved by any suitable mechanism known in the art , including , for example , endoscopic ultrasound ( eus ), or by using a small daughter endoscope ( e . g . a cystoscope ), or by using catheters incorporating small imaging sensors at the distal end ( e . g . avantis &# 39 ; third eye ) and fiber optic imaging bundles ( e . g . boston scientific &# 39 ; s spyglass ). visualization and guidance may also be achieved via external imaging methods , such as fluoroscopy ( with or without the use of contrast agent ), ultrasound , x - ray , etc . the outer diameter of the applicator 620 is smaller than a mammalian esophagus and can be larger than , for example , the diameter of the cystic duct 16 as illustrated . additionally , cryoablation can be used to effect treatment by flooding the entire gallbladder lumen or duct lumen with a fluid 517 ( fig5 ). localization of the gallbladder 14 can be performed via endoscopic ultrasound ( eus ) by accessing the wall of the gi tract with an endoscope 510 as shown in fig5 . thereafter , this can , for example , be performed with a liquid , but a gas may also be used . filling the lumen , or substantially filling the lumen , with such a working fluid 517 ensures even distribution of treatment . the fluid or gas may be initially a first temperature and then be altered such that the temperature achieves a desired therapeutic level . an applicator for this approach may have one or more apertures 522 for introducing fluids 587 into the gallbladder and optionally withdrawing fluids 586 from the gallbladder . a stirrer 524 can be provided that stirs or mixes the fluid or gas 517 that is delivered into the lumen . this feature may ensure uniformity of properties throughout the working fluid or gas and increase the rate of temperature change ( fig5 ). the working fluid 517 may be left in place , or actively withdrawn after treatment is completed . as will be appreciated from fig5 , access to the gallbladder 14 can be achieved through the wall of the duodenum 30 . the outer diameter of the applicator 520 is smaller than a mammalian esophagus and larger than , for example , the diameter of the cystic duct 16 as illustrated . in cases when the activatable material , such as a working fluid or gas 517 , remains in the gallbladder lumen or duct lumen , it may be selected so that it becomes a biocompatible gel or foam once it has reached a specific state , such as a low or high temperature , or contact with an activating agent , or when sufficient time has passed . the activating agent may be selected to be bile , so that the gel or foam becomes further activated in the presence of flow of bile . in this way , it a self - sealing mechanism is established . such a foam or gel may also be selected so that it is bioabsorable , and is self dissipating after a desired period of time . an amount of fluid , gas , or material delivered as described throughout can be such that it fills the gallbladder , substantially fills the gallbladder ( e . g ., fills more than 50 % of the gallbladder , more than 75 % of the gallbladder , more than 85 % of the gallbladder , more than 90 % of the gallbladder , more than 95 % of the gallbladder , or more than 99 % of the gallbladder ) or is activatable to fill or substantially fill the gallbladder . alternatively , in some instances , e . g ., where a vacuum is applied , the amount of fluid , gas , or material delivered as described throughout can be such that it coats the interior lumen of the gallbladder , or substantially coats the interior lumen of the gallbladder ( e . g ., coats more than 50 % of the gallbladder , more than 75 % of the gallbladder , more than 85 % of the gallbladder , more than 90 % of the gallbladder , more than 95 % of the gallbladder , or more than 99 % of the gallbladder ). in contrast to cryoablation , thermal ( or heat ) ablation may be applied to effect treatment . the same methods outlined above for cryoablation may also be used in the application of therapies based on heat ablation . this includes using working fluids that may be applied using a spray applicator , working fluids that completely fill , or substantially fill , the lumen , working fluids that are introduced at a non - therapeutic temperature and then altered so that the temperature is increased to therapeutic levels , and fluids that become gels or foams at a desired elevated temperature . these techniques may be used with any fluid or non - solid sclerosing agents in addition to those described above . in another approach thermal ablation is achieved through the use of infrared light to heat the tissue comprising the gallbladder 14 and / or cystic duct 16 . another alternate method of defunctionalizing the gallbladder 14 involves applying a vacuum . after occlusion of , for example , the cystic duct 16 , application of a vacuum to the gallbladder lumen causes it to collapse to a smaller volume . the internal volume of the gallbladder lumen may be eliminated altogether . making this collapsed volume permanent or semi - permanent results in the goal of defunctionalizing the gallbladder 14 . substances may be applied to the gallbladder walls prior to the application of vacuum , such as a bioadhesives , sclerosing agents , or fluids used in cryo - or thermal ablation . these fluids may serve to enhance the outcome or improve the efficacy of the treatment . the devices and methods disclosed herein facilitate defunctionalizing the gallbladder without the need for surgery . all of the devices required to deliver and install a conduit , treat and / or defunctionalize the gallbladder , may be packaged in a kit . bundling all devices , tools , components , materials , and accessories needed to perform these procedures into a kit may enhance the usability and convenience of the devices , and also improve the safety of the procedure by encouraging clinicians to use the items believed to result in the best outcomes . the kit may be single - use or reusable , or it may incorporate some disposable single - use elements and some reusable elements . the kit may contain , but is not limited to , the following : implantable and / or non - implantable devices ; delivery devices ( e . g . needles , guidewires , guidance catheters , dilators , etc . ); balloon inflation / deflation accessories ; syringes ; fluid flow , temperature , and pressure measurement instruments ; scissors ; scalpels ; clips ; ablation catheters ; endoscopic tools ( e . g . lithotripsy devices , snares , graspers , clamps , forceps , etc . ); fluids ; gels ; gas cartridges adaptable to communicate with the devices . the kit may be supplied in a tray , which organizes and retains all items so that they can be quickly identified and used . the techniques and devices described in this application may prove beneficial in applications beyond their initial use in the treatment of biliary disease . for example , they may prove to be an effective mechanism of treating cholangitis ( infection of the common bile duct 18 ). this condition is usually bacterial , and occurs when the bile duct is blocked by gallstones 20 ′ or a tumor . traditional treatment involves the insertion a stent or drainage catheter into the common bile duct 18 to allow bile to drain into the duodenum from locations above the obstruction . placement of a conduit into the gallbladder 14 may allow for an alternate method of draining bile and / or other fluids into the duodenum . any blockage in the common bile duct 18 between the entrance of the cystic duct and the duodenum may be treated in this way . see fig2 . another use of the devices and techniques described herein is for drainage of any body lumen into another body lumen in proximity , for example , the drainage of pancreatic pseudocysts . while preferred embodiments of the present invention have been shown and described herein , it will be obvious to those skilled in the art that such embodiments are provided by way of example only . numerous variations , changes , and substitutions will now occur to those skilled in the art without departing from the invention . it should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention . it is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby .

a device for treating biliary disease includes a component configured for deployment to a lumen of a gallbladder or gallbladder duct . the component has a proximal end and a distal end with a lumen extending therethrough and a fluid or gas delivery apparatus at its distal end .

fig1 schematically represents a control system for a coffee maker constructed in accordance with the invention . a controller 100 is preferably provided in the form of a microprocessor supplied with memory . a timer 110 , which may be external to the controller , is shown here as integral to the controller . the timer 100 is in data communication with the controller 100 so as to be adapted to rest to zero and start upon receipt of a timer start command signal from the controller 100 and to stop upon receipt of a timer stop command signal from the controller 100 . the controller 100 is in data communication with user inputs 330 , which derive from user controls on the coffee maker . the controller 100 is also in data communication with sensor inputs 130 , which may include the temperature of an evaporation chamber in which water is boiled for brewing and the temperature of a warming plate upon which a coffee pot sits , as well as any other physical data a designer may desire for the various operations of the coffee maker . the controller 100 is in data communication with various devices that effect the operation of the coffee maker , such as the controllable components of a coffee grinding system 140 and the controllable components of the brewing system 160 , so as to be able to control them with command signals . the controllable components of the brewing system can be no more than the separate heating elements in the evaporation chamber and the warming plate . the controller 100 will also be in data communication with a display 310 , such that the time registered by the timer 110 may be displayed thereon . display 310 can take the form of a led , lcd , plasma display or any other suitable display . also , the controller 100 may command the display to display other data , such as the current date and time , or system status , upon its own initiative or upon a user command . the controller 100 may read timer data from the timer 110 and transfer it to the display or may simply shut on and off a direct transfer of timer data from the timer 110 to the display 310 . as will be explained with respect to fig4 , this timer will be used to provide the time - since - brew . the controller will preferably also be in command of one or more indicator leds 335 as will be described with respect to fig2 . fig2 shows one example of a control panel design for the coffee maker . the arrangement of the controls on the panel is purely a matter of choice . the panel includes a number of user controls 330 , a display screen 310 and a plurality of indicator leds 335 . the type of controls and indicator leds will depend on what features the coffee maker has . what is necessary to the invention is the display 310 and a controller to initiate and terminate brewing . the display is preferably a display screen 310 having medium to high resolution graphical capability , generally at least 200 pixels per inch , preferably at least 300 pixels per inch . a lcd is preferred for its compactness , quality of image , and commercial availability . good graphical capability is desirable because it allows for simulating analog devices , as will be explained wit respect to fig3 . alternatively , costs may be reduced by foregoing a display screen and using a simple numeric led display . typical controls include a delay button 330 a with hour 330 b and minute 330 c buttons to allow the user to set the coffee maker to begin brewing at a specific time . a function button 330 d may be provided that allows the user to either place the coffee maker in an “ on ” mode to begin brewing immediately , a “ delay ” mode to have the coffee maker activate control 330 a , a “ clean ” mode to go through a process of cleaning out the evaporation chamber with vinegar , and an “ off ” mode to shut off the warming plate and the brewer apparatus as well if the coffee maker is in the middle of a brew . the function button 330 d operates by cycling the coffee maker through these modes , incrementing to the next mode each time the function button 330 d is pressed . leds 335 a through 335 d are activated in turn to indicate which function is currently selected , from on to off , respectively . other options include a brew strength control 330 e so the user may select either a regular or a strong brew , a warmer plate temperature control knob 330 f , and a display control 330 g that the user can use to cycle through the available displays , which might include , other than time - since - brew , the current date and time and various system parameters , such as warmer plate temperature . a power switch is not shown because it is not desirable to locate a power switch on a control panel where the user might mistakenly shut off the machine while in use . instead the power switch is generally located away from the control panel . fig3 a and 3 b depict typical graphical displays that may be provided on the display screen 310 . a simulated analog clock 340 is shown in fig3 a , which shows the current time of day . preferably , as shown , the graphics of the clock would be such as to give the illusion of 3 - dimensions , thereby giving the user the “ feel and comfort ” that analog devices are so much better at providing than digital devices . referring to fig3 b , there is shown a preferred embodiment of the time - since - brew display 350 . there are provided a plurality of gradations 360 indicating time in minutes . in the preferred embodiment , the maximum warming time 370 will be at the top of this dial , but this is purely optional . in the preferred embodiment of the invention , the plate warmer will shut down upon reaching the maximum warming time , as will be more fully explained with respect to fig4 . also provided are graphical time segments 380 that illuminate or activate to indicate the elapsed time . in the embodiment shown , an additional segment appears every two minutes . in fig3 b it can be seen that thirty minutes has elapsed since brewing . of course , fig3 b could be replaced with any number of creative designs , even a typical stopwatch design with hour and minute hands , but a reason a stopwatch or other clock - like design with a sweep hands is not preferred is because of the concern that the consumer might confuse such a display with the clock display of fig3 a . by making the displays plainly distinct from one another , the users know immediately what information they are looking at . referring to fig4 , there is shown a preferred embodiment of the logic and functioning of the invention . beginning at node 10 , the coffee maker is plugged in , the power switch is turned on , the clock is set for the correct time and the display screen 310 is showing the current time of day . control now flows to node 15 where the controller has received a brewing command signal , either because the user has manually initiated brewing or because the delay feature has auto - started brewing upon the time preset by the user . the controller issues the necessary brewing control signals to the brewing apparatus 160 . control now flows to node 20 where the controller issues a timer start command signal , causing the timer to start timing the time - since - brew . the controller also issues the necessary display command signals to cause the display screen 310 to show the time - since - brew display 350 . in an alternative embodiment , the controller could start the time - since - brew timer after brewing is completed or at any other desired time referenced to some point in time before , during or after brewing is completed . the completion of brewing can be signaled by the shutdown of the water heating chamber heating element , which may itself be controlled by the controller 100 when a sensor detects that the evaporation chamber temperature substantially exceeds the boiling point of water , thereby indicating that no water remains to be evaporated , and sends a brewing completion signal to the controller . control now flows to nodes 25 and 30 where the time - since - brew is divided by two , rounded down to the nearest integer , and displayed on the time - since - brew display 350 by graphically displaying integer x time segments 380 . this is purely optional . for the graphic display shown in fig3 b provided on a screen small enough to fit on a coffee maker control panel , there may not be enough display screen resolution to display a time segment every minute and get the graphic effect as shown . control now flows to decision node 35 where the system tests for whether 120 minutes has elapsed . if so , control flows to node 45 where the system goes into off mode , which simply means that the controller issues a shutdown command such that the warming plate is shut off , either the on indicator led 335 a or the delay indicator led 335 b goes off ( depending on which mode initiated the brewing ), the off indicator led 335 d goes on , and the display screen 310 shows the clock display 340 again . the choice of 120 minutes is purely arbitrary and based on the observation that coffee more than two hours old is generally of poor quality . there are those who don &# 39 ; t mind coffee much older than that , so this is a matter of design choice . it is not necessary to have such an automatic shut off feature , as one could skip this procedure altogether and allow the warming of the coffee to go on indefinitely , thereby allowing the user to decide when its time to clean the pot and make a fresh batch . in such case the time - since - brew display 350 would be modified to be able to show any time lapse . one way is to change the markings on the gradations so that the displayed maximum warming time 370 and other marked gradations change . to use fig3 as an example , initially the markings at every quadrant are 30 , 60 , 90 , and 120 as shown in the drawing . when the timer reaches 120 minutes , the markings change to 150 , 180 , 210 , and 240 . this change in markings can go on indefinitely . if at node 35 it is determined that two hours has not elapsed then control flows to decision node 40 where the system checks to see if the user might have pressed the display button 330 g . if so , the controller 100 cycles to the next display ( e . g ., system parameters ). if the time of day 340 and time - since - brew 350 are the only displays , then this display cycle will simply keep switching back and forth between the two each time the display button 330 g is pressed . control now flows to node 55 where the controller 100 checks to see if the user has selected the off function . if not , control returns to node 25 and the cycle repeated . if the off function has been selected with the function button 330 d , then control flows to node 45 , wherein the controller 100 shuts off the warmer , switches back to the time of day display , lights the off indicator led 335 d , and shuts off either the on indicator led 335 a or the delay indicator led 335 b . as can be seen , the use of a time - since - brew timer and display is a relatively inexpensive and effective method of alerting the user whether a new batch of coffee needs to be made . of course , this disclosure is not limited to coffee , but is applicable to any brewed beverage , such as tea . while various values , scalar and otherwise , may be disclosed herein , it is to be understood that these are not exact values , but rather to be interpreted as “ about ” such values , unless explicitly stated otherwise . further , the use of a modifier such as “ about ” or “ approximately ” in this specification with respect to any value is not to imply that the absence of such a modifier with respect to another value indicated the latter to be exact . changes and modifications can be made by those skilled in the art to the embodiments as disclosed herein and such examples , illustrations , and theories are for explanatory purposes and are not intended to limit the scope of the claims . further , the abstract of this disclosure is provided for the sole purpose of complying with the rules requiring an abstract so as to allow a searcher or other reader to quickly ascertain the subject matter of the disclosures contained herein and is submitted with the express understanding that it will not be used to interpret or to limit the scope or the meaning of the claims .

a freshness indicator for a coffee maker having a controller is adapted to initiate the brewing of a quantity of beverage upon receiving a brewing command signal . a timer is adapted to output the time since activation of the timer upon a timer start command signal , and a display is adapted to display the output of the timer . the controller is adapted to output the timer start command signal to the timer at a predetermined time before , during or after brewing .

referring to fig1 , in accordance with an exemplary embodiment , a transnasal ventilation apparatus might comprise an insertion guide 10 , a first tube 20 , a inner tube 25 , a junction 30 , a second tube 40 , and a third tube 50 . the first tube 20 might comprise a first end 24 and a second end 22 . the inner tube 25 might comprise a first end 26 and a second end 28 . the second tube 40 might comprise a first end 42 and a second end 44 . and the third tube 50 might comprise a first end 52 and a second end 54 . further , the insertion guide 10 , the first tube 20 , the inner tube 25 , the junction 30 , the second tube 40 , and the third tube 50 might comprise a single apparatus by , for example , being fused or otherwise bonded together or integral . other embodiments are possible as well . referring to fig1 , the insertion guide 10 might comprise a proximal end 12 and a distal end 14 . although it need not be , insertion guide 10 might be tapered . for example , the diameter of the distal end 14 might be larger than the diameter of the proximal end 12 . the outside diameters of the proximal end 12 and the distal end 14 may also vary , for example , to accommodate various size nostrils and / or nasal airway passages . the length of the insertion guide 10 may vary as well . in an exemplary embodiment , the distal end 14 of the insertion guide 10 can be inserted into a patient &# 39 ; s nasopharynx . in an exemplary embodiment , the insertion guide 10 might be made of a flexible material . for example , the insertion guide 10 might be made of polyvinyl chloride (“ pvc ”). other materials , whether flexible or inflexible , are possible as well . referring to fig1 , in an exemplary embodiment , the proximal end 12 of the insertion guide 10 might comprise a connector 16 and a cuff 18 . the connector 16 might receive the first end 22 of the first tube 20 . although not necessary , the connector 16 of the insertion guide 10 might be bonded to the first end 22 of the first tube 20 . for example , the connector 16 can be bonded to the first end 22 by an adhesive or through chemical or heat fusing . other methods of bonding are possible as well . in other embodiments , the connector 16 might be integral with the first end 22 . the cuff 18 might contact a patient &# 39 ; s nostril and , in addition , might help seal the insertion guide 10 against the patient &# 39 ; s nostril . the first tube 20 might comprise a flexible material , such as pvc . the first tube might also be made of the same material as the insertion guide 10 ( which might occur if the insertion guide 10 is integral with or fused to the first tube 20 , for instance ). further , the first tube 20 might be made of the same material as the junction 30 ( which might occur if the junction 30 is integral with or fused to the first tube 20 , for instance ). other 1 . 5 examples are possible as well . in an exemplary embodiment , the first tube 20 might comprise a inner tube 25 . for example , the inner tube 25 might be inside the first tube 20 such that the outer surface of the inner tube 25 and the inner surface of the first tube 20 can form a passage 23 . the passage 23 might , in turn , provide fluid communication between a patient &# 39 ; s air passageways and the junction 30 . the junction 30 might comprise any type of three - way junction . fig2 depicts an exemplary junction 30 that might comprise seven chambers : a first chamber 31 , a second chamber 32 , a third chamber 33 , a fourth chamber 34 , a fifth chamber 35 , a sixth chamber 36 , and a seventh chamber 37 . other embodiments of junction 30 are possible as well . in the exemplary embodiments of fig1 and 2 , the first chamber 31 of junction 30 might receive the second end 24 of the first tube 20 , and the seventh chamber 37 might receive the first end 42 of the second tube 40 . the second chamber 32 and the sixth chamber 36 can then provide fluid communication between the passage 23 and the second tube 40 . further , the third chamber 33 of junction 30 might receive the second end 28 of the inner tube 25 , and the fifth chamber 35 might receive the first end 52 of the third tube 50 . the fourth chamber 34 can then provide fluid communication between the inner tube 25 and the third tube 50 . although not necessary , any combination or all of the first , second , third , or inner tubes 20 , 40 , 50 , and 25 might be bonded to the junction 30 . for example , tubes can be bonded to the junction 30 by an adhesive or through chemical or heat fusing . other methods of bonding are possible as well . in other embodiments , any combination or all of the tubes might be integral with the junction 30 . other embodiments of the junction 30 and / or the first , second , third , or inner tubes 20 , 40 , 50 , and 25 are possible . for example , portions of the first , second , third , or inner tubes may comprise a single tube . the inner tube 25 and the third tube 50 might comprise a single tube , for instance . in such a case , the third , fourth , and fifth chambers 33 , 34 , and 35 of junction 30 might comprise a single chamber that can engage the single tube . other examples are possible as well . returning to fig1 , the second end 44 of the second tube 40 might be connected to a connector 72 . the connector 72 might then connect the second tube 40 to an oxygen supply 70 . the second end 54 of the third tube 50 might be connected to a connector 62 . the connector 62 might then connect the third tube 50 to a carbon dioxide monitor 60 . the second tube 40 can then fluidly connect the junction 30 to the oxygen supply 70 , and the third tube 50 can then fluidly connect the junction 30 to the carbon dioxide monitor 60 . the second tube 40 and the third tube 50 might each be made of a flexible material , such as pvc . other examples are possible as well . for instance , the material of the second tube 40 and the third tube 50 might not be flexible , and the material of any of the first tube 20 , the inner tube 25 , the second tube 40 , or the third tube 50 need not be the same as the material of any other tube . further , the first , second , third , and inner tubes might also all be made of the same material as the junction 30 , which might occur if the first , second , third , or inner tubes are integral with or fused to the junction 30 , for instance . the lengths of the first , second , third , and inner tubes might also vary . referring to fig1 , in an exemplary embodiment , a user such as an anesthesiologist ( or any other medical or non - medical person ) might insert the insertion guide 10 into a patient &# 39 ; s nasal passage such that the distal end 14 of the insertion guide 10 extends toward the patient &# 39 ; s nasopharynx . in such an arrangement , the proximal end 12 of the insertion guide 10 might frictionally engage the patient &# 39 ; s nostril . in an exemplary embodiment , the distal end 14 of the insertion guide 10 might extend beyond the second end 26 of the inner tube 25 . in another embodiment , the distal end 14 might not extend beyond the second end 26 . the cuff 18 of the insertion guide 10 might provide a seal around a patient &# 39 ; s nostril , thereby providing for more efficient oxygen supply and exhale gas withdrawal . further , as shown in the embodiment of fig1 , the insertion guide 10 , the first , second , third , and inner tubes 20 , 40 , 50 , and 25 , the junction 30 , and connectors 62 and 72 might comprise a single apparatus , thereby providing for quicker assembly and easier use . the single apparatus might also provide for safer use because there are fewer parts to assemble , thereby lowering the risk of improper assembly or other errors . referring back to the exemplary embodiment of fig1 , the second tube 40 might provide for fluid communication between the junction 30 and an oxygen supply 70 . the oxygen supply 70 , in turn , might apply a low , positive pressure through the second tube 40 , the sixth and second chambers 36 and 32 of junction 30 , and the passage 23 . the third tube 50 might provide for fluid communication between the junction 30 and a carbon dioxide monitor 60 . the carbon dioxide monitor 60 , in turn , might apply a low , negative pressure through the third tube 50 , the fourth chamber 34 of junction 30 , and the inner tube 25 . in accordance with an exemplary embodiment , the transnasal ventilation apparatus can provide for a steady state oxygen supply to / carbon dioxide collection from a patient . as the patient inhales , the patient can draw the lightly pressurized oxygen from the oxygen supply 70 through the passage 23 into the patient &# 39 ; s nasopharynx . as the patient exhales , the patient can overcome the supply pressure of the oxygen in the passage 23 and can discharge the exhale gases from the patient &# 39 ; s nasopharynx into the inner tube 25 . the negative pressure applied by the carbon dioxide monitor 60 can , in turn , withdraw the exhale gases to the carbon dioxide monitor 60 . referring to fig3 , in accordance with an exemplary embodiment , a transnasal ventilation apparatus might comprise an insertion guide 10 , a first tube 20 , a junction 30 , a second tube 40 , and a third tube 50 . referring to fig4 , in accordance with another exemplary embodiment , a transnasal ventilation apparatus might comprise an insertion guide 10 , a first tube 20 fixedly attached to the insertion guide 10 , a junction 30 , a second tube 40 , and a third tube 50 , the junction 30 being integral with the first , second , and third tubes . fig5 shows an exemplary embodiment similar to the exemplary embodiment of fig4 , but with the junction 30 being fused to the first , second , and third tubes . although not shown , other embodiments are also possible . for instance , in another embodiment , the insertion guide 10 might be fixedly attached to the first tube 20 , but the junction 30 might not be integral with or fused to any or all of the first , second , or third tubes . other examples are possible as well . referring to fig3 , and 5 , the insertion guide 10 might comprise a proximal end 12 and a distal end 14 . although it need not be , insertion guide 10 might be “ bugle ” shaped such that the proximal end 12 has a larger circumference than the distal end 14 . the outside diameters of the proximal end 12 and the distal end 14 may vary , for example , to accommodate various size nostrils and / or nasal airway passages . in an exemplary embodiment , the outside diameter of the proximal end 12 is 10 mm . in another embodiment , the outside diameter of the proximal end 12 is 8 . 7 mm . the length of the insertion guide 10 may vary as well . in an exemplary embodiment , the insertion guide 10 might comprise a cannula two examples of commercially available cannulae are the kendall argyle ™ nasopharyngeal airway and the robertazzi ™ nasopharyngeal airway . other examples are possible as well . in an exemplary embodiment , the insertion guide 10 might be made of a flexible material . for example , the insertion guide 10 might be made of rubber latex . as another example , the insertion guide 10 ′ might be made of pvc . other materials , whether flexible or inflexible , are possible as well . in an exemplary embodiment , the insertion guide 10 might hold within it a first tube 20 . as shown in fig3 , for example , the first tube 20 might be slidably inserted into the insertion guide 10 . as shown in the embodiments of fig4 and 5 , the first tube 20 might be fixedly attached to the insertion guide 10 . for instance , the first tube 20 might be integral with or fused to the insertion guide 10 . other examples are possible as well . the first tube 20 might comprise a flexible material , such as silastic ™. the first tube might also be made of the same material as the insertion guide 10 ( which might occur if the insertion guide 10 is integral with or fused to the first tube 20 , for instance ). further , the first tube 20 might be made of the same material as the junction 30 ( which might occur if the junction 30 is integral with or fused to the first tube 20 , for instance ). other examples are possible as well . the first tube 20 might , in turn , provide fluid communication between a patient &# 39 ; s air passageways and the junction 30 . the junction 30 might comprise any type of three - way junction . in one embodiment , the junction 30 might comprise an airlife ™ tri - flo ® control suction catheter . as shown in the embodiment of fig4 , the junction 30 might be integral with the first tube 20 , the second tube 40 , and the third tube 50 . further , as shown in the embodiment of fig5 , the junction 30 might be fused to the first tube 20 , the second tube 40 , and the third tube 50 . other examples are also possible . in an exemplary embodiment , the second tube 40 might fluidly connect the junction 30 to an oxygen supply 70 , and the third tube 50 might fluidly connect the junction 30 to a carbon dioxide monitor 60 . the second tube 40 and the third tube 50 might each be made of a flexible material , such as silastic ™. other examples are possible as well . for instance , the material of the second tube 40 and the third tube 50 might not be flexible , and the material of any of the first tube 20 , the second tube 40 , or the third tube 50 need not be the same as the material of any other tube . further , the first , second , and third tubes might also all be made of the same material as the junction 30 , which might occur if the first , second , and third tubes are integral with or fused to the junction 30 , for instance . the lengths of the first tube 20 , the second tube 40 , and the third tube 50 might also vary . referring to fig3 , in an exemplary embodiment , a user such as an anesthesiologist ( or any other medical or non - medical person ) might insert the insertion guide 10 into a patient &# 39 ; s nasal passage such that the distal end 14 of the insertion guide 10 extends toward the patient &# 39 ; s nasopharynx . the user can then insert a first , open end 16 of the first tube 20 through the insertion guide 10 , such that the first end 16 extends toward the patient &# 39 ; s nasopharynx . in such an arrangement , the proximal end 12 of the insertion guide 10 might frictionally engage the patient &# 39 ; s nostril . the distal end 14 of the insertion guide 10 might frictionally engage the first end 16 of the first tube 20 and thereby hold the first end 16 in place . in an exemplary embodiment , the insertion guide 10 might hold the first end 16 in place beyond the distal end 14 . in another embodiment , the first end 16 might not extend beyond the distal end 14 . the first end 16 might also be held in place in other ways as well . as shown in the embodiments of fig4 and 5 , the insertion guide 10 might be fixedly attached to the first tube 20 . the insertion guide 10 might then frictionally engage the nostril and thereby be held in place . in the embodiments of fig4 and 5 , the insertion guide 10 and the integral or fused first tube 20 might provide a seal around a patient &# 39 ; s nostril , thereby providing for more efficient oxygen supply and exhale gas withdrawal . further , as shown in the embodiments of fig4 and 5 , the insertion guide 10 and the first tube 20 might comprise a single component , thereby providing for quicker assembly and easier use . the single insertion guide 10 / first tube 20 might also provide for safer use because there are fewer parts to assemble , thereby lowering the risk of improper assembly or other errors . referring back to the exemplary embodiments of fig3 , and 5 , the second tube 40 might provide for fluid communication between the junction 30 and an oxygen supply 70 . the oxygen supply 70 , in turn , might apply a low , positive pressure through the second tube 40 . the third tube 50 might provide for fluid communication between the junction 30 and a carbon dioxide monitor 60 . the carbon dioxide monitor 60 , in turn , might apply a low , negative pressure through the third tube 50 . in accordance with an exemplary embodiment , the transnasal ventilation apparatus can provide for a steady state oxygen supply to / carbon dioxide collection from a patient . as the patient inhales , the patient can draw the lightly pressurized oxygen from the oxygen supply 70 through the second tube 40 and through the first tube 20 into the patient &# 39 ; s nasopharynx . as the patient exhales , the patient can overcome the supply pressure of the oxygen in the first tube 20 and can discharge the exhale gases from the patient &# 39 ; s nasopharynx into the first tube 20 . the negative pressure applied by the carbon dioxide monitor 60 can , in turn , withdraw the exhale gases to the carbon dioxide monitor 60 . referring to fig6 and 7 , in accordance with another embodiment , a transnasal ventilation apparatus might comprise an airway , such as an insertion guide 10 , a flow - through airway fitting 80 , a first tube 20 , a second tube 25 , a third tube 40 , and a fourth tube 50 . the first tube 20 might comprise a first end 24 and a second end 22 . the second tube 25 might comprise a first end 26 and a second end 28 . the third tube 40 might comprise a first end 42 and a second end 44 . and the fourth tube 50 might comprise a first end 52 and a second end 54 . although shown as separate components , the insertion guide 10 , the flow - through airway fitting 80 , the first tube 20 , the second tube 25 , the third tube 40 , and the fourth tube 50 might comprise a single apparatus by , for example , being fused or otherwise bonded together or integral . other embodiments are possible as well . as shown in fig6 , the first tube 20 and the second tube 25 can be coupled , with one or more cinches 88 , for example . ( in another embodiment , the tubes can be sold joined together as a pair .) in any case , the tubes can be similar to datex - ohmeda no . 73318 tubing , for example . as depicted in fig6 , the cinches 88 can prevent the tubing from separating , and can also provide a mount for other devices , such as for a clip 90 , for example . the clip 90 can then attach the tubing to the patient , the bed , etc ., to make for a neater , safer patient environment . as shown in fig7 , the third tube 40 and the fourth tube 50 can also be coupled . in one embodiment , the tubes can be sold joined together as a pair . ( in other embodiments , the tubes can be joined in other ways .) in any case , the tubes can be similar to datex - ohmeda no . 73318 tubing , for example . by being joined , the tubes can provide a neater , safer patient environment and can prevent the misconnecting of tubes . as shown in fig6 , the first tube 20 and the second tube 25 can each include one or more fittings on its ends to connect to other components . in one embodiment , the second end 24 of the first tube 20 can comprise a fitting 92 , such as a female luer lock , for example . likewise , the second end 28 of the second tube 25 can comprise a fitting 93 , such as a male luer lock , for example . by making the fittings 92 and 93 different ( such as by making one a male and one a female fitting , and / or by making the fittings different sizes , for example ), the risk of interchanging the tubes is minimized . as shown in fig7 , the third tube 40 and the fourth tube 50 can each also include one or more fittings on its ends to connect to other components . in one embodiment , the first end 42 of the third tube 40 can comprise a fitting 94 , such as a male luer lock , for example , and the second end 44 of the third tube 40 can comprise a fitting 96 , such as a male luer lock , for example . likewise , the first end 52 of the fourth tube 50 can comprise a fitting 95 , such as a female luer lock , for example , and the second end 54 of the fourth tube 50 can also comprise a fitting 97 , which can connect to an oxygen supply or other gas source ( or another tube , fitting , component , etc .). one advantage of using multiple supply and / or exhale tubes is that the length of some of the tubes can be reduced . in one embodiment , the first tube 20 and the second tube 25 can be disposable , and the cost of the disposable portion of the tubing can be reduced by reducing the length of the disposable portion . it can also be easier to pair supply and exhale tubes if multiple supply and / or exhale tubes are used . for instance , by keeping the length of the disposable first tube 20 and the second tube 25 relatively short , the length of the third tube 40 and the fourth tube 50 can be relatively long , and in one embodiment , can be prepackaged as a pair for neater and more convenient routing of the lines from the patient to the oxygen source , carbon dioxide monitor , etc . other examples are possible as well . referring to fig6 , the insertion guide 10 might comprise a proximal end 12 and a distal end 14 . although it need not be , insertion guide 10 might be tapered . for example , the diameter of the distal end 14 might be smaller than the diameter of the proximal end 12 . the outside diameters of the proximal end 12 and the distal end 14 may also be sized to accommodate various size nostrils and / or nasal airway passages , for example . the insertion guide 10 may be different lengths in different embodiments , but in one embodiment , the insertion guide 10 is long enough to allow the distal end 14 to be inserted into a patient &# 39 ; s nasopharynx . in an exemplary embodiment , the insertion guide 10 might be made of a flexible material . for example , the insertion guide 10 might be made of polyvinyl chloride (“ pvc ”). other materials , whether flexible or inflexible , are possible as well . fig8 depicts an exemplary insertion guide 10 around a portion of the first tube 20 and the second tube 25 . fig8 a depicts a plan view of the insertion guide 10 . fig8 b depicts a cross - section view of the insertion guide 10 , with exemplary dimensions included . fig8 c depicts an elevation view of the insertion guide 10 . and fig8 d depicts a detail of the insertion guide 10 around a portion of the first tube 20 and the second tube 25 . as shown in fig8 , the proximal end 12 of the insertion guide 10 can comprise a seat 86 . in one embodiment , the seat 86 is 10 mm long , has a 9 mm inside diameter , and has a 12 mm outside diameter . in one embodiment , the inside diameter at the seat 86 should be large enough to accommodate one or more tubes , such as the first tube 20 and the second tube 25 , for example . in one embodiment , the first tube 20 and the second tube 25 each have a 3 mm outside diameter . fig8 d depicts a cross - section of the insertion guide 10 at the seat 86 , and shows the first tube 20 , the second tube 25 , and an open space 89 . in operation , the open space 89 allows sufficient space for exhaled gas to escape , which , in turn , allows the exhale gas monitor ( such as a carbon dioxide monitor ) to sample the flow of exhaled gas . referring back to fig6 , as discussed above , the proximal end 12 of the insertion guide 10 might comprise the flow - through airway fitting 80 . in one embodiment , the flow - through airway fitting 80 can engage the seat 86 ( shown in fig8 ) of the insertion guide 10 . the airway fitting 80 can also engage a plurality of tubes , such as the first tube 20 and the second tube 25 , via one or more arms , such as a first arm 82 and a second arm 84 . each arm might comprise one of any number of mechanisms for engaging one or more tubes , such as an aperture ( as shown in fig9 ) or a clip , for example . fig9 depicts an exemplary flow - through airway fitting 80 . fig9 a depicts a plan view of the insertion guide 10 . fig9 b depicts an elevation view of the insertion guide 10 . and fig9 c depicts a cross - section view of the insertion guide 10 . some exemplary dimensions are included in these figures , although other examples are possible as well . as shown in fig9 , in one embodiment , the flow - through airway fitting 80 can engage the insertion guide 10 ( by being slid onto the proximal end of the insertion guide 10 , for example ). the airway fitting 80 might also be fixedly attached to the insertion guide 10 , such as by chemical or heat bonding or fusing , adhesives , or being integrally formed with the insertion guide 10 . other examples are possible as well . a feature of one embodiment of the flow - through airway fitting 80 is that it can hold one or more tubes , such as the first tube 20 and the second tube 25 , in place in the insertion guide 10 , while also providing for and maintaining the opening 89 between the tubes and the inside surface of the insertion guide 10 . in one embodiment , the first tube 20 and the second tube 25 can be slid into the openings in the first arm 82 and the second arm 84 of the flow - through airway fitting 80 . other examples are possible as well . the flow - through airway fitting 80 might also comprise a flange or a cuff 18 , which , in one embodiment , can contact a patient &# 39 ; s nostril and can help seal the insertion guide 10 against the patient &# 39 ; s nostril . the cuff 18 might also facilitate sliding the flow - through airway fitting 80 onto the insertion guide 10 . in one embodiment , the flow - through airway fitting 80 has a 12 mm inside diameter , a 15 mm outside diameter , and is 10 mm long . in one embodiment , the cuff 18 has a 22 mm outside diameter . as shown in fig9 c , in one embodiment , the arms 82 and 84 are connected to the non - cuff end of the flow - through airway fitting 80 , and extend 5 to 8 mm longitudinally from the non - cuff end . each arm can also extend transversely into the opening of the flow - through airway fitting 80 . fig9 a and 9b show some example dimensions of such a construction . each arm might also comprise an opening to accommodate a tube , and each opening might have an inside diameter of 3 mm ( to accommodate a tube with a 3 mm outside diameter , for example ). fig1 depicts an alternate embodiment of the flow - through airway fitting 80 . in an alternate embodiment , one or more of the arms , such as the first arm 82 , of the flow - through airway fitting 80 can be oriented to bend one or more of the tubes ( or to accommodate one or more bent tubes ), such as the first tube 20 , at an ( approximately ) 90 degree angle . in this way , the bent tube or tubes can be routed in any direction , such as over a patient &# 39 ; s ears , allowing access to a patient &# 39 ; s face . other examples are possible as well . referring to fig6 , in one embodiment , a user such as an anesthesiologist ( or any other medical or non - medical person ) might connect exhale and supply tubes , such as the first tube 20 and the second tube 25 , to the insertion guide 10 . for example , the first tube 20 and the second tube 25 might be threaded through the openings in each of the first arm 82 and the second arm 84 of the flow - through airway fitting 80 , as shown in fig6 . the first end 22 of the first tube 20 and the first end 26 of the second tube 25 might then each extend into the flow - through airway fitting 80 or the insertion guide 10 , and be held in place by the arms of the airway fitting 80 . to deliver oxygen to or exhale gas from a patient &# 39 ; s nasopharynx , the user can insert the insertion guide 10 into a patient &# 39 ; s nasal passage such that the distal end 14 of the insertion guide 10 extends toward the patient &# 39 ; s nasopharynx . the proximal end 12 of the insertion guide 10 might then frictionally engage the patient &# 39 ; s nostril , and might provide a seal or partial seal around the patient &# 39 ; s nostril . to place a patient &# 39 ; s nasopharynx in fluid communication with a gas source , such as an oxygen source , or with a gas monitor , such as a carbon dioxide monitor , the user might connect the first tube 20 directly to a gas monitor and might connect the second tube directly to a gas source . as shown in fig6 , however , the first tube 20 can be in fluid communication with the third tube 40 , and the third tube 40 might then directly connect to a gas monitor ( or to other tubes , connections , etc ., which might fluidly communicate with the gas monitor ). likewise , the second tube 25 can be in fluid communication with the fourth tube 50 , and the fourth tube 50 might then directly connect to a gas supply ( or to other tubes , connections , etc ., which might fluidly communicate with the gas supply ). other examples are possible as well . thus , in one embodiment , the second tube 25 and the fourth tube 50 might provide for fluid communication between the patient &# 39 ; s nasopharynx and an oxygen supply 70 . the oxygen supply 70 , in turn , might apply a low , positive pressure through the second tube 25 and the fourth tube 50 . likewise , the first tube 20 and the third tube 40 might provide for fluid communication between the patient &# 39 ; s nasopharynx and a carbon dioxide monitor 60 . the carbon dioxide monitor 60 , in turn , might apply a low , negative pressure through the first tube 20 and the third tube 40 . in accordance with one embodiment , the transnasal ventilation apparatus can provide for a steady state oxygen supply to / carbon dioxide collection from a patient . as the patient inhales , the patient can draw the lightly pressurized oxygen from the oxygen supply through the fourth tube 50 and through the second tube 25 into the patient &# 39 ; s nasopharynx . as the patient exhales , the patient can discharge the exhale gases from the patient &# 39 ; s nasopharynx into and through the first tube 20 and the third tube 40 to the carbon dioxide monitor , and through the opening 89 in the airway fitting 80 to the atmosphere . the negative pressure applied by the carbon dioxide monitor 60 can , in turn , withdraw the exhale gases to the carbon dioxide monitor 60 . both supply gas and exhale gas flow to and from the patient &# 39 ; s nasopharynx can be enhanced by the opening 89 in the flow - through airway fitting 80 . for example , as the patient exhales , some exhaled gas can escape through the opening 89 to the ambient air . the opening 89 , and the resultant escaped gas , can be important because some exhale gas monitors need to sample a flow of exhale gas to function properly . the opening 89 can help prevent the exhale gas flow from “ dead - ending ,” and can encourage and facilitate gas flow to the exhale gas monitor . several exemplary embodiments of the present invention have been described above . those skilled in the art will understand , however , that changes and modifications may be made to these embodiments without departing from the true scope and spirit of the present invention , which is defined by the claims .

an apparatus and method for delivering oxygen to a nasopharynx and withdrawing exhale gas from the nasopharynx to a carbon dioxide monitor . in one embodiment , the apparatus can comprise one or more tubes and an airway fitting forming an airway . the airway fitting can be configured to engage at least one of the tubes and maintain the one or more tubes within the airway , and to provide an outlet to the atmosphere for the airway . in another embodiment , the tube might be in fluid communication with a junction that can direct oxygen from an oxygen supply through the tube and exhale gas from the tube to the carbon dioxide monitor . further , the tube might comprise an outer tube and an inner tube .

in this detailed description there is described an apparatus for enabling the interchange , at an operative site , between different types of surgical instruments and in an automated fashion . in this way a substitution of one instrument for another can be readily accomplished , without manually withdrawing one instrument followed by manual insertion of another instrument . further , with this apparatus , and the associated use of a guide tube , or the like , for receiving and guiding the instrument , the interchange can be carried out quickly and safely , thus enabling medical procedures to be performed in a far shorter period of time . the guide tube preferably extends to the operative site os ( see fig7 ) so that the instrument can transition safely thereto . also , the guide tube preferably remains at the operative site even as the instruments are exchanged in the guide tube , so as to avoid any tissue or organ damage during an instrument exchange . the operative site may be defined as the general area in close proximity to where movement of the tool occurs in performing a surgical procedure , usually in the viewing area of the endoscope and away from the incision . in this description the instrument interchange principles are illustrated in association with two separate surgical systems , both of which are robotic systems , sometimes also referred to as telerobotic systems . however , the principles of this invention also apply to other surgical instrumentation , such as used in minimally invasive surgery ( mis ), where a number of instrument exchanges are typical in performing a medical or surgical procedure . it is assumed , by way of example , that the systems disclosed herein are for use in laparoscopic surgery . thus , one system is disclosed in fig1 through 8 a and 8 b , while a second system is disclosed in fig1 - 14 . a variation of the first system is illustrated in fig9 . it is noted that in fig9 , the instrument - to - driver registration is accomplished with a linear arrangement , while in the other versions described herein a rotating arrangement is employed , all to be described in further detail later . also , in the embodiments described herein the driver has only linear translation while the instrument storage chamber rotates ( fig1 and 10 ) or slides ( fig9 ). in an alternate embodiment the driver may rotate or otherwise move to different registration positions , as the instrument storage chamber remains stationary , as long as there is relative motion between the instrument driver and instrument storage chamber . before reference is made to the detailed embodiments described herein , consideration is given to co - pending applications that are hereby incorporated by reference herein in their entirety , and that describe in further detail aspects of the several components that make up the overall robotic surgery system . in connection with descriptions set forth herein reference is made to the applications set forth in the related application part of this application as well as to pending u . s . application ser . no . 09 / 783 , 637 filed feb . 14 , 2001 ; u . s . application ser . no . 10 / 014 , 143 filed nov . 11 , 2001 ; as well as issued u . s . pat . no . 6 , 197 , 017 . the first embodiment of the invention is illustrated in fig1 - 8 . fig1 shows a surgical instrument system 10 that performs surgical procedures . the system may be used to perform minimally invasive procedures . the system may also be used to perform open or endoscopic surgical procedures . the system 10 includes a surgeon interface 11 , computation system 12 , and drive unit 13 . the system controls the instrument so as to position the end effector ( tool ) 18 of the instrument 20 at the very distal end of and extending through the outlet guide tube 24 . during use , a surgeon may manipulate the handles 30 of the surgeon interface 11 , to effect desired motion of the end effector 18 within the patient , at the operative site which is schematically illustrated in fig7 . the movement of a handle 30 is interpreted by the computation system 12 to control the movement of the end effector ( tool ) 18 . the system may also include an endoscope with a camera to remotely view the operative site . the camera may be mounted on the distal end of the instrument , or may be positioned away from the site to provide additional perspective on the surgical operation . in certain situations , it may be desirable to provide the endoscope through an opening other than the one used by the instrument . the entire assembly illustrated in fig1 is shown supported over the surgical table 27 , and in a position so that the guide tube 24 can be inserted through an incision in the patient and directed to the operative site of the patient . the incision is represented in fig1 by the dashed line l . the surgical instrument system 10 of the present invention is preferably mounted on rigid post 19 which may be movably affixed to the surgical table 27 , at bracket 28 . the surgical system 10 includes two mechanical cable - in - conduit bundles 21 and 22 . these cable bundles 21 and 22 terminate at one end at the two connection modules ( couplers ) 23 a and 23 b , which removably attach to the drive unit 13 . the drive unit 13 is preferably located outside the sterile field , although it may be draped with a sterile barrier so that it may be operated within the sterile field . the other end of the bundles terminate at the surgical system 10 . these terminations are shown in further detail in the description of the second embodiment that is described later . basically cables in the bundle 21 may control ; the indexing for controlled rotation of the instrument storage chamber 40 ; rotation of the guide tube 24 ; as well as motion of the carriage 54 for control of the linear translation of the driver 50 . on the other hand the bundle 22 may control , for example , rotation of the instrument within the guide tube 24 , as well as actuation of the tool 18 . the instrument storage chamber is also referred to herein as an instrument retainer . fig1 also shows the instrument storage chamber 40 that is illustrated as supported over the base piece 51 , which , in turn , is supported from the rigid post 19 . the cable bundle 21 couples to the base piece 51 and controls motion of the instrument storage chamber 40 , as well as the driver 50 . the guide tube 24 is supported at the outlet port side of the instrument storage chamber 40 , and is controlled for rotation relative to the instrument storage chamber 40 . rotation of the guide tube 24 provides a corresponding rotation of the instrument and tool . the instrument storage chamber 40 has at its inlet side a port for receiving the driver 50 , and for permitting engagement of the driver with the one of the instruments in the instrument storage chamber 40 that is in registration with the driver 50 . the driver 50 is supported from the carriage 54 which transitions on rails 55 , and is controlled from cable bundle 22 . the driver may also be referred to herein as an instrument transporter . in accordance with the setup of the system of fig1 , the guide tube 24 of the surgical instrument system 10 is inserted into the patient usually through an incision . usually , a cannula is positioned in the incision , is maintained in position and receives the guide tube 24 . this incision is illustrated in fig1 by the dashed line l . the system is then mounted to the rigid post 19 . the cable bundles 21 and 22 are then coupled to the drive unit 13 . the connection modules or couplers 23 a and 23 b at the end of respective cable bundles 21 and 22 are then engaged into the drive unit 13 . the system is then ready for use and control from the master station side at surgeon interface 11 . for further details of the entire slave side of the system , including the drive unit , detachability at the drive unit , the cabling and cable couplers , refer to u . s . ser . nos . 09 / 783 , 637 ; and 10 / 014 , 143 , previously mentioned . now , reference is made , not only to fig1 but also to fig2 through 6 that illustrate further details depicting the interchangeable instrument concepts of the present invention . fig7 illustrates schematically a cabling scheme that may be used in the instrument . fig9 illustrates an alterative to the revolving chamber construction , in the form of a linearly translatable housing or chamber arrangement . the revolving instrument storage chamber 40 includes a base 42 , opposite end walls 43 and a cylindrical chamber or magazine 44 . in the embodiment illustrated herein , chamber 44 has six elongated passages 46 each for receiving an instrument . the chamber 44 is supported by a centrally disposed support rod 47 , such as illustrated in fig5 . the support rod 47 may be supported in bearings ( not shown ) at the opposite end walls 43 . the instrument storage chamber 40 has its rotation controlled at base piece 51 ( see fig1 ) so that when an operator at interface 11 wants to change instruments , a command can be sent from the master to the slave side to rotate the magazine 44 so that a different instrument is in alignment with the driver 50 . of course , this exchange only occurs when the driver has been withdrawn to its rest ( disengaged ) position . specific sequences of the interchange action are described later . the command that is sent may be initiated by any one of several means , some of which are described in some detail later . fig2 and 3 also illustrate the outlet guide tube 24 . the tube 24 is secured to one of the end walls 43 and is essentially fixed in axial position relative to that end wall 43 of the rotating instrument storage chamber 40 , but is capable of rotation on its own axis , and relative to the chamber 40 . details of this rotational support are described further in connection with the second embodiment described in fig1 - 14 . the end walls 43 supporting the magazine 44 are fixed to the base 42 , which is supported over the base piece 51 which , in turn , is fixed to the rigid post 19 . thus , in this particular embodiment the instrument storage chamber 40 rotates but does not have any significant linear movement toward or away from the operative site . thus , in this first embodiment the instrument control has a somewhat limited number of degrees - of - freedom . the degrees - of - freedom can be increased by providing the guide tube with a curved distal end , like that illustrated in the second embodiment of the invention in fig1 - 14 . fig1 through 6 also illustrates the instrument driver 50 . the instrument driver 50 is adapted to enter an end inlet port 49 in the wall 43 of the rotating chamber 40 . in this regard , refer to fig3 for the inlet port 49 . also , as discussed previously in connection with fig1 , in the base piece 51 there is an indexing mechanism that controls the rotation of the rotating storage chamber 44 so that different ones of the passages 46 are adapted to be aligned with the input driver port 49 . this registration control may be carried out using a detent mechanism so that the proper instrument is aligned and selected from the chamber by the instrument driver 50 . refer to fig2 and the cable bundle 21 that interconnects with the chamber 44 for selective and registered rotation thereof . also , refer to fig1 for an example of an indexing mechanism . in a similar manner , at the opposite end wall 43 of the chamber 40 , there is provided an outlet port 48 , such as illustrated in fig3 , and that aligns with the outlet guide tube 24 . also , in fig2 and 3 there is illustrated the carriage 54 that carries the instrument driver 50 and that transitions along the support rails 55 to enable the driver to selectively engage with and drive the instrument forward through the guide tube 24 and toward the operative site . fig3 illustrates a cross - sectional view of one embodiment of the interchangeable instrument apparatus of the present invention . an instrument 20 with its end effector ( tool ) 18 is illustrated disposed in one of the elongated chambers 46 of the rotating chamber 44 . in practice , each of the other passages 46 can contain other types of instruments , with a variety of different tool or end effectors . for the sake of clarity , only one of the instruments is illustrated in fig3 , it being understood that up to six other instruments of different types may be disposed in other ones of the elongated passages 46 . also , the magazine 44 may be constructed with fewer or more instrument - receiving passages . fig3 also illustrates the driver 50 in a position where the end 56 thereof is positioned just entering the inlet port 49 with the end 56 about to engage the end 25 of the instrument 20 . the position of the instrument driver 50 is considered as a “ rest position ” when the end 57 is disposed in wall 43 , but has not yet entered the magazine 44 so that the magazine 44 is free to rotate . to interlock and align the driver and the instrument , there is provided a post 58 ( see fig5 ) on the driver 50 and an accommodating recess 26 ( see fig5 ) in the instrument end 25 . as mentioned previously , there are mechanical cables extending in bundles 21 and 22 illustrated in fig1 . the cables in bundle 22 , in particular , couple by way of pulleys and then extend the length of the driver 50 to the instrument 20 . the cabling and control pulley arrangements are disclosed in further detail in the second embodiment as shown in fig1 - 14 . this cabling is for operating the end effector 18 illustrated in fig1 . to provide continuity of this mechanical control cabling , both the instrument driver as well as the instrument carry interconnecting cable connections . these are illustrated clearly in fig4 through 6 . also refer to the schematic perspective view of fig7 showing the manner in which the cables couple about pulleys 29 and extend through the driver to intercouple with cabling of the instrument 20 . these cable connections between the driver and instrument may also be considered as defining a coupling section or coupling interface 59 where the driver and instrument are releasably engageable . one may also consider the driver and instrument , such as illustrated in fig1 - 6 , as collectively being an instrument member including a work section ( instrument 20 and tool 18 ), and a driver section ( driver 50 ). the instrument driver 50 has passages 61 ( see fig4 ) for receiving a cable 62 ( see fig4 and 6 ). as illustrated in fig4 and 6 the end of cable 62 terminates in a hook 64 . the hook 64 is adapted to engage with a similar - configuration hook 66 at the end of cable 68 as illustrated in fig6 . fig4 illustrates a series of slots or passages 61 , which in the illustrated embodiment comprise six such slots 61 . each of these slots receives a cable 62 with its end hook 64 . referring further to fig4 , this illustrates the end 25 of the instrument 20 . also illustrated are the elongated slots 61 in the driver ( transporter ) 50 . fig4 illustrates the cables 68 and their associated hooks 66 associated with the instrument 20 . also shown is the cable 62 with its hook 64 disposed in slot 61 . fig5 illustrates the end 56 of the instrument driver 50 as the driver 50 is transitioning through the port 49 for engagement with the instrument 20 . the driver 50 has not yet engaged the instrument 20 , but has just left its rest position . the “ rest ” ( disengaged ) position for the instrument driver 50 is one in which the end 56 of the driver 50 is disposed in the end wall 43 and out of the passage 46 so that the chamber 44 is free to rotate . in the position of fig5 , the hook 66 associated with the instrument 20 is preferably biased to a somewhat outward deflected position . in this regard , it is noted that the passage 46 has an enlarged section 46 a that permits the hook 66 to deflect outwardly , as illustrated . the hooks are essentially spring biased outwardly so as to contact the inner wall surface of enlarged section 46 a . this enables the driver to pass by the hooks 66 for engagement with the instrument 20 . as the driver 50 proceeds from the position illustrated in fig5 , toward the position illustrated in fig6 , the hook 64 passes under the hook 66 and as the driver is driven further to the left , as viewed in fig3 , the hooks 64 and 66 become interlocked in the position illustrated in fig6 and there is thus cable continuity from cable 62 to cable 68 . as is discussed in further detail hereinafter , the operation of these cables provide operation of certain actions of the end effector 18 . as the driver end 56 engages the instrument end 25 , the post 58 engages with the recess 26 so as to properly align the driver and instrument . at the initial point of contact the hooks 66 are still out of engagement with the hooks 64 . however , as the driver moves further to the left the instrument starts to transition out of the storage chamber passage 46 , and the hooks 66 transition into the smaller diameter section of the passage 46 , causing them to deflect into engagement with the hooks 64 , such as illustrated in fig6 . the coupling interface 59 formed essentially between the hooks 64 and 66 is maintained as the instrument transitions out of the instrument storage chamber 40 . refer to fig7 . the driver 50 is of a sufficient length so that the selected instrument 20 is driven out of the chamber 44 and into the outlet guide tube 24 . the instrument is then transitioned through the guide tube 24 to the position illustrated in fig1 where the end effector or tool 18 of the instrument extends from the distal end of the guide tube 24 at a position inside the body cavity ( operative site ). all the while that the instrument is being transitioned to the end of the guide tube 24 , the interconnecting cables are maintained in an interlocked position such as illustrated by the engaged hooks 64 and 66 in fig6 . when it is desired to change to a different instrument , the driver 50 is withdrawn or in other words is moved in a direction to the right in fig3 . this carries the instrument with the instrument driver to the right and when the instrument reaches a position approximately as illustrated in fig5 , because of the increased diameter of the section 46 a illustrated in fig5 , the hooks 66 are biased outwardly and disengage from the hooks 64 . this essentially disengages the driver from the instrument and the driver is then in a position to be withdrawn through the port 49 , no longer engaging with the instrument . this also leaves the instrument 20 in place in the instrument storage chamber 44 in readiness for a subsequent usage . with the driver disengaged from the instrument , the instrument storage chamber can then be rotated to align a different instrument with the driver . the cabling in bundle 21 , via base piece 51 , controls the position of chamber 40 so as to select a different instrument by rotating the chamber 44 so that a different instrument registers with the driver 50 . for an example of a registration mechanism refer to fig1 . a different instrument would also carry cabling similar to that illustrated in fig5 . once the new instrument is in - line with the instrument driver 50 then the driver 50 may be engaged once again to pass through the port 49 engaging the new instrument and thus transitioning the new instrument out the outlet guide tube 24 to a position where the tool of the instrument is at the operative site in readiness for use and control from the master station surgeon interface . a wide variety of different instruments may be supported in the instrument storage chamber 40 . tool 18 may include a variety of articulated tools , such as jaws , scissors , graspers , needle holders , micro dissectors , staple appliers , tackers , suction irrigation tools , clip appliers , that have end effectors driven by wire links , eccentric cams , push - rods or other mechanisms . in addition , tool 18 may comprise a non - articulated instrument , such as cutting blades , probes , irrigators , catheters or suction orifices . alternatively , tool 18 may comprise an electrosurgical probe for ablating , resecting , cutting or coagulating tissue . to provide proper alignment of the instrument 20 in the chamber 40 and with the driver 50 there are preferably provided interlocking surfaces such as a tongue and groove ( not shown ) between the walls of the chamber passage and the outer surface off the instrument and / or driver . interlocking or guiding surfaces may also be provided within the guide tube 24 . thus , as the different instruments are moved in and out of the rotating chamber they will always be properly aligned with the driver so that the proper cabling is provided to control the instrument . reference is now made to fig7 for a schematic illustration of the cabling as it extends from the bundle 22 , through the driver 50 , to the instrument 20 , and the tool 18 . the cabling extends about pulleys 29 and into the slots 61 in the instrument driver 50 . fig7 illustrates the driver 50 in a position in which it has entered the guide tube 24 and transitions to a location essentially at the end of the guide tube where the tool 18 is located and at the operative site os . at the end of the driver where the cable hooks engage , such as illustrated in fig5 and 6 , there is the coupling or interface section 59 . fig7 also illustrates the passages 46 and another non - selected tool within the instrument storage chamber . the construction of one form of tool is illustrated in fig8 a and 8b . this is in the form of a set of jaws or grippers . this tool is shown for the purpose of illustration , it being understood that a variety of other tool may be used . fig8 a is a perspective view showing the tool pivoted at the wrist while fig8 b is an exploded view of the tool . the tool 18 is comprised of four members including the base 600 , link 601 , upper grip or jaw 602 and lower grip or jaw 603 . the base 600 is affixed to the flexible stem section 302 . this flexible section may be constructed of a ribbed plastic . this flexible section may be used when a curved end guide tube ( see fig1 ) is used so that the instrument will readily bend through the curved actuator tube 24 . the link 601 is rotatably connected to the base 600 about axis 604 . fig8 b illustrates a pivot pin at 620 . the upper and lower jaws 602 and 603 are rotatably connected to the link about axis 605 , where axis 605 is essentially perpendicular to axis 604 . fig8 b illustrates another pivot pin at 624 . six cables 606 - 611 , shown schematically in fig8 a and fig8 b , actuate the four members 600 - 603 of the tool . cable 606 travels through the insert stem ( section 302 ) and through a hole in the base 600 , wraps around curved surface 626 on link 601 , and then attaches on link 601 at 630 . tension on cable 606 rotates the link 601 , and attached upper and lower grips 602 and 603 , about axis 604 ( wrist pivot ). cable 607 provides the opposing action to cable 606 , and goes through the same routing pathway , but on the opposite sides of the insert . cable 607 may also attach to link 601 generally at 630 . cables 606 and 607 may be one continuous cable secured at 630 . cables 608 and 610 also travel through the stem 302 and though holes in the base 600 . the cables 608 and 610 then pass between two fixed posts 612 . these posts constrain the cables to pass substantially through the axis 604 , which defines rotation of the link 601 . this construction essentially allows free rotation of the link 601 with minimal length changes in cables 608 - 611 . in other words , the cables 608 - 611 , which actuate the grips 602 and 623 , are essentially decoupled from the motion of link 601 . cables 608 and 610 pass over rounded sections and terminate on grips 602 and 603 , respectively . tension on cables 608 and 610 rotate grips 602 and 603 counter - clockwise about axis 605 . finally , as shown in fig8 b , the cables 609 and 611 pass through the same routing pathway as cables 608 and 610 , but on the opposite side of the instrument . these cables 609 and 611 provide the clockwise motion to grips or jaws 602 and 603 , respectively . at the jaws 602 and 603 , as depicted in fig8 b , the ends of cables 608 - 611 may be secured at 635 . this securing may occur with the use of an adhesive such as an epoxy glue or the cables could be crimped to the jaw . reference is now made to fig9 . fig9 schematically illustrated an alternate embodiment of the present invention . in fig1 - 8 the different instruments are selected by means of a rotating arrangement . in fig9 the selection is made on an essentially linear basis . thus , instead of the rotating member illustrated in fig1 - 8 , there is a flat array 70 also having a series of elongated passages 72 extending therethrough . each of these passages accommodates an instrument . fig9 also schematically illustrates , by the same reference characters , the instrument driver 50 and the outlet guide tube 24 such as previously illustrated in fig1 - 8 . the flat array 70 may be driven selectively in the direction of arrow 74 so as to align different ones of the passages 72 with the driver 50 and guide tube 24 . mechanisms for selective linear drive are well known , as are mechanisms for registration so as to provide proper alignment between the instrument and instrument driver . in connection with the aforementioned description of the cables / hooks , it is noted that the interchange system is designed preferably to have all cabling maintained in tension . in this way , as an instrument is engaged , all of the cabling running therethrough is in tension and properly operative to control the end effector whether it be a set of jaws as illustrated in fig8 a and 8b or some other type of instrument . if an end effector has less degrees of movement than that illustrated in fig8 a and 8b this is still effectively controlled , but with the use of fewer cable control signals ( fewer cables will actually be activated ). reference is now made to the second robotic surgical system depicted in fig1 - 14 , and that discloses a system having a greater number of degrees - of - freedom than the system described in fig1 - 8 . in fig1 - 14 the same reference characters are used for similar components as depicted in fig1 - 8 . the surgical robotic system , as illustrated in fig1 - 14 , although preferably used to perform minimally invasive surgery , may also be used to perform other procedures as well , such as open or endoscopic surgical procedures . fig1 illustrates a surgical instrument system 10 that includes a master station m at which a surgeon 2 manipulates an input device , and a slave station s at which is disposed a surgical instrument . in fig1 the input device is illustrated at 3 being manipulated by the hand or hands of the surgeon . the surgeon is illustrated as seated in a comfortable chair 4 . the forearms of the surgeon are typically resting upon armrests 5 . fig1 illustrates a master assembly 7 associated with the master station m and a slave assembly 8 associated with the slave station s . assembly 8 may also be referred to as a drive unit . assemblies 7 and 8 are interconnected by means of cabling 6 with a controller 9 . as illustrated in fig1 , controller 9 typically has associated therewith one or more displays and a keyboard . reference is also made to , for example , the aforementioned u . s . ser . no . 10 / 014 , 143 , for further detailed descriptions of the robotic controller operation and associated algorithm . as noted in fig1 , the drive unit 8 is remote from the operative site and is preferably positioned a distance away from the sterile field . the drive unit 8 is controlled by a computer system , part of the controller 9 . the master station m may also be referred to as a user interface vis - vis the controller 9 . commands issued at the user interface are translated by the computer into an electronically driven motion in the drive unit 8 . the surgical instrument , which is tethered to the drive unit through the cabling connections , produces the desired replicated motion . fig1 , of course , also illustrates an operating table t upon which the patient p is placed . thus , the controller couples between the master station m and the slave station s and is operated in accordance with a computer algorithm . the controller receives a command from the input device 3 and controls the movement of the surgical instrument so as to replicate the input manipulation . with further reference to fig1 , associated with the patient p is the surgical instrument 14 , which in the illustrated embodiment actually comprises two separate instruments one on either side of an endoscope e . the endoscope includes a camera to remotely view the operative site . the camera may be mounted on the distal end of the instrument insert , or may be positioned away from the site to provide additional perspective on the surgical operation . in certain situations , it may be desirable to provide the endoscope through an opening other than the one used by the surgical instrument 14 . in this regard , in fig1 three separate incisions are shown , two for accommodating the surgical instruments and a centrally disposed incision that accommodates the viewing endoscope . a drape is also shown with a single opening . the surgical instrument 14 is generally comprised of two basic components including a surgical adaptor or guide 15 and an instrument 14 . fig1 illustrates the surgical adaptor 15 , which is comprised primarily of the guide tube 24 . in fig1 the instrument 14 is not clearly illustrated but extends through the guide tube 24 . the instrument 14 carries at its distal end the tool 18 . descriptions of the surgical instrument are found hereinafter in additional drawings , particularly fig1 . the surgical adaptor 15 is basically a passive mechanical device , driven by the attached cable array . in fig1 there is illustrated cabling 22 coupling from the instrument 14 to the drive unit 18 . the cabling 22 is preferably detachable from the drive unit 8 . furthermore , the surgical adaptor 15 may be of relatively simple construction . it may thus be designed for particular surgical applications such as abdominal , cardiac , spinal , arthroscopic , sinus , neural , etc . as indicated previously , the instrument 14 couples to the adaptor 15 and essentially provides a means for exchanging the instrument tools . the tools may include , for example , forceps , scissors , needle drivers , electrocautery etc . referring still to fig1 , the surgical system 10 may preferably be used to perform minimally invasive procedures , although it is to be understood that the system may also be used to perform other procedures , such as open or endoscopic surgical procedures . the system 10 includes a surgeon &# 39 ; s interface 11 , computation system or controller 9 , drive unit 8 and the surgical instrument 14 . the surgical system 10 , as mentioned previously , is comprised of an adaptor or guide 15 and the instrument 14 . the system is used by positioning a tool 18 of the instrument , which is inserted through the surgical adaptor or guide 15 . during use , a surgeon may manipulate the input device 3 at the surgeon &# 39 ; s interface 11 , to effect desired motion of the tool 18 within the patient . the movement of the handle or hand assembly at input device 3 is interpreted by the controller 9 to control the movement of the guide tube 24 , instrument , and tool 18 . the surgical instrument 14 , along with the guide tube 24 is mounted on a rigid post 19 which is illustrated in fig1 as removably affixed to the surgical table t . this mounting arrangement permits the instrument to remain fixed relative to the patient even if the table is repositioned . although , in fig1 there are illustrated two such instruments , even a single surgical instrument may be used . as indicated previously , connecting between the surgical instrument 14 and the drive unit 8 , are cablings . these include two mechanical cable - in - conduit bundles 21 and 22 . these cable bundles 21 and 22 may terminate at two connection modules , not illustrated in fig1 ( see fig1 ), which removably attach to the drive unit 8 . although two cable bundles are described here , it is to be understood that more or fewer cable bundles may be used . also , the drive unit 8 is preferably located outside the sterile field , although it may be draped with a sterile barrier so that it may be operated within the sterile field . in the preferred technique for setting up the system , and with reference to fig1 , the surgical instrument 14 is inserted into the patient through an incision or opening . the instrument 14 is then mounted to the rigid post 19 using a mounting bracket 31 . the cable bundles 21 and 22 are then passed away from the operative area to the drive unit 8 . the connection modules of the cable bundles are then engaged into the drive unit 8 . the separate instrument members of instrument 14 are then selectively passed through the guide tube 24 . this action is in accordance with the interchangeable instrument concepts of this invention . the instrument 14 is controlled by the input device 3 , which is be manipulated by the surgeon . movement of the hand assembly produces proportional movement of the instrument 14 through the coordinating action of the controller 9 . it is typical for the movement of a single hand control to control movement of a single instrument . however , fig1 shows a second input device that is used to control an additional instrument . accordingly , in fig1 two input devices are illustrated and two corresponding instruments . these input devices are usually for left and right hand control by the surgeon . the surgeon &# 39 ; s interface 11 is in electrical communication with the controller 9 . this electrical control is primarily by way of the cabling 6 illustrated in fig1 coupling from the bottom of the master assembly 7 . cabling 6 also couples from the controller 9 to the actuation or drive unit 8 . this cabling 6 is electrical cabling . the actuation or drive unit 8 , however , is in mechanical communication with the instrument 14 . the mechanical communication with the instrument allows the electromechanical components to be removed from the operative region , and preferably from the sterile field . the surgical instrument 14 provides a number of independent motions , or degrees - of - freedom , to the tool 18 . these degrees - of - freedom are provided by both the guide tube 24 and the instrument 14 . fig1 shows primarily the overall surgical system . fig1 - 14 show further details particularly of the interchangeable instrument concepts as applied to this system . fig1 illustrates a control algorithm for the system . the system of fig1 is adapted to provide seven degrees - of - freedom at the tool 18 . three of the degrees - of - freedom are provided by motions of the adaptor 15 , while four degrees - of - freedom may be provided by motions of the instrument 14 . as will be described in detail later , the adaptor is remotely controllable so that it pivots , translates linearly , and has its guide tube rotate . the instrument also rotates ( through the instrument driver ), pivots at its wrist , and has two jaw motions at the tool . now , reference is made to the more detailed drawings of fig1 - 14 . fig1 is a perspective view at the slave station of the system of fig1 illustrating the interchangeable instrument concepts . fig1 is a cross - sectional view through the storage chamber and as taken along line 12 - 12 of fig1 . fig1 is a longitudinal cross - sectional view , as taken along line 13 - 13 of fig1 . fig1 is a perspective schematic view of the indexing and registration mechanism used in the embodiment illustrated in fig1 - 13 . reference is now made to fig1 which is a perspective view illustrating the instrument 14 and the adaptor 15 at the slave station s . this instrument system is secured in the manner illustrated in fig1 to the rigid post 19 that supports the surgical instrument by way of the mounting bracket 31 illustrated in fig1 , but not shown in fig1 . fig1 also shows several cables that may be separated into five sets for controlling different motions and actions at the slave station . these are individual cables of the aforementioned bundles 21 and 22 referred to in fig1 . fig1 also illustrates the support yoke 220 that is secured to the mounting bracket 31 , the pivot piece 222 , and support rails 224 for the carriage 226 . the rails are supported in end pieces 241 and 262 with the end piece 241 attached to the pivot piece 222 . the pivot piece 222 pivots relative to the support yoke 220 about pivot pin 225 . a base piece 234 is supported under the carriage 226 by means of the support post 228 . the support post 228 in essence supports the entire instrument assembly , including the adaptor 15 and the instrument 14 . as indicated previously , the support yoke 220 is supported in a fixed position from the mounting bracket 31 . the support yoke 220 may be considered as having an upper leg 236 and a lower leg 238 . in the opening 239 between these legs 236 and 238 is arranged the pivot piece 222 . cabling extends into the support yoke 220 . this is illustrated in fig1 by the cable set 501 . associated with the pivot piece 222 and the carriage 226 are pulleys ( not shown ) that receive the cabling for control of two degrees - of - freedom . this control from the cable set 501 includes pivoting of the entire instrument assembly about the pivot pin 225 . this action pivots the guide tube 24 essentially in a single plane . this pivoting is preferably about an incision of the patient which is placed directly under , and in line with , the pivot pin 225 . other cables of set 501 control the carriage 226 in a linear path in the direction of the arrow 227 . see also the cables 229 extending between the carriage 226 and the end pieces 241 and 262 . the carriage moves the instrument and guide tube 24 back and forth in the direction of the operative site os . incidentally , in fig1 the instrument is in its fully advanced state with the tool at the operative site os . the base piece 234 is the main support for the interchangeable instrument apparatus of the invention . refer to fig1 - 14 . the base piece 234 supports the guide tube 24 , the instrument storage chamber 540 , and the instrument driver 550 . the instrument driver 550 is supported from another carriage , depicted in fig1 and 13 as the carriage 552 , and that , in turn , is supported for translation on the carriage rails 554 . the rails 554 are supported at opposite ends at end pieces 556 and 558 , in a manner similar to the support for the other carriage 226 . a support post 560 interconnects the carriage 552 with the instrument driver housing 570 . with further reference to fig1 , and as mentioned previously , there are a number of cable sets from bundles 21 and 22 coupled to and for controlling certain actions of the instrument system . mention has been made of the cable set 501 for controlling instrument pivoting and translation , as previously explained . in addition , fig1 depicts four other cable sets 503 , 505 , 507 , and 509 . cable set 503 controls rotation of the guide tube 24 . cable set 505 controls the carriage 552 , and , in turn , the extending and retracting of the instrument driver for instrument exchange . cable set 507 controls rotation of the instrument through rotation of the instrument driver . finally , cable set 509 controls the tool via the instrument driver and instrument . there is also one other set of control cables not specifically illustrated in fig1 that controls the indexing motor 565 , to be discussed in further detail later . fig1 shows a cross - sectional view through the interchangeable instrument portion of the overall instrument system . this clearly illustrates the internal cable and pulley arrangement for the various motion controls . there is a pulley 301 driven from the cable set 503 that controls rotation of the guide tube 24 . there is also a pulley 303 driven from cable set 505 , along with a companion pulley 305 that provides control for the carriage 552 . fig1 also illustrates another pulley 307 driven from cable set 507 , and for controlling the rotation of the instrument driver 550 , and , in turn , the selected instrument . fig1 illustrates the guide tube 24 supported from the base piece 234 . the guide tube 24 is hollow and is adapted to receive the individual instruments or work sections 541 disposed in the instrument storage chamber 540 , as well as the instrument driver 550 . refer to fig7 for an illustration of the instrument and instrument driver positioned in the guide tube 24 . fig1 shows the instrument driver 550 in its rest or disengaged position . the proximal end 24 a of the guide tube 24 is supported in the base piece 234 by means of a pair of bearings 235 so that the guide tube 24 is free to rotate in the base piece 234 . this rotation is controlled from the pulley 237 which is secured to the outer surface of the guide tube 24 by means of a set screw 231 . the pulley 237 is controlled to rotate by means of the cabling 310 that intercouples the pulleys 301 and 237 and that is an extension of the cabling 503 . thus , by means of the cable and pulley arrangement , and by means of the rotational support of the guide tube 24 , the rotational position of the guide tube 24 is controlled from cable set 503 . of course , this controlled rotation is effected from the master station via the controller 9 , as depicted in the system view of fig1 , and as a function of the movements made by the surgeon at the user interface 11 . as indicated before the proximal end 24 a of the guide tube 24 is supported from the base piece 234 . the distal end of the guide tube 24 , which is adapted to extend through the patient incision , and is disposed at the operative site os illustrated about the tool 18 in fig1 , and where a medical or surgical procedure is to be performed . in the system shown in fig1 the distal end of the guide tube 24 is curved at 24 b . in this way by rotating the guide tube 24 about its longitudinal axis there is provided a further degree - of - freedom so as to place the end tool at any position in three - dimensional space . the rotation of the guide tube 24 enables an orbiting of the end tool about the axis of the guide tube 24 . the guide tube 24 is preferably rigid and constructed of a metal such as aluminum . the tool 18 illustrated in fig1 may be the same tool as illustrated in fig8 a and 8b . also , when the instrument is fully engaged , as in fig1 , the cabling and cable interface is as illustrated in fig7 . fig1 also illustrates a cross - section of the instrument storage chamber 540 including the storage magazine 549 , and showing two of the six instrument passages 542 in the storage magazine 549 . the instrument storage chamber may also be referred to herein as an instrument retainer . in fig1 one of the instruments 541 is about to be engaged by the instrument driver 550 . the other instrument 541 is in place ( storage or rest position ) in the instrument storage chamber 540 , and out of the path of the instrument driver 550 . one of the instruments 541 carries a gripper tool illustrated at 543 , while the other instrument carries a scissors 544 . because these instruments are adapted to pass to the guide tube 24 and be positioned at the distal end 24 b thereof , the body 548 of the instrument is flexible so as to be able to curve with the curvature of the guide tube 24 . although reference is made herein to the separate instrument and instrument driver , such as illustrated in fig1 , once they are engaged they function as a single piece instrument member . accordingly reference is also made herein to the instrument driver 550 as a “ driver section ” of the overall one piece instrument member , and the instrument 541 as a “ working ” section of the instrument member . the instrument member has also been previously discussed as having a “ coupling section ” or “ interface section ”, which is defined between the working section and the driver section where the cables interlock by means of the engaging hook arrangement , such as clearly depicted in fig5 and 6 . this is shown in fig1 at 559 . this is analogous to the interface 59 illustrated in fig7 . the carriage 552 illustrated in fig1 is moved linearly by the cables 555 that extend between pulleys 303 and 305 . these cables attach to the carriage 552 . the carriage movement is controlled from cable set 505 . it is the movement of the carriage 552 that drives the instrument driver ( driver section ) 550 . the instrument driver 550 , in its rest or disengaged position , is supported between the instrument driver housing 570 and the wall 562 that is used for support of the instrument storage chamber 540 . the instrument magazine 549 is rotationally supported by means of the axle or shaft 547 , with the use of bushings or bearings , not shown . this support is between walls 562 and 563 . fig1 shows the very distal end 525 of the instrument driver ( transporter ) 550 supported at wall 562 . in the rest position of the instrument driver 550 the driver is out of engagement with the instruments and the magazine 549 , thus permitting rotation of the instrument storage chamber 540 . the proximal end 526 of the instrument driver 550 is supported at the instrument driver housing 570 . it may be rotationally supported by means of a bushing 527 . the instrument driver 550 is supported for rotation , but rotation is only enabled once the driver has engaged the instrument and preferably is at the operative site . the rotation of the instrument driver 550 is controlled from cable set 503 by way of the pulley 307 . in fig1 the cable set 509 is illustrated as controlling the instrument motions including tool actuation . these cables control a series of pulleys shown in fig1 as pulleys 529 . as indicted in fig1 these pulleys control cabling that extends through the instrument driver and the instrument for control of instrument and tool motions . the cables that are controlled from these pulleys may control three degrees - of - freedom of the instrument , including pivoting at the wrist and two for gripper action . for the details of the interlocking of the instrument and instrument driver refer to fig5 and 6 . the same engagement arrangement can be used in this second embodiment of the invention including the mating hook arrangement , interlocked at interface 559 when the instrument driver and instrument are engaged . reference has been made before to the indexing motor 565 . this motor is illustrated in fig1 positioned next to the base piece 234 , and is further illustrated in fig1 located for interaction with the instrument storage chamber 540 . the indexing motor 565 is controlled from the master station side , and accordingly there is another cable set ( not shown ) that actuates the indexing motor 565 . the indexing motor 565 may be a stepper motor having a degree of rotation that corresponds to the desired rotation of the instrument storage chamber 540 . the stepper motor may be designed to provide 60 degrees of rotation for each actuation , corresponding to an instrument storage chamber 540 having six passages ( 360 degrees divided by 6 ) for receiving instruments . in fig1 the stepper motor 565 has an output shaft 566 that supports an indexing disk 567 , shown also in dashed line in fig1 . the indexing disk 567 is fixed to the shaft 566 and so rotates with the shaft 566 . fig1 illustrates the disk 567 carrying four pins 568 disposed at the periphery of the disk 567 . fig1 also shows these pins 568 . the pins 568 selectively engage in indexing slots 569 in an end wall of the magazine 549 . to insure that the rotating chamber stays in proper registration with the instrument driver a spring and ball detent arrangement is employed . refer to fig1 - 14 illustrating a standard ball and spring member 575 supported in the wall 563 . the ball of member 575 is urged against an end wall surface 576 of the magazine 549 . this end wall has a series of detent dimples 577 ( see fig1 ) disposed at locations corresponding to the passages in the magazine 549 . the stepper motor 565 is selectively operated under surgeon control from the master station . each step rotates the disk 567 through 90 degrees . the engagement of the pins 568 with the slots 569 causes a corresponding rotation of the magazine 549 through 60 degrees . each subsequent rotation of the stepper motor 565 causes a further 60 degree rotation of the magazine 549 . the stepper motor 565 is controllable in a manner so that , with proper decoding , there may be multiple step actuations to get from one instrument to the next selected instrument . the operation of the slave instrument is in a robotic manner from the master station , such as illustrated in fig1 . the surgeon can control several degrees - of - freedom of the instrument system . in addition , when the surgeon wishes to exchange instruments this can be done directly from the master station from an actuation member and at the proper time in the surgical procedure . one type of actuation member may be by means of a foot switch 410 illustrated in fig1 within access of the surgeon . the foot switch 410 couples to the controller 9 . appropriate electrical signals are coupled from the master station to the slave station basically to control the stepper motor 565 for indexing the magazine 549 . the sequence of operation for the indexing is demonstrated in the flow chart of fig1 . this block diagram indicates the sequence of steps performed commencing with a rest position of the system in which the instruments are all in place in the storage chamber 540 , and the instrument driver is in the position substantially as illustrated in fig1 , just out of contact with the registered instrument and with the driver end 525 disposed in the wall 562 . it is this position that is illustrated in fig1 by box 420 . the next step is to check the registration of the instrument driver with the instrument itself . this is depicted by the box 422 . this step may involve the use of some known registration system , such as one using an optical sensing arrangement to determine proper registration between the instrument driver 550 and each of the passages in the magazine 549 , along with the instrument 541 . if proper registration is detected then the system proceeds to the next step indicated in fig1 by box 426 , which activates the instrument driver 550 . this starts the process of driving the instrument to the operative site os . this involves mechanical control signals on the cable set 505 controlling the carriage 552 , and in turn , the instrument driver 550 . if an improper registration is detected then box 424 indicates the step of correcting the registration . this may be carried out in a well known manner with the use of an optical system to provide slight rotation to the instrument storage chamber 540 so as to obtain proper registration . this system may also use some type of a feedback system . the next step in the system is indicated in fig1 by the box 428 which simply detects the fully engaged position of the instrument driver and instrument . this is the position illustrated in fig1 . again , this position can be readily detected by optical means . the next step illustrated in fig1 by box 430 is one that commences the interchange process . the intercoupled instrument and instrument driver are withdrawn . this involved movement of the carriage 552 in the opposite direction . next , indicated by box 432 , is where the instrument and instrument driver have reached the position illustrated in fig1 previously referred to as the “ rest position ”. in that position the instrument driver ( transporter ) 550 is clear of the instrument storage chamber 540 , and thus the instrument storage chamber 540 can be indexed ( rotated ). this is shown in fig1 by the box 434 . following these steps , from fig1 it is seen that there may be another registration check ( box 436 ), and a correction ( box 438 ), in a manner similar to the operation previously discussed regarding boxes 422 and 424 . the process can then repeat at a time determined by the surgeon &# 39 ; s instrument selection sequence . there has to be some correlation between the indexing , what and where particular instruments are stored , and how the indexing is controlled from the master station . as indicated previously a foot switch can be used , such as the switch 410 illustrated in fig1 . in one version of the control the switch 410 may be comprised of six separate actuation buttons , each one corresponding to one of the six instruments disposed in the instrument storage chamber 540 . indicia may be provided associated with the storage chamber to indicate what particular instrument is disposed in what particular instrument passage . in this way the surgeon would know what button to actuate to select the desired instrument . there could be corresponding indicia associated with the switch buttons so the surgeon knows what button corresponds exactly to what instrument . the control system for indexing may also include a decoding scheme so that when the surgeon makes a selection the decoder determines the number of rotations ( such as of the stepper motor 565 ) necessary to bring the instrument driver into proper registration with the selected instrument . because it may not always be clear as to the specific instrument sequence that the surgeon will use , the system has to determine how to index from one instrument to the next one selected . this selection process involves more than just sequencing from one instrument to an adjacent instrument . the process will have to accommodate a selection process in which the next selected instrument is not the adjacent instrument . thus a simple decoder can be used to determine the number of stepper motor steps necessary to move the storage chamber to the next selected instrument . another aid that can be provided to the surgeon is a visible display illustrated in fig1 , and on which there can be a diagram that matches the storage chamber pattern showing to the surgeon exactly where each instrument is placed including the type of instrument . this could be set up when the instruments are first selected the disposed in the instrument storage chamber 540 . in association with this display one could also provide , in place of the switch 410 , a voice activated system so that the surgeon simply indices by voice which instrument to select . this may be done by simply numbering the instruments , such as one through six . a further variation may use a touch screen so that the surgeon simply touches an area on the screen corresponding to the displayed image of the storage chamber with the stored instruments . in all of the above instances , there are electrical signals generated from the master station , through a touch screen , switch , etc . that are conveyed to the controller 9 and from there to the slave side . the activating signals at the slave side basically control the stepper motor 565 via a cable set not specifically shown in the drawings but that would couple to the stepper motor 565 illustrated in fig1 , 12 and 14 . reference is now made to fig1 for a schematic representation of a further alternate embodiment of the invention . in fig1 and 10 it is noted that the instruments are contained in a parallel array . in accordance with the invention the instruments may also be disposed in a series array , as depicted in the schematic diagram of fig1 . this embodiment includes a retainer 580 that is adapted to store a series of instruments 581 in a serial array , also referred to herein as a linear chamber or linear retainer . means are provided to enable the array to move laterally in the directions indicated by arrows 585 . this movement can be of either the retainer or the instruments themselves . there is an alignment that occurs so that a selected instrument may align with a port 584 from which the instrument may then be moved to location 583 . this is by a lateral or transverse movement of the instrument out of the retainer 580 . this movement is indicated in fig1 by the arrow 587 . the instrument , once moved , is then in registration with the driver or transporter 580 which is moveable in the direction of arrow 588 . the driver is controlled as in previous embodiments to transition the instrument to the operative site , through the represented output port 586 . although reference is made herein to “ surgical instrument ” it is contemplated that the principles of this invention also apply to other medical instruments , not necessarily for surgery , and including , but not limited to , such other implements as catheters , as well as diagnostic and therapeutic instruments and implements . having now described certain embodiments of the present invention , it should be apparent to one skilled in the art that numerous other embodiments and modifications thereof can be made , some of which have already been described , and all of which are intended to fall within the scope of the present invention . for example , the coupling sections or interface sections have been disclosed as intercoupled cables with hook arrangements , such as shown in fig6 . in another arrangement a different mechanical coupling scheme may be employed using a different interlock between cables . also , in place of mechanical couplings other technologies may be used for coupling action to the instrument and tool , such as sma technology . regarding the tool itself , one has been illustrated with a wrist pivot . instead the tool may include a bendable section at or near its distal end . in place of the stepper motor other indexing arrangements can be used , such as a ratchet and pawl system . also , encoders can be used at the rotating storage chamber to detect motions to provide feedback for controlling the overall system .

a robotic medical system comprises a medical instrument assembly having a retainer , a serial array of instruments disposed in the retainer , a chamber , and an instrument driver . the robotic medical system further comprises a user interface configured for generating at least one command signal , a drive unit coupled to the first mechanism , second mechanism , and instrument driver , and an electric controller configured , in response to the command signal , for directing the drive unit to linearly displace the array of instruments within the retainer , to displace a selected one of the instruments from the retainer into the chamber , and to distally advance the instrument driver within the chamber to engage the selected instrument .

the subject invention provides a method which increases intra - airway pressure in a patient , thus causing a positive expiratory pressure ( pep ), which is not airflow dependent . the method of the present invention utilizes a pressure relief valve , preferably a positive end - expiratory pressure ( peep ) valve . the pep is caused by obstructing the flow of gases exhaled by the patient through the peep valve until the pep is greater than the pressure threshold of the peep valve , so that such gases must be exhaled against the peep valve &# 39 ; s pressure threshold . examples of peep valves include , but are not limited to , u . s . pat . no . 5 , 878 , 743 to zdrojkowski , as shown in fig3 which discloses an unidirectional valve with a spring force to control exhalation pressure ; u . s . pat . no . 1 , 896 , 719 , to mckesson , discloses a mask having an exhaling valve with a spring force adjustable by a set screw to control exhalation pressure ; u . s . pat . no . 4 , 182 , 366 , to boehringer , discloses a spring connected to a diaphragm , whereby the spring urges the diaphragm to close the exhaust port . a thumb screw can be adjusted to control the pressure on the spring ; u . s . pat . no . 4 , 207 , 884 , to isaacson , discloses an annular seat on a disk - shaped valve , whereby a spring urges the valve against its seat in accordance with the setting on a graduated plunger . additional peep valves are disclosed in u . s . pat . nos . 4 , 403 , 616 , 4 , 345 , 593 , 4 , 870 , 963 , and 5 , 109 , 840 . in accordance with the practice of the subject invention the patient breathes out through a valve , generating sufficient pressure to overcome the valve &# 39 ; s pressure threshold , allowing air to flow through the valve . expiring through the valve creates a pep equal to the valve &# 39 ; s pressure threshold . the pep produced by the valve results in increased airway patency , such that the amount of gas trapped in the lung decreases ( reduced hyperinflation ) and the airway resistance decreases . the elevated pep from the valve , equal to the pressure threshold of the valve , remains in the airway throughout the expiration . this decreases end - expiratory lung volume , allows for better inspiratory pumping , increases alveolar ventilation , increases the o 2 in the blood , decreases the co 2 in the blood , and decreases the sense of breathlessness that causes great distress in these patients . also , the decreased hyperinflation returns the diaphragm closer to its normal length , increasing the ability of the diaphragm to generate the inspiratory pumping forces . this improves the ability of the patient to ventilate the lungs , increasing exercise tolerance and decreasing the sense of breathlessness . in an embodiment of the subject invention , a valve is utilized to increase intra - airway pressure in a patient , thus causing a positive expiratory pressure ( pep ) and functionally moving the equal pressure point ( epp ) closer to the mouth . the valve is aligned such that the valve &# 39 ; s threshold pressure resists the patients exhalation , whereby the threshold pressure is at a level such that the patient is capable of overcoming it upon exhalation through the valve . initially , the patient inhales , filling the lungs , and then exhales though the valve with sufficient force to overcome the valve &# 39 ; s threshold pressure . this inhalation and exhalation is referred to as a breathing cycle . in an embodiment , the valve comprises a mouth piece , which is placed in the patient &# 39 ; s mouth . in an embodiment , the method of the subject invention is performed while the patient is at rest , or at limited activity . the valve threshold pressure is set to a relatively low threshold pressure level , about 1 - 5 cmh 2 o . the patient continually exhales through the valve for a short duration of time , about 2 - 5 breaths , or about 0 . 05 - 1 . 5 minutes . the method is performed on regular basis , with the valve threshold pressure being increased as the patient &# 39 ; s tolerance increases . in the “ at rest ” embodiment , to increase the pressure in the patient &# 39 ; s intra - airway the valve &# 39 ; s threshold pressure is set to about 1 - 50 cm h 2 o . in a specific at rest embodiment , the valve threshold pressure is set to about 10 cmh 2 o . in an alternative at rest embodiment , the duration of continual valve usage is increased as the patient &# 39 ; s tolerance increases . to increase the pressure in a patient &# 39 ; s intra - airway , the patient breathes through the valve continually for about 2 - 30 breaths . in an alternative at rest embodiment , the patent continually breathes through the valve for about 0 . 05 to 30 minutes . in an alternative method of use , the patient utilizes the valve while performing physical exercise , such as cardiovascular training . the valve threshold pressure is set to a low threshold pressure level , about 1 - 5 cmh 2 o . while exercising , the patient continually exhales through the valve . initially , the patient will exercise for a relatively short duration , about 0 . 05 - 5 min . as the patient &# 39 ; s tolerance increases , the duration of the exercise increases . in the “ increased activity ” embodiment , to increase the pressure in the patient &# 39 ; s intra - airway , the pressure threshold of the valve is set to about 1 - 50 cm h 2 o . in a specific increased activity embodiment , the valve threshold pressure is set to about 10 cmh 2 o . in an alternative increased activity embodiment , the duration of continual exercise is for about 0 . 05 to 30 minutes . it should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and claims .

the present invention relates generally to the field of breathing exercise devices and more particularly to expiratory breathing methods which promote proper resistance breathing by the user . more specifically , the present invention discloses a method which utilizes a pressure relief valve , preferably a positive end - expiratory pressure valve , for providing positive expiratory pressure . the pep is provided by obstructing the flow of gases exhaled by the patient through the peep valve , so that such gases must be exhaled against the peep valve &# 39 ; s pressure threshold .

in fig1 a , 4 and 5 , one embodiment of a phototherapeutic apparatus 10 according to the invention is illustrated having a tubular sheath 12 and an inner optically - transmissive fiber element 14 . in fig5 this phototherapeutic apparatus 10 is shown schematically in operation . the diffuser apparatus with its fluted tubular sheath is coupled to a source of phototherapeutic radiation 36 , ( e . g ., a laser ) and positioned within a patient &# 39 ; s body to provide phototherapy . according to one embodiment , the diffuser assembly can fit within a standard guiding catheter 32 . the catheter 32 , as illustrated in fig4 includes an operating handle 50 with a trigger element 52 connected to the fiber element 14 forming a retractor element . the catheter further includes electrical sensing elements 34 and / or at least one additional channel 38 for introduction of saline or therapeutic solutions . the proximal end of the optically - transmissive fiber element 14 is coupled to a source of phototherapeutic radiation 36 . returning to fig1 the distal end of the sheath 12 is fluted such that axial compression of the sheath results in expansion of expansion elements 18 in the fluted region 16 . this expansion forces the expansion elements into the sides of a body lumen , as can be seen in fig6 a - 6c . in fig6 a , the use of the phototherapeutic apparatus of the present invention is shown schematically . as illustrated , the instrument 10 is positioned next to a segment of a patient &# 39 ; s lumen where insertion and radiation is desired . as shown , the apparatus includes an outer sheath 12 having a flexible fluted region 16 and an inner optically - transmissive fiber element 14 with tip 26 . in one preferred embodiment , the fiber 14 and sheath 12 are constructed with sufficient clearance to permit saline or other therapeutic liquids to be released during the procedure . in particular , saline flushing of the distal end of the optically - transmissive fiber element 14 may be desirable to cool the tissue surface proximal to the treatment site . in fig6 b , initial expansion of the sheath 12 is shown . in this illustration , the optically - transmissive fiber is inserted into the patient &# 39 ; s lumen . next the fluted region 16 is expanded to center the phototherapy device 10 within the patient &# 39 ; s lumen . the expansion of the fluted region is accomplished by axial compression of the sheath 12 . in one embodiment , the axial compression of the sheath is accomplished by pulling back on the optically - transmissive fiber element 14 . the fiber element 14 can be connected to the housing 28 and the end cap 26 . these elements can be bonded by melting . furthermore , the distal end of the fiber element 14 and the sheath 12 can be thermally bonded or assembled . thus , subsequent to insertion of the phototherapeutic device , an operator can cause relative sliding motion of the fiber element 14 and the sheath 12 to axially compress the sheath 12 . one method of achieving the relative sliding motion and axial compression is to pull back on the optical fiber element 14 while holding the sheath 12 still . the trigger element 52 is provided as a convenient means for pulling back on the optical fiber element 14 . thus , the trigger element 52 is coupled to the proximal end of the fiber element 14 and the proximal end of the sheath 12 so that the trigger element can control the expansion of the non - occluding expansion elements 18 . an alternative method of achieving axial compression is pushing the sheath 12 forward , while holding the fiber element 14 still . the compression of the sheath 12 , in turn , causes the expansion of the flexible fluted region 16 , thereby centering the device within the patient &# 39 ; s lumen . in fig6 c , sheath 12 has completely expanded in the patient &# 39 ; s lumen pushing into the surrounding tissue and centering the phototherapy device 10 in the lumen . importantly , the fluted region allows fluids , including gases , to pass the phototherapy device 10 while the device is in operation . according to the embodiment illustrated in fig1 there is sufficient clearance , e . g ., about 0 . 02 mm to about 2 mm , between the optical fiber 20 and the surrounding sheath 12 to facilitate delivery of therapeutic liquids to the radiation site . further , to provide a preferred amount of clearance between the wall of the lumen and the distal end of the phototherapeutic apparatus , and between the expansion elements 18 of the fluted region 16 , the length of the illustrated expansion elements are about 1 mm to about 5 cm , and the width of the expansion elements are about 0 . 2 mm to about 1 cm . this design allows reduction of hematocrit by flushing out the fluted region 16 . with reference to fig2 a , and 2b , another embodiment of a phototherapeutic apparatus includes distinct balloon expansion elements 18 . in the representation of fig2 b , the wall of the main artery undergoing treatment is represented by the numeral 11 . for treatment , an operator inserts the light - emitting portion of the catheter into the diseased blood vessel to a position adjacent the deposit of atheromatous plaque to be lysed . the catheter includes a tube 37 and balloon expansion elements 18 attached to the outside of the distal end of the tube 37 . the tube contains an optical fiber 20 and a gas delivery conduit 21 . the deflated state of the balloon elements is indicated by the dotted lines 17 in fig2 . inflation of the balloon expansion elements is provided for by the gas delivery conduit 21 which is in fluid communication with the interior of the balloon elements and which can be connected , at its opposite end , to a source of pressurized gas . importantly , upon inflation the balloon expansion elements do not occlude flow of air or liquid past the phototherapy treatment site . at least one optical fiber 20 is provided for transmitting light from an external source to a light - emitting tip 23 . the balloon expansion elements are preferably composed of material that transmits the light emitted by the light - emitting tip 23 . yet another embodiment of a phototherapeutic apparatus according to the invention is shown in fig3 and 3a . rigid expansion elements 18 are extended once the apparatus is inserted in a body lumen for treatment of the lumen . the rigid expansion elements are extended by distal movement of the expansion actuating element 41 relative to the tubular sheath 12 . again the rigid expansion elements 18 do not occlude flow of air or liquid past the phototherapy treatment site . fig4 is a more detailed cross - sectional view of the distal end of the apparatus of fig1 . the optically - transmissive element is shown having an optical fiber 20 with an optically transmissive core 22 surrounded by a cladding , and buffer coating . the end face of fiber core 22 is inserted into a housing 28 which contains a scattering medium 24 with optional individual scatterer particles 25 . preferably , the medium 24 has a greater refractive index than the housing 28 . at the distal end of the optical fiber 20 , an end cap 26 can be disposed . optionally , the end cap may also be fitted with a reflective mirror 40 . the end cap can further be ground or polished to an atraumatic blunt or rounded end 30 . at least one dosimetry detector 27 is included in an expansion element 18 . the dosimetry detector is connected to a control element 29 and is preferably located at the longitudinal midpoint of the expansion element 18 . light propagating through the optical fiber core 22 is transmitted into the scatterer medium and scattered in a cylindrical pattern along the length of the assembly 14 . each time the light encounters a scatterer particle , it is deflected and , at some point , the net deflection exceeds the critical angle for internal reflection at the interface between the housing 28 and the medium 24 . when this happens the light will exit . the housing can either be made sufficiently long to ensure that virtually all of the light entering it is eventually scattered and diffused in a single path , or as noted above , a reflective mirror can be fitted to the distal end of each diffuser assembly . when a mirror is employed , light propagating through the medium 24 will be at least partially scattered before it reaches mirror 40 . light which does not exit during this initial pass through the tip will be reflected by mirror 40 and returned through the tip assembly . during the second pass , the remaining radiation ( or at least a major portion of this returning radiation ) again encounters the scatterers which provide further circumferential diffusion of the light . the dosimetry detector 27 and control element 29 detect the amount of radiation delivered to the exposure area of the lumen . the control element 29 can automatically terminate the transmission of phototherapeutic radiation once the amount of radiation delivered reaches a predetermined level or the control element 29 can merely display the amount of radiation delivered to the exposure area . an exemplary manufacturing process suitable for joining a diffuser assembly to a glass - clad or polymer - clad optical fiber having an outer diameter of about 50 to about 1000 micrometers includes stripping off the buffer from the end of the optical fiber , e . g ., exposing about two or three millimeters of the inner fiber core and its cladding . ( it is not necessary to strip the cladding away from the core .) prior to stripping , the fiber end face preferably should be prepared and polished as known in the art to minimize boundary or interface losses . a transparent tubular structure which will form the housing for the scatterer medium is then slipped over the prepared fiber end and , preferably slid beyond the fiber end . for example , if a tip assembly of about 20 millimeters is desired , the tubing can be about 100 millimeters long and slid over about 75 millimeters of the fiber , leaving an empty lumen of about 25 millimeters in front of the fiber end face . in one preferred embodiment , the housing is teflon ® fep ( tetrafluoroethylene ) tubing , available , for example , from zeus industries ( raritan , n . j .). the assembly is then injected with a scatterer - loaded material , such as a silicone , epoxy or other polymeric material ( if a solid diffuser is desired ) or a suitable liquid , such as water or a deuterium oxide solution , containing colloidal scatterer particles , such as silica , alumina , or titania , ( if a liquid diffuser is desired ). one exemplary scatterer medium can be formulated by mixing 70 parts of clear silicone , mastersil ™ formula 151 - clear ( available from masterbond , inc . of hackensack , n . j .) with one part of titania filled silicone , mastersil ™ formula 151 - white ( also available from masterbond ), and a conventional silicone curing or hardening agent . the tube lumen should be completely filled with the silicone , epoxy or other carrier mixture to avoid entrapment of air bubbles . the reflector ( e . g ., an aluminum , gold or other reflector - coated plug ) is inserted into the distal end of the tube . the reflector at the distal end of the scatterer tube can be a deposited metal or dielectric coating . in one preferred embodiment , a room temperature hardening agent is used and the diffuser assembly is simply allowed to solidify overnight . it should be clear that the manufacturing processes described above are merely illustrative , and various alternative techniques can be practiced to construct the fiber tip assemblies of the present invention . for example , automated extrusion methods and / or injection molding approaches can be employed to mass produce fibers with integral diffusive tip assemblies . various other diffusive tip assemblies can be employed in the present invention . for a detailed discussion of various alternative embodiments see commonly - owned co - pending u . s . patent application ser . no . 08 / 827 , 631 , filed apr . 10 , 1997 , entitled &# 34 ; phototherapy methods and apparatus &# 34 ;, by edward l . sinofsky , incorporated herein by reference . various materials can be used to form the outer sheath 12 including , for example , teflon ® and other fluorocarbon polymers . in one embodiment , the fluted region is made of white fluoropolymers to further homogenize angular output of the radiation . the fluted region can also be made radiopaque with barium or bismuth fillers . the struts can be formed by axial slices at various locations on the sheath . for example to construct a four strut fluted region , one would make four longitudinal cuts into the sheath , separated by 90 ° from each other . the length of the cuts will determine the radial extent of the fluted region . in one embodiment it may also be desirable to fill the sheath polymer with a radio - opaque substance , such as barium in order to permit visualization under angiography . it will thus be seen that the invention efficiently attains the objects set forth above , among those made apparent from the preceding description . since certain changes can be made in the above constructions without departing from the scope of the invention , it is intended that all matter contained in the above description or shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense . it is also to be understood that the following claims are to cover all generic and specific features of the invention described herein , and all statements of scope of the invention which , as a matter of language , might be said to fall therebetween .

phototherapeutic instruments are disclosed for providing substantially uniform energy distribution to a major portion of an area exposed during phototherapy . these instruments include an element for directing radiation toward the walls of a lumen and a device for centering the radiation directing element within the lumen . the instruments also allow the flow of blood , therapeutic fluid , or air past the exposure site . the instruments are particularly useful as part of a fiber optic - based medical laser system for photodynamic therapy within the bronchia of the lung , blood vessels or other liquid - filled lumens .

preparation of the subject invention compositions from concentrated aqueous γ - cd solutions has proved advantageous . the acylglycerols comprising ω - 3 polyunsaturated fatty acids are added to the aqueous γ - cd solution . the cd concentration of the aqueous solution before the addition of acylglycerol is preferably between 5 and 60 % by weight . a cd concentration of 10 - 40 % by weight is especially preferred . the weight ratio of acylglycerols comprising ω - 3 polyunsaturated fatty acids to cd is preferably between 0 . 1 : 1 and 5 : 1 , especially preferably between 0 . 4 : 1 and 3 : 1 . the mixing of acylglycerol and γ - cd is preferably effected in a temperature range from above freezing point to 80 ° c . the process is most preferably carried out at 10 - 60 ° c ., particularly at approximately 15 - 50 ° c . the mixing time depends on the temperature and is preferably between one hour and a few days . as a rule , a mixing time of 10 to 30 hours will suffice . complexing is preferably effected under atmospheric pressure . complexing is preferably effected under a protective gas atmosphere ( nitrogen or argon ). according to the present invention , “ acylglycerol comprising ω - 3 polyunsaturated fatty acids ” preferably is a mono -, di -, tri - acyl glycerol , alkyl modified glycerol , or glycerol mono - phosphate , comprising at least 1 ω - 3 polyunsaturated fatty acid . “ ω - 3 polyunsaturated fatty acid ” is preferably a residue selected from the group epa , dha , dta or dpa . the especially prefered meaning of acylglycerol comprising ω - 3 polyunsaturated fatty acid is mono -, di -, or tri - acylglycerol or glycerol mono - phospate , with at least 1 epa or dha residue . the most preferred meaning of acylglycerol comprising ω - 3 polyunsaturated fatty acid is mono , di , tri -, acylglycerol comprising at least 1 epa residue , preferably in the amount of 5 - 30 %, or at least 1 dha residue , preferably in the amount of 5 - 30 %. the composition of the ω - 3 polyunsaturated fatty acids of the acylglycerols can be determined in a known manner by gas chromatographic analysis of the corresponding methyl esters . the acylglycerols comprising ω - 3 polyunsaturated fatty acids are obtained in a manner known per se , for example by wet rendering , often followed by continuous centrifugal separation of the fatty and aqueous phases . open hydraulic presses , cage presses and continuous screw presses are all used in the final recovery of oil from the rendering residues , and the latter are often solvent extracted after pressing . surprisingly , it has been discovered that acylglycerols comprising ω - 3 polyunsaturated fatty acids can be stabilized in an outstanding manner by complexation with γ - cyclodextrin , especially at epa and / or dha concentrations between 15 % and 40 % ( by weight ). a markedly higher stabilization of the unsaturated compounds was found in comparison with α - and β - cyclodextrin . when tested using a rancimat machine the γ - cd / acylglycerol complexes showed a much higher stability than those obtained with α - and β - cd . the gamma cyclodextrin complexes of acylglycerols comprising ω - 3 polyunsaturated fatty acids have a stability time on the rancimat machine ( induction time ) in excess of 24 hours at 100 ° c . the invention therefore also relates to a complex of γ - cd and acylglycerols comprising ω - 3 polyunsaturated fatty acids . a complex according to the invention consists of gamma cyclodextrin comprising preferably 5 - 50 % by weight of acylglycerols comprising ω - 3 polyunsaturated fatty acids . preferred is a content of 15 %- 40 % by weight of acylglycerols comprising ω - 3 polyunsaturated fatty acids . the acylglycerols comprising ω - 3 polyunsaturated fatty acids are preferably mono , di or triacylglycerols comprising at least 1 epa in a preferred content of 5 - 30 %, or at least 1 dha residue , in a preferred content of 5 - 30 %. the complexes , which are sparingly soluble in water , can be used directly in the form of the reaction mixture . alternatively , they can be isolated and processed by filtration , centrifugation , drying , grinding , sieving , screening , granulating or tableting to suit the procedure which is customary in each case . the complexes according to the present invention can be used , for example , in the food or dietary supplements sector to provide essential fatty acids . numerous studies have linked ω - 3 polyunsaturated fatty acids with the treatment and prevention of disease , especially of the cardiovascular system , and inflammatory disorders , e . g . decreased risk of coronary heart disease , reduction in triglyceride levels , lower blood pressure , arthitis , asthma , crohn &# 39 ; s disease , psoriasis , in human development , especially for brain and retina growth and development , and improvements in fitness and performance , promoting aerobic endurance and mucle recovery . the following examples are intended to illustrate the invention in greater detail . in the examples the stability of the complexes was measured by the rancimat method . the 679 rancimat machine is an instrument for the determination of oxidative and thermal stabilities . it is produced and supplied by metrohm ltd . ( ch - 9101 herisau , switzerland ). in the case of oils and fats or substances containing oils and fats , the stability towards oxidative decomposition can be determined . the 679 rancimat comprises a control unit and a wet section for 3 or 6 reaction and measuring vessels . in the wet section , the samples are exposed to a stream of atmospheric oxygen at elevated temperature . in the case of oils and fats , this gives rise to organic acids . the volatile decomposition products are trapped in a measuring vessel filled with distilled water and continuously detected with a conductivity cell . the control unit assumes control and evaluation of the measurements running in the wet section . the oxidative resistance of the acylglycerol / cd complexes was measured at 100 ° c . evaluation was done using modes 1 ( induction time ) and 2 ( stability time with δk set at 30 μs / cm ). in general , evaluation mode 1 ( induction time ) was used . airflow of 20 l / h was used for all samples . sample quantities of 2 . 0 g ( solid complex ) and 3 . 5 g ( liquid fish oil ) were used . induction time is calculated from the curve κ = f ( t ). induction time is the time needed to reach the break point of the curve . the induction time is a characteristic of the oxidative stability of the sample under evaluation and is in almost complete agreement with the results of the time consuming aom method . ( determination of the oxidative stability of fats and oils : comparison between the active oxygen method ( aocs cd 12 - 57 ) and the rancimat method , jaocs 63 , 792 - 795 ( 1986 ), laubli , m . w . and bruttel , p . a .) stability time is calculated from the curve κ = f ( t ). it is the time needed to reach a preset conductivity change ( δk set at 30 μs / cm ). to 150 ml of deionized and degassed water at 60 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry gamma - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 22 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 60 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 116 . 0 g ( 95 %). acylglycerol content : 18 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . stability time at 100 ° c . : & gt ; 24 hours . to 150 ml of deionized and degassed water at 20 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry gamma - cyclodextrin . the reaction vessel was shielded to exclude light then 22 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added and the mixture stirred under a nitrogen atmosphere at 20 ° c . for 24 hours . the solid was removed and dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 118 . 3 g ( 97 %). acylglycerol content : 18 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . stability time at 100 ° c . : & gt ; 24 hours . to 230 ml of deionized and degassed water at 40 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 43 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 40 ° c . for 48 hours . the product was obtained as a white powder in a yield of 138 . 2 g ( 97 %). acylglycerol content : 30 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 23 hours . stability time at 100 ° c . : & gt ; 20 hours . to 230 ml of deionized and degassed water at 40 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 67 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 162 . 2 g ( 97 %). acylglycerol content : 40 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 9 hours . stability time at 100 ° c . : & gt ; 9 hours . to 450 ml of deionized and degassed water at 40 ° c . in a stephan mixer was added 200 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 67 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 250 . 4 g ( 94 %). acylglycerol content : 25 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . stability time at 100 ° c . : & gt ; 11 hours . to 230 ml of deionized and degassed water at 40 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 25 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 50 ° c . for 3 days . the product was obtained as a white powder in a yield of 121 . 3 g ( 97 %). acylglycerol content : 20 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . stability time at 100 ° c . : & gt ; 24 hours . to 230 ml of deionized and degassed water at 40 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 17 . 7 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 109 . 0 g ( 93 %). acylglycerol content : 15 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . stability time at 100 ° c . : & gt ; 24 hours . to 50 ml of deionized and degassed water at 40 ° c . was added 20 . 0 g of dry beta - cd . the flask was covered to exclude light then 4 . 4 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added to the slurry . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 4 hours then allowed to cool overnight to ambient temperature . the solid was collected by filtration and dried under vacuum at 40 ° c . to give 24 . 0 g ( 98 %) of material as a light yellow powder . acylglycerol content : 18 % by weight . oxidation induction time at 100 ° c . ( it 100 ): 3 . 1 hours . stability time at 100 ° c . : 4 . 4 hours . to 50 ml of deionized and degassed water at 40 ° c . was added 20 . 0 g of dry alpha - cd . the flask was covered to exclude light then 4 . 4 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added to the slurry . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 4 hours then allowed to cool overnight to ambient temperature . the solid was collected by filtration and dried under vacuum at 40 ° c . to give 11 . 7 g ( 48 %) of material as a light yellow powder . acylglycerol content : 18 % by weight . oxidation induction time at 100 ° c . ( it 100 ): 3 . 4 hours . stability time at 100 ° c . : 4 hours . to 230 ml of deionized and degassed water at 40 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 100 . 0 g of acylglycerol solution containing approx . 5 % epa and min . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 40 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a yellow - white powder in a yield of 195 . 07 g ( 97 %). acylglycerol content : 50 % by weight . oxidation induction time at 100 ° c . ( it 100 ): 6 . 7 hours . stability time at 100 ° c . : 6 . 8 hours . to 250 ml of deionized and degassed water at 45 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 24 . 0 g of acylglycerol solution containing approx . 25 % dha was added . the mixture was stirred under a nitrogen atmosphere at 45 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 123 . 07 g ( 99 %). acylglycerol content : 20 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . to 250 ml of deionized and degassed water at 45 ° c . in a 1 - l reaction kettle was added 100 . 0 g of dry γ - cyclodextrin . the reaction vessel was shielded to exclude light and once the solids had dissolved , 24 . 0 g of acylglycerol solution containing approx . 25 % epa was added . the mixture was stirred under a nitrogen atmosphere at 45 ° c . for 24 hours then allowed to cool to ambient temperature . the resulting paste was filtered to remove water then dried under vacuum at 50 ° c . for 48 hours . the product was obtained as a white powder in a yield of 123 . 57 g ( 99 %). acylglycerol content : 20 % by weight . oxidation induction time at 100 ° c . ( it 100 ): & gt ; 24 hours . in general , complexes of acylglycerol ( 25 % by weight ) with gamma - cd showed no oxidation over 24 hours while control samples of 18 % acylglycerol mixed with alpha — or beta cd showed rapid oxidation ( less than 5 hours ). complexes of acylglycerol in excess of 40 % however began to exhibit oxidation . acyl - cd conc . rxn . temp . rxn . time induct . time stability ex . no . glycerol ( wt %) ( c ) ( hr ) yield (%) 100 ° c . ( hr ) time ( hr ) 1 18 40 60 24 95 & gt ; 24 & gt ; 24 2 18 40 20 24 97 & gt ; 24 & gt ; 24 3 30 30 40 24 97 & gt ; 23 & gt ; 20 4 40 30 40 24 97 9 . 2 9 . 0 5 25 30 0 24 94 & gt ; 24 & gt ; 11 6 20 30 40 24 97 & gt ; 24 & gt ; 24 7 15 30 40 24 93 & gt ; 24 & gt ; 24 8 * 18 28 40 24 99 3 . 1 4 . 4 9 * 18 28 40 24 48 3 . 4 4 10 * 50 30 . 40 24 97 6 . 7 6 . 8 11 20 30 45 24 99 & gt ; 24 n . d . 12 20 30 45 24 99 & gt ; 24 n . d . acyl - glycerol 100 - - - - 5 4 acyl - glycerol / ˜ 20 - - - - 3 . 3 4 γ - cd mixture while embodiments of the invention have been illustrated and described , it is not intended that these embodiments illustrate and describe all possible forms of the invention . rather , the words used in the specification are words of description rather than limitation , and it is understood that various changes may be made without departing from the spirit and scope of the invention .

a method to stabilize acylglycerols comprising ω - 3 polyunsaturated fatty acids against oxidative degradation characterized in that γ - cyclodextrin is mixed either batchwise or continuously with the acylglycerol comprising ω - 3 polyunsaturated fatty acids , thus forming a γ - cd / acylglycerol complex .

the present invention is a novel device and method designed to provide supplemental vertebral body end plate support for devices placed in the anterior lumbar region , such as threaded interbody fusion cages or bone dowels . the present invention generally contemplates two embodiments . one , an allograft , is made from an actual vertebral body . this embodiment is described and claimed in u . s . pat . no . ______ , issued — , 2006 , which is the parent of this application . the entire patent is incorporated herein by reference . the second embodiment is fabricated from man - made materials such as metal , plastic , or composites . the preferred material for the second embodiment is implex ® trabecular metal material made from tantalum , a product of zimmer spine of minneapolis , minn . this application includes a device and method using the man - made materials and a method using the allograft of the inventors &# 39 ; parent application . preliminarily , the surgeon will effectively perform an alif , typically installing a first support device such as a pair of threaded cages or bone dowels . fig1 , and 3 depict different views of a vertebral body 10 with prior art cages 20 mounted on the vertebral body 10 . typically such cages contain open spaces 22 that permit bone growth throughout cage 20 for a stronger and more stable fusion . after the surgeon installs the cages , dowels , or other such support 20 , he will then install a second support . in the present embodiment of the invention , the second support will be a man - made metal such as the implex ® trabecular metal material . the shape of the second or spinal fusion support 30 , such as that depicted in fig4 - 6 , will conform as much as practicable to the shape of the apophyseal ring of the adjacent vertebrae , which is generally semicircular or u - shaped . the closed portion of the semicircle or u is generally co - linear and co - planar to the anterior part of the adjacent vertebral body , where the apophyseal ring is the thickest . as depicted in fig5 , the spinal fusion support 30 will have an anterior cross member 40 and two lateral members 42 . the second support , or spinal fusion support , 30 is preferably 1 to 3 millimeters thick . larger thicknesses can be used , but the surgeon may have difficulty in placing them as easily as he does the thinner supports . the type of material can also affect the thickness of fusion support 30 . a solid material such as titanium or steel can be manufactured to a thinner dimension . because of the open , porous nature of implex ® trabecular material , the minimum practical thickness currently appears to be approximately 3 millimeters . one should not , however , consider the present invention so limited . future metallurgical and manufacturing developments may permit smaller and non - uniform dimensions . fig4 and 5 show the dimension designations of the invention . for ease of handling and manufacture , the preferred configuration of the fusion support device 30 has a constant height . to date , devices 11 , 13 , and 15 millimeters high have been manufactured . again , however , the invention should not be limited to those dimensions or to a constant height , although they represent the most typical configurations that will be required . support devices with a variety of heights , widths , and lengths can be manufactured , so that they can fit patients with different size vertebrae and intervertebral spaces . present widths that have been manufactured range from 38 to 44 millimeters , while so far the depth has remained constant at 27 . 6 millimeters . the support device can be fabricated in different sizes to match the size of the recipient &# 39 ; s vertebrae and to match the space available once the threaded cages 20 or such similar supports are inserted into the intervertebral space . as depicted in fig4 , the height of the spinal fusion support , or second support 30 , typically will vary to accommodate the patient . it should preferably be about 1 or 2 millimeters less than the distraction created on the vertebral end plates by the insertion of the cages , dowels , or other similar devices . this will allow a clearance of approximately 0 . 5 - 1 mm from each end plate to facilitate placement . as depicted in fig6 , the spinal fusion support 30 will be seated at the lateral and anterior apophyseal lines of the patient &# 39 ; s recipient vertebrae 10 . this will prevent subsidence by sharing the load with fusion devices like cages and dowels , i . e ., first support 20 , with allowance for approximately 0 . 5 to 1 . 0 mm settling of these devices into the end plates . the generally u - shaped or semicircular spinal fusion support 30 will be inserted around the already - implanted fusion devices or first support 20 . preferably the support 30 will be secured through apertures 36 drilled through support 30 . screws , dowels , or other securing devices ( not shown ) will pass through apertures or holes 36 to secure the first support 20 to the spinal fusion support 30 . the preferred arrangement is depicted in fig6 and 7 . fig8 depicts an alternative method of attachment , which avoids the necessity to drill holes 36 to attach the support body to the cages 20 . fig8 depicts the vertebral allograft of the spinal fusion support 30 disclosed and claimed in the parent application . the method claimed herein can employ such a spinal fusion support 30 , or a man - made material . fig9 represents an embodiment similar to the trabecular or allograft spinal fusion supports 30 , except the fusion support is not made of a trabecular material . the spinal fusion support 130 sits on vertebrae 110 . apertures 136 through fusion support 130 lead to cages 120 , to which to which support 130 is preferably secured . alternatively , the screw holes in the cages , dowels , or other devices can be used to attach a bracket ( not shown ) that can then be used to hold the fusion support device in place and prevent it from dislodging . this embodiment was depicted in the parent application . those of skill in the art will recognize that the attachment of the spinal fusion support 30 to a patient &# 39 ; s vertebral body is a matter of choice and can vary , depending on the material used for the spinal fusion support , the surgeons &# 39 ; technique , and the physiological conditions the surgeon encounters . it will be noted by those of skill in the art that changes may be made to the present invention without departing from its spirit or from the scope of the claims . for example , as noted above , the device can be made of a various materials . one such preferred material is titanium cobalt - chromium , although any implantable material with adequate strength could be used . the device may also be coated with material that will foster boney ingrowth for more mechanical strength and stability . others may develop first supports that are different from the traditional threaded cages and bone dowels used in alif . those of skill in the art will also understand that the dimensions provided here are only approximate , and are subject to variation depending upon the available allografts , manufacturing techniques and limitations , as well as limitations created by the patient &# 39 ; s physique and the operating technique used by the surgeon . likewise , the description of the invention as u - shaped or semicircular is quite general and should be interpreted broadly . for example , fig5 depicts more of a u - shape . the invention , however , could be more semicircular as shown in fig6 , or it could be almost circular , with perhaps 270 degrees of edge and a 90 degree opening at the posterior end . thus , the lateral members may not in a literal sense be parallel to the patient &# 39 ; s midline , nor will the cross member be absolutely perpendicular to the midline . as a practical matter , however , they can be considered to generally posses those mathematical properties . for example , the structure might have a fairly short cross member with lateral vertebral supports that are not exactly parallel to the patient &# 39 ; s midline . nevertheless , for purposes of the present invention , one should still consider the structure as u - shaped , in the sense that it is supported by significant portions of the anterior and lateral aspects of the apophyseal ring . in addition , how the cross member and lateral members are attached — whether they are unitary structures or welded or slidably connected — is also a matter of choice . as imaging and fabrication techniques improve , it may , for example , be possible to use fairly rigid unitary plastic devices to conform to the precise shape of the patient &# 39 ; s vertebrae . the same may be true of metal fusion supports . obviously , it is preferable that the device be supported by as much of the apophyseal ring as possible . as a practical matter , however , it is necessary that the device only be supported to the extent necessary to permanently limit or prevent subsidence . thus , the broad scope of the invention should be understood in the context of the specification and as it is defined in the following claims .

a support for vertebral fusion prevents subsidence and eliminates the need for posterior surgery and instrumentation . the support is constructed of an implantable man - made material . one embodiment is generally a u - shaped metal support that rests on the apophyseal ring of a patient &# 39 ; s vertebrae , with the open portion of the u facing the patient &# 39 ; s posterior . the metal support is connected to a previously placed threaded cage or bone dowel such as that used in anterior lumbar interbody fusion . the u - shaped support is preferably comprised of a trabecular metal such as tantalum .

referring to fig2 - 8 , the present invention provides a mouthpiece device of an electronic cigarette and a filtering device thereof . the mouthpiece device comprises an inhaling shell 1 with two open ends , an atomizing device 2 , a liquid - guiding tube 3 , a stopper 4 , and the filtering device which has a cap 5 or cap 5 ″. one of the open end of the inhaling shell 1 is used as a connecting end for connection with a power supply part of the electronic cigarette , and the other open end is used as an inhaling end for user &# 39 ; s suction and is covered with the cap 5 or 5 ″. the inhaling shell 1 comprises a liquid reservoir 11 , an aerosol passage 12 alongside the liquid reservoir 11 , a connection element 13 , an electrode element 14 , and an insulating ring 15 . the liquid reservoir 11 and the aerosol passage 12 are longitudinally set in the shell 1 . the first ends as inner ends of both the liquid reservoir 11 and the aerosol passage 12 are open side by side and facing the atomizing device 2 within the inhaling shell 1 , and the second ends of both the liquid reservoir 11 and the aerosol passage 12 are facing the inhaling end of the inhaling shell 1 . in this embodiment , the liquid reservoir 11 is integrated in the shell 1 . the liquid reservoir 11 is used to store tobacco liquid , and has the inner end thereof set with the stopper 4 , and has the second end set with the cap 5 . thus the stopper 4 and cap 5 together seal tobacco liquid in the reservoir 11 . the aerosol passage 12 is used for aerosol to flow therethrough to an inhaling end of the shell 1 after tobacco liquid is vaporized to generate aerosol by the atomizer 2 . a filtering layer is set on inner wall of the aerosol passage 12 . the filtering layer is set on the inner wall of the aerosol passage 12 , and is adapted for a cross section of the inner wall . in this embodiment , the filtering layer is a filtering plate 121 integrated with the inner wall of the aerosol passage 12 . the filtering plate 121 is set perpendicularly to a central line of the aerosol passage 12 , and defines at least one filtering hole 122 therethrough . the connection element 13 is disposed at the connecting end of the shell 1 . one end of the connection element 13 with external threads thereon is threadedly connected with the power supply part ( not shown ) of the electronic cigarette , and the other end thereof is inserted in the shell 1 . the connection element 13 defines a cylindrical chamber inside for receiving the atomizing device 2 , and defines a mounting groove inside for holding the electrode element 14 therein . the connecting part 13 itself as an electrode of the atomizing device 2 is electrically connected with electrode of the power supply part . the electrode element 14 is fitted in the mounting groove of the connection element 13 in virtue of inserting the insulating ring 15 therebetween . the electrode element 14 has an end contacted with a corresponding electrode of the power supply part so as to energize an electric circuit . the atomizing device 2 comprises an atomizer 21 and an atomizing cup 22 . the atomizer 21 comprises an electric heat wire 211 and an electric heat rod 212 . the electric heat wire 211 winds around the heat rod 212 , and is mounted in the atomizing cup 22 by means of the heat rod 212 . the atomizing cup 22 is an integrated and inseparable cup body made in one mould , and comprises an atomizing chamber 221 , a mounting seat 222 with a fixing groove therein , wire - through holes 223 , and a through heat - dissipation hole 224 in center of the atomizing cup 22 . the mounting seat 222 with the fixing groove therein integrally and inseparably extends from a bottom of the atomizing chamber 221 up to a certain height , which is used for holding the atomizer 21 . the electric heat rod 212 is fixed in the fixing groove of the mounting seat 222 in a diameter direction of the atomizing cup 22 and facing one end of the liquid - guiding tube 3 . the wire - through holes 223 are used to pass electric wires therethrough , and are disposed in the atomizing cup 22 and communicated to the atomizing chamber 221 . there are two wire - through holes in this embodiment . an electric wire connecting one end of the heat rod 212 passes one wire - through hole 223 to electrically connect with the connection element 13 , another electric wire connecting the other end of the heat rod 212 passes the other wire - through hole 223 to electrically connect with electrode element 14 . the heat - dissipation hole 224 is used to transfer heat from the atomizer to the power supply part . in this embodiment , the atomizing cup 22 is disposed in the shell 1 in virtue of the connection element 13 , the atomizing cup 22 is held in the connection element 13 , and the dimension and figuration thereof are designed corresponding to the cylindrical chamber of the connection element 13 . the material for the atomizing cup 22 has good heat resistance , such as silica gel , which renders the atomizing cup 22 with good heat insulation . the atomizing cup 22 is shaped as a cylinder , and has a diameter larger than that of the cylindrical chamber of connection element 13 so as to be tightly fitted in the connection element 13 . the atomizing cup 22 of this embodiment not only facilitates manufacturing of the mouthpiece device , but also reduces the cost . furthermore , since the atomizing cup 22 is made from silica gel with good heat resistance , which provides a good heat insulation , the temperature at outer wall of the mouthpiece device keeps relatively low , and will not burn hand or mouth . the liquid - guiding tube 3 is used to guide tobacco liquid from reservoir 11 to atomizing chamber 221 for atomization . the liquid - guiding tube 3 has a first end thereof directly passing through the stopper 4 and extending in the reservoir 11 and a second end extending into the atomizing device 2 . the liquid - guiding tube 3 is engaged with the stopper 4 by interference fit , and is made from glass fiber . the stopper 4 is used for sealing the liquid reservoir 11 , and defines a tube hole therein . the liquid - guiding tube 3 is engaged in the hole by interference fit , and sealing material is circularly inserted between contacts of both . referring to fig7 , in the first embodiment , the cap 5 comprises a main body 51 , a plug 52 extending from bottom of the main body , an air slot 53 , and a suction hole 54 . the cap 5 seals the reservoir 11 in such way that the plug 52 is inserted in the reservoir 11 from the inhaling end of the shell 1 . the air slot 53 is stepped and shaped as letter z . the air slot 53 is positioned along the same diameter as the plug 52 , and is communicated with the aerosol passage 12 . the suction hole 54 is used for air communicating between inside and outside of the shell 1 . the suction hole 54 is communicated with the air slot 53 , and the aerosol passage 12 communicates with the suction hole 54 through the air slot 53 . the dimension and figuration of the cap 5 are designed according to inner diameter of the inhaling end of the shell 1 . in this embodiment , the cap 5 is shaped as a cylinder , and is made from silica gel . the diameter of the cap 5 is larger than inner diameter of the shell 1 so that the cap 5 is tightly fitted in the shell 1 by means of a circumferential sidewall of the cap 5 being tightly fitted in a circumferential inner wall of the inhaling shell 1 . referring to fig8 , in the second embodiment , the cap 5 ″ comprises a main body 51 ″, a plug 52 ″ extending from bottom of the main body , air slots 53 ″, and suction hole 54 ″. the cap 5 ″ is mainly similar to the cap 5 in the first embodiment , but it is different that the air slot 53 ″ runs through the cap 5 ″ from a top end to a bottom end of the main body , is positioned in the sidewall of the cap 5 ″, and is a concave parallel to a center line of the cap . the air slots directly communicate with the aerosol passage 12 , and has a cross - section shaped as arc , letter u or v . the filtering layer and the cap 5 or cap 5 ″ constitute the filter device . the tobacco liquid is guided from reservoir 11 to atomizer 21 which vaporizes the liquid drops into aerosol mixed with tobacco particles . the aerosol flows into the aerosol passage 12 , and are firstly filtered by the filtering plate 121 . the aerosol passes through the filtering hole 122 of the filtering plate 121 to next part of the aerosol passage , while aerosol flows to the filtering plate 121 and thus confronts resistance thereof , tobacco particles mixed in aerosol deposit on the filtering plate 121 , so that tobacco particles are filtered from aerosol . then , aerosol keeps to flow along the passage 12 , and is secondly filtered by the cap 5 . aerosol flows from the passage 12 , then passes from the air slot 53 and through the suction hole 54 , and finally flows to outside of shell 1 . or , aerosol flows from the passage 12 and through the air slot 53 ″, then directly to outside of shell 1 . since air slot 53 or 53 ″ provides resistance to the movement of the aerosol , other tobacco particles are deposited in the air slot 53 or 53 ′ for the purpose of being filtered and so as to prevent more tobacco particles flowing to outside of the shell 1 or being inhaled by human body . in the view of disclosure to the embodiments of the present invention , it will be apparent to one skilled in the art that modifications and / or substitutes may be made without departing from the scope and spirit of the invention .

the present invention relates to a mouthpiece device of an electronic cigarette , including an atomizing device for vaporizing tobacco liquid into aerosol and a liquid reservoir for storing tobacco liquid in an inhaling shell . the atomizing device includes an atomizing cup with an atomizing chamber , and an atomizer held in the atomizing chamber . the atomizing cup is molded by an integrated process . the mouthpiece device further includes a cap at an end of the liquid reservoir , and an aerosol passage therein : the cap defines a stepped slot for filtering tobacco particles in aerosol . the stepped slot is communicated with the aerosol passage . the present invention mainly solves such problems of the existing mouthpiece device as complicated manufacturing , high cost , bad heat insulation , and failing to filter tobacco particles ; and obtains a mouthpiece device with simple manufacturing , lower cost , good heat insulation and better effectiveness of filtering tobacco particles .

referring now to fig1 there are shown vertical storage and dispensing devices 10 , 50 of the present invention . standing vertical storage and dispensing device 50 and suspendable vertical storage and dispensing device 10 are two possible alternate embodiments of the present invention . vertical storage and dispensing devices 10 , 50 include a plurality of slidably separatable storage and dispensing compartments 22 for storing and dispensing materials ( not shown ) within compartments 22 . storage and dispensing compartments 22 are adapted to be nestingly stacked upon each other . compartments 22 are also slidably and rotatably mated with upright metal rod 14 which serves as a track for compartments 22 when compartments 22 are slidably separated from each other . access to materials within an individual slidable storage compartment 22b may be obtained by one - handed slidable lifting of storage compartment 22a immediately above storage compartment 22b in order to open storage compartment 22b . storage compartment 22a is slidably lifted far enough to substantially separate storage compartments 22a , b . a free hand may then be moved through the space between slidably separated storage compartments 22a and inserted into storage compartment 22a to remove the stored materials . thus stored materials may be conveniently dispensed from within storage and dispensing compartment 22a using one hand to uncover the stored materials and one hand to remove them . to close compartment 22a after access and protect the materials within compartment 22a during further storage , compartment 22b is slidably lowered along upright metal rod 14 until compartment 22a nestingly rests upon compartment 22b . when compartment 22a rests upon compartment 22b the bottom of compartment 22a serves as a closure element for compartment 22b . it will be understood that access to storage compartments 22 of both device 10 and device 50 may be obtained as described for compartments 22a , b . it will therefore be understood that each storage and dispensing compartment 22 within vertical storage and dispensing devices 10 , 50 may serve as both a storage compartment 22 for storing materials and a dispensing compartment 22 for later dispensing the stored materials . additionally , it will be understood that each storage compartment 22 of devices 10 , 50 may provide closure for storage compartment 22 disposed below it . as previously described , slidably openable storage and dispensing compartments 22 within storage and dispensing devices 10 , 50 are adapted to nest with each other . to permit nesting of compartments 22 within storage and dispensing device 10 , annular nesting notch 20 is provided around the lower region of the sidewall of storage compartments 22 . annular nesting notch 20 of an upper compartment 22 receives upper lip edge 36 of a lower compartment 22 disposed below it . when annular nesting notch 20 at the bottom of upper storage and dispensing compartment 22 engages upper lip edge 36 of lower storage compartment 22 disposed below it , the two engaged storage and dispensing compartments 22 , or nested storage compartments 22 , are free to rotate with respect to each other around upright metal rod 14 . thus it will be understood that annular nesting notches 20 and upper lip edges 36 provide rotatable nesting of compartments 22 within device 10 . it will also be understood that it is in this nested relationship that the bottom wall of upper storage and dispensing compartment 22 serves as a closure element for lower storage and dispensing compartment 22 disposed beneath it within devices 10 . to permit nesting of compartments 22 within storage and dispensing device 50 , narrowed bottom portions 38 of device 50 are provided in the lower region of compartments 22 . narrowed portion 38 of an upper compartment 22 within device 50 is received by upper lip edge 36 of a lower compartment 22 disposed below it . when narrowed portion 38 at the bottom of upper storage and dispensing compartment 22 is engaged by upper lip edge 36 of lower storage compartment 22 disposed below it , the two engaged storage compartments 22 , or nested storage compartments 22 , are free to rotate with respect to each other around upright metal rod 14 . thus it will be understood that narrowed lower portion 38 and upper lip edges 36 provide rotatable nesting of compartments 22 within device 50 . it will be understood that it is in this nested relationship that the bottom wall of upper storage and dispensing compartment 22 serves as a closure element for lower storage and dispensing compartment 22 disclosed beneath it within device 50 . upright metal rod 14 or extending tracking rod 14 is formed long enough to accommodate the required number of stacked storage and dispensing compartments 22 within vertical storage and dispensing devices 10 , 50 . each storage and dispensing compartment 22 mated with upright metal rod 14 is provided with central mating opening 24 through the center of its bottom . central mating opening 24 of compartments 22 permits stackable , slidable and rotatable mating of compartments 22 with upright metal rod 14 . the diameter of central mating opening 24 through the bottom of compartment 22 is selected to be slightly larger than the diameter of upright metal rod 14 or extending track 14 with which it is mated . thus the entire stack of compartments 22 mated with rod 14 may rotate in unison . because central mating opening 24 is disposed in the center of the bottom of storage and dispensing compartment 22 , the weight of a plurality of stacked compartments 22 and the materials therein may be evenly distributed around supporting upright rod 14 . this makes it easier to raise storage compartments 22 along upright rod 14 with a single hand to slidably separate storage compartments 22 and gain access without sticking or jamming along upright rod 14 . additionally , the use of a single upright rod 14 for tracking compartments 22 , rather than a plurality of upright rods , helps prevent sticking and jamming of compartments 22 in devices 10 , 50 . further assisting easy one - handed vertical separation of storage and dispensing compartments 22 is the cooperative action of a plurality of central mating openings 24 through the bottoms of a plurality of nested compartments 22 which are lifted simultaneously . each compartment 22 of this plurality of simultaneously lifted compartments 22 is tracked and straightened by the cooperation of the plurality of tracking openings 24 and upright rod 14 . in the preferred embodiment of vertical storage and dispensing device 10 , eye loop 12 may be attached to the upper end of upright metal rod 14 for vertically attaching storage and dispensing device 10 to an overhanging feature . in this manner , storage and dispensing device 10 may be free hanging and not in contact with any surfaces . if device 10 is suspended by means of a wire ( not shown ) attached to eye loop 12 , the entire structure of device 10 may be easily rotated to easily gain access to materials in all regions of compartments 22 . it will be understood that the rotation of the entire structure of suspended storage and dispensing device 10 is distinguished from rotation of individual storage and dispensing compartments 22 with respect to each other within device 10 . additionally , individual compartments 22 may be rotated relative to each other around upright rod 14 during rotation of the entire structure of device 10 suspended by a wire whether rotating compartments 22 are separated or nested . furthermore , it will be understood that , notwithstanding these types of rotation , stacked compartments 22 may rotate in unison with each other around upright rod 14 . as previously described , standing vertical storage and dispensing device 50 is an alternate embodiment of suspendable vertical storage and dispensing device 10 . standing alternate embodiment 50 is provided with stand 34 or base 34 for permitting standing vertical storage and dispensing device 50 to be disposed upon a horizontal surface ( not shown ). stand 34 is attached to the bottom end of upright metal rod 14 . the attachment of stand 4 to upright metal 14 may be accomplished by means of machine screw nut 28 which is threadably mated with threaded portion 30 of upright metal rod 14 after stand 34 is mounted upon threaded portion 30 of upright metal rod 14 . however , it will be understood that any manner of attaching stand 34 and upright rod 14 may be used . stand 34 or base 34 should be of sufficient size and weight to permit standing vertical storage and dispensing device 50 to be stable when disposed upon a horizontal surface . as previously described , access to materials within slidably separatable storage and dispensing compartment 22b of vertical storage and dispensing devices 10 , 50 is gained by grasping upper storage and dispensing compartment 22a immediately above lower storage and dispensing compartment 22b into which access is required . thus the sides of compartment 22a , b are adapted to serve as a gripping device during the separation of compartments 22a , b , although compartment 22b need not be grasped when it is accessed . furthermore upper storage compartment 22a is adapted to be grasped with one hand by a user of devices 10 , grasped upper storage compartment 22a and the entire stack ( not shown ) of storage compartments 22 above grasped upper storage compartment 22a may then be slidably raised along upright metal rod 14 . it will be understood that extending track 14 may extend in a horizontal direction and that access to compartment 22b may be provided by slidably separating compartments 22a , b in a horizontal direction along track 14 . in this horizontal embodiment , slidable return closure may be provided resiliently or by force from the user , and the wall through which track 14 passes still serves as a closure element and compartments 22a , b may be secured in a non - separated position by a detente device ( not shown ). as also described previously , this stack of slidably raised storage compartments 22 , along with grasped storage compartment 22a is raised a sufficient distance to permit materials contained within lower storage compartment 22b to be accessed with the free hand of the user . because storage compartment 22b is mated with upright metal rod 14 passing through central mating opening 24 of compartment 22b , there is no danger of inadvertently removing or tipping over compartment 22b while removing material from it . after the dispensing of materials within dispensing compartment 22b , grasped storage compartment 22a and the stack of storage compartments 22 above it are released . the force of gravity causes them to slidably fall along upright metal rod 14 . when they come to rest , upper storage compartment 22 is guided into a nested relationship with lower storage compartment 22 by the - cooperative action of annular nesting notch 20 of upper compartment 22 and upper lip edge 36 of lower compartment 22 within device 10 . within device 50 , narrowed bottom portion 38 is guided into a nested relationship with upper lip edge 36 . this nesting closes lower storage compartment 22 to prevent loss of materials from lower storage compartment 22 . also , the nested closure of storage and dispensing compartments 22 protects materials within storage compartments 22 from dust and moisture . to achieve this closing , the bottom of upper compartment 22 serves a closure element for lower compartment 22 . cover lid 18 of vertical storage and dispensing devices 10 , 50 provides closure of topmost storage and dispensing compartment 22 . upright metal rod 14 , which passes through the center of cover lid 18 , may be provided with horizontal bore 16 through rod 14 immediately above cover lid 18 . horizontal bore 16 through upright metal rod 14 may be adapted for inserting the shank of a small lock ( not shown ) therethrough in order to block slidable vertical movement of cover lid 18 along upright metal rod 14 . preventing movement of cover lid 18 in this manner prevents separation of storage and dispensing compartments 22 within storage and dispensing device 10 , 50 to prevent unauthorized removal of materials from storage compartments 22 within devices 10 , 50 . while this invention has been described with respect to a specific and particularly preferred embodiments thereof , it is not limited thereto and the appended claims are intended to be construed to encompass not only the specific forms and variants of the inventions shown but also such other forms and variants as may be devised by those skilled in the art without departing from the true spirit and scope of this invention .

a storage and dispensing device having a plurality of individual storage and dispensing compartments is provided . each compartment is provided with a slidable mating opening through a wall of the compartment for slidably mating with an extending track . the compartments are adapted to be grasped and slidably moved along the track to separate the compartments and permit access to compartments opened thereby . the compartments are slidably returned to a non - separated position in which the wall of one compartment serves as a closure element for an adjacent compartment . the track may be an upstanding vertical rod requiring upward horizontal separation of the compartments in order to gain access . a plurality of these compartments , each having a mating opening for sliding along the extending track , act cooperatively to prevent jamming or sticking of the compartments as they slide along the track together . the compartments are rotatable with respect to each other and rotatable in unison around the track . additionally , the entire device may be suspended with a wire and rotated using the wire .

referring to the drawings in particular , the only figure shows a respirator for supplying a patient 2 with breathing gas via an inspiration line 3 . via an expiration line 4 and a positive end expiratory pressure ( peep ) valve 5 , the gas breathed out reaches an expiration outlet 6 , which sets an expiration pressure pe at the patient 2 during expiration . the peep valve 5 is actuated by a linear drive 7 , which is connected to a first control and operating unit 8 of the respirator . the inspiration line 3 and the expiration line 4 unite in a y - piece , from which a breathing gas line 10 common for the inspiration and expiration leads to the patient 2 . a humidifier 11 and a breathing gas flow sensor 12 for measuring the breathing gas flow v are arranged in the inspiration line 3 . in addition , an oxygen sensor 17 measures the inspiratory oxygen concentration and a temperature sensor 18 detects the inspiratory breathing gas temperature . the phases of breathing are controlled by means of a breathing flow control valve 15 . set point adjusters 14 for the inspiration pressure pi and the expiration pressure pe , which can be set by the user to preselected values , are connected to the first control and operating unit 8 . the breathing flow control valve 15 is connected to a pressurized gas source 19 , and the breathing flow control valve 15 receives preset values from a ramp generator 16 during the inspiration in such a way that a preset inspiration pressure pi is present during the inspiration , and a preset expiration pressure pe is present during the expiration , together with the peep valve 5 . as an alternative or in addition to the pressurized gas source 19 , a blower 20 is provided , which draws in breathing gas from the environment via a filter 21 . the breathing gas may be taken either entirely from the pressurized gas source 19 , for example , oxygen and compressed air , or ambient air is drawn in with the blower 20 and oxygen is added from the pressurized gas source 19 . the humidifier 11 contains a second control and operating unit 9 , which is connected via a connection cable of the first control and operating unit 8 of the respirator 1 . the connection cable 13 is provided for transmitting electricity to the humidifier 11 and for bidirectional data exchange between the control and operating units 8 , 9 . the humidifier 11 ( via second control and operating unit 9 ) will preferably poll the respirator 1 for the parameters inspiratory gas flow , inspiratory oxygen concentration , inspiratory gas temperature and the mode of operation of the respirator . if the communication is established via the connection means 13 between the humidifier control and operating unit ( second control and operating unit 9 ) of the humidifier 11 and the respirator control and operating unit ( first control and operating unit 8 ) of the respirator 1 , the humidifier 11 sends an inquiry to poll the identification code of the respirator 1 . the respirator 1 correspondingly identifies itself in the reply . it appears from the identification of the respirator 1 which code is to be assigned to which parameter and in what format and in which unit this parameter is to be assumed to express . the humidifier 11 first sends reading commands with the codes of the parameters to be polled to the connected respirator 1 . it appears , for example , from the reply of the respirator 1 that an oxygen concentration of 60 % is currently being sent to the patient and that a blower 20 is active , which delivers a maximum pressure of 75 mbar . the humidifier 11 will now either measure the humidity of the ambient air or assume that the usual moisture content of the ambient air is at a relative humidity of approximately 50 %. the gas fed to the patient thus already has a certain moisture content , so that only the moisture still missing from the breathing gas relative to the breathing gas temperature to be set must be added . the oxygen added to the ambient air from the central gas supply is assumed to be dry . combined , the gas mixture now already has a relative humidity of about 25 %. corresponding to the settings performed , the humidifier 11 has to introduce only the residual moisture into the breathing gas , so that a relative humidity of 95 % will be reached . undesired condensation of water is prevented from occurring by taking into account the basic moisture content already present in the breathing gas . the information that no gas is currently being released to the patient because the phase of expiration is present is sent when the connected respirator is next polled by the humidifier . the humidifier 11 determines from this information that no humidifying output is currently being needed . however , if the respirator 1 shows in the next step that a gas flow of 60 l per minute is being released to the patient , the inspiration starts and the humidifier must humidify the gas with maximum output . if the gas flow decreases during the phase of inspiration , the humidifier 11 can correspondingly adapt its humidification output and thus bring about optimal humidification of the breathing gas . it is especially advantageous now to make settings for the humidifier 11 via the respirator operating and control unit ( the first control and operating unit 8 ) of the respirator 1 . all alarms and other reports of the humidifier are now provided as an output on the operating unit . the user can thus change the preset set point for the humidifier , for example , on the operating unit , in such a way that the humidification output is reduced from 95 % relative humidity to 90 % relative humidity . on the other hand , the user receives the information , via the respirator operating and control unit ( the first control and operating unit 8 ) of the respirator 1 , that the water reserve in the humidifier is depleted and must be replenished . the user can thus monitor the humidifier from a central operating unit and change settings if needed . while specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention , it will be understood that the invention may be embodied otherwise without departing from such principles .

a device with a respirator and with a humidifier for breathing gas . breathing gas humidification is adapted to the different operating states of the respirator . a connection is provided for bidirectional data transmission between the control and operating unit of the respirator and the control and operating unit of the humidifier .

the present invention relates to design relationships and methods of measurement to improve the shape of a driver golf club head 20 . to verify the existence of conforming or non - conforming geometries of a driver club head 20 , a specific club head orientation with respect to a cartesian coordinate system ( ccs ) is used and is described herein . an exemplary ccs having an origin point 15 is shown in fig1 . as shown in fig2 , a driver club head 20 is oriented onto a ccs where three perpendicular planes exist . the point at which all three planes intersect each other is called the origin point 15 . the resulting lines of intersection of the three planes with each other are perpendicular lines representing the axis of the ccs , with each line or axis labeled appropriately x , y , and z and passing through the origin point of the ccs . the values on either side of the origin of the x , y , and z axis are labeled either positive or negative , as defined and understood in the ccs . in the preferred embodiment , the club head 20 placed within the ccs comprises a hosel 24 having a hosel axis 32 , a crown 26 , a sole 25 and a face 30 , as shown in fig2 . preferably , the driver type golf club head 20 placed within the ccs has a volume of less than 500 cubic centimeters . preferably , the sole 25 is composed of a metal material and the crown 26 is composed of a non - metal material . the sole of the golf club head 20 preferably is composed of a titanium alloy material . the driver golf club head 20 is oriented in the ccs in such a manner that the hosel line 32 lies in the yz plane and passes through the origin point 15 of the ccs . the driver golf club head 20 is further oriented such that the hosel axis line 32 of the golf club head 20 lies at a 60 degree angle measured from the - y axis , as shown in fig2 , 4 , and 6 . once the club head 20 is oriented as described above , it is further adjusted by rotating the club head 20 around the hosel axis line 32 until two points , a toe point 62 and a heel point 64 , each of which are approximately one inch on either side of the face center point 35 , have the same distance d to the yz plane , as shown in fig6 and 7 . the horizontal face center point 37 can be located as shown in fig3 a and 3b . if the golf club face 30 has scorelines 33 with a blank space 31 in the middle , as shown in fig3 a , diagonal lines are drawn from the central ends of the upper scorelines 33 to the central ends of the lower scorelines 33 across the blank space 31 to locate the horizontal center point 37 . if the golf club face 30 has scorelines 33 stretching across the face 30 , diagonal lines are drawn from the ends of the second scoreline 33 from the top to the ends of the second scoreline 33 from the bottom , as shown in fig3 b . in both fig3 a and 3b , the horizontal center point 37 is located where the diagonal lines intersect . the face center point 35 is shown in fig4 and 5 , which illustrate how to define the face center point 35 in relation to the bottom 30 a and top 30 b of the club face 30 . as shown in these figures , the golf club head 20 is sectioned along lines a - a parallel to the z axis through the horizontal face center point 37 measured along the y axis , and the height fh of the face 30 is measured and divided in half to arrive at the location of the center of the face 35 . when the golf club head 20 is oriented as described above and in fig1 - 7 , it is in the optimal position to obtain a preferred cross - sectional orientation through the club head . this can be accomplished using the largest tangent circle method ( ltcm ). pursuant to the ltcm , and as shown in fig8 and 9 , 3d silhouette curves of the sole 25 and crown 26 surfaces are projected onto a measurement plane 74 , parallel to the yz plane , along a vector parallel to the x axis , creating 2d curves 70 , 72 on the measurement plane . a circle 80 is then placed on the measurement plane 74 between the projected 2d sole curve 70 and crown curve 72 and enlarged until the circle 80 has the maximum diameter possible , preferably rounded to the nearest 0 . 001 inch , and is tangent to both the projected curves 70 , 72 . as shown in fig8 , a line 85 is then drawn from the tangent point where the circle 80 touches the projected crown silhouette curve 72 to the tangent point where the circle touches the projected sole silhouette curve 70 . as shown in fig9 , the line 85 created between the tangent points is projected in a direction parallel to the x axis , thus creating a plane 90 to derive the two - dimensional intersection curves 95 of the golf club head 20 . these two - dimensional intersection curves 95 represent the outline or cross - section of the club head 20 , as shown in fig1 , in an optimal orientation for determining the relationships between the face 30 , crown 26 , and sole 25 surfaces . computational fluid dynamics ( cfd ) analysis has shown that as the airflow moves from the face onto the crown and sole surfaces of the club head , it may accelerate and can promote negative drag on the transitional surfaces . according to the present invention , this desirable negative drag can be achieved by altering the dimensions a , b , c , d , e , and h , and preferably the dimensions a , b , d , and e , defined below , such that their values satisfy one or more of the following equations : a ≧ 0 . 36 inches and d & gt ; 1 . 0 inch ; b ≧ 0 . 3 inches and e & gt ; 1 . 0 inch ; a ≧ 0 . 25 inches and c ≦ 2 . 0 inches ; b ≧ 0 . 25 inches and c ≦ 2 . 0 inches ; a ≧ 0 . 25 inches and b ≧ 0 . 25 inches and c ≧ 2 . 0 inches ; and referring to the cross - section 95 derived according to the ltcm described above and in fig1 - 9 , which is illustrated in fig1 , h is defined as a distance along the tangent line 85 between the crown apex point 42 and the face - most sole nadir point 40 . c is defined as a distance along the tangent line 85 between the top of the club face 30 and the bottom of the club face 30 . a is defined as a distance along the tangent line 85 between the top of the club face 30 and the crown apex point 42 . b is defined as a distance along the tangent line 85 between the bottom of the club face and the face - most sole nadir point 40 . d is defined as a distance along the x axis between the top of the club face 30 and the crown apex point 42 . e is defined as a distance along the x axis between the bottom of the club face 30 and the face - most sole nadir point 40 . the cross - section 95 also includes transitional surfaces 92 , 94 between the face 30 and the sole 25 and crown 26 surfaces , the heights along the z axis of which are represented by values a and b . a preferred embodiment of the present invention is a driver having a shape optimized with regard to transitional heights a and b as a percentage of face height c , e . g ., (( a + b )/ c )≧ 30 %. when a driver optimized according to this embodiment is compared with six sample drivers , as shown in fig1 , it becomes evident that an optimized driver has a greater percentage of transitional height than sample drivers 1 through 6 . in a second embodiment of the present invention , when the golf club head 20 is oriented as described above according to the ltcm and as shown in fig1 - 9 , it is in an optimal position to obtain design relationships of the overall projected silhouette of the club head to the area of its face 30 . according to this embodiment of the present invention , the two - dimensional projected area of the face 30 surface of the golf club head is compared with the two - dimensional projected area of the club head 20 , excluding any attached ferrule or shaft , and before artwork , scorelines , dots , and graphics are added to the club face . according to this second embodiment , the two - dimensional silhouette 76 of the club head 20 is obtained by projecting a plane 74 parallel to the yz plane , as shown in fig1 and 13 . the face area 78 of the club head 20 is obtained by using an 8 . 0 inch radius gauge as shown in fig1 . the radius gauge is kept parallel with the xz plane and is touched against the club head 20 so that it contacts the top and bottom edges of the face 30 . as illustrated in fig1 , each successive contact location 100 is at 0 . 25 inch increments towards the toe and heel from the face center point 35 , with the exception of the last interval at the ends of the face . each location 100 touched by the radius gauge is marked . a smooth spline curve is ‘ fit ’ or ‘ lofted ’ to the marked contact points to create a boundary that sufficiently defines the area of the face 30 of the club head 20 . the newly determined face boundary 78 is then projected onto the same plane 74 as the silhouette curves 76 of the club head to obtain the two - dimensional projected area of face 30 , as shown in fig1 . the two - dimensional projected curves 78 , 76 of the face boundary and the driver club head &# 39 ; s silhouette curves are then obtained and measured using an optical comparator that can accurately report 1 : 1 projections . according to the present invention , improvements in club head drag can be obtained by designing a club head wherein the two - dimensional projected face area 78 is below 60 % of the overall two - dimensional projected area 76 of the driver club head 20 . as demonstrated in fig1 , driver club head designs with poor aerodynamic features have face areas that are more than 59 % of their overall projected club head areas . in other words , an optimized driver club head according to the present invention complies with the equation ( 2d projected face area / 2d projected driver club head silhouette area )≦ 59 %. computational fluid dynamics ( cfd ) analysis shows that the face 30 contributes significantly to the overall drag of the club head 20 . reducing the face area of the club head 20 according to the embodiments of the invention reduces the overall drag on the club head 20 in a proportional manner . in addition , when the face area of the club decreases , the designs of the transitional surfaces which connect the face to the body become influential in reducing club head drag . though a large face area can provide the golfer with a hitting surface that is forgiving with regard to mishits and offers good compliance properties ( coefficient of restitution and characteristic time ), the present invention reveals that a balance of face area , transitional surface shape , and overall projected area of the club head are important to reduce the overall drag on the club head while at the same time providing a club that is easy to hit and acceptable to golfers . driver type golf club heads 20 created using the methods discussed herein enable the golfer to benefit from an improved driver 20 design more suited to hitting shots with higher ball velocities due to the increased head speed produced by lower drag forces opposing the driver head 20 as it travels through the air . a conventional golf club head design that has not been optimized using the methods of the invention , shown in fig1 , has inferior air flow separation when compared to a golf club whose transitional surfaces have been optimized for drag reduction , shown in fig1 . cfd analysis shows that optimizing transitional surfaces of the club head reduces drag by over 100 % when compared with conventional golf club heads . the designs of the present invention have crown surfaces with increased curved shapes when compared to conventional golf club heads , and have apex points that are higher and farther back from the top of the face than conventional designs . similarly , the nadir points on the soles of the driver club heads of the invention are lower and further away from the bottom of the face . these design changes lead to a reduction in the face area . while making faces too small may lead to undesirable club performances , making the faces smaller in ways that still provide adequate hitting zones can produce a high performing and forgiving face as well as allow the apex and nadir points of the club head to be located optimally for reduced drag on the club head . the golf club head 20 of the present invention may be made of one or more materials , may include variable face thickness technology , and may have one or more of the structural features described in u . s . pat . no . 7 , 163 , 468 , u . s . pat . no . 7 , 163 , 470 , u . s . pat . no . 7 , 166 , 038 , u . s . pat . no . 7 , 214 , 143 , u . s . pat . no . 7 , 252 , 600 , u . s . pat . no . 7 , 258 , 626 , u . s . pat . no . 7 , 258 , 631 , u . s . pat . no . 7 , 273 , 419 , each of which is hereby incorporated by reference in its entirety . from the foregoing it is believed that those skilled in the pertinent art will recognize the meritorious advancement of this invention and will readily understand that while the present invention has been described in association with a preferred embodiment thereof , and other embodiments illustrated in the accompanying drawings , numerous changes , modifications and substitutions of equivalents may be made therein without departing from the spirit and scope of this invention which is intended to be unlimited by the foregoing except as may appear in the following appended claims . therefore , the embodiments of the invention in which an exclusive property or privilege is claimed are defined in the following appended claims .

methods of forming a golf club head having improved aerodynamic characteristics are disclosed herein . a preferred method is the largest tangent circle method , which utilizes a cartesian coordinate system . the method results in identification and measurement of certain club head features , which can be adjusted to improve aerodynamic properties of the golf club head . one method of the present invention lowers the drag of the club head by specifying dimensional relationships of the driver head based on location of apex and nadir points , while another method lowers the drag of the club head by improving overall face design .

firstly , the overall structure of a manipulator according to the invention is considered , as illustrated in fig1 to 12 . such a manipulator 100 generally comprises a control unit 1 , a connecting arm 2 and a working unit 3 . the control unit 1 is mounted on the proximal end 2 a of the connecting arm 2 whilst the working unit 3 is mounted on the distal end 2 b of the connecting arm 2 . the control unit 1 comprises a handle 4 capable of being held by one hand of an operator , and a control body 10 containing various drive means to produce the appropriate movements in the working unit 3 . the working unit 3 comprises a tool support 5 capable of supporting a tool 6 . in the figures , a tool 6 has been illustrated in the form of forceps with two arms 6 a and 6 b . the handle 4 comprises control members , for example a first control member 4 a , a second control member 4 b , a third control member 4 c and a forceps control member 4 d . as in the known devices , the connecting arm 2 passes into a trocar 7 providing the connection and passage into an opening 8 formed in the body wall 9 . the control unit 1 remains outside the body of the patient , whilst the working unit 3 penetrates inside the body of the patient to reach the operating area where the tool 6 has to carry out movements controlled by the control unit 1 . in fig1 to 4 , the tool 6 and the tool support 5 are in alignment with the longitudinal axis i - i of the connecting arm 2 . as may be seen in these figures , the operator is able to position the working unit in a precise manner in the operating area by the sliding co of the connecting arm 2 into the trocar 7 and by the inclination in of the connecting arm 2 and of the trocar 7 in the opening 8 of the body wall 9 . in fig5 , a first movement of the tool support 5 has been illustrated , namely an inclined movement 12 about a transverse axis of inclination 11 . said movement is obtained by the activation 13 of the first control member 4 a of the handle 4 which controls an inclination actuator housed in the control body 10 . by way of illustration , it is possible to refer to fig1 , illustrating the inclination actuator 40 a which is connected to the working unit 3 by an inclination transmission cable 41 a illustrated in fig1 . in fig5 , by actuation 13 of the first control member 4 a , the tool support 5 has been inclined to orientate it in a direction of inclination ii . now fig6 will be considered , which illustrates a second movement of the tool support 5 , namely a specific rotational movement 14 about the direction of inclination ii . said specific rotational movement 14 of the tool support 5 about the direction of inclination ii is obtained by an activation 15 of the second control member 4 b which controls one or more inclination actuators housed in the control body 10 . the generation of specific rotational movements 14 may advantageously be implemented according to the invention by the activation 15 of the second control member 4 b of the handle 4 which controls a specific rotation actuator 40 b housed in the control body 10 ( fig1 ). now fig7 will be considered , which illustrates a further movement of the tool support 5 , namely a movement by which the direction of inclination ii is oriented about the longitudinal axis i - i of the connecting arm 2 . said orientation movement is illustrated by the arrow 16 . according to the invention , it is possible to produce said orientation movement 16 either by causing the specific relative rotation of the connecting arm 2 about its longitudinal axis i - i relative to the handle 4 , or by a manipulation of the handle 4 for a rotation of the entire manipulator about the longitudinal axis i - i of the connecting arm 2 . in the first case , the rotation of the connecting arm 2 is obtained by the activation of the third control member 4 c of the handle 4 which controls an actuator for rotating the arm 40 c housed in the control body 10 ( fig1 ). as a variant to this first case , the rotation of the connecting arm 2 may be obtained , as illustrated in fig2 to 24 , by providing a joint for axial rotation relative to the handle 4 on the remainder of the manipulator , with means for indexing the position relative to the handle 4 . in practice , it is possible to provide that the handle 4 is mounted on a handle support 4 f which is itself articulated in axial rotation relative to the control body 10 . preferably , the control body comprises a gripping part 10 a which the operator is able to activate to produce the relative rotation of the handle 4 and the control body 10 . in the second case , to permit easy axial rotation of the entire manipulator 100 by manipulation of the single handle 4 , the handle 4 is itself articulated about an axis of articulation of the handle 4 e as illustrated in fig1 . thus , in fig7 , a first embodiment of the manipulator 100 has been illustrated , according to which the handle 4 comprises a first control member 4 a of which the actuation causes the motorized inclined movement 12 of the tool support 5 , a second control member 4 b of which the actuation causes the specific rotational movement 14 of the tool support 5 about its direction of inclination ii and a third control member 4 c to produce the specific rotational movement 16 of the connecting arm 2 about its longitudinal axis i - i . in this manner , it is possible to orientate the tool 6 in all directions of a cone covering the distal end 2 b of the connecting arm 2 . furthermore , in the embodiment of fig7 , as the tool 6 is forceps , the handle 4 comprises a forceps control member 4 d , providing the control of the forceps clamping movement illustrated by the arrow 60 . in practice , the clamping 60 of the forceps may be implemented by the actuation of the forceps control member 4 d which controls the rotation of a forceps actuator 40 d housed in the control unit 10 ( fig1 ). according to the variant illustrated in fig1 , the connecting arm 2 is fixed to the control body 10 whilst the handle 4 is articulated about an axis of articulation 4 e . in this case , the specific rotational movement 16 is obtained by rotation r ( fig2 ) of the entire control unit 1 — connecting arm 2 , the rotation r being produced by the hand of the operator who holds the handle 4 . such a rotation r is illustrated by the series of views of fig2 . the joint of the handle 4 allows the hand to maintain a correct grip of the handle 4 without exaggerated movement of the joint of the handle , during a sufficient rotation of the manipulator about the longitudinal axis i - i . the other movements of the tool support 5 are obtained in a motorized manner , as in the embodiment of fig7 . in the embodiment of fig8 , the orientation movement of the direction of inclination ii about the longitudinal axis i - i of the connecting arm 2 is obtained by activation of the third control member 4 c of the handle 4 , which controls a second inclination actuator located in the control body 10 , which actuator drives the tool support 5 in rotation along an intersecting transverse axis which is perpendicular to the transverse axis of inclination 11 and the longitudinal axis i - i . said second transverse axis of articulation is denoted by the reference numeral 20 in fig8 and the rotation is illustrated by the arrow 21 . thus , by combining the two inclined rotations about the axes 11 and 20 , it is possible to orientate the tool 6 in all orientations within a cone covering the distal end 2 b of the connecting arm 2 . the other movements of the tool support 5 are identical to those of fig7 and 11 and are motorized in the same manner . the first inclined movement 12 about the transverse inclination axis 11 , the forceps clamping movement 60 for the tool 6 , the second movement of inclination by rotation 21 about a second intersecting transverse axis 20 and the specific rotational movement 16 of the connecting arm 2 about its longitudinal axis i - i are in the embodiment illustrated in fig9 . in this case , it is not essential to provide further means to ensure the specific rotation of the tool 6 about its direction of inclination ii as this movement may be carried out by the synchronous combination of rotations about the axes 11 , 20 and i - i . however , a specific rotational movement of the tool 6 about its inclination axis ii may advantageously be added , as illustrated in fig1 . fig1 illustrates a variant in which a resilient compression system 70 is interposed between the trocar 7 and the control body 10 , to relieve the operator of part of the weight of the manipulator . in all the embodiments disclosed above , the control members 4 a - 4 d may be of the push - button , or touch button , type or any other type of device which is able to be actuated by a finger along a short path and using a small actuating force . in this manner , the risk of interference is further reduced between the actuation of the control members and the holding in position of the entire manipulator by the hand which carries the handle 4 . according to an advantageous embodiment , illustrated by fig2 , the second control member 4 b comprises a first input member h , of which the actuation causes the specific rotation of the tool support 5 in a first clockwise rotation and a second input member ah , of which the actuation causes the specific rotation of the tool support 5 in a second counter - clockwise direction of rotation . for example , the input members h and ah may be two push - buttons . said push - buttons h and ah may each control the rotation of the tool support 5 according to a speed of rotation which is substantially constant . alternatively , the push - buttons may be of the progressive type , each controlling the rotation of the tool support 5 according to a variable rotational speed between a rapid speed and a slow speed . according to a further possibility which is more advantageous , permitting in particular the preparatory stages of adapting the manipulator before an operating movement to be shortened , the buttons may be push - buttons of the “ all or nothing ” type in stepped mode , changing to continuous mode at higher speeds when maintaining the actuation . as regards the first control member 4 a , it may be advantageously produced in the form of a third input member d , of which the activation causes a positive increase in the angle of inclination , and a fourth input member g , of which the activation causes a negative increase in the angle of inclination . for example , there may be two push - buttons g and d which each control a motor in one respective rotational direction , and the motor stops when the buttons g and d are released . advantageously , it is also possible to provide the possibility of activation for rapid resetting , which returns the tool support 5 into the axis of the connecting arm 2 , for example if the two push - buttons g and d are pressed simultaneously . as regards the forceps control member 4 d , it is possible to produce it , for example , in the form of a ratchet - type push - button , which controls the clamping of the forceps following a first activation by pressing , and which controls the opening of the forceps following a second activation by pressing , controlling the forceps actuator 40 d in both rotational directions . advantageously , it is possible to control the forceps actuator with a forceps control member 4 d having a first open forceps position , a second forceps position closed by light clamping and a third forceps position closed by strong clamping . this permits the operator , for example , to place a needle in the forceps , to control the light clamping to perfect the positioning of the needle by sliding into the forceps , and then to lock the needle in position by controlling the strong clamping . now fig1 and 15 will be considered which illustrate an embodiment of the working unit 3 , in the case of a forceps - type tool 6 having a fixed jaw 6 a and a mobile jaw 6 b about a transverse axis of rotation 6 c . an axial input shaft 31 is provided for the clamping or unclamping movement of the forceps 6 , said axial input shaft being coupled to the forceps actuator , being oriented along the longitudinal axis i - i of the connecting arm 2 , carrying a conical end pinion 32 which drives a lateral conical pinion 33 rotating about a transverse axis 11 and driving the conical pinion 34 which is itself mounted at the end of a threaded and axially wedged output shaft 36 . a nut 37 is mounted on the threaded part of the output shaft 36 and is axially displaced during the rotation of the output shaft 36 to drive the mobile jaw 6 b of the tool 6 pivotably about the transverse rotational axis 6 c . the specific rotation of the tool 6 about the axis of inclination ii is provided by an input tube 38 oriented along the longitudinal axis i - i , driven in turn in rotation by the specific rotation actuator , and fixed to a conical end pinion 39 which itself drives in rotation a lateral conical pinion 40 rotating about a transverse axis 11 and which drives an axial tubular conical pinion 41 fixed to the tool support 5 ( fixed to the fixed jaw 6 a in the present case ). in other words , the tool 6 is mounted with its fixed jaw 6 a in the fixed position on the pinion 41 , which itself is mounted axially rotatably in the arched portion 50 . a bushing 42 guides the input tube 38 in its rotation about the axis i - i in the connecting arm 2 . the arched portion 50 is pivotably mounted about the transverse axis 11 on the distal end 2 b of the connecting arm 2 . in its rotation , the arched portion 50 is fixed to a pulley 43 urged in rotation by a cable 41 a , more clearly visible in fig1 . as may be seen in fig1 and 17 , the inclination actuator 40 a , of the motorized type , causes by its rotation the driving of the cable 41 a and the pulley 43 for the inclination of the arched portion 50 and the tool support 5 about the transverse axis 11 as far as a direction of inclination ii . the specific rotation actuator 40 b ensures the specific rotation of the tool support 5 about the direction of inclination ii , by driving the input tube 38 . the forceps actuator 40 d ensures the clamping of the forceps 6 by rotation of the input shaft 31 . in fig1 an actuator is also shown for rotating the arm 40 c which is capable of causing the rotation of the entire manipulator about the handle 4 . in the embodiment illustrated in fig1 , the tool support 5 is rotatably mounted according to a spherical joint 55 on the distal end 2 b of the connecting arm 2 . the oriented driving of the tool support 5 is provided by peripheral cables 57 for pivoting in all possible orientations of the sphere . the transmission of the clamping movement of the forceps 6 takes place by a central cable 56 whilst the specific rotational movement is carried out by transmission by a universal joint 58 . it is possible to consider the description of the french pending patent application no . 2 927 011 which is incorporated here by way of reference . in fig1 may be seen the entire manipulator according to this embodiment , with cables for the transmission of the movements . fig2 illustrates the specific rotational movement of the manipulator itself , in the case of an embodiment where the specific rotation of the connecting arm 2 is not motorized . due to the articulation of the handle 4 , the hand is able to follow the movements without the fingers being released from the handle 4 , ensuring sufficient rotation of the manipulator about its longitudinal axis . in fig2 and 17 the embodiment has been illustrated where the control body 10 and the connecting arm 2 , which are fixed together , are motorized in rotation relative to the handle 4 . in fig2 , the handle 4 is driven manually in axial rotation about the axis i - i due to an axial joint and a gripping part 10 a on the control body 10 . in practice , the handle 4 is articulated according to the transverse joint 4 e on a handle support 4 f , itself mounted in free axial rotation by an axial joint 4 g on the control body 10 . the axial joint 4 g and the gripping part 10 a form a member for manually driving in rotation the handle 4 relative to the remainder of the manipulator about the longitudinal axis i - i of the connecting arm 2 . the activation of the gripping part 10 a by a finger of the hand holding the handle 4 , or by a different hand , is useful for carrying out rotations of large amplitude for the orientation of the direction of inclination ii about the axis i - i . rotations of small amplitude , during the operating movement , are carried out ergonomically by manual activation of the handle 4 in rotation . in the variant illustrated in fig2 , the handle 4 is attached and fixed to the handle support 4 f . the joint 4 g is a bearing of which the external race is fixed to the handle support 4 and of which the internal race is fixed to the connecting arm 2 and the gripping part 10 a in the form of a thumbwheel attached to the connecting arm 2 . alternatively , in the variant illustrated in fig2 , the gripping part 10 a is directly fixed to the control body 10 . in fig2 and 26 , the handle 4 is connected to the control body 10 by a positioning arm 30 which may be used independently of the other features described here . by means of this positioning arm 30 , the handle 4 may be oriented differently or even offset at a distance from the longitudinal axis i - i of the manipulator , for more ergonomic gripping in certain operating conditions . in fig2 , the positioning arm 30 is a semi - rigid rod 5 to 30 cm long , deformable by flexion under flexional or torsional forces greater than the forces produced alone by the weight of the manipulator and the resistance of the tissue treated by the manipulator . the handle 4 may be fixed to the end of the semi - rigid rod 30 . alternatively , it may be articulated according to a transverse axis of articulation 4 e . in fig2 , the positioning arm 30 is a rigid rod , carrying at its proximal end the handle 4 with a possible transverse joint 4 e , and articulated at its distal end to the control body 10 by a joint 35 which may be locked in position . as disclosed in some of the preceding embodiments , the handle 4 may advantageously be mounted freely in rotation about an axis of articulation 4 e . for example , the axis of articulation 4 e may be a transverse axis relative to the longitudinal axis i - i of the connecting arm 2 . however , it is possible to provide further orientations of the axis of articulation 4 e , for example a longitudinal orientation or an oblique orientation , each possibility having respective advantages . in all embodiments , each of the actuators may be , for example , of the electric motor , hydraulic actuator or pneumatic actuator type . actuators of the electric motor type are preferable , in particular for the ease of power supply and flexibility of control . the present invention is not limited to the embodiments which have been specifically described but it incorporates different variants and generalizations contained within the scope of the following claims .

a manipulator includes a control unit , with handle and control buttons , and a connecting arm which , at its proximal end , carries the control unit and , at its distal end , carries a work unit . the control buttons control at least a first inclination motor , which causes a movement of inclination of a tool support of the work unit about a transverse inclination axis , and they control the actual rotation of the tool support about its direction of inclination and control the orientation of the direction of inclination about the longitudinal axis of the connecting arm . a particularly ergonomic manipulator is thus obtained which is easy to learn to use and which efficiently separates the stresses arising from movements of the tool support and the stresses arising from holding and moving the manipulator itself .

the preferred active compounds of the present invention are in an ionized , salt form or as the free base of the pharmaceutically acceptable salts thereof ( provided , for the aerosol or pump spray compositions , they are soluble in the spray solvent ). these compounds are soluble in the non - polar solvents of the invention at useful concentrations or can be prepared as pastes at useful concentrations . these concentrations may be less than the standard accepted dose for these compounds since there is enhanced absorption of the compounds through the oral mucosa . this aspect of the invention is especially important when there is a large ( 40 - 99 . 99 %) first pass effect . as propellants for the non polar sprays , propane , n - butane , iso - butane , n - pentane , iso - pentane , and neo - pentane , and mixtures thereof may be used . n - butane and iso - butane , as single gases , are the preferred propellants . it is permissible for the propellant to have a water content of no more than 0 . 2 %, typically 0 . 1 - 0 . 2 %. all percentages herein are by weight unless otherwise indicated . it is also preferable that the propellant be synthetically produced to minimize the presence of contaminants which are harmful to the active compounds . these contaminants include oxidizing agents , reducing agents , lewis acids or bases , and water . the concentration of each of these should be less than 0 . 1 %, except that water may be as high as 0 . 2 %. suitable non - polar solvents for the capsules and the non - polar sprays include ( c 2 - c 24 ) fatty acid ( c 2 - c 6 ) esters , c 7 - c 18 hydrocarbon , c 2 - c 6 alkanoyl esters , and the triglycerides of the corresponding acids . when the capsule fill is a paste , other liquid components may be used instead of the above low molecular weight solvents . these include soya oil , corn oil , other vegetable oils . as solvents for the polar capsules or sprays there may be used low molecular weight polyethyleneglycols ( peg ) of 400 - 1000 mw ( preferably 400 - 600 ), low molecular weight ( c 2 - c 8 ) mono and polyols and alcohols of c 7 - c 18 linear or branch chain hydrocarbons , glycerin may also be present and water may also be used in the sprays , but only in limited amount in the capsules . it is expected that some glycerin and water used to make the gelatin shell will migrate from the shell to the fill during the curing of the shell . likewise , there may be some migration of components from the fill to the shell during curing and even throughout the shelf - life of the capsule . therefore , the values given herein are for the compositions as prepared , it being within the scope of the invention that minor variations will occur . the preferred flavoring agents are synthetic or natural oil of peppermint , oil of spearmint , citrus oil , fruit flavors , sweeteners ( sugars , aspartame , saccharin , etc . ), and combinations thereof . the active substances include the active compounds selected from the group consisting of cyclosporine , sermorelin , octreotide acetate , calcitonin - salmon , insulin lispro , sumatriptan succinate , clozepine , cyclobenzaprine , dexfenfluramine hydrochloride , glyburide , zidovudine , erythromycin , ciprofloxacin , ondansetron hydrochloride , dimenhydrinate , cimetidine hydrochloride , famotidine , phenytoin sodium , phenytoin , carboprost thromethamine , carboprost , diphenhydramine hydrochloride , isoproterenol hydrochloride , terbutaline sulfate , terbutaline , theophylline , albuterol sulfate and neutraceuticals , that is to say nutrients with pharmacological action such as but not limited in another embodiment , the active compound is an endocrine modulator , glucose production inhibitor , agent for treatment of type ii diabetes , anti - secretory agent , glycolipid , glycoprotein , anti - hyperthyroid agent , thyroid hormone , or a mixture thereof . in one embodiment the active compound is an endocrine modulator . suitable endocrine modulators for use in the buccal sprays of the invention include , but are not limited to , methimazole , voglibose , finasteride , gi198745 , liothyronine , glyburide , metformin , nateglinide , ioglitazone , pegvisomant , minoxidil , and mixtures thereof . in one embodiment the active compound is a glucose production inhibitor . suitable glucose production inhibitors for use in the buccal sprays of the invention include , but are not limited to , acarbose , acetohexamide , chlorpropamide , glipizide , glyburide , metformin , miglitol , nateglinide , pioglitazone , rosiglitazone , tolbutamide , tolazamide , and mixtures thereof . in one embodiment the active compound is an agent for treatment of type ii diabetes . suitable agents for treatment of type ii diabetes for use in the buccal sprays of the invention include , but are not limited to , acarbose , acetohexamide , chlorpropamide , glipizide , glyburide , metformin , miglitol , nateglinide , pioglitazone , rosiglitazone , tolbutamide , tolazamide , and mixtures thereof . in one embodiment the active compound is an anti - secretory agent . suitable anti - secretory agents for use in the buccal sprays of the invention include , but are not limited to , esomeprazole , lansoprazole , omeprazole , pantoprazole , rabeprazole , tenetoprazole , ecabet , misoprostol , teprenone , and mixtures thereof . in one embodiment the active compound is a glycolipid . suitable glycolipids for use in the buccal sprays of the invention include , but are not limited to imigulcerase , vancomycin , vevesca ( ogt 918 ), gmk vaccine , and mixtures thereof . in one embodiment the active compound is a glycoprotein . suitable glycoproteins for use in the buccal sprays of the invention include , but are not limited to , staphvax , bimosiamose ( tbc1269 ), gcs - 100 , heparin , and mixtures thereof . in one embodiment the active compound is an anti - hyperthyroid agent . suitable anti - hyperthyroid agents for use in the buccal sprays of the invention include , but are not limited to , methimazol , propylthiouracil , and mixtures thereof . in one embodiment the active compound is a thyroid hormone . a suitable thyroid hormone for use in the buccal sprays of the invention includes , but is not limited to , levothyroxine . the formulations of the present invention comprise an active compound or a pharmaceutically acceptable salt thereof . the term “ pharmaceutically acceptable salts ” refers to salts prepared from pharmaceutically acceptable non - toxic acids or bases including organic and inorganic acids or bases . when an active compound of the present invention is acidic , salts may be prepared from pharmaceutically acceptable non - toxic bases . salts derived from all stable forms of inorganic bases include aluminum , ammonium , calcium , copper , iron , lithium , magnesium , manganese , potassium , sodium , zinc , etc . particularly preferred are the ammonium , calcium , magnesium , potassium , and sodium salts . salts derived from pharmaceutically acceptable organic non - toxic bases include salts of primary , secondary , and tertiary amines , substituted amines including naturally occurring substituted amines , cyclic amines and basic ion - exchange resins such as arginine , betaine , caffeine , choline , n , n dibenzylethylenediamine , diethylamine , 2 - diethylaminoethanol , 2 - dimethyl - aminoethanol , ethanolamine , ethylenediamine , n - ethylmorpholine , n - ethylpiperidine , glucamine , glucosamine , histidine , isopropylamine , lysine , methyl - glucosamine , morpholine , piperazine , piperidine , polyamine resins , procaine , purine , theobromine , triethylamine , trimethylamine , tripropylamine , etc . when an active compound of the present invention is basic , salts may be prepared from pharmaceutically acceptable non - toxic acids . such acids include acetic , benzenesulfonic , benzoic , camphorsulfonic , citric , ethane - sulfonic , fumaric , gluconic , glutamic , hydrobromic , hydrochloric , isethionic , lactic , maleic , mandelic , methanesulfonic , mucic , nitric , pamoic , pantothenic , phosphoric , succinic , sulfuric , tartaric , p - toluenesulfonic , etc . particularly preferred are citric , hydrobromic , maleic , phosphoric , sulfuric , and tartaric acids . in the discussion of methods of treatment herein , reference to the active compounds is meant to also include the pharmaceutically acceptable salts thereof . while certain formulations are set forth herein , the actual amounts to be administered to the mammal or man in need of same are to be determined by the treating physician . the invention is further defined by reference to the following examples , which are intended to be illustrative and not limiting . the following are examples of certain classes . all values unless otherwise specified are in weight percent . [ 0047 ] a . cyclosporine lingual spray amounts preferred amount most preferred amount cyclosporine 5 - 50 10 - 35 15 - 25 water 5 - 20 7 . 5 - 50 9 . 5 - 12 ethanol 5 - 60 7 . 5 - 50 10 - 20 polyethylene 20 - 60 30 - 45 35 - 40 glycol flavors 0 . 1 - 5 1 - 4 2 - 3 b . cyclosporine non - polar lingual spray amounts preferred amount most preferred amount cyclosporine 1 - 50 3 - 40 5 - 30 migylol 20 25 30 - 40 poly - 20 25 30 - 40 oxyethylated castor oil butane 25 - 80 30 - 70 33 - 50 flavors 0 . 1 - 5 1 - 4 2 - 3 c . cyclosporine non - polar bite caosule amounts preferred amount most preferred amount cyclosporine 1 - 35 5 - 25 10 - 20 olive oil 25 - 60 35 - 55 30 - 45 poly - 25 - 60 35 - 55 30 - 45 oxyethylated oleic glycerides flavors 0 . 1 - 5 1 - 4 2 - 3 d . cyclosporine bite capsule amounts preferred amount most preferred amount cyclosporine 5 - 50 10 - 35 15 - 25 polyethylene 20 - 60 30 - 45 35 - 40 glycol glycerin 5 - 30 7 . 5 - 25 10 - 20 propylene 5 - 30 7 . 5 - 25 10 - 20 glycol flavors 0 . 1 - 10 1 - 8 3 - 6 e . sermorelin ( as the acetate ) lingual spray amounts preferred amount most preferred sermorelin ( as . 01 - 5 . 1 - 3 . 2 - 1 . 0 the acetate ) mannitol 1 - 25 5 - 20 10 - 15 monobasic 0 . 1 - 5 1 - 31 . 5 - 2 . 5 sodium phosphate , dibasic sodium 0 . 01 - 5 . 05 - 3 0 . 1 - 0 . 5 phosphate water ethanol 5 - 30 7 . 5 - 25 9 . 5 - 15 polyethylene 20 - 60 30 - 45 35 - 40 glycol propylene 5 - 25 10 - 20 12 - 17 glycol flavors 0 . 1 - 5 1 - 4 2 - 3 f . octreotide acetate ( sandostatin ) lingual spray amounts preferred amount most preferred amount octreotide 0 . 001 - 0 . 5 0 . 005 - 0 . 250 0 . 01 - 0 . 10 acetate acetic acid 1 - 10 2 - 8 4 - 6 sodium acetate 1 - 10 2 - 8 4 - 6 sodium 3 - 30 . 5 - 25 15 - 20 chloride flavors 0 . 1 - 5 0 . 5 -. 4 2 - 3 ethanol 5 - 30 7 . 5 - 20 9 . 5 - 15 water 15 - 95 35 - 90 65 - 85 flavors 0 . 1 - 5 1 - 4 2 - 3 g . calcitonin - salmon lingual spray amounts preferred amount most preferred amount calcitonin - 0 . 001 - 5 0 . 005 - 2 01 - 1 . 5 salmon ethanol 2 - 15 3 - 10 7 - 9 . 5 water 30 - 95 50 - 90 60 - 80 polyethylene 2 - 15 3 - 10 7 - 9 . 5 glycol sodium 2 . 5 - 20 5 - 15 10 - 12 . 5 chloride flavors 0 . 1 - 5 1 - 4 2 - 3 h . insulin lispro , lingual spray amounts preferred amount most preferred amount insulin 20 - 60 4 - 55 5 - 50 glycerin 0 . 1 - 10 0 . 25 - 5 0 . 1 - 1 . 5 dibasic sodium 1 - 15 2 . 5 - 10 4 - 8 phosphate m - cresol , 1 - 25 5 - 25 7 . 5 - 12 . 5 zinc oxide 0 . 01 - 0 . 25 . 05 - 0 . 15 0 . 075 - 0 . 10 m - cresol 0 . 1 - 1 0 . 2 - 0 . 8 0 . 4 - 0 . 6 phenol trace trace amounts trace amounts amounts ethanol 5 - 20 7 . 5 - 15 9 - 12 water 30 - 90 40 - 80 50 - 75 propylene 5 - 20 7 . 5 - 15 9 - 12 glycol flavors 0 . 1 - 5 0 . 5 - 3 0 . 75 - 2 adjust ph to 7 . 0 - 7 . 8 with hci or naoh cns active amines and their salts : including but not limited to tricyclic amines , gaba analogues , thiazides , phenothiazine derivatives , serotonin antagonists and serotonin reuptake inhibitors a . sumatriptan succinate lingual spray amounts preferred amount most preferred amount sumatriptan 0 . 5 - 30 1 - 20 10 - 15 succinate ethanol 5 - 60 7 . 5 - 50 10 - 20 propylene 5 - 30 7 . 5 - 20 10 - 15 glycol polyethylene 0 - 60 30 - 45 35 - 40 glycol water 5 - 30 7 . 5 - 20 10 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 b . sumatriptan succinate bite capsule amounts preferred amount most preferred amount sumatriptan 0 . 01 - 5 0 . 05 - 3 . 5 0 . 075 - 1 . 75 succinate polyethylene 25 - 70 30 - 60 35 - 50 glycol glycerin 25 - 70 30 - 60 35 - 50 flavors 0 . 1 - 10 1 - 8 3 - 6 c . clozepine lingual spray amounts preferred amount most preferred amount clozepine 0 . 5 - 30 1 - 20 10 - 15 ethanol 5 - 60 7 . 5 - 50 10 - 20 propylene 5 - 30 7 . 5 - 20 10 - 15 glycol polyethylene 0 - 60 30 - 45 35 - 40 glycol water 5 - 30 7 . 5 - 20 10 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 d . clozepine non - polar linaual spray with propellant amounts preferred amount most preferred amount clozepine 0 . 5 - 30 1 - 20 10 - 15 migylol 20 - 85 25 - 70 30 - 40 butanol 5 - 80 30 - 75 60 - 70 flavors 0 . 1 - 5 1 - 4 2 - 3 e . clozepine non - polar lingual spray without propellant amounts preferred amount most preferred amount clozepine 0 . 5 - 30 1 - 20 10 - 15 migylol 70 - 99 . 5 80 - 99 85 - 90 flavors 0 . 1 - 5 1 - 4 2 - 3 f . cyclobenzaprine non - polar lingual spray amounts preferred amount most preferred amount cyclobenzaprine 0 . 5 - 30 1 - 20 10 - 15 ( base ) migylol 20 - 85 25 - 70 30 - 40 iso - butane 15 - 80 30 - 75 60 - 70 flavors 0 . 1 - 5 1 - 4 2 - 3 g . dexfenflurarnine hydrochloride lingual spray amounts preferred amount most preferred amount dexfenfluramine 5 - 30 7 . 5 - 20 10 - 15 hcl ethanol 5 - 60 7 . 5 - 50 10 - 20 propylene 5 - 30 7 . 5 - 20 10 - 15 glycol polyethylene 0 - 60 30 - 45 35 - 40 glycol water 5 - 30 7 . 5 - 20 10 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 [ 0049 ] a . glyburide lingual spray amounts preferred amount most preferred amount glyburide 0 . 25 - 25 0 . 5 - 20 0 . 75 - 15 ethanol 5 - 60 − 7 . 5 - 50 10 - 20 propylene 5 - 30 7 . 5 - 20 10 - 15 glycol polyethylene 0 - 60 30 - 45 35 - 40 glycol water 2 . 5 - 30 5 - 20 6 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 b . glyburide non - polar bite capsule amounts preferred amount most preferred amount glyburide 0 . 01 - 10 0 . 025 - 7 . 5 0 . 1 - 4 olive oil 30 - 60 35 - 55 30 - 50 polyoxyethylated 30 - 60 35 - 55 30 - 50 oleic glycerides flavors 0 . 1 - 5 1 - 4 2 - 3 [ 0050 ] a . zidovudine [ formerly called azidothymidine ( azt ) ( retrovir )] non - polar lingual spray amounts preferred amount most preferred amount zidovudine 10 - 50 15 - 40 25 - 35 soya oil 20 - 85 25 - 70 30 - 40 butane 15 - 80 30 - 75 60 - 70 flavors 0 . 1 - 5 1 - 4 2 - 3 b . erythromycin bite capsule bite capsule amounts preferred amount most preferred amount erythromycin 25 - 65 30 - 50 35 - 45 polyoxyethylene 5 - 70 30 - 60 45 - 55 glycol glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 flavors 1 - 10 2 - 8 3 - 6 c . ciprofloxacin hydrochloride bite capsule amounts preferred amount most preferred amount ciprofloxacin 25 - 65 35 - 55 40 - 50 hydrochloride glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 polyethylene 120 - 75 30 - 65 40 - 60 glycol flavors 1 - 10 2 - 8 3 - 6 d . zidovudine [ formerly called azidothymidine ( azt ) ( retrovir ] lingual spray amounts preferred amount most preferred amount zidovudine 10 - 50 15 - 40 25 - 35 water 30 - 80 40 - 75 45 - 70 ethanol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 polyethylene 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 glycol flavors 0 . 1 - 5 1 - 4 2 - 3 a . ondansetron hydrochloride lingual spray amounts preferred amount most preferred amount ondansetron 1 - 25 2 - 20 2 . 5 - 15 hydrochloride citric acid 1 - 10 2 - 8 2 . 5 - 5 monohydrate sodium citrate 0 . 5 - 5 1 - 4 1 . 25 - 2 . 5 dihydrate water 1 - 90 5 - 85 10 - 75 ethanol 5 - 30 7 . 5 - 20 9 . 5 - 15 propylene 5 - 30 7 . 5 - 20 9 . 5 - 15 glycol polyethylene 5 - 30 7 . 5 - 20 9 . 5 - 15 glycol flavors 1 - 10 3 - 8 5 - 7 . 5 b . dimenhydrinate bite capsule amounts preferred amount most preferred amount dimenhydrinate 0 . 5 - 30 2 - 25 3 - 15 glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 polyethylene 45 - 95 50 - 90 55 - 85 glycol flavors 1 - 10 2 - 8 3 - 6 c . dimenhydrinate polar lingual spray amounts preferred amount most preferred amount dimenhydrinate 3 - 50 4 - 40 5 - 35 water 5 - 90 10 - 80 15 - 75 ethanol 1 - 80 3 - 50 5 - 10 polyethylene 1 - 80 3 - 50 5 - 15 glycol sorbitol 0 . 1 - 5 0 . 2 - 40 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 a . cimetidine hydrochloride bite capsule amounts preferred amount most preferred amount cimetidine hcl 10 - 60 15 - 55 25 - 50 glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 polyethylene 20 - 90 25 - 85 30 - 75 glycol flavors 1 - 10 2 - 8 3 - 6 b . famotidine lingual spray amounts preferred amount most preferred amount famotidine 1 - 35 5 - 30 7 - 20 water 2 . 5 - 25 3 - 20 5 - 10 l - aspartic 0 . 1 - 20 1 - 15 5 - 10 acid polyethylene 20 - 97 30 - 95 50 - 85 glycol flavors 0 . 1 - 10 1 - 7 . 5 2 - 5 c . famotidine non - polar lingual spray amounts preferred amount most preferred amount famotidine 1 - 35 5 - 30 7 - 20 soya oil 10 - 50 15 - 40 15 - 20 butanel 5 - 80 30 - 75 45 - 70 poly - 10 - 50 15 - 40 15 - 20 oxyethylated oleic glycerides flavors 0 . 1 - 5 1 - 4 2 - 3 [ 0053 ] a . phenytoin sodium lingual spray amounts preferred amount most preferred amount phenytoin 10 - 60 15 - 55 20 - 40 sodium water 2 . 5 - 25 3 - 20 5 - 10 ethanol 5 - 30 7 . 5 - 20 9 . 5 - 15 propylene 5 - 30 7 . 5 - 20 9 . 5 - 15 glycol polyethylene 5 - 30 7 . 5 - 20 9 . 5 - 15 glycol flavors 1 - 10 3 - 8 5 - 7 . 5 b . phenytoin non - polar lingual spray amounts preferred amount most preferred amount phenytoin 5 - 45 10 - 40 15 - 35 migylol 10 - 50 15 - 40 15 - 20 butane 15 - 80 30 - 75 60 - 70 polyoxyethylated 10 - 50 15 - 40 15 - 20 oleic glycerides flavors 0 . 1 - 10 1 - 8 5 - 7 . 5 [ 0054 ] a . carboprost thromethamine lingual spray amounts preferred amount most preferred amount carboprost 0 . 05 - 5 0 . 1 - 3 0 . 25 - 2 . 5 thromethamine water 50 - 95 60 - 80 65 - 75 ethanol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 polyethylene 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 glycol sodium chloride 1 - 20 3 - 15 4 - 8 flavors 0 . 1 - 5 1 - 4 2 - 3 ph is adjusted with sodium hydroxide and / or hydrochloric acid b . carboprost non - polar lingual spray amounts preferred amount most preferred amount carboprost 0 . 05 - 5 0 . 1 - 3 0 . 25 - 2 . 5 migylol 25 - 50 30 - 45 35 - 40 butane 5 - 60 10 - 50 20 - 35 polyoxyethylated 25 - 50 30 - 45 35 - 40 oleic glycerides flavors 0 . 1 - 10 1 - 8 5 - 7 . 5 [ 0055 ] a . carnitine as bite capsule ( contents are a pastel amounts preferred amount most preferred amount camitine 6 - 80 30 - 70 45 - 65 fumarate soya oil 7 . 5 - 50 10 - 40 12 . 5 - 35 soya lecithin 0 . 001 - 0 . 005 - 0 . 5 . 01 - 0 . 1 1 . 0 soya fats 7 . 5 - 50 10 - 40 12 . 5 - 35 flavors 1 - 10 2 - 8 3 - 6 b . valerian as lingual spray amounts preferred amount most preferred amount valerian extract 0 . 1 - 10 0 . 2 - 7 0 . 25 - 5 water 50 - 95 60 - 80 65 - 75 ethanol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 polyethylene 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 glycol flavors 1 - 10 2 - 8 3 - 6 c . echinacea as bite capsule amounts preferred amount most preferred amount echinacea 30 - 85 40 - 75 45 - 55 extract soya oil 7 . 5 - 50 10 - 40 12 . 5 - 35 soya lecithin 0 . 001 - 0 . 005 - 0 . 5 . 01 - 0 . 1 1 . 0 soya fats 7 . 5 - 50 10 - 40 12 . 5 - 35 flavors 1 - 10 2 - 8 3 - 6 d . mixtures of ingredients amounts preferred amount most preferred amount magnesium oxide 15 - 40 20 - 35 25 - 30 chromium 0 . 01 - 1 . 0 0 . 02 - 0 . 5 . 025 - 0 . 75 picolinate folic acid . 025 - 3 . 0 0 . 05 - 2 . 0 0 . 25 - 0 . 5 vitamin b - 12 0 . 01 - 1 . 0 0 . 02 - 0 . 5 . 025 - 0 . 75 vitamin e 15 - 40 20 - 35 25 - 30 soya oil 10 - 40 12 . 5 - 35 12 15 - 20 soya lecithin 0 . 1 - 5 0 . 2 - 4 0 . 5 - 1 . 5 soya fat 10 - 40 15 - 35 17 . 5 - 20 [ 0056 ] a . diphenhydramine hydrochloride lingual spray amounts preferred amount most preferred amount diphenhydramine 3 - 50 . 4 - 40 5 - 35 hcl water 5 - 90 10 - 80 50 - 75 ethanol 1 - 80 3 - 50 5 - 10 polyethylene 1 - 80 3 - 50 5 - 15 glycol sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 [ 0057 ] a . isoproterenol hydrochloride as polar lingual spray amounts preferred amount most preferred amount isoproterenol 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 hydrochloride water 5 - 90 10 - 80 50 - 75 ethanol 1 - 80 3 - 50 5 - 10 polyethylene 1 - 80 3 - 50 5 - 15 glycol sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 b . terbutaline sulfate as polar lingual spray amounts preferred amount most preferred amount terbutaline 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 sulfate water 5 - 90 10 - 80 50 - 75 ethanol 1 - 10 2 - 8 2 . 5 - 5 sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 c . terbutaline as non - polar lingual spray amounts preferred amount most preferred amount terbutaline 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 migylol 25 - 50 30 - 45 35 - 40 isobutane 5 - 60 10 - 50 20 - 35 polyoxyethylated 25 - 50 30 - 45 35 - 40 oleic glycerides flavors 0 . 1 - 10 1 - 8 5 - 7 . 5 d . theophylline polar bite capsule amounts preferred amount most preferred amount theophylline 5 - 50 10 - 40 15 - 30 polyethylene 20 - 60 25 - 50 30 - 40 glycol glycerin 25 - 50 35 - 45 30 - 40 propylene 25 - 50 35 - 45 30 - 40 glycol flavors 0 . 1 - 5 1 - 4 2 - 3 e . albuterol sulfate as polar lingual spray amounts preferred amount most preferred amount albuterol 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 sulfate water 5 - 90 10 - 80 50 - 75 ethanol 1 - 10 2 - 8 2 . 5 - 5 sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 a . sulfonylurea amount preferred amount most - preferred amount glyburide 0 . 1 - 25 % 0 . 5 - 15 % 0 . 6 - 10 % ethanol 40 - 99 % 60 - 97 % 70 - 97 % water 0 . 01 - 0 . 1 - 4 % 0 . 2 - 2 % 5 % flavors 0 . 05 - 0 . 1 - 5 % 0 . 1 - 2 . 5 % 10 % propellant 2 - 10 % 3 - 5 % 3 - 4 % b . prostaglandin e ( vasodilator ) amount preferred amount most - preferred amount prostaglandin 0 . 01 - 0 . 1 - 5 % 0 . 2 - 3 % e 1 10 % ethanol 10 - 90 % 20 - 75 % 25 - 50 % propylene 1 - 90 % 5 - 80 % 10 - 75 % glycol water 0 . 01 - 0 . 1 - 4 % 0 . 2 - 2 % 5 % flavors 0 . 05 - 0 . 1 - 5 % 0 . 1 - 2 . 5 % 10 % propellant 2 - 10 % 3 - 5 % 3 - 4 % c . promethazine ( antiemetic , sleep inducer , and cns active amine ) amount preferred amount most - preferred amount promethazine 1 - 25 % 3 - 15 % 5 - 12 % ethanol 10 - 90 % 20 - 75 % 25 - 50 % propylene 1 - 90 % 5 - 80 % 10 - 75 % glycol water 0 . 01 - 0 . 1 - 4 % 0 . 2 - 2 % 5 % flavors 0 . 05 - 0 . 1 - 5 % 0 . 1 - 2 . 5 % 10 % propellant 2 - 10 % 3 - 5 % 3 - 4 % d . meclizine amount preferred amount most - preferred amount meclizine 1 - 25 % 3 - 15 % 5 - 12 % ethanol 1 - 15 % 2 - 10 % 3 - 6 propylene 20 - 98 % 5 - 90 % 10 - 85 % glycol water 0 . 01 - 0 . 1 - 4 % 0 . 2 - 2 % 5 % flavors 0 . 05 - 0 . 1 - 5 % 0 . 1 - 2 . 5 % 10 % propellant 2 - 10 % 3 - 5 % 3 - 4 %

buccal aerosol sprays or capsules using polar and non - polar solvent have now been developed which provide biologically active compounds for rapid absorption through the oral mucosa , resulting in fast onset of effect . the buccal polar compositions of the invention comprise formulation i : aqueous polar solvent , active compound , and optional flavoring agent ; formulation ii : aqueous polar solvent , active compound , optionally flavoring agent , and propellant ; formulation iii : non - polar solvent , active compound , and optional flavoring agent ; and formulation iv : non - polar solvent , active compound , optional flavoring agent , and propellant .

the present invention is a fishing jig head designated generally as 10 in fig3 . the jig head 10 is characterized by including two or more jig prongs 14 arranged away from a ring 12 . the body of the jig head 10 can be of any symmetrical or non - symmetrical shapes , such as a bomb , a ball , a bowling ball , or any shapes of a prior art jig head , such as those shown in fig1 - 2 . the prongs are arranged symmetrically or non - symmetrically , but preferably symmetrically , to the jig head 10 or to the ring 12 . in addition , the prongs are fixed to be ( 1 ) leveled with ( fig3 c , 3 f , 3 i ), ( 2 ) pointing above ( fig3 b , 3 e , 3 h ), or ( 3 ) pointing below ( fig3 a , 3 d , 3 g ), a ring plane . alternatively , the prongs can be manually adjusted to the ( 1 )-( 3 ) situations . fig5 shows a hook 16 molded or inserted into the jig head 10 of fig3 a - c . by adjusting the prongs 14 to the ( 1 )-( 3 ) situations , the hook 16 stands up at different angles form the bottom of water . fig4 shows a second embodiment according to the present invention . a fishing jig 20 include a fan or shovel 24 arranged opposite to a ring 22 . similarly , the fan or shovel 24 is fixed or adjustable to ( 1 ) level with ( fig4 c ), ( 2 ) lift above ( fig3 b ), or ( 3 ) lift below ( fig3 a ), a ring plane . fig6 shows a hook 26 molded or inserted into the jig head 20 of fig3 a - c . by adjusting the fan or shovel 24 to the ( 1 )-( 3 ) situations , the hook 16 stands up at different angles from the bottom of water . the fan or shovel 24 may be split as shown in fig1 c . fig7 - 8 show another two jig heads each with a different shape and four prongs , as examples . the prongs are ( 1 ) lighter than ⅛ of the weight of the jig head and ( 2 ) at least ½ of the diameter / length of the jig heads to prevent the jig from landing flat on the bottom of the water . fig9 shows a third embodiment of a fishing jig head and its variations according to the present invention . instead of the generally i - shaped prongs or shovel , the embodiment includes variations of one or more generally y - shaped ( fig9 a ) or fork - shaped ( fig9 b ) prongs , or one brush - shaped or broom - shaped prong ( fig9 c ). another exemplary variation of the shovel can be just one split in the middle . fig1 a - c show the prongs , shovel or the other variations of the prongs attached to the hook or the shank of the hook above or right at the head . optionally , the jig heads can be opened to replace the weight in order to vary the weight of the jig to adjust the speed at which the weight sinks and the degree of wobble during retrieval of the lure according to the type of game fish targeted , and according to the depth , bottom conditions , current , and other environmental factors relating to the waters being fished . in addition , any kinds of weedgurads , skirts and trailers may be applied to the invention as shown in fig1 . the jig heads can make from tungsten , lead , tin , stainless steel , hot or cold rolled steel , copper , brass , plastics , fiberglass , etc ., by casting the materials into a mold , by injection molding , or by other processes . in addition , the jig body and the jig prongs / shovel can be made of different materials . for example , the jig body is made of lead , while the prongs are made by thick fish lines . a jig body is made of tungsten is smaller than the one made of lead . a jig body is made of plastic or fiberglass may be transparent . representative dimensions for the jig head 10 include a diameter of 1 / 16 inches , and the prongs 14 of 1 / 64 inches long or longer ( such as ⅛ inches in fig1 a ), preferably longer than 1 / 32 inches . in other words , the length of a prong may range form ½ to 2 or more times of the diameter of the body . the fan / shovel 24 is 1 / 64 inches long or longer ( such as 1 / 16 inches in fig6 c ), preferably longer than 1 / 32 inches . in other words , the length of a fan / shovel may range from ½ to 1 or more times of the diameter of the body . regarding the width of the fan / shovel , it can be 1 / 32 to 1 / 16 inches wide or wider ( equivalent to ½ to 1 or more times of the diameter of the body ). the invention provide a very high percentage of success rate to stand up on the bottom of water , or even on slanted bottoms , rocks , logs , etc . the invention provides 100 % of success rate to stand up on the bottom of water . the inventor tested the invention in an olympic size pool ( a flat bottom without rocks , logs , or mud sand ) by a 45 - ft cast to 12 - foot of water . since the evolution jig ™ could not stand in a flat pool , it definitely would not stand in real fishing conditions . the invention stood up 10 times out of 10 casts . on the other hand , the existing competing products did not stand upon even once in 10 casts , with the hook laid completely on the bottom the principles , preferred embodiments and modes of operation of the present invention have been described in the foregoing specification . however , the invention which is intended to be protected is not limited to the particular embodiments disclosed . the embodiments described herein are illustrative rather than restrictive . variations and changes may be made by others , and equivalents employed , without departing from the spirit of the present invention . accordingly , it is expressly intended that all such variations , changes and equivalents which fall within the spirit and scope of the present invention as defined in the claims , be embraced thereby .

a fishing jig head to be molded with or inserted thereinto a hook thereby form a fishing jig , includes a body , a ring attached on the body , and plate or prong which is shaped and positioned to prevent the fishing jig from landing flat on a bottom of water after the fishing jig is cast into the water . a fishing jig includes the fishing jig head , a hook molded with or inserted into the jig head , and optionally at least one of a weedgurad , a skirt , and a trailer .

although the spreader shown in the figures is primarily for spreading manure , it can also be used for spreading other materials . the spreader comprises a frame 1 provided with a hopper 2 . four ground - engaging wheels are secured to the frame , with two wheels 3 and 4 disposed on each side . the axles of the wheels 3 are aligned with each other , as are the axles of the wheels 4 . at the front the frame is provided with a drawbar 5 having a coupling eyelet 6 . a pin 7 connects the coupling eyelet 6 with a mounting bar 8 of a tractor 9 or a similar vehicle . the hopper 2 is constituted by a loading trough arranged on the frame 1 . this trough comprises sidewalls 11 and 12 , a front wall 13 and a bottom 14 . a conveyor 15 passes over the bottom 14 . near the rear of the hopper are disposed two distribution members 16 and 17 . the two distribution members are located between the end of the walls 11 and 12 and together cover substantially the whole width between these walls . it would be possible to provide only one distribution member or more than two distribution members . just in front of the distribution members 16 and 17 , between the walls 11 and 12 , is arranged a closing member constituted by a closing slide 18 which is vertically movable to open and close the rear end of the hopper which constitutes a delivery outlet . to the rear of the frame 1 is attached a frame beam 21 extending transversely of the direction of length of the device , which coincides with the intended direction of travel in use . the rear ends of the walls 11 and 12 are each provided with vertical beams 22 and 23 , the top ends of which are interconnected by a beam 24 , which is located at substantially the same level as the top edges of the walls 11 , 12 and 13 . the frame beam 21 is provided with two bearing housings 25 and 26 accommodating transmission components . these bearing housings support vertical shafts 27 and 28 of the respective distribution members 16 and 17 . the top ends of these shafts are journalled in bearings fastened to the beam 24 , for example , the bearing 29 for the shaft 27 ( fig4 ). at a short distance above the bearing housings 25 and 26 the shafts 27 and 28 are provided with ejection members 31 and 32 . each of these ejection members comprises a round plate 33 arranged centrally on the shaft and having secured to it four ejection blades 34 . these blades are made from strips disposed perpendicular to the plate 33 . at their ends adjacent the shaft the ejection blades have a slightly greater height than they have at their ends adjacent the circumference of the plate 33 . from fig4 is will be appreciated that the ejection members 31 and 32 , which are located at the same vertical level , are disposed at a level lower than the bottom of the hopper . the bottom 14 , as will be seen from fig4 extends for a distance 36 over the top of each of the ejection members 31 and 32 . the distance 36 is equal to about one third of the diameter of the ejection members . the top surface of the bottom 14 is at a distance 35 above the plate 33 of each of the ejection members , the distance 35 is approximately equal to one quarter of the diameter 37 of the ejection members . the distribution members 16 and 17 are provided on the shafts 27 and 28 at a level higher than the top surface of the bottom 14 . the distribution members have identical shapes and dimensions and so fig4 to 6 show only the distribution member 16 . the distribution member has a central part comprising four tine carriers which are made from angle - section beams 40 , 41 , 42 and to 43 and extend parallel to the shaft 27 . the beams 40 to 43 open towards the rotary axis of the shaft 27 . the tine carriers 40 to 43 extend upwards from a position at a short distance above the bottom 14 to near the beam 24 . the upper and lower ends of the carriers 40 to 43 are secured to the shaft 27 by plates 45 and 44 . about halfway up the carriers 40 to 43 , they are also secured to the shaft 27 by a square plate 46 . at the top of the tine carriers 40 to 43 a ring 47 passes through the corners of the square plate 44 . in the same manner the lower side of the distribution member 16 is provided with a ring 48 . each of the tine carriers 40 to 43 carries four pairs of working members constituted by tines which are equally spaced apart by the same amount on all the carriers . near the bottom and top of each tine carrier is fastened a pair of tines with one of the tines of each pair located substantially in the same plane as the top and bottom ends respectively of the carriers 40 to 43 ( see fig4 ). the pairs of tines are all constructed and fastened to the beam concerned in the same way ; therefore , this is illustrated in detail for only one pair of tines 49 . working members other than tines may be used . each pair of tines 49 comprises two tines 50 and 51 spaced apart by a distance 52 . each of the tines lies in a plane perpendicular to the shaft 28 . the ends of the tines are located at a distance 53 from the center of the shaft 27 ; in this embodiment , the distance 53 is about forty - five cms . the tines extend substantially radially away from the shaft 27 ; see , for example , the tines 50 in fig5 . the end portion of each tine ( see the end 55 of the tine 50 ) extends for a distance 56 at a small angle 57 of about 6 ° to the rest of the tine . the distance 56 is approximately one fifth of the length of the entire tine . each of the tines 50 and 51 is coupled by three helical turns 58 and 59 respectively with a web portion 60 , which interconnects the tines 50 and 51 . each pair of tines 49 is made from a single curved length of steel rod or wire , the turns 58 and 59 forming springs so that the tines 50 and 51 respectively are mounted resiliently . the web portion 60 of each pair of tines is immovably but releasably fastened to the respective tine carrier by means of a clamping plate 61 and a bolt 62 . the clamping plate 61 has a groove 65 receiving the web portion 60 ( fig6 ). the web portion 60 is located midway between the tines 50 and 51 , the helical spring portions 58 and 59 extending inwardly towards each other from the tines 50 and 51 ( fig4 ). the helical spring portions 58 and 59 extend along one limb 63 of the l - shaped carrier , and the web portion 60 of the pair of tines concerned is connected to the other limb 64 of that carrier . the longitudinal axis of the portions 58 and 59 are parallel to the shaft 27 . between the distribution members 16 and 17 and the ejection members 31 and 32 below them are arranged guide members 70 and 71 for free rotation about the shaft 27 or 28 respectively . these guide members 70 and 71 are identical , and so only the member 70 is shown in detail in fig4 . the member 70 is freely rotatable about the shaft 27 on bearings 72 and 73 . the guide member 70 has a cylindrical portion 74 , which surrounds the shaft 27 with a small clearance ; the bearings 72 and 73 are provided at the ends of this cylindrical portion . the lower end of the cylindrical portion 74 is provided with a ring 75 . the upper end of the cylindrical portion 74 is provided with a conical portion 76 , which flares upwardly , with its outer circumference located inside the ring 48 . the outer circumference of the portion 76 fits within the inner circumference of the ring 48 with a small clearance . near the top of each of the distribution members 16 and 17 is arranged a plate 77 , see fig4 . this plate is positioned within the ring 47 and its outer circumference fits with a small clearance inside the inner circumference of the ring 47 . the transmission components in the bearing housings 26 are coupled with a driving shaft 80 . the shaft 80 extends away from the bearing housing 26 towards the front in the longitudinal direction of the spreader and is coupled at the front of the spreader with transmission components in a driving casing 81 . the casing 81 supports a shaft 82 , with which an auxiliary shaft 83 is releasably coupled . the shaft 83 is connected with a power take - off shaft of the tractor 9 . the transmission components in the bearing housings 25 and 26 are linked to one another by a shaft 84 . the bearing housings 25 and 26 and hence the shafts 27 and 28 are disposed across the width of the hopper 2 at a position in which the distribution members 16 and 17 are exactly located between the rear ends of the vertical walls 11 and 12 . the distribution members 16 and 17 have equal diameters , 85 each of which amounts to approximately half the distance between the inner sides of the walls 11 and 12 . the transmission components in the casing 26 connected with the shaft 80 are connected with a shaft 86 , which is coupled with the transmission gear in a transmission casing 87 . the transmission components in the casing 87 are coupled with a shaft 88 for driving the conveyor 15 . the conveyor 15 comprises chains 89 and 90 looped over sprockets 91 and 92 connected with the shaft 88 . the shaft 88 extends across the rear of the bottom of the hopper 2 . near the front of the hopper 2 is provided a shaft 93 carrying sprockets 94 and 95 around which are looped the chains 89 and 90 . the conveyor 15 also comprises crossbars 96 extending between the chains 89 and 90 and formed by channel - sections beams , the limbs of which extend upwardly on the top run of the conveyor 15 passing over the bottom 14 . the conveyor 15 constitutes an endless conveyor , the upper run of which is located over the top surface of the bottom 14 . the closing slide 18 covers the whole width of the hopper 2 between the walls 11 and 12 . the slide 18 is perpendicular to the walls 11 and 12 . the height of the slide 18 is substantially equal to the height of the hopper . a supporting beam 100 is provided at the top of the slide 18 , and ends of this beam are pivotally connected with supporting arms 101 and 102 . the supporting arms 101 and 102 have a length 103 and are mounted by aligned shafts 104 and 105 on the walls 11 and 12 . the supporting arms 101 and 102 are located on the outer side of the walls 11 and 12 respectively . in the position shown in fig1 and 7 , in which the lower end of thw slide 18 is located above the top surface of the bottom 14 by a distance equal to the height of the crossbars 96 , the slide is supported by the supporting beam 100 which bears on the tops of the walls 11 and 12 . the pivotal shafts 104 and 105 are located at a distance 106 below the tops of the walls 11 and 12 . midway along their length 103 the arms 101 and 102 are connected with supporting members 107 and 108 respectively . each of these supporting members constitutes a braking mechanism and , as is indicated for the supporting member 108 , comprises a cylinder 109 , which is pivotable about a shaft 110 which is coupled with the wall 12 of the hopper 2 at a level of the bottom 14 . a rod 111 is slidable with some friction in the cylinder 109 and is pivotally coupled with the arm 102 by a shaft 112 . near its ends the supporting beam 100 is provided with upwardly extending arms 113 and 114 , which are furthermore coupled with the beam 100 by means of struts 115 and 116 . control arms 118 and 119 are fastened to the top ends of the arms 113 and 114 by pivotal shafts 117 . these control arms are located on each side of the hopper 2 and are pivotally connected to the top sides of the walls 11 and 12 by aligned pivotal shafts 120 and 121 . the arms 118 and 119 have a length 122 , which is equal to about two thirds of the length 103 of the arms 101 and 102 . in operation , the spreader is coupled by the drawbar 5 with a tractor or similar vehicle as is shown in fig1 and 2 . the hopper 2 is loaded with the material to be spread , for example manure , after which the device can be driven to a field where the manure is to be distributed . the slide 18 is held in the position indicated by solid lines in fig1 the hopper 2 being then closed on all four sides by the walls 11 , 12 and 13 and the slide 18 . to spread the manure the slide 18 is moved into the position indicated by broken lines in fig1 . the slide may be lifted manually so that it moves upwardly and tilts in accordance with the turn of the control arms 118 and 119 about the pivotal shafts 120 and 121 and of the supporting arms 101 and 102 about the shafts 104 and 105 . the supports 107 and 108 are constructed so that the friction of the rods 111 , or pistons connected thereto , in the cylinders 109 is so great that the slide 18 remains in any set position . if desired , the supports 107 and 108 may be hydraulically actuated using the hydraulic system of the tractor . the distribution members 16 and 17 as well as the ejection members 31 and 32 and the conveyor 15 are coupled with the power take - off shaft of the tractor through the auxiliary shaft 83 and the various transmissions . during a run across a field , the conveyor 15 is moved so that the material is fed rearwardly through the hopper to the distribution members 16 and 17 . the distribution members 16 and 17 are rotated by their respective drives in the casings 25 and 26 in opposite directions as indicated by arrows 126 and 127 . the material fed beneath the slide 18 towards the distribution members 16 and 17 is engaged by the resilient tines of the distribution members and spread by the rotation of the distribution members across a width appreciably exceeding the width of the spreader . from fig2 is it particularly apparent that the distribution members 16 and 17 are disposed so that the ends of the group of tines on a tine carrier of one distribution member are moving centrally between the groups of tines of the other distribution member within the working range thereof . in other words , the distribution members 16 and 17 are angularly offset from each other by half the angular spacing between adjacent tine carriers . during rotation of the distribution members the tines are resiliently stressed when engaging the manure in the hopper ( about 150 ° of their arcs over bottom 14 as seen in fig2 ) fed by the conveyor to the distribution members . by the resilient tension the resilient tines perform a scraping action on the supplied manure so that the tines catch and carry along small batches of manure , which are subsequently spread . in this way a satisfactory , even distribution of the manure may be obtained . since the tines will bend slightly backwards with respect to the direction of rotation of the distribution member when they come into contact with the manure in the hopper , the path traced by the ends of the tines when they are in the hopper will be slightly flattened so that the manure can be satisfactorily captured , which enhances an even delivery . the width of spreading of the manure is thus increased , since at the release of the tines from the manure in the hopper the tension of the tines generated during the capture of the manure is released and the tines are accelerated in the direction of rotation of the distribution member concerned to flick the manure outwardly . the manure can thus be ejected farther . to improve the effect of the resilient tines it is important for the spring portions 58 and 59 to be at a distance from the shaft 27 . the distance 66 between the center line of the shaft 27 and the center line of the portions 58 and 59 is about one third of the distance 53 . it is furthermore important for the tine carriers to be at a distance 67 approximately equal to one third of the distance 53 from the shaft 27 . in order to enhance the effect of the tines in distributing and capturing the manure in the hopper the ends of the tines are slightly bent forwards , with respect to the direction of rotation of the distribution members . with respect to the direction of rotation of the distribution member , the helical spring portions , for example , the portions 58 and 59 of the tines ( fig5 ) are located behind the tines . the helical turns of the portions 58 and 59 are such that the tines are under stress when engaging the manure in the hopper . manure delivered by the conveyor 15 to the rear along the bottom and not captured completely by the lower tines of the distribution members will drop down when they reach the end of the bottom . this manure will fall onto one of the ejection members 31 or 32 and will be distributed by these ejection members . thus the uniform distribution obtained by the distribution members 16 and 17 is further improved by the ejection members 31 and 32 . consequently the manure delivered along the bottom side of the distribution members cannot drop onto the ground in the center of the strip of land to be covered . the guide members 70 and 71 around the shafts 27 and 28 do not rotate with the shafts . manure dropping down off the edge of the bottom 14 will move along the guide members so that it will not come into contact with the rotating shafts 27 and 28 . thus the manure is prevented from coming into contact with rotating parts such as the shafts 27 and 28 , about which it might be wound . in the case of long tailings found in manure this would be a disadvantage , but due to the presence of the guide members 70 and 71 , the manure can drop freely down onto the ejection members 31 and 32 . if the delivery of material to the distribution members has to be stopped , for example when turning at the ends of a field , the delivery of the slide 18 can be pressed down . since the slide 18 moves about two pivotal shafts in the pivots 104 and 105 and the pivots 120 and 121 spaced apart from one another in the manner shown , the slide will maintain a substantially vertical orientation , particularly along the first part of its movement out of the position shown in fig1 and afterwards , when it has risen above the walls 11 and 12 , it will move into the inclined position shown in fig1 by broken lines . consequently , in the closed position , the slide 18 can be near the cylindrical plane traced by the ends of the tines of the distribution members 16 and 17 . it is thus ensured that , when the slide 18 is opened , manure is fed almost immediately to the distribution members 16 and 17 over their whole height so that an advantageous delivery of manure is obtained . although in the embodiment described the feed of manure by the conveyor 15 is related to the speed of driven of the distribution members 16 and 17 , the conveyor 15 may , as an alternative , be coupled with the ground - engaging wheels so that the supply of manure varies with the speed of travel of the spreader . although various features of the spreader described and illustrated are set forth in the following claims as inventive features , it is to be understood that the invention is not necessarily limited to these features and encompasses all novel inventive features which have been closed both individually and in various combinations .

two spreading mechanisms disposed substantially completely across a rear outlet of a container - hopper having a movable deck , the spreader comprising a pair of two - part distribution members which rotate about vertical shafts which are disposed close to the edge of the deck . the upper part has four sets of resilient tines extending from angle irons spaced outwardly from the rotary shaft , the tines being bent at their ends and connected to the angle irons via coils whereby they are resiliently forced backward in their rotation through the fertilizer , usually manure , and when released resiliently spring forward whereby material engaged by the tines if flung outwardly . on the same shaft the lower part is a disc type ejector extending in substantial part under the moving deck to receive fertilizer which the tines miss . a freely rotatable guide member surrounds the shaft between the ejector and the tined portion to preclude material from winding around the shaft . a plate closure for the hopper outlet is raised vertically by two pairs of arms , one pair pivotally connected on each side of the hopper whereby the closure is lifted first vertically and then pivoted at its upper part somewhat forwardly whereby its lower edge which penetrates the fertilizer moves in a substantially vertical motion just ahead of the distribution members . the spreaders and the underlying deck are powered by a tractor power take - off . the closure is frictionally connected to piston and cylinder assembly on each side of the hopper and can be adjusted to various open or closed positions .

the invention provides seg unit dosage forms that utilize the novel carrier medium , maltitol syrup . maltitol syrup is a medium viscosity liquid , manufactured by hydrogenation of glucose syrup to produce sugar alcohols . it has been available commercially since the late 1950 &# 39 ; s . inclusion of water in maltitol syrup is required to produce a mobile liquid and water is present in the syrup as commercially supplied . maltitol syrup can be formulated with many drugs and biological actives and diagnostic agents for use as a solution or a pumpable suspension . pharmaceutical active ingredients may include , e . g ., monograph drugs and proprietary drugs . nutritional supplements in the maltitol carrier may include vitamins , active metabolites , minerals , and plant extracts , as well as other nutritional additives or agents . diagnostic agents include radiolabelled biochemicals and other diagnostic tools . biologically active agents suitable for use with the present invention include , without limitation , those selected from the group consisting of antihistamine formulations , analgesic formulations including non - steroidal antiinflammatory drugs ( nsaid &# 39 ; s ), antibiotics / antibacterials , antacid formulations , breath freshener formulations , allergy / sinus formulations , expectorants , sedatives , sore throat soothers , local anesthetics , laxative formulations , steroids , bronchodilators , prophylactic dental products such as fluoride or dentifrices , cough suppressants , vitamins , herbal extracts , motion sickness preventatives , antifungal formulations , anti - yeast formulations and diet aids . maltitol syrup may also serve as a carrier for cosmetic and confectionery products . the novel maltitol syrup carrier system may be used instead of or combined with other conventional liquids for one or more of the following reasons : 1 ) improved stability , 2 ) solubility , 3 ) greater biocompatibility , 4 ) improved dissolution , 5 ) legislative constraints , 6 ) novelty and 7 ) palatability . the major component ( about 20 % or greater ) of the carrier liquid would always be maltitol syrup . preferably , the maltitol has a solids loading of approximately 75 % or 85 %. suspensions of active ingredients in maltitol syrup may benefit by containing rheological modifiers to prevent sedimentation . as noted above , the carrier system of the present invention comprises at least about 20 % maltitol syrup . however , the benefits of the invention are particularly evident when the carrier system comprises at least about 50 % maltitol syrup . the inventive dosage forms may be used to administer biologically active agents both for human and animal consumption . for example , the novel liquid carrier system of the invention may be used in seg capsules to provide prescription pharmaceuticals , over the counter drugs , nutritional supplements or diagnostics introduced orally , buccally , rectally , or by vaginal insertion in both human and veterinary applications . preparations of either solutions or suspensions of actives in maltitol syrup are prepared by the following methods : maltitol syrup is dispensed into a suitable mixing vessel . actives and solubilizing agents are added in sequence to the liquid and homogenized with high shear blending . if required , heat can be applied to the system to facilitate dissolution ; normally temperatures in excess of 60 degrees centigrade are not required . the mixture once clear and free of particular matter is cooled and deaerated . during deaeration care must be taken to ensure that water loss is minimized ; otherwise there may be an adverse effect on drug solubility . encapsulation of the liquid is performed on a standard rotary die encapsulation machine . capsules are dried in low humidity conditions . care must be taken not to over dry the capsules , as this could lead to deformed capsules due to excessive loss of water from the fill . maltitol syrup is dispensed into a suitable mixing vessel . actives are added to the liquid and the mixture homogenized using high shear mixing techniques . suspending agents if required are added to the system and depending on the nature of the material homogenized using the appropriate degree of shear . the mixture is deaerated ; care is taken during this process to minimize any water loss . capsules are manufactured using the rotary die encapsulation machine . excessive drying of the capsules must be avoided . capsule size will be determined by the required potency of the active ingredient , the application and product aesthetics . examples of both solution and suspension fill formulations in maltitol syrup are provided below : ______________________________________allergy formulationcomponent mg / softgel______________________________________maltitol syrup 75 % 719 . 0pseudoephedrine hydrochloride 30 . 0brompheniramine maleate 1 . 0capsule fill weight 750 . 0______________________________________ ______________________________________antihistamine formulationcomponent mg / softgel______________________________________maltitol syrup 85 % 210 . 0diphenylhydramine hydrochloride 50 . 0capsule fill weight 260 . 0______________________________________ ______________________________________antacid formulationcomponent mg / softgel______________________________________maltitol syrup 75 % 434 . 0calcium carbonate 540 . 0simethicone 20 . 0polysorbate 80 6 . 0capsule fill weight 1000 . 0______________________________________ ______________________________________chewable antacid formulationcomponent mg / softgel______________________________________maltitol syrup 75 % 1401 . 0calcium carbonate 1030 . 0peppermint oil 4 . 0sodium crosscarmelose gum 20 . 0capsule fill weight 2455 . 0______________________________________ ______________________________________chewable breath freshener formulationcomponent mg / softgel______________________________________lycasin 75 % 584 . 0peppermint oil 3 . 0polysorbate 80 3 . 0capsule fill weight 590 . 0______________________________________ ______________________________________laxative formulationcomponent mg / softgel______________________________________lycasin 75 % 966 . 7senna extract 60 % a + b 33 . 3capsule fill weight 1000 . 0______________________________________ it should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that all modifications or alternatives equivalent thereto are within the spirit or scope of the invention as set forth in the appended claims .

a dosage unit form comprises a biologically active agent , such as a pharmaceutical , nutritional supplement or diagnostic , dissolved or suspended in a carrier liquid encapsulated in a soft elastic gel capsule . the carrier liquid comprises maltitol syrup as a major component . maltitol syrup may be the only component of the carrier liquid , or may be blended with other liquids and / or excipients .

opioid analgesics are well known and have been used for many years for the treatment of moderate to severe pain . the term opioid analgesic when used herein includes but is not limited to hydrocodone , oxycodone , and codeine . hydrocodone , oxycodone , and codeine are preferred because they are the opioid analgesics commonly combined with acetaminophen in combination analgesic products . the controlled substance act ( csa ), enacted into law by the congress of the united states as title ii of the comprehensive drug abuse prevention and control act of 1970 scheduled hydrocodone , oxycodone , and codeine as schedule iii narcotics when combined at certain doses with non - narcotic analgesics ( e . g . aspirin , ibuprofen ), but the more strictly regulated as schedule ii in stand - alone dosage units . the use of “ opioid ” is meant to include any drug that activates the opioid receptors found in the brain , spinal cord and gut . there are four broad classes of opioids : naturally occurring opium alkaloids , such as morphine ( the prototypical opioid ), codeine and thebaine ; endogenous opioid peptides ; semi - synthetics such as heroine , oxycodone and hydrocodone that are produced by modifying natural opium alkaloids ( opiates ) and have similar chemical structures ; and pure synthetics such as fentanyl and methadone that are not produced from opium and may have very different chemical structures than the opium alkaloids . additional examples of opioids are hydromorphone , oxymorphone , levorphanol , dihydrocodeine , meperidine , diphenoxylate , sufentanil , alfentanil , propoxyphene , pentazocine , nalbuphine , butorphanol , buprenorphine , meptazinol , dezocine , and pharmaceutically acceptable salts thereof . hydrocodone is a narcotic analgesic , which acts as a weak agonist at opioid receptors in the central nervous system ( cns ). it primarily affects the ( mu ) receptor ( op3 ), but also exhibits agonist activity at the delta receptor ( op1 ) and kappa receptor ( op2 ). additionally , hydrocodone displays antitussive properties by suppressing the cough reflex in the medullary cough center of the brain . the use of “ hydrocodone ” is meant to include a semisynthetic narcotic analgesic and antitussive derived from either codeine or thebaine with multiple actions qualitatively similar to those of codeine . it is commonly used for the relief of moderate to moderately severe pain . other salt forms of hydrocodone , such as hydrocodone bitartrate and hydrocodone polistirex , are encompassed by the present invention . hydrocodone is used for the treatment of moderate to moderately severe pain and for inhibition of cough ( especially dry , nonproductive cough ). the prodrugs of hydrocodone may be administered for the relief of pain or for cough depression or for the treatment of any condition that may require the blocking of opioid receptors . hydrocodone produgs and other prodrugs of opioids may provide reduced potential for overdose , reduced potential for abuse or addiction and / or improve hydrocodone &# 39 ; s characteristics with regard to high toxicities or suboptimal release profiles . without wishing to be limited by theory , it is believed that overdose protection may occur due to the prodrug &# 39 ; s being exposed to different enzymes and / or metabolic pathways by oral administration where the conjugate is exposed through the gut and first - pass metabolism as opposed to the exposure to enzymes in the circulation or mucosal membranes which limits the ability of hydrocodone to be released from the pro - drug . therefore , abuse resistance is provided by limiting the “ rush ” or “ high ” available from the active hydrocodone released by the prodrug and limiting the effectiveness of alternative routes of administration . hydrocodone prodrugs of this type preferably have no or a substantially decreased pharmacological activity when administered through injection or intranasal routes of administration . however , they remain orally bioavailable . when the terms opioid analgesic or 3 - hydroxyacetanilide are used herein , it is to be understood that any of the pharmaceutically suitable salts thereof which have analgesic properties in man and other mammals are included by the term . such salts include the hydrochlorides , hydrobromides , hydroiodides , sulfates , bisulfates , nitrates , citrates , tartrates , bitartrates , phosphates , malates , maleates , fumarates , succinates , acetates , terephthalates , pamoates , aluminum , calcium , potassium , and sodium . in one embodiment the invention provides a combination of chemical compounds useful in the management of pain in a mammal . the combination is an opioid analgesic and 3 - hydroxyacetanilide . certain specific opioid analgesics include hydrocodone , oxycodone , and codeine . in one embodiment of the invention the opioid analgesic is selected from the group consisting of oxycodone or hydrocodone , or a pharmacologically acceptable salt , thereof . in one embodiment of the invention the opioid analgesic is codeine , or a pharmacologically acceptable salt , thereof . in one embodiment of the invention the opioid analgesic is hydrocodone , or a pharmacologically acceptable salt , thereof at a dose per 100 ml ( i . e ., a liquid ), which has no more than 300 mg of ( dissolved ) hydrocodone in addition to the therapeutic amount of 3 - hydroxacetanilide . in one embodiment of the invention the opioid analgesic is hydrocodone , or a pharmacologically acceptable salt , thereof at a dose per dosage unit ( i . e ., a solid , pill or capsule ), which has no more than 15 mg of hydrocodone in addition to the therapeutic amount of 3 - hydroxacetanilide . in one embodiment of the invention the opioid analgesic is oxycodone , or a pharmacologically acceptable salt , thereof at a dose per dosage unit ( i . e ., a solid , pill or capsule ), which has no more than 10 mg of oxycodone in addition to the therapeutic amount of 3 - hydroxacetanilide . in one embodiment of the invention the opioid analgesic is codeine , or a pharmacologically acceptable salt , thereof , at a dose per dosage unit ( i . e ., a solid , pill or capsule ), which has no more than 60 mg of codeine in addition to the therapeutic amount of 3 - hydroxacetanilide . in one embodiment of the invention the opioid analgesic is selected from the group consisting of a prodrug of oxycodone or a prodrug of hydrocodone , or a pharmacologically acceptable salt , thereof . the opioid analgesic and 3 - hydroxyacetanilide can be administered in the same dosage unit or can be prepared in separate dosage units and the dosage units administered at the same time . different forms of dosage units can be used ( i . e ., a tablet of 3 - hydroxyacetanilide , and an injection of opioid ). the compositions of the present invention are preferably presented for systemic administration to humans and animals in unit dosage forms , such as tablets , capsules , pills , powders , granules , suppositories , sterile parenteral solutions or suspensions , sterile non - parenteral solutions or suspensions , and oral solutions or suspensions and the like , containing suitable quantities of the combination of active ingredients . the efficacious doses used for treating pain in a human for of the combination of an opioid with 3 - hydroxyacetanilide ; either administered in the same dosage unit , or in separate dosage units administered at the same time , can be determined by a physician using known means , taking into consideration that the demonstrated synergistic action of the combination may allow for a lower dose of the both compounds in the combination compared to their individual doses if they were to be dosed alone . the demonstrated synergistic action could lower the opioid dose by as much as 50 % ( e . g . from 20 mg to 10 mg of hydrocodone ) in the combination product compared to the dose of the opioid administered alone . for oral administration either solid or fluid unit dosage forms can be prepared . powders are prepared quite simply by comminuting the active ingredients to a suitably fine size and mixing with a similarly comminuted diluent . the diluent can be an edible carbohydrate material such as lactose or starch . advantageously , a sweetening agent or sugar is present as well as a flavoring oil . capsules are produced by preparing a powder mixture and filling into formed gelatin sheaths . advantageously , as an adjuvant to the filling operation , lubricant such as talc magnesium stearate , calcium stearate and the like is added to the powder mixture before the filling operation . soft gelatin capsules are prepared by machine encapsulation of a slurry of active ingredients with an acceptable vegetable oil , light liquid petrolatum or other inert oil or triglyceride . tablets are made by preparing a powder mixture , granulating or slugging , adding a lubricant and pressing into tablets . the powder mixture is prepared by mixing the active ingredients , suitably comminuted , with a diluent or base such as starch lactose , kaolin , dicalcium phosphate and the like . the powder mixture can be granulated by wetting with a binder such as corn syrup , gelating solution , methylcellulose solution or acacia mucilage and forcing through a screen . as an alternative to granulating , the powder mixture can be slugged , i . e ., run through the tablet machine and the resulting imperfectly formed tablets broken into pieces ( slugs ). the slugs can be lubricated to prevent sticking to the tablet - forming dies by means of the addition of stearic acid , a stearate salt , talc or mineral oil . the lubricated mixture is then compressed into tablets . advantageously , the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac , a coating of sugar and methylcellulose and a polish coating of carnauba wax . fluid unit dosage forms for oral administration such as syrups , elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of the active ingredients for administration . the water - soluble forms can be dissolved in an aqueous vehicle together with sugar , flavoring agents and preservatives to form a syrup . an elixir is prepared by using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent . suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia , tragacanth , methylcellulose and the like . for parenteral administration , fluid unit dosage forms are prepared utilizing the active ingredients and a sterile vehicle , water being preferred . the active ingredients , depending on the form and concentration used , can be either suspended or dissolved in the vehicle . in preparing solutions the water - soluble active ingredients can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing . advantageously , adjuvants such as a local anesthetic , preservative and buffering agents can be dissolved in the vehicle . cosolvents such as ethanol or propylene glycol can be used in the solvent system . parenteral suspensions are prepared in substantially the same manner except that the active ingredients are suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration . the active ingredients can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle . advantageously , a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredients . in addition to oral and parenteral administration , the rectal and vaginal routes can be utilized . active ingredients can be administered by means of a suppository . a vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized . for example , cocoa butter and various polyethylene glycols ( carbowaxes ) can serve as the vehicle . the term “ unit dosage form ” as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human and animal subjects , each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent , carrier or vehicle . the specification for the novel unit dosage forms of this invention are dictated by and are directly dependent on ( a ) the unique characteristics of the active material and the particular therapeutic effect to be achieved , and ( b ) the limitation inherent in the art of compounding such an active material for therapeutic use in humans , as disclosed in this specification , these being features of the present invention . examples of suitable unit dosages forms in accord with this invention are tablets , capsules , troches , suppositories , powder packets , wafers , cachets , teaspoonfuls , tablespoonfuls , dropperfuls , ampules , vials , segregated multiples of any of the foregoing and other forms as herein described . the following example is illustrative of the present invention , but is not intended to be limiting . in order to test the analgesic activity of the combination of an opioid ( hydrocodone ) and 3 - hydroxyacetanilide , both compounds were tested separately and in combination in a visceral pain model in mice . experimental animals : one hundred fifty - five 4 - week old , male swiss webster mice ( stock number 024 ) were purchased from charles river laboratories ( portage , mich .). the study animals were allowed an acclimation period of 1 - 2 weeks prior to dose initiation . the mice were housed 4 - 6 per cage and maintained in the innovive caging system ( san diego , calif .) upon arrival at . in accordance with the guide for care and use of laboratory animals ( eighth edition ), mouse rooms were maintained at temperatures of 66 - 75 degrees fahrenheit and relative humidity between 30 % and 70 %. cages were monitored daily to ensure the innovive system maintained 50 air changes per hour and positive pressure . the rooms were lit by artificial light for 12 hours each day ( 7 : 00 am - 7 : 00 pm ). animals had free access to distilled water and teklad global rodent diet 2018 ( harlan laboratories , madison , wis .) for the duration of the study except during the experiment when food and water access was withheld . vehicle and compound formulations : the vehicle ( 0 . 5 % carboxy methyl cellulose , cmc ) was formulated on - site weekly for the duration of the study , stored at 4 ° c ., and allowed to come to room temperature prior to formulation every day . carboxy methyl cellulose was provided by the client from sigma aldrich ( catalog number c9481 ). the test articles and acetic acid ( 0 . 6 %) were formulated on - site daily for the duration of the study . 3 - hydroxyacetanilde and hydrocodone (+)- bitartrate were purchased from sigma aldrich ( catalog numbers a7205 & amp ; h4516 , st . louis , mo .) and acetic acid was purchased from thermo fisher scientific ( acros # 42322 - 5000 , pittsburgh , pa .). compound solutions were sonicated and vortexed as needed prior to dosing to create a homogenous solution . study design : vehicle and test articles were administered via oral gavage ( po ) in dosing volumes of 10 ml / kg at t =− 45 minutes ( min ) on day 1 of the study . at t = 0 min , acetic acid was administered via intraperitoneal ( ip ) injection at a dosing volume of 10 ml / kg . the writhing protocol ( abdominal contortion test ) was subsequently carried out on each animal . animals were euthanized immediately following the writhing protocol on day 1 . the study design and treatment groups for all mice are represented in table 1 . abdominal contortion procedure ( writhing protocol ): a writhe was characterized by a wave of contraction of the abdominal musculature followed by the extension of the hind limbs . every day of the procedure began with a vehicle - treated animal for baseline measurements . during the first 10 days of the study , each day contained animals from groups 2 - 11 . during the last 4 days of the study , each day contained animals from groups 12 - 15 . animals were allowed to acclimate to the testing room for a minimum of 1 hour prior to the experiment . immediately following administration of vehicle or test compounds ( t =− 45 min ), animals were placed into individual clear , plexiglass cylindrical holders for the duration of the experiment . therefore , animals were acclimated to the holders for 45 minutes prior to acetic acid administration . acetic acid was administered at t = 0 min , which began the writhing protocol experiment . the number of writhes over a 5 min duration were counted ( 5 - 10 and 15 - 20 min post - dose ) starting 5 min after acetic acid administration . statistical analysis : all treatment groups started the study with n = 10 mice . the data were reviewed for identification and elimination of non - responders . a non - responder was defined as an animal that did not appear to respond to the acetic acid injection ( i . e ., no apparent abdominal contortions ) in reference to the vehicle control animal assessed at the beginning of each experimental day . in addition , during the calculation of the ed 50 concentrations as well as during the final data review , any negative percents calculated for the percent antinociceptive activity (% aa ) were changed to 0 %. after groups 2 - 11 measurements were completed , statistical calculations for the ed 50 concentrations of hydrocodone and 3 - hydroxyacetanilide were calculated in prism 5 . 0d ( graphpad software ) using the percent antinociceptive activity (% aa ) and the log of each dose . because 3 - hydroxyacetanilde &# 39 ; s dose response curve was bell - shaped , the lowest dose ( 50 mpk ) was removed from further analysis , as it appeared to be an outlier . outliers were screened by testing the group &# 39 ; s mean versus the standard error of the mean ( sem ) for said time point . if the relationship of sem to mean was in excess of 10 %, then the data points of that group at that time point were carried through an outlier test . data points outside a z - score variation of 3 . 0 were listed as outliers and not included in the mean or sem for the group . no statistical outliers were found in the study data after removal of non - responders . doses and % antinociceptive activity data were analyzed for synergistic interactions using the pharmatools pro suite of programs ( the mccary group , inc ). linear regression analysis ( effect vs . log dose ) and ( effect vs dose ) for hydrocodone , 3 - hydroxyacetanilide , and the experimental combination along with the theoretical line representing the expected additive effect from the combination are shown in fig7 and 8 , respectively . the theoretical line of additive effect was calculated by analyzing the log linear regressions of the individual drugs and their maximum effects to give an additive effect for the dose pairs that had been tested experimentally . a comparison of the two regression lines ( experimental vs theoretical ) using the f - distribution to detect a difference in either the slope , the intercept ( position ), or both , for the lines returned a calculated f = 9 . 800 and tabular f = 9 . 550 suggesting that the regression lines differ significantly . a significant difference in the regressions can be interpreted as a departure from simple additivity . using the computed slopes and y intercepts from the linear regression analysis : effect vs . log dose for hydrocodone and 3 - hydroxyacetanlide the calculated interaction indecies are shown in table 3 below . interactions with calculated interaction indecies of & lt ; 1 are considered to be synergistic . in this experiment 3 of the 4 dose combinations tested have interaction indecies less than 1 . one thousand tablets , each containing 350 mg of 3 - hydroxyacetanilide and 10 mg hydrocodone bitartrate are prepared from the following types and amounts of ingredients : 3 - hydroxyacetanilide micronized 350 gm , hydrocodone bitartrate 10 gm , lactose 75 gm , corn starch 50 gm , magnesium stearate 4 gm , and light liquid petrolatum 5 gm . the 3 - hydroxyacetanilide and hydrocodone bitartrate ( finely divided by means of an air micronizer ) are added to the other ingredients and then thoroughly mixed and slugged . the slugs are broken down by forcing then through a number sixteen screen . the resulting granules are then compressed into tablets , each tablet containing 350 mg of 3 - hydroxyacetanilide and 10 mg of hydrocodone bitartrate . using the procedure above , tablets are similarly prepared containing hydrocodone bitartrate in 7 . 5 mg and 3 . 75 mg amounts by substituting 7 . 5 gm and 3 . 75 gm of hydrocodone bitartrate the 10 gm used above . these tablets are used to reduce the narcotic dose of the preceding example . all publications , patents , and patent documents are incorporated by reference herein , as though individually incorporated by reference . the invention has been described with reference to various specific and preferred embodiments and techniques . however , it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention .

pharmaceutical combinations of opioid analgesics and analgesics that act through non - opioid mechanisms are commonly used to provide pain relief . an example of this pharmaceutical combination is the product vicodin ™, where the opioid analgesic is hydrocodone and the non - opioid is acetaminophen . however , liver toxicity from the acetaminophen component is common . the invention provides an improvement over the opioid and acetaminophen pharmaceutical combinations for the management of pain by the concomitant administration of an opioid analgesics and the non - opioid analgesic 3 - hydroxyacetanilide . this combination has been found to exhibit unexpectedly enhanced analgesic activity when dosed orally in a mammal .

it has long been recognized that the application of cryotherapy ( cold therapy ) can help heal injuries and bring the user relief from discomfort . generally relief occurs when the intramuscular temperature can be reduced significantly . because blood circulation makes this interior temperature reduction difficult , a great deal of cold must be applied at the skin level . this creates a risk of frostbite to the skin . when the temperature at the skin level is 32 degrees or less , this risk is very real , and yet temperatures near this level are necessary to cause significant intramuscular temperature reduction . while numerous patents have been issued in the area of cold therapy and ice packs in particular , there has been no effort to address the temperature problem . the invention in its preferred embodiment attempts to fill this very real need for maximum cold with complete safety , unaddressed in the prior art . the invention includes a flexible sleeve for ice and a compression strap to allow that sleeve to be applied to any body part with compression . several sleeves and / or straps may be fastened together to cover different sized areas . the use of real ice , the percolation of melt water from that ice through the sleeve and against the skin , and the compression of the sleeve against the skin by the compression strap to maximize water loss , delivers the lowest possible safe temperature for cold therapy . a preferred embodiment of the sleeve is made of two rectangular pieces of material , approximately 7 inches wide and 25 inches long , with one of the pieces about an inch longer than the other . the shorter of these pieces is water - permeable , and the longer is water - impermeable . they are placed facing one another , and securely fastened along three edges with a water tight seal . the fourth edge , which forms the mouth of the sleeve , is open . a piece of hook velcro ® approximately 5 inches by 2 inches is sewed to the back of the impermeable material at the open mouth , and a smaller piece of loop velcro ® is sewed to the back of the permeable material , adjacent the hook velcro ®, which allows the user to close the mouth of the sleeve after ice has been inserted . the outward face of the impermeable material has 23 / 4 inch strips of loop velcro ® sewn parallel to each other starting at the foot of the sleeve and continuing for about 12 inches . a similar third piece of loop velcro ® is sewn along the edge of the sleeve adjacent to these strips , which allows two sleeves to be fastened together for about 50 percent of their length . the second element of the invention , the compression strap , in its preferred embodiment is an elastic strap about 24 inches long and 4 inches wide , with hook velcro ® and loop velcro ® sewn width - wise across the elastic to allow the strap to be fastened in different positions to the sleeve and / or itself . this combination allows the application of cold therapy using real ice , on any body part , with a layer of water against the skin to prevent frostbite , and the delivery of cold therapy at the skin at the lowest possible safe temperature for animals or humans . a more complete understanding of the invention and its advantages will be apparent from the detailed description in conjunction with the drawings in which : fig1 is a perspective view of the inner side of an ice sleeve showing the water - permeable face ; fig2 is a perspective view of the outer side of the ice sleeve of fig1 showing the water - impermeable face ; fig3 is a left side view of the ice sleeve showing the position of the velcro ® strips used to fasten two sleeves together ; fig3 a is a partially broken away , enlarged , side view of a portion of fig3 ; fig5 is a partial perspective view illustrating interface of the ice sleeve and compression strap ; fig6 is a perspective view that shows two ice sleeves fastened to their respective compression straps and interlocked for dual use by means of the velcro ® edge on each sleeve ; fig7 is a partial perspective view illustrating the interface of two ice sleeves fastened longitudinally ; fig8 shows the invention in single use on a knee ; fig9 shows the invention in dual use on a shoulder ; and fig1 shows the invention in single use wrapping an ankle . referring initially to fig1 - 3a , where like numerals indicate like and corresponding elements , ice sleeve 10 has an inner side 12 which will be applied against the skin . inner side 12 is composed primarily of a piece of water - permeable material 14 . in the preferred embodiment , water - permeable material 14 is nine ounce terry cloth , approximately 7 inches wide and 24 inches long . outer side 16 is primarily composed of a piece of water - impermeable material 18 . outer side 16 of sleeve 10 , which will be applied facing away from the skin , is made of coated nylon in the preferred embodiment . water - impermeable material 18 is approximately 7 inches wide and 23 inches long , and is placed against water - permeable material 14 and sealed on three edges 6a , 6b , 6c . this sealing system should be water tight and able to withstand the later pressure created when ice is crushed in the sleeve 10 by striking the nylon face of water - impermeable material 18 . in the preferred embodiment edges 6a , 6b , 6c are rolled and stitched . a piece of hook velcro ® 26 , 5 inches by 2 inches , is sewn to the inner face of the water - impermeable material 18 , flush with its open end . a smaller 1 inch by 4 inch piece of loop velcro ® 24 ( fig3 a ) is sewn to the inner face of the water - permeable material 14 so that the inner and outer sides 12 , 16 may be fastened shut at the open end 22 when desired . a piece of hook velcro ® 26 , 3 / 4 inch by 12 inches , is sewn to the inside edge 6c of the water - permeable inner side 12 of the sleeve 10 , beginning about 2 inches from the foot 28 of the sleeve 10 . two strips 30 of 3 / 4 inch loop velcro ®, 12 inches long , are sewn to the outer side 16 beginning at the foot 28 of the sleeve 10 and running parallel in a way which trisects the nylon surface of outer side 16 . a third piece 32 of loop velcro ®, approximately the same size as strip 30 , is sewn to the top outer edge 6c of the sleeve 10 , beginning 2 inches from the foot 28 of the sleeve 10 . this allows two similarly - constructed sleeves 10 to be fastened together for dual use at corresponding strips 26 and 32 . a velcro ® strip 32 of a first sleeve 10 will be connected to the corresponding hook velcro ® edge 26 on the inner face of an adjacent second sleeve 10 . fig4 shows the compression strap 50 . in the preferred embodiment this is a strap of elastic 52 measuring 24 inches by 4 inches . sewn width - wise at variable spacing are 3 / 4 inch by 4 inch strips 54 of loop velcro ®, beginning at one end 56 of the strap 50 . at the opposite end 58 and on the opposite side of the strap 50 is sewn a 1 inch by 4 inch piece of hook velcro ® 60 . these velcro ® strips 54 , 60 allow the strap 50 to be fastened to the sleeve 10 or to itself . fig5 shows the attachment of the strap 50 to the sleeve 10 . one of the loop velcro ® strips 54 on end 56 of the strap 50 is fastened to the hook velcro ® strip 20 sewn to the open end 22 of the sleeve 10 . fig6 shows two straps 50 fastened to their respective sleeves 10 , and the two sleeves 10 fastened together for dual use . the fastening point of the sleeves 10 is the velcro ® strip 26 on the inner face of one sleeve 10 , and the loop velcro ® piece 32 on the outer face of the other sleeve 10 . this fastening system can be used to create any width of coverage desired by the user through fastening more and more sleeves 10 together . in fig6 the surface area of ice coverage has been doubled . fig7 shows the connecting of two sleeves 10 joined longitudinally . the velcro ® strip 20 at the opening 22 of a first sleeve 10 is placed against the loop velcro ® pieces 30 sewn to the nylon outer side 16 of the second sleeve 10 . fig8 shows a single sleeve 10 and compression strap 50 in use on a knee . the user inserts a few handfuls of ice in the sleeve 10 . he then crushes that ice if desired by striking the nylon outer face 16 . the opening 22 of the sleeve 10 is fastened shut using the velcro ® strips 20 , 24 the compression strap 50 is fastened to the velcro ® strap 20 at the opening of the sleeve 10 using one of the hook velcro ® strap 54 and the strap 50 , and the terry cloth inner face 12 of the sleeve 10 is applied against the area of the knee to be cooled . the ends of the sleeve 10 are wrapped cylindrically around the knee , the compression strap 50 is wrapped around the sleeve 10 , and the hook velcro ® end 60 of the strap 50 is affixed to one of the loop velcro ® strips 54 on the strap 50 fastening the sleeve 10 securely in place . this strap may be tightened or loosened at will to increase the effective temperature of the sleeve 10 against the skin . as the ice in the sleeve 10 melts , the melt water is forced by the pressure of the strap 50 and the impermeable quality of the nylon outer layer 18 to percolate through the terry cloth face 14 and come in contact with the skin of the knee , cooling the knee . as the ice continues to melt in the sleeve 10 , the compression strap 50 and the nylon layer 18 force new melt water to either wick away into the dry terry cloth or force earlier melt water already in the terry to drip away . the result is a sleeve of ice , separated from the skin by a thin water layer at a temperature of 33 degrees . this low temperature is constantly fed by new 33 degree melt water being forced through the terry . the higher temperature water drips away , and the sleeve continues to percolate fresh melt water against the skin , maintaining this 33 degree temperature until all the ice has liquified . fig9 shows the invention in dual use on the shoulder . the same procedural steps are followed except that two sleeves 10 are fastened together width - wise using the velcro ® edging 26 , 32 as shown in fig6 . at the time of application , the terry cloth face 12 is placed against the skin and the straps 50 wrapped around the back . the hook velcro ® end 56 of the strap 50 is then fastened to the loop velcro ® strips 30 on the nylon face 18 at the compression level desired by the user . fig1 shows the invention in single use on an ankle . the middle of the terry cloth face 14 is placed against the achilles tendon , and the ends laid over the top of the foot . the compression strap 50 , already affixed to the sleeve 10 , is then wrapped in a figure eight around the bottom of the foot and the back of the ankle . once again the desired pressure is applied by the user , as the velcro ® end 56 of the strap is fastened to a selected one of the loop velcro strips 54 on the strap . it can thus be seen that the primary feature of the invention is a sleeve of opposing materials designed to contain real ice , to utilize the melt water from the ice as safety against frostbite and to maximize water loss for achieving the minimum safe temperature when using the sleeve as a source of cold therapy . another important feature is an ice sleeve made of opposing materials and employing an elastic compression strap to force the water from ice melting in the sleeve through the permeable surface of the sleeve and forcing it to drip away from the surface against which the sleeve is fastened , resulting in the lowest possible safe temperature at the skin . the sleeve made of opposing materials allows ice to be crushed within the sleeve without damage to the materials or their respective qualities of permeability and impermeability . the strap is made of elastic material which is wide enough to allow the application of uniform compression when wrapped around a surface in conjunction with this sleeve . the sleeve being made of opposing materials , one being impermeable to water and the other permeable , allows the temperature of the sleeve placed against a surface to be controllable and adjustable through variations in the insulating properties ( including thickness ) of the permeable material and the pressure with which the sleeve is applied . another important feature is a sleeve made of opposing materials which can be fastened in multiple together both widthwise or lengthwise , or both , to create a variable sized permeable surface for the delivery of cold therapy . finally , the strap may also be fastened in multiple together lengthwise to allow the use of compression on any size or shape of surface .

the universal moist ice wrap is made of two parts , a sleeve designed to allow the crushing and containment of real ice , and an elastic strap called a compression strap which can be used to fasten the sleeve in place and increase cold transmission at the desire of the user . the sleeve is made of two faces , one of water - permeable material and the other of a water - impermeable material , sealed with a watertight edge and one edge opened , which can be closed at will using the velcro ® edging fastened to the opposing materials . straps and sleeves may be joined in a series of different combinations to allow the sleeve to be used by humans and animals for cryotherapy at the lowest possible safe temperature which can be applied against the skin .

in the illustrations given , and with reference first to fig1 the reference numeral 10 designates generally a fabric column system which may be formed from a kit in accordance with the present invention . the system 10 includes a pair of fabric supports 12 each adapted for selected positioning in spaced apart relation . as also shown in fig1 the system 10 includes a fabric 14 having opposite ends 14a and 14b adapted for positioning adjacent respective ones of the fabric supports 12 ( see , also , fig2 ). as best shown in fig3 the system 10 includes means for releasably securing the opposite ends 14a and 14b of the fabric 14 to the respective ones of the fabric supports 12 . in particular , the releasable securing means includes a rod pocket ring 16 for the fabric 14 and the fabric supports 12 each include a base plate 18 and a hold down plate 20 whereby the rings 16 are adapted to fit through rod pockets 22 at the opposite ends 14a and 14b of the fabric 14 . further , the system 10 includes means for securing the hold down plates 20 to the base plates 18 in such a manner that the rings 16 are firmly retained in position therebetween . as will be appreciated from fig4 the base plates 18 are larger than the rings 16 and the rings 16 are larger than the hold down plates 20 . it will also be seen and appreciated that the hold down plates 20 are advantageously generally of the same shape but smaller than the rings 16 . preferably , the securing means comprises a bolt 24 extending from each of the base plates 18 through the respective one of the hold down plates 20 to cooperate with a wing nut 26 . still referring to fig4 the rings 16 and hold down plates 20 may advantageously be formed so as to be generally arcuate . it will be seen that the hold down plates 20 each have an outer perimeter 20a radially inwardly of the outer perimeter 16a of the respective one of the rings 16 when the hold down plates 20 are secured to the base plates 18 by means of the bolt 24 and wing nut 26 . as best shown in fig2 and 3 , the fabric 14 will extend about the rings 16 so as to hide the hold down plates 20 from view . referring once again to fig4 the rings 16 and hold down plates 20 may be generally arcuate and still be of a wide variety of different shapes and sizes . it will be appreciated that each of the illustrated rings 16 , 16 &# 39 ;, etc . define an arc extending through at least 180 ° so as to form a fabric column 28 also extending through at least 180 ° ( see fig3 ). in the embodiment illustrated in fig1 through 4 , the base plates 18 are larger than the rings 16 with the rings 16 and hold down plates 20 being centered thereon . as will be appreciated from fig1 the selected positions for fixedly mounting the fabric supports 12 are at vertically spaced locations generally at opposite sides of a window 30 . the rings 16 and hold down plates 20 may each have a drapery - receiving void as at 32 ( see fig3 ). in this embodiment , the drapery - receiving voids 32 of the respective pairs of fabric supports 12 face each other and the window 30 so permit drawing draperies thereinto . alternatively , and referring to fig5 the selected positions for mounting the fabric supports may be at vertically spaced locations generally adjacent a doorway 34 . the embodiment illustrated in fig5 is slightly different , and the details will be described hereinafter , but if the embodiment illustrated in fig1 and 4 is placed in a doorway , the rings 16 and hold down plates 20 each will have a wall - facing void essentially corresponding to the drapery - receiving void 32 previously described but possibly enlarged as would be the case by utilizing either of rings 16 &# 34 ;&# 34 ; or 16 &# 34 ;&# 34 ;&# 39 ; ( see fig4 ). with such arrangements , the wall - facing void will naturally cause the fabric column 28 to have a corresponding wall - facing void generally facing a wall 36 or other rigid surface associated with the doorway 34 . referring to fig4 the system 10 also includes means for fixedly mounting the fabric supports 12 to a rigid surface such as a wall in selected positions . the mounting means preferably includes what comprises a pair of retention brackets 38 and each of the retention brackets 38 is formed so as to extend between the rigid surface or wall and the respective one of the fabric supports 12 as will be appreciated from fig4 . in the illustrated embodiment , the retention brackets 38 comprise angle brackets such as the one secured to the top surface 12a of the fixed support 12 . referring now to fig6 and 7 , an alternative embodiment of the present invention has been illustrated which includes a different form of fabric supports 112 . the fabric supports 112 , as illustrated , each comprise an open ring which is made to fit through the respective one of the rod pockets 22 . as shown in fig6 the mounting means comprises a pair of brackets 138 and the rigid surface comprises a wall 136 upon which the brackets 138 can be fixedly mounted . as best shown in fig7 the open rings 112 can be formed so as to have a variety of different sizes and / or shapes each defining an arc extending through at least 180 °. the rings 112 &# 39 ;, 112 &# 34 ;, etc . can thereby form a fabric column ( such as 28 which is illustrated in fig3 in connection with 180 °. as shown in fig6 the brackets 138 each have a pair of parallel , spaced apart openings 140 adapted to receive opposite ends 142 of the respective one of the open rings 112 . as will be appreciated , the brackets 138 each comprise a wall plate having a pair cf parallel slots 144 each adapted to receive a tension screw 146 for adjustment of wall plate position on the wall 136 . it will also be seen that each of the wall plates 138 has a pair of tubular extensions 148 for receiving the opposite ends 142 of the respective one of the open rings 112 therein . these tubular extensions 148 define the spaced apart openings 140 ( see fig6 ). it will further be seen that the tubular extensions 148 include means for retaining the respective one of the opposite ends 142 of the open rings 112 therein . in the embodiment illustrated in fig6 the retaining means may by way of example comprise set screws 150 for threadingly engaging the opposite ends 142 of the open rings 112 in the tubular extensions 148 . still referring to fig6 and 7 , the wall brackets 138 each include a pair of spaced apart holes 152 adapted to receive a final positioning screw for fixedly mounting the wall brackets 138 in the selected positions therefor . it will also be seen that the wall plates 138 may each have a rigid ring support 154 extending from the wall plate 138 to the open ring 112 at a central point remote therefrom . in this manner , the rigid ring support 154 can adequately support the open ring 112 in a preselected orientation relative to the wall 136 against the weight of the fabric . as before , the selected positions for mounting the fabric supports 112 may be vertically spaced at opposite sides of a window or adjacent a doorway . it can be appreciated from fig7 that the open rings such as 112 &# 39 ; may include a drapery - receiving void 132 generally corresponding to the drapery - receiving void 32 in connection with the earlier described embodiment illustrated in fig1 through 4 . alternatively , a wall - facing void may be provided , also as previously suggested , by forming an open ring such as 112 &# 34 ;. referring to fig8 through 11 , yet another embodiment of fabric column system has been illustrated wherein the releasable securing means comprises a first strip 260 of a hook and loop fastening means at each of the opposite ends of a fabric 214 . the fabric supports 212 each include a base plate 216 having a recess or recesses 262 formed into a desired shape for a fabric column 228 . as will be appreciated by those skilled in the art , the releasable securing means will further include a second strip 264 of the hook and loop fastening means about the outer perimeter of the base plates 216 to cooperate with the first strip 260 . as best shown in fig1 , the base plates 216 &# 39 ;, 216 &# 34 ;, etc . have outer perimeters which have been formed into various desired shapes for fabric columns . the overall configurations are generally circular or arcuate , although fig9 illustrates that virtually any shape is a possibility . however , in keeping with typical column design , fig1 is believed to illustrate the versatility of the invention in conformity with the shape of standard columns . with the embodiment illustrated in fig8 through 10 , the base plates 216 are essentially entirely hidden from view . thus , the fabric columns 228 will essentially include no exposed base plates whatsoever at the opposite ends thereof . if desired , an entirely different form of base plate 266 may be utilized as shown in fig1 through 13 . in this connection , the base plate 266 may be formed as a capital . thus , it may have a recess 268 wherein the first strip 260 of hook and loop fastening means is provided on the outwardly facing surface of & amp ; he fabric and the second strip 264 is provided on the inner surface of the recess 268 of the capital 266 . in this manner , a fabric column system may be formed substantially as illustrated in fig1 . as for fig1 and 13 , they illustrate the utilization of capitals 266 with the embodiment previously described in connection with fig6 through 8 . it will be seen and appreciated that the wall plates 138 are simply mounted such that the open rings 112 will be suitably positioned within the recesses 268 of the capitals 266 . as a result , the capitals 266 provide for two alternative means of forming a fabric column therewith . in another respect , the present invention will be understood to be directed toward and to provide a fabric column kit . the kit includes a plurality of fabric supports of different sizes and / or shapes adapted for selected positioning in spaced apart relation in compatible pairs . this can be appreciated by referring , e . g ., to fig4 , 9 , 10 and 13 . the kit also includes a plurality of means of different sizes and / or shapes for releasably securing opposite ends of a fabric to the respective ones of the fabric supports . with such an arrangement , the kit will allow the purchaser to have a great deal of flexibility in designing a fabric column . while in the foregoing there have been set forth preferred embodiments of the invention , it will be appreciated that the details hereingiven may be varied by those skilled in the art without departing from the true spirit and scope of the appended claims .

in order to enhance the aesthetics of the interior of a home or building , a fabric column kit and system is disclosed . the fabric column kit or system includes at least a pair and , preferably , a plurality of fabric supports which may advantageously be of different sizes and / or shapes wherein the supports are adapted for selected positioning in spaced apart relation in compatible pairs . the fabric supports are fixedly mounted to a rigid surface in selected positions . the fabric column kit or system also includes at least a pair and preferably a plurality of rings which may advantageously be of different sizes and / or shapes wherein the rings are adapted to releasably secure opposite ends of a fabric to the respective ones of the fabric supports . with the fabric column kit or system , a fabric column may be formed between the fabric supports to aesthetically enhance the interior space of any building structure .

as discussed in detail below , the present invention provides a powdery material removal and recovery means comprising a distribution head having vacuum means for drawing material from a surface by suction and for transferring the material to a recovery chamber and onwards to a recovery hopper and an air distribution means for directing air onto the surface via a pressure chamber to assist in the removal of the powdery material by the vacuum means . typically , the surface is that of a receiver such as a board , and the board travels on a conveyor located beneath the distribution head . in use , the recovery chamber and the pressure chamber are located transverse to the surface of the board in the direction of relative travel between the distribution head and the board . ideally the distribution head of the recovery means comprises at least two recovery chambers . conveniently , the distribution head comprises a boxed channel section with sealed edges and is open at the top and bottom . advantageously , the distribution head comprises an inwardly tapered funnel - shaped lower section that forms a restricted nozzle opening at the bottom . preferably , the at least two recovery chambers of the distribution head formed by spaced apart baffles extending from a position level with the upper edge of the top opening of the distribution head to a position level with the lower edge of the bottom opening of said distribution head . in a preferred arrangement , the pressure chamber is formed by a baffle extending from a position level with the upper edge of the top opening to a position level with the lower edge of the bottom opening of said distribution head . ideally , the bottom opening of the distribution head is covered by a base plate having a plurality of slots arranged in spaced apart rows so that the respective bottom openings of the distribution head chambers are reduced or restricted in aperture . the distribution head guides pressurised air onto the surface of a board in order to disturb loose powdery material residing on the board surface and to dislodge any material that may be adhered to the board surface . this assists the removal of all powdery residues and clumped material from the board surface to the recovery chamber or chambers . blowing pressurised air on to the board also facilitates the drying of any damp powdery material on the board which further assists its removal from the board surface by the vacuum means . upon removal of the floury residues , the boards are available for re - use . prior to receiving new dough for proving , boards may be re - sprinkled with sifted semolina which can be fresh material or material recovered from the hopper . the removal of clumped powder clusters from the previous cycle and the provision of a freshly sprinkled coating of semolina on the boards ensures that bread products are consistently and easily removable from the boards and are produced with smooth surfaces free of clumped baked - on semolina flour . advantageously , the distribution head is mounted adjacent the board by an adjustable bracket which allows the clearance between the distribution head and the board surface to be altered . in a preferred arrangement the distribution head includes a removable lid . this provides access to interior duct compartments of the distribution head for cleansing and maintenance purposes . the removable lid is ideally provided with a depending skirt that forms a lip sized so that when positioned on the distribution head , the inner surfaces of the lip contact the coincident outer edges of the distribution head to form a seal . the invention also provides a dough handling system incorporating the material removal and recovery means described above . the invention will now be described more particularly with reference to the accompanying drawings , in which are shown , by way of example only , one embodiment of a material recovery system according to the invention . referring initially to fig1 , a powdery material removal and recovery means according to the invention comprises a distribution apparatus 1 , a blower unit 2 , a vacuum unit 3 , a recovered powder receiving hopper 4 , a powder sifter 5 and a conveyor 6 . in this example , the powdery material is semolina flour , but it will be appreciated that the system may equally be employed with other powdery substances . the distribution apparatus includes a distribution head 100 , a removable lid 200 , a base plate 300 and a mounting ( system ) bracket 400 . the distribution head 100 comprises a container having two substantially spaced apart parallel end walls 101 , 102 and two spaced apart parallel side walls 103 , 104 . each side wall 103 , 104 is formed from an initially flat rectangular stainless steel sheet that is bent in a straight line along its length to create two flat sections such that an upper flat section which may be placed substantially vertically with a lower flat section being angled obtusely inwardly . positioning the two side walls 103 , 104 in this manner and connecting them to the end walls 101 , 102 provides a boxed channel section with sealed edges that is open at the top and has an inwardly tapered funnel - shaped lower section that forms a substantially rectangular restricted nozzle opening 105 at the bottom . referring to fig2 c , within the confines of the distribution head walls three separate duct compartments 108 , 109 and 110 are formed by the provision of two spaced apart baffles 106 , 107 that are attached perpendicularly at each end to the end walls and that extend from a position level with the upper edge of the top opening to a position level with the lower edge of the bottom opening 105 . the bottom nozzle opening 105 is thus divided into three separate parallel narrow elongate orifices . the central compartment 109 is a pressure chamber and the outer compartments 108 and 110 are vacuum chambers . the baffles 106 , 107 are formed using the same process used for the side walls described herein . however , the lower inwardly bent sections of the baffles are at a shallower angle than those of the side walls . the vertical upper sections of the baffles are spaced parallel to the side walls 103 , 104 . referring to fig2 a and 2 b , a substantially rectangular removable lid 200 is constructed from sheet stainless steel material and has a depending skirt that forms a lip 201 that extends downwardly around its entirety . when positioned over the top opening of the distribution head 100 the underside of the lid rests on the upper edges of the distribution head walls 101 , 102 , 103 , 104 and the baffles 106 , 107 and the inner surfaces of the lip 201 contact the coincident outer edges of the distribution head walls to form a seal . fastening of the lid to the distribution head 100 is achieved using a plurality of draw clamp latches 111 mounted to the distribution head side walls 103 , 104 that engage with corresponding latch keepers 211 connected to the outer surface of the lip 201 . the lid has four circular holes arranged to provide two pressurized air inlet ports 203 , 204 for compartment 109 , a vacuum outlet port 208 to compartment 108 and a vacuum outlet port 210 to compartment 110 . bolted directly about the bore of each hole is a cylindrical and flanged pipe tail section 212 that protrudes upwards from the lid upper surface to facilitate connection to conduits that carry air or vacuum pressure to the respective compartments . connection of the conduits to the pipe tail sections may be made using jubilee clips or other suitable removable fasteners . typically , the conduits will be constructed as a flexible hose with clamps or clips provided to connect the hose to a pipe tail section . referring to fig3 , the base plate 300 comprises a covering that fits flush over the bottom nozzle opening 105 of the distribution head when connected by welding to the lower edges of end walls 101 , 102 and side walls 103 , 104 . it comprises a flat elongate stainless steel sheet that contains a plurality of substantially rectangular slots arranged in two spaced apart rows 308 , 310 , each row being provided to either side of , and parallel to , a single long central slot 306 as shown . the spacing between the rows and the central slot is of a sufficient distance such that connection of the base plate to the bottom ends of the baffles 106 , 107 can be made . the central slot 306 of the base plate reduces the aperture of the central orifice of the nozzle opening 105 that corresponds to central compartment 109 . rows 308 and 310 restrict the outer orifices of the nozzle 105 that correspond to the outer compartments 108 and 110 respectively . in one embodiment the slots of rows 308 and 310 are approximately 45 mm in length and 8 mm in width with an end - to - end spacing of approximately 5 mm . other dimensions will be suitable and selected for other systems . referring to fig4 , the distribution head 100 is mounted on a bracket 400 that comprises two spaced apart arms 401 , 402 hinged at their distal ends and each pivotally mounted on a pivoting mechanism 421 , 422 , respectively , such that the clearance between the distribution head base plate 300 and the conveyor 6 can be adjusted upon actuation of a handle bar 418 that extends between levers 416 , 417 that are connected to the respective pivoting mechanism of each arm . the respective proximal ends of the arms 401 , 402 are each connected by a plurality of bolts to the lower sections of the distribution head end walls 101 , 102 . the arms each extend from the distribution head towards distal upright members 403 , 405 which are each bolted at their bases to outer rails 601 , 602 of a conveyor system frame . pins 407 , 408 , each provided with an axially aligned threaded hole at one end and an axially aligned threaded shank at the other , extend between the respective arms 401 , 402 and upright members 403 , 405 . connection of the arms 401 , 402 to the pins 407 , 408 is effected by bolts 419 that extend through apertures in the arms 401 , 402 to engage with the threaded holes of the pins 407 , 408 , respectively . the threaded shanks of the pins 407 , 408 each extend through apertures provided through the upright members 403 , 405 , respectively , and are fastened at their free ends by lock - nuts 420 . in this arrangement , upright members 403 , 405 and pins 407 , 408 , provide a hinge mechanism whereby the arms 401 , 402 raise and lower the distribution head 100 . control over the raising and lowering of the distribution head 100 is facilitated by mechanisms 421 , 422 , each connected to the respective arms at a position intermediate the proximal and distal ends . referring to mechanism 421 operating on the arm 401 , an upright member 404 , bolted at its base to the outer rail 601 of the conveyor system frame , supports a fulcrum pin 409 . the pin 409 , which is secured at its outer end by a lock - nut 423 , extends inwardly to contact a disk 411 such that their respective axes are in alignment . a bolt ( not shown ) extending through an aperture formed in the rear of the disk 411 and engaging with an axially threaded hole that is provided at the inner end of the pin 409 , fastens the disk 411 and pin 409 together . a second pin 413 , radially off - set from pin 409 , extends from the disk 411 through a slot 415 that is provided through the arm 401 . the pin 413 , which has threaded ends , is secured at both ends by hexagonal nuts ( not shown ) and the mechanism is assembled such that when positioned through the most distal end of the slot 415 , the central axis of pin 413 lies vertically above the central axis of pin 409 , as shown in fig4 . in this configuration the distribution head 100 is raised to its highest position and the lever 416 extends distally from the disk 411 to which it is connected at an angle such that the underside of the handle bar 418 , which spans perpendicularly across the conveyor system to connect with lever 417 on the opposing side , is clear of the arms 401 , 402 below . connection of the lever 416 to the disk 411 is effected by welding . to lower the distribution head , an operator raises the handle bar 418 so that the inertia of the mechanism is overcome and the disks 411 , 412 rotate about fulcrum pins 409 and 410 , respectively . the rotation of the disks imparts motion to the off - set pins 413 , 414 which is translated into forward and downward motion components by the slots 415 and 416 , along which the pins 413 , 414 are able to slide , respectively . in turn , this moves the arms 401 , 402 downwards thus lowering the distribution head . lugs 431 , 432 projecting from arms 401 , 402 , respectively , prevent the distribution head from descending below a predetermined working height , determined by pillars 441 , 442 upon which the lugs impinge . the pillars 441 , 442 , which are height - adjustable , have threaded proximal ends . each pillar 441 , 442 is connected to the conveyor system frame by an upper nut and a lower lock - nut ( only upper nuts 443 are shown ) that are located above and below the outer rails 601 , 602 of the conveyor system frame , respectively . by altering the position of the upper nuts 443 along the pillars 441 , 442 , the height to which the pillars 441 , 442 extend above the surface of the outer rails 601 , 602 may be varied . by using the lower lock - nuts ( not shown ) to fasten the pillars 441 , 442 to the underside of the outer rails 601 , 602 , the desired height is thus locked in position . the use of the apparatus for removing powdery residue , such as semolina flour , will now be described . the blower unit 2 is connected via a conduit 21 to the inlet ports 203 , 204 of the central chamber 109 of the distribution head 100 . a vacuum unit 3 is connected , via a recovered semolina receiving hopper 4 , by a conduit 31 to the outlet ports 208 , 210 of the outer chambers 108 and 110 respectively . the distribution head is mounted by a bracket 400 so as to be positioned upright above a conveyor 6 that conveys peel - boards . the distribution head is mounted such that the base plate 103 is oriented transversely across a longitudinal axis of the peel - boards in the direction of travel of the conveyor and is situated at a distance of ideally less than 10 mm from the surface of the peel - boards below . with the vacuum unit in operation , semolina flour is vacuumed from the entire surface of the peel - boards as they travel on the conveyor through the outer slots 308 , 310 of the base plate 300 into the outer chambers of the distribution head . from these chambers the flour is sucked further through the outlet ports 208 , 210 via conduit 31 to the remotely located recovered semolina receiving hopper 4 . simultaneously with the vacuuming operation , air from the blower 2 unit enters the central chamber of the distribution head and is ducted downwards towards the nozzle opening 105 at the bottom . the pressurised air is expelled through the central slot 306 of the base plate 300 . the pressurised air impinges on the peel - board surface and dislodges any remnants of flour that may be remaining . for more complete flour recovery , these disturbed particles are vacuumed into the outer chambers of the distribution head and up to the recovered semolina receiving hopper as previously described . while the system has been described such that the distribution head 100 is in a fixed position so as to remove powder from the boards passing beneath it on a conveyor , it will be appreciated that other configurations are possible . for example , the distribution head may be located on a carriage which acts to move the distribution head over stationary or moving boards . additionally , any desired number of vacuum chambers may be provided . it will of course , be understood that the invention is not limited to the specific details described herein , which are given by way of example only and that various modifications and alterations are possible within the scope of the invention as defined in the appended claims .

a powdery material removal and recovery system comprises a distribution apparatus , a blower unit , a vacuum unit , a recovered powder receiving hopper , a powder sifter and a conveyor . the vacuum unit sucks material particles from the surface of boards passing along conveyor below and transfers the material to receiving hopper . air from the blower unit is expelled through a pressure chamber of the distribution apparatus onto the surface of the boards below so that any remaining remnants of particles are dried and dislodged and can then be removed via the outer duct compartments . recovered material deposited into the receiving hopper may then be transferred to the powder sifter for sifting and reuse .

in the following description , numerous specific details are set forth in order to provide a thorough understanding of the present invention . it will be obvious , however , to one skilled in the art that the present invention may be practiced without these specific details . in other instances , well - known aspects of strontium carbonate and nutritional supplements in general have not been described in particular detail in order to avoid unnecessarily obscuring the present invention . the present invention provides for new and improved compositions and methods of introducing strontium into the human diet to enhance osteoblastic activity and inhibit osteoclastic activity in bone . it is believed that the present invention not only provides compositions and methods for assisting in strengthening bones , but also for increasing adult stature by increasing epiphyseal bone growth , the healing of fractures , and treating metabolic bone disease . the inventive compositions preferably include at least 100 mg of strontium in the form of a neutral salt , such as carbonate , gluconate , lactate , chloride , citrate , etc ., although the carbonate form is currently the most preferred . it is also currently preferred that a daily dosage of elemental strontium be administered in the range of about 600 to about 700 mg . the strontium is preferably administered as an additive in a food , such as a nutritional bar , dessert , confection or other food . the inventive formulations can be quickly adsorbed into the human digestive tract and result in mitigating bone loss , treating metabolic bone disease , aiding in the healing of fractures , increasing stature in children , and the like . the strontium is preferably administered in a formulation and environment free of calcium and other divalent cations or materials that compete with strontium through absorption pathways in the digestive tract . this increases the effectiveness of the dosage and helps protect the strontium from being passed through the digestive tract without being absorbed . the skeleton is the body &# 39 ; s organ of structural support . the skeleton is also a reservoir for essential body chemicals , including calcium , phosphate , and sodium . the skeleton consists primarily of bone , and bone consists of two forms : compact bone and trabecular bone . compact bone is the dense outer shell of the skeleton , while trabecular bone consists of plates , rods , arches , and struts of bone contained within compact bone . both compact and trabecular bone are made from protein and mineral . bone is strong and hard because calcium phosphate crystals , hydroxyapatite , are deposited around the protein matrix . strontium can substitute for calcium in hydroxyapatite . hydroxyapatite is similar to limestone , and bone can be thought of as stone crystals held together by proteins . strontium exchanges with calcium in already formed hydroxyapatite crystals within bone mineral and is also incorporated directly into newly formed bone . bone is a living and dynamic material . with repeated use and over time , bone sustains microdamage and needs to be renewed or replaced . the process of replacing old and damaged bone is called remodeling . the bone cells responsible for remodeling are osteoblasts and osteoclasts . the process of remodeling is initiated by osteoclasts excavating out old and damaged bone , followed by osteoblasts filling in the excavated bone with new bone . osteoclast activity followed by osteoblast activity in remodeling is tightly linked and is referred to as coupling . all the bone in the body is turned over every six years . as mentioned above , strontium can replace calcium in the mineral crystals , hydroxyapatite , in bone . strontium &# 39 ; s effects on bone are to inhibit osteoclasts , that is to decrease the excavation of old bone , and to stimulate osteoblasts so that new bone is made . strontium uncouples bone remodeling . no longer is bone made only following bone resorption ; new bone is made independent of bone resorption . the net effect is an increase in bone . strontium stimulates the process of bone building . the presence of strontium in bone correlates with bone compression strength . various bone building vitamins which do not interfere with the absorption of strontium can also be added to the foods . for example , compounds such as vitamin d3 ( cholecalciferol ) and / or vitamin k may be advantageously added . vitamin d3 in this example aids in bone growth by increasing the absorption of strontium . vitamin k1 is used by the body to form hydroxyproline , an amino acid used for bone formation . similarly , other natural products such as quercetin dihydrate and hesperidin can be added to enhance the formulation . other conventional additives , stabilizers , ph adjusters , and the like can also added . in addition to quercetin ( and its glycone , rutin ) and hesperidin , a number of other natural products can be included in a bone building food . examples of such natural products include carnitine , acetyl carnitine , juniper berry oil , pine oil , dwarf pine oil , maritime pine bark extract , oil of rosemary , oil of sage , thujone , eucalyptol , camphor , borneol , menthol , a - pinene , b - pinene , thyrmol , bornylacetate , erbenol , cousmestrol , zearalenol , isolflavones , genistein , diadzin , humulone , phlorizin , horsetail extract , melatonin , and cistanche salsa extract . it is currently believed that the molecular effects of strontium on bone are mediated by the cellular calcium receptor . all mammals have a sensitive system to maintain blood calcium levels within a very narrow range . this system involves cell types in organs throughout the body , including bone , kidney , parathyroid , thyroid , and the small intestine . the cells in this system have receptors on their cell surface which respond to the extracellular calcium concentration and trigger specific cellular responses . strontium mimics the effects of calcium on this cell membrane calcium sensing mechanism , but only when there is a sufficiently high concentration of strontium . because 99 % of the body &# 39 ; s strontium is found in bone , a strontium concentration sufficient to activate the calcium receptor can only be achieved in bone . calcium , which is preferentially absorbed compared to strontium , interferes with strontium absorption , as do chelating agents , phytic acid , oxalates , fiber , and phosphate . as a result , ninety percent of absorbed strontium is typically excreted by the kidney ; while 10 % is excreted via the fecal stream . the kidney preferentially excretes strontium over calcium due to increased tubular resorption of the later cation . accordingly , strontium is preferably administered in the absence of calcium . it is also preferred that strontium be administered in the absence of chelating agents , phytic acid , oxalates , phosphate , and other divalent cations . also , it is preferable to ingest strontium on an empty stomach or separate from a meal in order to increase absorption of the strontium . it may be useful to ingest substances along with strontium that facilitate strontium absorption . for example , suitable compositions and methods for administration of strontium may include the co - administration of lysine , lactose and / or arginine . it is preferred that strontium carbonate be used having a purity of at least 99 . 4 %, and that it does not include significant amounts of aluminum , arsenic , barium , cadmium , copper , magnesium , molybdenum , mercury , lead , iron , sodium , tin , sulfur , or vanadium . by way of example , the inventive compositions can include a strontium carbonate blend which contains 59 . 3 % by weight elemental strontium that has a minimum of impurities . one form of strontium is strontium carbonate . each gram of strontium carbonate contains 593 . 5 mg of elemental strontium , so ingesting 1100 mg of strontium carbonate a day provides 653 mg of strontium . the food compositions preferably include at least about 100 mg strontium carbonate . alternatively , the food compositions preferably include from about 100 mg to about 1500 mg strontium carbonate , preferably from about 400 mg to about 1100 mg strontium carbonate , most preferably about 1000 mg strontium carbonate . the food compositions can also include other ingredients . for example , the compositions can include from 10 to 900 international units vitamin d3 powder , more preferably from about 100 to 400 iu vitamin d3 powder . the food compositions can also preferably include from about 0 . 001 to about 10 mg vitamin k1 powder , and more preferably about 1 mg vitamin k1 powder . the compositions also preferably include from about 0 . 01 to about 1000 mg of one or more bioflavonoids such as quercetin or hesperidin , more preferably from about 0 . 05 to about 1000 mg , most preferably about 100 mg . the formulations may also include other active and inactive ingredients and / or may contain conventional excipients , carriers and diluents provided they do not interfere with the absorption of strontium . the biological effects of strontium are independent of the type of strontium salt administered , as strontium is absorbed from the gut and resorbed from the kidney as a cation . the effects of strontium on the skeleton result solely from the strontium ion , as only the strontium is absorbed by the intestinal mucosa . the biological effects of strontium are independent of the anion with which strontium is administered . as a result , strontium salts in addition to strontium carbonate fall within the scope of various embodiments of the invention . a variety of suitable forms of providing for human ingestion of the disclosed compositions can be used and provided . general examples include nutritional supplements , pharmaceutical preparations , and foods supplemented with the specified compositions of the invention . many such packaging and administration forms for the compositions are known to those skilled in the art and are not discussed in detail herein to avoid obscuring the invention . for example , the formulation can be in the form of a pill , tablet , capsule , or similar dosage form . however , single dose solid tablets or capsules having the herein disclosed quantities of strontium carbonate can be relatively large . this is due in part because of the density of strontium in strontium carbonate require a relatively large volume be consumed . although the size of such tablets or capsules is not prohibitive for everyone , much of the consuming population , particularly aging women in highest need of the disclosed strontium supplements , has difficulty swallowing such large capsules and tablets . further , even after a tablet or capsule is swallowed , it can cause discomfort as it travels down the esophagus . accordingly , a preferred method of delivering strontium carbonate is in the form of a food such as a nutritional bar , candy , or other confection for administering to a user . more particularly , a particularly preferred method of delivering strontium carbonate is in the form of a chewable food such as a confectionary having strontium carbonate mixed with a chewable food - stuff matrix . in one embodiment , a chewable food - stuff matrix preferably includes one or more of a bulking agent ( for example carbohydrates , corn syrup , fructose and / or maltodextrin ), protein ( for example casein , soy , and / or whey ) a vegetable based oil , an emulsifier , a surfactant , a thickening agent ( for example gum and / or cellulose ) a natural flavoring additive , and a sweetener . for example , the chewable food - stuff matrix may include hydrogenated starch hydrolysate , corn syrup , sweetened condensed whole milk , cocoa , palm kernel oil , monoglyceride , diglycerides , natural flavors , sugar alcohol , and soy lecithin . the amount of strontium carbonate in a chewable food may be as broad as 5 % to about 60 % by weight , but for purposes of consistency , texture , and taste it is more preferably from about 18 % to about 21 by weight , most preferably about 20 %. in addition to strontium carbonate , the chewable food may include other additives , for example vitamin d and vitamin k . vitamin d may be , for example , added at from about 10 iu to about 800 iu , more preferably from about 100 iu to about 400 iu , in either case preferably limited by dietary guidelines such as the government &# 39 ; s recommended daily allowances and desired intake . similarly , vitamin k is preferably added at from about 1 mg to about 250 mg , more preferably from about 50 mg to about 90 mg , also as limited by dietary guidelines such as the government &# 39 ; s recommended daily allowances and desired intake . by way of example , a preferred chewable food can weigh between 1 . 5 grams to 20 grams , preferably about 5 . 5 grams . in lieu of corn syrup , other suitable ingredients of a chewable food matrix can be added for viscoelasticity and may include , for example , sucrose , polydextrose , maltodextrin , rice syrup , fructose syrup , or a hydrogenated glucose syrup ( hsh ) or the like and mixtures thereof in combination with a humectant such as glycerine , propylene glycol or the like . as a vegetable oil , palm kernel oil is particularly preferred , but other suitable examples may include coconut oil , partially hydrogenated soybean oil , partially hydrogenated cottonseed oil or the like or any other vegetable oil or any fat derived emulsifier . emulsifiers may also be utilized in the composition , for example lecithin or the like . additional materials which can be incorporated into a chewable food to enhance its appearance , taste , and consistency include , for example , flavors , sweeteners , and colorants . flavors may be chosen from natural and synthetic flavoring liquids . an illustrative list of such agents includes volatile oils , synthetic flavor oils , flavoring aromatics , oils , liquids , oleoresins or organic extracts and combination thereof . other useful flavorings and mixtures thereof are known in the art , including specific chemicals as well as other flavorings such as whole and partial fruits and nuts , peanut butter , candy bits , chocolate chips , bran flakes , etc . sweeteners may also be added to the chewable foods of the invention . these enhance the flavor and impart a palatable sweetness to the food . the sweeteners may be chosen from one or more of the following non - limiting list in addition to other ingredients having a sweetening effect . example sweeteners include : glucose , dextrose , invert sugar , fructose , and mixtures thereof saccharin and its various salts such as the sodium salt , dipeptide sweeteners such as aspartame , dihydrochalcone compounds , glycyrrhizin , stevia rebaudiana ( stevioside ), chloro derivatives of sucrose such as sucralose , sugar alcohols such as sorbitol , mannitol , xylitol , and natural sweeteners such as lo han guo , and the like . also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3 , 6 - dihydro - 6 - methyl - 1 - 1 - 1 , 2 , 3 - oxathiazin - 4 - one - 2 , 2 - dioxide , particularly the potassium salt ( acesulfame - k ), and sodium and calcium salts thereof . other sweeteners may also be used as are known in the art . the sweeteners are preferably added in amounts equal to about 0 - 10 % of the composition , and preferably about 0 . 1 - 5 %. surfactants or emulsifiers may also be included in the composition of the invention . these may be any food grade emulsifying material , for example , lecithin or other phospholipid material , monoglycerides and / or diglycerides , and mixtures thereof in amounts of from about 0 - 3 %, more desirably about 0 . 1 - 1 %. other examples of suitable dosage forms include supplemented foods , liquids , powders , syrups , and the like as are known in the art . the following example of the invention is shown by way of illustration only . a single dose composition was prepared according to the following table . the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics . the described embodiments are to be considered in all respects only as illustrative and not restrictive . the scope of the invention is , therefore , indicated by the appended claims rather than by the foregoing description . all changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope .

a composition of matter includes an effective amount of strontium carbonate for affecting bone metabolism . the composition is substantially free of calcium to avoid absorption competition in the digestive tract . the composition is also preferably substantially free of chelating agents , phosphate , phytic acid , oxalates , insoluble fibers , and non - strontium divalent cations or other materials that compete with strontium ions for absorption in the human digestive tract . other ingredients are optionally added to increase strontium absorption or for their independent positive effective on bone health , including for example vitamin d and vitamin k , quercetin dihydrate , and hesperidin . the composition is preferably administered as a chewable food by blending with a chewable food matrix to form a palatable food that is readily consumed .

this invention features an extensible , proteinaceous formulation of modified wheat protein , proteinaceous materials / concentrates / isolates , fats / oils , and less than 75 % select carbohydrates having controlled break elongation functional characteristics ; the blending of such ingredients in a mixer ; the conversion to an extensible reduced carbohydrate , high protein dough through the addition of water and thorough mixing ; the transfer , reduction and / or molding of the dough to a desired thickness and shape through extrusion and die cutting and / or reduction sheeting and / or lamination sheeting processes and die cutting , direct deposit , and / or rotary molding ( e . g ., rotary piston molding ); followed by baking , drying , microwave , frying , steaming , boiling , or a combination of such for desired moisture reduction and proteinaceous matrix curing / setting , with the option of topical seasoning / coating of the final product . the invention consists generally of the following : mixing of a reduced carbohydrate protein blend consisting of modified wheat protein ( s ) and proteinaceous concentrates and / or isolates , and / or fats and oils , and / or lecithin , and / or select carbohydrate materials , if desired for flavor and / or texture and / or seasoning and / or bulking and / or gelatinization ; the addition of water to the blend to form a soft , extensible , cohesive , non - adhesive dough ; followed by the transfer of the moist yet solid dough to an extrusion , reduction sheeter system , lamination sheeting , direct deposit , and / or rotary molding system , for final product depositing or dough forming / sheeting / molding to a thickness from 300 mm to 0 . 10 mm . the reduced thickness dough is then optionally processed by a die cutting device for the cutting / formation of the protein chips , bars , snacks , crackers , wafers , flat breads , cookies , biscuits , breads , bagels , cakes , french fries , meat analogs , pasta , pastries , and doughnuts . the extruded dough can optionally be combined with another product such as a fruit paste , and / or the individual cut / deposited unit items can be placed directly onto a conveyor band . the items are then transferred to a moisture - reduction process , including baking , drying , microwaving , frying , steaming , boiling , or a combination of such , until the extensible protein based food reaches the desired moisture percentage for durable handling strength , shelf stability , texture , flavor , and crunch . the final fabricated proteinaceous food can then be optionally seasoned , flavored , layered , and / or enrobed with a topical seasoning and / or coating , and then packaged . the following tables illustrate the elongation of the inventive dough that allows it to be processed on small kitchen and industrial - scale food processing equipment designed for processing carbohydrate - based products . the three doughs were prepared using the sodium metabisulfite , chemically modified , non - viscoelastic , film forming wheat protein isolate fp 5000 from midwest grain products labeled “ w ”. this product has 90 % minimum protein ( n × 6 . 25 ), 4 % maximum ash , 7 % maximum moisture , 2 % maximum fat , 1 % maximum fiber , and 5 % maximum starch . it has an average molecular weight of less than 100 , 000 daltons . the doughs also include a common soy protein isolate profam 781 from archer daniels midland labeled “ s ”, and a common vegetable oil labeled “ o ” and room temperature process water labeled “ pw ” under standard room temperature ( 70 °- 78 ° f .) conditions . formulation break elongation (%) 11 % w , 35 % s , 14 % 0 , 40 % pw 38 . 45 11 % w , 35 % s , 14 % 0 , 40 % pw 35 . 73 11 % w , 35 % s , 14 % 0 , 40 % pw 56 . 56 11 % w , 35 % s , 14 % 0 , 40 % pw 25 . 23 [ 0023 ] table 2 formulation break elongation (%) 23 % w , 23 % s , 14 % 0 , 40 % pw 143 . 67 23 % w , 23 % s , 14 % 0 , 40 % pw 81 . 19 23 % w , 23 % s , 14 % 0 , 40 % pw 116 . 31 [ 0024 ] table 3 control formulation break elongation (%) 0 % w , 47 % s , 14 % 0 , 40 % pw 3 . 38 0 % w , 47 % s , 14 % 0 , 40 % pw 4 . 21 0 % w , 47 % s , 14 % 0 , 40 % pw 7 . 59 0 % w , 47 % s . 14 % 0 , 40 % pw 5 . 73 as is evident , the use of at least 11 % modified wheat protein isolate dramatically increases the break elongation functional characteristics of the proteinaceous dough , thus allowing it to have properties necessary for many industrial / commercial processes . 100 parts modified wheat protein isolate ( 90 % protein ), 130 parts soy protein isolate ( 90 % protein ) were placed in a stainless steel single arm dough mixer . the powders were blended together for 1 minute at medium speed . 10 parts liquid lecithin and 10 parts vegetable oil was then added directly to the powder blend and mixed at high speed for 2 minutes . 24 parts water ( 60 - 72 ° f .) was added directly to the dough and blended at high speed for 3 minutes . 5 parts ammonia bicarbonate was then added to the wet dough ( for leavening of the product in the oven ) and blended in for an additional 3 minutes . the final pliable extensible protein dough product was then transferred to a flat service and reduction sheeted to a thickness of 2 mm and cut into rectangular shapes . the cut crackers were then placed on into a convection oven , without any overlap , and baked for 10 minutes at temperatures of 330 ° f . to 350 ° f . final unseasoned rectangular cracker composition was approximately 2 . 0 % moisture , 75 % protein , 10 % fat , and 3 % carbohydrate per 28 gram serving . 40 parts milled textured wheat protein powder ( 75 % protein ), 80 parts modified wheat protein isolate ( 90 % protein ), 80 parts soy protein isolate ( 90 % protein ), 10 parts deactivated yeast protein concentrate ( 50 % protein ), 15 parts pregelatinized starch , 5 parts double acting baking powder , 5 parts lecithin , and 5 parts lecithin powder were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 15 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 2 mm and cut into triangular shaped chips . the cut chips were then placed on a baking tray , without any overlap , and baked in a convection oven at 320 ° f . for approximately 5 minutes for moisture reduction / drying . the dried reduced moisture chips were then transferred to a deep fryer and fried in 360 ° f . vegetable oil for 2 minutes . final unseasoned chip composition was approximately 2 % moisture , 56 % protein , 25 % fat , and 10 % carbohydrates per 28 gram serving . 160 parts textured wheat protein powder ( 75 % protein ), 140 parts modified wheat protein isolate ( 90 % protein ), and 140 parts soy protein isolate ( 90 % protein ), 60 parts egg protein , and 10 parts lecithin powder , were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 250 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 2 mm and cut into triangular shaped chips . the cut chips were then placed in a convection oven , without any overlap , and baked at 350 ° f . for approximately 8 - 10 minutes . final unseasoned chip composition was approximately 2 . 0 % moisture , 76 % protein , 8 % carbohydrate , and 8 % fat per 28 gram serving . 80 parts textured wheat protein powder ( 75 % protein ), 220 parts modified wheat protein isolate ( 90 % protein ), and 140 parts soy protein isolate ( 90 % protein ), and 10 parts lecithin powder , were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 30 parts vegetable oil and 250 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 2 mm and cut into triangular shaped chips . the cut chips were then placed in a convection oven and baked at 320 ° f . for approximately 5 minutes for moisture reduction . the product was then transferred to a deep frying unit and fried in canola oil at 360 ° f . for less than 2 minutes . final composition of the unseasoned chips was approximately 2 . 0 % moisture , 54 % protein , 25 % fat , and 4 % carbohydrate per 28 gram serving . 40 parts textured wheat protein powder ( 75 % protein ), 110 parts modified wheat protein isolate ( 90 % protein ), 70 parts soy protein isolate ( 90 % protein ), 20 parts deactivated yeast protein concentrate ( 50 % protein ), 5 parts leavening , 50 parts vegetable oil , and 5 parts lecithin powder , were placed in a single arm dough mixer . the ingredients were blended together for 1 minute at medium speed . 15 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 1 . 5 mm and cut into triangular shaped chips . the cut chips were then placed in a convection oven at 335 ° f . for approximately 8 - 10 minutes . final composition of the unseasoned chips was approximately 2 . 0 % moisture , 71 % protein , 20 % fat , and 8 % carbohydrates per 28 gram serving . 50 parts viscoelastic wheat protein isolate ( 88 % protein ), 30 parts modified wheat protein isolate ( 90 % protein ), 20 parts soy protein concentrate ( 70 % protein ), 1 part deactivated yeast protein concentrate ( 50 % protein ), 100 parts potato granule , 5 parts double acting baking powder , 5 parts lecithin , and 5 parts lecithin powder , were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 16 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 20 mm and cut into shoestring french fries . the cut strips were then placed in a convection oven at 320 ° f . for approximately 5 minutes for moisture reduction / drying . the dried reduced moisture shoestring french fry snack was then transferred to a deep fryer and fried in 360 ° f . vegetable oil for 2 minutes . final shoestring french fry snack composition was approximately 2 % moisture , 29 % protein , 23 % fat , 29 % carbohydrates per 28 gram serving . 50 parts viscoelastic wheat protein isolate ( 88 % protein ), 30 parts modified wheat protein isolate ( 90 % protein ), 50 parts soy protein concentrate ( 70 % protein ), 0 . 5 part deactivated yeast protein concentrate ( 50 % protein ), 100 parts corn masa , and 5 parts lecithin powder , were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 16 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 1 . 5 mm and cut into rectangular strips . the cut strips were then directly deep fried in canola oil for 4 minutes . final corn chip snack composition was approximately 3 % moisture , 32 % protein , 25 % fat , 28 % carbohydrates per 28 gram serving . 50 parts viscoelastic wheat protein isolate ( 88 % protein ), 30 parts modified wheat protein isolate ( 90 % protein ), 20 parts soy protein concentrate ( 70 % protein ), 1 part deactivated yeast protein concentrate ( 50 % protein ), 100 parts potato granule , 5 parts double acting baking powder , 5 parts lecithin , and 5 parts lecithin powder , were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 16 parts water ( 60 - 80 ° f .) was added directly to the dough and blended at high speed for 3 minutes . the final dough product was then rolled to a thickness of approximately 20 mm and cut into round chips . the cut strips were then placed in a convection oven at 320 ° f . for approximately 5 minutes for moisture reduction / drying . the dried reduced moisture potato chip snack was then transferred to a deep fryer and fried in 360 ° f . vegetable oil for 2 minutes . final potato chip snack composition was approximately 2 % moisture , 29 % protein , 23 % fat , 29 % carbohydrates per 28 gram serving . 140 pounds textured wheat protein ( 75 % protein ), 360 pounds modified wheat protein isolate ( 90 % protein ), 396 pounds soy protein isolate ( 90 % protein ), 40 pounds lecithin , 40 pound safflower oil , and 4 pounds of masking agent ( sucralose ), were placed in a 2000 pound single arm dough mixer . mixer was started and 750 pounds of water ( 77 ° f .) was added directly to the dough and blended at low speed for an additional 5 minutes after water was added . the final dough product was then transferred to a large industrial scale vertical lamination / sheeting unit . the material was reduced to a thick 200 mm sheet , reduced further , then laminated , and further reduced in thickness through reduction rolls , where it was completed at a thickness of approximately 1 mm . the product was then dockered and die cut into potato chip shaped roundish chips . the cut chips were then transferred to a direct fire 275 ′ oven and baked for 2 . 40 minutes at temperatures ranging from 250 to 485 ° f . the baked product was then further dried in a radio frequency drying oven followed by topical oiling and seasoning . final protein chip snack composition was approximately 2 % moisture , 64 % protein , 18 % fat , 11 % carbohydrates per 28 gram serving . 7 parts textured wheat protein ( 75 % protein ), 7 parts modified wheat protein isolate ( 90 % protein ), 11 parts whey protein concentrate ( 80 % protein ), 1 part lecithin , 1 part rice bran oil , 0 . 1 parts ammonia bicarbonate , and 0 . 1 parts masking agent ( sucralose ), were placed in a single arm dough mixer . mixer was started and 10 parts of water ( 77 ° f .) was added directly to the blend and mixed at low speed for an additional 5 minutes after water was added . the final dough product was then transferred to a sheeting unit and rolled to a thickness of approximately 10 mm and die cut into rectangular bar shaped products . the cut bars were then transferred to a convection oven and baked for 7 minutes at temperatures ranging from 250 to 485 ° f . the final baked product was then enrobed in compound protein rich chocolate . final protein bar composition was approximately 2 % moisture , 67 % protein , 17 % fat , 13 % carbohydrates per 30 gram bar . 7 parts modified wheat protein isolate ( 90 % protein ), 14 parts whey protein concentrate ( 80 % protein ), 1 part lecithin , 1 part rice bran oil , 0 . 1 parts ammonia bicarbonate , and 0 . 1 parts masking agent ( sucralose ), were placed in a single arm dough mixer . mixer was started and 7 parts water ( 72 ° f .) was added directly to the blend and mixed at low speed for an additional 5 minutes after water was added . the final dough product was left sitting for 10 minutes and remixed , breaking the dough into pieces and thus forming a blend dough particles . the broken dough was then transferred to a sheet , in a thin layer , and then transferred to a convection oven and baked for 7 minutes at temperatures ranging from 250 to 485 ° f . the final baked product was then further disturbed and broken via tumbling and packaged as a protein trail mix . final protein trail mix composition was approximately 2 % moisture , 75 % protein , 7 % fat , 11 % carbohydrates per 28 gram serving . 3 parts modified wheat protein isolate , 10 parts textured wheat protein , and 11 parts casein were blended in a single arm mixing vessel . 6 . 5 parts water , 2 parts rice bran oil , 2 parts lecithin , 0 . 20 parts sucralose , and 0 . 10 parts emulsifying agent were added to dry blend and mixed thoroughly . the proteinaceous dough was then transferred to a dockered uhmw polymeric die mold where the product was molded into several bars . the bars were then placed on a sheet and placed in a convection oven at 350 degrees for 10 minutes and then transferred to another convection at 250 degrees for final moisture removal . final rotary molded protein bar is 72 % protein , 6 % carbohydrate , and 12 % fat . 50 parts non - viscoelastic wheat protein isolate ( arise 6000 , 85 % protein ), 200 parts sweetened non - gelling composite wheat - egg - soy protein ( beta 3000 , 85 % protein ), 65 parts palm kernel oil , and 5 parts lecithin , were placed in a single arm dough mixer . the powders were blended together for 1 minute at medium speed . 140 parts water ( 70 - 75 ° f .) was added directly to the dry mix and blended at high speed for 3 minutes . the final dough product was then transferred to the barrel of a dough extruder . the soft dough was then extruded through a double ¾ ″ tape die to form two proteinaceous tapes in a thickness of approximately 5 mm . the tape was guillotined at 4 ″ lengths to form rectangular strips . the cut strips were then placed onto a metal sheet , then placed into convection oven and dried for 6 minutes at 350 ° f . final extruded cookie bar snack composition was approximately 5 % moisture , 66 % protein , 22 % fat , 6 % carbohydrates per 32 gram serving . materials of importance used for these examples include wheat protein isolates ( arise 5000 , arise 6000 , both from mgp , atchison , kans . ); soy protein isolates ( profam 781 , profam 985 , profam 891 , products of adm , decatur , ill . ); whey protein isolate and concentrate ( both from proteint , st . paul , minn . ); textured wheat protein powder ( mgp , atchison , kans . ); viscoelastic wheat gluten protein ( prolite wheat gluten , adm , decatur , ill . ); sweetened composite protein ( beta 3000 , betafoods , natick , mass .) each of the above features of the invention may be combined within the scope of the invention as understood by those skilled in the art . other embodiments will occur to those skilled in the art and are within the scope of the following claims .

a novel high - protein , reduced carbohydrate food material technology , and high - protein , reduced carbohydrate food products made therefrom , in which the food products meet high organoleptic , stability , and taste / texture standards . this novel material technology possesses numerous controllable functional characteristics , including high to low adhesion , high to low volume expansion , high to low tensile strength , and high to low break elongation , all of which are critical to both processing needs as well as final food product specifications . the material technology allows for the processing of proteinaceous foods on common process equipment , the foods including but not limited to chips , snacks , crackers , wafers , bars , flat breads , cookies , biscuits , breads , bagels , cakes , waffles , pancakes , french fries , pasta , pizza dough , breakfast cereals , muffins , doughnuts , pastries , and meat analogs . the material is an edible dough that possesses the material characteristics necessary for numerous industrial food processes , including direct reduction sheeting , lamination sheeting , extrusion , die cutting , and rotary molding , followed by on or more of baking , drying , microwaving , boiling , steaming , frying , seasoning , and enrobing .

fig1 illustrates a block diagram of a patient monitor 100 , such as a pulse oximeter , and associated sensor 110 . generally , in the case of a pulse oximeter , the sensor 110 has led emitters 112 , generally one at a red wavelength and one at an infrared wavelength , and a photodiode detector 114 . the sensor 110 is generally attached to an adult patient &# 39 ; s finger or an infant patient &# 39 ; s foot . for a finger , the sensor 110 is configured so that the emitters 112 project light through the fingernail and through the blood vessels and capillaries underneath . the led emitters 112 are activated by drive signals 122 from the pulse oximeter 100 . the detector 114 is positioned at the fingertip opposite the fingernail so as to detect the led emitted light as it emerges from the finger tissues . the photodiode generated signal 124 is relayed by a cable to the pulse oximeter 100 . a pulse oximeter 100 determines oxygen saturation ( spo2 ) by computing the differential absorption by arterial blood of the two wavelengths emitted by the sensor 110 . a typical pulse oximeter 100 contains a sensor interface 120 , one or more processors 130 , such as a spo2 processor , an instrument manager 140 , a display 150 , an audible indicator ( tone generator ) 160 , and a keypad 170 . the sensor interface 120 provides led drive current 122 which alternately activates the sensor &# 39 ; s red and infrared led emitters 112 . the sensor interface 120 also has input circuitry for amplification and filtering of the signal 124 generated by the photodiode detector 114 , which corresponds to the red and infrared light energy attenuated from transmission through the patient tissue site . the spo2 processor 130 calculates a ratio of detected red and infrared intensities , and an arterial oxygen saturation value is empirically determined based on that ratio . the instrument manager 140 provides hardware and software interfaces for managing the display 150 , audible indicator 160 , and keypad 170 . the display 150 shows the computed oxygen saturation status , as described above . similarly , other patient parameters including hbco , hbmet , hbt , hct , oxygen concentrations , glucose concentrations , pulse rate , pi , siq , and / or pvi can be computed . the audible indicator 160 provides the pulse beep as well as alarms indicating desaturation events . the keypad 170 provides a user interface for such things as alarm thresholds , alarm enablement , and / or display options . computation of spo2 relies on the differential light absorption of oxygenated hemoglobin , hbo 2 , and deoxygenated hemoglobin , hb , to determine their respective concentrations in the arterial blood . specifically , pulse oximetry measurements are made at red ( r ) and infrared ( ir ) wavelengths chosen such that deoxygenated hemoglobin absorbs more red light than oxygenated hemoglobin , and , conversely , oxygenated hemoglobin absorbs more infrared light than deoxygenated hemoglobin , for example 660 nm ( r ) and 905 nm ( ir ). to distinguish between tissue absorption at the two wavelengths , the red and infrared emitters 112 are provided drive current 122 so that only one is emitting light at a given time . for example , the emitters 112 can be cycled on and off alternately , in sequence , with each only active for a quarter cycle and with a quarter cycle separating the active times . this allows for separation of red and infrared signals and removal of ambient light levels by downstream signal processing . because only a single detector 114 is used , it responds to both the red and infrared emitted light and generates a time - division - multiplexed (“ modulated ”) output signal 124 . this modulated signal 124 is coupled to the input of the sensor interface 120 . in addition to the differential absorption of hemoglobin derivatives , pulse oximetry relies on the pulsatile nature of arterial blood to differentiate hemoglobin absorption from absorption of other constituents in the surrounding tissues . light absorption between systole and diastole varies due to the blood volume change from the inflow and outflow of arterial blood at a peripheral tissue site . this tissue site might also comprise skin , muscle , bone , venous blood , fat , pigment , and / or the like , each of which absorbs light . it is assumed that the background absorption due to these surrounding tissues is invariant and can be ignored . thus , blood oxygen saturation measurements are based upon a ratio of the time - varying or ac portion of the detected red and infrared signals with respect to the time - invariant or dc portion : r / ir =( red ac / red dc )/( ir ac / ir dc ). the desired spo2 measurement is then computed from this ratio . the relationship between r / ir and spo2 can be determined by statistical regression of experimental measurements obtained from human volunteers and calibrated measurements of oxygen saturation . in a pulse oximeter device , this empirical relationship can be stored as a “ calibration curve ” in a read - only memory ( rom ) look - up table so that spo2 can be directly read - out of the memory in response to input r / ir measurements . the pulse oximeter 100 can also measure perfusion index , pi , which is a numerical value that indicates the strength of the ir signal returned from a monitoring site and provides a relative assessment of the pulse strength at the monitoring site . the perfusion index can be defined as follows : pi =( ir max − ir min )/ ir dc , where ir max is the maximum value , ir min is the minimum value , and ir dc is the average value of the invariant portion . as the light absorption characteristic of blood is typically “ flatter ” or less sensitive to oxygen saturation around the infrared wavelength , the infrared signal from a sensor is influenced primarily by the amount of the blood at the monitoring site , not by the level of oxygenation in the blood . accordingly , the perfusion index , which is a numerical value that indicates the strength of the ir signal returned from a monitoring site , provides a relative assessment of the pulse strength at the monitoring site . pi values generally range from 0 . 02 % ( very weak pulse strength ) to 20 % ( very strong pulse strength ). in some embodiments , pi can be measured using other wavelengths . for example , red , near red , near ir , as well as other wavelengths can be used . in an embodiment , the sensor 110 also includes a memory device 116 . the memory 116 can include any one or more of a wide variety of memory devices known to an artisan from the disclosure herein , including erasable programmable read only memory ( eprom ), electrically erasable programmable read - only memory ( eeprom ), flash memory , other non - volatile memory , a combination of the same or the like . the memory 116 can include read - only memory such as read - only memory ( rom ), a read and write device such as a random - access memory ( ram ), combinations of the same , or the like . the remainder of the present disclosure will refer to such combination as simply eprom for ease of disclosure ; however , an artisan will recognize from the disclosure herein that the memory can include rom , ram , single wire memory , other types of memory , combinations of the same , or the like . the memory device 116 can advantageously store some or all of a wide variety of data and information , including , for example , information on the type or operation of the sensor , type of patient or body tissue , buyer or manufacturer information , sensor characteristics including the number of wavelengths capable of being emitted , emitter specifications , emitter drive requirements , demodulation data , calculation mode data , calibration data , software such as scripts , executable code , or the like , sensor electronic elements , sensor life data indicating whether some or all sensor components have expired and should be replaced , encryption information , monitor or algorithm upgrade instructions or data , or the like . in an embodiment , the memory device can also include oxygen saturation to perfusion index and r / ir ratio to perfusion index ratios and / or data . in certain situations , pulse oximetry sensors may produce anomalous readings , such as when a patient suffers from cyanosis . in a patient suffering from cyanosis , blood cells are uncharacteristically low on oxygen , leading to oxygen deficiency and giving the patient &# 39 ; s skin a bluish - hue . one potential cause is that the patient &# 39 ; s body produces too much hemoglobin , making the blood “ thicker ” or slower flowing , making microcirculation vessels more prone to blockage . thus , a “ blocked ” microcirculation state can indicate cyanosis . a “ blocked ” microcirculation state can also indicate other medical conditions , such as sepsis , systemic inflammatory response syndrome ( sirs ), or septicemia . sepsis is a potentially deadly medical condition that is characterized by a whole - body inflammatory state ( called sirs ) and the presence of a known or suspected infection . the body may develop this inflammatory response by the immune system to microbes in the blood , urine , lungs , skin , or other tissue . septicemia is a related medical term referring to the presence of pathogenic organisms in the bloodstream , which can lead to sepsis . sepsis can also be referred to as blood poisoning . during sepsis or sirs , inflammation in the body can cause constriction in blood vessels , leading to low blood pressure or insufficient blood flow . during a “ blocked ” microcirculation state , blood cells can get blocked in the microcirculation vessels , such as the arterioles and capillaries . blood cells can clump together or otherwise catch against the wall of blood vessels , creating a blockage that prevents blood cells , including red blood cells carrying hemoglobin , from passing through the blockage . however , plasma , which is composed of mostly water and in which the blood cells are suspended , is generally able to flow through passages in the blockage . in some situations , some blood vessels at the monitoring site may continue to have normal flow while some vessels are blocked . thus , a “ blocked ” microcirculation state can indicate that some microcirculation vessels in an area are blocked and not necessarily all vessels in the area are blocked . with the blockage preventing most or all the red blood cells from passing a blood vessel , at most only a limited amount of hemoglobin passes through a blocked blood vessel . in some situations , the blood vessel may only be partially blocked , where some hemoglobin passes through but less than when the blood vessel is unblocked . normally , blood is made up of about 40 - 50 % of red blood cells , of which about 95 % is hemoglobin . plasma , which is about 95 % water , normally constitutes about 55 % of the blood &# 39 ; s volume . accordingly , a pulse oximeter placed on a tissue site experiencing blockage in microcirculation vessels may detect mostly plasma passing through with no or only a small percentage of red blood cells , at least at part of the monitoring site . the resulting change in the normal composition of blood can cause anomalous readings in the pulse oximetry monitor . as plasma has generally different absorption characteristics for red and infrared wavelengths than normal blood , pulse oximetry readings may become skewed . red ac and / or ir ac can be affected , causing measured r / ir ratio to change . for example , if red ac rises or ir ac drops , the r / ir ratio increases . alternatively , if red ac drops or ir ac rises , the r / ir ratio decreases . thus , the value of r / ir can change due to a change in the light absorption of blood even if the underlying oxygen saturation of the blood remains the same . however , by comparing oxygen saturation and pi for normal microcirculation to the oxygen saturation and pi for blocked microcirculation , such as by calculating and comparing ratios , the monitor can determine the existence of an abnormal situation . typically , spo2 is mostly independent of pi , with spo2 varying minimally as pi increases . however , spo2 varying by more than normal as pi increases can indicate an anomalous microcirculation state , such as a blockage . in one embodiment , by analyzing the measured ratios , the pulse oximeter 100 can determine the microcirculation state , such as whether a blocked vessel exists in the microcirculation vessels . fig2 illustrates an example graph depicting the optical absorption characteristic of normal blood and plasma . the graph depicts sampling wavelengths at 660 nm 220 and at 905 nm 225 . as illustrated , ir absorption for plasma at a frequency of 905 nm is on a “ steeper ” section of the curve compared to the “ flatter ” section of the curve for normal blood . this can imply that readings for ir for plasma would be more sensitive to changes in the absorption quality of the blood . in contrast , the ir measurement for normal blood , for example at 905 nm , is usually insensitive to a change in oxygenation of normal blood , but more affected by change in the amount of blood . as illustrated in the graph , plasma can have a “ flatter ” section in its absorption curve at a different wavelength , for example at 970 nm 230 . fig3 a and 3b illustrate graphs of oxygen saturation values for a normal microcirculation state data set . fig3 a has an y - axis 305 corresponding to the measured ratio , r / ir , and a x - axis 310 corresponding to perfusion index , pi . fig3 b has a y - axis 320 corresponding to measured oxygen saturation , and an x - axis 325 corresponding to perfusion index , pi . fig3 a and 3b represent multiple data points with a best fit line 315 , 330 indicating the trend of the data points . each data point represents a measurement . as illustrated , the best fit line for fig3 a trends slightly downward and the best fit line for fig3 b trends slightly upwards . however , there is generally only a small change in the y - axis for the best fit line as pi increases , with the change in fig3 a around 0 . 1 and the change in fig3 b around 4 . fig4 a and 4b illustrate graphs of oxygen saturation values for another normal microcirculation state data set . fig4 a has a y - axis 405 corresponding to the measured ratio , r / ir , and an x - axis 410 corresponding to perfusion index , pi . fig4 b has a y - axis 420 corresponding to measured oxygen saturation , and an x - axis 425 corresponding to perfusion index , pi . fig4 a and 4b represent multiple data points with a best fit line 415 , 430 indicating the trend of the data points . each data point represents a measurement . as illustrated , the best fit line for fig4 a trends slightly upwards and the best fit line for fig4 b trends slightly downwards . however , there is generally only a small change in the y - axis for the best fit line as pi increases , with the change in fig4 a around 0 . 1 and the change in fig4 b around 3 . fig5 a and 5b illustrate graphs of oxygen saturation values for an anomalous microcirculation state data set . fig5 a has a y - axis 505 corresponding to the measured ratio , r / ir , and an x - axis 510 corresponding to perfusion index , pi . fig5 b has a y - axis 520 corresponding to measured oxygen saturation , and an x - axis 525 corresponding to perfusion index , pi . fig5 a and 5b represent multiple data points with a best fit line 515 , 530 indicating the trend of the data points . each data point represents a measurement . as illustrated , the best fit line for fig5 a trends significantly upwards on the y - axis by around 0 . 3 and the best fit line for fig5 b trends significantly downwards on the y - axis by around 13 as pi increases . in comparison to fig3 a and 4a , fig5 a shows a high r / ir ratio for low values of pi that becomes a high r / ir ratio as pi increases . in comparison to fig3 b and 4b , fig5 b shows a high reading for low values of pi that becomes a low reading as pi increases . differences between the graphs can be explained by the microcirculation state in fig5 a and 5b being different from the microcirculation state in fig3 a - 4b . for example , fig5 a and 5b can represent a “ blocked ” or partially blocked microcirculation state where the blood passing through the sensor includes mostly plasma . as discussed above , this can skew r / ir and the measured oxygen saturation derived from r / ir . fig6 illustrates a flow diagram for a process 600 for determining the state of microcirculation usable by a pulse oximeter . microcirculation state can be determined by comparison with microcirculation data stored on a patient monitor , such as the pulse oximeter 100 of fig1 . the process 600 can be implemented by embodiments of the sensor 110 and / or patient monitor 100 of fig1 or other suitable device . while in conventional pulse oximetry , measurements are generally taken pulse - by - pulse and averaged over pulses , microcirculation measurements can be measured using only a single pulse or a portion of a single pulse . this can be done , for example , at the minimum and / or maximum blood flow of a pulse . microcirculation measurements can also be determined over multiple pulses . in some embodiments , microcirculation measurements are taken during a portion of the normal measurement time used by a physiological sensor to take a measurement of a parameter , thereby allowing detection of aberrant parameter measurements using the microcirculation measurements . for example , while a pulse oximeter is measuring spo2 over several pulses , microcirculation measurements can be taken per pulse and a warning given if an irregular microcirculation state is detected , thereby notifying a user of a possible aberration in the current spo2 reading . at block 610 , oxygen saturation is measured at a tissue monitoring site . in one embodiment , oxygen saturation is determined using a pulse oximeter sensor . at block 620 , perfusion index or pulse strength is measured . in one embodiment , the perfusion index is determined using the same sensor used to measure oxygen saturation so that readings are taken at the same monitoring site . at block 630 , a ratio of oxygen saturation to perfusion index is determined . oxygen saturation can be a spo2 value based on the measured r / ir ratio looked - up against a calibration curve . alternatively , the ratio can be perfusion index to oxygen saturation . in other embodiments , the measured r / ir ratio can be used directly instead of spo2 . in some embodiments , multiple readings of perfusion index and oxygen saturation can be taken and averaged together before determining the ratio in order to account for outliers . the multiple readings can be filtered before averaging . for example , readings can first be filtered based on closeness of pi values before the readings are averaged together . at block 640 , the determined ratio in block 630 is compared to stored microcirculation data . the stored data can be data sets for microcirculation states . in some embodiments , a ratio , a curve , a line , table , data points , or formula can be stored that corresponds to a data set . the measured perfusion index and oxygen saturation can then be compared to the stored data . in some embodiments , multiple readings are taken and a best fit line or curve is generated and compared to a stored best fit line or curve . in some embodiments , readings are collected at various pi values in order to generate a trend line . at block 650 , the microcirculation state is determined from comparison of the stored microcirculation data . for example , if the determined ratio is similar to a stored ratio corresponding to a data set for unblocked microcirculation , the microcirculation state is determined to be unblocked . other data sets for other microcirculation states , such as blocked and / or partially blocked can also be stored . where multiple data sets are stored , the state can be determined by selecting the state corresponding to the stored ratio closest to the measured ratio . at block 660 , the monitor can optionally generate an alarm and / or display the microcirculation state . for example , an alarm signal can be generated by the monitor to indicate that the readings may be anomalous , such as when a blocked or partially blocked microcirculation state is detected . the alarm can be a visual indicator ( e . g ., icon , message or image ) and / or an audio indicator . in an embodiment , the alarm can indicate the detection of cyanosis , sepsis , sirs or other medical condition based at least partly on the determined microcirculation state . in some situations , no action is taken , such as when readings are determined to be normal or non - threatening . at block 670 , the monitor can optionally compensate for the microcirculation state in order to improve accuracy of the readings . after the microcirculation state returns to normal , the compensation process can be ended . in one embodiment , an offset can be added to the measured parameter value , such as spo2 . the offset can be calculated based on data sets for microcirculation state . different microcirculation states can have different offsets . for example , if a “ blocked ” microcirculation state produces high readings for low pi values , a negative offset can be used . however , if a “ blocked ” state produces a low value for high pi values , then a positive offset can be used . in one embodiment , a varying offset can be used depending on the value of pi . in one embodiment , a different wavelength emitter can be used to compensate for a microcirculation state . for example , rather than using a regular infrared emitter , typically 905 nm , an emitter with a different infrared wavelength , such as 970 nm can be used . in one embodiment , the different wavelength is selected such that the wavelength is at a “ flat ” section of the light absorption curve for plasma , that is , where the light absorption is not much affected by changes in oxygen saturation . in one embodiment , the selected wavelength with regards to plasma mimics the properties of the regular wavelength with regards to normal flowing blood . in some embodiments , a different wavelength red emitter can be used instead of the regular red wavelength emitter . in some embodiments , the pulse oximeter sensor used to measure oxygen saturation and pi can be provided with an additional emitter at a different wavelength than the existing emitters . when a certain microcirculation state is detected , such as a “ blocked ” state , the additional emitter can be used . for example , a pulse oximetry sensor can be equipped with led &# 39 ; s capable of emitting at 660 nm , 905 nm , and at 970 nm wavelengths . under normal operation , the 660 nm and 905 nm emitters are active . however , upon detecting a blocked microcirculation state , the 905 nm emitter can be deactivated and the 970 nm emitter activated in its place . in some embodiments , a variable wavelength emitter can be used rather than separate emitters . in some embodiments , the additional emitter can be a red wavelength emitter . fig7 illustrates a flow diagram for a process 700 for determining the state of microcirculation wherein multiple data points are collected . the process 700 can be implemented by embodiments of the sensor 110 and / or patient monitor 100 of fig1 or other suitable device . at block 710 and block 720 , oxygen saturation and perfusion index are measured . at block 725 , measured values are stored in memory . each paired measurement forms a data point . at block 730 , the number of stored data points is checked to determine if sufficient data has been collected to determine the microcirculation state . data can be sufficient if a set number of data points have been collected , a set amount of time has passed , and / or a spectrum of data points have been collected , such as for differing values of pi . at block 740 , the stored measured data is compared with stored microcirculation data . typically , the microcirculation data is pre - stored on the pulse oximeter before use , as opposed to collected during use . a comparison can involve generating a curve or line from the measured data , calculating a rate of change for the stored data , generating a trend line for the measured data or the like and comparing with the stored microcirculation data . at block 750 , the microcirculation state is determined from comparison of the stored microcirculation data . for example , if the measured data is similar to microcirculation data corresponding to a data set for unblocked microcirculation , the microcirculation state is determined to be unblocked . other data sets for other microcirculation states , such as for blocked and / or partially blocked can also be stored . where multiple data sets are stored , the state can be determined by selecting the state corresponding to the stored ratio closest to the measured ratio . blocks 760 and 770 are similar to steps 660 and 670 described in fig6 . as will be apparent from the above description , the r / ir ratio corresponds to oxygen saturation or spo2 and can be used in place of oxygen saturation or spo2 for the above comparisons , and vice versa . while the above systems and methods have been described in terms of oxygen saturation and pi , other physiological parameters can be measured in place of or in addition to oxygen saturation and / or perfusion index and used to determine microcirculation state . for example , perfusion index is an indication of amplitude and / or signal strength and other parameters or measurements indicating amplitude and / or signal strength can be used . in some embodiments , one or more different sensors can be used in place of or in addition to a pulse oximeter sensor . conditional language used herein , such as , among others , “ can ,” “ could ,” “ might ,” “ may ,” “ e . g .,” and the like , unless specifically stated otherwise , or otherwise understood within the context as used , is generally intended to convey that certain embodiments include , while other embodiments do not include , certain features , elements and / or states . thus , such conditional language is not generally intended to imply that features , elements and / or states are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding , with or without author input or prompting , whether these features , elements and / or states are included or are to be performed in any particular embodiment . the terms “ comprising ,” “ including ,” “ having ,” and the like are synonymous and are used inclusively , in an open - ended fashion , and do not exclude additional elements , features , acts , operations , and so forth . also , the term “ or ” is used in its inclusive sense ( and not in its exclusive sense ) so that when used , for example , to connect a list of elements , the term “ or ” means one , some , or all of the elements in the list . various systems and processes for determining microcirculation state have been disclosed in detail in connection with various embodiments . these embodiments are disclosed by way of examples only and are not to limit the scope of the claims that follow . indeed , the novel methods and systems described herein can be embodied in a variety of other forms ; furthermore , various omissions , substitutions and changes in the form of the methods and systems described herein can be made without departing from the spirit of the inventions disclosed herein . the claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of certain of the inventions disclosed herein . one of ordinary skill in the art will appreciate the many variations , modifications and combinations . for example , the various embodiments of the microcirculation determination process can be used with other oxygen saturation sensors and with both disposable and reusable sensors . in some embodiments , the determination process can be applied to other blood vessels to detect a blockage , even in vessels not involved in microcirculation . furthermore , in certain embodiments , the systems and methods described herein can advantageously be implemented using computer software , hardware , firmware , or any combination of software , hardware , and firmware . in one embodiment , the system includes a number of software modules that comprise computer executable code for performing the functions described herein . in certain embodiments , the computer - executable code is executed on one or more general purpose computers or processors . however , a skilled artisan will appreciate , in light of this disclosure , that any module that can be implemented using software can also be implemented using a different combination of hardware , software or firmware . for example , such a module can be implemented completely in hardware using a combination of integrated circuits . alternatively or additionally , such a module can be implemented completely or partially using specialized computers or processors designed to perform the particular functions described herein rather than by general purpose computers or processors . moreover , certain embodiments of the invention are described with reference to methods , apparatus ( systems ) and computer program products that can be implemented by computer program instructions . these computer program instructions can be provided to a processor of a general purpose computer , special purpose computer , or other programmable data processing apparatus to produce a machine , such that the instructions , which execute via the processor of the computer or other programmable data processing apparatus , create means for implementing the acts specified herein to transform data from a first state to a second state . each of the processes , methods , and algorithms described in the preceding sections may be embodied in , and fully or partially automated by , code modules executed by one or more computers or computer processors . the code modules may be stored on any type of non - transitory computer - readable medium or computer storage device , such as hard drives , solid state memory , optical disc , and / or the like . the processes and algorithms may be implemented partially or wholly in application - specific circuitry . the results of the disclosed processes and process steps may be stored , persistently or otherwise , in any type of non - transitory computer storage such as , e . g ., volatile or non - volatile storage . the various features and processes described above may be used independently of one another , or may be combined in various ways . all possible combinations and subcombinations are intended to fall within the scope of this disclosure . in addition , certain method or process blocks may be omitted in some implementations . the methods and processes described herein are also not limited to any particular sequence , and the blocks or states relating thereto can be performed in other sequences that are appropriate . for example , described blocks or states may be performed in an order other than that specifically disclosed , or multiple blocks or states may be combined in a single block or state . the example blocks or states may be performed in serial , in parallel , or in some other manner . blocks or states may be added to or removed from the disclosed example embodiments . the example systems and components described herein may be configured differently than described . for example , elements may be added to , removed from , or rearranged compared to the disclosed example embodiments . while certain example embodiments have been described , these embodiments have been presented by way of example only , and are not intended to limit the scope of the inventions disclosed herein . thus , nothing in the foregoing description is intended to imply that any particular feature , characteristic , step , module , or block is necessary or indispensable . indeed , the novel methods and systems described herein may be embodied in a variety of other forms ; furthermore , various omissions , substitutions and changes in the form of the methods and systems described herein may be made without departing from the spirit of the inventions disclosed herein . the accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of certain of the inventions disclosed herein .

as placement of a physiological monitoring sensor is typically at a sensor site located at an extremity of the body , the state of microcirculation , such as whether vessels are blocked or open , can have a significant effect on the readings at the sensor site . it is therefore desirable to provide a patient monitor and / or physiological monitoring sensor capable of distinguishing the microcirculation state of blood vessels . in some embodiments , the patient monitor and / or sensor provide a warning and / or compensates a measurement based on the microcirculation state . in some embodiments , a microcirculation determination process implementable by the patient monitor and / or sensor is used to determine the state of microcirculation of the patient .

1 . an accurate representation of the subject &# 39 ; s actual body measurements is obtained and referred to herein as the “ custom measurement chart ”. the astm charts provide one example of the list of body measurements required to manufacture custom apparel ( refer to fig3 ). this chart represents the actual body dimensions . garments manufactured to these measures will be form - fitted or skin - tight . as shown in step s 100 in fig2 , this chart can be obtained by a variety of methods , including but not limited to : a . subject takes their own measurements with help from a family member , friend , tailor , seamstress , or body measuring professional or service . b . measurements are obtained from any of the commercial body scanners . c . measurements are obtained from a home - based body scanning device . 2 . with some body types , a better fit can be obtained by separately measuring front and back waist , front and back bust , and by also separately measuring the abdomen or ab measurement at the point of largest girth below the waist , but above the hips . ease amounts used for these more refined measurements are provided . for total girth waist or bust measurements , the average of front and back ease amounts should be used . 3 . the “ custom measurement chart ” will be converted to garment specific measurements by adding ease . the ease amounts required include : a . design ease — added room required based on the nature of the garment type ( underwear to outerwear ). b . wear ease — the room to move based on the preference of the customer . wear ease includes the difference between the range from stretch - to - fit ( gym wear ), form - fit ( no wear ease ), standard fit ( some wear ease ), casual fit ( more room for non - dressy situations ), comfort fit ( loose fit for lounging at home ) and unfitted ( hide the form , overalls , baggy over - clothing , etc .). c . fabric ease . for those fabrics that have some stretch to them , the ease used for the garment &# 39 ; s manufacture should be reduced somewhat as the fabric itself can provide some of the ease required as it stretches to accommodate movement . 4 . as shown in step s 102 in fig2 , the customer must provide information about the garment to be made . to determine what ease percentages are required , you must know the type of garment desired ( pants , skirt , dress , blouse , shirt , jacket , etc . ), the type of fit preferred ( form - fit , standard , casual , comfort , unfitted , etc .) and the type of fabric to be used to manufacture it . 5 . as shown in step s 104 in fig2 , use the table in fig4 ( for pants and skirts only , use table 5 ) to look up the ease percentage amounts to be used for the selected garment and preferred fit type . note that there are different horizontal and vertical ease amounts for some garment types like swimsuits . 6 . as shown in step s 106 in fig2 , use the table in fig6 to adjust each ease amount obtained in step 4 above , by multiplying it by the appropriate fabric stretch adjustment . 7 . as shown in step s 108 in fig2 , the values in the “ custom measurement chart ” that are associated with the ease amounts from step 6 ( the name of the ease amount determines which body measurement it applies to ) will be multiplied by those amounts to produce a “ garment measurement chart ” that is based on the subject &# 39 ; s actual body measurements increased by the amount of ease required for the chosen garment , in the desired fit style , made with the selected fabric . 8 . as shown in step s 112 in fig2 , the resultant “ garment measurement chart ” is suitable to manufacture custom apparel . for the purposes of this example , we will postulate a female customer whose measurements ( those that need to be adjusted for design , wear , and fabric ease ) are : step s 102 of fig2 : this customer wishes to purchase a close fit blouse made with a cotton blend interlock knit fabric . step s 104 in fig2 : we first look in the design and wear ease table of fig4 and find that the relevant ease amounts are : step s 106 in fig2 : next , we look up the fabric stretch adjustment amount from fig6 . a blouse made with a cotton blend interlock knit fabric should have ease adjustments of − 1 . 8 %, so each of the ease amounts obtained in step 1 is reduced by this adjustment . the resulting ease for these measurements becomes : steps s 108 - s 110 in fig2 : with these ease amounts , we now increase each of the relevant body measurements by the percentage specified . for “ front bust ”, we multiply the original 20 ″ amount by 1 . 007 ( 0 . 7 % greater ) to get a new “ front bust ” measurement of 20 . 14 ″. that particular adjustment was pretty trivial as it involved a close fit knit . other garments and fabric combinations produce more significant ease amounts . the final values for each of these measurements becomes : step 112 in fig2 : if the cotton interlock knit blouse is manufactured using these measurements , it should be as close fitting as possible while still comfortably providing room for unrestricted movement .

a method for automatically generating custom garment specific measurement charts is disclosed . the method derives charts from an individual &# 39 ; s anthropomorphic body measurements plus ease amounts that are proportional to those measurements and which vary based on the type of garment to be made , the intended fit preference , and the stretch amount of fabric to be used .

the present invention is a tablet docking station for a tablet 88 having a tablet dock 40 which has been optimized for barbecue outdoor usage . the present invention can assist a user while the user is outdoors cooking using a portable barbecue grill 28 . the tablet dock is , preferably an electrical connector that is connected to a wire harness and the wire harness can be powered by a photovoltaic panel on the shade , or by a direct current power supply which has a plug for receiving household electric current in an alternating current standard that is converted to direct current at the tablet dock . the electrical connector can be a standard or proprietary electrical connector and can be recessed as part of the tablet dock 40 , or can be separately formed on the tablet dock 40 with a power cord , data cord or a combination power and data cord . the tablet rests on a tablet area 80 that is defined between an angled resting plank 41 and a tablet connector base 42 . the tablet area 80 is a resting area for the tablet . the angled resting plank 41 is preferably perpendicular to the tablet connector base 42 . the angled resting plank 41 can have a nonslip surface such as a silicone outside layer . the tablet area 80 optionally is covered be a tablet shade 81 for defining a tablet niche 82 . the tablet niche 82 provides shelter from light and water elements to allow a tablet 88 to be used outdoors . the base post 36 supports an upper post 33 that can be telescopically retracted into the base post 36 . the upper post 33 can terminate at an arm joint 32 at an upper end of the upper post 33 . the arm joint 32 is preferably adjustable such as by releasing when a circular button like latch is depressed on a side of the arm joint 32 . the arm joint 32 provides an adjustable angle for an extension arm 31 . the extension arm 31 is likewise telescopically adjustable to provide for different geometric configurations and heights of users . the tablet dock 40 is supported by a base post 36 . the base post 36 has a lower end that acts as a footing on the ground . additionally , the base post 36 can be structurally stabilized by being connected to an insulated chest 34 . the insulated chest preferably includes a chest base 37 arid a chest lid 35 . the chest lid 35 can swivel , or can be a removable lid . the insulated chest 34 can be an ice chest if it is made to hold ice and water . the insulated chest 34 can further include a spigot for draining water . the insulated chest 34 can have a refrigeration feature if supplied with a refrigeration unit such as a thermoelectric peltier cooler , or a traditional compressor and evaporator refrigeration unit . the base post 36 is preferably hollow and can hold speakers 59 mounted on an outside surface of the base post 36 . the base post 36 has an upper end that supports the tablet dock 40 and also supports a table having a table top 43 and a table side 49 . the table side 49 can include a plurality of hooks including a towel hook 44 , a fork hook , and a tongs hook 45 . the towel hook 44 can hold a towel 46 suspended from the towel hook 44 . the fork hook can hold a fork 48 suspended from the fork hook . the tongs hook 45 can hold a pair of tongs 47 suspended from the tongs hook 45 . the tabletop 43 can be rigidly or swivel mounted to the base post 36 so as to be adjustable in position for allowing a swiveling of the tabletop 43 and optionally a swiveling of the tablet dock 40 . the tablet dock 40 can be connected , or independent of the table top 43 . optionally , the table is connected to the base post 36 by a table arm extension 58 the table arm extension 58 can be telescopically mounted or swivel mounted to provide an adjustable configuration . the base post 36 can have a wide bottom portion that terminates as a base footing 38 to provide stability . the base footing 38 can be weighted to provide stability by a metal , or sandbag or water bag weight for example . a canopy shade 26 and / or a fan assembly 20 can be attached to the extension arm 31 . the canopy shade 26 can be at least partially photovoltaic to provide an electrical charging source for the tablet computer 88 . direct current can be passed from the canopy shade 26 through an electrical cable down to the tablet connector base 42 and optionally mediated by a battery or charge controller . the electrical cable can supply a direct current voltage and provide the tablet 88 with electrical charging through the tablet connector base 42 . the tablet connector base 42 can be made as an electrical connector , or can have an electrical connector that connects the tablet 88 to an electrical cable . the electrical cable can be part of an electrical cable harness that connects to speakers 59 for playing sound files from the tablet 88 . the electrical cable harness can fit inside the base post 36 , upper post 33 and an extension arm 31 when the base post 36 , upper post 33 and the extension on 31 are made as hollow members . the electrical harness can also have an alternating current ac plug for connecting to household current . the canopy shade 26 can be formed as a rectangular member , which can also shade a fan assembly that is underneath the canopy shade 26 . the canopy shade 26 can include a flexible photovoltaic panel mounted on an upper surface of the canopy shade 26 that conforms to a curve of the canopy shade 26 . the canopy shade 26 can be made in other shapes such as an umbrella shape . spray mist tubing 24 can emit a mist through mist nozzles or small openings formed on the spray mist tubing 24 . the spray mist tubing 24 can be pressurized using garden hose pressure and controlled by a misting valve having a valve handle such as when a garden hose is connected to the spray mist tubing 24 such as at a threaded garden hose adapter socket that is configured to receive a garden hose thread . alternatively or in conjunction with regular garden hose pressure , ac current can provide power for a water pump that pumps water through a spray tubing 24 to provide spray mist 25 . spray tubing 24 can have spray tubing openings 27 that direct spray mist or water on or near a user for providing evaporative cooling on a hot dry day . spray tubing 24 can be disposed around a fan housing 21 such as on a circumferential periphery of the fan housing 21 as seen in fig1 . the fan housing 21 is preferably a wire grille housing and can be made in a circular configuration to match a circular oriented fan . the fan can have four fan blades 22 that rotate within the fan housing 21 to direct spray mist 25 toward a user when a user is operating a barbecue grill 50 on a hot and dry day . the present invention could work with a variety of different outdoor cooking devices such as a barbecue grill 50 , smoker or the like . the fan assembly 20 includes a fan mounted within a fan housing 21 . the fan assembly 20 is mounted on the extension on 31 and the spray tubing 24 that sprays water can pass through a hollow portion of the extension arm 31 . the spray tubing 24 can be also be externally mounted to the fan housing 21 . the fan assembly 20 optionally includes an led light 23 that provides a light during dusk hours of barbecue grill 50 operation . the barbecue grill 50 preferably includes a cooking surface 53 mounted on a grill frame 51 . the grill frame 51 also preferably includes a flame control knob 54 mounted on the grill frame 51 . below the flame control knob 54 , a storage cabinet 55 can store a propane tank . the barbecue grill 50 also has wheels 56 for ease of adjustment . a heat sensor 89 can provide a wired or wireless signal to the tablet 88 so that the tablet optionally has a remote sensor capability to provide barbecue cooking programs on a screen of the tablet 88 . the heat sensor 89 can also be mounted on the grill cover 52 and can be powered by means such as a thermoelectric peltier module instead of a battery . when the canopy shade 26 is formed as a rectangular sheet as seen in fig2 , an axial or radial fan can be disposed internally within the extension arm 31 to provide a flow of air toward a user . alternatively , the fan can be external to the extension arm 31 . for example , the canopy shade can have a slot opening along the extension arm 31 where the slot opening provides an air outlet for air that is driven toward the user by the fan . alternatively , the canopy shade can provide the spray mist 25 without forced air from the fan . the spray mist 25 provides an evaporative environmental cooling for a user such as a user standing in front of the barbecue grill 50 as shown in fig2 . an edge of the extension on 31 can attach to an edge of the canopy shade 26 . a program on the tablet 88 can activate the rotation of the fan blades 22 , provide the activation of the light 23 , provide the activation of water passing through the spray tubing 24 and provide an indicator based upon an output of a heat sensor 89 . the tablet 88 has a cpu that can monitor the status of the fan , light , photovoltaic charging , and water delivery through the spray tubing while having a programmed cooking schedule based upon heat sensor 89 . thus , the tablet 88 provides an environmental control for both a user and cooking device . a power supply cord 83 can provide ac power . the barbecue grill cover 29 can have a linearly oriented upper edge that aligns with a linearly oriented lower edge of the fan assembly 20 . the barbecue grill 50 , or the portable barbecue grill 28 can have an air intake 61 for receiving air , an air exhaust 62 for blowing air up . the barbecue grill can also have an air canopy 63 at the air intake 61 for funneling the air through the fan assembly 20 like a range hood . the fan assembly 20 can be formed as a range hood . the fan on the range hood can reverse so that it blows up for exhausting smoke or blows down such as in the fourth figure two allow evaporative cooling .

a tablet docking station comprising a tablet dock configured for receiving a tablet , an upper post extending from the tablet dock , and an extension arm extending from the upper post . the spray tubing can be mounted to the extension arm . the spray tubing provides a water mist for cooling a user when the spray is activated . the tablet docking station optionally includes a fan assembly including a fan housing . the spray tubing has one or more spray outlets configured to provide a water mist for evaporative cooling of an area near a user . the tablet docking station may provide an electronic control for the fan assembly providing a fan control speed adjustable by a graphical use interface on the tablet .

the present invention is based on transmitting ultrasonic ( us ) waves through a guided jet of liquid , such as distilled water , targeted to a bone or other tissue or a combination thereof ( hereinafter — bone ), in order to determine the internal structure along a path in the direction of the impinging jet . the echoes of the us waves are used to determine changes in the acoustical impedance of the bone characterizing changes in the internal structure , and determine their location along that path . in one preferred embodiment , according to the present invention , the device is incorporated in a drill or other penetrating medical device , so as to provide the surgeon with information on the path along which the tool is penetrating the bone , and specifically distances to structural changes in the bone , thereby preventing or greatly reducing the risk of inflicting damage to vulnerable tissue . however , the present invention is not limited to such incorporation , and a basic device , in accordance with some preferred embodiments of the present invention , would include only the provision of us transducer for provision of us waves carried by a liquid jet towards the surface of the bone , and for detecting echoes reflected from structural changes within the bone along a path in front of the impinging jet . the measurement provided by the present invention is based on us wave propagation through a material . when there is a change in the velocity of propagation ( i . e . a change in the acoustic impedance ), reflections are obtained . these echoes are detected and provide finally electronic signals , which are finally interpreted as distances ( given the velocity of propagation through the examined medium is known from these us measurements ) where the reflections appeared . it is known that the velocity of propagation of us waves through the bone varies . it is different for the upper and lower jaws . it is also different between males and females . it may vary with age . it also varies in different locations within the bone . in order to overcome this and take it into consideration in the measurement several methods may be incorporated . these include , for example , measuring the time intervals between the transmitted pulses and the received echoes , and at the same time measuring the velocity of propagation in the bone . accordingly , in order to properly conduct a distance measurement , it is important to measure simultaneously both the time between the transmitted and received waves as well as the velocity of propagation at the desired depth . the us waves are transmitted through the jet of liquid , which is directed toward the bottom part of the bore produced by the drill , and into the bone under the bottom of the bore . abrupt changes in the acoustic properties of the matter traversed by the us waves produce us echoes ( reflections ). fig1 illustrates in principle how this property of us waves is put to use in the present invention . power signals 32 are sent from power 33 circuits to us transducer 68 . the control electronics 31 controls the power circuits 33 . in the following case , us transducer 68 transmits us waves 34 through soft layers 26 and through a bone 22 . us waves 34 encounter nerve canal 20 ( containing nerve 24 ), which generates a distinct ( mirror like ) reflection 36 . when reflection 36 returns from canal 20 via bone 22 and soft layers 26 , a similar ( attenuated ) reflection is obtained , but with an opposite polarity . reflection 36 is received by us transducer 68 , which passes data signals 38 back to signal processing unit 37 , which calculates ( by means of a software ) the distance to the cause of the reflection and presents the results to the surgeon , typically as text or graphic output 39 . in a preferred embodiment of the present invention it is possible to preprogram the us examination of the patient with a typical us wave duration of 1 μsec or less , comprising sinusoidal waveforms that are typically in a frequency range of 10 to 20 mhz and with every wave lasting a fraction of a period to several periods . these are sample specifications and they can vary according to the application . they are presented here for illustrative purposes and do not limit the scope of the present invention . fig2 a illustrates a us transducer integrated into a liquid jet in a interactive ultrasound - based depth measurement device 81 in accordance with a preferred embodiment of the present invention . us transducer 68 is located in vessel 67 through which liquid 52 ( usually distilled water ) flows . liquid 52 starts in main reservoir 50 and is pumped by pump 54 , when tap 56 is open , through pipe 58 to front reservoir 62 . liquid output from front reservoir 62 passes out of funnel and tube 72 ( typically with a diameter in the range of 1 mm to 2 . 5 mm ) and flows against the adjacent tissue or directly on the bone . the pump is preferably a pump that delivers constant mass flow rate , due to medical considerations , but this is not a requirement of the ultrasonic measuring system , hence the present invention is not limited to such pump . an example of such pump is osseocare ™ drilling equipment from nobel biocare ab , sweden and which also includes a torque limiter in order to avoid the mechanical overloading of the bone tissue . us transducer 68 is connected electrically 64 to electronic circuitry , such as a control unit , a power unit , a signal processing unit , an output unit , and sub - units of the transducer . us transmit and receive signals 70 from / to us transducer 68 follow the path 74 of liquid 52 . it should be noted that what is germane to the present invention is that the us transducer be located such that the wave that it transmits and reflection that it receives pass through the liquid jet , such that the jet provides the medium between the transducer and adjacent tissue or bone . several mechanisms for providing a liquid jet are known . which specific mechanism is used to generate the liquid jet for the present invention can vary and is not essential to the invention as long as the transducer of the present invention is situated such that it transmits and receives via the jet to the adjacent tissue or bone . in a preferred embodiment of the present invention , the liquid jet is adapted to serve both for the regular operation of a dental drill ( cooling the bone and the drill and cleaning the bore from the drilled materials ) and for operation of the interactive ultrasound - based depth measurement of the present invention . fig2 b illustrates an interactive ultrasound - based depth measurement device 81 in accordance with another preferred embodiment of the present invention , wherein front - end electronics 76 are located close to us transducer 68 in order to reduce signal loss and therefore increase the signal - to - noise ratio ( s / n ). front - end electronics 76 contains parts of the electronic circuitry , such as a pre - amplifier and parts of the signal processing unit . fig3 a illustrates an interactive ultrasound - based depth measurement device 81 integrated with a surgical dental drill 84 in accordance with a preferred embodiment of the present invention . drill 84 is a standard dental drill , typically comprising power cable 80 , which supplies voltage to the electrical motor 82 , which turns shaft 84 , which is geared to turn drill bit 88 ( which is locked in place with drill lock 90 ). the jet is directed along side the drill 88 , aimed at the tip of the drill , or a target just in front of the tip , having a certain angle defined between the jet and the drill . fig3 b depicts a tip of a dental drill similar to the one shown in fig3 a , but the liquid jet in this tip passes through the drill , via a duct provided along the drill . the actual distance measurement using the device of the present invention may be carried out while the drill is in use ( such as in the case of the embodiment shown in fig3 b , where the jet passes through the drill ), or when the drill is inactivated , or even retracted from the bore that was drilled , while at the same time directing the jet into that bore . when the jet is along side the drill , and defining a small angle with the drill , it may be practical to withdraw the drill from the drilled bore and direct the jet substantially perpendicular to the bottom of the bore for best results . interactive ultrasound - based depth measurement device comprises the components described earlier in this specification with several components adapted for integration with drill 84 . these include : additional section of flexible pipe 53 running from funnel and tube 72 to metal tube 55 , which exits drill 84 at a point next to drill bit 88 , thereby creating egress next to drill bit 88 for liquid carrying transmitted us waves . the liquid serves both its normal function of cleaning and cooling the bore of the drill and its new function ( as provided by the present invention ) of acting as a medium for transmission of the us waves . ( in the embodiment shown in fig3 a or the one shown in fig3 b , front - end electronics 76 are installed to reduce signal loss ( and therefore increases the s / n ), as in fig2 b . alternatively , all depth measurement device 81 electronics can be implemented at the back end , connected to us transducer via electrical connection 64 .) with reference to fig1 and to fig3 a and 3 b , during the drilling process , control unit 31 triggers ( automatically or manually ) transmission of us waves 34 by transducer 68 . us wave reflections received back from different density tissues by transducer 68 are passed via link 64 to processing unit 37 , which calculates the distance from the bottom of the drilled bore in the mandible to the upper part of the canal 20 ( that has a mirror - like reflection ) and which contains the nerve and outputs the results to output unit 39 where the surgeon can view them . typically this output is provided to the surgeon displayed on an alphanumeric or graphical display . fig4 illustrates how us waves propagate through the jet of liquid in a dental drill integrated with an interactive ultrasound - based depth measurement device in accordance with a preferred embodiment of the present invention . jet of liquid 52 flowing into bore 94 in bone 22 serves as medium for transmission 34 of us waves into bone 22 and reception of us reflections 36 from nerve canal 20 . in the case of the mandible , the depth is measured in real time between the bottom of bore 94 and the upper part of nerve canal 20 . the depth measurement results are preferably displayed as alphanumeric information , providing the surgeon with an accurate indication of the distance ( depth ) between the lower part of drilled bore 94 and the upper edge of the sensitive tissue , such as nerve canal 20 , that must be avoided with the drill . alternative displays are also possible ( for example graphic representation of the distance ). fig5 illustrates a detailed block diagram of a circuitry for a dental drill with an interactive ultrasound - based depth measurement device in accordance with a preferred embodiment of the present invention . this block diagram operates in an analog 200 mode , and others — which operate in a digital 300 mode . these circuits provide improved noise filtering and signal amplification of transmission of us waves and reception of us wave reflections . the timing of the amplified signals is measured , and assuming known propagation velocity of the ultrasound pulses through bone , the distance from the bottom of the drill bore to the nerve canal is measured and displayed , as described above . power is supplied from power supply 100 to transmitter 104 , which receives signal from signal generator 102 . transmitter 104 transmits us wave and activates the electronic switch 106 , which activates receiver preamplifier and amplifier 110 , which receives reflection of wave from different density tissue and time - gain compensation 108 . analog signal is converted 112 to digital and after time - gain compensation 114 is filtered 116 , compressed 118 , and stitched and offset 120 . calculated time of reflection return is converted to depth measurement 122 and the result is output to display 124 . in a preferred embodiment of the present invention , depth measurement using the present invention can be performed in real time while the drilling is in process or in steps : drilling for a short distance ( depth ), typically 1 mm to 2 mm and then measuring the distance between the bottom of the drilled bore and the upper edge of the nerve canal before proceeding . in another preferred embodiment of the present invention , the measurement method can be applied for side measurements ( for example , through the gums ). one use of this application is identifying the three - dimensional location of the nerve canal ( rather than just the linear direction to it ). in another preferred embodiment of the present invention , depth measurement can be applied for other medical applications involving drilling , such as bone implantation , to avoid drilling injury to nerves or blood vessels beneath the drill . in another preferred embodiment of the present invention , depth measurement can be applied for veterinary medical applications . in another preferred embodiment of the present invention , it is possible to store the above - mentioned depth measurement on magnetic or other media — for further analysis , comparison , and documentation . in another preferred embodiment of the present invention , it is possible to incorporate software to control the data transmission to the signal - processing unit and to enable configuring parameters of the invention , for example , to customize the device for pediatric patients . it should be clear that the description of the embodiments and attached figures set forth in this specification serves only for a better understanding of the invention , without limiting its scope as covered by the following claims . it should also be clear that a person skilled in the art , after reading the present specification could make adjustments or amendments to the attached figures and above described embodiments that would still be covered by the following claims .

a device for determining the internal structure of a bone along a path directed into the bone is disclosed . the device comprises a nozzle fluidically connected to a liquid reservoir for providing a liquid jet directed at the bone in the direction of the path ; an ultrasonic transducer for generating ultrasonic waves through the liquid jet and for detecting echoes of the ultrasonic waves caused by changes in the acoustical impedance in the bone characterizing changes in the structure of the bone along the path ; and an analyzer for interpreting the echoes into meaningful information relating to the location of the structural changes along the path .

in this detailed description and the appended claims , terms such as left , right , bottom and top refer to the figure where the reference is first introduced . the exception to the terminology is made when referring to an infant &# 39 ; s left arm and right arm ; where the usual meaning applies . the term swaddling cloth refers to any blanket , cloth or other garment that is used for swaddling an infant . the terms front and back refer to the front and back of the swaddling accessory when the infant is lying on the swaddling accessory . the term hook component and loop component refer to components of a hook and loop pair of removable attachment means such as , but not limited to velcro brand hook and loop fasteners . two hook and loop pairs may have share a single component . the same numeral is used to refer to a specific item in different figures if it refers to the same physical item , independent of the figure &# 39 ; s view . the term flexible material refers to a cloth or other fabric or material suitable for use in swaddling an infant . fig1 a and 1b refer to a first embodiment 100 of the present invention . fig1 a illustrates a front view of the first embodiment 100 , looking at it from the front while it is positioned on a surface such as a floor or bed . first embodiment 100 is comprised of an elongate piece of an elongate flexible material 102 having a left wing 110 l and a right wing 110 r . the elongate flexible material 102 has one piece of center loop component 104 lc and two pieces of hook component , left hook component 104 hl and right hook component 104 hr attached to the back of the elongate flexible material 102 ; and one piece of left loop component 104 ll attached to the front of the elongate flexible material 102 . the center loop component 104 lc is positioned on the back of the elongate flexible material 102 centered on the elongate flexible material 102 so it is bisected by the vertical axis 100 v . the left loop component 104 ll is positioned on the front of the elongate flexible material 102 on the left side towards the left end 108 l : the right hook component 104 hr is positioned on the front of the elongate flexible material 102 on the right side towards the right end 108 r . the left hook component 104 hl is positioned on the back of the elongate flexible material 102 on the left side towards the left end 108 l . all the hook and loop components , center loop component 104 lc , left hook component , 104 hl , right hook component 104 hr , and left loop component 104 ll are positioned centered on the horizontal axis 100 h located midway between the top and bottom of the elongate flexible material 102 . fig1 b shows the back of first embodiment 100 . the same numerals used in fig1 a apply to fig1 b . fig2 a through 2c illustrate an overview of the steps involved in wrapping the first embodiment of the present invention on an infant while fig3 a and 3b give a cross section view of first embodiment 100 when wrapped on a moderately sized infant and a small infant respectively . referring to fig2 a , the first step is to place the elongate flexible material 102 on a flat horizontal surface such as a floor or a bed with the front of the elongate flexible material 102 facing upward and the cloth extended with the horizontal axis 100 h going from left to right . the infant 100 b is then placed on elongate flexible material 102 facing front with the infant &# 39 ; s back lying on elongate flexible material 102 . the infant is positioned so the bottom edge of the elongate flexible material 102 is just above the infant &# 39 ; s wrist and the infant is centered on the elongate flexible material 102 . fig2 b shows the second step . the left wing 110 l of elongate flexible material 102 is placed between the torso 100 bt of the infant and the right arm 100 br and then extended over the right arm 100 br toward the left . the right wing 110 r of elongate flexible material 102 is placed between the torso 100 bt of the infant and left arm 100 bl , then extended over the left arm 100 bl , and extended to the right . the third step , also discussed later with reference to fig3 a and 3b , is performed as follows : the left wing 110 l is then placed to the back of elongate flexible material 102 ; the right wing 110 r is then placed to the back of elongate flexible material 102 ; and the two wings 110 r and 110 l are secured to the back of elongate flexible material 102 so that that the left arm 102 bl and right arm 102 br are secured snugly . fig2 c illustrates a front view of first embodiment 100 when wrapped on the infant with the arms snugly secured at the sides of the torso 100 bt . the specific details illustrating how first embodiment 100 secures the infant &# 39 ; s arms are illustrated in the cross section views of fig3 a and 3b . fig3 a and 3b show two methods for securing first embodiment 100 on the infant . both fig3 a and 3b are cross section of fig2 c . fig3 a illustrates how first embodiment 100 is wrapped on a moderate sized infant while fig3 b shows how first embodiment 100 is wrapped on a small infant . refer now to fig3 a . with the infant &# 39 ; s back lying on the front side of first embodiment 100 , the left wing 110 l of first embodiment 100 is threaded between the right arm 100 br of the infant and torso 100 bt , then around the front of the right arm 100 br of the infant and then under the infant . the left end 108 l is then pulled firmly to the right under the infant &# 39 ; s back so the right arm 100 br of the infant is held snugly . the left hook component 104 hl is then attached to the left side of the center loop component 104 lc . this secures the infant &# 39 ; s right arm . the left arm 100 bl of the infant is secured similarly . the right wing 110 r of first embodiment 100 is threaded between the left arm 100 bl of the infant and torso 100 bt , then around the front of the left arm 100 bl of the infant and then under the infant . the right end 108 r is pulled firmly to the left under the infant &# 39 ; s back so the left arm 100 bl of the infant is held snugly . the right hook component 1041 - 1 r is then attached to the right side of the center loop component 104 lc . this secures the infant &# 39 ; s left arm . fig3 b illustrates how first embodiment 100 is attached to an infant that is smaller then the infant illustrated in fig3 a . the left wing 110 l of first embodiment 100 is wrapped around the infant &# 39 ; s right arm in the same manner as described for fig3 a . the right wing of first embodiment 100 is also wrapped around the infant &# 39 ; s left arm as described for fig3 a , but with one difference . the right hook component 104 hr is attached to the left loop component 104 ll . this secures both of the infant &# 39 ; s arms . it is therefore seen that first embodiment 100 can accommodate the infant as she grows in size . fig3 b accommodates a small infant while fig3 a accommodates a larger infant . fig4 a and 4b illustrate a second embodiment 200 of the present invention . fig4 a has the same design as fig1 a with the following wing differences . second embodiment 200 is divided into two wings vertically , separating them into approximately two halves , a left wing 110 l and a right wing 110 r . the left wing 110 l has a left side hook component 204 hl attached to the back near the edge 202 l ; and the right wing 1108 has right side loop component 204 lr attached to the front of the right wing 110 r near the edge 202 r . the center loop component 104 lc of first embodiment 100 is replaced by two loop components 206 ll and 206 lr . fig4 b is a cross section of second embodiment 200 as illustrated in fig2 c . the left wing 110 l and right wing 110 r are joined with the right side hook component 204 hr attached to the left side loop component 204 ll . once these two wings are attached , securing the infant with embodiment two is done in the same manner as embodiment one . the primary advantage of embodiment two is that after the appropriate sizing is done once , the two wings can stay attached and both arms can easily be secured in subsequent uses of this embodiment without having to reach behind and / or around the infant as compared to the first embodiment . fig5 a through 5d illustrate the use of first embodiment 100 together with an infant blanket 112 used as a swaddling cloth . fig5 a indicated first embodiment 100 , positioned diagonally on a flat horizontal surface . fig5 b indicates the top corner 114 of the infant blanket folded down . fig5 c indicated laying the infant 100 b on the infant blanket 112 , the top crease 116 of the blanket level with the infant &# 39 ; s neck , with first embodiment 100 already secured on the infant . fig5 d indicates the infant blanket 112 wrapped around the infant 100 b , the wrapping done in the usual manner . fig6 a through 6c illustrate a third embodiment 300 of the present invention . referring to fig6 a , third embodiment 300 modifies first embodiment 100 by having a piece of additional right hook component 302 hr positioned on the right side of the front of first embodiment 100 . third embodiment 300 permits the swaddling cloth to be used in the same way as first embodiment 100 . however , it also allows third embodiment 300 to be used as a one - arm swaddling cloth . fig6 b illustrates a sectional view of third embodiment 300 as it is used as a swaddling accessory securing only one arm . third embodiment 300 swaddles an infant torso bt and left arm 100 bl of infant while keeping the right arm 100 br free . fig6 c illustrates third embodiment 300 as used with an infant . as illustrated in fig6 b , additional right hook component 302 hr engages left loop component 104 ll in a manner that keeps left arm 100 bl of the infant free . the location and configuration of the components of third embodiment 300 are determined so that third embodiment 300 functions as indicated . the one arm swaddle of third embodiment 300 assists parents with weaning their infant off the swaddle blanket . one - arm swaddling is a fairly typical approach to this transition . the challenge with this is similar to the challenge with swaddling in general ; babies often work their way out of them . parents are highly motivated to keep their infant &# 39 ; s arms secured for as long as they can because of the “ startle - reflex ” which is a known term to depict the infant &# 39 ; s inability to control their arms from moving around while they sleep which often wakes them up . therefore many want to swaddle as long as is practical and when they are ready to transition out of swaddling , they often attempt to do this one arm at a time . third embodiment 300 will assist with this . the three embodiments are dimensioned and configured so they functions as described . the actual dimensions of the swaddling accessory are a design option . typical dimensions for the first embodiment are 15 cm ( 6 in ) height and 70 cm ( 23 . 5 ) length ; however , these dimensions can vary , depending on the size of the infant using the swaddling accessory . the shape of the swaddling accessory can also vary as long as it functions as described herein . other removable attaching mechanisms may be used instead of the hook and loop means such as buckles or snaps . a knitted fabric of the swaddling accessory works well when also used as the material for a companion swaddling cloth ; however , other fabrics may also be used . several different sizes of swaddling accessories may be used to accommodate the infant from birth until a swaddling accessory is no longer used . the swaddling accessory can also be used in certain situations without a swaddling cloth ; for example in a doctor &# 39 ; s office to secure the infant &# 39 ; s arms during an exam . the elongate flexible material my be made from on or more pieces of material that are attached together by attachment means such as gluing , or stitching . the disclosure presented herein describes three embodiments of the invention . these embodiments are to be considered as only illustrative of the invention and not a limitation of the scope of the invention . various permutations , combinations , variations , and extensions of these embodiments are considered to fall within the scope of this invention . therefore , the scope of this invention should be determined with reference to the claims and not just by the embodiments presented herein .

a swaddling accessory comprised of elongate flexible material divided into a left wing and a right wing , the elongate flexible material having attached hook and loop components . the swaddling accessory secures the babies arms by : placing the infant on the swaddling accessory ; weaving the left wing between the right arm and the torso , then passing the left wing around the right arm ; repeating a similar weaving with the left arm and the right wing ; and then securing the left wing and right wing at the back of the infant with hook and loop fasteners installed on the elongate flexible material . the swaddling accessory may be used with a swaddling cloth . several embodiments and variations are presented , including an embodiment with a capability of securing either one arm or two arms , and an embodiment constructed out of two removably attachable pieces of flexible material .

the present invention allows to overcome the above said problem thanks to the compounds of formula ( i ) as above defined . according to the present invention zn ( ii )- phthalocyanines are preferred wherein r is as previously defined , and r 1 is represented by the group ( x ) p r 2 , previously defined . according to the invention , the definition “ suitable linker ” it is intended in the sense commonly given to this definition in the field of protein and nucleic acid modification ( s . s . wang , chemistry of protein conjugation and cross - linking crc press , inc . 1993 , g . t . hermanson bioconjugate techniques academic press , 1996 ) i . e . an aliphatic or aromatic moiety which act as a spacer between the phthalocyanine nucleus and the biological macromolecules , in order to satisfy wanted sterical and / or structural requirements . by saturated or unsaturated heterocycle possibly substituted , as defined in the above general formula , the following are preferably meant : morpholine , piperidine , pyridine , pyrimidine , piperazine , pyrrolidine , pyrroline , imidazole , aniline , and julolidine ( 2 , 3 , 6 , 7 - tetrahydro - 1h , 5h - pyrido [ 3 , 2 , 1 - ij ] quinoline ). according to the invention , the preferred products are those in which the group ( x ) p r 2 contains substituents bearing tertiary or quaternary nitrogen . in particular , the said group ( x ) p r 2 is preferably represented by : the compound in the present invention can be prepared in homogeneous as well heterogeneous phase , according to synthesis known in organic chemistry ( and also described in the above cited patent ) as well as by using the sub - phthalocyanine route . cationic phthalocyanines of formula ( i ) can be prepared by reacting the corresponding neutral compounds previously described , with an excess of alkyl iodide , with or without organic solvents , at temperature comprised between room temperature and reflux , for a time comprised between 1 h and 200 h . pharmaceutically acceptable salts of the phthalocyanine compounds of the present invention , bearing basic substituents , include conventional acid addition salts , obtained by the addition of hcl , h 3 po 4 , h 2 so 4 , hbr , etc . additionally , salts obtained by reaction from the carboxylic function or acid groups within the phthalocyanine ring are within the scope of the present invention . such salts include , for example , salts of carboxylic and sulfonic acid with amine derivatives , basic amino acids and inorganic bases . the present compounds possess both value as pdt agents themselves and also allows for their binding to carrier structures able to recognize biological targets involved in diseases , thus for the preparation of target specific derivatives . the compounds having formula ( i ) have utility as pdt dyes for treatment of infectious diseases of viral , fungal and bacterial origin , for use in cancer therapy and for dermatological diseases , moreover they may have applications as diagnostic aid in localizing pathologically affected areas . by conventional chemistry , the mono - carboxy phthalocyanines are convertible to a wide range of aliphatic and aromatic esters or amides , bearing one or more substituents on the alkyl or aromatic groups . derivatives include esters , amides , amino acids , peptides , proteins ( in particular antibodies ), sugars , aptamers , sulfonic acid esters , etc . phthalocyanines polyhydroxylated derivatives , such as glycosides compounds containing mono or polysaccharides , are of great utility as pdt agents , since the resultant derivatives are hydrophilic in contrast to the more hydrophobic phthalocyanines lacking such substituents . as hydrophobic and hydrophilic phthalocyanines concentrate selectively at different sites in a cellular environment , they may have useful applications . by conventional chemistry the amino phthalocyanines are converted to alkyl , alicyclic , arilalkyl or aromatic secondary and tertiary amines or to amides . the primary amino substituent may also be converted to a diazonium salt and , by subsequent displacement reactions , halo and related derivatives are obtained . the amino group of mono amino substituted phthalocyanine also facilitates easy linkage of the phthalocyanine ring to peptides and proteins with the accompanying transport and binding benefits described above . of particular interest are the phthalocyanine derivatives in which amino groups not involved in the linkage with the carrier are further converted to quaternary ammonium salts with various alkylating agents , since for these compound selective activity against gram −/+ or yeasts micro - organism have been found . by using solid phase organic synthesis strategies , it is possible to bind the phthalocyanine moiety to a pre - assembled side chain protected polypeptide or polynucleotide attached to a solid phase , allowing for a specific binding of phthalocyanine to the n - terminal of peptide or nucleotide with no disturbance to its structure , thus improving the overall recognition of the target . as it can be seen from formula ( i ), the phthalocyanine derivatives object of this invention are aromatic compounds exhibiting improved absorption and singlet oxygen photosensitization characteristics . these compounds contain substituents able to improve their photosensitizing properties and / or to cause a red shift in their light absorption , while retaining the photodynamic characteristics . these compounds have a side chain capable of attachment to predetermined functional groups , which serves as an handle for attachment to protein or to others carriers which may recognize a specific target on a biological structure . either the substituents introduced or the conjugation of the phthalocyanines with proteins may accelerate metabolism of the phthalocyanine moiety by interaction with light , thus destroying in vivo the light absorbing chromophore , in order to generate non - photoactivatable metabolites which are photochemically innocuous and thus unable to cause post - pdt phototoxicity . for example , the presence of hydrophilic substituents and the conjugation is able to accelerate the elimination of those molecules that have not reached the in vivo target . the absorbing chromophore can be eliminated in vivo , thus avoiding the insurgence of delayed cutaneous or systemic toxicity , generating not - photoactivatable , not toxic photodecomposition products . derivatives such as quaternary ammonium salts or sulphonate salts are also important , since cationic and anionic dyes are able to concentrate in different areas of cells . phthalocyanines covalently bound through peptide linkages to peptides or proteins provide pdt agents with valuable specific transport and selective binding characteristics . compounds of the present invention are therefore superior to simple derivatized phthalocyanines , with regard to rapid clearance from the body after administration . they are also superior with regards to the toxicity after conjugation to specific carriers , because of the minor dosage due to the specific localization in the ill area . a major improvement of the molecules object of the present invention is the red shifted absorption they have . red light of wavelength higher than 670 nm is very much suitable for safe treatment of various diseases . since light of wavelength lower than 650 nm loses most of its energy after penetrating into human tissues , higher wavelengths are more appropriate than short - penetrating lower wavelengths for dye activation , in applications such as tumours and infectious diseases not superficially located . the conjugation to macromolecules provides a way to further increase the maximum wavelength absorbance . compounds which can be used for conjugation with the phthalocyanines according to the invention are for example : amino acids , peptides , proteins , antibodies , glycosides , aptamers ; for example : avidine , concanavalin a , succinil concanavalin a , monoclonal and recombinant antibodies or fragments thereof etc . further , since the transport , mobility , binding to cell receptors is matter related to chemical structure and , in particular , to the hydrophilic or hydrophobic character of the dye , it is clearly beneficial to have an available primary chemical structure which can be subject to extensive chemical structural manipulation . when the compound contains a linked amino acid , a peptide or a protein , they are generally bonded to the compounds by means of an amide , thioether , disulfide or an ester linkage . for example , an amino acid may be bound through a carboxyl group on the phthalocyanine , by means of the alpha - amino or other amino group present in the amino acid to form an amide linkage , or the amino group on the phthalocyanine can be bound to the carboxyl group present on the amino acid . suitable amino acids include the 20 naturally occurring amino acids in both the r and s forms , as well as non naturally occurring synthetic amino acids . peptides may be similarly bound to the ring structure of phthalocyanine and generally contain 2 – 20 amino acids , although a complete protein ( especially the ones showing specificity for a target ) may be used as carriers . the phthalocyanine may be linked to proteins by the above mentioned carboxyl or amino groups or by using other specific functional groups as thiols , maleimide derivatives , alpha bromo esters and amides , diazonium salts and azide derivatives . in the phthalocyanine glycosides derivatives , the sugar moiety , which may consists of a single sugar , either in the open or cyclic form , an oligosaccharide or a polysaccharide , may be attached to the phthalocyanine ring system by means of a conventional glycoside bond . any of the common monosaccharide sugars and oligosaccharides thereof may be used to prepare the phthalocyanine glycosides of the present invention . by using closely related conventional chemistry , conjugates constituted by the phthalocyanine derivatives described and aptamers can be prepared . all of the many possible derivatives embrace the intact macrocyclic phtalocyanine chromophore and all are capable of generating singlet oxygen or radicals under appropriate irradiation conditions , each constituting therefore a prospective photoactivatable dye for use in pdt . using the above described procedure , the following products were obtained ; in particular in examples 1 – 15 amino reactive compounds ( i . e . compounds wherein r is a group capable of reacting with an amino - group ) are described , in example 16 , r is a group capable of reacting with tyr and his , in examples 17 – 19 biotine functionalised derivative are described , in examples 20 – 21 r , is a group capable of reacting with a thiol - group and in example 23 , r is a group capable of reacting with a carbohydrate . in example 23 , r is a group capable of forming ester linkages with carboxyl groups . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]-{[ 9 , 10 ][ 16 , 17 ][ 23 , 24 ]- tribenzo } zinc ( ii ) phthalo cyanine . c 51 h 26 n 8 o 3 zn ; green - blue solid ; uv - vis ( dmf ) λ max 746 , 725 , 339 ; esi - ms , m / z 863 [ m + h ] + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 ( 10 ), 16 ( 17 ), 23 ( 24 )- tri [ 2 -( morfolin - 1 - yl ) ethoxy ] zinc ( ii ) phthalocyanine . c 57 h 53 n 11 o 9 zn ; green - blue solid ; uv - vis ( dmf ) λ max 678 , 611 , 358 , 276 ; 1 h - nmr ( dmsod 6 ), δ 9 . 5 – 9 . 3 ( m , 1h ), 9 . 3 – 9 . 0 ( m , 4h ), 9 . 0 – 8 . 8 ( m , 3h ), 8 . 2 – 8 . 0 ( m , 2h ), 7 . 8 – 7 . 6 ( m , 4h ), 7 . 5 – 7 . 3 ( m , 2h ), 4 . 8 – 4 . 5 ( m , 6h ), 3 . 85 – 3 . 65 ( m , 12h ), 3 . 1 – 2 . 9 ( m , 6h ), 2 . 8 – 2 . 6 ( m , 12h ); esi - ms m / z 1100 . 6 [ m + h ] + , 987 . 6 [ m + c 6 h 13 no ] + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 2 ( 3 ), 9 ( 10 ), 16 ( 17 ), 23 ( 24 )- tri [ 2 -( piperidin - 1 - yl ) ethoxy ] zinc ( ii ) phthalocyanine . c 60 h 59 n 11 o 6 zn ; uv - vis ( dmf ) λ max , ( ε , m − 1 cm − 1 ) 678 ( 1 . 308 × 10 5 ), 612 , 355 ; 1 h nmr ( dmso - d 6 ) δ 9 . 55 – 8 . 60 ( m , 10 h ), 8 . 00 – 7 . 55 ( m , 6 h ), 4 . 95 – 4 . 35 ( m , 6 h ), 3 . 10 – 2 . 80 ( m , 6 h ), 2 . 80 – 2 . 35 ( m , 12 h ), 1 . 85 – 1 . 35 ( m , 18 h ); esi - ms m / z 1094 . 7 [ m + h ] + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 1 ( 4 ), 8 ( 11 ), 15 ( 18 ), 22 ( 25 )- tri [ 2 -( morfolin - 1 - yl ) ethoxy ] zinc ( ii ) phthalocyanine . c 57 h 53 n 11 o 9 zn ; green - blue solid ; uv - vis ( dmf ) λ max 762 , 691 , 623 , 340 , 268 , 259 ; 1 h - nmr ( dmsod 6 ) δ 9 . 5 – 8 . 6 ( m , 4h ), 8 . 3 – 7 . 1 ( m , 12h ), 5 . 2 – 5 . 0 ( m , 2h ), 5 . 0 – 4 . 75 ( m , 4h ), 3 . 75 – 3 . 65 ( m , 8h ), 3 . 65 – 3 . 5 ( m , 4h ), 3 . 3 – 3 . 15 ( m , 2h ), 3 . 0 – 22 . 85 ( m , 8h ), 2 . 8 – 2 . 7 ( m , 4h ); fab - ms m / z 1101 [ m + h ] + , 987 [ m + c 6 h 13 no ] + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 ( 10 ), 16 ( 17 ), 23 ( 24 )- tri [ 3 -( dimethylamino ) phenoxy ] zinc ( ii ) phthalocyanine . c 63 h 47 n 11 o 6 zn ; green - blue solid ; uv - vis ( dmf ) λ max ( ε , m − 1 cm − 1 ) 678 ( 1 . 4680 × 10 5 ), 632 , 611 , 355 ; 1 h nmr ( dmso - d 6 ) δ 9 . 35 – 8 . 90 ( m , 4 h ), 8 . 85 – 8 . 50 ( m , 3 h ), 7 . 95 – 7 . 48 ( m , 7 h ), 7 . 52 – 7 . 25 ( m , 5 h ), 6 . 95 – 6 . 55 ( m , 9 h ), 3 . 10 – 2 . 80 ( m , 18 h ); fab - ms m / z 1118 [ m + h ] + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 8 ( 11 ), 15 ( 18 ), 22 ( 25 ) tri [ 3 -( dimethylamino ) phenoxy ] zinc ( ii ) phthalocyanine . c 63 h 47 n 11 o 6 zn ; green - blue solid ; uv - vis ( dmf ) λ max ( ε , m − 1 cm − 1 ) 689 ( 1 . 5064 × 10 5 ), 620 , 333 ; 1 h nmr ( dmso - d 6 ) δ 9 . 50 – 8 . 70 ( m , 6 h ), 8 . 68 – 7 . 72 ( m , 6h ), 7 . 58 – 6 . 95 ( m , 5h ), 6 . 85 – 6 . 45 ( m , 9 h ), 6 . 40 – 6 . 30 ( m , 2 h ), 3 . 10 – 2 . 79 ( m , 18 h ); fab - ms m / z 1118 [ m + h ] + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 ( 10 ), 16 ( 17 ), 23 ( 24 )- tri [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine triiodide . c 66 h 56 i 3 n 11 o 6 zn ; green - blue solid . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 8 ( 11 ), 15 ( 18 ), 22 ( 25 )- tri [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine triiodide . c 66 h 56 i 3 n 11 o 6 zn ; green - blue solid ; uv - vis ( dmf ) λ max 689 , 620 , 333 ; esi - ms m / z 388 [ m − 31 − ] 3 + . 2 -[( 4 - hydroxycarbonyl ) phenoxy ] zinc ( ii ) phthalocyanine . c 39 h 21 n 8 o 3 zn ; blue solid ; uv - vis ( dmf ) λ max 669 , 606 , 343 ; 1 h nmr ( dmso - d 6 ) δ 9 . 32 – 9 . 14 ( m , 7 h ), 8 . 77 ( broad s , 1 h ), 8 . 26 – 8 . 18 ( m , 8 h ), 7 . 96 – 7 . 90 ( dd , 1 h , j 1 = 8 . 67 hz , j 2 = 1 . 73 hz ), 7 . 53 ( d , 1 h , j = 8 . 59 hz ). 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 , 10 , 16 , 17 , 23 , 24 - esa [ 3 -( dimethylamino ) phenoxy ] zinc ( ii ) phthalocyanine . c 87 h 74 n 14 o 9 zn ; green - blue solid ; fab - ms m / z 1524 [ m + ]. 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 , 10 , 16 , 17 , 23 , 24 - esa [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine esaiodide . c 93 h 92 i 6 n 14 o 9 zn ; green - blue solid . 2 -[( 4 - sulphonate ) phenoxy ]- 9 , 10 , 16 , 17 , 23 , 24 - esa [ 3 -( dimethylamino ) phenoxy ] zinc ( ii ) phthalocyanine . c 86 h 74 n 14 o 10 szn ; green - blue solid ; esi - ms m / z 1562 [( m + h ) + ]. 2 -[( 4 - sulphonate ) phenoxy ]- 9 , 10 , 16 , 17 , 23 , 24 - esa [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine esaiodide . c 92 h 92 i 6 n 14 o 10 szn ; green - blue solid . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 , 10 , 16 , 17 , 23 , 24 - esa [ 2 -( n , n - diethylamino ) ethylthio ] zinc ( ii ) phthalocyanine . c 75 h 98 n 14 o 3 s 6 zn ; green - blue solid . 2 -[( 4 - hydroxycarbonyl ) phenoxy ]- 9 , 10 , 16 , 17 , 23 , 24 - esa [ 2 -( n , n , n - triethylammonium ) ethylthio ] zinc ( ii ) phthalocyan esaiodide . c 81 h 116 i 6 n 14 o 3 s 6 zn ; green - blue solid . 2 -[( 4 - aminobenzamidyl )- phenoxy ]- 8 ( 11 ), 15 ( 18 ), 22 ( 25 )- tri [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine triiodide λ max 668 , 607 , 345 , blue crystals n , n ′- dimethyl - n - 2 -( 4 - oxybenzoyl )- 8 ( 11 ), 15 ( 18 ), 22 ( 25 )- tri [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine n ′- biotinyl - 1 , 2 - diaminoethane triiodide ; λ max 669 , 605 , 344 , deep blue crystals . 2 -[( 4 - hydrazidomethyl )- phenoxy ]- 8 ( 11 ), 15 ( 18 ), 22 ( 25 )- tri [ 3 -( trimethylammonium ) phenoxy ] zinc ( ii ) phthalocyanine triiodide ; λ max 669 , 605 , 344 , blue crystals . 2 -[( 2 - hydroxy ) ethyoxy ] zinc ( ii ) phthalocyanine . c 34 h 20 n 8 o 2 zn , green - blue solid . 12 . 5 and 25 equivalents of the succinimidyl ester of compound according to ex . 9 ( previously prepared by reacting the corresponding asymmetric anhydride with n - hydroxysuccinimido esters ) as dmso solution , are slowly added to 200 μl of a 5 mg / ml solution of bovine serum albumin ( bsa ) in pbs ( ph = 8 . 5 ) maintaining the obtained suspension under gentle stirring at room temperature for 90 minutes . the green - blue conjugation product is purified from the solution by gel filtration ( sephadex g25 ) eluting with pbs ( ph = 7 . 2 ), collecting fractions having a volume of ca . 1 ml . the labelling ratio has been determined spectrophotometrically measuring the protein concentration and the number of moles of the compound of ex . 9 per mole of bsa . in the practiced experimental conditions the labelling ratio resulted comprised between 4 . 2 and 5 . 0 . 100 μl of a 1 . 54 mg / ml solution of the succinimidyl ester of compound of ex . 7 in dmso are added to 2 mg of avidine ( 4 mg / ml in 100 mm pbs ph = 8 . 5 ). the obtained suspension is gently stirred for 12 hours at 4 ° c ., then centrifuged . a purification step is carried out by gel filtration ( sephadex g25 ) eluting with 100 mm pbs ( ph = 8 . 4 ), collecting the coloured fractions , from which the conjugation product is recovered . the labelling ratio , determined as reported in the preceding example . 16 was 7 . 100 μl of a solution of the succinimidyl esther of the compound of ex . 8 , 1 . 5 mg / ml in dmso are slowly added to 2 mg of concanavalin a ( sigma ) solubilized in 0 . 25 ml of 100 mm phosphate biuffer ( ph : 8 ). the obtained suspension is gently stirred for one night at 4 ° c . in the dark . after centrifugation the supernatant is purified by gel filtration on sephadex g25 collecting the fractions showing a characteristic fluorescence . the conjugate has been characterised in terms of moles of phthalocyanine per mole of protein , value turned out to range between 3 and 7 the procedure is as reported for concanavalin a . the ratio was found to range from 3to 5 . monoclonal antibody α - d specific for the repeat d of type iii fn like of human tenascin ( tn ) ( balza et al . febs , 332 , 39 1993 ) has been labelled by using the compound of ex . 4 . the labelling procedure has been carried out with the monoclonal bound to the sepharose 4b immobilised antigen , represented from the recombinant tn containing repeats b , c , d type iii fn - like . the labelling ratio mab / compound of ex . 4 was found to be 1 : 5 . after labelling the binding specificity of the labelled antibody was determined by immunohystochemistry on human fibroblasts ( gm6114 ) and found to be the same of the unlabelled one . compound of ex . 4 and the labelling procedure used does not cause aggregation to occur or protein denaturation as demonstrated by the above immuno hystochemistry experiments and can therefore be used to produce photoactives immunoconjugates . peptides were assembled using fmoc chemistry and various resins suitable for this type of synthesis . the compound of ex . 7 was coupled to the n terminus of the peptide , branched peptides or loligomers by first activating its carboxylic group with 0 . 5 molar equiv . of dicycloexylcarbodiimide in dmf overnight at room temperature or alternatively after having formed a mixed anhydride or a succinimidyl esther . the activated compound ( 5 times molar excess to the n terminal amino groups ) was added to the peptide resin in the dark and left to proceed for 24 h at room temperature . the compound of ex . 7 - peptides were cleaved from the resin , worked up by using the solid phase synthesis standard procedures and desalted by using g10 or g25 according to the need and pbs ph : 7 . 2 . the conjugated were analyzed either by mass spectrometry and by their amino acid composition and found consistent with the expected figures . compound of ex . 12 ( thiol directed phthalocyanine derivative ) was solubilized in dmf and directly added in the dark to a solution of cysteine elongated : peptides , branched peptides and loligomers , in a degassed , nitrogen flushed pbs ph 8 . 1 solutions . the reaction was left to occur for 24 h at room temperature , then the compound of ex . 12 - peptides were desalted by using g10 or g25 according to the need and pbs ph 7 . 2 . the conjugated were analysed either by mass spectrometry and by their amino acid composition and found consistent with the expected figures . the lack of non specific toxicity has been assessed by using human fibroblasts cultured for six days . aliquots of the compound according to ex . 4 at various concentrations have been added to cells in dmem 10 % fcs . after treatment the cell were irradiated for 10 min with red light ( intralux 4000 equipped with filter bp700 / 100chroma technology corp .). in a parallel experiment cells were treated with the same amounts of compound of ex . 4 , however no light was provided . no differences in mortality or morphology was detected in comparison to not treated - not irradiated cells up to a 40 μm compound of ex . 4 concentration . in a second experiment , not related cell still in dmem 10 % fcs were treated with several aliquots of mab compound of ex . 4 conjugated at an equivalent compound of ex . 4 concentration up to 40 μm . after incubation , the cells were finally exposed for 10 min . to red light ( intralux 4000 equipped with filter bp700 / 100 chroma technology corp .) and the viability and morphology compared with treated but not irradiated and with not treated , not irradiated cells . no differences were noticed . those experiments demonstrate that the compound of ex . 4 by itself or as mab conjugated is not toxic for fibroblasts or toward not related cells , well above the standard concentration used to inactivate living form by using pdt . the usefulness of the compound of the present invention is further demonstrated through their activity against a variety of micro - organisms . the following example refer to the activity against c . albicans . fig1 shows the photoinactivation of c . albicans by the compounds according to ex . 7 and 8 ( indicated in the figure with mrlp 090 and mrlp 091 respectively ). compounds as previously described may be used either for topical treatment of superficial diseases or after parenteral administration . therapeutic compositions containing the compounds of the present invention include liposome or microvesicle preparations , dispersions , ointments , solutions for parenteral injection , etc . and include topical dermatological preparations . the photoactivatable phthalocyanines generally are used with additional solvents and adjuvants to prepare solutions suitable for intravenous injection . a number of solvents and co - solvents , that are miscible with water and suitable surfactants , can be used to achieve solutions for parenteral use . the most important solvents in this group are ethanol , polyethylene glycols of the liquid series and propylene glycol . a more comprehensive listing includes dimethyl sulfoxide , ethanol , glycerin , polyethylene glycol 300 and 400 , propylene glycol , sorbitol , polyoxyethylene sorbitan fatty acid esters such as laurate , palmitate , stearate , and oleate , polyoxyethylated vegetable oil , sorbitan monopalmitate , 2 - pyrrolidone , n - methylpyrrolidine , n - ethylpyrrolidine and tetrahydrofurfuryl alcohol . other additives may be necessary to enhance or maintain chemical stability and physiological suitability . examples are antioxidants , chelating agents , inert gases , buffers and isotonicifiers . the phthalocyanine compounds of the present invention may be formulated for topical application in penetrating solvents or in the form of a lotion , cream , ointment or gel containing a sufficient amount of the phthalocyanine compound to be effective for pdt . suitable penetrating solvents are those which will enhance percutaneous penetration of the phthalocyanine compound . solvents having this property include dimethyl sulfoxide , 1 - methyl - 2 - pyrrolidone , azone and propylene glycol . dmso solutions containing 0 – 50 wt . % water are particularly desirable . liposomes are microvesicles which encapsulate a liquid within lipid or polymeric membranes ; the methods of preparing liposomes for both topical and parenteral ( injectable ) preparations are known in the art . the phthalocyanine compounds of the present invention having lipophilic characteristic may be incorporated into liposome microvesicles and used in this form for both topical and parenteral application . photodynamic therapy using the phthalocyanine compounds of the present invention has a number of advantages . the phthalocyanine compounds itself are minimally toxic in the unexcited state . each phthalocyanine molecule can be repeatedly photoactivated and leads each time to cell - lethal events , that is the generation of singlet molecular oxygen or radicals . the half - life of singlet oxygen is such that the target cell is affected without the opportunity for migration of the lethal singlet oxygen to neighbouring healthy tissue cells . singlet oxygen molecules rupture chemical bonds in the cell dna , target cell wall , or destroy intracellular structures such as mitochondria , resulting in destruction of the target cell . destruction of target cell tissue commences promptly upon irradiation of the phthalocyanine compounds and ceases abruptly when irradiation is stopped . photodynamic therapy using the compounds of the present invention is therefore selective and minimally toxic to healthy tissue . singlet oxygen molecules produced which do not react rapidly with neighboring molecules rapidly decay . a variety of phototherapy and irradiation methodologies are known to those skilled in the art and can be used with the novel phthalocyanine compounds of the present invention . the time and duration of therapy and repetition of the irradiation treatment can be selected by the physician according to known photodynamic therapy criteria . the dosage of the phthalocyanine compound may be varied according to the size and location of the target tissues which are to be destroyed and the method of administration . generally , the dosage will be in the range of 0 . 1 – 20 mg of phthalocyanine compound per kilogram of body weight , more preferably in the range of 0 . 1 – 5 . 0 mg / kg . for cancer therapy ad treatment of infectious diseases , irradiation generally takes place not less than one hour and nor more than four days after administration of the phthalocyanine compound . usually , phototherapy is begun approximately 10 hours to 24 hours after administration of the photodynamic therapy agent . for dermatological applications like psoriasis , but also for infectious diseases or cancer treatment , radiation therapy can commence immediately after topical application of the phthalocyanine or up to 12 hours later . systemic application for treatment of dermatological diseases is followed by radiation usually 15 to 24 hours after systemic administration of the pdt agent . exposure to non therapeutic light sources should be avoided immediately following phototherapy to minimise light toxicity . appropriate cover of the patient can be used , to limit the area affected by phototherapy . light sources appropriate for the use in pdt are well known in the art and may vary from white light sources associated with appropriate filters to lasers settled to the right wavelength . as noted above , preferred wavelengths are from 600 to 950 nm , preferably from about 650 to about 750 nm . the total amount of light which is applied to the affected area will vary with the treatment method used and with the location of the lesion . generally , the amount of light is in the range of about 50 to 1000 jcm − 2 , preferably in the range of 100 to 350 jcm − 2 .

phthalocyanine analogues having an active group able to link the phthalocyanine t carriers molecules and phthalocyanine to carriers molecules and phthalocyanine analogues as phthalocyanine - carrier conjugates showing enhanced photodynamic properties , red shifted absorption characteristic , all useful for photodynamic therapy , are described . photosensitizers themselves or the photosensitizers - carriers conjugates are useful compounds either for treatment of various infectious diseases , the in vivo eradication of micro - organisms as well as diseases characterized by cellular hyperproliferation , in particular tumours psoriasis , actinic keratosis , atheromas , endoarterial hyperplasia and prostate hyperplasia . the above compounds can be also useful for blood and blood derivatives sterilization and in vivo / vitro diagnostics .

referring to fig1 and 2 , in one exemplary embodiment , the mis pedicle screw system 10 of the present invention includes a plurality of slotted guides 12 , 14 that are inserted through small incisions in the skin and musculature proximate to the bony structures ( i . e . pedicles ) of adjacent vertebrae of the spine of a patient . each of the slotted guides 12 , 14 is an elongate structure and is configured to securely receive the head 16 , 18 of a pedicle screw 17 , 19 , such that the slotted guides 12 , 14 may be used to drive the pedicle screws 17 , 19 into the adjacent pedicles . preferably , each of the slotted guides 12 , 14 is a substantially hollow structure defining a track 20 , 22 along its major axis that is configured to receive another structure , as described in greater detail herein below . the first slotted guide 12 is configured to receive a pendulum mechanism 24 that includes a body portion 26 , a pivot structure 28 attached to or integrally formed with the body portion 26 , and an elongate portion 30 . the elongate portion 30 of the pendulum mechanism 24 may be manufactured from any suitable flexible , semi - rigid , or rigid material . the second slotted guide 14 is configured to receive a connecting rod 32 that also , optionally , includes a pivot structure ( not illustrated ) attached to or integrally formed with the connecting rod 32 . the connecting rod 32 may also be substantially flexible , semi - rigid , or rigid . in operation , the elongate portion 30 of the pendulum mechanism 24 is selectively connected to the connecting rod 32 at an attachment point 34 located at one end of the connecting rod 32 . referring now specifically to fig1 , in operation , the elongate portion 30 of the pendulum mechanism 24 is selectively connected to the connecting rod 32 at the attachment point 34 located at one end of the connecting rod 32 . the elongate portion 30 is then pulled upwards through the first slotted guide 12 and pivoted via an associated handle 36 attached to the elongate portion 30 . this action causes the pivot structure 28 attached to or integrally formed with the body portion 26 of the pendulum mechanism 24 to translate upwards within the first track 20 , as well as to pivot . accordingly , the first slotted guide 12 includes an elongate opening ( not illustrated ) along each side through which the body portion 26 and elongate portion 30 of the pendulum mechanism 24 protrude . because the elongate portion 30 of the pendulum mechanism 24 is connected to the connecting rod 32 at the attachment point 34 located at one end of the connecting rod 32 , this action causes the pivot structure ( not illustrated ) attached to or integrally formed with the connecting rod 32 to translate downwards within the second track 22 , as well as to pivot . accordingly , the second slotted guide 14 includes an elongate opening ( not illustrated ) along each side through which the connecting rod 32 protrudes . referring now specifically to fig2 , the connecting rod 32 is eventually drawn into place within the heads 16 , 18 of the pedicle screws 17 , 19 . at this point , a threaded set screw 38 or the like is disposed through the second slotted guide 14 and secured to lock the connecting rod 32 in place relative to the second pedicle screw 19 . optionally , a threaded set screw ( not illustrated ) or the like is disposed through the first slotted guide 12 and secured to lock the connecting rod 32 in place relative to the first pedicle screw 17 . at this point , the pendulum mechanism 24 is withdrawn from the first slotted guide 12 , and both slotted guides 12 , 14 are disengaged from their respective pedicle screws 17 , 19 and removed from the surgical site , which is subsequently closed . it should be noted that either single or multi - level procedures may be performed using the systems and methods of the present invention . referring to fig3 , in another exemplary embodiment , the mis pedicle screw system 50 of the present invention again includes a plurality of slotted guides 12 , 14 that are inserted through small incisions in the skin and musculature proximate to the bony structures ( i . e . pedicles ) of adjacent vertebrae of the spine of a patient . each of the slotted guides 12 , 14 is configured to securely receive the head 16 , 18 of a pedicle screw 17 , 19 , such that the slotted guides 12 , 14 may be used to drive the pedicle screws 17 , 19 into the adjacent pedicles . preferably , each of the slotted guides 12 , 14 is a substantially hollow structure defining a track 20 , 22 along its major axis that is configured to receive another structure , as described in greater detail herein below . the first slotted guide 12 again is configured to receive a pendulum mechanism 24 that includes a body portion 26 , a pivot structure 28 attached to or integrally formed with the body portion 26 , and an elongate portion 30 . the elongate portion 30 of the pendulum mechanism 24 may be manufactured from any suitable flexible , semi - rigid , or rigid material . the second slotted guide 14 is configured to receive a rack fascia perforator 52 that engages a pinion pivot drive structure 54 . in operation , the elongate portion 30 of the pendulum mechanism 24 is selectively connected to the rack fascia perforator 52 at an attachment point 56 located at one end of the rack fascia perforator 52 . in operation , the elongate portion 30 of the pendulum mechanism 24 is selectively connected to the rack fascia perforator 52 at an attachment point 56 located at one end of the rack fascia perforator 52 . the elongate portion 30 is then pulled upwards through the first slotted guide 12 and pivoted via an associated handle 36 attached to the elongate portion 30 . this action causes the pivot structure 28 attached to or integrally formed with the body portion 26 of the pendulum mechanism 24 to translate upwards within the first track 20 , as well as to pivot . accordingly , the first slotted guide 12 includes an elongate opening ( not illustrated ) along each side through which the body portion 26 and elongate portion 30 of the pendulum mechanism 24 protrude . because the elongate portion 30 of the pendulum mechanism 24 is connected to the rack fascia perforator 52 at the attachment point 56 located at one end of the rack fascia perforator 52 , this action causes the pinion pivot drive structure 54 to translate downwards within the second track 22 , as well as to pivot . accordingly , the second slotted guide 14 includes an elongate opening ( not illustrated ) along each side through which the connecting rod 32 protrudes . optionally , the pinion pivot drive structure 54 drives the motion of the rack fascia perforator 52 and the pendulum mechanism 24 . although the present invention has been illustrated and described herein with reference to preferred embodiments and specific examples thereof , it will be readily apparent to those of ordinary skill in the art that other embodiments and examples may perform similar functions and / or achieve like results . all such equivalent embodiments and examples are within the spirit and scope of the present invention , are contemplated thereby , and are intended to be covered by the following claims .

the present invention provides a minimally invasive surgery pedicle screw system , including : a plurality of slotted guides that are selectively inserted through one or more surgical incisions ; a plurality of pedicle screws selectively coupled to the plurality of slotted guides that are selectively secured to one or more bony anatomical structures ; a pendulum mechanism selectively translatably and pivotably coupled to one of the plurality of slotted guides ; and a connecting rod selectively translatably and pivotably coupled to one of the plurality of slotted guides ; wherein the pendulum mechanism is selectively coupled to the connecting rod . the connecting rod is selectively secured to one or more of the plurality of pedicle screws .

for a better understanding of the invention , it is explained in more detail based on the following description . the prophylactic article according to the invention in addition to gloves , in particular medical operation or examination gloves , can also be condoms , finger stalls or protective gloves for work in cleanroom areas , etc . prophylactic articles of this type have already been adequately described in the applicant &# 39 ; s at 413 471 b or at 503 090 a with respect to their composition regarding the elastomer , i . e ., the natural or synthetic latices , e . g ., natural rubber , neoprene , synthetic polyisoprene , nitrile - butadiene and styrene - butadiene rubber , or a mixture thereof , and regarding the optionally arranged sliding layer , wherein this sliding layer can be formed by a sliding film , for example , a silicone oil , but also from the latex itself , for example through halogenation , such as , e . g ., chlorination , or by certain surface modifications and designs , also with respect to the microcapsules used , in particular the size in the range between 0 . 1 μm to 100 μm , wherein in the scope of the present invention microcapsules are preferably used which have a size selected from a range between 0 . 1 μm and 10 μm , as with respect to the capsule material itself , wherein here preferably a polymer on a melamine - formaldehyde basis , e . g ., according to de 29 40 786 a is used . the application of the microcapsules themselves on or in the prophylactic article through the production of corresponding suspensions or emulsions from the latices , has already been dealt with extensively in these documents , so that a more detailed discussion is not necessary at this point and reference is therefore made to these two documents for these points of the invention , which in this respect are therefore part of the content of the present invention . preferably the prophylactic articles are produced in a dipping process with corresponding dipping forms . however , these can also be , e . g ., sprayed , etc . the microencapsulation of the combination of active substances , in particular of the oil , has the advantage that active substances can thus also be used , which are incompatible or compatible only to a lesser extent with respect to the carrier material or a possibly present sliding layer . in other words , the microcapsules have a protective function for the active substance ( s ) of the prophylactic article . moreover , the oil can thus be prevented from diffusing into the prophylactic article and thus is available for the actual function only to a reduced extent . it is therefore achieved thereby that the combination of active substances is better available for the wearer &# 39 ; s skin . the ingredients of the combination of active substances provided according to the invention have already been sufficiently described above . at this point , therefore , only the individual effect will be briefly described , wherein it is noted that these are conventional active substances , which are used in the cosmetics industry and thus the action thereof per se has already been adequately documented . this active ingredient makes the skin supple and smoothes it . moreover , it makes it possible to easily distribute the combination of active substances on the skin . the preferred proportion in the combination of active substances is between 25 % by weight and 50 % by weight , or between 30 % by weight and 40 % by weight . this active ingredient makes the skin supple and smoothes it . moreover the skin is protected from dryness and chapping . the preferred proportion is between 10 % by weight and 25 % by weight or between 15 % by weight and 20 % by weight . this active ingredient also makes the skin supple and smoothes it , without visibly greasing . the preferred proportion is 10 % by weight and 30 % by weight or between 15 % by weight and 20 % by weight . olive oil has a high proportion of unsaturated fatty acids for strengthening the skin barrier . this active ingredient also makes the skin supple and smoothes it . the preferred proportion is between 10 % by weight and 25 % by weight or between 15 % by weight and 20 % by weight . again this active ingredient — it is a type of silicone oil — has a smoothing effect on the skin and makes it supple . furthermore , cyclomethicone has an antistatic effect , whereby the production of the microcapsules can be improved , a film - forming , viscosity - regulating and moisturizing effect . this is also a moisturizing factor . the preferred proportion is between 1 % by weight and 5 % by weight , or 2 % by weight and 3 % by weight . in addition to the effect that this active substance makes the skin supple and smoothes it , squalane has a regreasing effect , in general conditioning for the skin . it is an extract of olive oil . the preferred proportion is between 1 % by weight and 5 % by weight or between 2 % by weight and 3 % by weight , but in individual exemplary embodiments can also be up to 20 % by weight . borage oil makes the skin supple and smoothes it . the preferred proportion is between 1 % by weight and 5 % by weight or between 2 % by weight and 3 % by weight , but in individual exemplary embodiments can also be up to 25 % by weight . shea butter or a liquid extract thereof has a particularly marked conditioning and skin - friendly effect . the preferred proportion is between 1 % by weight and 5 % by weight , in particular between 2 % by weight and 3 % by weight . however / the proportion can also be up to 40 % by weight . macadamia oil has an excellent conditioning effect , since it is rich in unsaturated fatty acids . the preferred proportion is between 1 % by weight and 5 % by weight or between 2 % by weight and 3 % by weight . however , the proportion can also be up to 40 % by weight . benzyl alcohol has a preservative effect , primarily inhibits the development of microorganisms in the combination of active substances . furthermore , benzyl alcohol gives the combination of active substances a jasmine - like scent . the preferred proportion is up to a max . of 0 . 5 % by weight , in particular up to a max . of 0 . 1 % by weight . benzyl benzoate is a very well tolerated preservative and has a similar effect to benzyl alcohol , but without giving the combination of active substances a specific scent . the preferred proportion is up to a max . of 0 . 5 % by weight or max . of 0 . 1 % by weight . potassium sorbate is used in particular for prophylactic articles that must have a particularly high tolerance level by the skin , i . e ., in particular for gloves , the wearers of which quickly react to latices with a skin irritation . this is a mild preservative , which gives the combination of active substances longer durability . the preferred proportion is up to a max . of 0 . 5 % by weight or a max . of 0 . 1 % by weight . sodium hydroacetate is likewise a preservative that is well tolerated , similar to potassium sorbate . the preferred proportion is in turn up a max . of 0 . 5 % by weight or a max . of 0 . 1 % by weight . these active ingredients have a masking effect , prevent or inhibit the odor of the combination of active substances . the preferred proportion is up to a max . of 5 % by weight or a max . of 0 . 5 % by weight or a max . of 0 . 1 % by weight for each of these active substances , if they are contained individually in the combination of active substances . linalool has a deodorizing effect . the preferred proportion is up to a max . of 0 . 5 % by weight or up to a max . of 0 . 1 % by weight . limonene has a skin - conditioning and odor - inhibiting effect . the preferred proportion is up to a max . of 0 . 5 % by weight or up to a max . of 0 . 1 % by weight . these are antioxidants , i . e ., these active ingredients prevent individual constituents of the combination of active substances from oxidizing due to longer storage or also already during production and are thus impaired in their effect or prevent the odor from any odor - forming breakdown products of the combination of active substances that may develop . these are usually radical interceptors . the preferred proportion of each of these representatives of the antioxidants is up to a max . of 0 . 5 % by weight or up to a max . of 0 . 1 % by weight . these active substances are humectant factors , i . e ., they prevent the skin from drying out . each of these active substances can preferably be present in a proportion of up to a max . of 3 % by weight or up to a max . of 1 % by weight , wherein these active substances in total are contained in a proportion of a max . of 3 % by weight , if several of these humectant factors are used . the humectant factors can be contained in particular individually in a proportion of 0 . 1 % by weight to 1 % by weight . geraniol has a strengthening effect and produces a pleasant feeling on the skin . moreover it can be used for odor correction . the preferred proportion is up to a max . of 0 . 3 % by weight or up to a max . of 0 . 1 % by weight . allantonin , arnica extract ( arnica montana ), oat extract ( avena sativa ), calendula oil ( calendula officinalis ), chamomile extract ( chamomilla recutita ), ethylhexyl stearate , azulene ( guajazulene ): allantonin has a soothing effect on the skin and promotes the formation of tissues , i . e ., it has a positive effect when the wearer of the prophylactic article has a superficial skin injury . arnica extract has a regenerating effect and stimulates the blood flow . oat extract has a mild conditioning effect , soothes the skin and is antipruritic . calendula oil has a skin soothing and regenerating effect in the case of chapped and cracked skin . chamomile extract is used in particular when the wearer of the prophylactic article has a very tender , sensitive skin . ethylhexyl stearate improves the dispersibility of the combination of active substances on the skin . the preferred proportion of these active ingredients can be individually up to a max . of 10 % by weight or up to 5 % by weight or up to a max . of 2 . 5 % by weight , wherein , if several of these active ingredients are contained , the total proportion in the combination of active substances is a max . of 10 % by weight . the combination of active substances is given a specific fragrance direction by perfume active substances and the basic odor of the combination of active substances can also be better covered thereby . the preferred proportion of perfume ingredients is up to a max . of 1 . 5 % by weight or preferably between 0 . 1 % by weight and 1 % by weight . in order to be better able to encapsulate the combination of active substances produced by mixing the individual ingredients , as already stated above , this skin protection oil can be diluted . in this respect , reference is made to the above statements . furthermore , extracts or at least partially hydrated representatives of these active substances can be used . the combination of active substances can contain up to 98 % by weight of at least one of the skin conditioning agents . in this case proportions of preservatives , odor - inhibiting agents and antioxidants are restricted to a total of a max . of 2 % by weight . on the other hand it is possible for the combination of active substances to contain a max . of 90 % by weight of skin conditioning substances , so that the other ingredients of the combination of active substances therefore have a proportion of a max . of 10 % by weight . the constituent amounts of the dilution relate to the entire combination of active substances , i . e ., the relative proportions of the individual ingredients in the combination of active substances with respect to one another are not changed by the dilution . since it is not possible to list all of the combinations of active substances within the scope of this description , only the particularly preferred exemplary embodiments are listed below . the data given on the constituent amounts are thereby to be understood as % by weight . the respectively preferred ranges of the compounds are given in parentheses , within which the respective ingredients or active substances can be varied . the active substances are commercially available products . microcapsules were produced with these combinations of active substances , optionally after the dilution described above , with a method according to the prior art for the microencapsulation of active substances . these microcapsules were subsequently added to a conventional elastomer compound corresponding to the prior art in a concentration of between 0 . 1 % by weight and 10 % by weight , based on the total latex dispersion . from this subsequently gloves were produced by means of a conventional dipping process , as is described , for example , in the applicant &# 39 ; s two above - referenced documents from the prior art . to evaluate the functional properties , gloves of this type with combinations of active substances according to the exemplary embodiments 1 through 6 were worn by respectively 100 test persons over a period of respectively 8 hours . each of these test persons thereby wore respectively one glove according to exemplary embodiments 1 through 6 . after the end of 8 hours , on the one hand , the skin of the test persons was visually evaluated , on the other hand , the subjective perception of these test persons was verified by means of questionnaires that did not reveal the respective identities and contained questions regarding itchy feeling during wear , etc . it turned out that virtually 100 % of the test persons found a glove with a combination of active substances according to exemplary embodiment 4 the most pleasant to wear . embodiments of a glove with combinations of active substances according to exemplary embodiments 1 through 3 and 5 and 6 were evaluated by between 97 % and 99 % of the test persons as very positive with regard to wearing comfort and the feeling on the skin . the visual evaluation of the skin after the gloves were removed from the hands of the test persons did not show a reddening of the skin in any of the cases . the combinations of active substances according to exemplary embodiments 1 through 6 all have an oily consistency . as already stated above , to increase the lipid penetration through the combination of active substances , i . e ., individual constituents of this combination of active substances , the viscosity of this combination of active substances at 37 ° c . can have a value of a max . of 250 mpas and / or a saponification value according to din 53401 of no more than 250 . to adjust these values the individual ingredients can be varied according to their proportion in the combination of active substances . to further improve the lipid penetration , it is advantageous if the proportion of triglyceride skin conditioning agents in the combination of active substances is no more than 50 % by weight . all of the data on value ranges in this specification are to be understood to cover any and all partial ranges therefrom , e . g ., 1 - 10 is to be understood in that all partial ranges starting from the lower limit 1 and the upper limit 10 are covered , i . e ., all partial ranges begin with a lower limit of 1 or greater and end with an upper limit of 10 or less , e . g ., 1 to 1 . 7 , or 3 . 2 to 8 . 1 or 5 . 5 to 10 . the exemplary embodiments show possible embodiment variants of the prophylactic article , wherein it is noted at this point that the invention is not limited to the embodiment variants of the same specifically shown , but instead various combinations of the individual embodiment variants among one another are possible and this variation possibility based on the teaching for technical actions through the present invention lies within the ability of one skilled in the art in this technical field .

the invention relates to a prophylactic article with a carrier element , which comprises at least in part a natural or synthetic elastomer , and with a combination of active substances that is contained in microcapsules , wherein the microcapsules are arranged at least in part in and / or on the carrier element . the combination of active substances contains at least one skin care agent , at least one preservative , at least one odor - inhibiting agent and at least one antioxidant .

according to a first variant of a first embodiment , a head 1 according to the invention is illustrated in perspective in fig1 , from an angle making it possible to distinguish a front , or hitting , surface 2 , and upper face , or crown , 3 , a belt 4 , and a hosel 5 . the belt 4 in turn comprises an upper portion 6 and a lower portion 7 separated by a strip 8 whose function will be explained below . two ends of the hitting surface 2 form a heel 9 and a toe 10 at the spot where they connect with the belt 4 . a view of the head 1 from another angle as illustrated in fig2 shows that a lower face , or sole - plate 11 , is attached to the belt 4 . the entire group of faces , including the hitting surface 2 , the crown 3 , the belt 4 , and the sole - plate 11 , form the jacket of a head 1 , in this case the head of a metal - wood . the head 1 is made of three main elements , as illustrated in an exploded view in fig3 : a first , or upper , part 12 formed by the combination of the crown 3 , the hitting surface 2 , the hosel 5 , and the upper portion 6 of the belt 4 ; a second , or lower part 13 formed by the combination of the sole - plate 11 and the lower portion 7 of the center strip 4 ; an intermediate part formed by the peripheral strip 8 . the upper part 12 is preferably produced using casting techniques and a metal which may have a low density . for example , it is possible to use a titanium - or aluminum - based alloy . a steel could prove suitable , however , if the thickness of the faces is sufficiently thin , the goal being to produce a part 12 which is light in relation to the weight of the head 1 . the upper part 12 comprises means for connecting and positioning the peripheral strip 8 , which take the form , for example , of a peripheral edge 14 of the upper portion 6 and eyes 15 , 16 , 17 , 18 in the upper part 12 , which are spaced along the peripheral edge 14 . the peripheral edge 14 may be produced directly by casting , or it may be machined . it functions as a surface supporting the peripheral strip 8 , which serves as a weight extending along the peripheral edge 14 , substantially from the heel 9 to the toe 10 . the peripheral strip , or weight , 8 preferably has a shape matching that of the peripheral edge 14 and of the eyes 15 , 16 , 17 , 18 . to this end , it comprises an arch 19 and projections 20 , 21 , 22 , 23 . the weight 8 acts to add weight to the head 1 at the spot where it is located , i . e ., substantially on the sides and to the rear of the head 1 , but not on the front portion . it is preferably made of a high - density material , e . g ., an alloy containing copper , tin , or other metal . a steel weight 8 may be suitable if it has sufficient thickness . the lower part 13 is preferably supported both on the weight 8 and on an inner side 24 of the hitting surface 2 , so as to complete the jacket of the head 1 . it is preferably made of a metal , in order to be both light and wear - resistant . in fact , it is the weight 8 which must govern the dynamic performance of the head 1 , while the sole - plate 11 must resist friction on the ground . assembly means , for example screws 25 , 26 , 27 , 28 , are provided to hold together the upper part 12 , the weight 8 , and the lower part 13 . the screws 25 , 26 , 27 , 28 extend simultaneously through the holes in the lower portion 7 of the belt 4 and through the holes in the projections 20 , 21 , 22 , 23 belonging to the weight 8 , before being housed in the eyes 15 , 16 , 17 , 18 in the upper portion 12 . thus , when the screws 25 , 26 , 27 , 28 are tightened , the head 1 is assembled and ready for use . the structure of the head 1 makes it possible to position the weight 8 with great precision , in order to impart to the head 1 good mechanical properties . in fact , the lateral portions of the weight 8 adjoining the heel 9 and the toe 10 create a stabilizing effect during rotation of the head 1 in relation to a vertical axis at the moment of impact on a ball . as a result , ball trajectories are more accurate . the rear portion of . the weight 8 allows the head 1 to pivot around a substantially horizontal axis , by virtue of an inertial phenomenon called dynamic loft . this phenomenon occurs as a result of club shaft flection during the swing and helps accentuate the original angle of inclination of the hitting surface 2 . as a result , the balls climb higher into the air and travel farther . surprisingly , the continuous extension of the weight 8 along the belt 4 makes it possible to combine the effect of stabilization during rotation and the dynamic loft phenomenon in order to achieve optimal effectiveness . the head 1 is thus advantageously accurate and capable of producing long strokes . moreover , this structure facilitates manufacture enormously as compared with traditional methods . in fact , it is not necessary to use complex cored molds comprising multiple parts , nor is it necessary to carry out welding , sanding , or heat treatment operations . production costs and time are thus advantageously reduced . the head 1 produced is a hollow volume that can be filled with a light material capable of damping vibrations generated by impacts with the ball . as one example , a plastic foam is highly effective . the head 1 may be produced in accordance with other variants , such as that illustrated in fig4 . for reasons of convenience , identical references are used to designate the same components . the head 1 according to this variant comprises a block formed by assembling the hitting surface 2 , the crown 3 , the sole - plate 11 , the belt 4 , and the hosel 5 . a recess 36 in the belt 4 and extending along the belt 4 substantially from the heel 9 to the toe 10 is provided to house an arc - shaped portion 32 made of a high - density material , the other parts of the head 1 being made of a material possessing lower density . for example , the portion 32 is made of a copper - based metal alloy , while the rest of the head 1 is made of a titanium - based metal alloy . the arc - shaped portion 32 is assembled with the block of the head 1 and is positioned in the recess 36 , preferably in such a way that the volume of the recess 36 is entirely filled by the arc - shaped portion 32 . as a result , the volume of the head 1 remains unchanged despite the presence of the arc - shaped portion 32 . any means of attaching the block and the arc - shaped portion 32 can be used . for example , the portion 32 can be welded to the block , with or without adding material in the form , for example , of a brazed seam , an electric spot weld , etc . the two elements can also be glued , screwed together , riveted , etc . another variant of the head 1 according to this embodiment is illustrated in fig5 . it differs from the variant in fig4 only by virtue of the fact that the shape of the arc - shaped portion and the housing recess do not have uniform width . the arc - shaped portion 33 incorporates three extensions 29 , 30 , 31 located respectively on the toe 10 side , to the rear , and on the heel 9 side . these extensions 29 , 30 , 31 of the arc - shaped portion 33 further improve the dynamic performance of the head 1 while increasing its total weight , but without exceeding the values which would make the golf swing difficult to perform . moreover , by virtue of their shape , these extensions 29 , 30 , 31 combine with the sole - plate 11 to facilitate the movement of the head 1 in the grass or in gravel . in fact , the shape of the sole - plate 11 corresponds to the areas of heaviest friction and wear . now , the harder material used to manufacture the sole - plate 11 is relatively expensive . consequently , savings are achieved by combining the extensions 29 , 30 , 31 of the arc - shaped portion 33 with the shape of the sole - plate 11 . fig6 illustrates a second embodiment of a head 1 according to the invention . this head 1 comprises two arc - shaped portions 34 , 35 intended to be made integral with a block incorporating , in particular , the hitting surface 2 , the sole - plate 11 , the crown 3 , the peripheral strip 4 , and the hosel 5 . in this instance , the arc - shaped portions 34 , 35 partially fill cavities 37 , 38 in the head 1 and are attached to the head 1 , as was previously described . the cavities 37 , 38 are open , but do not prevent the block from retaining a volume substantially identical to that of the variants of the previous embodiment . on the other hand , the shape of the arc - shaped portions 34 , 35 of the cavities 37 , 38 and of the sole - plate 11 are combined so as to ensure simultaneously good dynamic equilibrium of the head 1 and the enhanced capacity to describe a line tangent to the ground is during the swing . in all of the variants and according to all of the embodiments of the invention , the head is distinguished from all other existing club heads on the market by the fact that , for a given volume , inertial properties are enhanced , since they are greater in magnitude . knowing that the golf market requires wood - type heads having a volume of approximately 260 cm 3 , the invention can be compared to existing heads using the table below , in which : 13 is the mechanical inertia of the head in relation to a vertical axis passing through the center of gravity when the head 1 is in the ball - address position , in g / mm 2 , preferably , the arc - shaped portion 8 , 32 , 33 weighs approximately 50 grams and is between 40 and 60 grams . the arc - shaped portions 34 , 35 preferably weigh between 16 and 34 grams . furthermore , this type of construction can be used for all of the heads in a set of clubs .

a golf club head whose volume is delimited by a crown , a sole - plate , a belt , and a hitting surface , junctions between the belt and the hitting surface delimiting a heel and a toe . the belt comprises at least one arc - shaped portion which forms a visible layer of - the belt , while extending along the belt between the heel and the tip , the arc - shaped portion being a peripheral weight made of a high - density material .

referring now to fig1 of the drawing , the expansion band , shown generally at 1 includes a first or upper row of links 2 and a second or lower row of links 3 . the links are arranged in overlapping fashion and employ clip members for connecting alternate links between rows . the upper row 2 is made up of individual upper link assemblies 5 and similarly the lower row 3 is made up of lower link assemblies 6 . very often , the upper link assemblies 5 have decorative covers , while the lower link assemblies 6 simply have turned up tabs on the end to retain the clip members , these details not being material to the present invention . fig6 shows the plan view of the upper link assemblies 5 and , fig3 which is an enlarged section view shows the typical and well - known means of construction whereby u - shaped clips 4 interconnect the upper and lower assemblies , whereas leaf - spring members contained within the links serve to press the legs of the clips against the walls of the links so as to provide a spring return action when the band is stretched . the foregoing construction is known in the art . referring to the improvements which comprise the present invention , a typical link 8 is shown in fig4 which may be identical for both the upper and lower link assemblies 5 , 6 respectively . link 8 is a rectangular sheet metal enclosure with turned up end tabs 9 opposite ends and open on one longitudinal side thereof except for oppositely directed tabs 10 on one end thereof and oppositely directed tabs 11 spaced from the opposite end thereof . crimped portions 12 on tabs 10 and 11 serve to lock the spring retainers in engaged or in disengaged positions as will be further described . shown in fig5 is a spring retainer 13 , which may be identical in the upper and lower link assemblies 5 , 6 respectively . spring retainer 13 is an open - ended rectangular sheet metal enclosure which is slightly smaller in its width and height so that it will fit inside a link 8 , and shorter than link 8 so that it can slide longitudinally therein between engaged and disengaged positions . the retainer 13 has folded over sections 14 extending toward one another and adding oppositely directed apertures 15 and crimped portions 16 spaced so as to register with crimped portions 12 in the links 8 . shown in fig6 are the leaf spring members 17 which include oppositely extending spring legs 18 on either side of a bowed portion 19 having turned up ends 20 . referring to fig7 the clip members are shown as 21 to be generally u - shaped with a base section 22 and legs 23 , 24 , of unequal length . the aforementioned spring members 17 and clip members 21 are preferably all interchangeable and may be used either in upper or lower link assemblies or at opposite ends of the links as will be evident from the description which follows . referring to fig8 a and fig8 b of the drawing , and upper link assembly 5 and a lower link assembly 6 are shown separated from one another and with the spring retainers in the unlocked position . the spring retainer 13 in the upper assembly is moved all the way to the right ( be means of using a tool or probe in hole 15 .) similarly the lower retainer 13 is moved all the way to the left . the spring members 17 are disposed within the retainers , and held in position by the bow portion 19 resting in a slot 25 in the bottom wall ( see fig5 ). the clip members 21 are arranged with the long legs 24 held in place by one end of the spring and the short legs 23 free to engage or disengage the opposing link assemblies to the position of the spring retainers . referring now to fig9 of the drawing , the upper and lower link assemblies 5 , 6 are shown in a locked and engaged position . the upper spring retainer 13 has been moved longitudinally to the left so that the end of the spring arm 18 rests on the short arm 23 of the left - hand clip . the lower retainer 13 has been similarly moved to the right so that the right hand spring arm 18 also rests on the short arm 23 of the clip . the retainers are locked in this position , since the crimped sections 16 , 12 no longer are in registry , but now the crimped portion 16 is positioned against the tab members 10 , 11 . when the assemblies are engaged in locked as shown in fig9 the spring members 17 cooperate with opposite ends of clip members 21 in the same fashion as a conventional expansion band of this type . reference to the perspective exploded view of fig1 further illustrates the manner in which the parts are assembled . in operation , when the parts are assembled and it is wished to disengage them , it is only necessary to spread the link assemblies slightly to expose the slots 15 and to utilize a probe or pointed instrument to slide the spring retainers 13 longitudinally within the links . the upper spring retainer is slid in one direction and the lower spring retainer in the opposite direction , whereupon the upper and lower link assemblies , and thus the attached expansion band sections , may be disengaged since the parts will now all pass by the short legs 23 of the clip members . reengagement of the sections or removal of one or more links is accomplished in the same manner . the expansion band may be entirely composed of links as described , or the spring retainers , special springs and clips omitted and conventional springs and clips substituted , the appearance of the expansion band to all intents and purposes being entirely the same whether or not the special parts are employed . while there has been described what is considered at present to be the preferred embodiment of the invention , other modifications will occur to those skilled in the art . it should be apparent that various types of asymmetric clip members and means for moving the spring members to avoid same in a locked and unlocked position can be accomplished within the scope of the present invention .

an adjustable expansion band for a wristwatch of the type having two rows of overlapping links , having clips connecting alternating links between rows , and containing spring members within the links . the construction utilizes u - shaped clip members having asymmetrical legs and selectively engaging the springs which are held in slideable spring retainers inside the links . adjacent expansion band sections can be disengaged by sliding the spring retainers to the unlocked positions .

anastomotic junctions between blood vessels and / or a blood vessel and a biological or synthetic graft are subject to occlusion due to hyperplasia and other injury responses , as discussed above . the present invention relies on exposure of such anastomotic junctions to vibrational energy at a mechanical index , and for a time sufficient to inhibit hyperplasia and thus reduce the risk of occlusion of the anastomotic junction and failure of the graft or fistula which has been created . the vibrational energy can be directed at the anastomotic junction in a variety of ways and at a variety of different times . when surgical access is available , e . g ., at the time of fistula creation or graft implantation , it will often be desirable to apply the vibrational energy directly to an exterior surface of the junction using a probe or other suitable acoustic generator . it will be appreciated that the probe can be engaged directly against the surface of the blood vessels or blood vessel and graft . when surgical access is not available , the vibrational energy can be provided using an intravascular catheter introduced to the patient &# 39 ; s vasculature and advanced to the anastomotic junction or junctions using conventional guidewire and fluoroscopic techniques . the ultrasonic energy can then be directed at the anastomotic junction from the interior of the blood vessel , usually in a radially outward direction . if surgical access is unavailable and catheter access is undesirable , it will be possible to focus acoustic energy through the patient &# 39 ; s skin to the anastomotic junction ( s ). a suitable external probe can be placed on the skin over the junction site and acoustic energy of the desired frequency , intensity , and mechanical index applied through the overlying skin . in some instances , it will be desirable to combine two or more of these specific approaches in order to optimize treatment . the application of vibrational energy according to the methods of the present invention may be performed at various times during and after graft implantation or fistula formation . vibrational energy will frequently be applied immediately after graft implantation or fistula formation using a probe which is introduced through a surgical access site , as described above . after the surgical site is closed , it will frequently be desirable to apply vibrational energy in the period from one day to one week following the surgical procedure . it is presently believed that hyperplastic activity is at a peak approximately several days after the initial procedure . the therapeutic use of vibrational energy according to the present invention may be applied at any other time when it is believed that the anastomotic junction is at risk of hyperplasia . in some instances , it will be desirable to perform the vibrational treatments periodically , e . g ., daily , weekly , monthly , or at other regular intervals . it may also be desirable to apply the vibrational inhibition methods of the present invention in conjunction with other interventions for clearing established occlusion at anastomotic junctions . for example , the methods of the present invention may be used following angioplasty , atherectomy , laser angioplasty , or other intravascular procedures for reducing or removing stenotic material within an anastomotic junction . a variety of specific procedures employing the principles of the present invention will now be described . it will be appreciated that these specific procedures are meant to be exemplary and that the present invention may be applied to virtually any surgical procedure which results in the surgical creation of an anastomotic junction within a patient &# 39 ; s vasculature . referring now to fig1 and 2 , hemodialysis access is frequently provided by placing a graft between a radial artery ra and a radial vein rv in a patient &# 39 ; s arm . the graft may be made from a vessel harvested from the patient or from a human donor , or may be a tubular synthetic graft formed from polyester , ptfe , or the like . the graft 10 , referred to as an arterio - venous shunt , is connected at one end 12 via an end - to - side anastomotic junction 14 and at the other end 16 via an end - to - side anastomotic junction 18 . in a first exemplary treatment protocol ( fig1 ), an intravascular catheter 20 may be introduced into the graft 10 over a guidewire 22 . a suitable ultrasonic transducer 24 on the catheter 20 may then be positioned within the anastomotic junction 14 . the transducer 24 will then be energized to deliver vibrational energy within the parameters set forth above . use of the intravascular catheter 20 may occur at any time from the initial implantation of the graft ( even prior to incision closure ) to after closure of the incision in the days , weeks , and months , following implantation . use of the catheter 20 will be particularly suitable for treatment of either anastomotic junction after treatment with angioplasty , atherectomy , or the like . an alternative treatment of the anastomotic junction 16 using a vibrational probe 30 is illustrated fig2 . the probe 30 is introduced through the incision in the arm used to initially implant the graft 10 . initially , the junctions 14 and 18 may also be treated using an external probe after the incision has been closed , although this particular approach is not illustrated . referring now to fig3 and 4 , treatment of a side - to - side anastomotic junction 50 formed between a brachial artery ba and a basilic vein bv is described . the anastomotic junction 50 may be formed by conventional surgical techniques , usually through an incision i in the arm as illustrated in fig4 . after the junction 50 is formed , it may be treated , either using an intravascular catheter 20 introduced over a guidewire 22 where an ultrasonic transducer 24 is located within the junction ( fig3 ). the junction is then treated with vibrational energy by energizing the transducer , generally as described above . alternatively or additionally , the junction 50 may be treated with an external probe 60 while the incision remains open ( fig4 ). treatment of an end - to - end anastomotic junction 70 between a radial artery ra and a radial vein rv is illustrated in fig5 . while use of an ultrasonic probe 60 is shown , it will be appreciated that use of an intravascular catheter or other external probe could also be used . referring now to fig6 the methods of the present invention can be used to treat the anastomotic junctions 80 , 82 , and 84 , which are formed when a graft 86 is implanted in the abdominal aorta aa to connect to the right and left iliacs il . as shown , a catheter 10 can be used to treat any of the anastomotic junctions 80 , 82 , or 84 . alternatively or additionally , a probe 60 can be used to treat the outsides of these junctions while a surgical incision remains open . additionally , external probes may be used on the surface of the skin after the incision has been closed . referring now to fig7 use of a probe 60 for treating anastomotic junctions 90 and 92 formed at either end of a cardiac bypass graft is illustrated . the bypass graft 94 may be implanted using conventional open surgical techniques , and the probe 60 introduced through the opening in the sternum to perform the methods of the present invention . alternatively ( and not illustrated ) intravascular catheters can be used to treat the anastomotic junctions following catheter - based techniques for performing cardiopulmonary bypass , such as those presently commercialized by heartport , inc . use of an external skin probe 100 for treating the anastomotic junctions 90 and 92 of a cardiac bypass graft 94 is illustrated in fig8 . the probe will usually contain an ultrasonic array 102 configured to focus the energy through tissue overlying the heart so that the vibrational energy can be delivered in a focused manner to each of the anastomotic junctions . methods and devices suitable for performing such external vibrational treatment protocols are described in copending application ser . no . 09 / 343 , 950 filed jun . 30 , 1999 , ( attorney docket no . 17148 - 003000 / psi - 030 ), the full disclosure of which is incorporated herein by reference . referring now to fig9 the present invention comprises kits including at least one of a catheter 10 and probe 60 for applying vibrational energy according to the methods described above . the kits will further comprise instructions for use ifu setting forth methods according to the present invention . the kit components , including at least one of the catheter 10 and the probe 60 , and the instructions for use will typically be packaged together in a conventional medical device package 120 , typically a box , tube , tray , pouch , or the like . preferably , at least some of the kit components will be maintained in a sterile condition within the kit . while the above is a complete description of the preferred embodiments of the invention , various alternatives , modifications , and equivalents may be used . therefore , the above description should not be taken as limiting the scope of the invention which is defined by the appended claims .

a method for inhibiting hyperplasia at an anastomotic junction of a vascular fistula or vascular graft comprises exposing the anastomotic junction to vibrational energy at a mechanical index and for a time sufficient to inhibit hyperplasia . kits are described comprising the catheter or a probe suitable for performing the methods together with instructions for use setting forth the methods . the methods and kits are particularly suitable for treating anastomotic junctions formed to provide vascular access for hemodialysis , hemofiltration , and the like . the methods and kits are also suitable for treating other vascular grafts , such as those formed during cardiac bypass graft surgery , vascular repair , and the like .

referring to fig1 to 3 , a sprinkler head body 1 comprises a screw portion 2 having a water discharge port 3 axially formed therein and male threads formed on its outer periphery , a hexagonal flange 5 formed at a lower end of the screw portion 2 in an integral structure therewith , and a pair of arms 6a and 6b extending downwardly from a lower surface of the flange 5 in opposite relation to each other . as shown in fig3 the body 1 has a recess 4 formed along an inner peripheral wall defining a lower end of the water discharge port 3 . the arms 6a and 6b are provided in positions opposed to each other with draft holes 9a to 9f penetrating the arms toward a central axis of the body 1 , and have respective lower ends coupled together on the central axis of the body 1 to form a receiver seat 7 . note that the flange 5 is not necessarily limited in its shape to a hexagon , but it may be formed into a disk - like shape , for example , with engagement portions provided on an outer periphery thereof which is to be engaged with an attaching / detaching tool . a valve 10 is configured such that a disk - like flange is radially extended from a lower end of a column . a recess 11 is formed on a lower surface of the flange , and a bottom - equipped guide hole 12 opening to the recess 11 is formed to extend along a central axis of the valve . the flange of the valve 10 has a diameter slightly larger than that of the water discharge port 3 of the body 1 , and is held in abutment against the recess 4 of the body 1 with the intervention of a packing 13 made of elastic materials therebetween . a threaded hole 8 is formed in the receiver seat 7 of the body 1 to extend in the axial direction of the body 1 , and a setting screw 14 is screwed into the threaded hole 8 . between the valve 10 and the setting screw 14 , there is held a glass bulb 15 which is filled with a thermally expanding agent , such as alcohol . a deflector 16 is attached to a lower end of the receiver seat 7 . a sprinkler head comprising the above - mentioned components such as the body 1 , the valve 10 , the setting screw 14 , and the glass bulb 15 is assembled by first inserting the column portion of the valve 10 into the water discharge port 3 of the body 1 through an open space between the arms 6a and 6b with the intervention of a packing 13 therebetween . then , the setting screw 14 is loosened and a distal end portion of the glass bulb 15 is inserted into the guide hole 12 of the valve 10 , while the glass bulb 15 is held at an opposite end by the setting screw 14 . by screwing the setting screw 14 into the threaded hole 8 , the glass bulb 15 is fixedly supported between the valve 10 and the setting screw 14 . in this connection , the load imposed on the glass bulb 15 is adjusted by changing the amount through which the setting screw 14 is screwed into the threaded hole 8 . the sprinkler head thus assembled is attached to a ceiling surface by screwing the screw portion 2 into a water supply pipe provided in the ceiling . at this time , a great load is imposed on the valve 10 by pressurized water introduced through the water supply pipe , but there is no fear of leakage of the pressurized water because the valve 10 is held in place by the glass bulb 15 interposed between itself and the setting screw 14 and the gap between the body 1 and the valve 10 is sealed by the packing 13 made of elastic materials . if a fire occurs and a hot air stream is produced , the hot air stream moves upwardly , passes through the open space between the arms 6a and 6b , and then contacts the glass bulb 15 to heat it . when the hot air stream comes closer while flowing in the direction of the arm 6a ( or 6b ) toward the glass bulb 15 , it passes through the draft holes 9a , 9c , 9e ( or 9b , 9d , 9f ) provided in the arms 6a ( or 6b ), and then contacts the glass bulb 15 . therefore , the presence of the arms 6a , 6b gives rise to no appreciable undesired effect . if the glass bulb 15 is heated by the hot air stream , the thermally expanding agent filled therein is expanded and pressurized to blow up the glass bulb 15 supporting the valve 10 . the valve 10 falls down through the space between the arms 6a and 6b to open the water discharge port 3 so that the pressurized water is discharged and sprinkled through the deflector 16 . generally , the hot air stream in the vicinity of the ceiling flows along the ceiling , and the hot air stream in lower part flows toward the ceiling . therefore , the hot air stream can more smoothly pass through the draft holes by forming them such that the draft holes 9a , 9b provided in upper portions of the arms 6a , 6b are substantially parallel to the ceiling surface , whereas the draft holes 9c , 9d , 9e , 9f provided in middle and lower portions of the arms 6a , 6b are inclined downwardly . thus , with this embodiment , since the plurality of draft holes 9a to 9f allowing the hot air stream to pass therethrough are provided in the arms 6a , 6b , a heat sensitive member , i . e ., the glass bulb 15 , has no appreciable directionality in sensitivity and hence has an improved sensitivity . as a modification , the arms 6a , 6b may have a ladder - like shape by forming the arms 6a , 6b in a wider width and increasing the size of the draft holes 9a to 9f so as to cover the glass bulb 15 by the arms in a larger circumferential range . this makes it possible to increase a function of protecting the glass bulb 15 . further , the draft holes 9a to 9f may be joined to each other into the slit form for each arm . fig4 shows a sprinkler head according to embodiment 2 . note that the same parts as those in embodiment 1 are denoted by the same reference numerals and will not be described here . in this embodiment , a pair of opposing arms 17a , 17b are provided in an integral structure with the screw portion 2 and the flange 5 , and are twisted in opposite directions ( inclined with respect to the glass bulb 15 ), lower ends of the arms being coupled together to the receives seat 7 . with this embodiment thus arranged , since the pair of opposing arms 17a , 17b are inclined in opposite directions with respect to the glass bulb 15 , the glass bulb 15 is not entirely concealed by the arms 17a , 17b in any direction . accordingly , even if a hot air stream produced by a fire comes closer in any direction , it is not totally blocked by the arms 17a , 17b and contacts the glass bulb 15 to heat it . as a result , it is possible to eliminate directionality in sensitivity of the heat sensitive member and hence improve a sensitivity thereof . although the arms 17a , 17b are inclined in opposite directions with respect to the glass bulb 15 in the illustrated embodiment , they may be inclined in the same direction with respect to the glass bulb 15 . fig5 to 7 show a sprinkler head according to embodiment 3 . note that the same parts as those in embodiments 1 and 2 are denoted by the same reference numerals and will not be described here . in this embodiment , a pair of opposing arms 18a , 18b are formed in a substantially y - or v - shape , the arms having upper ends joined together to the screw portion 2 and lower ends coupled together to the receiver seat 7 . with this embodiment , since the arms 18a , 18b are formed in a substantially y - or v - shape , a hot air stream produced by a fire and coming closer in a direction of the arm 18a or 18b toward the glass bulb 15 passes through a void 19a or 19b defined in the arm 18a or 18b and contacts the glass bulb 15 to heat it without being undesirably affected by the arm 18a or 18b . also , for a hot air stream coming closer in a direction vertical to the drawing sheet of fig6 a similar effect to that in the above embodiment 2 can be obtained because the arms 18a , 18b are inclined . it is thus possible to eliminate directionality in sensitivity of the heat sensitive member and hence improve a sensitivity thereof . further , since the arms 18a , 18b cover the glass bulb 15 in a larger circumferential range , a function of protecting the glass bulb can be increased . next , test results of the conventional frame type sprinkler head shown in fig1 and the sprinkler head of this embodiment having the y - shaped arms 18a , 18b are shown in table 1 below . the test was conducted by setting each of the sprinkler heads in an atmosphere with temperature of 100 (° c .) and wind velocity of 1 . 5 ( m / s ), and measuring a time constant of a curve plotted on condition that the horizontal axis represents time and the vertical axis represents temperature . table 1______________________________________ hot air stream sent in hot air stream sent direction perpendicular in direction of arm to arm______________________________________conventional type 342 . 8 56 . 4embodiment 77 . 6 31 . 5______________________________________ as is apparent from the values measured for the conventional type in table 1 , when a hot air stream is sent in a direction of the arm toward the glass bulb , the time constant value is about six times as large as the value resulted when a hot air stream is sent in a direction perpendicular to the arm toward the glass bulb . in other words , it is found that the sensitivity is remarkably different depending on directions and is much reduced for the hot air stream coming closer in the direction of the arm toward the glass bulb . by contrast , in this embodiment , the difference between the two measured values can be held down on the order of twice and , hence , directionality in sensitivity can substantially be eliminated . although the body 1 is constructed by forming the arms 6a , 6b ; 17a , 17b ; or 18a , 18b in an integral structure with the flange 5 in the above . embodiments 1 to 3 , it may be constructed by forming the arms 6a , 6b ; 17a , 17b ; or 18a , 18b as separate members . in this case , the body 1 may be constituted by threading respective upper end portions of the arms 6a , 6b ; 17a , 17b ; or 18a , 18b , inserting the threaded portions into insertion holes bored through the flange 5 , and fastening bolts or the like over the threaded portions , as with the prior art shown in fig1 , or by providing an annular tube at upper ends of the arms 6a , 6b ; 17a , 17b ; or 18a , 18b so as to interconnect the pair of arms , threading an inner ( or outer ) peripheral wall of the annular tube and an outer ( or inner ) peripheral wall of the flange , and fixedly screwing the arms to the flange through the threaded portions . fig8 and 9 show a sprinkler head according to embodiment 4 . a sprinkler head body 41 comprises a screw portion 42 having a water discharge port 43 axially formed therein and male threads formed on its outer periphery , and a flange 45 formed at a lower end of the screw portion 42 in an integral structure therewith and having engagement portions provided on an outer periphery for an attaching / detaching tool . the flange 45 has female threads 46 formed on its inner peripheral surface , and also has a recess 47 formed at the axial center thereof having a larger diameter than that of the water discharge port 43 . denoted by 48 is a convex valve comprising a large - diameter portion and a small - diameter portion . the large - diameter portion is formed to be capable of fitting to the recess 47 of the body 41 , and has a cylindrical recess 49 defined at the center of its lower surface . 50 is a seal packing formed by coating a fluororesin over a belleville spring made of , for example , ring - shaped metal materials ( spring steel ) such as iron and stainless steel . incidentally , a packing made of a fluororesin may be used instead of the packing formed by coating a fluororesin over metal materials . denoted by 51 is a convex valve guide having a penetration hole 52 defined through the center thereof and comprising a large - diameter portion and a small - diameter portion , the small - diameter portion being formed to be fitted to the recess 49 of the valve 48 . 53 is a belleville spring for adjusting the load , which is interposed between the valve 48 and the valve guide 51 as shown in fig9 if the seal packing 50 is not used as a belleville spring . alternatively , if a belleville spring is used as the seal packing 50 , the valve 48 and the valve guide 51 may be formed in an integral structure by omitting the belleville spring 53 . denoted by 55 is a frame which has , on an outer periphery of its one end , a male thread portion 56 in the form of a ring to be engaged with the female threads 46 provided in the flange 45 of the body 41 , and also has three arms 57a , 57b , 57c extending downwardly from a lower surface of the male thread portion 56 at equal intervals ( 120 °) therebetween . the arms 57a to 57c are bent in respective lower portions toward the central axis of the frame 55 and are joined together to form a receiver seat 58 . 59 is a support portion provided in the receiver seat 58 for supporting a glass bulb 61 described later . incidentally , the arms 57a to 57c are each formed to have a rectangular or elliptical cross - section being elongated in a direction toward the central axis of the frame 55 . denoted by 60 is a deflector attached to a lower end of the frame 55 , and 61 is a columnar glass bulb which is filled with a thermally expanding agent , such as alcohol , the glass bulb having a thinned distal end portion . the intervals between the arms 57a to 57c of the frame 55 are selected to such an extent that the valve 48 surely falls down when the glass bulb 61 is blown up . since the frame 55 comprises the three arms 57a to 57c , a cross - sectional area of each of the arms 57a to 57c can be set smaller than that in the case of using only two arms . in the illustrated embodiment , the width of each of the arms 57a to 57c is set to about 4 mm . the sprinkler head comprising the above - mentioned parts is assembled as shown in fig1 . the valve 48 is first fitted into the recess 47 of the body 41 with the intervention of the packing 50 coated by a fluororesin therebetween . the small - diameter portion of the valve guide 51 is then fitted into the recess 49 of the valve 48 with the intervention of the belleville spring 53 urging downwardly therebetween . under this condition , the male thread portion 56 of the frame 55 is tentatively screwed into the female threads 46 of the body 41 , and the distal end portion of the glass bulb 61 is inserted into the penetration hole 52 of the valve guide 51 while the opposite end thereof is fitted into the support portion 59 of the frame 55 . subsequently , by screwing the male thread portion 56 of the frame 55 into the female threads 46 of the body 41 , the glass bulb 61 is supported between the valve guide 51 and the frame 55 , and the body 41 and the frame 55 are coupled together . in this connection , the load imposed on the glass bulb 61 is adjusted by changing the amount through which the frame 55 is screwed into the body 41 . as a modification , the distal end portion of the glass bulb 61 may directly be supported by the valve 48 by omitting the valve guide 51 . the sprinkler head thus assembled is attached to a ceiling surface by screwing the screw portion 42 into a water supply pipe provided in the ceiling . at this time , a great load is imposed on the valve 48 by pressurized water introduced through the water supply pipe , but there is no fear of leakage of the pressurized water because the valve 48 is held in place by the glass bulb 61 interposed between the valve guide 51 and the support portion 59 of the receiver seat 58 while the gap between the body 41 and the valve 48 is sealed by the packing 50 coated with a fluororesin having high elasticity . if a fire occurs and a hot air stream is produced , the hot air stream passes through open spaces between the arms 57a to 57c of the frame 55 and then contacts the glass bulb 61 to heat it , as shown in fig1 . on this occasion , since the arms 57a to 57c each have a small cross - sectional area as mentioned above , undesirable influences caused by the presence of the arms 57a to 57c are small . also , since the arms 57a to 57c are provided with equal intervals , part of the hot air stream comes closer in the direction of the arm 57a , for example , strikes against rear sides ( reflecting surfaces ) of the other arms 57b , 57c and is reflected by them to contact the glass bulb 61 , thereby accelerating the heating of the glass bulb 61 . as a result , the glass bulb 61 has no directionality in its sensitivity and becomes more sensitive . if the glass bulb 61 is heated by the hot air stream and the thermally expanding agent filled therein is expanded and pressurized to blow up the glass bulb 61 , the valve 48 falls down while passing among the arms 57a to 57c , causing the water to be discharged from the water discharge port 43 and sprinkled through the deflector 60 . next , test results of the conventional frame type sprinkler head , shown in fig1 , having two arms and the sprinkler head of this embodiment are shown in table 2 below . the test was conducted by setting each of the sprinkler heads in an atmosphere with temperature of 100 (° c .) and wind velocity of 1 . 5 ( m / s ), and measuring a time constant of a curve plotted on condition that the horizontal axis represents time and the vertical axis represents temperature . table 2______________________________________ hot air stream sent in hot air stream sent direction perpendicular in direction of arm to arm______________________________________conventional type 342 . 8 56 . 4embodiment 143 . 5 56 . 1______________________________________ as is apparent from the values measured for the conventional type in table 2 , when a hot air stream is sent in a direction of the arm , the time constant value is about six times as large as the value resulted when a hot air stream is sent in a direction perpendicular to the arm . in other words , it is found that the sensitivity is remarkably different depending on directions and is much reduced for the hot air stream coming closer in the direction of the arm . by contrast , in this embodiment , the difference between the two measured values can be held down on the order of 2 . 5 times and , hence , directionality in sensitivity can substantially be eliminated . as shown in fig1 , the two piece threaded assembly of fig9 including a body with a threaded portion and a y - shaped frame as shown in fig7 may be employed . such frame has arms 18a &# 39 ; and 18b &# 39 ; having therethrough voids 19a &# 39 ; and 19b &# 39 ;. such arrangement further can have a packing 50 &# 39 ; formed of a fluororesin . fig1 shows a sprinkler head according to embodiment 5 . in this embodiment , four arms 67a , 67b , 67c , 67d are provided at equal intervals therebetween instead of the arms 57a to 57c in embodiment 4 . with the increased number of arms 67a to 67d , the thickness ( or diameter ) of each arm can be reduced ( thinned ) in comparison with that in the case of using three arms , which is effective to eliminate directionality in sensitivity and increase a function of protecting the glass bulb 61 . also , in this embodiment , the arms 67a to 67d are each formed to have an elongate rectangular cross section , and a side face of each arm defined by the longer side of the cross section serves as a reflecting surface to reflect a hot air stream coming closer in a direction of the adjacent arm toward the glass bulb 61 . for example , a hot air stream flowing toward the glass bulb 61 in a direction of the arm 67b strikes against the reflecting surfaces of the arms 67a , 67c and is divided into two streams by each reflecting surface such that one flows outwardly , but the other flows toward the glass bulb 61 to efficiently heat it . although the body is formed in an integral structure with the frame in embodiment 5 shown in fig1 , the body and the frame may be separatedly formed and be joined together by screw fitting , as in embodiment 4 . in embodiments 4 and 5 , since three or four arms are provided , the function of protecting the heat sensitive member ( glass bulb ) disposed inside the arms can be increased . since the body and the frame are joined together by screw fitting and the load imposed on the valve and the heat sensitive member is adjusted by the screwing operation , it is possible to easily assemble the valve and the heat sensitive member , dispense with an additional screw for adjusting the load , and reduce the number of parts . in spite of the frame having a rather complex structure , since the frame is made separate from the body and is joined thereto by screw fitting , the mold structure is simplified , resulting in that a large number of frames can be molded by a single process and a remarkable cost reduction can be achieved . since the heat sensitive member is formed of a glass bulb and a highly elastic packing formed by coating a fluororesin over metal materials is interposed between the body and the valve , the valve can positively be sealed by a relatively small load ( about 40 kgf ). therefore , a glass bulb which has a small resisting load and hence which is thin and has a small diameter ( outer diameter of 3 mm in the illustrated embodiments ) can be used , which results in an improved sensitivity . although three or four arms are provided on the frame in embodiments 4 and 5 , five or more arms may be provided so long as the valve can surely fall down while passing among the arms . although the valve is allowed to more easily fall down through between the arms by providing the arms at equal intervals therebetween , the arms are not necessarily provided at equal intervals if another measure such as reducing the valve size is achieved . while the above description is made as constructing the body comprising the screw portion and the flange separately from the frame comprising the male thread portion , the arms and the receiver seat and joining the body and the frame together by screw fitting , the present invention is not limited to such arrangements . the present invention is also applicable to , for example , the sprinkler head shown in fig1 in which the screw portion and the frame are formed in an integral structure , or the sprinkler head shown in fig1 in which the arms of the frame are inserted through the flange and fixed by nuts . in these case , however , a setting screw for supporting the heat sensitive member and adjusting the load is required to be provided in the receiver seat . in the case of inserting the arms through the flange and fixing them by nuts , load adjustment is troublesome due to the necessity of evenly tightening three nuts on the flange , and the flange size must be increased correspondingly to the nut size . the necessity of providing threads in upper portions of the arms brings about another problem of increasing the arm length . while the foregoing embodiments 1 to 5 are described as applying the present invention principally to frame type sprinkler heads using heat sensitive members formed of glass bulbs , the present invention can also be applied to other frame type sprinkler heads using low melting - point alloys or the like .

a sprinkler head includes a body having a water discharge port formed at the center thereof , a valve for opening and closing the water discharge port of the body , a receiver seat provided in a position opposing the valve , a heat sensitive member disposed between the valve and the receiver seat for supporting the valve , the heat sensitive member being disintegratable when heated , causing the valve to mote away from the water discharge port of the body , and a frame for supporting the receiver seat with respect to the body . to reduce directional dependency of exposure of a hot air stream to the heat sensitive member for an improvement in sensitivity of the heat sensitive member , the frame includes a plurality of y - shaped arms each having at least one draft hole formed therein and a portion inclined with respect to the heat sensitive member .

embodiments of the present invention are generally directed to systems and software for measuring or determining aberrations of an input wavefront based on an output wavefront produced when the input wavefront passes through an imaging system that produces an output wavefront that is received by a wavefront sensor . the measurement or determination of the input wavefront is provided by correcting for , compensating for , or reducing system errors and / or input wavefront errors that may alter the error produced by the system . embodiments of the present invention will be illustrated using aberrometer systems used in the area of ophthalmic measurement and correction . however , it will be understood that embodiments of the present invention may be utilized in other optical applications where measurement of a wavefront or image may be affected by transfer of the wavefront or image through a transfer optical system . referring to fig1 , in certain embodiments of the present invention , an aberrometer or wavefront measurement system 10 is configured to provide a characterization of an input or object wavefront w of a subject eye 20 containing a cornea 22 and a retina 25 . the wavefront measurement system 10 comprises an illumination optical system 30 that includes an illumination source 32 and may include one or more lenses 35 or other optical elements that are configured to direct light from the light source 32 to the eye 20 and to preferably focus the light onto the retina 25 . the wavefront measurement system 10 also includes a computer or processor 36 that is used to control various components of the system 10 , to collect input data from the system 10 , and to make calculations regarding aberrations of the wavefronts w and / or w ′, aberrations of the system 10 , and / or aberrations of the eye 20 . the wavefront measurement system 10 also comprises an optical relay or image relay system 40 that is configured to receive and relay an input wavefront w from the eye 20 . the input wavefront w is transformed by the relay system or telescope 40 into a wavefront w ′ that is received by a wavefront sensor 38 . in certain embodiments , the optical relay system 40 comprises a first lens 42 and a second lens 45 . as the input wavefront w passes through the first lens 42 of relay system 40 , light is generally directed or focused onto an internal focal plane . this light then passes through the second lens 45 to form the wavefront w ′, which is received by the wavefront sensor 38 . some embodiments , at least one of the lenses 42 , 45 may be replaced or supplemented by another optical element , for example , a diffractive optical element ( doe ) or mirror . in general , aberrations may be introduced into the wavefront w ′ that were not present in the input wavefront w , for example , by misalignment between the lenses 42 , 45 in translation ( dx , dy , dz ) or rotation ( dθx , dθy , dθz ). alternatively or additionally , aberrations may be introduced due to inherent optical characteristics of the optical relay system 40 , for example , spherical aberrations introduced through the use of spherical lenses . in the illustrated embodiment , the wavefront sensor 38 is a shack - hartmann wavefront sensor comprising a lenslet array 55 and a detector 60 , which may be a ccd , cmos , or similar type detector comprising an array of pixel elements . alternatively , other types of wavefront sensors may be used , for example , an interferometer or phase diversity sensor arrangement . in the illustrated embodiment shown in fig2 , the test object is an eye 70 which produces the wavefront w at an exit pupil 75 . the wavefront w is produced by focused light reflected by the eyes retina that passes through the eye . in such embodiments , a mathematical relationship may be built of the wavefront aberrations in between the entrance pupil of the eye and the exit pupil of the relay system using fourier polynomials and zernike polynomials . in certain embodiments , the wavefront w also includes aberrations as it passes from the cornea of the eye to the pupil 75 , which may be included in the aberrations calculated for the transferred wavefront w ′. in other embodiments , aberrations introduced into the wavefront sensor 50 may also be included in the wavefront analysis . in some embodiments , more than one relay system may be disposed between the test object and the wavefront sensor 50 , in which case an analysis according to embodiments of the present invention may be used to calculate aberrations introduced into the wavefront from the test object . in certain embodiments , the computer or processor 36 contains memory including instructions for calculating aberrations of the wavefront w ′, for example , by representing the wavefront w ′ as a polynomial , such as a zernike polynomial or fourier polynomial , for example as taught in u . s . pat . nos . 6 , 609 , 793 , 6 , 830 , 332 , which are incorporated by reference in their entirety . the computer 36 may be a desktop or portable computer . alternatively , the computer 36 may be incorporated into an electronic circuit board or chip containing on - board memory or in communications with separate external memory . in some embodiments , a memory for the computer 36 contains value for certain parameters . for example , the memory may contain one or more system error parameters . for example , the system error parameters may include errors , aberrations , or misalignment information regarding the wavefront measurement system 10 and / or the optical relay system 40 . the system error parameters may include coefficients of a polynomial equation representing an error or aberration , such as zernike polynomial , a taylor polynomial , or the like . referring to fig3 , in certain embodiments , a corneal refractive surgical system 100 includes a laser for performing a corneal refractive surgery such as a lasik or prk procedure , for example , as disclosed in u . s . pat . no . 6 , 964 , 659 , which is herein incorporated by reference in its entirety . the surgical system 100 is provided with a treatment profile for a cornea based on the wavefront w ′ that is calculated based on the wavefront w and corrections or compensations for the transfer system 40 and / or cross - terms of the transfer system and the input wavefront w in accordance to embodiments discussed herein , or the like . in some embodiments , a method or formulas are used in wavefront measurements using a confocal system from one point ( pin hole or small aperture ) to another conjugated point ( pin hole or small aperture ) instead of from one plane to another plane . in other embodiments , a method may be applied for any other aerometer or device to measure accurately the aberrations of human eye or other optical system that uses a relay system before the wavefront sensor . in certain embodiments , the aberrations introduced into the object wavefront w may reduced or eliminated by adjusted , supplementing , or replacing optical elements of the relay system 40 or some other optical element of the measurement system 10 . in some embodiments , the final design of a wavefront measurement system or relay system 10 may be adjusted to reduce or eliminate the sensitivity to misalignment of certain optical elements of the system . in some embodiments , a wavefront propagation theory may be used to derive mathematical expressions of the wavefront propagation through the optical relay system 40 . the basis for the wavefront propagation may be based on : in such embodiments , the wavefront transfer function or matrix may be given by : additionally or alternatively , ray tracing simulations may be used to derive mathematical expressions of the wavefront propagation through the optical relay system 40 , as discussed in further detail below . embodiments of the present invention generally relate to optical imaging systems and methods of determining the image errors produced by such optical imaging systems . embodiments of the present invention discussed below are for illustrative purposes and are not intended to limit the scope of the present invention . aspects of the present invention are discussed below in conjunction with the “ slides ” referenced therein and include with this disclosure . as discussed above , it is typically assumed that the output at an image plane of an optical system is given as : this assumes that the input and the system errors or aberrations may be independently assessed , and that , accordingly , there is no “ cross - talk ” among the input , system , and pupil diffraction . however , the inventors have found that such cross - talk can exist . for example , aberrations in the term “ input ” in equation ( 6 ) may affect the magnitude of the term “ system ” in such embodiment , the output may be calculated , for example , according to the relation : if either input or system errors are zero or very close to zero , then the cross - term , input * system , is zero , equation ( 6 ) is valid . the inventor have found that in cases where either the input or the system have no error or aberrations , there is no cross - talk and the above relationship is valid . however , the inventors have also found that in some situations , cross - talk can actually have a significant affect on the output , particularly in terms of higher order aberration ( e . g ., above 4th order ). accordingly , a more accurate assessment of the output may be provided by : error function 2 =( output − input − system error )/ input referring to equations ( 9 ) referring to equations ( 3 ) through ( 5 ) above , the inventors used fresnel - kirchhoff &# 39 ; s approximate formula to provide a more accurate analysis of an optical imaging system output that accounts for cross - talk . the need for such an approach has been illustrated by the inventors using the following method 200 : 1 . at input plane , provide values in zernike coefficients . 2 . at lens 42 and lens 45 ( see fig2 ), input aberrations ( e . g ., 0 . 1 microns spherical aberration ) 3 . using a ray tracing program , decenter lens 42 relative to lens 45 ( e . g ., 0 . 1 mm to 0 . 5 mm ) and introduce relative tilt ( 2 to 5 degrees ) and defocused ( e . g ., 0 . 1 mm ); 4 . calculate the wavefront at an output plane by wavefront maps and zernike coefficients ; 5 . calculate an error function using the wavefront maps and fit to zernike polynomials . 6 . repeat 1 - 5 with lens 42 shifted left by 10 mm . 7 . repeat 1 - 5 with zero input ( 2 ) or zero system error ( zero all in 4 ) will make the error function 2 zero . accordingly , and by way of example , the relay system shown in fig2 was used to demonstrate the effects of cross - talk in producing significant output error . it will be appreciated that this specific example is not meant to limit the scope of the present invention , but is give as a way of demonstrating the importance of using an analysis according to embodiments of the present invention in the design of optical systems , for example in the field of ophthalmic diagnostic . in steps 1 - 3 of method 200 above , various errors are introduced into the input and system shown in fig2 . input errors are shown in terms of zernike coefficients in the second column of table 1 below . the column labeled “ output ” in table 1 shows the resulting output after the system errors are subtracted out . thus , the error in percent introduced by cross - talk is shown in the column in table 1 labeled “ error function 2 ”. as can be seen , these errors are significant for many of the zernike terms . in table 2 , an additional error is introduce by way of displacement of the object plan by 10 millimeters . this amount of displacement error is typical in aberrometers used to measure aberrations of a subjects eye or cornea . 1 . a real relay system can introduce an input - dependent error due to the crosstalk between the input , the system , and the pupil diffraction to the output wavefront 2 . error could be introduced if the measured wavefront plane is not conjugated to the pupil plane because of changes in the wavefront during propagation 3 . the quality of the relay optics and the alignment of the relay system are critical . 4 . errors measuring lower order aberrations of the input wavefront may be relatively low , while those of higher order aberrations may be relatively high , as summarized in the following table : the above presents a description of the best mode contemplated of carrying out the present invention , and of the manner and process of making and using it , in such full , clear , concise , and exact terms as to enable any person skilled in the art to which it pertains to make and use this invention . this invention is , however , susceptible to modifications and alternate constructions from that discussed above which are fully equivalent . consequently , it is not the intention to limit this invention to the particular embodiments disclosed . on the contrary , the intention is to cover modifications and alternate constructions coming within the spirit and scope of the invention as generally expressed by the following claims , which particularly point out and distinctly claim the subject matter of the invention .

a system for providing vision contains an aberrometer , a wavefront sensor , and a transfer optical system . the aberrometer is configured to measure a received wavefront . the aberrometer includes a wavefront sensor and a transfer optical system for transferring an input wavefront so as to the provide the received wavefront at or near the wavefront sensor . the system also includes a processor in communication with the aberrometer , a readable memory , and instructions located within the memory . the readable memory contains one or more system error parameters and instructions for calculating the input wavefront based on the received wavefront and the one or more system error parameters .

referring now to the drawings , there is shown in fig1 – 5 the vegetable and plant growing cage 10 which provides for optimum plant growth without the conventional tying requirement . the apparatus 10 is particularly adapted for supporting growing plants which cannot provide self support including but not limited to peas , tomatoes , snow peas , cucumbers , dahlias , and morning glories . the apparatus 10 provides easy , convenient , and effective use and storage for the aforesaid applications . the drawings show the apparatus 10 comprising , in a preferred embodiment , a flexible polypropylene coil 12 of approximately 15 inches diameter with an anchor peg 38 at a first exterior end 36 and a universal clamp 16 at another second interior end 14 . again in its preferred form , the universal clamp 16 is attachable to a square , round , or other cross sectional shaped stake 50 of up to 1⅝ inches in diameter . alternative embodiments may utilize a plurality of other materials with coil 12 diameters greater or lesser than 15 inches and clamping capability greater than 1⅝ inches . when clamped onto a conventional stake 50 , the coil 12 tapers from the aforesaid diameter at the stake base 54 , to a smaller diameter at the top 52 of the stake 50 and finally terminates on the universal clamp 16 . in its flattened and unconnected form , the coil 12 spirals as a helicoid inward from the aforesaid diameter toward the universal clamp 16 located near the center of said spiral . the universal clamp 16 preferably comprises a housing 18 having a threaded hole 30 and a threaded retainer 32 or thumbscrew within said hole 30 . said housing 18 fits over said stake 50 and is compressively held thereon by tightening the threaded retainer 32 or thumbscrew . the housing 18 in its preferred form has a substantially rectangular opening 20 through which said stake 50 fits but may be elliptical or any polygonal shape in alternative embodiments . in its preferred form , said opening 20 has a bearing plate 24 of approximately 1½ inches height on a first interior wall 22 and said threaded hole 30 on a second interior wall 28 opposite said bearing plate 24 . said bearing plate 24 preferably contains a “ v ”- shaped cross - section seat 26 or channel substantially lengthwise perpendicular with the plane of said opening 20 . said “ v ”- shape provides a seat 26 or holding channel for the stake 50 onto which the apparatus 10 is attached when said threaded retainer 32 or thumbscrew is tightened . alternative embodiments may utilize bearing plates 24 of different shapes , sizes , and with or without said “ v ”- shaped channel 26 or forego use of the bearing plate 24 altogether without departing from the scope and spirit of the present invention . said seat 26 or channel may further be positioned at various angles relative to the plane of the opening 20 or be of “ u ”, rectangular , or other cross sectional shapes . the threaded retainer 32 or thumbscrew , via mating with said threaded hole 30 , provides the force to hold said clamp 16 onto to the stake 50 . the aforesaid holding function may be achieved with a plurality of other mechanisms such as clamps , pins , screws , adhesives , or frictional fits . the threaded retainer 32 preferably has a head 34 which is sized for easy rotation when attaching the universal clamp 16 . the anchor peg 38 at the first exterior end 36 preferably comprises a substantially pointed 42 first end 40 and a second end 44 of said anchor peg 38 attached via a flexible or , as known in the industry , a “ living ” hinge 48 . that is , the hinge 48 , coil 12 , and anchor peg 38 are molded together in a preferred embodiment . the aforesaid hinge 48 allows the anchor 38 to be placed into the ground or growing medium while not bending the coil 12 of the device 10 . in a preferred embodiment , near said hinge 48 and near the second end 44 of said anchor peg 38 is a peg stop 46 which limits the distance which the anchor peg 38 may be pushed into the ground and also allows for a hammer to be used to drive said peg 38 into the ground , soil , earth , or growing medium . said peg stop 46 preferably is formed as a flat wall which is substantially perpendicular with the length axis of said peg 38 and extends from said peg 38 , but may be of any geometric form which limits the peg 38 travel into the ground or provides for driving into the soil . as aforesaid , preferably said anchor peg 38 is integrally molded with the plant growing cage 10 and the universal clamp 16 , but alternative embodiments may utilize clamps 16 and pegs 38 which are molded or formed separately and attached with said cage 10 or coil 12 . further alternative embodiments may not utilize said point 42 on the first end 40 or the peg stop 46 on said second end 44 . a unique aspect of a preferred embodiment of the present invention is that the aforesaid integral molding allows for all of the aforesaid components to be molded and created with one mold . that is , the coil 12 , universal clamp 16 , bearing plate 24 , threaded hole 30 , thrumbscrew 32 , and anchor peg 38 are all formed together with small plastic connections or sprues between each of the aforesaid components . this unique formation allows the complete cage 10 to be removed from the mold as a substantially flat form , placed in packaging , and sold . in operation , a user simply drives a conventional stake 50 into the ground , soil , or growing medium next to the plant which requires support . the user then simply breaks the plastic connections or sprues to separate the aforesaid components , installs the thumbscrew 32 into the threaded hole 30 and begins placement . thereafter , the user places the vegetable and plant growing cage 10 over the stake 50 and places the opening 20 of the housing 18 of the universal clamp 16 over the top 52 of the stake 50 . the user then secures the universal clamp 16 to the stake 50 via the retainer 32 or thumbscrew , thereby compressibly holding the clamp 16 to the stake 50 . thereafter the user expands the coil 12 toward the ground and drives the anchor peg 38 into the ground to secure the base of the cage 10 . once the aforesaid is completed , the user simply waters and fertilizes the plant as usual and the plant grows within said vegetable and plant growing cage 10 . as the plant grows , the branches and shoots of the plant grow through the openings between the helical coils 12 and the coils 12 thereby support said branches and shoots . no further tying or attachment is required during the growing season . although the device 10 may be manufactured in any color , the preferred green color allows for the device 10 to mask itself with the green plant leaves and stems so that the device 10 becomes inconspicuous as the plant grows . upon completion of the growing season , the user loosens the universal clamp 16 , removes the anchor peg 38 from the ground , and easily collapses or non - destructively compresses the vegetable and plant growing cage 10 into a flat coiled form . obviously , the user would also remove the stake 50 and expired plant . once collapsed into a flat form , the user may store the vegetable and plant growing cage 10 by stacking or hanging upon a hook . from the foregoing description , those skilled in the art will appreciate that all objects of the present invention are realized . an apparatus , method of use , and method of manufacture for a vegetable and plant growing cage has been shown and described . the apparatus provides convenient and lightweight plant support and off season storage at a minimum of cost . having described the invention in detail , those skilled in the art will appreciate that modifications may be made of the invention without departing from its spirit . therefore , it is not intended that the scope of the invention be limited to the specific embodiments illustrated and described . rather it is intended that the scope of this invention be determined by the appended claims and their equivalents .

a vegetable and plant growing cage and method of use and manufacture comprising a tapered , flexible , and lightweight helical coil which is capable of attaching to a conventional stake and which allows a gardener , farmer , or grower to alleviate the need for tying a plant during the growing season . the device allows a plant to grow within the coil and further allows the coil to support the branches , stems , fruits , and flowers of the plant . the apparatus and method of use allows for the user to non - destructively collapse or compress the helical coil into a substantially flat helicoid for storage during the non - growing season .

as used above and throughout the description of the invention , the following terms , unless otherwise indicated , shall be understood to have the following meanings : “ effective amount ” is meant to describe an amount of compound or composition according to the present invention effective in producing the desired therapeutic effect . “ partial regression of heart failure ” means a reduction of preexisting fibrosis in the heart of a patient and / or an improvement of the function of the heart . a subthreshold dose of ramipril , that is a dose which has no lowering effect on blood pressure , lies for a rat typically in a range between 1 and 50 μg per kg weight and per day . for a human of about 70 kg body weight the subthreshold dose of ramipril conventionally is in a range between 0 . 1 and 1 . 0 mg per day and patient , preferably between 0 . 3 and 0 . 7 mg per day and patient , for example 0 . 625 mg per day and patient . in one aspect the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and pharmaceutically effective amounts of cariporide and ramipril . in another aspect , the present invention provides methods of inhibiting the development of age - related disorders , inhibiting age - related organ damage , prolonging life , effecting a partial regression of heart failure , and of inhibiting progression of heart failure , in patients in need thereof , comprising administering to said patient pharmaceutically effective amounts of cariporide and ramipril . in yet another aspect , the present invention provides for the use of pharmaceutically effective amounts of cariporide and ramipril in the preparation of medicaments for inhibiting the development of age - related disorders , inhibiting age - related organ damage , prolonging life , effecting a partial regression of heart failure , and of inhibiting progression of heart failure , in patients in need thereof . for the experiments , old spontaneously hypertensive rats ( age = 18 months ) were treated either with the nhe inhibitor cariporide , or with a subthreshold dose , which did not lower the blood pressure , of the ace inhibitor ramipril or with a corresponding combination of the two active ingredients . the pharmacological model of spontaneously hypertensive rat is generally accepted to be representative of human essential hypertony . in each experimental group initially 27 18 - months old rats were employed . 3 months after the start of treatment , when the number of surviving animals in the placebo control group was only 7 , an interim analysis was carried out on 7 animals from each group . the hearts of the shrs treated with low ramipril doses showed a significant reduction in the force of myocardial contraction compared with the placebo control hearts . in contrast to this , cariporide and the ramipril / cariporide combination significantly improved the function of the heart . likewise , myocardial fibrosis , which correlates with heart failure , was significantly reduced by cariporide monotherapy and by the ramipril / cariporide combination . the significantly smaller weights of the hearts likewise show the antifibrotic effect , which is directed against the development of heart failure , of the ramipril / cariporide combination and of cariporide . the individual products ramipril and cariporide lead to an improvement in the survival rate compared with the placebo treatment . no significant differences in the survival rates between cariporide and ramipril were detectable in this case . surprisingly , the cariporide / ramipril combination leads to a significant increase in the survival rate compared with the effects produced by the individual compounds . the effect of a ramipril and cariporide combination product on the survival rate of rats with genetically related hypertension was investigated . in the experiment old hypertensive rats ( age : 18 months ) were treated with the nhe inhibitor cariporide or with a subthreshold dose of ramipril with no lowering effect on the blood pressure or with a combination of both substances . for each of the four treatments 27 18 - month old rats were employed . a daily dose of 400 mg of cariporide per kg body weight ( 0 . 6 % cariporide in standard rat feed ) and 10 μg ramipril per kg body weight ( in the drinking water ) were given . 3 months after the start of treatment , when the number of surviving animals in the placebo control group was only 7 , an interim analysis was carried out on 7 animals from each group . the remaining , still living rats per group were continuously treated as mentioned above since they were 18 months old . thus , in the determination of the survival time 20 18 - month old rats were employed in each experimental group ( table 1 ). an investigation of whether an improvement in the survival rate compared with placebo is detectable for the product groups , and whether an improvement in the survival rate compared with the individual products is detectable for the combination product follows . fig1 shows the profile of the survival rate for all treatment groups in detail . there are evidently distinct differences between placebo and product groups on the one hand and between the individual products and the combination after the experiment had lasted only 3 - 4 months . fig1 shows kaplan - meier survival times with the y axis being the survival distribution function which corresponds to the survival rate ( 1 = 100 %), and the x axis is time , which corresponds to the time in months from the start of the treatment , where x = 0 is identical to the 18th month of life the combination treatment provided the best results throughout the experimental period . it is likewise evident that the placebo control was distinctly inferior to all the treatments . table 3 shows the results of all pairwise comparisons of treatment groups . the test results apply at a multiple significance level of 5 %. all the product groups are statistically significantly different from the placebo group , which can be interpreted together with fig1 as efficacy of the treatments . fig1 additionally reveals distinct advantages of the combination product compared with the individual products . table 4 shows estimates of the median down time , the time at which the survival rate in the population of experimental animals just reaches 50 %. according to this , the proportion of surviving animals in the placebo group has fallen to 50 % after only 1 . 5 months , whereas this is not to be expected until after 8 months with a combination treatment . the individual products achieve a median survival time of 4 months which is less than half that of the combination product . the statistical analysis was carried out essentially using the sas / stat procedure lifetest [ sas institute inc . ( 1989 ): sas / stat user &# 39 ; s guide , version 6 , 4th edition , volume 2 , cary , n . c . ; sas institute inc .]. the log rank tests were carried out pairwise on the experimental groups and adjusted to obtain a multiple significance level of 5 % according to holm [ s . holm ( 1979 ): a simple sequentally rejective multiple test procedure ; scand . j . statist . ; 6 , pp 65 - 70 ]. the individual products ramipril and cariporide lead to a statistically significant improvement in the survival rate compared with the placebo treatment . no significant differences in the survival rates between cariporide and ramipril were detectable at the chosen significance level . the combination treatment is significantly superior to the two individual products . chronic hypertension leads in the old spontaneously hypertensive animals to transformation processes in myocardial tissue which essentially correspond to those taking place in humans ( in an early phase ( months 10 - 15 of life ) compensated heart failure with hypertrophy ( nyha stage i - ii ) and in the later phase ( months 16 - 21 of life ) decompensated heart failure with ventricular dilatation and fibrosis ( nyha stage iii - iv )). as mentioned above , 3 months after the start of treatment , when the number of surviving animals in the placebo control group was only 7 , an interim analysis was carried out on 7 animals from each group . the weight of the complete heart and the weight of the left and right ventricle were measured . just so , the molar ratio of hydroxyproline and ariginine in the heart tissues was measured ( measured via hplc ), which is a marker for the myocardial fibrosis . interestingly , it was possible for a preexisting fibrosis to be reduced by late - onset treatment with cariporide but not with ramipril ( fig2 ). fig2 shows the effect of late treatment with cariporide and ramipril on myocardial fibrosis in old spontaneously hypertensive rats . hyp / arg is the ratio of hydroxyproline to arginine and is regarded as a fibrosis marker . these effects are also reflected in the weights of the hearts ( fig3 ). fig3 shows the effect of late treatment with cariporide and ramipril on the weight of the hearts of spontaneously hypertensive rats . the present results show that a therapy with a combination of the nhe1 inhibitor cariporide and ramipril has a life - prolonging effect and inhibits the progression of or partially reverses age - related organ damage , in particular heart failure , even with a late - onset therapy and / or in the presence of high blood pressure . in the methods according to the invention cariporide and ramipril may be administered in different ways , such as in combination therapies optionally employing medical procedures . for example , cariporide and ramipril may be administered to a patient concomitantly or at different times in any order provided that they are administered such that at some period of time there are pharmaceutically effective amounts of both compounds present in the patient such that a therapeutic effect according to the invention results . it is a further object of the invention to provide a kit for inhibiting the development of age - related organ damage , inhibiting progression of heart failure , effecting a partial regression of heart failure , or inhibiting the development of age - related disorders or prolonging life in a patient , said kit comprising a plurality of separate containers , wherein at least one of said containers contains cariporide and at least another of said containers contains ramipril , and said containers optionally contain a pharmaceutical carrier , which kit may be effectively utilized for carrying out combination therapies according to the invention . a further embodiment for a kit would be wherein of said containers at least one of said containers should contain cariporide without the presence of the ramipril , and at least another of said containers should contain ramipril without the presence of cariporide . in practice , cariporide and ramipril may be administered parenterally , topically , rectally , transdermally or orally , but they are preferably administered parenterally and / or orally . suitable compositions containing the compounds used according to the invention may be prepared by conventional means . for example , the compounds used according to the invention may be dissolved or suspended in a suitable carrier . the compounds used according to the invention should be presented in forms permitting administration by the most suitable route , and the invention also relates to a pharmaceutical composition containing the compounds used according to the invention which are suitable for use in human or veterinary medicine . these compositions may be prepared according to the customary methods , using one or more pharmaceutically acceptable carrier , which comprise adjuvants or excipients . the adjuvants comprise , inter alia , diluents , sterile aqueous media and the various non - toxic organic solvents . the compositions may be presented in the form of tablets , pills , capsules , lozenges , troches , hard candies , granules , powders , aqueous solutions or suspensions , injectable solutions , elixirs or syrups and can contain one or more agents chosen from the group comprising sweeteners , flavorings , colorings , or stabilizers in order to obtain pharmaceutically acceptable preparations . the choice of vehicle and the content of compounds used according to the invention in the vehicle are generally determined in accordance with the solubility and chemical properties of the compounds , the particular mode of administration and the provisions to be observed in pharmaceutical practice . for example , excipients such as sterile water , ringer &# 39 ; s solution , lactose , sodium citrate , isotonic saline solutions ( monosodium or disodium phosphate , sodium , potassium , calcium or magnesium chloride , or mixtures of such salts ), calcium carbonate and disintegrating agents such as starch , alginic acids and certain complex silicates combined with lubricants such as magnesium stearate , sodium lauryl sulfate and talc may be used for preparing tablets . to prepare a capsule , it is advantageous to use lactose and high molecular weight polyethylene glycols . when aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension . diluents such as sucrose , ethanol , polyethylene glycol , propylene glycol , glycerol and chloroform or mixtures thereof may also be used . for parenteral administration , emulsions , suspensions or solutions of the compounds used according to the invention in vegetable oil , for example sesame oil , groundnut oil or olive oil , or aqueous - organic solutions such as water and propylene glycol , injectable organic esters such as ethyl oleate , as well as sterile aqueous solutions of the pharmaceutically acceptable salts , are useful . the solutions of the salts of the compounds used according to the invention are especially useful for administration by intramuscular , intravenous , intraarterial or subcutaneous injection or infusion techniques . the aqueous solutions , also comprising solutions of the salts in pure distilled water , may be used for intravenous administration with the proviso that their ph is suitably adjusted , that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating , irradiation or microfiltration . the percentage in galenic formulations of cariporide and ramipril used according to the invention may be varied in the range between 0 . 1 and 90 percent by weight . the compounds should constitute a proportion such that a suitable dosage shall be obtained . obviously , several unit dosage forms may be administered . the dose employed will be determined by the physician , and depends upon the desired therapeutic effect , the route of administration and the duration of the treatment , and the condition of the patient . in each particular case , the doses will be determined in accordance with the factors distinctive to the subject to be treated , such as age , weight , general state of health and other characteristics which can influence the efficacy of the medicinal product . the ratio by weight of cariporide and ramipril in the combinations according to the invention conventionally lies in the range between 1 : 0 . 0001 and 1 : 1 , preferably between 1 : 0 . 0001 and 1 : 0 . 1 , for example between 1 : 0 . 0005 and 1 : 0 . 01 . the dose employed of the active substances cariporide and / or ramipril depends on the individual case and must be adapted to the present circumstances to reach an optimal effect . obviously the dose is dependent on the frequency of giving the substances and on the kind of the galenic formulation , and also dependent on the kind and severity of the disease and the condition of the patient and whether it is used for acute and / or chronic treatment or prevention . when used for mammals , especially on humans , the dosage of ramipril can vary in a range between 0 . 1 and 10 mg per day and patient ( with a body weight of about 70 kg ), preferably between 0 . 1 and 5 mg per day and patient , further preferably between 0 . 2 and 2 . 5 mg per day and patient . the dosages of ramipril can also be in a subthreshold range from about 0 . 1 to 1 mg per day and patient , preferably 0 . 3 to 0 . 7 mg per day and patient . the dosages of cariporide are generally from about 50 mg to 1 g per day and patient , preferably 100 to 500 mg per day and patient . for example , the ramipril dose can be 0 . 625 mg per day and patient and the dose of cariporide 200 mg per day and patient . cariporide and ramipril may be administered in dosages which are pharmaceutically effective for each compound , or in dosages which are sub - clinical , i . e ., less than pharmaceutically effective for each , or a combination thereof , provided that the combined dosages are pharmaceutically effective . cariporide and ramipril used according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect . the dosage regimen in carrying out the method of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief . some patients may respond rapidly to a higher or lower dose and may find much lower maintenance doses adequate . both short - and long - term treatments regimens are contemplated for the invention . treatments at the rate of about 1 to about 4 doses per day are also contemplated , in accordance with the physiological requirements of each particular patient , bearing in mind , of course , that in selecting the appropriate dosages in any specific case , consideration must be given to the patient &# 39 ; s weight , general health , age , and other factors which may influence response to the drug . continuous parenteral infusion , in order to maintain therapeutically effective blood levels of cariporide and ramipril is also contemplated .

this invention is directed to a pharmaceutical composition comprising the sodium - hydrogen exchanger inhibitor cariporide and an angiotensin converting enzyme inhibitor which exhibits unexpectedly efficacious properties for preventing heart failure and other age - related organ dysfunctions , age - related disorders and for prolonging life , and to methods of preventing heart failure and other age - related organ dysfunctions , age - related disorders and for prolonging life comprising administering pharmaceutically effective amounts of the sodium - hydrogen exchange inhibitor cariporide and an ace inhibitor .

other objects , features and aspects of the present invention are disclosed in , or are obvious from , the following detailed description . it is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not intended as limiting the broader aspects of the present invention , which broader aspects are embodied in the exemplary construction . in fact , it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention . for instance , features illustrated or described as part of one embodiment can be used in another embodiment to yield a still further embodiment . it is intended that the present invention cover such modifications and variations as come within the scope of the appended claims and their equivalents . for convenience , certain terms employed in the specification , examples , and appended claims are collected here . definitions : as used herein , the term “ comprising ” in this disclosure can mean “ including ” or can have the meaning commonly given to the term “ comprising ” in u . s . patent law . preferred topical formulations include those formulations wherein the 1 - arylpyrazol is a compound of the formula : in which : r 1 is a halogen atom , cn or alkyl ; r 2 is s ( o ) n r 3 or 4 , 5 - dicyanoimidazol - 2 - yl or haloalkyl ; r 3 is alkyl , alkenyl , alkynyl , haloalkyl , haloalkenyl or haloalkyl ; r 4 is hydrogen , halogen , nr 5 r 6 , s ( o ) m r 7 , c ( o ) r 7 , c ( o ) or 7 , alkyl , haloalkyl , or 8 or — n ═ c ( r 9 )( r 10 ) substituent ; r 5 and r 6 independently represent a hydrogen atom , alkyl , haloalkyl , c ( o ) alkyl , s ( o ) r cf 3 or alkoxycarbonyl or r 5 and r 6 together may combine to form a ring of 5 to 7 members . r 7 represents an alkyl or haloalkyl group ; r 8 represents an alkyl , haloalkyl or a hydrogen ; r 9 represents an alkyl or a hydrogen ; r 10 represents an optionally substituted aryl or an optionally substituted heteroaryl group ; r 11 and r 12 represent , independently of one another , hydrogen , halogen cn or no 2 ; r 13 represents a halogen atom or a haloalkyl , haloalkoxy , s ( o ) q cf 3 or sf 5 group ; m , n , q and r represent , independently of one another , an integer equal to 0 , 1 or 2 ; x represents a trivalent nitrogen atom or a c — r 12 , the three other valencies of the carbon atom forming part of the aromatic ring optionally with a pharmaceutically acceptable carrier or excipient . a more preferred formulation is one wherein the 1 - n - arylpyrazole is a compound of the formula : in which : r 1 is a halogen atom , cn or methyl ; r 2 is s ( o ) n r 3 or 4 , 5 - dicyanoimidazol - 2 - yl or haloalkyl ; r 3 is alkyl , haloalkyl , haloalkenyl or haloalkynyl ; r 4 represents a hydrogen or halogen atom or an nr 5 r 6 , s ( o ) m r 7 , c ( o ) r 7 or c ( o ) or 7 , alkyl , haloalkyl or or 8 or an — n ═ c ( r 9 )( r 10 ) group ; r 5 and r 6 independently represent a hydrogen atom or an alkyl , haloalkyl , c ( o ) alkyl , s ( o ) r cf 3 or alkoxycarbonyl group or r 5 , and r 6 together may form a ring of 5 to 7 members ; r 7 represents an alkyl or haloalkyl substituent ; r 8 represents an alkyl or haloalkyl or a hydrogen ; r 9 represents an alkyl or a hydrogen atom ; r 10 represents an optionally substituted aryl or an optionally substituted heteroaryl group ; r 11 and r 12 represent , independently of one another , hydrogen , halogen cn or no 2 ; r 13 represents a halogen atom or a haloalkyl , haloalkoxy , s ( o ) q cf 3 or sf 5 group ; m , n , q and r represent , independently of one another , an integer equal to 0 , 1 or 2 ; x represents a trivalent nitrogen atom or a c — r 12 , the three other valencies of the carbon atom forming part of the aromatic ring ; with the proviso that , when r is methyl , then either r 3 is haloalkyl , r 4 is nh 2 , r 11 is cl , r 13 is cf 3 and x is n or else r 2 is 4 , 5 - dicyanoimidazol - 2 - yl , r 4 is cl , r 11 is cl , r 13 is cf 3 and x is c - cl ; and / or more preferably , this invention provides for a parasitical spot - on formulation wherein the 1 - n - arylpyrazole in the ectoparasitical combination is a compound of the formula ( i ) wherein : r 1 is a halogen atom , cn or methyl ; r 2 is s ( o ) n r 3 or 4 , 5 - dicyanoimidazol - 2 - yl or haloalkyl ; r 3 is c 1 - c 6 - alkyl or c 1 - c 6 - haloalkyl ; r 4 represents a hydrogen or halogen atom ; or nr 5 r 6 , s ( o ) m r 7 , c ( o ) r 7 or c ( o ) or 7 , alkyl , haloalkyl or or 8 or — n ═ c ( r 9 ) ( r 10 ); r 5 and r 6 independently represent a hydrogen atom or a c 1 - c 6 alkyl , c 1 - c 6 - haloalkyl , c ( o ) c 1 - c 6 - alkyl , s ( o ) r cf 3 , c 1 - c 6 - acyl or c 1 - c 6 - alkoxycarbonyl ; r 5 and r 6 together may combine to form a ring of 5 to 7 members , which may include one or two divalent heteroatoms selected from the group consisting of oxygen or sulphur ; r 7 represents a c 1 - c 6 - alkyl or c 1 - c 6 - haloalkyl ; r 8 represents a c 1 - c 6 - alkyl or c 1 - c 6 - haloalkyl or a hydrogen atom ; r 9 represents a c 1 - c 6 - alkyl or a hydrogen atom ; r 10 represents an optionally substituted phenyl or optionally substituted heteroaryl group wherein the substituents are selected from the group consisting of halogen , oh , — o — c 1 - c 6 alkyl , — s — c 1 - c 6 - alkyl , cyano or c 1 - c 6 - alkyl ; r 11 and r 12 , independently of one another represent hydrogen , halogen , cn or no 2 ; r 13 represents a halogen , c 1 - c 6 - haloalkyl , c 1 - c 6 - haloalkoxy , s ( o ) q cl 3 or sf 5 group ; and , m , n , q and r independently of one another are 0 , 1 , or 2 ; ( b ) the liquid carrier vehicle comprises a solvent and a cosolvent wherein the solvent is selected from the group consisting of acetone , acetonitrile , benzyl alcohol , butyl diglycol , dimethylacetamide , dimethylformamide , dipropylene glycol n - butyl ether , ethylene glycol monoethyl ether , monomethylacetamide , d ipropylene glycol monomethyl ether , liquid polyoxyethylene glycols , propylene glycol , 2 - pyrrolidone , in particular n - methylpyrrolidone , diethylene glycol monoethyl ether , ethylene glycol , diethyl phthalate fatty acid esters , such as the diethyl ester or diisobutyl adipate , and a mixture of at least two of these solvents and the cosolvent is selected from the group consisting of ethanol , isopropanol or methanol ; and ( c ) a crystallization inhibitor selected from the group consisting of an anionic surfactant , a cationic surfactant , a non - ionic surfactant , an amine salt , an amphoteric surfactant or polyvinylpyrrolidone , polyvinyl alcohols , copolymers of vinyl acetate and vinylpyrrolidone , polyethylene glycols , benzyl alcohol , mannitol , glycerol , sorbitol , polyoxyethylenated sorbitan esters ; lecithin , sodium carboxymethylcellulose , and acrylic derivatives , or a mixture of these crystallization inhibitors . especially preferred as spot - on formulations are those wherein the 1 - n - arylpyrazole derivative in the ectoparasitical combination is a compound wherein the ring formed by the divalent alkylene substituent representing r 5 and r 6 and the nitrogen atom to which r 5 and r 6 are attached has 5 , 6 or 7 members or wherein r 1 is cn , r 3 is c 1 - c 6 - haloalkyl , r 4 is nh 2 , r 11 , and r 12 are , independently of one another , hydrogen or halogen and r 13 is c 1 - c 6 - haloalkyl . most especially preferred 1 - n - arylpyrazoles to be used in the inventive spot - on and pour - on formulations are : other 1 - n - arylpyrazole derivatives to be used in the formulation to the invention which are preferred are those of the formula ( ii ) r 101 is cyano , — c ( o ) alkyl , c ( s ) nh 2 , alkyl , haloalkyl , c (═ noh ) nh 2 or c (═ nnh 2 ) nh 2 ; r 102 is s ( o ) n , r 103 , alkenyl , haloalkenyl , cycloalkyl , halocycloalkyl or alkynyl ; r 103 is alkyl , alkenyl , alkynyl , haloalkyl , haloalkenyl or haloalkynyl ; r 104 is — n ═ c ( r 105 )- z - r 106 , — n ═ c ( r 105 )— n ( r 107 )— r 108 ; or — n ( r 109 )— c ( r 105 )= nr 106 ; r 105 is hydrogen ; alkyl ; or alkyl substituted by halogen , alkoxy , haloalkoxy or — s ( o ) m , r 105 ; r 106 and r 107 each independently represent hydrogen , alkyl , alkenyl or alkynyl , or alkyl substituted by one or more halogen , alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , cyano or — s ( o ) m , r 115 ; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen , nitro and alkyl group ; or r 107 and r 108 may form together with the nitrogen to which they are attached a 3 - to 7 - membered ring which may additionally contain one or more heteroatoms selected from oxygen , nitrogen or sulfur ; r 108 is alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , — c ( o ) r 114 or — s ( o ) t , r 110 ; r 109 , r 110 and r 114 are alkyl or haloalkyl ; r 111 and r 112 are independently selected from halogen , hydrogen , cn and no 2 r 113 is selected from halogen , haloalkyl , haloalkoxy , — s ( o ) q , cf 3 , and — sf 5 ; r 15 is alkyl or haloalkyl ; x is selected from nitrogen and c — r 112 ; z is o , s ( o ) a ′; or nr 107 ; a ′, m ′, n ′ and q ′ are independently selected from 0 , 1 , and 2 ; and t ′ is 0 , 1 or 2 ; and veterinary acceptable salts thereof . other preferred 1 - n - arylpyrazole derivatives that may be included in the inventive formulations are those compounds of formula ( iii ): r 201 is cyano , c ( o ) alkyl , c ( s ) nh 2 , alkyl , c (═ noh ) nh 2 or c (═ nnh 2 ) nh 2 ; r 202 is s ( o ) h r 203 , alkenyl , haloalkenyl , cycloalkyl , halocycloalkyl or alkynyl ; r 203 is alkyl , alkenyl , alkynyl , haloalkyl , haloalkenyl or haloalkynyl ; r 204 is — n ( r 205 ) c ( o ) cr 206 r 207 r 208 , — n ( r 205 ) c ( o ) aryl , or — n ( r 205 ) c ( o ) or 207 ; r 205 is alkyl , haloalkyl , cycloalkyl , halocycloalkyl , cycloalkylalkyl , halocycloalkylalkyl , alkoxyalkyl , haloalkoxyalkyl , alkenyl , haloalkenyl , alkynyl , haloalkynyl ; r 206 is hydrogen , halogen , alkoxy , haloalkoxy , alkoxyalkyl , haloalkoxyalkyl , formyloxy , alkylcarbonyloxy , haloalkylcarbonyloxy , alkylthio , haloalkylthio , alkylsulfinyl , haloalkylsulfinyl , alkylsulfonyl , haloalkylsulfonyl , alkylamino , dialkylamino , haloalkylamino , di ( haloalkyl ) amino , cycloalkyloxy , halocycloalkyloxy , alkoxyalkoxy , haloalkoxyalkoxy , alkoxyalkoxyalkoxy , aryloxy , or arylalkoxy ; r 207 and r 208 are independently hydrogen , alkyl , haloalkyl , cycloalkyl , or halocycloalkyl ; or r 207 and r 208 may form together with the carbon to which they are attached a 3 - to 7 - membered ring which additionally may contain one or more heteroatoms selected from nitrogen , oxygen and sulfur ; x 1 is selected from nitrogen and c — r 212 ; r 211 , and r 212 are independently selected from halogen , hydrogen , cn and no 2 ; r 213 is selected from halogen , haloalkyl , haloalkoxy , — s ( o ) k cf 3 , and — sf 5 ; and h and k are independently selected from 0 , 1 , and 2 ; and veterinary acceptable carrier , excipients and salts thereof . a preferred class of compounds of formula ( ii ) for use in the inventive formulation is those wherein : r 103 is cyano or alkyl ; r 102 is s ( o ) n , r 103 ; r 103 is alkyl or haloalkyl ; r 104 is — n ═ c ( r 105 )- z - r 106 ; r 105 is hydrogen , alkyl or haloalkyl ; z is o , s ( o ) a ′; or nr 107 ; r 106 and r 107 are independently selected from hydrogen and unsubstituted or substituted alkyl ; or r 106 and r 107 may form together with the nitrogen to which they are attached a 3 - to 7 - membered ring which may additionally contain one or more heteroatoms selected from oxygen , nitrogen or sulfur ; x is selected from nitrogen and c — r 112 ; r 111 and r 112 are independently selected from halogen , hydrogen , cn and no 2 ; r 113 is selected from halogen , haloalkyl , haloalkoxy , — s ( o ) q , cf 3 , and — sf 5 ; a ′, n ′ and q ′ are independently selected from 0 , 1 , and 2 . preferably , r 106 is alkyl which is substituted by one or more halogen , alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , sulfide , sulfoxide , sulfone , or phenyl or pyridyl moieties of which each phenyl or pyridyl moiety is optionally substituted with one or more groups selected from halo , nitro , and alkyl . r 101 is cyano ; r 104 is — n ═ c ( r 105 )- z - r 106 and z is — nr 107 ; x is c — r 112 ; r 111 and r 112 represent a chlorine atom ; and r 113 is cf 3 , ocf 3 , or — sf 5 ; r 112 is — s ( o ) n , cf 3 and n is 0 , 1 , or 2 . a further preferred class of 1 - n - arylpyrazoles that may be included in the inventive formulations or approaches are those of formula ii wherein : r 101 is cyano or alkyl ; r 104 is — n ═ c ( r 105 )- z - r 106 ; and r 1 05 is hydrogen or c 1 - c 3 alkyl . the compounds of formula ( ii ) preferably have one or more of the following features : r 101 is cyano or methyl ; r 103 is halomethyl ( preferably cf 3 ); r 111 and r 112 each independently represent a halogen atom ; x is c — r 112 ; r 113 is haloalkyl ( preferably cf 3 haloalkoxy ( preferably ocf 3 ), or — sf 5 ; or n ′ is 0 , 1 or 2 ( preferably 0 or 1 ). a further preferred class of compounds of formula ( ii ) for use in the inventive formulations and methods are those wherein : r 101 is cyano ; r 102 is s ( o ) n , r 103 ; r 103 is halomethyl ; r 104 is — n ═ c ( r 105 )- z - r 106 ; z is nr 107 ; r 105 is hydrogen or alkyl ; r 106 and r 107 each independently represent hydrogen , alkyl , alkenyl or alkynyl ; or alkyl substituted by one or more halogen , alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , cyano or — s ( o ) m r 15 ; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen , nitro and alkyl ; x is selected from nitrogen and c — r 112 ; r 106 and r 112 each independently represent a halogen atom ; r 113 is selected from haloalkyl , haloalkoxy and — sf 5 ; r 115 is alkyl or haloalkyl ; and m ′ and n ′ are independently selected from 0 , 1 , and 2 . a further preferred class of compounds of formula ( ii ) is that wherein : r 101 is cyano ; r 102 is s ( o ) n , r 103 ; r 104 is — n ═ c ( r 105 )- z - r 106 or — n ═ c ( r 05 )— n ( r 107 )— r 108 ; z is nr 107 ; r 105 is hydrogen or alkyl ; r 106 and r 107 each independently represent hydrogen , alkyl , alkenyl or alkynyl ; or alkyl substituted by one or more halogen , alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , cyano or — s ( o ) r 115 ; or methyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen , nitro and alkyl ; r 108 is alkoxy , haloalkoxy , amino , alkylamino , dialkylamino or — s ( o ) t , r 110 ; x is selected from nitrogen and c — r 112 ; r 109 , r 110 and r 114 independently represent alkyl or haloalkyl ; r 111 and r 112 each represent a chlorine atom ; r 113 is cf 3 or — sf 5 ; and m ′ and n ′ are 0 , 1 or 2 ; and t ′ is 0 or 2 . a further preferred class of compounds of formula ( ii ) are those wherein : r 101 is cyano ; r 102 is s ( o ) n1 cf 3 ; r 104 is — n ═ c ( r 105 )- z - r 106 ; z is nr 107 ; r 105 is hydrogen or methyl ; r 106 and r 107 each independently represent hydrogen , alkyl , alkenyl or alkynyl ; or alkyl substituted by one or more halogen , alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , cyano or — s ( o ) m , r 115 ; or alkyl substituted by phenyl or pyridyl which rings are optionally substituted with one or more groups selected from halogen , nitro and alkyl ; x is c — r 112 r 111 and r 112 each represent a chlorine atom ; r 113 is cf 3 or — sf 5 ; m ′ is zero , one or two ; and n ′ is 0 or 1 . a further preferred class of compounds of formula ( ii ) is those wherein : r 101 is cyano ; r 102 is s ( o ) n , cf 3 ; r 104 is — n ═ c ( r 105 )- z - r 106 ; z is nr 107 ; r 105 and r 107 each represent a hydrogen atom ; r 106 is alkyl or haloalkyl ; x is c — r 112 ; r 111 and r 112 each represent a chlorine atom ; r 113 is cf 3 or — sf 5 ; and n ′ is 0 . compounds of formula ( iii ) which are preferred according to the present invention are those wherein : r 201 is cyano ; r 202 is s ( o ) h r 203 ; r 203 is alkyl or haloalkyl ; r 204 is — n ( r 20 5 ) c ( o ) cr 206 r 207 r 20 8 ; r 205 is alkyl , haloalkyl , cycloalkyl , cycloalkylalkyl and halocycloalkylalkyl ; r 206 is alkoxy , haloalkoxy , or hydrogen ; r 207 and r 208 are independently hydrogen , alkyl , or haloalkyl ; or r 207 and r 208 may form together with the carbon to which they are attached to a 3 - to 7 - membered ring which additionally may contain one or more heteroatoms selected from nitrogen , oxygen and sulfur ; x 1 is selected from nitrogen and c — r 212 ; r 211 and r 212 are independently selected from halogen , hydrogen , cn and no 2 ; r 213 is selected from halogen , haloalkyl , haloalkoxy , — s ( o ) k cf 3 , and — sf 5 ; and h and k are independently selected from 0 , 1 , and 2 . a preferred group of compounds of formula ( iii ) is that wherein the ring which is formed by r 207 and r 208 contains one or more heteroatoms , more preferably one oxygen atom . the compounds of formula ( iii ) of the present invention preferably have one or more of the following features : r 201 is cyano ; r 203 is halomethyl , preferably cf 3 ; r 211 and r 212 are independently halogen ; x 1 is c — r 212 ; r 213 is haloalkyl , haloalkoxy or — sf 5 ; or h is 0 or 1 , or 2 , preferably 0 or 1 . a preferred class of compounds that wherein r 204 is n ( r 205 ) c ( o ) cr 206 r 207 r 208 . another preferred class of compounds that wherein r 204 is n ( r 205 ) c ( o ) aryl . another preferred class of compounds that wherein r 204 is n ( r 205 ) c ( o ) or 207 . preferably r 205 is c 1 - c 4 alkyl , more preferably c 1 - c 2 alkyl , most preferably methyl . preferably r 206 is alkoxy , most preferably methoxy , ethoxy or propoxy . another especially preferred group of 1 - n - arylpyrazole derivatives is 4 - thiocarbonylpyrazole derivatives of the formula : r 301 is h 2 n — c ( s )—, r 302 is halogenoalkyl , halogenoalkenyl or halogenoalkynyl , r 303 is hydrogen , amino or one of the following groups : where r 304 represents alkyl , halogenoalkyl , alkoxyalkyl or in each case optionally substituted phenyl or pyridyl , r 305 represents hydrogen or alkyl , r 306 represents hydrogen , alkyl or in each case optionally substituted phenyl or pyridyl and r 307 represents alkyl , alkenyl , alkinyl , formyl , alkylcarbonyl , halogenoalkylcarbonyl or alkoxycarbonyl ; ar represents in each case optionally substituted phenyl or pyridyl and n represents a number 0 , 1 or 2 . r 301 represents h 2 n — c ( s )—; r 302 preferably represents ( c 1 - c 6 )- halogenoalkyl having 1 to 12 halogen atoms ; ( c 2 - c 6 )- halogenoalkenyl having 1 to 8 halogen atoms or ( c 1 - c 6 )- halogenoalkinyl having 1 to 6 halogen atoms ; r 303 preferably represents hydrogen , amino or one of the following groups : wherein : r 304 represents ( c 1 - c 6 )- alkyl , ( c 1 - c 6 )- halogenoalkyl having 1 to 3 halogen atoms , ( c 1 - c 6 )- alkoxy -( c 1 - c 6 )- alkyl , or represents phenyl or pyridyl , each of which is optionally monosubstituted to trisubstituted by identical or different substituents from the group consisting of cyano , nitro , halogen , c 1 - c 6 - alkyl , c 1 - c 6 - alkoxy , c 1 - c 6 - alkylthio , c 1 - c 4 - halogenoalkyl , c 1 - c 4 halogenoalkoxy or c 1 - c 4 - halogenoalkylthio having in each case 1 to 5 halogen atoms , r 305 represents hydrogen or ( c 1 - c 6 )- alkyl , r 306 represents hydrogen , ( c 1 - c 6 )- alkyl , phenyl which is optionally monosubstituted to trisubstituted by identical or different substituents from the group consisting of cyano , nitro , halogen , c 1 - c 6 - alkyl , c 1 - c 6 - alkoxy , c 1 - c 6 - alkylthio , c 1 - c 4 - halogenoalkyl , c 1 - c 4 - halogenoalkoxy or c 1 - c 4 - halogenoalkylthio having in each case 1 to 5 halogen atoms or hydroxyl , or represents pyridyl which is substituted by cyano , nitro , halogen , c 1 - c 6 - alkyl , c 1 - c 6 - alkoxy , c 1 - c 6 - alkylthio , c 1 - c 4 - halogenoalkyl , c 1 - c 4 - halogenoalkoxy or c 1 - c 4 - halogenoalkylthio having in each case 1 to 5 halogen atoms , and r 307 represents ( c 1 - c 6 )- alkyl , ( c 2 - c 6 )- alkenyl , ( c 2 - c 6 )- alkynyl , formyl , ( c 1 - c 6 )- alkylcarbonyl , ( c 1 - c 6 )- halogenoalkylcarbonyl having 1 to 6 halogen atoms or ( c 1 - c 6 )- alkoxycarbonyl ; ar preferably represents phenyl or pyridyl , each of which is optionally monosubstituted to trisubstituted by identical or different substituents from the group consisting of halogen halogeno ( c 1 - c 6 ) alkyl , halogeno ( c 1 - c 6 ) alkylthio , halogeno ( c 1 - c 6 ) alkoxy , ( c 1 - c 6 ) alkoxy , methoxy , hydrazine , ( c 1 - c 6 )- dialkylhydrazino , amino , ( c 1 - c 6 ) alkylamino , di ( c 1 - c 6 ) alkylamino , ( c 1 - c 6 ) alkylimino , cyano , ( c 1 - c 6 ) alkylthio or the group in which r 308 and r 309 are identical or different and represent hydrogen or ( c 1 - c 6 )- alkyl n 111 preferably represents a number 0 , 1 or 2 . r 301 represents h 2 n — c ( s )—; r 302 particularly preferably represents ( c 1 - c 4 )- halogenoalkyl having 1 or 9 identical or different halogen atoms from the group consisting of fluorine , chlorine and bromine , ( c 2 - c 4 )- halogenoalkenyl having 1 to 5 identical or different halogen atoms from the group consisting of fluorine , chlorine or bromine or ( c 2 - c 4 )- halogenoalkynyl having 1 to 5 identical or different halogen atoms from the group consisting of fluorine , chlorine and bromine ; r 303 especially preferably represents hydrogen , amino or one of the following groups : where r 304 represents ( c 1 - c 4 )- alkyl , ( c 1 - c 4 )- halogenoalkyl having 1 - 3 halogen atoms , ( c 1 - c 4 )- alkoxy ( c 1 - c 2 )- alkyl , or phenyl which is optionally monosubstituted to trisubstituted by identical or different substituents from the group consisting of hydroxyl , cyano , nitro , halogen , c 1 - c 4 - alkyl , c 1 - c 4 - alkoxy , ( c 1 - c 2 - halogenoalkyl , c 1 - c 2 - halogenoalkoxy or c 1 - c 2 - halogenoalkylthio having in each case 1 to 3 halogen atoms , r 305 represents hydrogen or ( c 1 - c 4 )- alkyl , r 306 represents hydrogen , ( c 1 - c 4 )- alkyl or phenyl which is optionally monosubstituted or disubstituted by identical or different substituents from the group consisting of hydroxyl , cyano , nitro , halogen , c 1 - c 4 - alkyl , c 1 - c 4 - alkoxy , c 1 - c 2 - halogenoalkyl , c 1 - c 2 halogenoalkoxy or c 1 - c 2 halogenoalkylthio having in each case 1 to 3 halogen atoms , in particular 4 - hydroxy - 3 - methoxy - phenyl , and r 307 represents ( c 1 - c 4 )- alkyl , ( c 2 - c 4 )- alkenyl , ( c 2 - c 4 )- alkynyl , formyl , ( c 1 - c 4 )- alkylcarbonyl , ( c 1 - c 4 ,)- halogenoalkylcarbonyl having 1 to 5 identical or different halogen atoms from the group consisting of fluorine , chlorine or bromine or ( c 1 - c 4 )- alkoxycarbonyl ; ar especially preferably represents phenyl or pyridyl , each of which is optionally monosubstituted to trisubstituted by identical or different substituents from the group consisting of fluorine , chlorine , trifluoromethyl , trifluoromethylthio , trifluoromethoxy , methoxy , hydrazine , dimethylhydrazino , amino , methylamino , dimethylamino , iminomethyl , cyano , methylthio or the group where r 308 and r 309 are identical or different and represent hydrogen or ( c 1 - c 4 )- alkyl ; n 111 especially preferably represents a number 0 , 1 or 2 . compounds of formula ( iv ) which are most preferably preferred are those where r 301 represents h 2 n — c ( s )—; r 302 most preferably represents one of the following groups : — cf 3 , — chf 2 — cf 2 — ch 3 — cf 3 — chf 2 , — cf 2 chfcl , — ch 2 — cf 3 , — ch 2 cf 2 ci , — ch 2 — cf 2 — chf 2 , — cf 2 — cfc 1 - cf 3 , — c ( cl )( cf 3 )— cf 2 ci , — c ( cl )( cf 3 )— chcl — cf 3 , — c ( cf 3 )═ ccl 2 r 303 most preferably represents hydrogen , amino or one of the groups : ( 1 ) phenyl which is disubstituted or trisubstituted by identical or different substituents , where fluorine or chlorine occupies the 2 - position , trifluoromethyl the 4 - position and fluorine , chlorine , cyano , methoxy , methylthio , trifluoromethyl , trifluoromethoxy , trifluoromethylthio or hydrazino the 6 - position ; or ( 2 ) a 2 - pyridyl substituent which is substituted in the 4 - position by trifluoromethyl and in the 6 - position by fluorine or chlorine . n 111 most preferably represents one of the integers 0 , 1 or 2 . a most especially preferred compound is one wherein r 302 is — cf 3 , r 303 is amino , ar is a phenyl which is trisubstituted and the substituents are a 2 - position chloro group , a 4 - position trifluoromethyl group and a 6 - position chloro group , and n 111 is 1 . in addition to the patent discussing 1 - n - arylpyrazoles derivatives discussed previously , one skilled in the art could make these compounds by adopting procedures described in de 19928155 , de 19853560 , wo 2000031043 , de 19650197 , wo 9824769 , u . s . pat . no . 6 , 265 , 430 , u . s . 2001007876 , all of which are herein incorporated by reference . the alkyl groups of the definition of the compounds ( 1 ) of the formula ( i ) generally comprise from 1 to 6 carbon atoms . the ring formed by r 5 and r 6 and the nitrogen atom to which they are attached is generally a 5 -, 6 - or 7 - membered ring . unless otherwise specified , alkyl and alkoxy groups are generally lower alkyl and alkoxy groups , that is having from one to six carbon atoms , preferably from one to four carbon atoms . generally , the haloalkyl , haloalkoxy and alkylamino groups have from one to four carbon atoms . the haloalkyl and haloalkoxy groups can bear one or more halogen atoms ; preferred groups of this type include — cf 3 and — ocf 3 . cycloalkyl groups generally have from 3 to 6 carbon atoms , preferably from 3 to 5 carbon atoms , and may be substituted by one or more halogen atoms . alkenyl , haloalkenyl , alkynyl , and haloalkynyl groups generally contain from 3 to 5 carbon atoms . by the term aryl is generally meant phenyl , pyridyl , furyl , and thiophenyl , each of which is optionally substituted by one or more halogen , alkyl , haloalkyl , nitro , alkoxy , haloalkoxy , hydroxy , amino , alkylamino or dialkylamino . in compounds of formulae ( 1 ) to ( iii ), by the term substituted alkyl is meant alkyl which is substituted by , for example , one or more halogen , alkoxy , haloalkoxy , amino , alkylamino , dialkylamino , cyano or — s ( o ) m r 115 ; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen , nitro and alkyl ; wherein r 115 is alkyl or haloalkyl and m is zero , one or two . preferably in compounds of formula ( i ), alkyl groups are generally substituted by from one to five halogen atoms , preferably from one to three halogen atoms . chlorine and fluorine atoms are preferred . compounds of formula wherein r 104 is — n ═ c ( r 105 )- z - r 106 , z is nr 107 and r 106 represent a hydrogen atom may exist as the tautomeric double bond isomer form — nh — c ( r 105 )═ n — r 107 . it is to be understood that both such forms are embraced by the present invention . in compounds of formula ( iii ) the following examples of substituents are provided : an example of alkoxyalkyl is ch 3 och 2 —; an example of alkoxyalkoxy is ch 3 och 2 o —; an example of alkoxyalkoxyalkoxy is ch 3 och 2 och 2 o —; an example of aryloxy is the phenoxy group ; and an example of the arylalkoxy group is benzyloxy or 2 - phenylethoxy . generally , in dialkylamino or di ( haloalkyl ) amino groups , the alkyl and haloalkyl groups on nitrogen may be chosen independently of one another . a preferred class of compounds of formula ( i ) comprises the compounds such that r 1 is cn , r 3 is haloalkyl , r 4 is nh 2 , r 11 and r 12 are , independently of one another , a halogen atom and r 13 is haloalkyl . preferably still , x is c — r 12 . a compound of formula ( i ) which is very particularly preferred in the invention is 5 - amino - 3 - cyano - 1 -( 2 , 6 - dichloro - 4 - trifluoromethylphenyl )- 4 - trifluoromethylsulfinylpyrazole or fipronil . compounds of formulae ( i )-( iii ) can be prepared according to one or other of the processes described in patent applications wo 87 / 3781 , 93 / 6089 and 94 / 21606 , and 00 / 59862 or european patent application 295 , 117 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis . for the chemical preparation of the products of the invention , a person skilled in the art is regarded as having at his disposal , inter alia , the entire contents of “ chemical abstracts ” and of the documents which are cited therein . as discussed above , amitraz is well known in the art and can be obtained from commercial source . igr compounds are another class of insecticides or acaricides , which are provided for in the bait formulations in this invention . compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes . these compounds all act by interfering with the development or growth of the insect pests . compounds with an ovicidal and / or larvicidal effect on the immature stages of various ectoparasites are already known , for example from u . s . pat . no . 5 , 439 , 924 . among these compounds described are those igr compounds which act either by blocking the development of the immature stages ( eggs and larvae ) into adult stages , or by inhibiting the synthesis of chitin . insect growth regulators are described , for example , in u . s . pat . no . 3 , 748 , 356 ; u . s . pat . no . 3 , 818 , 047 ; u . s . pat . no . 4 , 225 , 598 ; u . s . pat . no . 4 , 798 , 837 ; and u . s . pat . no . 4 , 751 , 225 , as well as in ep 179 , 022 or u . k . 2 , 140 , 010 . french patent no . a - 2 , 713 , 889 generally describes an igr combination comprising at least one compound with juvenile hormone activity and chitin synthesis inhibitors , with at least one of three n - arylpyrazole compounds , in particular fipronil , to control many harmful insects belonging to very varied orders . examples of igr compounds which may be used in this invention include compounds which mimic juvenile hormones , in particular : azadirchtin ( agridyne ) diofenolan ( novartis ) fenoxycarb ( novartis ) hydroprene ( novartis ) kinoprene ( novartis ) methoprene ( novartis ) pyriproxyfen ( sumitomo / mgk ) tetrahydroazadirachtin ( agridyne ) 4 - chloro - 2 -( 2 - chloro - 2 - methylpropyl )- 5 -( 6 - iodo - 3 - pyridylmethoxy ) pyridizin - 3 ( 2h )- one and chitin - synthesis inhibitors , in particular : chlorfluazuron ( ishihara sangyo ) cyromazine ( novartis ) diflubenzuron ( solvay duphar ) fluazuron ( novartis ) flucycloxuron ( solvay duphar ) flufenoxuron ( cyanamid ) hexaflumuron ( dow elanco ) lufenuron ( novartis ) tebufenozide ( rohm & amp ; haas ) teflubenzuron ( cyanamid ) triflumuron ( bayer ). these compounds are defined by their international common name ( the pesticide manual , 10 th edition , 1994 , ed . clive tomlin , great britain ). chitin - synthesis inhibitors also include compounds such as 1 -( 2 , 6 - difluorobenzoyl )- 3 -( 2 - fluoro - 4 -(( trifluoromethyl )) phenylurea , 1 -( 2 , 6 - difluorobenzoyl )- 3 -( 2 - fluoro - 4 -( 1 , 1 , 2 , 2 - tetrafluoroethoxy )) phenylurea and 1 -( 2 , 6 - difluorobenzoyl )- 3 -( 2 - fluoro - 4 - trifluoro - methyl ) phenylurea . novaluron ( isagro , italian company ) is also an example of an igr compound . preferred igr compounds include methoprenes , pyriproxyfens , hydroprene , cyromazine , lufenuron , 1 -( 2 , 6 - difluorobenzoyl )- 3 -( 2 - fluoro - 4 -( trifluoromethyl ) phenylurea and novaluron . other class compounds which maybe combined with the inventive ectoparasitical combination include avermectin and milbemycin derivatives , pyrethroids , benzamidazoles and imidazoles . preferred avermectins or milbemycins include doramectin , enamectin , abamectin , eprinomectin , ivermectin , selamectin , moxidectin and milbemycin oxime . preferred pyrethroids include the pyrethrins , permethrin , resmethrin and sumithrin . preferred benzimidazole include albendazole , fenbenazole , mebendazole , oxibendazole and triclabendazole . a preferred imidazoleothiazole is levamisole . the amount of these compounds to be included with the inventive ectoparasitical combination depends on the type of animal and the degree of infestation . the amounts of these compounds are easily determined by one skilled in the art . representative amounts include 0 . 001 mg / kg to 100 mg / kg , with the avermectins having preferred range of 0 . 001 mg / kg to 10 mg / kg and the other classes from 0 . 1 mg / kg to 100 mg / kg . administration of the inventive formulation may be intermittent in time and may be administered daily , weekly , biweekly , monthly , bimonthly , quarterly , or even for longer durations of time . the time period between treatments depends upon factors such as the parasite ( s ) being treated , the degree of infestation , the type of animal , mammal or bird , and the environment where it resides . it is well within the skill level of the practitioner to determine a specific administration period for a particular situation . this invention contemplates a method for permanently combating a parasite in an environment in which the animal is subjected to strong parasitic pressure where the administration is at a frequency far below a daily administration in this case . for example , it is preferable for the treatment according to the invention to be carried out monthly on mammals , such as on dogs and on cats . spot - on formulations may be prepared by dissolving the active ingredients into the pharmaceutically or veterinary acceptable vehicle . alternatively , the spot - on formulation can be prepared by encapsulation of the active ingredient to leave a residue of the therapeutic agent on the surface of the animal . these formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the species of host animal to be treated , the severity and type of infection and the body weight of the host . the compounds may be administered continuously , particularly for prophylaxis , by known methods . generally , a dose of from about 0 . 001 to about 10 mg per kg of body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but , of course , there can be instance where higher or lower dosage ranges are indicated and such are within the scope of this specific administration period for a particular situation . this invention contemplates a method for combating mosquitoes in an environment in which the animal is subjected to strong mosquito pressure where the administration is at a frequency far below a daily administration in this case . for example , it is preferable for the treatment according to the invention to be carried out monthly on dogs and on cats and or birds . spot - on and pour - on formulations may be prepared by dissolving the active ingredients into the pharmaceutically or veterinary acceptable vehicle . alternatively , the spot - on formulation can be prepared by encapsulation of the active ingredient to leave a residue of the therapeutic agent on the surface of the animal . these formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the species of host animal to be treated , the severity and type of infection and the body weight of the host . the compounds may be administered continuously , particularly for prophylaxis , by known methods . generally , a dose of from about 0 . 001 to about 100 mg per kg of body weight of 1 - n - arylpyrazole and 0 . 01 to about 100 mg / kg of amitraz given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but , of course , there can be instance where higher or lower dosage ranges are indicated and such are within the scope of this invention . it is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific host and parasite . preferably , a single formulation containing the 1 - n - arylpyrazole derivative is in a substantially liquid carrier and is in a form which makes possible a single application or an application repeated a small number of times . the formulation will be administered to the animal over a highly localized region of the animal , preferably between the two shoulders . it is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific host and parasite . most preferably , this localized region has a surface area of less than 10 cm 2 , especially between 5 and 10 cm 2 area . remarkably , it has been discovered that such a formulation is highly effective against both the targeted parasites . the treatment is preferably carried out so as to administer to the host , on a single occasion , a dose containing between about 0 . 001 and about 100 mg / kg of a compound of formula ( ii ). the amount of compounds of 1 - n - aylpyrazole for animals which are small in size is preferably greater than about 0 . 01 mg and in a particularly preferred way between about 1 and about 50 mg / kg of weight of animal . this invention also provides for a method for cleaning the coats and the skin of animals by removal of the parasites which are present and of their waste and excreta . the animals treated thus exhibit a coat which is more pleasing to the eye and more pleasant to the touch . the invention also relates to such a method with a therapeutic aim intended for the treatment and prevention of parasitoses having pathogenic consequences . in another preferred embodiment this provides for a composition for combating fleas in small mammals , in particular dogs and cats , characterized in that it contains at 1 east one of formula ( ii ) as defined above . the formulations of the present invention provide for the topical administration of a concentrated solution , suspension , microemulsion or emulsion for intermittent application to a spot on the animal , generally between the two shoulders ( solution of spot - on type ). it has been discovered that the inventive formulations are especially active against parasites when the formulations are applied to animals , such as mammals , especially dogs , cats , sheep , pigs , cattle and horses and birds , especially chickens , turkeys and quails . the ectoparasitical combination can advantageously be present in this formulation in a proportion of about 1 to about 20 %, preferably of about 5 to about 15 % ( percentages as weight by volume = w / v ). the liquid carrier vehicle comprises a pharmaceutically or veterinary acceptable organic solvent and optionally an organic cosolvent . also contemplated are the pharmaceutically or veterinary acceptable acid or base salts , where applicable , of the active compounds provided for herein . the term “ acid ” contemplates all pharmaceutically or veterinary acceptable inorganic or organic acids . inorganic acids include mineral acids such as hydrohalic acids , such as hydrobromic and hydrochloric acids , sulfuric acids , phosphoric acids and nitric acids . organic acids include all pharmaceutically or veterinary acceptable aliphatic , alicyclic and aromatic carboxylic acids , dicarboxylic acids tricarboxylic acids and fatty acids . preferred acids are straight chain or branched , saturated or unsaturated c 1 - c 20 aliphatic carboxylic acids , which are optionally substituted by halogen or by hydroxyl groups , or c 6 - c 12 aromatic carboxylic acids . examples of such acids are carbonic acid , formic acid , fumaric acid , acetic acid , propionic acid , isopropionic acid , valeric acid , α - hydroxy acids , such as glycolic acid and lactic acid , chloroacetic acid , benzoic acid , methane sulfonic acid , and salicylic acid . examples of dicarboxylic acids include oxalic acid , malic acid , succinic acid , tartaric acid and maleic acid . an example of a tricarboxylic acid is citric acid . fatty acids include all pharmaceutically or veterinary acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms . examples include butyric acid , isobutyric acid , sec - butyric acid , lauric acid , palmitic acid , stearic acid , oleic acid , linoleic acid , linolenic acid , and phenylsteric acid . other acids include gluconic acid , glycoheptonic acid and lactobionic acid . the term “ base ” contemplates all pharmaceutically or veterinary acceptable inorganic or organic bases . such bases include , for example , the alkali metal and alkaline earth metal salts , such as the lithium , sodium , potassium , magnesium or calcium salts . organic bases include the common hydrocarbyl and heterocyclic amine salts , which include , for example , the morpholine and piperidine salts . the organic solvent for the liquid carrier vehicle will preferably have a dielectric constant of between about 10 and about 35 , preferably between about 20 and about 30 , the content of this solvent in the overall composition preferably representing the remainder to 100 % of the composition . it is well within the skill level of the practitioner to select a suitable solvent on the basis of these parameters . the organic cosolvent for the liquid carrier vehicle will preferably have a boiling point of less than about 100 ° c ., preferably of less than about 80 ° c ., and will have a dielectric constant of between about 10 and about 40 , preferably between about 20 and about 30 ; this cosolvent can advantageously be present in the composition according to a weight / weight ( w / w ) ratio with respect to the solvent of between about { fraction ( 1 / 15 )} and about ½ ; the cosolvent is volatile in order to act in particular as drying promoter and is miscible with water and / or with the solvent . again , it is well within the skill level of the practitioner to select a suitable solvent on the basis of these parameters . the organic solvent for the liquid carrier includes the commonly acceptable organic solvents known in the formulation art . these solvents may be found , for example , in remington pharmaceutical science , 16 th edition ( 1986 ). these solvents include , for example , acetone , ethyl acetate , methanol , ethanol , isopropanol , dimethylformamide , dichloromethane or diethylene glycol monoethyl ether ( transcutol ). these solvents can be supplemented by various excipients according to the nature of the desired phases , such as c 8 - c 10 caprylic / capric triglyceride ( estasan or miglyol 812 ), oleic acid or propylene glycol . the liquid carrier may also comprise a microemulsion . microemulsions are also well suited as the liquid carrier vehicle . microemulsions are quaternary systems comprising an aqueous phase , an oily phase , a surfactant and a cosurfactant . they are translucent and isotropic liquids . microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase . the size of these microdroplets is less than 200 nm ( 1000 to 100 , 000 nm for emulsions ). the interfacial film is composed of an alternation of surface - active ( sa ) and co - surface - active ( co - sa ) molecules which , by lowering the interfacial tension , allows the microemulsion to be formed spontaneously . the oily phase can in particular be formed from mineral or vegetable oils , from unsaturated polyglycosylated glycerides or from triglycerides , or alternatively from mixtures of such compounds . the oily phase preferably comprises triglycerides and more preferably medium - chain triglycerides , for example c 8 - c 10 caprylic / capric triglyceride . the oily phase will represent , in particular , from about 2 to about 15 %, more particularly from about 7 to about 10 %, preferably from about 8 to about 9 %, v / v of the microemulsion . the aqueous phase includes , for example water or glycol derivatives , such as propylene glycol , glycol ethers , polyethylene glycols or glycerol . propylene glycol , diethylene glycol monoethyl ether and dipropylene glycol monoethyl ether are especially preferred . generally , the aqueous phase will represent a proportion from about 1 to about 4 % v / v in the microemulsion . surfactants for the microemulsion include diethylene glycol monoethyl ether , dipropyelene glycol monomethyl ether , polyglycolysed c 8 - c 10 glycerides or polyglyceryl - 6 dioleate . in addition to these surfactants , the cosurfactants include short - chain alcohols , such as ethanol and propanol . some compounds are common to the three components discussed above , i . e ., aqueous phase , surfactant and cosurfactant . however , it is well within the skill level of the practitioner to use different compounds for each component of the same formulation . the cosurfactant to surfactant ratio will preferably be from about { fraction ( 1 / 7 )} to about ½ . there will preferably be from about 25 to about 75 % v / v of surfactant and from about 10 to about 55 % v / v of cosurfactant in the microemulsion . likewise , the co - solvents are also well known to a practitioner in the formulation art . preferred co - solvents are those which is a promoter of drying and include , for example , absolute ethanol , isopropanol ( 2 - propanol ) or methanol . the crystallization inhibitor can in particular be present in a proportion of about 1 to about 20 % ( w / v ), preferably of about 5 to about 15 %. the inhibitor preferably corresponds to the test in which 0 . 3 ml of a solution comprising 10 % ( w / v ) of the compound of formula ( i ) in the liquid carrier and 10 % of the inhibitor are deposited on a glass slide at 20 ° c . and allowed to stand for 24 hours . the slide is then observed with the naked eye . acceptable inhibitors are those whose addition provides for few or no crystals , and in particular less than 10 crystals , preferably 0 crystals . although this is not preferred , the formulation can optionally comprise water , in particular in a proportion of 0 to about 30 % ( volume by volume v / v ), in particular of 0 to about 5 %. the formulation can also comprise an antioxidizing agent intended to inhibit oxidation in air , this agent being in particular present in a proportion of about 0 . 005 to about 1 % ( w / v ), preferably of about 0 . 01 to about 0 . 05 %. polyvinylpyrrolidone , polyvinyl alcohols , copolymers of vinyl acetate and of vinylpyrrolidone , polyethylene glycols , benzyl alcohol , mannitol , glycerol , sorbitol or polyoxyethylenated esters of sorbitan ; lecithin or sodium carboxymethylcellulose ; or acrylic derivatives , such as methacrylates and others , anionic surfactants , such as alkaline stearates , in particular sodium , potassium or ammonium stearate ; calcium stearate or triethanolamine stearate ; sodium abietate ; alkyl sulphates , in particular sodium lauryl sulphate and sodium cetyl sulphate ; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate ; or fatty acids , in particular those derived from coconut oil , cationic surfactants , such as water - soluble quaternary ammonium salts of formula n + r ′ r ″ r ′″ r ″″ y − , in which the r radicals are identical or different optionally hydroxylated hydrocarbon radicals and y − is an anion of a strong acid , such as halide , sulphate and sulphonate anions ; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used , a mine salts of formula n + r ′ r ″ r ′″, in which the r radicals are identical or different optionally hydroxylated hydrocarbon radicals ; octadecylamine hydrochloride is one of the cationic surfactants which can be used , non - ionic surfactants , such as optionally polyoxyethylenated esters of sorbitan , in particular polysorbate 80 , or polyoxyethylenated alkyl ethers ; polyethylene glycol stearate , polyoxyethylenated derivatives of castor oil , polyglycerol esters , polyoxyethylenated fatty alcohols , polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide , amphoteric surfactants , such as substituted lauryl compounds of betaine , or preferably a mixture of at least two of the compounds listed above . in a particularly preferred embodiment , a crystallization inhibitor pair will be used . such pairs include , for example , the combination of a film - forming agent of polymeric type and of a surface - active agent . these agents will be selected in particular from the compounds mentioned above as crystallization inhibitor . the various grades of polyvinylpyrrolidone , polyvinyl alcohols , and copolymers of vinyl acetate and of vinylpyrrolidone . especially preferred surface - active agents , include those made of non - ionic surfactants , preferably polyoxyethylenated esters of sorbitan and in particular the various grades of polysorbate , for example polysorbate 80 . the film - forming agent and the surface - active agent can in particular be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere . the pair thus constituted secures , in a noteworthy way , the objectives of absence of crystallization on the coat and of maintenance of the cosmetic appearance of the fur , that is to say without a tendency towards sticking or towards a sticky appearance , despite the high concentration of active material . particularly preferred antioxidizing agents are those conventional in the art and include , for example , butylated hydroxyanisole , butylated hydroxytoluene , ascorbic acid , sodium metabisulphite , propyl gallate , sodium thiosulphate or a mixture of not more than two of them . the formulation adjuvants discussed above are well known to the practitioner in this art and may be obtained commercially or through known techniques . these concentrated compositions are generally prepared by simple mixing of the constituents as defined above ; advantageously , the starting point is to mix the active material in the main solvent and then the other ingredients or adjuvants are added . the volume applied can be of the order of about 0 . 3 to about 1 ml , preferably of the order of about 0 . 5 ml , for cats and of the order of about 0 . 3 to about 5 ml for dogs , depending on the weight of the animal . the pour - on solutions according to the invention , which are advantageously oily , generally comprise a diluent or vehicle and also a solvent ( organic solvent ) for the compound of formula ( ii ) if the latter is not soluble in the diluent . low concentrations of from about 0 . 05 to about 10 % weight / volume , more particularly from about 0 . 1 to about 2 %, are preferred . optimally , the value is between about 0 . 25 and about 1 . 5 %, in particular in the region of about 1 %. organic solvents which can be used in the inventive pour - on solutions , mention may be made in particular of : acetyltributyl citrate , fatty acid esters such as the dimethyl ester , diisobutyl adipate , acetone , acetonitrile , benzyl alcohol , butyl diglycol , dimethylacetamide , dimethylformamide , dipropylene glycol n - butyl ether , ethanol , isopropanol , methanol , ethylene glycol monoethyl ether , ethylene glycol monomethyl ether , monomethylacetamide , dipropylene glycol monomethyl ether , liquid polyoxyethylene glycols , propylene glycol , 2 - pyrrolidone , in particular n - methylpyrrolidone , diethylene glycol monoethyl ether , ethylene glycol and diethyl phthalate , or a mixture of at least two of these solvents . as vehicle or diluent for the inventive pour - on solutions , mention may be made in particular of : plant oils such as soybean oil , groundnut oil , castor oil , corn oil , cotton oil , olive oil , grape seed oil , sunflower oil , etc . ; mineral oils such as petrolatum , paraffin , silicone , etc . ; aliphatic or cyclic hydrocarbons or alternatively , for example , medium - chain ( c 8 to c 12 in particular ) triglycerides . an emollient and / or spreading and / or film - forming agent will preferably be added , this agent being selected in particular from : polyvinylpyrrolidone , polyvinyl alcohols , copolymers of vinyl acetate and vinylpyrrolidone , polyethylene glycols , benzyl alcohol , mannitol , glycerol , sorbitol , polyoxyethylenated sorbitan esters ; lecithin , sodium carboxymethylcellulose , silicone oils , polydiorganosiloxane oils , in particular polydimethylsiloxane ( pdms ) oils , for example those containing silanol functionalities , or a 45v2 oil , anionic surfactants such as alkaline stearates , in particular sodium , potassium or ammonium stearates ; calcium stearate , triethanolamine stearate ; sodium abietate ; alkyl sulphates , in particular sodium lauryl sulphate and sodium cetyl sulphate ; sodium dodecylbenzenesulphonate , sodium dioctylsulphosuccinate ; fatty acids , in particular those derived from coconut oil , cationic surfactants such as water - soluble quaternary ammonium salts of formula n + r ′ r ″ r ′″ r ″″, y − in which the radicals r are optionally hydroxylated hydrocarbon radicals and y − is an anion of a strong acid such as the halide , sulphate and sulphonate anions ; cetyltrimethylammonium bromide is among the cationic surfactants which can be used , amine salts of formula n + r ′ r ″ r ′″ in which the radicals r are optionally hydroxylated hydrocarbon radicals ; octadecylamine hydrochloride is among the cationic surfactants which can be used , nonionic surfactants such as sorbitan esters , which are optionally polyoxyethylenated , in particular polysorbate 80 , polyoxyethylenated alkyl ethers ; polyoxypropylated fatty alcohols such as polyoxypropylene - styrol ether ; polyethylene glycol stearate , polyoxyethylenated derivatives of castor oil , polyglycerol esters , polyoxyethylenated fatty alcohols , polyoxyethylenated fatty acids , copolymers of ethylene oxide and propylene oxide , amphoteric surfactants such as the substituted lauryl compounds of betaine ; or a mixture of at least two of these agents . the solvent will be used in proportion with the concentration of the compound ii and its solubility in this solvent . the emollient is preferably used in a proportion of from about 0 . 1 to about 10 %, in particular from about 0 . 25 to about 5 %, by volume . a ) an effective amount of an ectoparasitical combination comprising 1 - n - arylpyrazole derivative and amitraz ; and b ) a pharmaceutical or veterinary acceptable liquid carrier vehicle . preferred carrier vehicles include isopropanol , ethanol , methanol , acetone , ether ( s ), propylene glycol , polyethylene glycol , glycol formal , dgme and dmso . the following formulation according to the present invention was prepared by conventional techniques : ingredient amount (% w / v ) fipronil 10 . 0 amitraz 5 . 0 ethanol 10 . 0 polyvidone 5 . 0 polysorbate 80 5 . 0 butylated hydroxyanisole 0 . 02 butylated hydroxytoluene 0 . 01 diethyleneglycol monoethyl ether qs 100 the following formulation according to the present invention was prepared by conventional techniques : ingredient amount (% w / v ) fipronil 10 . 0 amitraz 15 . 0 ethanol 10 . 0 polyvidone 5 . 0 polysorbate 80 5 . 0 butylated hydroxyanisole 0 . 02 butylated hydroxytoluene 0 . 01 diethyleneglycol monoethyl ether qs 100 the following formulation according to the present invention was prepared by conventional techniques : ingredient amount (% w / v ) fipronil 10 . 0 amitraz 12 . 0 ethanol 10 . 0 polyvidone 5 . 0 polysorbate 80 5 . 0 butylated hydroxyanisole 0 . 02 butylated hydroxytoluene 0 . 01 diethyleneglycol monoethyl ether qs 100 the following formulation not according to the present invention was prepared by conventional techniques : ingredient amount (% w / v ) fipronil 10 . 0 ethanol 10 . 0 polyvidone 5 . 0 polysorbate 80 5 . 0 butylated hydroxyanisole 0 . 02 butylated hydroxytoluene 0 . 01 diethyleneglycol monoethyl ether qs 100 the duration of the efficacy of the formulation of example 3 ( according to the present invention ) was compared with the formulation of comparative example 4 against ticks on dogs . the results are presented below : duration of efficacy against rhipicephalus sanguineus ticks on dogs . (% efficacy at 48 - hour counts ) days after treatment 2 9 16 23 30 37 44 51 58 fipronil 10 % 99 . 1 % 100 . 0 % 100 . 0 % 100 . 0 % 100 . 0 % 87 . 6 % 74 . 8 % 66 . 2 % 36 . 3 % fipronil 10 % + 99 . 1 % 100 . 0 % 100 . 0 % 100 . 0 % 100 . 0 % 100 . 0 % 94 . 8 % 84 . 1 % 83 . 5 % amitraz 12 % as can be seen the formulation according to the present invention remained effective for a far longer period than fipronil alone . the speed of the efficacy of the formulation of example 3 ( according to the present invention ) was compared with the formulation of comparative example 4 against ticks on dogs . the results are presented below : speed of efficacy against rhipicephalus sanguineus ticks on dogs . ( efficacy counts were performed 6 hours after each weekly infestation ) days after treatment 0 7 14 21 28 35 42 fipronil 10 % — 98 . 6 % 91 . 0 % 21 . 3 % 18 . 8 % 7 . 9 % — fipronil 10 % + amitraz 12 % 23 . 8 % 100 . 0 % 100 . 0 % 95 . 6 % 95 . 2 % 52 . 2 % 7 . 6 % as can be seen the formulation according to the present invention exhibit a faster rate of efficacy than a formulation comprising fipronil alone . the duration of the efficacy of the formulation of example 3 ( according to the present invention ) was compared with the formulation of comparative example 4 against fleas on dogs . the results are presented below : duration of efficacy against fleas (% efficacy against fleas measured 24 hours after each weekly infestation ) days after treatment 2 23 30 37 44 51 fipronil 10 % 100 . 0 % 100 . 0 % 99 . 0 % 93 . 8 % 69 . 4 % 41 . 48 % fipronil 10 % + 100 . 0 % 100 . 0 % 100 . 0 % 98 . 4 % 96 . 3 % 94 . 6 % amitraz 12 % as can be seen the formulation according to the present invention remained effective for a far longer period of time than a formulation comprising fipronil alone . this enhanced efficacy is surprising since amitraz is not known in the art to be used in treating flea infestations on mammals and birds . the above description is intended to be illustrative and not limiting . various changes or modifications in the embodiments described herein may occur to those skilled in the art . these changes can be made without departing from the scope or spirit of the invention .

the present invention provides for , inter alia , novel topical formulations comprising at least one 1 - n - arypyrazole derivative and amitraz and to methods for treating , controlling , or preventing parasite infestations on mammals or birds the inventive formulations include spot - on , pour - on or spray formulations and may include a further ectoparasiticide , such as an igr compound , an avermectin or milbemycin derivative , or a pyrethroid insecticides , and anthelmintics , such as benzimidazoles and imidazothiazoles . the inventive formulation provides a larger duration of parasite control at a faster rate of control . the inventive formula remains effective up to three months from the first application . moreover , the inventive formulations prevent tick attachment to the animal , thereby providing protection against tick borne diseases . the ectoparasites which may be controlled , treated or prevented by the present invention includes ticks , fleas , mites , mange , lice , mosquitoes , flies and cattle grubs .

the compound of the invention , 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione , is described in u . s . pat . no . 7 , 141 , 597 , the contents of which are incorporated by reference herein . the compound is an alpha - 2 adrenergic receptor agonist having the following structure : it occurs as two enantiomers . the r - enantiomer is depicted here on the left ; the s - enantiomer on the right : one can use in the methods of the invention either enantiomer , or a mixture of both , as well as any pharmaceutically acceptable salt or prodrug of these compounds . the compound of the invention may be used as its pharmaceutically acceptable salt . a “ pharmaceutically acceptable salt ” is any salt that retains the activity of the parent compound and does not impart any additional deleterious or untoward effects on the subject to which it is administered and in the context in which it is administered compared to the parent compound . a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid , another salt , or a prodrug which is converted into an acid or salt . pharmaceutically acceptable salts of acidic functional groups may be derived from organic or inorganic bases . the salt may comprise a mono or polyvalent ion . of particular interest are the inorganic ions lithium , sodium , potassium , calcium , and magnesium . organic salts may be made with amines , particularly ammonium salts such as mono -, di - and trialkyl amines or ethanol amines . salts may also be formed with caffeine , tromethamine and similar molecules . hydrochloric acid or some other pharmaceutically acceptable acid may form a salt with a compound that includes a basic group , such as an amine or a pyridine ring . one can use in the methods of the invention a prodrug of the compound of 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione . a “ prodrug ” is a compound which is converted to a therapeutically active compound after administration , and the term should be interpreted as broadly herein as is generally understood in the art . while not intending to limit the scope of the invention , conversion may occur by hydrolysis of an ester group or some other biologically labile group . generally , but not necessarily , a prodrug is inactive or less active than the therapeutically active compound to which it is converted . ester prodrugs of the compounds disclosed herein are specifically contemplated . an ester may be derived from a carboxylic acid of c1 ( i . e ., the terminal carboxylic acid of a natural prostaglandin ), or an ester may be derived from a carboxylic acid functional group on another part of the molecule , such as on a phenyl ring . while not intending to be limiting , an ester may be an alkyl ester , an aryl ester , or a heteroaryl ester . the term alkyl has the meaning generally understood by those skilled in the art and refers to linear , branched , or cyclic alkyl moieties . c 1 - 6 alkyl esters are particularly useful , where alkyl part of the ester has from 1 to 6 carbon atoms and includes , but is not limited to , methyl , ethyl , propyl , isopropyl , n - butyl , sec - butyl , iso - butyl , t - butyl , pentyl isomers , hexyl isomers , cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , and combinations thereof having from 1 - 6 carbon atoms , etc . 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione may be either synthetically produced , or may be produced within the body after administration of a prodrug . hence , “ 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione ” encompasses both compounds produced by a manufacturing process and those compounds formed in vivo only when another drug administered . the precise dose and frequency of administration depends on the severity and nature of the patient &# 39 ; s condition , on the manner of administration , on the potency and pharmacodynamics of the particular compound employed , and on the judgment of the prescribing physician . determining dose is a routine matter that is well within the capability of someone of ordinary skill in the art . in general , the compound of the invention is administered in therapeutically effective doses , that is , at a dose that is sufficient to produce the desired therapeutic effect . those skilled in the art will readily understand that the compound of the invention can be admixed with pharmaceutically acceptable excipients which are well known in the art . a pharmaceutical composition to be administered systemically may be confected as a powder , pill , tablet or the like , or as a solution , emulsion , suspension , aerosol , syrup or elixir suitable for oral or parenteral administration or inhalation . for solid dosage forms or medicaments , non - toxic solid carriers include , but are not limited to , pharmaceutical grades of mannitol , lactose , starch , magnesium stearate , sodium saccharin , the polyalkylene glycols , talcum , cellulose , glucose , sucrose and magnesium carbonate . the solid dosage forms may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period . for example , a time delay material such as glyceryl monostearate or glyceryl distearate may be employed . they may also be coated by the technique described in u . s . pat . no . 4 , 256 , 108 , u . s . pat . no . 4 , 166 , 452 , and u . s . pat . no . 4 , 265 , 874 to form osmotic therapeutic tablets for control release . liquid pharmaceutically administrable dosage forms can , for example , comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier , such as for example , water , saline , aqueous dextrose , glycerol , ethanol and the like , to thereby form a solution or suspension . if desired , the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents , ph buffering agents and the like . typical examples of such auxiliary agents are sodium acetate , sorbitan monolaurate , triethanolamine , sodium acetate , triethanolamine oleate , etc . actual methods of preparing such dosage forms are known , or will be apparent , to those skilled in this art ; for example , see remington &# 39 ; s pharmaceutical sciences , mack publishing company , easton , pa ., 16th edition , 1980 . the composition of the formulation to be administered , in any event , contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect . parenteral administration is generally characterized by injection , either subcutaneously , intramuscularly or intravenously . injectables can be prepared in conventional forms , either as liquid solutions or suspensions , solid forms suitable for solution or suspension in liquid prior to injection , or as emulsions . suitable excipients are , for example , water , saline , dextrose , glycerol , ethanol and the like . in addition , if desired , the injectable pharmaceutical compositions to be administered may also contain minor amounts of non - toxic auxiliary substances such as wetting or emulsifying agents , ph buffering agents and the like . 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione is useful in motor disorders . to “ treat ,” as used here , means to deal with medically . it includes administering the compound of the invention to prevent the onset of a condition , to diminish its severity , and to prevent its reoccurrence . the inventors have discovered that the compound of the invention may be used to treat motor disorders without causing the sedation that ordinarily accompanies the administration of alpha - 2 agonists . a “ motor disorder ,” as that term is used here , is any condition in which a subject experiences involuntary , undesirable movements that are independent of any deficits in sensorimotor gating ; that is , the movement is not the result of abnormal motor output in response to sensory input information . in one embodiment , the motor disorder is mediated by changes ( for example , an increase or a decrease ) in the availability or utilization of dopamine in the nervous system ; hence , compounds of the invention may be used to treat motor disorders associated with hyper - or hypo - dopamine conditions of the nervous system . exemplary motor disorders which may be treated with the compounds of the invention include , for example , l - dopa - induced dyskinesias , tardive dyskinesias , cervical dystonia , spinal torticollis , blepharospasm / meige &# 39 ; s disease , restless leg syndrome , essential tremor , rigidity ( parkinson &# 39 ; s disease - associated or otherwise specified ), ataxic disorder , spasticity . the invention is illustrated by the following examples . this is provided for illustration only ; many more embodiments are possible . 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione was evaluated in tests of amphetamine - induced hyperlocomotion , cocaine - induced hyperlocomotion , and nigrostriatal - lesion - induced rotational behavior following amphetamine administration . amphetamine - induced and cocaine - induced hyperactivity are models of increased dopamine - mediated locomotion . the nigrostriatal lesion - induced rotation model exploits the imbalance in dopaminergic innervation following a unilateral lesion of the dopamine - containing substantia nigra pars compacta ( snc ), thereby creating a hemiparkinsonian condition . the subsequent rotational behavior in these animals induced by various drugs can be used to infer the level of dopamine imbalance on the lesioned and unlesioned side of the brain . in amphetamine - and cocaine - induced hyperactivity , the compound of the invention was able to effectively inhibit increased locomotion associated with psychostimulant administration . in addition , this compounds was also able to inhibit amphetamine - induced rotational behavior in nigrostriatal - lesioned animals . importantly , the compounds is orally active , and therefore could be administered in solution , tablet or capsule . table 1 , below , indicates the locomotor responses of mice treated with various combinations of 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione and the psychostimulant amphetamine . drug 1 was administered 30 minutes after the animal was placed in the open field . drug 2 was administered subcutaneously ( sc ) at 45 minutes after the animal was placed in the open field ( 15 minutes after drug 1 ). auc indicates the total amount of locomotor activity after administration of drug 2 . “% decrease activity ” indicates the percentage decrease in total activity relative to the vehicle + amphetamine group . ⋄ significant difference ( p & lt ; 0 . 05 ) relative to vehicle + amphetamine treated animals . * indicates significant difference ( p ≦ 0 . 05 ) relative to vehicle + vehicle treated animals . table 2 , below , indicates the locomotor responses of mice treated with various combinations of 4 -( 1 -( 2 , 3 - dimethylphenyl ) ethyl )- 1h - imidazole - 2 ( 3h )- thione and the psychostimulant cocaine . drug 1 was administered 30 minutes after the animal was placed in the open field . drug 2 was administered subcutaneously ( sc ) at 45 minutes after the animal was placed in the open field ( 15 minutes after drug 1 ). auc indicates the total amount of locomotor activity after administration of drug 2 . “% decrease activity ” indicates the percentage decrease in total activity relative to the vehicle + cocaine group . ⋄ indicates significant difference ( p ≦ 0 . 05 ) relative to vehicle + cocaine treated animals . * indicates significant difference ( p ≦ 0 . 05 ) relative to vehicle + vehicle treated animals . table 3 , below , indicates the changes in rotational behavior in nigrostriatal - lesioned rats treated with the compound of the invention and the psychostimulant amphetamine . drug 1 was administered 15 minutes before amphetamine , and 10 minutes post - amphetamine , the animals were placed into the rotometer for 30 or 60 minutes . “% decrease rotations ” indicates the percentage decrease in total rotations relative to the vehicle + amphetamine group . ⋄ indicates significant difference ( p ≦ 0 . 05 ) relative to vehicle + amphetamine treated animals . * indicates significant difference ( p + 0 . 05 ) relative to vehicle + vehicle treated animals . amphetamine - or cocaine - induced hyperactivity . mice were placed in an open field apparatus ( flexfield , san diego instruments , san diego , calif .). after 30 minutes of habituation , they received a vehicle or haloperidol injection or injection of agn compound followed by an injection of amphetamine ( 2 mg / kg , s . c .) or cocaine ( 10 mg / kg , i . p .) at minute 45 . their activity levels were subsequently measured for another 1 hour post - injection . total activity over each 5 minute bin ( 21 total bins ) was added to establish activity curve over the 105 minute testing . amphetamine - induced rotational behavior . pre - apomorphine - screened ( rotated ) rats ( with lesions ≧ 95 % da cell loss ) were purchased from charles rivers laboratories . animals were given ˜ 4 days to acclimate prior to testing . all animals weighted 250 - 300 g at the beginning of the study . animals were treated with various combinations of vehicle or the compound of the invention and amphetamine . vehicle or the compound of the invention was administered ( p . o .) 15 minutes before amphetamine ( 2 mg / kg s . c .). rotational behavior was assessed 15 minutes post - amphetamine administration and was monitored for 60 minutes using a rotometer system from san diego instruments ( san diego , calif .). for i . p . administration , the compounds are formulated in h 2 o with 0 . 5 % dmso and given in a volume of 1 ml / kg body weight by injecting into the intraperitoneal cavity . for p . o . administration , the compounds are formulated in h 2 o with 0 . 5 % dmso and given in a volume of 2 ml / kg body weight using a 25 - gauge , 1 . 5 inch gavage needle that is slowly inserted through the esophagus into the stomach .

disclosed herein is a method of treating motor disorders comprising administering to a subject in need of such treatment 4 - ethyl )- 1h - imidazole - 2 - thione .

the invention relates to reducing or preventing a body passage from constricting by inactivating or therapeutically damaging the smooth muscle which causes contraction of the body passage . although the invention described herein may have applications throughout the body , the variation of the invention described below relates to treating airway smooth muscle tissue to prevent or reduce constriction of the airways within a lung . as noted above , preventing or reducing constriction of the airways allows for improved breathing for individual suffering from a pulmonary condition , such as asthma . the inventive treatment reduces the ability of the airways to constrict , narrow or to reduce in diameter due to airway smooth muscle contraction . the reduction in the ability of the smooth muscle to contract may be achieved by treating the smooth muscle itself or by treating other tissues to affect smooth muscle contraction or the response of the airway to the smooth muscle contraction . treatment may also reduce airway responsiveness or the tendency of the airway to narrow or to constrict in response to a stimulus . the reduction in smooth muscle and surrounding tissue may also have the added potential benefit of increasing the caliber or diameter of the airways , this benefit reduces the resistance to airflow through the airways . in addition to the use of debulking smooth muscle tissue to open up the airways , the devices and / or approach of the present invention may eliminate smooth muscle altogether by damaging or destroying the muscle . in the airways , the smooth muscle is arranged externally to an airway in a generally helical pattern with pitch angles ranging from about − 30 to about + 30 degrees . thus , the treatment of the smooth muscle , which may be selectively given in an appropriate pattern , interrupts or cuts through the helical pattern at a proper pitch and prevents the airway from constricting . therefore , a variation of the invention may include treating the airway smooth muscle in one or more sites or in a pattern to eliminates contraction of the airways without completely eradicating smooth muscle and other airway tissue . alternatively , a variation of the invention includes treating at one or a few sites to inactivate all or a significant portion of the airway smooth muscle . fig1 and 2 illustrate cross sections of an airway and a bronchiole , respectively , in a healthy patient . the airway of fig1 is a medium sized bronchus having an airway diameter d 1 of about 3 mm . fig2 shows a section through a bronchiole having an airway diameter d 2 of about 1 . 5 mm . each airway includes a folded inner surface or epithelium 10 surrounded by stroma 12 and smooth muscle tissue 14 . the larger airways including the bronchus shown in fig1 also have mucous glands 16 and cartilage 18 surrounding the smooth muscle tissue 14 . nerve fibers 20 and blood vessels 22 also surround the airway . fig3 illustrates the bronchus of fig1 in which the smooth muscle 14 hypertrophied and increased in thickness causing the airway diameter to be reduced from the diameter d 1 to a diameter d 3 . in any case , the smooth muscle tissue 14 is responsible for constriction of the airways . as noted herein , the adverse affects of excessive airway constriction may be alleviated by directly inactivating or deactivating the function of the airway smooth muscle . the airway smooth muscle relies upon the bronchial vasculature for its blood supply . therefore , any altering of the blood supply in the bronchial system significantly affects the airway smooth muscle as compared to the remaining airway wall or bronchial tissue . because of this , the airway smooth muscle &# 39 ; s blood supply may be treated so that the effects of the treatment are acceptably limited to the airway smooth muscle . furthermore , the blood - air exchange function of the alveoli ( the most distal portion of the airway that provides a gas exchange function ), relies upon a separate vasculature network . so any actions taken on the bronchial vasculature may be controlled so that they will have little or no effect upon the remaining circulatory system , including the pulmonary vasculature . fig4 is a representative illustration of the lungs 2 , airways 4 , pulmonary arteries 6 , pulmonary veins 8 , and bronchial veins and arteries 22 . to deliver the treatment in accordance with the teachings described herein , a treatment location is selected . generally , the bronchial arteries 24 run within the airway wall . it is noted that the location or treatment site may be selected either from sensing within the airway 4 ( e . g ., via doppler sensing ), external means by any mode of non - invasive detection , and / or by any other means of locating an acceptable site to provide the treatment . fig4 also illustrates a variation of the treatment where a catheter 40 advances into the airways . the catheter 40 may be equipped to perform the procedure as discussed herein . by advancing the catheter 40 through the airways , the treatment may be delivered to the bronchial artery without having to puncture the pleura . fig5 shows a representation of an airway 4 terminating into the alveolus 3 . as shown , the airway 4 includes a bronchial artery 6 and a bronchial vein 8 running exterior to the lumen of the airway . as illustrated , the bronchial arteries 6 and veins 8 run externally along either side of the main bronchus and follow the branching of the airways 4 . the location of the bronchial artery 6 allows for any number of modes of detection ( e . g ., doppler , thermal , etc .) to locate a possible treatment site . the treatment described herein may be provided via a minimally invasive approach . for example , a medical practitioner advances a treatment device 40 ( e . g ., a bronchoscope carrying a catheter , a catheter , etc .) into the airways 4 . alternatively , or in combination , the medical practitioner may apply the treatment from outside the body through injection , or even oral administration . some variations of the treatment described herein allow for treatment of the airway smooth muscle tissue , which is located in a considerable number of airways , could be applied in a single or relatively few locations ( e . g ., one or more sites in the bronchial arteries .) this advantage allows for treatment at relatively few sites as opposed to having to treat the entire ( or considerable portion ) of the bronchial network . in one variation of the treatment , the medical practitioner injects an agent into the bronchial artery or arteries 6 supplying the airways 4 . as noted above , the agent affects the blood supplied to the smooth muscle tissue within the airway . in turn , the agent reaches the smooth muscle tissue to deactivate , kill or impair the function of the smooth muscle tissue . as a result , the inability of the smooth muscle tissue to constrict the airways improves the breathing condition of the patient ( e . g ., in cases of an asthma attack .) the agents described herein may include toxins , radioactive agents , viral agents , and / or drugs . example of such agents includes toxins such as natural , animal or insect toxins , or engineered toxins , i - 131 ( iodine 131 ), laser absorptive dye , agents that bind to constituents of airway smooth muscle ( e . g ., myosin , actin ), neutrophils , paralytic agents , embolizing agents , etc . examples of agents that selectively affect smooth muscle tissue include : snake myotoxins ; anti - bodies that bind to actin or myosin , with the impairment agent bound to the antibody . the agent may also include microspheres the size of the capillaries at the smooth muscle . these micropspheres could also contain an additional agent . a variation of the treatment may include delivering a second agent which counteracts the effect of the first agent . in such a case , the second agent is provided so that the treatment is limited to the desired part of the body ( e . g ., the airways .) for example , if a toxin is applied to the bronchial artery , a counteracting agent may be introduced systemically or locally but in a way so that the initial treatment is not rendered ineffective . for example , if the agent is cyanide the counteragent or protectant agent could be amyl nitrate accordingly , as the agent affect the smooth muscle in the airways , the counteracting agent minimizes adverse effect on other smooth muscle that is not a subject of the treatment . examples of such counteragents include , but is not limited to , antivenom . it is also contemplated that instead of a counter - agent , a mechanical filter or binding substance may be used to collect or deactivate the agent before the agent is able to affect non - target tissues . furthermore , a counteractive measure may be applied to the same effect as a counter agent . for example , an agent may be applied where the agent may be rendered ineffective under certain environments ( e . g ., upon the application of current , an electric field , or other chemical reaction .) the counteragent may be provided in such a way that it allows for “ dosing ” of the agent . for example , the agent may be applied in a concentration strong enough to have the desired effect , but through dilution , degradation , or through systemic counteragent ( at a dose that cannot protect the targeted tissues which see a “ too strong ” dose of agent ) cannot affect other organ systems . a variation of the treatment described herein includes ligating or reducing flow within the bronchial vessel or vessels so that the agent is trapped or delayed in the desired treatment location until a significant amount of the agent is absorbed or until the agent decays or is rendered inactive . for example , a radioactive agent with a properly selected half - life may be used . in this case , reducing the flow of the agent trapping the agent within the bronchial vessels may allow a sufficient amount of time to pass so that the radioactive agent decays sufficiently so that any of the agent that passes to other portions of the body is rendered sufficiently ineffective to cause any concern of side effects . this approach of reducing the blood flow may be accomplished at the arterial side of the flow ( i . e ., the inflow side ), and / or may be accomplished at the venous side of the flow ( i . e ., the outflow side ). in another example of the inventive treatment , the blood supply to the target smooth muscle may be interrupted or reduced to starve the smooth muscle by reducing oxygen supply to the muscle to induce temporary or permanent deactivation of the muscle . in this variation of the treatment , the blood supply may be altered by introducing an agent that occludes blood flow in the vessel . in some cases , the blood vessels may be starved of necessary nutrients or otherwise induced to create damaging toxins on their own . the occluding agent could be any agent , combination of agents and / or devices that restricts blood flow . alternatively , or in addition , the blood supply may be altered by simply damaging the blood vessel or shunting blood flow to a different region so that blood does not reach the targeted smooth muscle tissue . for example , the bronchial artery may be coagulated to stop flow . in another variation , the blood flow in the bronchial artery may be shunted to the pulmonary vessels or the bronchial vein . the bronchial vein may also be closed to accomplish the appropriate result of affecting the smooth muscle tissue . the treatment described herein may be combined with other conventional treatments . for example , for asthma management , the treatments herein may be combined with stimulus avoidance or pharmacological management of asthma . in addition , the treatments may be combined with the treatments described in the following commonly assigned patents and applications . u . s . patent applications : ser . no . 09 / 095 , 323 filed jun . 10 , 1998 ; ser . no . 09 / 436 , 455 filed nov . 8 , 1999 . u . s . published application : 20030233099a1 ; 20040010289a1 ; 20020091379a1 . u . s . patents : u . s . pat . nos . 6 , 411 , 852 ; 6 , 634 , 363 the entirety of all of which are incorporated by reference herein so that they may be combined with the inventive procedures and treatments described herein . the effectiveness of the treatments and procedures described above may be further improved through exercise or activation of the target smooth muscle while the treatment or procedure is in process . for example , the smooth muscle may be stimulated during treatment to increase its demand for oxygen from the blood system . in turn , the increased demand for oxygen may cause , either more of the agent to pass to the target smooth muscle , or in cases where the blood flow is interrupted , the lack of oxygen causes ischemic of the “ activated ” smooth muscle at an increased rate . in addition , the effectiveness of the treatments and procedures described herein may be titrated . in this case , the treatment may be performed under stimulated constriction of the airways . a medical practitioner would then observe the effects of the treatment ( either real time and / or under direct observation , or through other measurement modes ). upon reaching the desired effect , the medical practitioner would stop the treatment . for example , methocholine , which stimulates smooth muscle activity , may be placed in the airway to stimulate the smooth muscle . alternatively , or in combination , the smooth muscle may be stimulated electrically , or by other stimulus . the treatments and / or agents described herein may also be combined with temperature , dyes , or other detectible additives . for example , blood on the arterial side of the airway smooth muscle may be heated or cooled ( alternatively , it may be the agent that is heated or cooled .) then , by measuring the blood flow on the venous side of the airway smooth muscle , one is able to confirm when the agent or effect has passed through the smooth muscle . for example , one variation of the invention includes cooling the agent , injecting the agent into the blood flow , then measuring the temperature of the vein or venous flow . a drop in temperature ( or observation of the additive ) at this location informs the medical practitioner that the agent or altered blood passed through the smooth muscle . while the invention has been described in detail with reference to the preferred embodiments thereof , it will be apparent to one skilled in the art that various changes and modifications can be made and equivalents employed , without departing from the present invention . furthermore , the above illustrations and descriptions are examples of a number of non - exhaustive variations the invention described herein . it is contemplated that combinations of aspects of specific embodiments or combinations of the specific embodiments themselves are within the scope of this disclosure .

treatment and procedures for treating bodily conduits involves deactivating , killing , or otherwise treating smooth muscle tissue of the conduit .

the invention incorporates a catheter containing an optical fiber . the optical fiber is coupled at the proximal end to a high repetition rate laser system which injects pulses of light into the fiber . the light emerging from the fiber at the distal end is absorbed by the fluid surrounding the catheter . this fluid may be blood , a biological saline solution containing an absorbing dye , a thrombolytic pharmaceutical or thrombus itself the optical fiber functions as a means of energy transmission such that the optical energy produced by the laser is delivered to the end of the fiber . the laser light emerging from the distal end of the fiber optic has a pulse frequency within the range of 10 hz to 100 khz , a wavelength within the range of 200 nm to 5000 nm and an energy density within the range of 0 . 01 j / cm 2 to 4 j / cm 2 . in one embodiment , the pulse frequency is within the range of 5 khz to 25 khz . lysis of thrombus , atherosclerotic plaque or any other occluding material in the tubular tissue is facilitated by an ultrasonic radiation field created in the fluids near the occlusion . as an adjunct treatment , a working channel which surrounds or runs parallel to the optical fiber may be used to dispense small quantities of thrombolytic drugs to facilitate further lysis of any significantly sized debris (& gt ; 5 μm dia . particles ) left over from the acoustic thrombolysis process . the conversion of optical to acoustic energy may proceed through several mechanisms that may be thermoelastic , thermodynamic or a combination of these . fig1 a shows an optical fiber 10 with a parallel working channel 12 , where both the fiber 10 and the working channel 12 are both located within a catheter 14 which has been inserted into a blood vessel 16 . the distal end of fiber 10 is placed near thrombus 18 and stenotic plaque 20 within blood vessel 16 . a laser 2 , controlled by laser controller 4 , provides laser light 6 into fiber 10 . in fig1 b , fiber 10 delivers laser light to produce a collapsing cavitation bubble 11 and the resulting expanding acoustic wave 13 . a parallel working channel 12 in catheter 14 delivers an adjunct fluid 15 to aid in the removal of occlusion 17 from inside blood vessel 16 . as depicted in fig2 a - c , in the thermoelastic mode , each laser pulse 22 delivers a controlled level of energy in the fluid 24 which creates a large thermoelastic stress in a small volume of the fluid . the expanding direction of this stress is indicated by arrows 25 in fig2 a . the volume of fluid 24 which is heated by the laser pulse 22 is determined by the absorption depth of the laser light in the fluid 24 , and must be controlled to produce a desired size . for example , an appropriate size may be the fiber diameter , or a distance comparable to some fraction of the vessel containing the occlusion . this can be adjusted by controlling the laser wavelength or the composition of the fluid such that most of the laser energy is deposited in a fluid depth of the desired size . the laser pulse duration is short enough to deposit all of the laser energy into the absorbing fluid in a time scale shorter than the acoustic transit time across the smallest dimension of absorbing region . this is an isochoric ( constant volume ) heating process . for an absorption volume of approximately 100 μm in diameter the acoustic transit time is approximately 70 ns , so the deposition time must be significantly less than this , e . g ., around 10 ns . the absorbing fluid responds thermoelasticaly to the deposition of energy such that a region of high pressure is created in the fluid in the heated volume . the boundary of the high pressure zone decays into a pattern of acoustic waves : a compression wave propagates away from the energy deposition region ( diverging wave front ) and a rarefaction wave propagates towards the center of the energy deposition region ( converging wave front ). when the rarefaction wave converges on the center of the initial deposition region , it creates a region 26 of tensile stress that promotes the formation of a cloud of cavitation bubbles which coalesce to form a larger bubble 30 . eventually , the cavitation bubble collapses ( 32 ), resulting in an expanding acoustic wave 33 . collapse and subsequent rebound of the cavitation bubble will generate acoustic impulses in the surrounding fluid , which will carry off a portion of the energy of the cavity . the collapse and rebound processes take place on a time scale governed principally by the fluid density and the maximum size of the initial cavity . the first collapse and rebound will be followed by subsequent collapse and rebound events of diminishing intensity until the energy of the cavity is dissipated in the fluid . subsequent laser pulses are delivered to repeat or continue this cycle and generate an ultrasonic radiation field at a frequency or frequencies determined by the laser pulse frequency . to summarize , a device operating through the first mode produces an ultrasonic radiation field in the fluid by : ( i ) depositing laser energy in a volume of fluid comparable to the fiber dimension in a time scale of duration less than the acoustic transit time across this dimension ( as controlled by choice of laser wavelength and absorbing fluid as the case may be ); ( ii ) controlling the laser energy such that the maximum size of the cavitation bubble is approximately the same as the fiber diameter ; and ( iii ) pulsing the laser at a repetition rate such that multiple cycles of this process generate an acoustic radiation field in the surrounding fluid ; resonant operation may be achieved by synchronizing the laser pulse repetition rate with the cavity lifetime . typical operation leads to a fluid - based transducer that cycles at 1 - 100 khz with a reciprocating displacement of 100 - 200 μm ( for typical optical fiber dimensions ). this displacement is very similar to that found in mechanically - activated ultrasound angioplasty devices . in the superheated vapor expansion mode , as shown in fig3 a - c , in fiber optic 41 , each laser pulse 40 delivers a controlled level of energy in the fluid within an absorption depth which is very small compared to the characteristic size of the vessel containing the catheter , or even small compared to the fiber diameter . the absorption depth may also be small compared to the distance that a sound wave travels in the duration of the laser pulse . the laser energy deposits a sufficient level of energy to heat all of the fluid within the absorption depth well above the vaporization temperature of the fluid at the ambient pressure . in the process of depositing the laser energy , a thermoelastically - generated acoustic wave is launched in the fluid , which propagates out from the heated region . on time scales longer than 1 μs , the superheated fluid 42 undergoes vaporization , which creates a bubble of vapor . as the fluid vaporizes , its volume 44 increases by a large factor , hence the need for involving only a small layer of fluid such that the ultimate size of the vapor bubble does not exceed , for example , the vessel diameter . the laser pulse duration need not be restricted to times as short as in the thermoelastic mode since the bubble expansion is nearly an isobaric process ; however , the laser pulse duration should be shorter than the bubble expansion time , and it should be much shorter than a typical thermal relaxation time for the superheated region . ( according to the rayleigh bubble collapse theory the bubble lifetime is approximately 25 μs for a 50 μm diameter bubble ; thermal relaxation occurs on a few hundred microsecond time scale , so the laser pulse should be several microseconds or less in duration ). the vapor bubble expands up to a maximum radius which depends on the vapor pressure initially created in the fluid . at the maximum bubble radius , the vapor pressure in the expanded bubble has dropped to well below the ambient pressure and the bubble 46 undergoes collapse , resulting in an expanding acoustic wave 48 . rebound and subsequent collapse events may take place following the first collapse . the bubble expansion and collapse couples acoustic energy into the fluid . subsequent laser pulses are delivered to repeat or continue this cycle and generate an ultrasonic radiation field at a frequency or frequencies determined by the laser pulse frequency . similar to the first mode , a resonant operation may be achieved by matching the laser pulse period to the lifetime of the vapor bubble . to summarize , a device operating through the second mode produces an ultrasonic radiation field in the fluid by : ( i ) depositing laser energy in a small volume of fluid ( as controlled by choice of laser wavelength and absorbing fluid as the case may be ); ( ii ) controlling the laser energy such that the maximum size of the vapor bubble is approximately the same as or less than the diameter of the vessel being treated ; and ( iii ) pulsing the laser energy at a repetition rate such that multiple cycles of the bubble generation and collapse process generates an acoustic radiation field in the surrounding fluid . unlike the first mode , the delivery time is not a significant issue , so longer pulse duration lasers ( up to several μs ) may be useful . for either mode of operation the laser wavelength , laser pulse duration and laser absorption depth must be precisely , controlled such that an adequate acoustic response is obtained with a minimum of laser pulse energy . for the first mode this entails matching the absorption volume to a characteristic dimension of the system such as the fiber diameter or some fraction of the vessel diameter , and using a short laser pulse ( less than 20 ns ). for second mode this entails depositing the laser energy in a very small absorption depth to achieve a sufficient level of superheat in a small fluid mass such as can be accommodated by a small energy budget and without creating a vapor bubble so large as to be damaging to the surrounding tissues . these opto - acoustic modes of coupling laser energy into acoustic excitations in tissues include a number of features . low to moderate laser pulse energy combined with high repetition rate avoids excessive tissue heating or intense shock generation . localized absorption of the laser energy occurs . laser energy may interact thermoelastically or thermodynamically with the ambient fluids . an acoustic radiation field is generated by repeated expansion and collapse of a bubble at the tip of the fiber . resonant operation may be achieved by matching the laser pulse period to the lifetime of the generated bubble . soft fibrous occlusions ( thrombus ) may be dissolved by generating the bubbles directly within the thrombus . control and / or manipulation of the spatial and temporal distribution of energy deposited in the fluid at the fiber tip can be used modify the near field acoustic radiation pattern , for example , to concentrate acoustic energy on an object in proximity to the fiber , or to distribute the acoustic radiation more uniformly . techniques based on this strategy will be most successful for a special case of thermoelastic response ( first mode ) where the laser pulse duration is short and the fluid absorption is also relatively strong , such that the laser energy is deposited in a thin layer adjacent to the surface of the fiber tip . for example , by forming a concave surface on the fiber tip , the optical energy is deposited in the fluid in a similar shaped distribution . acoustic waves emitted from this concave distribution will tend to focus to a point at a distance r from the fiber tip , where r is the radius of curvature of the concave surface . a planar fiber tip will generate an initially planar acoustic wavefront in proximity the fiber tip . a convex fiber tip will produce a diverging spherical wavefront which will disperse the acoustic energy over a larger solid angle . another means of modifying the near field radiation pattern may be to use a fiber bundle through which the laser energy is delivered , and control the temporal distribution of deposited laser energy . the laser energy may be arranged to arrive at individual fiber strands in the catheter tip at different times , which , in combination with the different spatial positions of these individual strands , can be adjusted to control the directionality and shape of the acoustic radiation pattern , similar to phased - array techniques used in radar . fig4 a shows a modified fiber optic 50 having a concave distal end 52 . fig4 b shows a fiber optic 50 with a convex distal end 54 . fig5 shows a modified fiber optic 56 consisting of a bundle of fiber strands 58 , through each of which laser pulse energy is delivered at varying times . commercial fibers are usually jacketed to protect them from the environment . &# 34 ; bare &# 34 ; or unjacketed fibers are available . it is helpful to use coatings on fibers to make them slide more easily through catheters . as shown in fig6 a variable diameter optical fiber 60 allows for greater physical strength at the proximal end 62 and greater access at the distal end 64 . this can be accomplished through modifying existing fibers ( stripping the protective sheath from around the core ) or by making custom fibers . custom fabrication can be accomplished by varying the extrusion or draw rate for the fiber . glass or plastic composition can be changed as a function of drawing the fiber so that greater control of the fiber from a distal end is achieved without sacrificing optical quality . one particular instance of this is to treat the tip so that it is &# 34 ; soft ,&# 34 ; so the end will not jam in the catheter sheath . also , shape memory in the tip allows steering of the fiber when it protrudes from the distal end of the catheter sheath . fig7 shows a composite of a glass / plastic fiber . fiber 70 comprises a glass portion 72 with a relatively short plastic tip 74 which has a length within the range of a millimeter to a several centimeters . due to the rigidity of the glass portion 72 , a fiber optic having this configuration is easily pushed through vasculature . the softer plastic tip 74 is less likely to puncture a vein wall than a glass tip . this configuration could include an additional glass tip to increase the durability of the fiber optic . acoustic energy at many frequencies is generated in the present invention , and may be considered as a signal source for producing acoustic images of structures in body tissues . any signal detection and analysis system which relies on a point source of acoustic radiation to produce the signal may be used with this invention . applications envisioned for this invention include any method or procedure whereby localized ultrasonic excitations are to be produced in the body &# 39 ; s tissues through application of a catheter . the invention may be used in ( i ) endovascular treatment of vascular occlusions that lead to ischemic stroke ( this technology can lyse thrombus and lead to reperfusion of the affected cerebral tissue ), ( ii ) endovascular treatment of cerebral vasospasm ( this technology can relax vaso - constriction leading to restoration of normal perfusion and therefore prevent further transient ischemic attacks or other abnormal perfusion situations ), ( iii ) endovascular treatment of cardiovascular occlusions ( this technology can lyse thrombus or remove atherosclerotic plaque from arteries ), ( iv ) endovascular treatment of stenoses of the carotid arteries , ( v ) endovascular treatment of stenoses of peripheral arteries , ( vi ) general restoration of patency in any of the body &# 39 ; s luminal passageways wherein access can be facilitated via percutaneous insertion , ( vii ) any ultrasonic imaging application where a localized ( point ) source of ultrasonic excitation is needed within an organ or tissue location accessible through insertion of a catheter , ( viii ) lithotriptic applications including therapeutic removal of gallstones , kidney stones or other calcified objects in the body and ( ix ) as a source of ultrasound in ultrasound modulated optical tomography . the pulsed laser energy source used by this invention can be based on a gaseous , liquid or solid state medium . rare earth - doped solid state lasers , ruby lasers , alexandrite lasers , nd : yag lasers and ho : ylf lasers are all examples of lasers that can be operated in a pulsed mode at high repetition rate and used in the present invention . any of these solid state lasers may incorporate non - linear frequency - doubling or frequency - tripling crystals to produce harmonics of the fundamental lasing wavelength . a solid state laser producing a coherent beam of ultraviolet radiation may be employed directly with the invention or used in conjunction with a dye laser to produce an output beam which is tunable over a wide portion of the ultraviolet and visible spectrum . tunability over a wide spectrum provides a broad range of flexibility for matching the laser wavelength to the absorption characteristics of the fluids located at the distal end of the catheter . the output beam is coupled by an optical fiber to the surgical site through , for example , a percutaneous catheter . in operation , a pulsed beam of light drives the ultrasonic excitation which removes and / or emulsifies thrombus or atherosclerotic plaque with less damage to the underlying tissue and less chance of perforating the blood vessel wall than prior art devices . various other pulsed lasers can be substituted for the disclosed laser sources . similarly , various dye materials and configurations can be used in the dye laser . configurations other than a free - flowing dye , such as dye - impregnated plastic films or cuvette - encased dyes , can be substituted in the dye laser . the dye laser can also store a plurality of different dyes and substitute one for another automatically in response to user - initiated control signals or conditions encountered during use ( e . g . when switching from a blood - filled field to a saline field or in response to calcific deposits ). suitable dyes for use in the dye laser components of the invention include , for example , p - terphenyl ( peak wavelength 339 ); bibuq ( peak wavelength : 385 ); dps ( peak wavelength : 405 ); and coumarin 2 ( peak wavelength : 448 ). in yet another embodiment the pulsed light source may be an optical parametric oscillator ( opo ) pumped by a frequency - doubled or frequency - tripled solid - state laser . opo systems allow for a wide range of wavelength tunability in a compact system comprised entirely of solid state optical elements . the laser wavelength in opo systems may also be varied automatically in response to user - initiated control signals or conditions encountered during use . catheters , useful in practicing the present invention , can take various forms . for example , one embodiment can consist of a catheter having an outer diameter of 3 . 5 millimeters or less , preferably 2 . 5 millimeters or less . disposed within the catheter is the optical fiber which can be a 400 micron diameter or smaller silica ( fused quartz ) fiber such as the model sg 800 fiber manufactured by spectran , inc . of sturbridge , mass . the catheter may be multi - lumen to provide flushing and suction ports . in one embodiment the catheter tip can be constructed of radio - opaque and heat resistant material . the radio - opaque tip can be used to locate the catheter under fluoroscopy . the invention can be used with various catheter devices , including devices which operate under fluoroscopic guidance as well as devices which incorporate imaging systems , such as echographic or photoacoustic imaging systems or optical viewing systems . for one example of a photoacoustic imaging system which can be specifically adapted for the catheter environment , see u . s . pat . no . 4 , 504 , 727 incorporated herein by reference . changes and modifications in the specifically described embodiments can be carried out without departing from the scope of the invention , which is intended to be limited by the scope of the appended claims .

this invention is a catheter - based device for generating an ultrasound excitation in biological tissue . pulsed laser light is guided through an optical fiber to provide the energy for producing the acoustic vibrations . the optical energy is deposited in a water - based absorbing fluid , e . g . saline , thrombolytic agent , blood or thrombus , and generates an acoustic impulse in the fluid through thermoelastic and / or thermodynamic mechanisms . by pulsing the laser at a repetition rate an ultrasonic radiation field can be established locally in the medium . this method of producing ultrasonic vibrations can be used in vivo for the treatment of stroke - related conditions in humans , particularly for dissolving thrombus or treating vasospasm . the catheter can also incorporate thrombolytic drug treatments as an adjunct therapy and it can be operated in conjunction with ultrasonic detection equipment for imaging and feedback control and with optical sensors for characterization of thrombus type and consistency .

examples of the invention will now be described with reference to the accompanying drawings . the first example in fig1 to 5 of the drawings show the actual size of an extermination device designed for rats or stoats . it is to be appreciated that for other animals the overall size and dimensions of the extermination device may be larger or smaller as needed to suit the size of the target pests . in fig1 is shown an extermination device including a holder 100 and a front cover 3 . the holder 100 is shown in more detail in fig2 to 4 . the holder 100 comprises a central section 1 and a cover 2 , and is tubular , with an internal bore 4 . the holder may be circular in cross - section as shown in the drawings , or may have another suitable cross - section . the diameter of the bore 4 is chosen to suit the target pest and the tube has an entrance or open mouth 5 at a first end where the pest enters . for small pests such as mice , rats and stoats the diameter is preferably in the range 25 to 40 mm . for larger pests such as polecats , possums and cats , the diameter is preferably in the range 60 to 100 mm . the second end of the holder 100 is formed by the cover 2 , creating a closed region in which food or an attractant is placed . the extermination device has a trigger operated by a trigger mechanism 6 shown in fig3 . to set the trigger mechanism , it is pushed backwards in a slot 25 and to the right ( as shown in fig4 ), such that it sits in a notch 24 in the holder . when a pest enters the trap , the trigger mechanism 6 moves accurately ( as shown by arrow 7 in fig3 ), so that it is released from the notch and is forced forwards by a spring 20 to release the resilient ring 8 . the resilient ring 8 is mounted relative to the mouth 5 of the extermination device in a release position , adjacent to the open mouth 5 , such that after it slides off the open mouth 5 it contracts around whatever is within the open mouth 5 of the holder 1 00 . other trigger mechanisms may also be suitable . the resilient ring 8 may be formed of natural or synthetic rubber or a composite material . it could also be formed from metal in the form of a spring , or at least partly of rigid material with a biasing means tending to force sides of the ring together . while the resilient ring is preferably circular in shape , it could , for example , be formed from a rectangle of resilient material with a hole cut through it . other configurations may also be suitable . the resilient ring 8 has a normal diameter that is significantly less than the diameter of the holder at the release position so that on release from the open mouth 5 it contracts to its normal size which is less than the size of the neck of the target pest . on activation of the trigger mechanism 6 by a pest whose head is within the mouth 5 the rubber or composite ring 8 traps whatever is in the mouth of the extermination device . any animal or pest that activates the trip arm 6 therefore has immediately placed around its neck a resilient ring which will cut off the blood and air supply to the animal thereby killing it humanely . since the ring 8 is not retained by the extermination means , the animal may still move away from the site of the extermination means , so that other pests will be able to actuate the trigger mechanism . as shown in fig1 , a front cover 3 can be provided and is designed to protect against accidental tripping of the trip arm . the front cover 3 has an opening 9 to allow a pest to access the opening 5 . the front cover 3 connects with the holder at surface 10 and is positioned so that the target animal can still reach and actuate the trigger mechanism . in the second example shown in fig6 the extermination device has similar parts to those incorporated in the first example referenced by the same numerals . in this case the exterminator device has an automatic loading mechanism . the loading mechanism includes a moveable shaft 11 with a ratchet mechanism 12 operated by the trigger mechanism 6 . movement of the shaft 11 is under the bias of a spring 13 . the shaft 11 includes stops 14 . a hinged cover 15 is provided to enable access to the mechanism when it is being reloaded with more or additional rings 8 . in use when an animal pest tries to eat bait or attractant 16 it knocks the trigger mechanism 6 . a first ring is released from the release position , contracting around the pest &# 39 ; s neck . the spring 13 will then push forward and the trigger mechanism will be reset on its next notch ready to be tripped again . the forward movement of the shaft 11 presents the next in the succession of rings 8 to the release position adjacent to the mouth 5 of the holder 100 . fig7 and 8 show a third example of an extermination device according to the invention . this example differs from the device described above in that the trigger mechanism is located within the holder . this protects the trigger mechanism from dirt , twigs and the like , which may prevent it from functioning correctly . the trigger functions in a manner similar to that described above . these figures also show the device with a base plate 21 for mounting the extermination device in a suitable position . the base plate 21 preferably includes holes 22 , 23 to facilitate such mounting . a preferred embodiment of the invention is shown in fig9 to 19 . fig9 is a front plan view , and fig1 is a perspective view , of the extermination device 1 , showing the trigger mechanism 6 , firing hammer 30 and resilient ring 8 . with reference to fig1 , the firing hammer 30 includes a generally cylindrical section 32 and a protrusion 33 . the cylindrical section 32 slides on rod 35 , which is joined to the rear face of the device housing by a screw 36 , as shown in fig1 . a spring 34 is mounted on the rod 35 , to urge the firing hammer 30 along the rod 35 towards the resilient ring 8 . with reference to fig1 , the trigger mechanism 6 is formed integrally with a lug 31 and is attached to the device housing by a screw 37 . in the cocked position shown in fig1 , the firing hammer compresses the spring 34 and is held in position by the lug 31 , as best shown in fig9 . when a pest enters the trap , forcing the trigger mechanism 6 upwards , the trigger mechanism pivots around the screw 37 , such that the lug 31 no longer restricts movement of the firing hammer 30 . the firing hammer slides along the rod 35 towards the resilient ring 8 . the protrusion 33 forces the resilient ring 8 off the holder , onto the pest . the position of the extermination device in the fired position as shown in fig1 and 16 . fig1 shows a cover 42 for use with the extermination device of this embodiment . the cover 42 includes a base section 40 and a cylindrical section 41 . the base section 40 may include holes and / or slots for securing the extermination device to the ground , a tree etc . the device shown in fig9 to 16 is assembled with the cover 42 , as shown in fig1 . fig1 shows the device and cover in a partially assembled state . the device is pushed into the cover through the cylindrical section 41 . in a fully assembled state the device would rest against the end 43 of the cover . this arrangement protects the mechanism of the device from contamination by dirt etc and prevents animals of a size greater than the diameter of the cylindrical section 41 from activating the trap . fig1 shows a loading device for use with the extermination device of fig9 to 16 . the loading device includes a generally conical section 50 and a coupling section 51 . in use , the device is set in the cocked position and the coupling section 51 is inserted into the device , such that the shoulder 52 sits flush with the open mouth 5 of the device . a resilient ring 8 can then be forced along the generally conical section 50 and into the release position on the extermination device . the loading device is then removed . the device may be placed in any position that a targeted pest can access . the device may be placed on the ground , in a tree or attached to a board or post , for example . while the present invention has been illustrated by the description of the embodiments thereof ; and while the embodiments have been described in detail , it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail . additional advantages and modifications will readily appear to those skilled in the art . therefore , the invention in its broader aspects is not limited to the specific details , representative apparatus and method , and illustrative examples shown and described . accordingly , departures may be made from such details without departure from the spirit or scope of the applicant &# 39 ; s general inventive concept .

an extermination device for exterminating pests includes a holder , trigger mechanism and a resilient ring mounted on the holder . when a pest actuates the trigger mechanism , the ring is released from the holder onto the pest , thereby killing the pest in a humane manner . a cover may be provided to protect the trigger mechanism from dirt and animals larger than target pest size . a loading device having a tapering body adapted to allow a resilient ring to be expanded from the narrow end to the wide end of the tapering body , wherein the wide end includes a formation adapted to engage with a holder of an extermination device .

the present disclosure applies to golf clubs , which includes wedges irons , drivers and woods . the groove design of this invention is ideal for tailoring golf ball spin based on shot type through controlling spin . the design allows for maximum golf ball performance by increasing spin when needed , while simultaneously reducing cover damage of the golf ball . referring to the drawing , and particularly fig1 and 2 , it will be seen that the illustrative golf clubhead of one embodiment includes a blade member 2 having a toe portion 4 , a top ridge 6 , a bottom sole portion 8 and a heel portion 10 . extending from the heel portion region of the clubhead is a hosel portion 12 adapted to receive and be retained on a shaft member ( not shown ). the club head is provided with preferably a substantially flat surface or club face 16 , but the club face is not limited to being flat , having therein a center of percussion 18 , which is the spot ideally adapted to engage a golf ball at impact , and a rear surface 20 having a perimeter 22 defining an optional cavity 24 . cut into the club face 16 are a series of grooves 14 that may be arranged in parallel fashion and are usually uniformly spaced in relation to one another in accordance with one embodiment of the invention ; however , in a different embodiment , said grooves can be spaced non - uniformly and / or can be arranged in a non - parallel fashion . the number of grooves 14 can vary , but a typical number across the club face ranges from at least one to about twenty five grooves . before a groove is cut into the club face , the club face may be preferably milled perfectly flat , thereby removing any and all variations in face flatness . in addition , the milled club face may be finished or treated . once the work on the club face is completed , each individual groove is typically engraved into the club face one at time but they may be molded or stamped depending on the process of manufacturing chosen . it should be noted that all of the groove configurations described herein apply to the full range of wedges ( 48 to 64 degree ), as well as to all other golf clubs including irons , drivers and woods and any other known or future discovered golf clubs . furthermore , in all groove configurations described below , the individual grooves in each configuration may be spaced 0 . 05 to 0 . 2 inch apart , more particularly , 0 . 1 to 0 . 15 inches , most particularly , about 0 . 105 inch apart . fig3 a shows a reduced volume grove configuration , wherein the “ v ” groove configuration may be selected because it has a reduced volume and has a centerline spacing 32 of about 0 . 05 to about 0 . 300 inches between at least one additional v groove configuration as displayed in fig3 b , a first surface angle 26 that is about 20 to about 50 degrees from the center of the groove 29 , a second surface angle 27 that is about 20 to about 50 degrees from the center of the groove 29 , a groove depth 30 of about 0 . 005 to about 0 . 04 inches , and a groove width 28 of about 0 . 01 to about 0 . 05 inches . the groove depth 30 is between 0 . 005 and 0 . 040 inches deep . the centerline groove spacing width 32 measures the distance from the two centers of adjacent “ v ” grooves . the centerline groove width can vary from 0 . 07 to 0 . 5 inches and may be held constant throughout the club face or it may be variable as discussed herein either closer or further apart depending on the grooves position on the club face . the measurement of the spacing from groove edge to groove edge is edge spacing 34 of 0 . 05 to 0 . 3 inches as displayed in fig3 b . fig4 shows an example of modified groove spacing configuration to create a reduced groove volume . the grooves 14 can be spaced equally apart with identical dimensions as in fig1 or the spacing can be unevenly spaced as displayed in fig4 ( 5 % to 50 % further apart in center grooves 36 ) with outer groove spacing 38 being closer together than center groove spacing 36 . alternatively increased groove spacing may be combined with a reduced depth ( 5 % to 50 % less depth respectively ) and may also be used in conjunction with “ v ” grooves . this modified spacing in the center , compared to grooves at the outer portion 38 of the club face , optimizes the focal point of the club face for ball impact . the decreased volume grooves being wider spaced apart in the center decreases the effective groove volume in contact with the ball thus decreasing spin and also creating a flyer condition through increased hydroplaning in wet conditions . fig5 shows a groove cross - section with a reduced center depth 40 to decrease groove volume . while this may be a “ v ” groove as displayed in fig3 a , the groove can also have a reduced width 28 or reduced depth 30 ( 5 % to 50 % respectively ) in the center of the club face compared to the outer groove portion 38 of the club face . the groove edge depth 42 is optionally deeper than center groove depth 40 . the reduced depth in the center further decreases spin imparted to the ball when struck and increases a flyer condition from having a reduced groove volume . the groove can be produced through molding , casting , injection molding , stamping and most preferably through cnc machining process . the depth of the “ v ” grooves can be produced easily by one skilled in machining by varying the height of the tool relative to the face of the club thus cutting deeper at the edges than the center where the machining height is raised . it is likely that a second machining operation is required for each groove to keep width constant . fig6 shows a top view of a reduced volume groove having a reduced width in the center . this may be combined with a reduced depth also in the center 40 . this allows for reduced volume in the groove in the center . the groove edge width 44 is wider than the center groove width 46 . the reduced width in the center further decreases spin imparted to the ball when struck and increases a flyer condition from having a reduced groove volume . the groove can be produced through molding , casting , injection molding , stamping and most preferably through cnc machining process . the grooves width can be produced easily by one skilled in machining by varying the height of the tool relative to the face of the club thus cutting deeper at the edges than in the center where the machining height is raised . it is likely that only one machining operation is required for each groove to increase width at the edges . if the depth is desired to be held constant and not vary with the width it will be necessary to perform multiple machining operations or produce a tool that has a cutting angle which changes with cutting depth . this tool can be produced easily by one skilled in the art of cnc machining . fig7 a and 7b show an increased volume groove , specifically , a “ u ” groove configuration of one embodiment of the invention . the “ u ” groove configuration has a first surface angle 50 that is about 5 to about 25 degrees relative to an imaginary surface 90 degrees to the club surface 16 , and a second surface angle 52 that is about 5 to about 25 degrees relative to an imaginary surface 90 degrees to the club surface 16 that may be set equal to each other making total groove angle 48 being twice that of either first or second surface angle 50 , 52 , or to different angles calculated by the sum of the first and second surface angles 50 , 52 . the “ u ” configuration has a “ u ” groove depth 54 of about 0 . 005 to about 0 . 04 inches which can be set equal along the length of the groove or vary with the deepest portion placed in the center of the club face . the “ u ” groove configuration has a groove width 55 of about 0 . 01 to about 0 . 05 inches that in fig1 can vary from the club edge “ u ” groove width 53 to the center “ u ” groove width 51 , with the width being greatest in the center . in fig7 b the u groove centerline width 56 can be about 0 . 14 ″± 20 %. the u groove edge spacing 58 can be 0 . 105 ″± 30 %. the “ u ” configuration &# 39 ; s additional surface area imparts better grip and more spin upon the ball leading to better control in the greens . also the “ u ” configuration reduces the “ flyer ” condition in wet grass due to the ability to channel the water away from the ball / club interface when hitting the ball , which thus minimizes the hydroplaning effect . fig8 shows an increased volume groove configuration cross - sectional view having an arced bottom with an increased center depth 60 that can be flat across the groove width . the modified depth groove may also have a center “ u ” groove portion 60 that has a greater depth than the outer “ u ” groove portion 62 . this allows for greater groove volume in the center to maximize water dispersion when playing in wet grass to prevent a “ flyer ” condition caused by hydroplaning . additionally , the deeper grooves impart greater spin on the ball allowing for more control . the groove can be produced similar to the “ v ” groove as discussed above , preferably with a cnc milling machine produced with a custom tool . one skilled in the art of cnc machining would be able to produce the tool with minimal guidance . the depth of the groove is controlled by varying the position of the machine tool in relation to the club face . the first and second “ u ” groove edges can be produced in one operation if the angles are the same or in two or more operations depending on the configuration combination selected . fig9 shows an increased volume groove configuration having closer spaced center grooves 68 in the center of the club face . the outer groove spacing 66 is spaced wider apart than the inner groove spacing 68 allowing for more grip and greater spin to be imparted on the ball during desired shots that would correspond to the selected club . furthermore , the decreased spacing in the center between grooves would help to reduce hydroplaning and decrease a “ flyer ” condition in wet grass conditions . fig1 shows another embodiment of the increased volume grooves with a configuration having wider groove center width , which can vary from the club edge groove width 53 to the center groove width 51 , with the width being greatest in the center . the groove width variations can be produced easily by one skilled in the art of cnc machining arts . fig1 shows an embodiment of a combination of a “ u ” groove and a “ v ” groove configuration , wherein the combination centerline width can be 0 . 14 ″+( 20 - 50 %) with a plurality of the “ v ” grooves located in the center for the reduced volume configuration . conversely , for the increased volume groove configuration the “ u ” groove is in the center and the centerline width is 0 . 14 ″−( 20 - 50 %). all modifications to the configurations can be made to this embodiment as directed above depending on the driver selected and whether a reduced or increased volume is desired . it will be appreciated that the lengths , angles and radii of the modified groove configurations described above can be varied to create different spin characteristics of a golf ball when struck by a golf club employing any of the groove configurations of the present invention . all grooves can be combined in different combinations with any other type of groove to modify the clubs performance . while various embodiments have been shown and described , it will be understood that the present invention is by no means limited to the particular constructions herein disclosed and / or depicted in the drawings , but also comprises any modifications or equivalents within the spirit and scope of the disclosure . having thus described my invention , what i claim as new and desire to secure by letters patent of the united states is : “ this is a continuation of , and a claim of benefit is made to , u . s . ser . no . 10 / 765 , 825 , filed jan . 26 , 2004 , which is a continuation - in - part of u . s . ser . no . 60 / 442 , 248 , filed jan . 24 , 2003 , the contents of each are incorporated by reference herein in their entirety .”

the golf club uses specific type grooves specialized for individual types of known golf clubs , wherein the modified grooves maximises control of the golf ball through tailoring backspin to the club selected . clubs 1 , 2 , 3 , 4 , 5 , 6 , and 7 wherein selected club configuration has a reduced groove volume to maximise performance . clubs 8 , 9 , pitching wedge , gap wedge and sand wedge has an increased groove volume to maximize performance .

referring now more particularly to the drawings and fig1 to 5 inclusive in fig1 a typical individual &# 39 ; s feet f and f &# 39 ; are illustrated with ten chambers where individual weight bearing points will be determined . a shoe sh is shown in fragmentary form which includes a sole s , two layers , s1 which is the outer sole , s2 which is the inner sole , and an inner liner l1 . the outer sole s1 is of conventional configuration and the inner sole s2 has the ten chambers located in it as described below . the shoe sh also includes a heel h as shown in fig5 and fill points fp for the chambers to be described . more or less chambers can be used as desired however it has been determined that ten stragetically located chambers provide the necessary support for most uses . these ten chambers are : these norms have been selected for standard dress shoes under walking conditions . a different set of norms are used for each type of shoe and the predominant mode of ambulation ( walking , jogging , running , etc .). in addition , three neutral chambers are included in this example , which will be filled with an elastomer at the mean compressive strength . the mean compressive strength is determined by considering the type of shoe , the mode of amublation , and the user &# 39 ; s body weight . these neutral chambers are important for filling all areas of the sole , forming a custom arch support and may become active if a person &# 39 ; s pathology causes these areas to become weight bearing . the assumptions used in determining an individual foot profile as described below are based on existing materials and data gathering equipment . many other systems and materials are available and these assumptions are in no way restrictive or the only means to make the sole useful . the elastomer is available from polytech corp ., p . o . box 384 , lebanon , n . j . 08833 , and the data gathering device is available from the langer biomechanical group , inc ., 21 east industry court , deer park , new york 11729 . 1 . the elastomer ( e ) is a type which is modifiable in its compressive strength ( d ) by the addition of a plasticizer and / or a foaming agent ( p ) at manufacturing . 2 . the elastomer without modification has a set hardness of 55 shore a durameter . 3 . for each 400 parts of the elastomer the addition of 1 each part of the modifier p will have the effect of reducing the compressive strength to cushion 1 pound per square inch more of pressure at peak compression . 4 . since the mean compressive strength of the elastomer will require a certain amount of p for normal , the reverse is also true . the lowering of each 1 part of p will stiffen the elastomer to resist 1 pound per square inch more of pressure at peak compression . 5 . these changes in compressive strength are all relative to the mean compressive strength . 6 . the unmodified compressive strength ( id ) will cushion 100 pounds per square inch . 1 . a data source should be available to analyze the foot strike of an individual corresponding to the chambers ( c ) of the sole . 2 . the data will be representative of the type of ambulation that the sole will be used for . 3 . the data will be formatted as a percent of total body weight ( pw ) plus or minus the norm for that specific weight ( b .). the mean compressive strength ( d ) is determined by considering the shoe type ( st ) that the sole will be used in ( i . e . dress shoe , running shoe , etc .) and the body weight of the user ( w ). st is a factor to set the largest percent of body weight pw ) that the sole would undergo while in use . each type of use ( running , walking , dancing , tennis , etc .) has its own maximum percent of body weight stress and it also has a unique percentage distribution pattern amongst the chambers of the sole . the w factor is to establish the best compessive strength for the normal weight , while allowing enough range of modification in the elastomer to compensate for out of normal weight readings . the formulas for mixing the mean compressive strength elastomer is as follows . the following formula is used to establish the compressive strength for any chamber . ______________________________________datapeak force normal out______________________________________left foot : 1 12 % b . w . 20 % b . w . - 8 % 2 neutral3 18 % b . w . 12 % b . w . + 6 % 4 23 % b . w . 20 % b . w . + 3 % 5 16 % b . w . 14 % b . w . + 2 % 6 14 % b . w . 8 % b . w . + 6 % 7 neutral8 neutral9 15 % b . w . 16 % b . w . - 1 % 10 13 % b . w . 16 % b . w . - 3 % right foot : 1 16 % b . w . 20 % b . w . - 4 % 2 neutral3 14 % b . w . 12 % b . w . + 2 % 4 20 % b . w . 20 % b . w . 0 % 5 . 14 % b . w . 14 % b . w . 0 % 6 11 % b . w . 8 % b . w . + 3 % 7 . neutral8 . neutral9 14 % b . w . 16 % b . w . - 2 % 10 15 % b . w . 16 % b . w . - 1 % ______________________________________ the data was obtained by using the well known langer measuring equipment , however it is expected that other such equipment would also provide useful data from which suitable soles could be constructed . the cushioning needed for d is obtained by adding 34 . 5 parts [ p ( d )] to every 400 parts of e the cushioning needed for a chamber d ( c ) is obtained by multiplying the out of norm load ( pw ) ( plus or minus ) by the total weight ( w ). then multiplying that result by the parts of p needed per pound per sq . inch cushioning . then adding that to the mean p ( d ). each batch will have a 600 gram amount of e . also a ratio of 1 part p to modify 400 parts e by 1 lb . per sq . inch of cushioning . results will be rounded to the nearest hundredth gram . neutral chambers will be filled with mean compressive strength elastomer . ______________________________________chamber e batch total p______________________________________left foot1 600 gr 29 . 31 gr2 600 gr 51 . 75 gr3 600 gr 78 . 58 gr4 600 gr 60 . 17 gr5 600 gr 57 . 36 gr6 600 gr 78 . 58 gr7 600 gr 51 . 75 gr8 600 gr 51 . 75 gr9 600 gr 48 . 94 gr10 600 gr 43 . 33 grright foot1 600 gr 40 . 08 gr2 600 gr 51 . 75 gr3 . 600 gr 57 . 36 gr4 600 gr 60 . 17 gr5 600 gr 51 . 75 gr6 600 gr 60 . 17 gr7 600 gr 51 . 75 gr8 600 gr 46 . 14 gr10 600 gr 48 . 94 gr______________________________________ construction of the soles with the described material in the identified chambers resulted in soles which compensated for the user &# 39 ; s weight bearing pattern . while the tests were conducted for a walking shoe , tests for athletic and other special purpose shoes can be expected to develop useful data which can be used to manufacture soles for use in such shoes . it will thus be seen that soles have been provided with which the objects of the invention are achieved .

a differentially responsive sole for shoes is disclosed which includes a conventional outer sole , an inner sole and an inner liner , the inner sole having a plurality of empty chambers located to support biomechanical weight bearing pressure prints for which a norm has been established . measurements are made of the individual user at the points and the chambers filled with an elastomer of certain durometer and compressive strength to compensate for the weight load at each weight bearing pressure point .

fig1 a illustrates a side view of an exemplary embodiment of a door breaching system 100 . fig1 b and 1 c illustrate front and side views of an exemplary embodiment of door breaching system 100 in use . door breaching system 100 includes main tether 10 , master link 20 , at least one hook strap 30 , at least one hook 40 , at least one sling 50 , and a vehicle anchor 60 . main tether 10 includes tether strap 11 and a plurality of tether eyelets 12 . tether strap 11 is approximately 1 foot to approximately 100 feet long , approximately 1 inch to approximately 3 inches wide and approximately 0 . 25 inches to approximately 0 . 5 inches thick . in the exemplary embodiment , tether strap 11 is a woven polymer such as , but not limited to nylon . in one embodiment , tether strap 11 is green treated nylon sling web . tether strap 11 has a break strength of at least approximately 16 , 000 lbs . with a minimum 5 , 000 lbs . working load limit . in the exemplary embodiment , ten tether eyelets 12 are located on a proximal section of tether strap 11 , spaced apart approximately 5 feet . in other embodiments , the number of tether eyelets 12 ranges from approximately 5 to approximately 20 , while the spacing from approximately 5 feet to approximately 10 feet . in the exemplary embodiment , tether eyelets 12 are loops manufactured from a woven polymer such as , but not limited to nylon . in one embodiment , tether eyelets 12 are green treated nylon sling web . tether eyelets 12 have an inner diameter ranging from approximately 8 inches to approximately 12 inches . master link 20 connects a distal end of main tether 10 to proximal ends of hook straps 30 . in the exemplary embodiment , master link 20 is a welded steel ring with a thickness of approximately 0 . 5 inches . in other embodiments , master link 20 is a metallic alloy oblong hook or a metallic alloy oblong ring . in certain embodiments , master link 20 has dimensions of approximately 2 . 5 inches wide by 5 inches long , with a thickness of 0 . 5 inches . hook straps 30 interconnect master link 20 and sling hooks 40 . the exemplary embodiment of fig1 includes two hook straps 30 , but other embodiments may include between approximately 1 and approximately 6 hook straps 30 . each hook strap 30 is approximately 12 inches to approximately 72 inches long , approximately 1 inch to approximately 3 inches wide and approximately 0 . 25 inches to approximately 0 . 75 inches thick . in the exemplary embodiment , hook straps 30 are a woven polymer such as , but not limited to nylon . in one embodiment , hook straps 30 are green treated nylon sling web . hooks 40 interconnect distal ends of hook straps 30 and slings 50 . the exemplary embodiment of fig1 includes two hooks 40 , but other embodiments may include between approximately 1 and approximately 12 hooks 40 . in the exemplary embodiment , hooks 40 are steel eye sling hooks with a self - closing latch . in one embodiment , hooks 40 are steel eye sling hooks with a thickness of 9 / 32 of an inch and a spring operated latch . other embodiments of hooks 40 may include sorting hooks , oblong hooks , clevis sling hooks , clevis grab hooks , clevis foundry hooks and eye grab hooks , with or without a self - closing or manually closing latch . slings 50 loop around portions of a door , connecting the door to door breaching system 100 . the exemplary embodiment of fig1 includes two slings 50 , but other embodiments may include between 1 and 6 slings 50 . each sling 50 includes a sling strap 51 and a plurality of sling eyelets 52 . sling strap 51 is approximately 3 feet to approximately 6 feet long , approximately 1 inch to approximately 3 inches wide and approximately 0 . 25 inches to approximately 0 . 75 inches thick . in the exemplary embodiment , sling strap 51 is a woven polymer such as , but not limited to nylon . in one embodiment , sling strap 51 is green treated nylon sling web . sling strap 51 has a break strength of at least approximately 16 , 000 lbs . with a minimum 5 , 000 lbs . working load limit sling eyelets 52 are located on each end of sling strap 51 . in the exemplary embodiment , sling eyelets 52 are loops manufactured from a woven polymer such as , but not limited to nylon . in one embodiment , sling eyelets 52 are green treated nylon sling web . sling eyelets 52 have an inner diameter ranging from approximately 12 inches to approximately 18 inches . vehicle anchor 60 provides a connection between a vehicle and door breaching system 100 . at least one tether eyelet 12 connects to vehicle anchor 60 . vehicle anchor 60 is made from hardened steel . in one embodiment , vehicle anchor 60 is a hook attached to a vehicle bumper . another embodiment of vehicle anchor 60 is a post welded to a vehicle bumper . fig2 shows a side view of an exemplary embodiment of optional vehicle pivot 70 . in the exemplary embodiment , vehicle pivot 70 includes a hitch assembly bar 71 with hitch pin apertures 72 that receive a hitch pin 73 to attach hitch assembly bar 71 to a vehicle &# 39 ; s trailer hitch receiver . in the exemplary embodiment , hitch assembly bar 71 is made from hollow or solid steel , with a square cross - section , and has a length ranging from approximately 18 inches to approximately 36 inches . reinforced gussets 74 on either side of hitch assembly bar 71 connect hitch assembly bar 71 to a post sleeve 75 . in the exemplary embodiment , post sleeve 75 is made from hollow steel , with a square or circular cross - section , a length ranging from approximately 6 inches to approximately 12 inches and an inner diameter ranging from approximately 1 . 5 inches to approximately 4 inches . post sleeve 75 receives a first end of a removable vertical post 76 . vertical post 76 is made from solid or hollow steel , with a square or circular cross - section , a length ranging from approximately 3 inches to approximately 8 inches and an outer diameter ranging from approximately 1 . 5 inches to approximately 4 inches . an integral end cap 77 at a second end of vertical post 76 prevents main tether 10 from sliding off vertical post 76 . end cap 77 is made from steel plating having a thickness of approximately 0 . 25 inches and a diameter ranging from approximately 4 inches to approximately 12 inches . in use , vehicle pivot 70 attaches to a second vehicle . main tether 10 extends around vehicle pivot 70 between the door and vehicle anchor 60 . this permits the first vehicle to remove the door at an angle if , for example , there is insufficient space to safely remove the door . fig3 illustrates a flowchart of a method 300 for using door breaching system 100 . in step 302 , method 300 aligns a vehicle to face directly in front or to the side of a door . in step 304 , method 300 extends main tether 10 from the vehicle to the door . in step 306 , method 300 feeds slings 50 around at least two separate and substantial points of the door such as the frame , main reinforced cross section or security bars . in step 308 , method 300 attaches sling eyelets 52 to hooks 40 . only one sling 50 attaches to each hook 40 . in step 310 , method 300 removes slack from tether strap 12 by pulling it taut . in optional step 312 , method 300 passes main tether 10 around vehicle pivot 70 . in step 314 , method 300 attaches one of tether eyelets 12 to vehicle anchor 60 while keeping tether strap 12 as taut as possible . in step 316 , method 300 backs the vehicle away from the door to remove any remaining slack from door breaching system 100 . in step 318 , method 300 backs the vehicle away from the door to transfer a pulling force from the vehicle to the door until the door is opened or removed from the structure . in optional step 320 , method 300 removes any remaining pulling force on door breaching system 100 by placing the vehicle in “ neutral ” or slowly returning the vehicle to its original starting position . it will be understood that many additional changes in the details , materials , procedures and arrangement of parts , which have been herein described and illustrated to explain the nature of the invention , may be made by those skilled in the art within the principle and scope of the invention as expressed in the appended claims . it should be further understood that the drawings are not necessarily to scale ; instead , emphasis has been placed upon illustrating the principles of the invention . moreover , the terms “ about ,” “ substantially ” or “ approximately ” as used herein may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function to which it is related .

the door breaching system is capable of removing or opening a door attached to a structure . a main tether made up of a tether strap and multiple eyelets attaches to a vehicle through one of the eyelets at one end of the tether strap . the other end of the tether strap attaches to at least one hook strap through a master link . each hook strap has a hook at a distal end . in use , at least one sling loops through part of the door . sling eyelets on either end of a sling strap connect to the hook . due to the secure connection between the door and the door breaching system , moving the vehicle away from the structure removes the door in a controllable fashion .

hereinafter , embodiments of the present invention will be explained with reference to the drawings . however , the scope of the invention is not limited to the illustrated figures . description will be made in detail of a first embodiment according to the present invention with reference to fig1 to fig1 . in this embodiment , a baseball game is exemplified in which a club possessing a plurality of players arranges a team which repeatedly plays games over an official game period . the official game period herein refers to a competition period , corresponding to the so - called “ pennant race period ” or “ championship season .” that is , the official game period is a virtual period which the players play the games to win the championship during a predetermined schedule . note that the present invention is not only applicable to a baseball game , but also to a game such as a soccer , basketball , volleyball , or hockey game , in which a club possessing a plurality of players arranges a team which repeatedly plays games over an official game period . fig1 is a diagram showing an example of a home game unit to which the present invention is applied . as shown in fig1 , the home game unit 1200 has game controllers 1202 and a main unit 1210 , and is connected to a display 1220 equipped with a speaker 1222 . the game information required to execute the game , such as a game program and initial data , is stored in the information storage medium detachable from the main unit 1210 , for example , a cd - rom 1212 , an ic memory 1214 , and a memory card 1216 . alternatively , the game information is obtained from an external device through a communication device 1218 which is equipped on the main unit 1210 and connected to a communication line 1230 . the communication line 1230 refers to a communication channel which allows data transmission and reception . in other words , the communication line 1230 may be a dedicated line ( dedicated cable ) for direct connection , a lan through ethernet ( registered trademark ) or the like , and a communication network such as a telephone network , a cable network , or the internet , whether its communication method is wired or wireless . the main unit 1210 is equipped with a processing unit such as a cpu , and a reader for the information storage medium such as the ic memory 1214 and cd - rom 1212 . the main unit executes various game processing based on the game information read from the cd - rom 1212 or the like and operation signals inputted from the game controller 1202 , displays game screens on the display 1220 , and outputs game sounds from the speaker 1222 . the game player operates a direction key 1204 , a button switch 1206 , and the like provided on the game controller 1202 while watching the game screens shown on the display 1220 to enjoy playing the baseball game . in this embodiment , the direction key 1204 is operated to select a player character to be the subject of a trade and the condition of the trade , and the push switch 1206 is operated to input the decision or the cancellation , for example . in the baseball game in this embodiment , six teams play one hundred and thirty ( 130 ) games in total against one another over the official game period set within one year in the game world to win the so - called “ pennant race .” the game player selects any one of the six teams as the game player &# 39 ; s team . the game player arranges a team from the player characters of the group ( the same meaning as the player character belonging to the group , which may be hereinafter referred to as “ possessed player ” as appropriate ) to play a game against a team played by the computer ( or by another game player ). during the game , the game player can input a variety of operations of pitching , fielding , base - running , batting , and the like to enjoy the baseball game . fig2 a and fig2 b are diagrams for describing the conceptual configuration of a team in this embodiment . as shown in the diagram , the player characters of each team 2 include domestic players 4 and foreign players 6 having different attributes , on which a domestic players quota and a foreign players quota are set , respectively , to limit the maximum number of players that can be in the roster . in the diagram , the foreign players quota is 4 . the information of each team 2 contains team parameter 11 for the team . the configuration of the player characters for each team can be changed even during the official game period . the change in the configuration of the player characters is performed in a “ trade ” event , in which two teams exchange their domestic players , and in a “ foreign player acquirement negotiation ” event , in which a team pays virtual contract money to acquire a foreign player that does not belong to any of the teams . in the present specification , the removal of a player character from the configuration is referred to as “ to release ” or “ to delete from the registration ,” and the addition to the configuration is referred to as “ to acquire ” or “ to register ” as appropriate . a “ trade ” event in this embodiment occurs with random timing during the official game period . a team with a lower ranking in the pennant race is more likely to be selected as one of the two teams that make a trade . a “ foreign player acquirement negotiation ” event in this embodiment occurs during the official game period to a team with “ team parameters ,” as parameters set for each team , falling short of a predetermined condition . it also occurs at random during the official game period . the team parameters are parameters set for each team , and vary depending on the results of games played in the pennant race . the team parameters in this embodiment include , for example , the team &# 39 ; s ranking in the pennant race , the virtual tv rating average value corresponding to the team &# 39 ; s popularity , and the number of registered foreign players of the team ( the number of foreign players ). team parameters are determined to fall short of a predetermined condition when the tv rating average value does not satisfy a predetermined condition , or when the number of registered foreign players is less than its maximum , for example . a trade will serve to enhance recovery of the team &# 39 ; s lowered popularity in the former case , or will serve as a reinforcement of the team &# 39 ; s strength in the latter case . that is , in this embodiment , events such as a “ trade ” and a “ foreign player acquirement negotiation ,” which involve changing the configuration of player characters of a team , occur according to the state of each team ( team parameters ), which changes as the game proceeds . in this way , a more real pennant race can be materialized as in the actual professional baseball world , in which teams make a trade and acquire a foreign player even during the official game period to increase the team &# 39 ; s strength . fig3 is a block diagram showing an example of the functional configuration of this embodiment . as shown in the drawing , the home game unit 1200 is provided with an operation input section 10 for inputting operations from the game player , a processing section 20 for processing operations to control the unit and the game , an image displaying section 30 for outputting game screens to be displayed , a sound output section 40 for outputting game sounds to be sounded , a communication section 50 , and a storage section 70 for storing a variety of programs and data . the operation input section 10 functions by section of a button switch , lever , dial , mouse , keyboard , or other various sensors , is inputted operations by a player , and outputs operation input signals to the processing section 20 . in this embodiment , the game controllers 1202 correspond to this operation input section . the processing section 20 controls the whole of the home game unit 1200 as well as executing various computing processes such as game computing . the functions thereof are implemented by hardware such as a cpu ( cisc type and risc type ) or an asic ( gate array ), and the related control programs . the processing unit , such as the cpu , equipped with the main unit 1210 in fig1 corresponds to this processing section . the processing section 20 includes a game computing section 22 serving for mainly game computing , the image generating section 24 for generating the image signals to display the game screens based on various data obtained from the processes executed by the game computing section 22 , and the sound generating section 26 for generating game sounds to be output as sound effects or bgm . the game computing section 22 executes various game processing based on the signals inputted through the operation input section 10 , or the program and data loaded from the storage section 70 . as the game processing , for example , arranging objects in a virtual space , controlling motions of objects of player characters based on signals inputted from the operation input section 10 , computing paths of pitched and batted balls , crossing detection for objects ( hit check ), calculating the batting results , calculating the game results ( records ), arranging view points , determining view directions or the like , are performed . the game computing section 22 in this embodiment includes : ( 1 ) a parameter varying section 220 for varying parameters set for each team and player character according to the progress and play results of the game ; ( 2 ) a change - intended team determining section 221 for selecting a team which can change its configuration of the player characters as a change - intended team ; ( 3 ) a changes contents setting section 222 for determining the contents of the configuration change of the team selected as the change - intended team based on its team parameters ; ( 4 ) a players configuration changing section 223 for carrying out the process of changing the configuration of the player characters ; ( 5 ) a baseball game plan setting section 224 for setting the schedule of games during the official game period and for setting several of the games as special event games which are held on virtual tv broadcast dates ; ( 6 ) a tv rating calculating section 225 for calculating a virtual tv audience rating , which is a virtual point determined based on the results of a game held on the tv broadcast date ; and ( 7 ) a money reward calculating section 226 for calculating a virtual money reward based on the calculated tv rating . the parameter varying section 220 varies team parameters set for each team and player parameters set for each player character according to the progress and play results of the game . as examples of the team parameters , the ranking in the pennant race ( pennant ranking ), the number of registered foreign players , the tv rating average value , and the fund of the team may be used . the tv rating average value is the average value of tv ratings calculated by the tv rating calculating section 225 , and is an index of the team &# 39 ; s popularity . the fund is the total amount of cash rewards which have already been received by the team . as examples of the player parameters , the playing record and the name value of the player character may be used . the name value is determined according to the playing record of the player character , and is an index of the player character &# 39 ; s popularity . the change - intended team determining section 221 has functions of : ( 1 ) determining a team with its team parameters falling short of a predetermined condition as the change - intended team ; and ( 2 ) automatically selecting two teams which make a trade as the change - intended teams . more specifically , in the former case , the change - intended team determining section 221 selects as the change - intended team a team with its tv rating average value lower than a predetermined tv rating value or a team with the number of registered foreign players less than its foreign players quota , for example , to allow acquiring a foreign player . in the latter case , the change - intended team determining section 221 divides the official game period into a first half and a latter half , for example , and arranges that events occur with a predetermined probability ( 5 %, for example ) in the first half , and that events occur with a higher probability ( 8 %, for example ) in the latter half . in the selection of two change - intended teams , a team with a lower ranking in the pennant race is selected with a higher probability , and a team with a higher ranking is selected with a lower probability . the changes contents setting section 222 decides , for the team selected as the change - intended team by the change - intended team determining section 221 , the contents of the configuration change of the player characters , that is , the contents of the “ trade ” and “ foreign player acquirement negotiation ,” and determines whether the configuration change succeeds or fails ( corresponding to the success or failure of the trade or foreign player acquirement negotiation ). more specifically , in the case that only one team is selected as the change - intended team , that is , the change - intended team determining section 221 determines that its team parameters fall short of a predetermined condition , the team carries out an acquirement of a foreign player . that is , if the change - intended team already has the full number of registered foreign players to the maximum of its foreign player registration quota , the player character with the lowest name value of the player parameters is automatically released to make room available in the foreign players quota . if there is room available in the foreign player registration quota , a player character to be acquired is selected among non - belonged foreign players . at this time , if the change - intended team is the game player &# 39 ; s team , the game player makes an input to select the foreign player to be acquired . then , if the fund of the team is more than the acquired money ( corresponding to the contract money ) set in advance for each foreign player , it is determined that the negotiation goes through , that is , the acquirement goes through , and , to the contrary , if the fund is less than the acquired money , it is determined that the negotiation does not go through , that is , the acquirement does not go through . in the case that two teams are selected as the change - intended teams , that is , selected by the change - intended team determining section 221 as teams which make a trade , player characters as trade personnel are selected to carry out the so - called trade process . more specifically , first , the number of player characters to be traded ( one to one , plural to plural , for example ) is determined at random . when the number of players to be traded is determined , player characters to be released by the trade ( trade personnel ) are selected . the determined number of player characters ( hereinafter referred to as “ first trade - intended players ”) are first selected from one of the teams , with a higher probability as the player character &# 39 ; s name value is lower . the same number of player characters ( hereinafter referred to as “ second trade - intended players ”) are then selected from the other team , of which fielding positions are the same as , and of which name values are generally equivalent to those of the first trade - intended players . if the second trade - intended players can be successfully selected , it is determined that the negotiation goes through , that is , the trade goes through . on the contrary , if the second trade - intended characters cannot be selected because , for example , player characters corresponding to the first trade - intended players do not exist , it is determined that the negotiation does not go through , that is , the trade does not go through . the players configuration changing section 223 changes the configuration of player characters of the team and changes to which team the player characters subjected to the change belong , according to the change contents of the negotiation that is determined to go through by the changes contents setting section 222 . the baseball game plan setting section 224 sets the schedule of games before the official game period starts , and sets several of the games as held on virtual tv broadcast dates . fig4 shows an example of the game schedule and tv broadcast dates during the official game period in this embodiment , corresponding to a screen showing the game schedule to which the game player can refer to any time during the game . as shown in the drawing , the calendar displays a team 1 against which the game player &# 39 ; s team plays a game , and a camera mark 5 indicating that the date with the mark is a tv broadcast date . at the lower section of the screen is shown a list 7 of games held on the date selected by a selector 3 . in the drawing , the screen shows that , for example , the game player &# 39 ; s team has a game against the team b on april 2 , which is not a tv broadcast date . it also shows that the game player &# 39 ; s team has a game against the team d on april 19 , which is a tv broadcast date . it can also show the results of games that have already been finished , and , if a tv broadcast date is selected by the selector 3 , show a tv rating 9 . in the drawing , the tv rating 9 is “ 0 . 0 %” since the game on april 19 has not yet been played . the tv rating calculating section 225 calculates a virtual tv rating based on the game results of a game held on a virtual tv on - air date set by the baseball game plan setting section 224 . fig5 a shows an example of the calculation formula , and fig5 b shows an example of tv rating setting information 738 to which the tv rating calculating section 225 refers in the calculation . the tv rating in this embodiment is calculated according to the game results or the game contents of a game held on a tv broadcast date . that is , the tv rating is determined as the total sum of basic tv ranking additional values ( 738 a to 738 d ), which are shown in fig5 b , multiplied by each of baseball game contents correction values ( 738 e to 738 h ). the basic tv rating additional values are set in advance as the number of wins and losses of the games , the team &# 39 ; s ranking , and the day of the week of the tv broadcast date , for example . the baseball game contents correction values are set in advance as the number of innings of 1 score difference , the number of changes of leads in the game , the type of the game - ending homerun , and the number of entries by player characters with higher name values , for example . as a result , if teams with high rankings play a close , thus dramatic and impressive game with many upsets on a day of the week on which the game draw more viewers , the game produces a high tv rating . the entry of a player character with a high popularity also produces a high tv ranking . the contents of elements , the additional values and the correction values may be set as appropriate . the cash reward calculating section 226 calculates a virtual cash reward in response to the value of the tv rating calculated by the tv rating calculating section 225 . the total sum of cash rewards that have been already paid to a team is the “ fund ” as one of the team parameters . the fund of a team is virtual money obtainable in the game , and serves , in this embodiment , as virtual contract money for a foreign player . that is , in order to acquire a foreign player , the team &# 39 ; s fund ( total sum of cash rewards ) needs to have reached the “ acquired money ,” which is set in advance for each foreign player , corresponding to the desired amount of contract money . relation for calculating a cash reward from a tv rating may be set as appropriate . the functions of the image generating section 24 are implemented by the processing unit such as the cpu or dsp , the control program and the ic memory for image frames such as a frame buffer . the image generating section 24 executes a geometry conversion process and a shading process based on the results computed by the game computing section 22 , and generates the 3d cg images for displaying the game screen . furthermore , the image generating section 24 also combines images with the 3d cg images . then , the image generating section 24 outputs the image signals of the generated game images to the image displaying section 30 . the sound generating section 26 , which is implemented by a processing unit such as a cpu or dsp and its control program , generates sounds used in the game such as sound effect and bgm , and outputs the sound signals to the sound output section 40 . the image displaying section 30 is designed to display the game screen by refreshing a screen of one frame per 1 / 60 second , for instance , based on the image signals from the image generating section 24 . the image displaying section 30 is implemented by hardware such as a crt , lcd , eld , pdp or hmd . the display 1220 in the example of fig1 corresponds to this section . the sound output section 40 outputs game sounds including sound effects and bgm based on the sound signals generated the sound generating section 26 . the speaker 1222 in the example of fig1 corresponds to this section . the communication section 50 connects with a communication line to transmit and receive data to and from an external device . the communication section 50 is implemented by , for example , a module of , for example , bluetooth ( registered trademark ) or irda , modem , ta , communication cable jack , and control circuit . the communication device 1218 in fig1 corresponds to this section . information such as protocol used in the communication by the communication section 50 is stored in the storage section 70 , for example , to be read as necessary . the storage section 70 stores a system program ( not shown ) which implements various functions of permitting the processing section 20 to synthetically control the home game unit 1200 , game information 72 including the program and data required for it to execute the game . the functions of the storage section 70 are implemented by an information storage medium such as various types of ic memories , a hard disc , cd - rom , dvd and mo . the cd - rom 1212 , the ic memory 1214 , and the memory card 1216 equipped with the main unit in fig1 correspond to this information storage medium . game information 72 includes programs and data to permit the processing section 20 to function as the game computing section 22 . the programs include a parameter varying program 720 for permitting the processing section 20 to function as the parameter varying section 220 , a change - intended team determining program 721 for permitting it to function as the change - intended team determining section 221 , a changes contents setting program 722 for permitting it to function as the changes contents setting section 222 , a players configuration changing program 723 for permitting it to function as the players configuration changing section 223 , a baseball game plan setting program 724 for permitting it to function as the baseball game plan setting section 224 , a tv rating calculating program 725 for permitting it to function as the tv rating calculating section 225 , and a cash reward calculating program 726 for permitting it to function as the cash reward calculating section 226 . the data include stage information 730 , player information 732 , team information 734 , baseball game setting information 736 , tv rating setting information 738 , cash reward setting information 740 , date counter 742 , and negotiation contents information 744 . although not shown in the drawing , the data also include a variety of information used during a baseball game in progress , such as the number of the inning , top and bottom of the inning , count of balls and strikes , batting order , and data for replay . the stage information 730 includes , for example , information on objects ( modeling data , texture data , displaying position setting , and sound data such as sound effects , for example ), which are used to display in a virtual space , a stage and items used in the baseball game , such as a stadium , a count display , spectators , a ball and a bat . fig6 a and fig6 b show an example of the player information 732 in this embodiment . as shown in fig6 a , the player information 732 includes information on each of the player characters having different attributes , namely domestic players 732 - 1 and foreign players 732 - 2 , related to and stored for each of them . as shown in fig6 b , examples of the player information 732 on one player character include player identification information 732 a ( or player &# 39 ; s name ), belonged team 732 b , display model , motion data , initial setting values of parameters (“ 1 ” to “ 5 ,” for example ), and season values updated as the game proceeds . in this embodiment , the player information 732 particularly includes name value 732 c (“ 0 ” to “ 100 ,” for example ), which shows the player character &# 39 ; s popularity , and acquired money 732 d . domestic players 732 - 1 also have similar information related to and stored for each of them . the team information 734 is provided for each team , and stores team parameters and identification information of player characters of the team . fig7 shows an example of the team information 734 in this embodiment . as shown in the drawing , the team information 734 includes team identification information 734 a , team parameters such as tv rating average value 734 b , fund 734 c and number of foreign players 734 d , team player information 734 e , and pennant ranking 734 j , mutually related and stored therein . the tv rating average value 734 b is the average value of past tv ratings set by the tv rating calculating section 225 , corresponding to an index of the team &# 39 ; s popularity . the team player information 734 e includes registered domestic player identification information 734 f , which shows the domestic players registered on the team , and registered foreign player identification information 734 g , which shows the foreign players registered on the team . when the players configuration changing section 223 changes the configuration of player characters of a team , the character information 734 e is updated as appropriate . fig8 shows an example of the baseball game setting information 736 in this embodiment . the baseball game setting information 736 includes date 736 a , day of the week 736 b , broadcast date flag 736 c , match - up combination 736 d , and match - up result information 736 e , mutually related and stored therein . the date 736 a , day of the week 736 b , and broadcast date flag 736 c are set by the baseball game plan setting section 224 . the date 736 a and day of the week 736 b are set corresponding to the virtual calendar during the official game period . the broadcast date flag 736 c shows whether or not the date is set as a tv broadcast date by the baseball game plan setting section 224 . the match - up combination 736 d stores the team identification information of pairs of opposing teams . the match - up result information 736 e stores , for example , score , tv rating , and amount of the acquired cash reward . the match - up result information 736 e may include data for displaying replay pictures . the tv rating setting information 738 stores the settings of the basic tv rating additional values and baseball game contents correction values , which are set in advance for calculating a tv rating . the tv rating calculating section 225 calculates a tv rating with reference to the tv rating setting information 738 . preferably a plurality of sets of tv rating setting information 738 are provided , for example , one for the pennant race and another for the championship , in which the winners of respective leagues in the pennant race play games , and the set for the latter is arranged to provide a higher tv rating , thereby enhancing the reality of the game . the cash reward setting information 740 stores information ( table data , coefficients , and correction values , for example ), which is set in advance for calculating a cash reward according to the tv rating . the cash reward calculating section 226 calculates a cash reward with reference to the cash reward setting information 740 . fig9 shows an example of the negotiation contents information 744 in this embodiment . the negotiation contents information 744 stores information on the changes contents set by the changes contents setting section 222 for managing a trade or foreign player acquirement negotiation . the negotiation contents information 744 stores , for example , change - intended team identification information 744 a , which shows a team subjected to a foreign player acquirement or trade , change - intended player identification information 744 b , which shows a player character subjected to the acquirement or trade , success or failure flag 744 c , which shows whether the negotiation is a success or failure , and negotiation starting date 744 d , on which the virtual negotiation is started . the players configuration changing section 223 carries out a configuration change of the player characters according to the contents of the trade or foreign player acquirement , if a predetermined number of days have elapsed from its negotiation starting date stored in the negotiation contents information 744 and if its success or failure flag is “ 1 ,” which represents a success . then , description will be made of a flow of the process of changing the configuration of player characters of a team (“ trade ” and “ foreign player acquirement negotiation ”) in this embodiment with reference to fig1 to fig1 . this process is implemented by the processing section 20 , which reads from the game information 72 and executes the parameter varying program 720 , the change - intended team determining program 721 , the changes contents setting program 722 , the players configuration setting program 723 , the baseball game plan setting program 724 , the tv rating calculating program 725 , the cash reward calculating program 726 , and , not to mention , the game program . fig1 is a flowchart for describing the entire process of changing the configuration of player characters of the game player &# 39 ; s team in this embodiment . the game player &# 39 ; s team refers to the team operated by the game player , which has been selected by the game player among the six teams . the teams other than the game player &# 39 ; s team are controlled by the computer . in the drawing , first , the baseball game plan setting section 224 sets the schedule of baseball games during the official game period on the game world calendar , and sets a predetermined number of tv broadcast dates among the set baseball games ( step s 2 ). the tv broadcast dates may be selected at random from the baseball games held each month , for example . the set information is stored as the baseball game setting information 736 . at this time , the game computing section 22 sets the date counter 742 to january 1 or to the first day of the official game period , for example , as an initial state . the game computing section 22 refers to the baseball game setting information 736 , and , if there exists any baseball game set on the date ( step s 4 ; yes ), executes the set baseball game ( step s 6 ). that is , if there exists a baseball game for the game player &# 39 ; s team , the baseball game is played by the game player &# 39 ; s team and a computer team , as in the conventional baseball games . if there exists a baseball game to be played by two computer teams , the game computing section 22 controls ( computer control ) both the teams to execute the baseball game . when the baseball game is over , the game computing section 22 stores the baseball game results in the match - up result information 736 e of the baseball game setting information 736 ( step s 8 ). based on the baseball game results , the parameter varying section 220 updates the team parameters such as pennant ranking ( step s 10 ). the game computing section 22 refers to the baseball game setting information 736 to determine whether or not the date is set as a tv broadcast date ( step s 12 ). if the date is set as a tv broadcast date ( step s 12 ; yes ), all the teams having a game are subjected to the process below ( loop 1 ; step 14 to step 26 ). that is , the tv rating calculating section 225 refers to the contents of the match - up result information 736 e to calculate the tv rating according to the tv rating setting information 738 ( step s 16 ). the calculated tv rating is stored in the match - up result information 736 e ( step s 18 ), and the tv rating average value 734 b of the teams that have matched in the baseball game is updated ( step s 20 ). the cash reward calculating section 226 calculates the cash reward according to the cash reward setting information 740 with reference to the tv rating stored in the match - up result information 736 e ( step s 22 ), and adds the calculated cash reward to the fund 734 c of the teams that have matched in the baseball game ( step s 24 ). when loop 1 is executed for all the teams having a baseball game on the date , the negotiation contents setting process is then executed ( step s 30 ). the change - intended team determining section 221 selects a change - intended team which can change the configuration of its player characters , and the changes contents setting section 222 determines the contents of a change of the player characters of the selected team by a trade or foreign player acquirement . the information on the contents of the change of the player characters is registered in the negotiation contents information 744 . the players configuration changing section 223 then executes the player configuration changing process , in which the players configuration changing section 223 searches the contents of changes of the players ( contents of “ trade ” and “ foreign player acquirement negotiation ”) registered in the negotiation contents information 744 , and , if any change is found with a predetermined number of days having elapsed from the negotiation starting date in the game world time , implements the contents of the found change sequentially to change the configuration of the player characters ( step s 32 ). the implemented “ trade ” or “ foreign player acquirement negotiation ” is deleted from the registration in the negotiation contents information 744 . when the changes of the configuration of the player characters are complete , the game computing section 22 determines whether or not the official game period has ended . if the official game period has not ended ( step s 34 ; no ), the date counter is increased by a day ( step s 36 ) to return to step 2 . if the official game period has ended ( step s 34 ; yes ), it is determined that the pennant race is over to end the game . as in the conventional baseball games , it may be arranged that , if the game player &# 39 ; s team is at the top of the pennant race when the game is over , the game player &# 39 ; s team plays games in the championship race against the team that has won in another league . fig1 to fig1 are flowcharts for describing the negotiation contents setting process in this embodiment . first , the change - intended team determining section 221 refers to the tv rating average values 734 b of the teams , and searches for a team of which tv rating average value 734 b is less than a predetermined reference value ( 3 %, for example ) ( step s 102 ). the change - intended team determining section 221 defines any found team as a change - intended team ( step s 104 ), judging that the team &# 39 ; s popularity has become lower and that a change in the configuration of foreign players of the team would be required to enhance recovery of its popularity . if the change - intended team is the game player &# 39 ; s team ( step s 106 ; yes ), the changes contents setting section 222 allows displaying a picture in which the game player selects to or not to execute a change in the configuration of foreign players ( foreign player acquisition ) ( step s 108 ). if the game player selects to execute a foreign player acquisition ( step s 110 ; yes ), it is determined whether or not the number of foreign players of the change - intended team has reached its foreigners registration quota ( step s 112 ). if the foreigners registration quota is reached ( step s 112 ; yes ), the foreign players that are registered in the registered foreign player identification information 734 g are displayed so as to be selectable ( step s 114 ). when the game player has made an input of selection , the changes contents setting section 222 determines the player character to be released according to the operation input ( step s 116 ), and the players configuration changing section 223 deletes the selected player character from the registration in the registered foreign player identification information 734 g to store “ 0 ”, which represents that the foreign player does not belong to any teams , to information relating to the belonged team 732 b for the foreign player character ( step s 118 ). the changes contents setting section 222 searches the player information 732 to allow displaying a list of non - belonged foreign players so as to be selectable ( step s 120 ). when the game player has made an input of selection , the changes contents setting section 222 determines the acquirement - intended foreign player according to the operation input ( step s 122 ). on the other hand , if the change - intended team is a team operated by the computer ( step s 106 ; no ), the changes contents setting section 222 searches for a player character with the lowest name value 732 c among the foreign players of ( registered on ) the team ( step s 124 ), and the players configuration changing section 223 deletes the player character from the registration ( step s 126 ). the changes contents setting section 222 searches for a predetermined number of ( 10 , for example ) foreign players with highest name values 732 c among non - belonged foreign players in the player information 732 ( step s 128 ), and selects a player character from the foreign players at random ( step s 130 ). when the foreign player desired to be acquired is selected , a comparison is made between the fund 734 c of the change - intended team and the acquired money 732 d of the selected foreign player . if the fund 734 c exceeds the acquired money 732 d ( step s 132 ; yes ), the changes contents setting section 222 judges the success of the negotiation , that is , the success of the acquirement ( step s 134 ), and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 1 ( negotiation succeeded )” ( step s 138 ). if the fund 734 c does not exceed the acquired money 732 d ( step s 132 ; no ), the changes contents setting section 222 judges the failure of the negotiation , that is , the failure of the acquirement ( step s 136 ), and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 0 ( negotiation failed )” ( step s 138 ). then , in fig1 , the change - intended team determining section 221 searches for a team of which number of foreign players 734 d has not reached the foreign players quota “ 4 ” ( step s 140 ), and defines any found team as a change - intended team ( step s 142 ). if the change - intended team is the game player &# 39 ; s team ( step s 144 ; yes ), the changes contents setting section 222 allows displaying a screen in which the game player selects to or not to execute a change in the configuration of foreign players ( foreign player acquisition ) ( step s 146 ). if the game player selects to execute a foreign player acquisition ( step s 148 ; yes ), the changes contents setting section 222 searches the player information 732 to allow displaying a list of non - belonged foreign players so as to be selectable ( step s 150 ). when the game player has made an input of selection , the changes contents setting section 222 determines the acquirement - intended foreign player according to the operation input ( step s 152 ). if the change - intended team is a team operated by the computer ( step s 144 ; no ), the changes contents setting section 222 searches for a predetermined number of ( 10 , for example ) foreign players with highest name values 732 c among non - belonged foreign players in the player information 732 ( step s 154 ), and selects a player character from the foreign players at random ( step s 156 ). when the foreign player desired to be acquired is selected , a comparison is made between the fund 734 c of the change - intended team and the acquired money 732 d of the selected foreign player . if the fund 734 c exceeds the acquired money 732 d ( step s 158 ; yes ), the changes contents setting section 222 judges the success of the negotiation , that is , the success of the acquirement ( step s 160 ), and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 1 ( negotiation succeeded )” ( step s 164 ). if the fund 734 c does not exceed the acquired money 732 d ( step s 158 ; no ), the changes contents setting section 222 judges the failure of the negotiation , that is , the failure of the acquirement ( step s 162 ), and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 0 ( negotiation failed )” ( step s 164 ). then , in fig1 , the change - intended team determining section 221 determines whether or not a trade is generated at random with a predetermined probability ( step s 170 ). specifically , a random number is generated so as to generate a trade with a probability of 5 % in the first half of the competition period , and with a probability of 3 % in the latter half of the competition period , for example . if a trade is generated ( step s 172 ; yes ), the change - intended team determining section 221 determines two teams that make a trade according to the rankings in the pennant race ( step s 174 ). specifically , a random number is generated for each team in sequence so as to determine whether or not the team is selected with a probability according to its ranking in the pennant race , until two teams are selected as trading teams , for example . the probability in the selection is set in advance to be lower ( 5 %, for example ) for a team with a higher ranking , and to be higher ( 35 %, for example ) for a team with a lower ranking . when two teams are selected as the trading teams , the changes contents setting section 222 selects a player character to be released in the trade ( first trade - intended player ) from the team other than the game player &# 39 ; s team ( step s 176 ). specifically , the domestic players registered in the registered domestic player identification information 734 f of the team are ranked according to their name values 732 c , and a player character with a low name value and ranked in the lowest rank is selected at random , for example . if the other team as a trading partner is the game player &# 39 ; s team ( step s 178 ; yes ), the changes contents setting section 222 allows displaying a screen which informs the game player that a trade is offered and which allows the game player to select to or not to accept the trade ( step s 180 ). if the game player makes an input to accept the trade ( step s 182 ; yes ), the changes contents setting section 222 allows displaying the fielding position and rank of the name value 732 c of the player character already selected ( first trade - intended player ) ( step s 184 ). the list of the domestic players registered in the registered domestic player identification information 734 f is displayed so as to be selectable , to allow the game player to select a player character to be traded ( second trade - intended player ) or to select to cancel the trade ( step s 186 ). if the other team as a trading partner is not the game player &# 39 ; s team ( step s 178 ; no ), the changes contents setting section 221 searches for a player character generally at the same level as the player character already selected ( first trade - intended player ) ( step s 188 ). specifically , a player character with the same fielding position as and generally in the same rank as the parameters of the player character already selected to be traded is searched for from the domestic players registered in the registered domestic player identification information 734 f of the team , for example . if any player characters are found ( step s 190 ; yes ), a player character is selected at random from the found player characters ( step s 192 ). the changes contents setting section 222 judges whether or not the negotiation goes through ( step s 194 ). if the game player does not select a second trade - intended player , or if a second trade - intended player equivalent to the first trade - intended player is not selected from the team operated by the computer ( step s 194 ; no ), the changes contents setting section 222 judges the failure of the negotiation , that is , the configuration of the player characters cannot be changed ( step s 196 ), and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 0 ( negotiation failed )” ( step s 198 ). if a second trade - intended player is selected ( step s 194 ; yes ), the changes contents setting section 222 judges the success of the negotiation , that is , the configuration of the player characters can be changed ( step s 197 ), and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 1 ( negotiation succeeded )” ( step s 198 ). fig1 is a flowchart for describing the player configuration changing process in this embodiment . as shown in the drawing , the players configuration changing section 223 refers to the negotiation contents information 744 ( step s 202 ), and compares the negotiation starting dates 744 d of the registered foreign player acquirement negotiations or trades with the present date in the game world to search for a negotiation or trade with a predetermined number of days having elapsed from the negotiation starting date ( step s 204 ). according to the contents of any found foreign player acquirement negotiation or trade , the configuration of player characters of the team in the change - intended team identification information 744 a is changed . specifically , in the case of a foreign player acquirement negotiation ( step s 206 ; yes ), for example , if the success or failure flag 744 c stored is “ 1 ,” which indicates that the negotiation goes through ( step s 208 ; yes ), the team identification information of the negotiation partner is stored in the belonged team 732 b of the foreign player in the change - intended player identification information 744 b registered in the negotiation contents information 744 ( step s 210 ), and the player identification information of the foreign player is registered in the registered foreign player identification information 734 g of the team in the change - intended team identification information 744 a ( step s 212 ). the players configuration changing section 223 allows displaying on the game screen the success of the acquirement of the foreign player ( step s 214 ). if the success or failure flag 744 c stored is “ 0 ,” which indicates that the negotiation does not go through ( step s 208 ; no ), the players configuration changing section 223 allows displaying on the game screen the failure of the acquirement of the foreign player ( step s 215 ). in the case of a trade of player characters between teams ( step s 206 ; no ), for example , if the success or failure flag 744 c stored is “ 1 ,” which indicates that the negotiation goes through ( step s 216 ; yes ), the registered domestic player identification information 734 f of each team and the belonged team 732 b of the player information 732 are changed so that the two trade - intended teams exchange their trade - intended players ( step s 218 ). the players configuration changing section 223 allows displaying on the game screen the success of the trade ( step s 220 ). if the success or failure flag 744 c stored is “ 0 ,” which indicates that the negotiation does not go through ( step s 216 ; no ), the registered domestic player identification information 734 f and the belonged team 732 b of the player information 732 are not changed , and the players configuration changing section 223 allows displaying on the game screen the failure of the trade ( step s 222 ). as a result of the processing above , events such as a trade and foreign player acquirement negotiation can be carried out in response to the state of the teams even during the pennant race , thereby enhancing the reality and appeal of the game . fig1 a to fig1 d show examples of game screens in this embodiment , showing examples of the screens concerning a foreign player acquirement negotiation . fig1 a is a game screen corresponding to step 108 in the negotiation contents setting process . the game screen displays a message “ popularity of your team is flagging . acquire a foreign player as a popularity - recovering plan ,” for example , and also displays choices of whether or not to acquire a foreign player so as to be selectable . fig1 b is a game screen corresponding to step 120 in the negotiation contents setting process . the game screen displays an at - a - glance chart 80 showing non - belonged foreign players together with their parameters . note that the at - a - glance chart 80 does not show the acquired money 732 d in this embodiment . the game player takes into consideration the amount of team &# 39 ; s fund available and the foreign players &# 39 ; parameters by reference to a fund displaying field 82 to select one player character , in the case of the drawing . since the acquired money 732 d of each player is not known at this time , the game player selects a foreign player so that the acquired money 732 d of the selected foreign player will not exceed the fund of the game player &# 39 ; s team , bearing in mind that the values of the foreign players &# 39 ; parameters are more or less proportional to their amount of acquired money , for example . in other words , price negotiation is executed . fig1 c and fig1 d are game screens corresponding to step 214 and step 215 , respectively , in the player configuration changing process . the success or failure of a foreign player acquirement negotiation is informed on the game screen . if the acquired money 732 d of the foreign player selected by the game player does not exceed the fund of the game player &# 39 ; s team , the game screen of fig1 c is displayed , and if it does , the game screen of fig1 d is displayed . descriptions will be next made of a hardware construction which could implement the functions of the home game unit 1200 . fig1 is a diagram showing an example of the hardware construction according to the embodiment of the present invention . the home game unit 1200 has a cpu 1000 , a rom 1002 , a ram 1004 , a data storage medium 1006 , a sound generation ic 1008 , an image generating ic 1010 , and i / o ports 1012 and 1014 . they are connected to each other via a system bus 1016 so as to input / output data . the cpu 1000 corresponds to the processing section 40 in fig3 , and performs total control of the home game unit 1200 and various data processes , according to a program stored in the data storage medium 1006 , a system program stored in the rom 1002 , the operation input signals inputted through the control device 1022 or the like . the rom 1002 , the ram 1004 and the data storage medium 1006 correspond to the storage section 70 in fig3 . the rom 1002 corresponds to the ic memory implemented in the main unit 1210 in fig1 , and stores programs and data such as the system program or the like related to the control of the main unit 1210 . the ram 1004 is a storage section used as a work area of the cpu 1000 . the ram 1004 stores , for example , given contents in the rom 1002 or the data storage medium 1006 , results computed by the cpu 1000 and the like . the data storage medium 1006 corresponds to the cd - rom 1212 , the ic memory 1214 and the memory card 1216 in fig1 . the functions of the data storage medium 1006 could be implemented by an ic memory card , a hard disc unit detachable from the main unit , mo or the like . furthermore , the data storage medium 1006 stores data stored in the rom 1002 , and loads the data to use , as needed . the sound generation ic 1008 is an integrated circuit designed to generate game sounds such as sound effects and bgm based on the data stored in the data storage medium 1006 or the rom 1002 . the generated game sounds are output from a speaker 1020 . the speaker 1020 corresponds to the sound output section 40 in fig3 or the speaker 1222 in fig1 . the image generating ic 1010 is an integrated circuit designed to generate pixel information for outputting images to a display 1018 . the image generating ic 1010 corresponds to the image generating section 24 in fig3 . the display 1018 corresponds to the image displaying section 30 in fig3 or the display 1220 in fig1 . the i / o port 1012 connects to a control device 1022 . the i / o port 1014 connects to a communication device 1024 . the control device 1022 corresponds to the operation input section 10 in fig3 , or the game controllers 1202 in fig1 . the control device 1022 is designed to permit a player to input various operation data the communication device 1024 is designed to input / output various information to be used in the game unit to / from an external device . it connects to another game device in order to transmit / receive information required for the game program . it also transmits / receives the game program information via a communication line . the communication device 1024 corresponds to the communication section 50 in fig3 or the communication device 1218 in fig1 . software execution with the cpu 1000 or a general - purpose dsp may also be allowed for processes which could be executed by the sound generating ic 1008 or the image generating ic 1010 . the present invention applies not only to the home game unit 1200 shown in fig1 , but also to various devices including an arcade game device , a mobile game device , a general - purpose computer such as a personal computer , a large - sized attraction device in which many players can participate , or the like . fig1 shows an example of the exterior of an arcade game unit 1300 to which the present invention is applied , for example . as shown in the drawing , an arcade game unit 1300 is provided with a display 1302 for displaying game pictures , a speaker 1304 for outputting sound effects and bgm in the game , a joystick 1306 for inputting vertical and horizontal operations , push buttons 1308 , and a control unit 1320 for integrally controlling the arcade game unit 1300 by computer processing to execute a given game . the control unit 1320 is equipped with a processing unit such as a cpu , and a rom 1322 in which game programs and data are stored that are required to control the arcade game unit 1300 and to execute the game . the cpu mounted on the control unit 1320 reads from the rom 1322 as appropriate and computes the programs and data to execute a variety of processes . the game player operates the joystick 1306 and push buttons 1308 while watching the game pictures displayed on the display 1302 to enjoy playing the game . it should be understood that the application of the present invention is not limited to games to be executed on a stand - alone device , but the present invention may be applied to those called network games . examples of the system configuration designed to implement a network game are as follows : ( 1 ) configuration having a home pc or home game system as a game terminal to be connected to a server via a wired / wireless communication line such as the internet or a dedicated line network ; ( 2 ) configuration connecting multiple game terminals to each other via a communication line without a server ; ( 3 ) configuration connecting multiple game terminals via a communication line , one of which functions as a server ; and ( 4 ) configuration physically linking multiple game terminals with each other to serve as a single system ( e . g . arcade game system ). description will be made of a second embodiment to which the present invention is applied with reference to fig1 to fig2 . this embodiment is characterized by a virtual manager provided for each team , according to the parameters of which a player character is selected in a trade or foreign player acquirement negotiation . note that this embodiment can be implemented basically by the same constituent elements as those in the first embodiment , to which the same reference numerals and symbols are affixed and of which description will be omitted as appropriate . fig1 is a functional block diagram showing an example of the functional configuration of this embodiment . as shown in the drawing , the team information 734 includes manager type 734 h , and the game information 72 includes manager parameters 747 for each manager type . fig1 shows an example of the manager parameters in this embodiment . the manager parameters 747 correspond to the team arrangement and team management policy of the virtual manager . in this embodiment , the manager parameters 747 include fielding position when active 747 a , demanded extra hitting power 747 b , demanded safe hitting power 747 c , demanded running power 747 d , demanded starting power 747 e , and demanded relief power 747 f , for example . the manager_parameters 747 may also include a predetermined thinking routine concerning strategies of , for example , utilization of players , bunting , and hit - and - run play . the fielding position when active 747 a is the fielding position of the virtual manager when active , and arranges that a player character of the same fielding position is selected with a higher probability in the negotiation setting process . the demanded extra hitting power 747 b , demanded safe hitting power 747 c , and demanded running power 747 d correspond to the tendencies in quality required of fielders , that is , a player character satisfying these requirements is selected with priority . for example , if the demanded extra hitting power 747 b is “ 4 and above ” and the demanded safe hitting power 747 c is “ 1 and above ” in their comparison , the manager has a tendency to think much of long hits rather than the batting average . if the parameters have the opposite relation , the manager has a tendency to gain points step by step with a high batting average , rather than to gain points by long hits . the demanded starting power 747 e and demanded relief power 747 f show the tendencies in quality required of pitchers , that is , a player character satisfying these requirements is selected with priority . for example , if the demanded starting power 747 e is large and the demanded relief power 747 f is small in their comparison , the manager has a tendency to think much of starting pitchers , and if opposite , the manager has a tendency to think much of relief pitchers . the game player &# 39 ; s team is not provided with a virtual manager , since the game player itself serves as the manager in command . fig2 to fig2 are flowcharts for describing the changes contents setting processing in this embodiment . note that steps different from those in the first embodiment are affixed with numerals in the 300s . as shown in fig2 , in the changes contents setting processing in this embodiment , the players configuration changing section 223 refers to the demanded parameter values for foreign players based on the manager parameters 747 of the team in the selection of a foreign player ( step s 300 ). foreign players with parameters satisfying such demands are searched for ( step s 302 ), and , if any player characters satisfying the demands are found ( step s 304 ; yes ), a foreign player is selected at random from the found player characters ( step s 306 ). on the other hand , if any player character with parameters satisfying the demands is not found ( step s 304 ; no ), the negotiation is cancelled . in fig2 , likewise , the players configuration changing section 223 refers to the demanded parameter values for foreign players based on the manager parameters 747 of the team in the selection of a foreign player ( step s 310 ). foreign players with parameters satisfying such demands are searched for ( step s 312 ), and , if any player characters satisfying the demands are found ( step s 314 ; yes ), a foreign player is selected at random from the found player characters ( step s 316 ). on the other hand , if any player character with parameters satisfying the demands is not found ( step s 314 ; no ), the negotiation is cancelled . in fig2 , in the selection of trade - intended player characters , the demanded parameter values for domestic players are referred to based on the manager parameters 747 of the team other than the game player &# 39 ; s team ( step s 320 ). the player information 732 of the player characters registered in the registered domestic player identification information 734 f of the team is referred to , the player characters with parameters satisfying such demands are removed from the objects of the selection ( step s 322 ), and a player character is selected from the other domestic players ( step s 324 ). likewise , in the selection of a second trade - intended player from a team operated by the computer , the demanded parameter values for domestic players are referred to based on the manager parameters 747 ( step s 326 ) before step 176 , the player information 732 of the player characters registered in the registered domestic player identification information 734 f of the team is referred to , and the player characters with parameters satisfying such demands are removed from the objects of the selection ( step s 328 ). in this way , according to the arrangement that a virtual manager is provided to reflect its characteristic in the configuration change of player characters of the team , each team controlled by the computer can be gradually characterized over trades and foreign player acquirement negotiations . thus , the game player can play games against teams with more distinct characteristics as the game proceeds , thereby increasing the enjoyment in the game play . description will be made of a third embodiment to which the present invention is applied with reference to fig2 . this embodiment is characterized by a function of automatically generating non - belonged , unregistered foreign players . note that this embodiment can be implemented basically by the same constituent elements as those in the first and the second embodiment , to which the same reference numerals and symbols are affixed and of which description will be omitted as appropriate . fig2 is a functional block diagram showing an example of the functional configuration of this embodiment . as shown in the drawing , the game computing section 22 in this embodiment includes a character generating section 227 and a scouting section 228 . the game information 72 includes a character generating program 727 for permitting the processing section 20 to function as the character generating section 227 , and a scouting program 728 for permitting it to function as the scouting section 228 . the character generating section 227 generates a non - belonged , unregistered foreign player to be added to the player information 732 . more specifically , a player list may be provided in advance that includes player identification information 732 a and player &# 39 ; s names related thereto , and , each time a new foreign player is to be generated , one may be selected at random from the player list and the parameters of the selected player identification information 732 a may be set at random to be added to the player information 732 . in this embodiment , the character generating section 227 generates 1 to 3 new characters for every predetermined period of time ( 2 months , for example ) in the game world . alternatively , the character generating section 227 may generate characters a predetermined number of times with random timing during the official game period . in this way , the character generating section 227 creates new foreign players other than the prearranged foreign players , thereby allowing the acquirement of a completely new foreign player as if the player was scouted from a foreign baseball league . in this embodiment , additionally , since the parameters of a newly generated foreign player are set at random , there may happen to appear an all - round player character or a player character with a particular specialty , thereby adding unpredictability to the game . when the game player sets in advance the conditions of a foreign player desired to be acquired , the scouting section 228 regularly searches the player information 732 to judge whether or not any non - belonged foreign player satisfying such conditions exists . if a foreign player satisfying such conditions is found , the game player is informed on the game screen that a desired foreign player exists . that is , the game player can use a virtual scouter by the scouting section 228 , thereby the operability of the game can be increased . this is especially effective if the character generating section 227 generates foreign players with random timing . the conditions set in advance by the game player , which are used by the scouting section 228 as the search conditions , are temporarily stored in the game information 72 as scout condition information 748 . in the same manner as the manager parameters 747 in the second embodiment , for example , the contents of the scout condition information 748 may include the fielding position when active 747 a , demanded extra hitting power 747 b , demanded safe hitting power 747 c , demanded running power 747 d , demanded starting power 747 e , and demanded relief power 747 f . note that the present invention is not limited to the first to third preferable embodiments described above , and that its constituent elements may be added , omitted , or modified as appropriate within the scope of the invention . although a configuration change of player characters of a team can be made during the official game period in the embodiments above , it may be arranged that it can be made before or after the official game period ( competition period ), that is , in the off - season , for example . during the off - season , the changes contents setting processing and player configuration changing process are executed when a predetermined operation is made , for example . at this time , the parameter values at the end of the last official game period are used as the team parameters . although the player configuration changing process is arranged so that a trade or foreign player acquirement negotiation with a predetermined number of days having elapsed from the negotiation starting date is brought into execution ( reflected in the game ), such conditions may be omitted . although a trade is described as an exchange of a player character for another player character , the so - called “ money trade ,” which is an exchange of a player character for money , may also be possible . the acquired money 732 d is set in advance also for domestic players , for example . in step 174 , a player character desired to be acquired is selected as a first trade - intended player from the domestic players of the team as a trading partner . if the releasing team is the game player &# 39 ; s team , the game player selects to or not to accept the trade , and if the releasing team is a computer team , the decision is made at random . when the trade is accepted , a comparison is made between the fund 734 c of the team desiring the acquirement and the acquired money 732 d of the selected player character . if the fund 734 c exceeds the acquired money 732 d , the changes contents setting section 222 judges the success of the negotiation , that is , the success of the acquirement , and registers in the negotiation contents information 744 the identification information of the player character and information on the negotiation contents to set the success or failure flag 744 c to “ 1 ( negotiation succeeded ).” to the contrary , if the fund 734 c does not exceed the acquired money 732 d , the changes contents setting section 222 judges the failure of the negotiation , that is , the failure of the acquirement , and registers in the negotiation contents information 744 information on the negotiation contents to set the success or failure flag 744 c to “ 0 ( negotiation failed )” ( see step 158 to step 164 ). when the negotiation goes through , the players configuration changing section 223 transfers the change - intended player from the releasing team to the acquiring team , and transfers the acquired money from the fund 734 c of the acquiring team to that of the releasing team . the entire disclosure of japanese patent application no . tokugan 2003 - 067374 filed on mar . 12 , 2003 including specification , claims , drawings and summary are incorporated herein by reference in its entirety .

a game performing method for executing a given sports game which is proceeded by performing match - ups by a plurality of teams arranged for every game owning a plurality of player characters a plurality of times during a virtual competition period , involves varying a value of a team parameter provided for each of the teams according to how a game is proceeding ; determining a change - intended team , of which configuration of owned player characters is to be changed by addition and / or release of player characters , among the plurality of teams ; judging approval or disapproval of a change of a configuration of owned player characters of the change - intended team based on the current value of the team parameter of the change - intended team ; and changing the configuration of the owned player characters of the change - intended team , when it is judged that the change is approved .

surgical illumination system 10 of fig1 includes surgical retractor 12 with handle 12 h , waveguide 14 and fiber optic light guide cable 16 , which is attached to any suitable light source . waveguide 14 functions to receive and conduct light from light guide cable 16 and the waveguide contains the light through total internal reflection . without any surface interruptions , light energy contained in the waveguide would stay contained in the waveguide , subject to minor absorption , refraction and other losses as they occur over time . stick - on illuminator film 17 is made from an optical film that changes the refractive index of the area of waveguide 14 to which the film is attached . stick - on illuminator film 17 is provided with tab 18 to facilitate handling of the illuminator film . when stick - on illuminator film 17 is attached to waveguide 14 , directional light 20 is allowed to escape and illuminate a surgical area of interest . waveguide 14 may be connected to an external light source , such as a xenon light source through fiber optic light guide cable 16 , or it may have an integrated light source , such as an integrated led including drive electronics and battery . alternatively , waveguide 14 may be attached to a portable light source , such as a portable led light source . the shape of stick - on illuminator 17 may be any suitable shape and the shape geometry may be determined , at least in part , by the desired illumination target . for example , a circular precut section may be more suitable for a round illumination target and a rectangular precut section may be suitable for a wide angle illumination target . such suitable illumination target geometries may be combined to create a combined illumination target . for example , a precut section may include a rectangular portion for providing a percentage of the available light for wide angle illumination and a circular portion for providing a percentage of the available light for spot illumination . in an alternative configuration , waveguide retractor 22 of fig2 serves as the mechanical retractor and the light waveguide and is attached to any suitable light source through fiber optic light guide cable 23 . in this configuration , stick - on illuminator film 24 is not provided with a tab , and it also provides diffuse illumination 26 that may be suitable for illuminating a larger surgical area than stick - on illuminator film 17 of fig1 . in this instance , illumination 26 may be hemispherical , but it may be preferred to reduce the amount of light be reflected back up into a surgeon &# 39 ; s eyes . waveguide retractor 22 may be a rigid device formed of any suitable material , e . g ., molded polycarbonate or acrylic , or may be a flexible device , e . g ., molded silicone . waveguide retractor 22 may be in any suitable shape , e . g ., bar , tube , etc . and includes handle 22 h . fig3 provides a close - up view of surgical illuminator 28 showing distal end 29 of waveguide 30 . directional stick - on illuminator films 32 and 34 are shown with respective tabs 33 and 35 that also mark the direction of the respective directed light output 32 l and 34 l , i . e ., the light output is in the direction opposite of the tabs . tab 33 of stick - on illuminator film 32 is pointed to the right , indicating that the direction of illumination output 32 l is to the left to illuminate area of interest 36 that is to the left of waveguide 30 . tab 35 of stick - on illuminator film 34 is pointed to the left , indicating that the direction of illumination output 34 l is to the right to illuminate a particular area of interest 37 that is to the right of waveguide 30 . referring now to fig4 , combination pre - cut illuminator film 38 incorporates diffuse and focused illumination features . pre - cut , stick - on film element 38 is attached to a light conducting waveguide such as waveguide 40 . stick - on film element 38 has a diffuse light output portion 42 that creates diffuse light 43 to illuminate a general surgical area and has a directed light output portion 44 that creates directed light 45 that illuminates a specific surgical area such as area 46 . pre - cut , stick - on film element 38 is fabricated using standard film converting techniques . again , the user positions the waveguide , then applies the stick - on illuminator film , or the illuminator film may be pre - applied to the waveguide before positioning the waveguide into the surgical field . the diffuse output portion may be designed to provide any pattern of diffuse light , e . g ., lambertian , planar , curved , etc . the directed output portion may be designed to provide any pattern of directed light , e . g ., circular , polygonal , etc . the diffuse output portion may even be constructed using two or more directional optical films providing two or more directional illumination outputs , e . g ., a circular spot of light to the right of the waveguide midline and a square spot of light to the left of the waveguide midline . optical termination 48 of fig5 is formed of laminated optical film elements such as film elements 49 and 50 at the end of any suitable light guide such as fiber optic cable 52 . optical film 49 is illustrated as the lower portion with adhesive layer 53 and preferably serves a reflective function sending light to the upper portion . optical film 50 is the transmissive upper portion with adhesive layer 55 and may operate in a focused light directing function or a light diffusing mode or both . in this configuration , adhesive layers 53 and 55 are thick enough and have sufficient optical clarity to allow light from fiber 52 , which may be a fiber bundle or a fiber ribbon cable or other suitable arrangement of fibers , to propagate at least partially along the adhesive layers so that light exits substantially along output surface 54 of optical film 50 that extends beyond fiber 52 . if the adhesive layers are not so configured , then the film layers may be shortened as shown in fig5 a , showing alternative cable illuminator 58 which includes light cable 60 , upper light directing film 62 and lower light reflecting film 64 . light exiting light cable 60 encounters lower reflecting film 64 , causing the light to be directed toward upper light directing film 62 , which may be configured to deliver diffuse light such as light 65 , directed light such as light 66 or some combination thereof . depending on the thickness of upper light directing film 62 , the distribution of the light angles from light cable 60 and the paths that light rays take within the film laminate , some light may shine out the end of illuminator 58 and may actually shine downward direction past lower light reflecting film 64 . in an alternative configuration , lower light reflecting film 64 may be replaced with another piece of upper light directing film 62 to convert the highly gaussian distributed light from light cable 60 to a more diffuse distribution that may be more useful in a diagnostic or therapeutic application or in an application where light shining in more than one direction is desired . referring now to fig6 , laminated optical termination 68 is configured to engage any suitable light input structure such as an optical fiber bundle or a single core optical fiber or a length of polycarbonate , acrylic , silicone or other suitable light - conducting material such as light conduit or cable 70 . light reflecting film 71 directs light from light cable 70 above to light output film 72 , which may provide diffuse illumination , directional illumination or a combination thereof . in this configuration , an air chamber such as air chamber 73 is created to allow all the light from light cable 70 above to be directed down the length of the optical film laminate structure created by joining films 71 above and 72 above along their edges . films 71 above and 72 above are preferably cut in a rectangular shape , but may also be cut in any other suitable shape . as shown in fig6 a , air chamber 74 of laminated optical termination 76 may be supported by a frame such as frame 77 made of a suitable material , e . g ., plastic or metal , to help keep the air chamber open during use . directing film 78 and reflecting film 79 perform the same function as the respective films in fig6 . frame 77 may have a reflective surface at end 77 e opposite of the light input from input cable 80 or may have a layer of reflective film 81 to help ensure that light only exits directing film 78 . referring now to fig7 , laminated film terminator 82 is sized to engage light input cable 84 , which is preferably a fiber optic ribbon with the fibers generally planar in a side by side orientation . the ends of the fibers , ends 86 , contact waveguide 88 , which propagates light along the length 82 l of the laminate structure . reflecting film 89 serves to direct light toward output film 87 . termination waveguide 88 may be fabricated from any suitable optical material such as polycarbonate , acrylic or silicone or another layer of optical film . in this configuration , the thickness of termination waveguide 88 is at least the same thickness as light input cable 84 to help ensure that all light from light input cable 84 enters termination waveguide 88 . termination waveguide 88 may also incorporate optical structures , e . g ., that are molded in or created via a hot stamp process that may help direct the light from light input cable 84 out to a surgical area to be illuminated . alternatively , a laminated film termination such as termination 90 of fig8 engages a suitable light input element , for example , a fiber optic ribbon cable such as ribbon cable 92 . output or top film 93 and reflective or bottom film 94 are adhered together along terminator edges 90 e . in this configuration , fiber optic ribbon cable 92 may have fibers extending the entire length of the laminated termination . in this case , the light may escape individual fibers where each fiber contacts top film 93 and / or bottom film 94 , or the fibers may be nicked or otherwise treated to allow light to escape the fibers directly without the need to contact either the top film or the bottom film . fiber optic ribbon cable 92 may be a bundle of fibers whose cut ends are arranged in a particular shape , e . g ., the bundle may be round at the input connector and may be rectangular or some other shape at the film laminate end , it may be a ribbon cable where fibers are typically arranged side to side , or it may be a single core fiber . laminated illuminator system 96 of fig9 includes laminated film termination 97 on light input cable 98 attached to a retractor such as retractor 99 having handle 99 h . input connector 100 serves to connect the illuminator system to a source of light . light input cable 98 conducts light from connector 100 to the film laminate structure 97 , which directs light 101 to a surgical area 102 to be illuminated . adhesive may be provided along light input cable 98 and / or film laminate structure 97 for attaching the illuminator film assembly to retractor 99 . a film illumination system according to the present disclosure may comprise one or more pre - cut sections of optical film , the pre - cut film sections including optical structures , for example , prismatic structures 1004 , for directing or focusing or diffusing light entering one side of the film 1002 as it exits the opposite side of the film 1002 . while the preferred embodiments of the devices and methods have been described in reference to the environment in which they were developed , they are merely illustrative of the principles of the inventions . other embodiments and configurations may be devised without departing from the spirit of the inventions and the scope of the appended claims .

an illuminator film system may include one or more pre - cut sections of optical film applied to a waveguide to allow light to exit the waveguide through the film in a predetermined manner . the one or more pre - cut sections may be removed and reapplied during a procedure to redirect the light . a laminated illuminator film may be provided that uses a laminated optical film structure to direct light from a fiber optic input . such a laminated illuminator film may be very low profile , low cost and easy to apply to a retractor for providing illumination during a surgical procedure .

with reference to fig1 the present invention is shown as a kit of rods 10 and a plurality of associated brackets 12 in combination with a hardside waterbed 14 . hardside waterbeds are characterized by a rigid frame 16 of wood or the like having a lower planar sheet 17 and upstanding side walls 18 and an open top . positioned within the structure of the top is a water impervious bladder 20 in which water 22 is provided to generate an upper surface for sleeping which is essentially at a common elevational level with the upper edge of the side walls . a lower rigid support structure 26 , as of wood , is located beneath the primary support structure interior of the side walls for thereby providing a proper elevational orientation . fig3 and 4 illustrate yard good material 30 operatively coupled therewith . the rod and bracket assembly 34 is attached to a wooden frame 16 in the lower portion of the frame above the lower support 26 and supports in proper position the yard good material 30 as a bed skirt , often called a dust ruffle . as can be clearly seen in the drawings , each bracket 12 comprises a flat horizontally positionable plate 38 coupled to a vertically positionable face 40 which terminates in downwardly extending free ends 42 . the free ends 42 include a plurality of fingers or prongs 44 , 46 and 48 , three in the disclosed embodiment , shaped to form grooves in a generally circular shape . the fingers or prongs 44 , 46 and 48 are upwardly directed and resilient for releasably supporting the rods 10 of a kit . as can be seen in fig2 the upwardly extending central finger 46 and associated fingers 44 and 48 are in an interleafed relationship with two spaced fingers 44 and 48 on the opposite side thereof . holes 50 at the center of the horizontal plate 38 of each bracket 12 accommodate screws 52 for securement into the wooden frame 16 normally found at the lower portion of modern waterbeds 14 . the horizontal plate 38 of each bracket 12 is set flush under the sheet 17 with the back of its vertical face 40 generally parallel with but between the sides of the frame 54 so that the fingers 44 , 46 and 48 extend upwardly beneath the frame 54 . the upper ends of the brackets 12 terminate alongside the lower edge of the frame . for hardside waterbeds , the corners of the frame and support structure are sharper , more rectangular than the broad curve of softside waterbeds and conventional box springs and mattresses . in order to accommodate such difference , the corners of the rod assembly 58 at the foot end of the bed are formed with bent corner rods 60 of a solid material . this is necessitated since the larger tubular corner of the prior devices would be incapable of such sharp bends . the sides and foot end of the bed are then provided with tubular rods or tubes 62 and 64 . while in the optimum condition a single tube at each linear extent would work , it has been found that the use of such single tubes is inconvenient for handling and shipping . thinner tubes 62 and thicker tubes 64 are slidingly joined together to give the functional effect of the single longer tube . across the foot end of the bed two tube segments are utilized . one of the tubes 62 would be of the smaller diameter , the other tube 64 of the larger diameter . the smaller diameter tube 62 would be fitted over one end of a corner rod 60 and its other end would be located within the adjacent end of the larger tube 64 . the larger tube 64 would be fitted over the end of the adjacent solid corner rod 60 . but since such an arrangement would create excess play therebetween , a small length of adapter tube 68 of a diameter equal to the smaller tube is swedged permanently onto the adjacent corner of the solid corner rod 60 through a dimple arrangement 70 . the tubes 62 and 64 , one larger , one smaller , are located one within the other with the opposite end of the smaller tube over its adjacent end of the solid corner rod 60 and with the opposite end of the larger tube slidably received over the short adapter tube 68 . similarly , along the sides of the bed extending in parallel relationship are four tubes on each bed side . two such tubes 62 are essentially the same as the smaller diameter tubes at the foot end and two such tubes 64 are essentially the same as the larger diameter tubes at the foot end . the ends of the smaller tubes are placed over the parallel ends of the solid corner rods 60 with the remote ends of the smaller tubes 62 receiving the adjacent ends of the adjacent larger tubes 64 . another pair of larger and smaller tubes 64 , 62 are then placed in succession at the sides of the bed along the entire length thereof . the opened ends of the larger tubes 64 are then fitted with finned fasteners 72 , each having a longitudinal slot 74 . each fastener 72 is placed with its slot 74 in alignment with an internal dimple 76 on the end of the adjacent larger tube 64 . it is then inserted and then provided with a quarter turn in a clockwise direction for locking . such finned fasteners are conventional in the art but constitute the most preferred way to effect such coupling . the upward positioning of the fingers of the brackets is such that the force of gravity will support the rods in proper position within the brackets adjacent the lower edge of the waterbed frame . in addition , by constructing the fingers resilient and partially circular in shape , conforming to the cross - sectional shape of the rods , the resilience of the fingers will further retain the rods in proper position . the resilience of the fingers is such , however , that upward movement of the rods will effect separation of the fingers and allow for the removal of the rods from the brackets for their replacement therein . the visible part of the bed skirt or dust ruffle is the yard good material 30 adapted to be supported on the tubes and rods which together couple to form the u - shaped assembly of a common cross - sectional diameter . the material is of a length equal to , but preferably greater than , the lengths of the tubes and solid rods when coupled together and supported by the brackets by constructing the material of the greater length , up to fifty percent ( 50 %) greater than the length of the u - shaped structure in the preferred mode , the material may be eventually gathered together along its length to form tucks or a shirred effect which is more pleasing in appearance . a loop or casing 78 is formed into the upper edge 80 of the yard good material by a line of stitching 82 . the casing is of such size as to easily receive the tubes and rods . this size relationship allows for the shirring of the bed skirt as well as the receipt of the tubes and rods and material into the resilient upper free ends at the upper edges of the brackets 12 . as can be seen with particular reference to fig3 the yard good material hangs from the rods for the majority of the extent of the material . in the region of the brackets , however , the fabric supported on the rods will be tucked into the region within the fingers of the brackets and will , thereby , depend from the top of the brackets . when sufficient material is utilized and shirred , no noticeable raising of the fabric adjacent the brackets will be visible to detract from the preferred appearance of the bed skirt . the length of the material hanging from the tubes and rods is preferably of a length equal to the height from the floor up to the lower edge of the sidewalls . in this manner the material will effectively hide the area therebeneath the entire way to the floor . the height of the material is such that when standard bedding , in the nature of sheets or a color - coordinated comforter , is placed on the bed , the lower edges thereof will slightly overlap the material of the bed skirt to present a layered look for optimum appearance . when the bed skirt has been installed on the tube assembly and the tube assembly has been snapped onto the brackets , the finned fasteners are pushed into the ends of the tubes at the head end 88 of the bed and given a 90 degree turn to lock in place and thereby prevent the bed skirt from slipping off the ends of the tubes . thus it can be seen that the bed skirt rod assembly , whether it is made of wood , metal , plastic or any other suitable material or combination of materials , provides a simple and effective device for mounting preselected yard good material thereon resulting in a bed skirt or dust ruffle which is simple to fabricate , which always retains its position and which is easy to remove and replace . during fabrication , the bracket is bent 90 degrees near the upper edge to form the horizontal section and holes are formed therein . the vertical section is cut in an inverted u - shaped configuration to form the fingers . the central finger is bent into an arcuate configuration while the other fingers on opposite sides of the central finger are bent into an oppositely disposed arcuate configuration to form a region for receiving a rod portion . lastly , the upper edge of the central finger is bent outwardly to facilitate separating the fingers and inserting the rod . the sequence of these steps may be done in various sequences for convenience . the present disclosure includes that contained in the appended claims , as well as that of the foregoing description . although this invention has been described in its preferred form with a certain degree of particularity , it is understood that the present disclosure of the preferred form has been made only by way of example and that numerous changes in the details of construction and the combination and arrangement of parts may be resorted to without departing from the spirit and scope of the invention .

a hardside waterbed over which bedding is to be placed ; a rod and bracket assembly secured to the waterbed , such rod and bracket assembly including rods , and a plurality of brackets secured to the waterbed by their upper extents with upwardly projecting resilient fingers of a size as to receive the rods around the opposite sides and bottom end of the waterbed , and a bed skirt having means at its upper end for coupling the bed skirt to the rod means .

turning now descriptively to the drawings , fig1 illustrates the instant ayradent ™ tissue retractor system and apparatus 10 in use with a standard dental handle , wherein the retractor 10 is attached by the arm of the retractor 50 using a threaded end 51 . in the instant embodiment , the ayradent ™ tissue retractor system comprises a uni - body attachment head 10 consisting of two substantially rectangular side pieces comprising substantially radial corners 20 , that house two reflective surfaces , in one embodiment , mirrors 21 , 31 which face each other and are connected by a bridge with a minimal curve 40 . in numerous embodiments , mirrors 21 , 31 are flat , concave , convex , multi surfaced or any combination thereof . in one embodiment , the retractor 10 can come in two forms , the first being a disposable type preferably made of polycarbonate composite or other such material and constructed as a unitary housing the head and containing two front surface mirrors 21 , 31 . this form can also be made of autoclavable , inexpensive composite or another suitable plastic material . this composition allows for a uni - mold one piece assembly . the second form may be a metal - type constructed from stainless steel or a similar material that can be safely used in the human oral cavity and features a head composed of two rectangles with interior mirrors 21 , 31 and a bridge 40 connecting the two rectangles . in the present invention the metal form includes a threaded end 51 on the arm 50 that extends from one rectangle 30 in order for the unit head to be attached to standard dental instrument handles . the instant apparatus allows the user to simply flip the retractor over for effective use on the left or right side of the patient &# 39 ; s mouth . the present apparatus can also be manufactured in a child size which would still allow for a full quadrant view of the oral cavity but can be proportioned to the standard size of a child . it is also possible that this retractor can be manufactured in various adult sizes to best suit the diversity of the size of adult oral cavities . exact dimensions and materials used may vary depending on manufacturing needs . in an additional embodiment of the present system , a top view of the attachable head 10 is illustrated in fig2 . this view more clearly demonstrates the overall shape of the present design and its solid body form . the present invention is a unibody structure and can be composed of solid material without the need for numerous parts and attachments . the two rectangular retractors 20 30 have mirrored surfaces that oppose one another and form a lateral view for the dental practitioner , joined by bridge 40 . this embodiment also emphasizes the size of the device and its capability of being place in one quadrant of the oral cavity without need for repositioning due to its sturdy structure and a substantially “ v ” or “ u ” shape 10 . in one embodiment , the soft tissue retractor comprises a housing for the two mirrors wherein the mirrors are structured in a substantially linear alignment and are disposed to retain the mirror flat against the rectangular component . in a further embodiment of the present system is illustrated in fig3 and emphasizes the bridge 40 . the preferable design for the bridge connecting the two rectangular retractors 20 , 30 is one with a minimal curve and forming an arch that is capable of resting behind the posterior molars and maintaining the overall shape of the device so as to retract tissue . in an additional embodiment , the bridge is capable of extension via a telescoping mechanism or a ratcheting mechanism as exemplified by fig4 and fig5 . the telescoping mechanism can have an internal arm 41 , 42 inside in the hollow interior of the rectangular retractor sides 20 , 30 . this interior arm is smaller than the hollowed bridge receiver and can slide in and out of the bridge from both sides . the present design features a stop 43 , 44 on the end of the retractable arm that prevent the bridge piece from following out of the rectangular retractor sides . the interior arms can be manufactured in either the composite material mentioned above of the overall design or the metal . the present invention also considers a ratcheting mechanism as shown in fig5 that could aid in adjustment of the bridge . the internal arm 45 can be made similar to the arm of the telescoping design but in this embodiment features notches or stops 48 that allows the pawl 47 to lock the arm into place and allow a ratcheting motion . the ratchet 46 incrementally extends the arm by pulling on the bridge 40 . in an additional embodiment of this design is illustrated by fig6 . the rectangular retractor sides 20 , 30 have attached mirrors 21 , 31 that are adhered to the inside surface of each rectangle facing each other . the retractor sides are rectangular in shape but also feature rounded corners 22 , 32 . these corners aid in holding the mirrors in the housing of the rectangle . the mirror can be adhered by the use of glue , epoxy or any other adhesive that is safe for use in a human oral cavity on the back surface of the mirror and then is secured by clipping it into the housing 20 , 30 . due to the linear and rectangular shape of the retractor sides the mirror is positioned flat against the linear plan and contains no convex or concave features as seen in the side profile crosscut view of the mirror in fig6 . the mirror 21 , 31 is a reflective surface that when placed in opposition of another mirror yields a lateral view of the working area . the present invention allows for the mirror to be magnified allowing the practitioner a more precise view and in the case of adjustable bridge length it may house led or other light source to improve vision and to allow the practitioner to complete the treatment in case of power failure . additionally , fig7 illustrates an isometric view of an additional embodiment of an adjustable mechanism of the bridge arm , illustrating supplementary sliding or retractable mechanism of the bridge arm and fig8 illustrates an isometric view of an additional embodiment of an adjustable mechanism of within the bridge arm and a bite block 70 according to the present invention . moreover , in one embodiment , the instant soft tissue retractor may comprise a housing wherein the two mirrors are linear and thus the mirror will sit flat against a rectangular component . this linear edge provides stability and as such , when in position , reduces / eliminates the need for repositioning of the apparatus by the practitioner . thus , the instant system further reduces or even eliminates the need for four handed dentistry and thus dental assistants can then be free to perform their other duties more efficiently . moreover the instant system may be utilized in conjunction with a bite guard or bite block apparatus which may be positioned above the bridge area . the patient would remain open while retraction is maintained . the instant invention could simply comprise a rubber bite block with a slot for the bridge to fit in . the bite guard or bite block may be composed of a suitable material for contact with a human oral surfaces including , appropriate metals , rubber , polymers , plastic , composites including resin composites and carbon fiber composites .

a tissue retractor , for use by dental practitioners , in order to provide clear viewage of a large sector of the oral cavity . the retractor includes a unibody construction in one embodiment , which is intended for attachment to any of the numerous standard dental instrument handles , with two oblong mirrors connected by a bridge , which is static in some embodiments and retractably dynamic in some embodiments . the retractor pulls oral tissue away from the field of work and allows a dental practitioner without the assistance of a dental assistant to have easy access to the oral workspace and eliminates the need to continually maneuver mirrored tools during procedures .

fig1 shows an exercise machine 10 having a moving treadmill or endless belt 12 and an upstanding portion 14 , encased in a suitable housing 15 . the upraised portion 14 is provided with a control panel 16 , which has the conventional on / off switches , speed controls , dials , and lights , normally found in this type of machine . the inventive safety switch system employs two safety handles , 18 and 20 . these handles , 18 and 20 , are formed of round pipe or steel tubing and have a bent configuration , not unlike the crook of a staff . these handles are connected to the inventive safety switch linkage , which is located inside the upstanding portion 14 , beneath the housing 15 . to operate the inventive switch system , the participant on the exercise machine need only exert a downward thrust on either or both of the handles , 18 and 20 . in this regard , and as may be seen in fig1 the handles are positioned such that not only are the handles easy to grasp and to reach when a person is using the machine , but also the user may simply rest his hands on these handles during the operation of the machine , so that in the event an emergency stop is required , such stop may be quickly and simply effected . fig2 shows the machine 10 of fig1 in a side elevation view , with two portions of the housing cover 15 having been broken away , to show the internal workings of the exercise machine 10 . in fig2 it may be seen that the exercise machine is raised from the vertical , by means of an arm 22 and a wheel 24 . another arm and wheel set are arranged on the side of the machine not seen in fig2 . this is typical in many exercise machines and represents the ability to adjust the treadmill from a 0 % to a 25 % grade . by increasing the grade of the endless belt , the amount of effort put forth by the user is also increased . this further aggravates the problem solved by the present invention , since the user is farther above the floor and can be hurt more seriously upon falling . the portion of the housing 15 , which has been broken away at 26 , shows the location and the internal arrangement of the inventive emergency switch linkage . this will be shown in detail in the subsequent figures . the portion of the housing , which is broken away at 28 , reveals the location of the main drive motor 30 , which is connected by a belt 32 to a pulley or roller 34 , which comprises the drive roller of the endless belt treadmill 12 . turning then to fig3 the actuation handle , 20 of fig1 is connected internally to a tubular bar 40 . similarly , the handle , 18 of fig1 is connected to the other end of the curved tubular bar . the tubular rod 40 is located by means of a collar 42 , which comprises a tube having an inner diameter only slightly larger than the outer diameter of the tube 40 . collar 42 is welded or affixed to an angular bracket 44 , which is rigidly bolted , by means of conventional bolts , washers , and nuts , shown typically at 46 , to a vertical upright support beam 48 . this beam is a hollow , square , tubular member , which forms a major structural portion of the frame of the exercise machine . the tubular rod 40 , after being loosely located by the cylindrical collar 42 is welded at 49 and 50 to an actuating bar 51 , which is formed of a solid piece of steel . the rear portion of the bar 51 extends through a stop plate 54 , which has an opening through which the rear portion 52 of the bar 51 extends . the rear portion 52 of the bar 51 has a lower surface 56 , which serves to actuate the safety switch 58 mounted on the stop plate 54 by bolts and nuts , shown typically at 60 and 62 . the manner in which the surface 56 cooperates with the switch 58 will be seen more clearly in fig5 . a hook 64 is welded to the rear portion 52 of bar 51 at 66 . a mounting bracket 68 is attached to the rear portion of the angle bracket 44 by a bolt and nut arrangement , shown typically at 70 . the lower end of bracket 68 is formed with two holes and a u - bolt 71 or shackle bolt is arranged in these two holes and secured at each end , by nuts , 72 and 74 , respectively . a specially - formed extension spring 76 is then extended between hook 64 and u - bolt 71 . the spring 76 is formed having a 400 pound per inch spring rate and being capable of approximately 1 / 2 inch of travel . the threshold actuation pressure is made to be adjustable by means of the threaded u - bolt and the nuts , 72 and 74 . by varying the amount of extension of the u - bolt , the extent of spring expansion is varied . this , in turn , varies the amount of pressure needed to extend the spring . thus , the emergency switch actuation pressure threshold can be adjusted . turning then to fig4 the inventive safety switch linkage is shown from the top , wherein the loop 78 of the spring 76 is seen to be looped over the hook 64 . the hook 64 is welded at 66 to the rear portion 52 of bar 51 , which extends towards the front of the machine , where it is welded to the tubular rod 40 , at 49 and 50 . the tubular rod 40 has a first bend 100 in it at one end to accept handle 20 , and a second bend 102 in it to accept handle 18 . the switch 58 is bolted to the stop plate 54 and the actuation lever of switch 58 is shown at 106 . in order to show the switch 58 and bar 51 arrangement in more detail , reference is made to fig5 which is a cross - sectional view , taken along lines 5 -- 5 in fig4 . in fig5 the stop plate 54 is seen to have a central aperture or opening 108 located therein . the opening 108 has a height which is only slightly greater than the height of the operable end 52 of the stop bar 51 . the switch 58 is affixed to the stop plate 54 by nuts and bolts , 60 and 62 , at a position such that the actuating lever 106 of switch 58 is depressed by the operating end 52 of the bar 51 . in this position , the switch contacts are in the closed position . referring , once again , to fig3 it may be seen that the spring 76 acts to hold the surface 56 of the operable end 52 of bar 51 down against the actuating lever 106 of switch 58 , thereby keeping the switch contacts in their closed position . the space 110 at the top of the opening 108 then permits the operable end 52 of bar 50 to be moved upwardly against the action of the spring , thereby permitting switch lever 106 to rise and open the contacts of switch 58 . fig6 is a brief schematic diagram showing the effects of the safety switch 58 on the operation of the exercise machine . the exercise apparatus is connected to a typical source of alternating - current electric power at terminals 120 and 122 . an on / off switch 124 is provided and upon actuation of the switch , current is caused to flow in line 126 and will flow through a coil 128 of a relay . current flowing in coil 128 closes the switch contacts 130 of the relay . this energizes the motor 30 and the meters , lights , and the like , on the display panel 16 . the contacts of switch 58 are held in the closed position by action of the bar 51 and the spring 76 , which act to depress the lever 106 of switch 58 . in this manner , it may be seen that , if the main power switch 124 is closed , then a voltage will appear across relay coil 128 , thereby closing the main relay contacts 130 , keeping the motor energized . in the event that switch 58 should open , then the voltage is removed from coil 128 and the main relay then drops out and the motor is instantaneously de - energized . in operation then , the inventive safety switch mechanism acts to interrupt the power to the drive motor 30 of the treadmill 10 . more specifically , upon the user or participant exerting a downward pressure on either handle 18 or 20 , or on both handles simultaneously , the pressure being in excess of the tension adjusted into spring 76 , the bar 51 will be caused to be raised upwardly into the space 110 provided in the stop plate 54 , thereby permitting the actuating lever 106 to be raised and open the contacts of switch 58 . as may be seen in fig6 the opening of switch 58 then drops out the main power relay and the exercise apparatus is caused to stop . it is understood , of course , that the foregoing description is presented by way of example only and is not intended to limit the scope of the present invention , except as set forth in the appended claims .

a safety switch for use with a personal exercise machine , of the type having a driven endless belt , permits the drive motor to be shut off immediately by a quick downward thrust by the user of two prominent handles . the extent of travel of the linkage in the switch system is extremely short and the pressure necessary to actuate the safety switch is adjustable . downward thrust of the handles , by overcoming an adjustable tension spring , frees the switch actuating lever so that the switch is biased to an open position thereby breaking the circuit to the drive motor .

fig1 depicts a perspective view of one embodiment of an exercise apparatus 2 for use as a barrier or hurdle for plyometric or other exercise activities . fig2 - 5 show other views of the exercise apparatus 2 . exercise apparatus 2 is shown as a long unitary barrier - like structure including a substantially planar base 4 and a tower 6 . substantially all of exercise apparatus 2 is made from polymeric material . the base 4 is preferably made of polypropylene and the tower 6 is preferably made of a thermoplastic elastomer . in one embodiment , the base 4 preferably has a hardness ranging from about 70 shore r to about 80 shore r , and more preferably having a hardness of about 75 shore r . the tower 6 preferably has a hardness ranging from about 55 shore a to about 65 shore a , and more preferably having a hardness of about 60 shore a . in other embodiments , other suitable polymers with other suitable hardness ranges may be used . in the embodiment shown in fig1 - 5 , the base 4 extends outwardly from a lower edge 8 of the tower 6 a distance “ d ,” ranging from about 15 mm to about 70 mm . the base 4 has a thickness “ t ” preferably ranging from about 5 mm to about 20 mm . the base length “ l ,” running along a first elongate side 10 a and a second elongate side 10 b , preferably ranges from about 300 mm to about 600 mm . the base width “ w ,” running along a first narrow side 12 a and a second narrow side 12 b , preferably ranges from about 80 mm to about 200 mm . in other embodiments , the exercise hurdle may have substantially different dimensions suitable for use in exercise activities . the tower 6 extends upward from the interface between the base 4 and the tower 6 along the first narrow side 12 a and the second narrow side 12 b at an angle preferably ranging from about 93 degrees to about 97 degrees . similarly , the angle of the tower 6 at the interface between the base 4 and the tower 6 along the first elongate side 10 a and the second elongate side 10 b ranges from about 97 degrees to about 101 degrees . in one embodiment , the tower 6 includes orifices 13 along the elongate sides 10 , preferably with two orifices 13 per elongate side as shown in fig1 - 3 . the orifices 13 provide a place for air to flow through the tower 6 . this feature is particularly useful when the exercise apparatus 2 is stepped on because the orifices 13 allow air to more readily escape , allowing the hurdle to collapse quickly . by increasing the rate at which the exercise apparatus 2 collapses when stepped on , many injuries may be avoided . the orifices preferably have a height of about 11 mm and a width of about 8 mm . the orifices are preferably positioned about 55 mm from the edge of the elongate sides 10 . in a preferred embodiment , the base includes a plurality of extension members 14 protruding from a lower surface 16 of the base to provide stability for the exercise apparatus 2 . extension members 14 preferably include rounded or hemispherical shaped members molded into the lower surface 16 of the base 4 . however , extension members such as extension members 14 may come in various shapes and relative sizes . further , extension members 14 may not be included in some embodiments of the exercise apparatus . as shown in fig3 - 5 , the tower 6 is substantially hollow and has an angled outer surface 18 including first broad surface 20 a , second broad surface 20 b , first slender surface 22 a , and second slender surface 22 b . exercise apparatus 2 has a height “ h ” measured between a lower surface 16 of the base 4 and a crest line 24 on the tower 6 defined by the merging of all of the side surfaces ( 20 a , 20 b , 22 a , and 22 b ) at substantially the same elevation from the base 4 . height h preferably ranges from about 125 mm to about 500 mm . side surfaces 20 a , 20 b , 22 a , and 22 b preferably begin to curve and merge together at “ j ” located from about 10 to about 16 mm below the crest line 24 . at “ j ,” the width of tower 4 preferably ranges from about 16 mm to about 22 mm . the crest line 24 has a crest line length “ cl ” ranging from about 300 mm to about 500 mm , and , more preferably , from about 325 mm to about 425 mm . in the illustrated embodiment , the tower 6 includes an orifice 26 located at approximately the midpoint of the crest line 24 for storage as discussed in more detail herein . an embodiment of the invention also includes a method for storing an exercise apparatus 2 . the method includes the step of providing a storage apparatus 28 including a vertical extension member 30 as shown in fig6 . the method includes the additional step of placing at least one of the exercise apparatus 2 on the storage apparatus 28 by situating orifice 26 of the exercise apparatus about the vertical extension member 30 of the storage apparatus 28 such that the vertical extension member 30 protrudes through the orifice 26 in the crest line 24 of the exercise apparatus 2 . in a related embodiment , the method described above further includes securing at least one exercise apparatus 2 to storage apparatus 28 using a securing mechanism . the securing mechanism preferably includes a rod 32 for extending through a rod orifice 34 located near a first end 36 of the vertical extension member 30 . rod 32 is preferably made of steel and oriented in an l - shape . however , other robust materials such as metals or hard plastics may be used . rod 32 is then attached to an end piece 38 to prevent the rod 32 from easily slipping back out of the rod orifice 34 . in a preferred embodiment , rod 32 is threaded at one end in order to easily and securely screw into a female threaded port 40 of end piece 38 . however , those skilled in the art appreciate that a variety of different mechanisms for rod 32 to be attached to end piece 38 are available . additionally , rod 32 may come in a variety of shapes so long as rod 32 is capable of being extended through rod orifice 34 for attachment to an end piece such as end piece 38 . fig7 shows a plurality of exercise apparatus 2 stored along vertical extension member 30 of storage apparatus 28 including a securing mechanism similar to the ones described above . the exercise apparatus 2 described above in various embodiments may be manufactured by a method including the steps of forming the base 4 , attaching the base 4 to a tower mold , and forming the tower 6 . the base 4 is preferably formed from a polypropylene material during a base molding step using injection molding techniques known to those skilled in the art . after the base 4 is attached to a tower mold , a similar or identical molding technique is preferably used to form the tower 6 from a thermoplastic elastomer material during a tower molding step . the tower 6 is preferably molded to the base 4 during the tower molding step . the base molding step is preferably carried to substantial completion at about 55 seconds to about 65 seconds . the tower molding step is preferably carried to substantial completion at about 115 to about 155 seconds . in a particular embodiment wherein the height h ranges from about 148 mm to about 157 mm , the tower molding step is preferably carried to substantial completion in about 120 seconds . in a particular embodiment wherein the height h ranges from about 300 mm to about 310 mm , the tower molding step is preferably carried to substantial completion in about 150 seconds . during the tower molding step , the base 4 is preferably kept at a temperature ranging from about 150 degrees centigrade to about 200 degrees centigrade . during the tower molding step , the tower 6 is preferably kept at a temperature ranging from about 130 degrees centigrade to about 190 degrees centigrade . the foregoing description of preferred embodiments for this invention have been presented for purposes of illustration and description . they are not intended to be exhaustive or to limit the invention to the precise form disclosed . obvious modifications or variations are possible in light of the above teachings . the embodiments are chosen and described in an effort to provide the best illustrations of the principles of the invention and its practical applications , and to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated . all such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly , legally , and equitably entitled .

an exercise hurdle including a base extending substantially horizontally outwardly from adjacent a periphery of a bottom end of a substantially wedge - shaped upwardly extending tower that angles inwardly from its bottom end to define an elongate crest line . the tower is composed of a soft , resilient polymeric material to prevent injury during use of the exercise hurdle .

the present tongue and groove ice wrap contours around the joint and adjacent tissues , provides total anterior to posterior coverage , provides a sleeve to insert an ice pack , and applies compression around the extremity . however , this product is not limited to total knee or total hip replacement patients . patients recovering from arthroscopy , ligament repairs ( acl for example ), labral repairs , fractures , or non - surgical candidates also benefit from this ice wrap design . fig1 shows a top plan view of the current invention with 3 extending arms , 12 , 14 , and 16 with stitching , 30 , 32 through the upper and lower layers to create their own sleeves , 20 , 22 , 24 to contain an ice pack or heat pack . fig2 shows corner piece under the top layer , creating a simple envelope style opening for the sleeves , 20 , 22 , and 24 shown in fig1 . fig3 shows the bottom view of the ice pack with velcro hooks , 26 , at the distal ends of the 3 radially extending arms which can wrap around and attach to the velcro loops , 28 , located on the proximal end of the 3 arms shown in fig1 . fig4 shows the ice wrap on a patient &# 39 ; s knee , 60 . the ice wrap totally surrounds the front , sides , and back of the knee , lower thigh , and upper calf to decrease post - operative swelling , pain , and edema . the middle of the ice wrap is centered over the patella . the upper , 12 , middle , 14 , and lower , 16 , radially extending arms are pulled snugly around the sides and posterior aspect of the knee , thigh , and calf and attached by the velcro , 26 to 28 . the ice pack contours around the entire knee , lower thigh and upper calf giving total ice coverage . fig5 shows the ice wrap on a patient &# 39 ; s hip , 80 . the ice wrap totally surrounds the front , sides , and back of the hip , and upper thigh to mid - thigh to decrease post - operative swelling , pain , and edema . the middle of the ice wrap is centered over the lateral hip . the upper 12 , middle 14 , and lower 16 , radially extended arms are pulled snugly around the hip and thigh and attached by the velcro . the ice pack contours around the entire hip and thigh giving total ice coverage . 1 . a mobile wrap apparatus for applying cryo - therapy ( or heat therapy ) to the front , sides , and to the back of the knee concurrently . 2 . the wrap apparatus has a middle area that is applied over the patella ; with 3 extending arms , that are a certain length , run transverse to the thigh and leg , and are long enough to make a wrap around the knee , thigh , and leg . 3 . the upper and lower arms radially extend transversely to the limb . 4 . the middle arm radially extends transversely to the limb , in the opposite direction of the top and bottom arms . 5 . the upper and lower arms run parallel to each other with a concave opening with space between the upper and lower arms . the middle arm , is convex , and when wrapped around the knee , fits into the concave space between the upper and lower arms , like a “ tongue and groove ” attachment . 6 . each arm has a distal velcro hook portion that wraps around the extremity and attaches to the central velcro loop portion . 7 . the arms each contain an opening pocket , sleeve , that houses a cold pack ( or heat pack ) that extends the entire length of the sleeve to provide a cooling ( or heating ) effect to the front , sides , and back of the knee . 8 . the material that approximates the skin is made of flexible and woven properties that provide compression to the extremity . 9 . the wrap apparatus is a flexible shape and when applied to the extremity contours around the extremity to provide total anterior to posterior ice ( or heat ) coverage . step 2 : once frozen , slide the ice inserts into each sleeve of the ice wrap . there are 3 sleeves and 3 ice packs . the ice packs should slide to the end of the sleeve for optimal ice coverage . step 3 : straighten leg and center ice wrap over the knee cap . step 4 : pull the middle arm snugly behind the back of the knee and fasten to the middle velcro . step 5 : pull the upper arm snugly behind the back of the thigh and fasten to the top velcro . step 6 : pull the lower arm snugly behind the back of the thigh and fasten to the bottom velcro . step 7 : elevate lower extremity above the heart with 2 - 3 pillows . step 9 : fold ice wrap as directed and place into freezer for approximately 2 hours between applications . the term “ comprise ” and variations of the term , such as “ comprising ” and “ comprises ,” are not intended to exclude other additives , components , integers or steps . the terms “ a ,” “ an ,” and “ the ” and similar referents used herein are to be construed to cover both the singular and the plural unless their usage in context indicates otherwise . although the present invention has been described in considerable detail with reference to certain preferred embodiments , other embodiments are possible . the steps disclosed for the present methods , for example , are not intended to be limiting nor are they intended to indicate that each step is necessarily essential to the method , but instead are exemplary steps only . therefore , the scope of the appended claims should not be limited to the description of preferred embodiments contained in this disclosure . recitation of value ranges herein is merely intended to serve as a shorthand method for referring individually to each separate value falling within the range . unless otherwise indicated herein , each individual value is incorporated into the specification as if it were individually recited herein . all references cited herein are incorporated by reference in their entirety .

a wrap apparatus with 3 equal length radially extending arms with 3 pockets or “ sleeves ” extending the entire length of the arms to house either ice or heat packs . the radially extending arms wrap around the limb contouring and covering the front , sides , and back of the extremity to supply total ice / heat coverage . the 3 pockets are also wide enough to extend the ice above and below the knee to the adjacent tissues . the ice pack surrounding the extremity , such as a knee or hip , is useful to reduce post - operative swelling .

preferred embodiments of the present invention will now be described in detail in accordance with the accompanying drawings . the present invention will be described in detail with reference to embodiments shown in the drawings . fig1 is a schematic external view showing an apparatus according to the first embodiment of the present invention . a case 1 including an optical system is mounted on a stage 2 so as to be three - dimensionally movable in its position and posture for alignment with an eye to be examined e . a magnification changing switch 3 , a focus knob 4 , and an electronic image taking means 5 composed of a digital camera or the like are mounted on the case 1 . an output of the electronic image taking means 5 is connected with a display means 7 through an image handling means 6 . an operating panel 8 having plural kinds of switches is provided on the stage 2 . a joystick 10 having an image taking switch 9 at a top thereof is provided on the operating panel 8 . fig2 is an optical and electrical structural diagram showing an inner portion of the case 1 applied to an eye fundus camera . a condenser lens 13 , a strobe tube 14 serving as an image taking light source , a condenser lens 15 , a field lens 16 , a ring slit 17 , a light shielding member 18 for blocking harmful light , a relay lens 19 , a light shielding member 20 , and a holed mirror 21 are disposed from an examination light source 11 side on an optical path from the examination light source 11 serving as a continuous light emitting source to an objective lens 12 . a concave mirror 22 is disposed in the rear of the examination light source 11 . a focus lens 23 which is movable in the optical axis direction by the focus knob 4 , an imaging lens 24 , and an electronic image taking means 5 are disposed in the rear of the holed mirror 21 . the electronic image taking means 5 includes an image taking element 25 and an image taking circuit 26 . the image taking element 25 converts into a charge an optical image of an eye fundus portion ea which is formed at “ image taking optical system basic imaging power ” which is minimal imaging power ( widest view angle ) of an image taking optical system . the image taking circuit 26 reads as a signal waveform the charge from the image taking element 25 while effecting synchronous control . an output of the image taking circuit 26 is connected with the image handling means 6 and a control means 27 . the image handling means 6 is connected with the display means 7 and the control means 27 . the control means 27 is connected with the examination light source 11 , the strobe tube 14 , the magnification changing switch 3 , the operating panel 8 , and the image taking switch 9 . the control means 27 receives operation signals from the magnification changing switch 3 and the image taking switch 9 and controls the entire apparatus including the examination light source 11 and the strobe tube 14 according to the operation signals . in addition , the control means 27 communicates control signals , trigger signals , input data , and the like to and from the electronic image taking means 5 and the image handling means 6 . fig3 is a block diagram showing the image handling means 6 . the image handling means 6 includes a memory 31 , a processing unit 32 , and a recording means 33 . the processing unit 32 is connected with the memory 31 and the recording means 33 . the memory 31 is connected with an output of the electronic image taking means 5 . the processing unit 32 is connected with the control means 27 and the display means 7 . illumination light emitted from the examination light source 11 or the strobe tube 14 is formed into a ring shape by the field lens 16 and the ring slit 17 through the condenser lenses 13 and 15 . the illumination light transmits through the relay lens 19 and the light shielding members 18 and 20 , which constitute an illumination optical system . then , the illumination light is reflected on a peripheral portion of the holed mirror 21 to be irradiated on the eye fundus portion ea of the eye to be examined e through the objective lens 12 . reflection light from the eye fundus portion ea transmits through the objective lens 12 , a hole portion of the holed mirror 21 , the focus lens 23 , and the imaging lens 24 , and an image of the reflection light is taken by the electronic image taking means 5 . the objective lens 12 , the holed mirror 21 , the focus lens 23 , the imaging lens 24 , the electronic image taking means 5 constitute the image taking optical system . the signal waveform read from the image taking element 25 of the electronic image taking means 5 is ad - converted into digital image data by the image taking circuit 26 . the digital image data is output together with a synchronous signal to the image handling means 6 . the image data and the synchronous signal which are input to the image handling means 6 are temporarily stored in the memory 31 . the processing unit 32 performs a predetermined process on the image data stored in the memory 31 and causes the recording means 33 to store the processed image data or the display means 7 to display an image . as described later , the processing unit 32 changes data processing contents according to an input from the control means 27 . when an image of the eye fundus portion ea is to be taken , in order to perform an alignment with an image taking site and focusing thereon , the apparatus is generally operated in a moving image mode . when operating in the moving image mode , the control means 27 instructs the image handling means 6 and the electronic image taking means 5 to operate in the moving image mode . in response to this , the electronic image taking means 5 successively takes image data of the eye fundus portion ea corresponding to several frames per second to several tens of frames per second . the image handling means 6 acquires the taken image data . an image is successively prepared for each frame based on the plural image data acquired by the image handling means 6 . the prepared images are continuously displayed on the display means 7 in real time to provide a moving image of the eye to be examined e to an examiner . the examiner conducts an alignment with a predetermined site of the eye fundus portion ea and focusing thereon while examining the moving image of the eye to be examined e which is displayed on the display means 7 . then , when the image taking switch 9 provided on the joystick 10 is pressed , the control means 27 performs the following operation based on a known control method . that is , a predetermined amount of light is emitted from the strobe tube 14 for a predetermined time . simultaneously , the control signals and the trigger signals are sent to the electronic image taking means 5 and the image handling means 6 to stop the acquisition of the moving image . a still image ( one frame image ) of the eye fundus portion ea is taken by the electronic image taking means 5 in synchronization with the light emission of the strobe tube 14 . a taken still image f shown in fig1 and 2 is stored in the image handling means 6 . simultaneously , the still image f is displayed on the display means 7 . fig4 is a flow chart in the case of magnified image taking . in the magnified image taking , as shown by an arrow in fig5 , the magnification changing switch 3 is operated as indicated by an arrow in fig5 during the above - mentioned moving image examination to set magnifying power to n - times (* n ) ( steps s 201 to s 203 ). the magnifying power * n input from the magnification changing switch 3 is input to the image handling means 6 through the control means 27 ( step s 204 ). the term “ n - times ” described here indicates power relative to * n0 which is the above - mentioned image taking optical system basic imaging power . as shown in fig5 , an image f 1 of a region corresponding to the magnifying power * n is extracted from a * n0 image f 0 of the eye fundus portion ea which is acquired in the moving image mode by the processing unit 32 of the image handling means 6 . the center of the image f 1 corresponds to the center of the image f 0 . the extracted * n magnified image f 2 is displayed on the display means 7 ( step s 205 ). the extraction of the region corresponding to the magnifying power of n - times may be performed by any of various known image process methods . an example thereof is as follows . when the number of effective image taking pixels of the image taking element 25 in column and row are given by l and w , respectively , the number of pixels in the region extracted at n - times power in column and row are calculated from ln = int ( l / n ) and wn = int ( w / n ), respectively . here , “ int ( )” indicates a function for rounding a real number in ( ) to obtain an integral number . pixel addresses cx and cy corresponding to positions of pixels near an imaging center of the image in the image taking element 25 are determined . pixel data in an area defined by ln and wn around the pixel addresses are extracted from the * n0 image f 0 and reconstructed to obtain an image . therefore , the * n magnified image f 2 can be extracted from the * n0 image f 0 . when the image taking switch 9 is pressed to perform the still image taking in a state in which the magnification changing switch 3 is set to the magnifying power * n ( step s 206 ), the moving image examination is stopped by the control means 27 ( step s 207 ). the processing unit 32 in the image handling means 6 causes the recording means 33 to record the * n0 image f 0 with the magnifying power * n appended thereto as header information ( step s 209 ) without producing the * n magnified image f 2 from the * n0 image f 0 taken by the electronic image taking means 5 ( step s 208 ). in this case , the information of * n and the image data may be separately stored without appending the information of * n to the image data and associated with each other to construct a database . fig6 shows an example in which images f 3 , f 4 , and f 5 which are taken as described above and recorded in the image handling means 6 are selected with a selection switch provided on the operating panel 8 , a touch sensor provided on the display means 7 , or the like according to a known selection method using an image list , a thumbnail , or the like , and the selected images are displayed on the display means 7 . in the image handling means 6 , information on the magnifying power is appended to each of the images f 3 , f 4 , and f 5 and recorded . that is , the image f 3 is appended with information of * n1 , the image f 4 with * n2 , and the image f 5 with * n3 ( unit magnifying power ). these images are recorded as * n0 images in the recording means 33 . for example , according to a flow chart shown in fig7 , when an image selection signal for the image f 3 is input from the control means 27 to the image handling means 6 ( step s 213 ), the processing unit 32 reads out the image f 3 and * n1 from the recording means 33 ( step s 214 ). then , as described with respect to fig5 , the processing unit 32 extracts a region corresponding to * n1 from the * n0 image f 3 to prepare an image f 6 and causes the display means 7 to display the magnified image ( steps s 215 and s 216 ). the same process is successively performed on the images f 4 and f 5 . as shown in fig6 , a * n2 image f 7 of the image f 4 and a * n 3 image f 8 of the image f 5 are displayed in parallel . as described above , when images are displayed in a reproduction mode desired for image taking , the images are represented based on the field of view with which the images were initially examined at image taking . when a signal for changing image display power is input to the control means 27 with a magnifying power changing switch provided in the operating panel 8 ( steps s 218 and s 219 ), the control means 27 transmits an instruction to the image handling means 6 so as to perform a corresponding image process . in response to the instruction , the processing unit 32 of the image handling means 6 can change the display power of the selected image and perform an image display process on the display means 7 ( step s 220 ). when the display power is changed , it is possible to view a peripheral region of the initially displayed image and conduct a detail examination at a higher power . fig8 is a flow chart showing an image taking operation according to a second embodiment of the present invention . as shown in fig9 , an examiner conducts an alignment with the eye to be examined e while viewing a moving image f 10 displayed on the display means 7 ( step s 223 ). during this process , a pointer is moved on the moving image f 10 through the control means 27 by the operation of a pointer switch provided in the operating panel 8 to designate a pointer p ( step s 224 ). the information of the pointer p is sent to the image handling means 6 ( step s 255 ). in the image handling means 6 , the processing unit 32 converts the position of the designated pointer p to a pixel address p =( x , y ) on the image taking element 25 ( step s 226 ). when the image taking switch 9 is pressed for image taking ( step s 227 ), in the image handling means 6 , the pixel address p is appended to the taken image f 10 , which is then stored in the recording means 33 ( steps s 228 to s 230 ). fig1 is a flow chart illustrating how a composite image of the image taken as described above is displayed . fig1 shows an example in which images f 11 , f 12 , and f 13 recorded in the image handling means 6 after the above - mentioned image taking are displayed on the display means 7 in the reproduction mode described above . the images f 11 , f 12 , and f 13 which are taken as described above and recorded in the image handling means 6 are selected ( step s 234 ). in the image handling means 6 , the processing unit 32 reads out the recorded image f 1 and a pixel address ( p 1 ) of a designated point p 1 which is appended and recorded during the image taking ( step s 235 ). the processing unit 32 prepares a composite image f 14 in which a predetermined pointer p 1 corresponding to a square area around the pixel address ( p 1 )=( x1 , y1 ) as shown in fig1 is composited on the image f 1 ( step s 236 ) and causes the display means 7 to display the composite image f 14 ( s 237 ). the same display process is performed on the images f 12 and the f 13 , so that an image to be displayed f 15 and an image to be displayed f 16 are displayed as indicated by a pointer p 2 and a pointer p 3 , respectively . because the pointers p 1 , p 2 , and p 3 are only for composite display , the pointers can be deleted if necessary ( steps s 239 to s 241 ). to set the pointer , the eye - point position of a person who conducts image taking on the examined image may be detected using a known sight line detecting apparatus and input as the position of the pointer . alternatively , a touch sensor may be provided on the surface of the display means 7 , and the position of the pointer may be input by directly touching the examined image displayed on the display means 7 . fig1 is a flow chart for image taking according to a third embodiment of the present invention . in fig1 , as described above , a moving image examination is conducted on an eye fundus image f 20 of the eye fundus ea of the eye to be examined e , which is taken by the electronic image taking means 5 . during the examination , a pointer p 4 is designated as described above and the magnification changing switch 3 is operated to set the magnifying power to n - times (* n ) ( steps s 244 to s 246 ). then , the processes described in fig4 and 8 are performed in a composite manner , so that a * n magnified image f 21 with the pointer p 4 as the center thereof is displayed on the display means 7 ( steps s 247 to s 249 ). when the image taking switch 9 is pressed to perform the still image taking ( steps s 250 to s 252 ), the processes described in fig4 and 8 are performed in a composite manner . in the image handling means 6 , information on the magnifying power * n and the pixel address ( p )=( x , y ) is appended to the * n0 image f 20 as header information , and recorded ( s 253 ). in order to facilitate the alignment with the eye to be examined e , the * n0 image may be displayed without displaying the magnified image f 21 during the examination . a switching means for switching between the * n0 image and the magnified image f 21 may be provided . fig1 is a flow chart showing an operation for displaying the taken image . fig1 shows an example in which the recorded still image data is displayed again on the display means 7 . as described above , images f 23 , f 24 , and f 25 are selected ( step s 257 ). for example , when the image f 23 is to be displayed , the image f 23 , and a pixel address ( p 5 )=( x5 , y5 ) corresponding to a designated point p 5 and magnifying power * n5 , which are appended and recorded during the image taking are read out in the image handling means 6 ( step s 258 ). the pixel address is converted to a position on the image f 23 that is to be displayed . a * n5 magnified image f 26 with the pixel address ( p 5 )=( x5 , y5 ) as the center thereof is prepared ( step s 259 ) and displayed on the display means 7 ( step s 260 ). the same display process is performed on the images f 24 and the f 25 , so that a * n 6 magnified image f 27 with a pixel address p 6 as the center thereof and * n7 magnified image f 28 with a pixel address p 7 as the center thereof are displayed . changing of the magnifying power and the center of the magnified image ( steps s 262 to s 264 ) are possible by a known means if necessary . therefore , the description thereof is omitted here . fig1 shows an apparatus according to a fourth embodiment of the present invention . according to this example , in order to improve the viewability of an examination image during image taking for examination , the examination image is taken while being subjected to an edge enhancing process using a known method . fig1 is a flow chart according to the fourth embodiment . an edge enhancing process switch provided in the operating panel 8 is operated during the examination of a moving image f 30 . in the image handling means 6 , a moving image f 31 having been subjected to a predetermined edge enhancing process is displayed on the display means 7 ( steps s 271 to s 275 ). when the image taking switch 9 is pressed to perform the still image taking ( steps s 276 to s 278 ), the * n0 image f 30 is added with edge enhancing process information “ a ” indicating a manner of the edge enhancing process and recorded in the image handling means 6 ( step s 279 ). fig1 is a flow chart illustrating how the image taken as described above is displayed . as described above , an image to be displayed is selected ( step s 283 ). in the image handling means 6 , the image f 30 and the edge enhancing process information “ a ” are read out ( step s 284 ). the image f 31 obtained by subjecting the image f 30 to the edge enhancing process based on the edge enhancing process information “ a ” is displayed on the display means 7 ( steps s 285 and s 286 ). if necessary , it can be easily realized using a known method to cancel the edge enhancing process and display the original image f 30 ( steps s 288 to s 290 ). in addition to the above - mentioned edge enhancing process , a known image process such as a contrast enhancement , an rgb - corrected display , or a band compression and extension can be performed using the same method . in the present invention , the minimal imaging power ( widest view angle ) of the image taking optical system with respect to a subject image to be taken is defined as “ the image taking optical system basic imaging power .” even in the magnified image taking , a widest view angle image is always taken at this power . the information on the magnifying power with respect to the magnified image is simultaneously recorded together with the taken image . when the taken image is to be displayed again on the display means , the display means always displays not the recorded wide view angle image but a magnified image that has been subjected to the image process based on the magnifying power recorded simultaneously with the taken image . when the display magnifying power is reduced as required , it is possible to view the wide view angle image recorded as an original image . an image of a peripheral portion can be also read at once . a region of interest for the person who conducts image taking during the examination of the image taking site is simply recorded , and position information of the region of interest is simultaneously recorded together with the taken image . when the taken image is to be displayed again , a maker indicating the region of interest is superposed on the taken image based on the position information of the region of interest which is simultaneously recorded . therefore , even in the case of a medical image taken such that a site of interest is offset from the center , it is possible to intuitively understand an image taking purpose with respect to the taken medical image . in order to leave an examination image that has been subjected to an image process , an original image is taken at the image taking optical system basic imaging power by the same method as described above and information related to the image process is simultaneously recorded . when the taken image is to be displayed again , the original image is subjected to the image process based on the information related to the image process and then displayed . therefore , it is possible to view not only the processed image but also the original image if necessary . when the thus processed ophthalmologic image is to be read , it is possible to intuitively and speedy understand the image taking purpose , so that the image reading operation can be accurately and efficiently conducted . in addition , an original image in the widest possible range that can be taken can be utilized as needed . therefore , the efficiency of detailed image reading and the ease of application of the image to multiple purposes are improved , with the result that the use value of a medical image can be significantly increased . as described above , according to the present invention , it is possible to provide an ophthalmologic image taking apparatus capable of displaying an image in a favorable manner . this application claims priority from japanese patent application no . 2003 - 207471 filed on aug . 13 , 2003 , which is hereby incorporated by reference herein .

disclosed is an ophthalmologic image taking apparatus in which , when a processed medical image is read , an intended purpose of image taking can be intuitively and speedy understood , so that an image reading operation is accurately and efficiently conducted . the ophthalmologic image taking apparatus includes : an image taking optical system for taking an optical image of an eye to be examined ; an electronic image taking portion for converting the optical image of the eye to be examined , which is formed by the image taking optical system , into digital image data ; an input portion for inputting at least a magnification ; a processing portion for processing the digital image data at the magnification at least for a magnification changing process ; a display portion for displaying an image obtained by the magnification changing process ; and an image storing portion for storing the digital image data and at least the magnification . further , a control unit controls the image storing portion to store the digital image data and at least the magnification in association with each other .

the term “ transdominant ” means that the effect of the gene is operational when the gene is expressed from some genetic element not necessarily linked to the virus . the term “ negative ” means that the gene reduces replication of the retrovirus . the term “ transdominant negative ” means a gene that can inhibit replication of a retrovirus without necessarily being genetically linked to the retrovirus . the term “ transdominant negative integrase gene ” includes an intact retroviral integrase gene , fragments thereof , and both active and catalytically inactive mutants thereof . the term “ transfected gene ” means a gene introduced into a cell by some exogenous means , such that a gene is added that the cell did not receive from the germ line of the animal from which it was derived . the term “ transient expression ” means the expression of a transfected gene that is temporary , usually lasting only a few days . the term “ stable expression ” means the expression of a transfected gene where the expression is sustained for weeks . the present invention includes 293 - cd4 cells . human cells expressing the cd4 gene are generally infectable with hiv , since cd4 is the receptor used by hiv for cell entry . the literature teaches that candidate transdominant negative genes are tested by expressing the transfected gene in a stable cell line , and then testing that stable cell line for its ability to resist infection by hiv ( see yu m ., et al ., gene therapy , 1 : 13 - 26 ( 1994 ) and references cited therein ). making such a stable cell line expressing the candidate gene is laborious , taking more than 1 month of selection and screening cells for expression . a faster method would be to use so - called “ transient expression ” of the candidate gene , where cells are tested within 24 - 48 hours after transfection . however , in most cell lines , transient expression is inefficient . inefficiency refers to the percentage of cells in the population that take up and express the gene being introduced . in most cell lines , fewer than 10 % and often around 1 % of the cells in a population take up and express the transiently transfected gene . this would clearly be unacceptable for evaluating candidate transdominant negative genes , since if over 90 % of a cell population remains untransfected and fully susceptible to hiv infection , a small percentage of resistant cells would not be experimentally detectable . the present invention solves this problem by introducing the gene for cd4 in an expression vector into the transformed human kidney cell line 293 ( available from american type culture collection ). this is exemplified in example 1 . the result is a cell line that can be transiently transfected at a frequency of greater than 50 %, and by virtue of its cd4 expression , is infectable with hiv . this enables a test of candidate dominant negative genes by transfection and infection a day later . this is both surprising and unexpected since it could not be predicted that such a cell line would be useful for testing candidate dominant negative genes . thus , prior to the present disclosure , it was not known that 293 - cd4 cells would be infectable with hiv or that the 293 - cd4 cells would retain the highly efficient transient expression capability of the 293 cell parent . moreover , prior to the present disclosure , it was not known that the kinetics of transient expression ( e . g ., expression of the transfected gene declines after about 2 days ) would allow significant protection from an hiv challenge or that protection of 293 - cd4 cells from hiv challenge by transient expression would be predictive for protection of a naturally susceptible cell population . therefore , the present invention affords a cell line and protocol that can be used to discover the transdominant negative effect of integrase genes ; and that will be broadly useful in research on dominant negative mutants of hiv proteins , as well as other kinds of protective genes such as ribozymes . also , the present invention incudes a vector for production of hiv transdominant negative integrase in a mammalian cell incorporating a synthetic integrase gene , e . g ., a dna sequence which contains a substantial number of codons different from the natural codons such as , for example , 10 or more codons different from the natural codons or a fragment thereof that encodes at least 150 amino acids . preferably , the dna sequence is seq id no . : 1 or a dna sequence containing 10 or less codons different from seq id no . : 1 , or a fragment thereof that encodes at least 150 amino acids . additionally , the present invention includes transdominant negative retroviral integrase genes and methods to use these transdominant negative integrase genes to render cells resistant to retroviral infection . this would include making a population of cells in an hiv infected person resistant to hiv via delivery of such genes . the transdominant negative retroviral integrase gene can be introduced into cells by any of the many methods known for introducing dna into cells , either transiently or permanently . the methods for introducing dna into cells include calcium phosphate co - precipitation , cationic liposomes , electroporation , receptor mediated endocytosis , particle - mediated gene transfer , or for some cell types , naked dna can be used . the transdominant negative integrase genes can also be introduced by any of the well - known viral vectors , including retroviruses , adenovirus , adeno - associated virus , and herpes viruses . for some applications , e . g ., making an animal resistant to a retrovirus , the transdominant negative integrase might be introduced into the germ line of an animal by the methods for making transgenic animals ( including pronuclear microinjection , embryonic stem cells , and other technologies known in the art ). thus , the transdominant negative integrase gene of the present invention can be introduced into cells by conventional gene transfer technology known to those skilled in the art . in addition , the transdominant negative integrase gene could be combined with any of the variety of other approaches for gene therapy inhibition of hiv ( yu m ., et al ., gene therapy , 1 : 13 - 26 ( 1994 ) and yamada o ., et al ., gene therapy : 1 : 38 - 45 ( 1994 )). thus , the transdominant negative integrase gene may be combined with one or more agents selected from the group consisting of : a ) a transdominant negative gene such as , for example , a transdominant negative rev gene , a transdominant negative tat gene , a transdominant negative gag gene , a transdominant negative env gene , a transdominant negative vpx gene , and the like ; b ) a soluble ( s ) cd4 gene such as , for example , a scd4 gene , a scd4 - kdel gene , and the like ; d ) an interferon - inducible gene such as , for example , a rbp9 - 27 gene and the like ; e ) a rna decoy gene such as , for example , hiv - 1 tar , hiv - 1 rre , and the like ; g ) a ribozyme such as , for example , a hammerhead ribozyme , a hairpin ribozyme , and the like . preferably , a transdominant negative integrase gene of the present invention may be combined with a transdominant negative rev gene such as , for example , a transdominant negative rev m10 gene as described by malim m . h ., et al ., cell , 58 : 205 - 214 ( 1989 ) and / or a ribozyme that cleaves hiv rnas . ribozymes and methods for their preparation have been disclosed in u . s . pat nos . 4 , 987 , 071 , 5 , 037 , 746 , 5 , 116 , 742 , 5 , 093 , 246 , and 5 , 180 , 818 which are hereby incorporated by reference . additionally , specific anti - hiv ribozymes have been disclosed in international published patent applications wo 9401549 - a1 , wo 9324133 - a1 , wo 933569 - a1 , wo 9207065 - a1 , wo 9201806 - a , wo 9110453 - a , wo 9103162 - a , wo 9013641 - a ; european published patent application ep 360257 - a , and u . s . pat . no . 5 , 144 , 019 which are hereby incorporated by reference . optimal treatment of a patient receiving dominant negative integrase gene therapy will often involve coadministration with a chemical antiviral drug or interleukin - 2 . currently approved drugs that can be combined with integrase gene therapy are azidothymidine , dideoxyinosine , dideoxycytosine , or d4t . the invention envisions combination with future antivirals in the classes of nucleoside and non - nucleoside reverse transcriptase inhibitors , hiv protease inhibitors , and tat inhibitors . a suitable pharmaceutical delivery method for the dominant negative integrase genes is either by ex vivo or in vivo delivery . in the case of ex vivo delivery , cd4 + t cells , monocytes , or hematopoietic progenitor cells , are removed by plasmapheresis from either the patient or a suitable donor . the dominant negative integrase gene is then introduced into these cells by transduction with a retroviral vector or by microprojectiles ( nabel g ., et al ., human gene therapy , 5 : 79 - 92 ( 1994 )). alternatively , the genes could be introduced via adeno - associated virus ( e . g ., zhou s . z ., et al ., j . exp . med ., 179 : 1867 - 1875 ( 1994 )) or liposomes . the transduced cells , either with or without selection for survival of transduced cells , are then administered to the patient to be treated . usually a dose of 1 × 10 7 to 1 × 10 11 transduced t cells , or from 1 to 1 × 10 6 transduced hematopoietic progenitor cells are administered per course of treatment . the patient may be given repeat courses of treatment periodically as required to maintain a suitable level of transduced cd4 + t cells , usually with 3 months to 3 years between treatments . for in vivo delivery , a suitable viral or nonviral delivery system is used to administer the dominant negative integrase gene to the patient . this administration may be intravenous . the formulation could be , for example , using cationic liposomes ( philip r ., et al ., j . biol . chem ., 268 : 16087 - 16090 ( 1993 )), where from 10 μg to 10 mg of a vector expressing the dominant negative integrase is delivered . for in vivo administration , it will usually be preferred to use a vector that will direct tissue - specific gene expression , e . g ., the promoter of the human cd4 gene . the following nonlimiting examples illustrate the inventor &# 39 ; s preferred methods for preparing a transdominant negative integrase gene of the present invention . 293 cells are a transformed human cell line ( available from the american type culture collection ) that are particularly useful for efficient transient expression of transfected genes . the gene for human cd4 ( the receptor for hiv ) is introduced into these cells to make them susceptible to hiv infection . a 3 . 0 kb fragment containing 1 . 8 kg of cd4 coding sequence is removed from the t4 - pmv7 plasmid ( maddon p . j ., et al ., cell , 47 : 333 - 348 ( 1986 )) using ecori . the ends are made blunt by klenow polymerase . the prsv pap plasmid ( lin , et al ., biotechniques , 3 : 344 - 348 , 350 - 351 ( 1991 )) is cut with hindiii and xbai to remove the insert , and the ends made blunt with klenow polymerase . the cd4 fragment is then ligated into the plasmid backbone . a calcium phosphate transfection is performed to introduce the rsv - cd4 vector into 293 cells , using the method described in sambrook j ., et al ., molecular cloning . a laboratory manual , cold spring harbor laboratory press , 1989 , 16 . 30 - 16 . 40 . the cells are transfected at 20 % confluence , washed with dulbecco &# 39 ; s modified eagle &# 39 ; s medium ( dmem ) plus 10 % fetal calf serum 24 hours posttransfection , and selected in g418 at 0 . 5 mg / ml 48 hours posttransfection . following g418 selection , individual clones are isolated and screened by fluorescence activated cell sourcing ( facs ) for cd4 using a monoclonal antibody to cd4 . construction of a vector expressing hiv integrase in mammalian cells using a synthetic gene the synthetic genes coding for wild - type (“ ndei ”) and an inactive mutant (“ d116n ”) integrase ( in ) had previously been cloned into the e . coli expression vector pkk223 ( holler t . p ., et al ., gene , 136 : 323 - 328 ( 1993 )). constructs for the ndei and d116n gene are done in parallel ; all manipulations described are done for both genes . the first unique restriction site in the synthetic gene is a clai site at nucleotide 17 ( relative to the atg ). the plasmid pkk223 / ny5in - ndei ( or d 116n ) is digested with clai and dephosphorylated using bacterial alkaline phosphatase ( brl ). synthetic oligonucleotides alm 1 ( 5 ′- ccaagctgg gccacc atg g cc ttc ctg gac ggt at - 3 ′) ( seq id no : 3 ) and its complement alm 2 ( 5 ′- cgat acc gtc cag gaa ggc cat ggt ggc cca agc ttgg - 3 ′) ( seq id no : 4 ) containing a hindiii site at the 5 ′ end , a clai site at the 3 ′ end , and a kozak consensus ( underlined ) ( kozak m ., journal of biological chemistry , 266 : 19867 - 19870 ( 1991 )) for translation initiation are synthesized on an abi oligonucleotide synthesizer . following gel purification , the oligos are annealed and the ends of the fragment phosphorylated using t4 polynucleotide kinase ( neb ) and atp . the oligonucleotide pair alm 1 / 2 was ligated to the linearized pkk223 / ny5in - ndei ( d116n ) and the product of the ligation reaction digested with hindiii , to expose the hindiii site on the 5 ′ end ( from the oligos ), and to remove the entire in coding sequence from the bacterial expression vector . the in gene , optimized for mammalian translation , is isolated from the agarose gel . the sequence of the synthetic gene so modified for translation in mammalian cells ( seq id no . : 1 ) is shown in fig1 . the mammalian expresion vector prcrsv is purchased from invitrogen . plasmid prcrsv is digested with hindiii and the ends dephosphorylated . linearized plasmid is isolated from an agarose gel . the in gene is ligated into the hindiii site of prcrsv to produce the plasmid prsv / in - ndei ( d116n ). correct orientation of the insert is determined by restriction endonuclease digestion , and the sequence at the 5 ′ end of the gene ( through the clai site ) confirmed by dna sequencing . a vector expressing the synthetic gene of integrase is demonstrated to have dominant negative activity against hiv infection by the following experiment . the integrase gene is transiently expressed in 293 - cd4 cells , which are subsequently infected by hiv . the cells expressing hiv integrase support hiv replication substantially less than cells with no integrase . the 293 - cd4 cells are split into 6 - well plates at a cell density of 2 - 4 × 10 5 per well . cells are allowed to attach and grow for 6 hours prior to transfections with the expression vector dna . following the protocol of example 4 for 293 cell 10 transfections , the cells are incubated with calcium phosphate precipitates for 24 hours . the medium on the cells is then changed immediately prior to infection with hiv - 1 . 4 - 8 × 10 4 infectious hiv - iiib particles are added i15 per well . infection is allowed to proceed for approximately 12 hours , and then the medium is changed . at various times after infection , samples of medium are removed for reverse transcriptase assay following the protocol of example 5 . the following data is an example of the counts per minute obtained in the reverse transcriptase assay from samples from such an assay : this , and other experiments , establishes that expression of integrase can substantially slow infection of hiv . it should be noted that absolute blockage of viral replication cannot be expected in a transient expression system , since not all of the cells are expressing integrase . the transfection protocol has been modified for use specifically on 293 and 293 / cd4 + cell lines . the same protocol is used for the expression and transdominant experiments to introduce expression vectors . transfection efficiencies as high as 85 - 90 % are routinely observed . 1 . the 293 cell line is split out into appropriate tissue culture dishes . the cells are allowed to adhere and spread for 6 hours prior to transfection . 2 . place 5 μg of vector dna into 250 μl of hbss ( sufficient for one 6 - well or one 10 cm 2 dish ). add 31 μ of 2m cacl 2 and vortex gently for 1 to 2 minutes to thoroughly mix . 4 . add the capo 4 / dna precipitate directly to a minimal amount of tissue culture media covering the cells . 5 . incubate cells in the presence of precipitate overnight at 37 ° c . do not glycerol shock or you will lose the majority of cells . 6 . the next morning , aspirate off the old media and replace with new media . then incubate for the necessary length of time for the experiment . the reverse transcriptase ( rt ) assay measures the expression of viral proteins in the cultures . 8 μci / ml 32 p - datp ( 400 ci / mmol ) is added immediately before assay . 1 . place two genunc polypropylene modules ( 120 μl , cat # 2 - 32549 ) in a genunc frame ( cat # 2 - 32042 ) for each assay plate . 2 . transfer 5 μl of culture media from each well of the assay plate to the corresponding well of the genunc module . using a 12 - channel pipettor , transfer row h , change tips , and complete the rest of the plate starting at row a and moving to row g . by moving from the lowest to highest rt activity , the rest of the plate can be transferred without changing tips . 3 . prepare 2 . 5 ml rt reaction cocktail for each plate by adding 2 . 5 μl 32 p - datp ( 400 ci / mmol , 10 μci / μl ) to 2 . 5 ml 1 . 25 × rt reaction stock . 4 . dispense 2 . 5 ml rt reaction cocktail into the trough of an 8 - channel reagent reservoir for each assay plate . use a p1 , 000 pipetman so that the radioactive tip can be discarded in the ziplock waste bag . 5 . add 20 μl rt reaction cocktail to each well of the genunc module . using a 12 - channel pipettor , transfer row h , change tips , and finish the rest of the plate stating at row a and moving to row g . by moving from the lowest to highest rt activity , the rest of the plate can be filled from one trough of the reagent reservoir without changing tips . 8 . mark a 96 - well array on a sheet of whatman de81 anion exchange filter paper using the rubber stamp . 9 . spot 4 μl of the rt reaction from each well of the genunc module onto the corresponding mark of the de81 filter . using a 12 - channel pipettor , transfer row h , change tips , and finish the rest of the module starting at row a and moving to row g . by moving from the lowest to highest rt activity , the rest of the module can be spotted without changing tips . 10 . wash the filter five times , 3 minutes each , in 2 × ssc ( 300 mm nacl , 30 mm nacitrate , ph 7 ). 13 . quantitate the rt activity by counting the incorporated 32 p for each well using the betagen betascope 603 with the slot / dot blot analysis program as described in the applications manual . data is collected for 30 minutes in the 32 p mode and reported as total counts per well . cem cells are a line of cd4 + human lymphoblastoid cells ( obtainable from american type culture collection ). cem cells were maintained in rpmi 1640 medium supplemented with 10 % fetal calf serum , 50 u / ml penicillin , 50 u / ml streptomycin . all tissue culture reagents were obtained from gibco brl , gaithersburg , md . cem cells were transfected by electroporation according to the method of aldovini and feinberg ( pp . 147 - 159 in : techniques in hiv research , stockton press , new york , ny , 1990 ). twenty micrograms each of plasmid dna ( either prc / rsv , prsv / in - nde , or prsv / in - d116n ) were added to a 0 . 4 ml suspension of 5 million cem cells in serum free rpmi 1640 medium . the dna - cell suspensions were incubated on ice for 10 minutes in a gene pulsar cuvette and then subjected to a single pulse of 960 μf at 300 volts using a bio - rad gene pulsar electroporator ( bio - rad , richmond , calif . following electroporation , the cells were incubated on ice for 10 minutes and then diluted in 10 ml rpmi 1640 medium with 10 % fetal calf serum . the cells were incubated in 75 cm 2 tissue culture flasks at 37 ° c . in a 5 % co 2 incubator for 48 hours . the cells from each flask were centrifuged to pellet the cells and the supernatants removed . the cell pellets were diluted in rpmi 1640 medium supplemented with 10 % fetal calf serum and 750 μg / ml g418 ( geneticin , gibco brl ) at a density of 200 , 000 cells per ml . the diluted cells were transferred to 96 well plates , 100 μl / well , and incubated at 37 ° c . for 7 days . the g418 selection was then increased to 1 mg / ml . colonies appeared in 2 - 3 weeks . these colonies were transfered to 6 well plates and were diluted in 3 ml rpmi 1640 medium plus 1 mg / ml g418 . after the cells had reached a density of 1 , 000 , 000 cells per ml , they were screened by western blot techniques for expression of hiv - 1 integrase , using a polyclonal rabbit antiserum prepared against integrase produced in e . coli ( holler t . p ., et al ., gene , 136 : 323 - 328 ( 1993 )). the procedure used for this western blot is described . one million cells were suspended in laemmli buffer , and loaded onto a 12 % polyacrylamide gel . the separated protein bands were transferred to nitrocellulose paper by electroblotting . the blots were blocked with 10 % nonfat dry milk in phosphate buffered saline ( pbs ) plus 0 . 3 % tween 80 for 1 hour . the blocked blots were then incubated for 2 hours with a 1 / 1000 dilution of the rabbit antiserum . the blots were then washed 3 times in pbs / tween , then incubated for 1 hour with a 1 / 2000 dilution of goat antirabbit igg conjugated with horseradish peroxidase . after 4 washes in pbs - tween , the integrase expression was detected with an enhanced chemiluminescence ( ecl ) kit ( amersham , arlington heights , il ). of 50 wells which grew under g418 expression , two each expressing wild type integrase or d116n were obtained . demonstration of protection against hiv infection in cem cells expressing a dominant negative integrase gene cem cell lines prepared in example 6 were grown in the presence of 1 mg / ml g418 , and density adjusted to 4 × 10 6 cells / ml . fifty microliters of suspended cells was combined with 40 μl hiv stock virus ( 2 × 10 3 pfu / ml ) and 10 μl medium . cells and virus were coincubated at 37 ° c . for 2 hours , then washed once in 1 ml medium . each washed pellet was resuspended in 3 ml medium , then 1 ml aliquots were plated in triplicate wells of a 24 well plate . fifty microliter samples were taken from each well of infected cells on days 1 - 5 and 7 postinfection . cell cultures were split 1 : 3 on days 3 and 5 after sampling , by adding 2 ml medium , mixing the culture , then removing 2 ml of medium and infected cells . the data is not corrected for these splits . the samples were assayed using the reverse transcriptase assay described in example 5 . the counts per minute from the triplicate samples at each time point were averaged . this experiment shows that expression of either the wild type integrase ( nde ) or the d116n mutant retards the growth of hiv - 1 in a human lymphoblastoid cell line , as predicted by the results in the 293 - cd4 cells . it should be noted that since these cells were not cloned before testing , even though all were g418 resistant , not all of them were expressing integrase . therefore , the level of protection observed is a minimal level to be expected in a population expressing the dominant negative integrase genes . met ala phe leu asp gly ile asp lys ala gln glu glu his glu lys tyr his ser asn trp arg ala met ala ser asp phe asn leu pro pro gly glu ala met his gly gln val asp cys ser pro gly ile trp gln leu asp cys thr his leu glu gly lys val ile leu val ala val his gln glu thr ala tyr phe leu leu lys leu ala gly arg trp pro val tyr asn pro gln ser gln gly val ile glu ser met asn lys glu leu lys lys ile ile gly gln val arg asp gln ala glu his leu lys thr ala val gln met ala val phe ile his asn phe lys arg lys gly gly ala lys leu leu trp lys gly glu gly ala val val ile gln asp asn tyr gly lys gln met ala gly asp asp cys val ala ser arg gln asp

a method of using a transdominant negative integrase gene to make at least one cell resistant to a retroviral infection which includes retroviral infections resulting from hiv ; a method for introducing a transdominant negative integrase gene into at least one mammalian cell to make said cell resistant to a retroviral infection as well as vectors , cells , and methods of constructing same useful in the afore - mentioned methods ; a method of treating aids comprising administering to a patient an effective amount of a transdominant negative integrase gene alone or combined with agents useful for gene therapy inhibition of hiv , antiviral agents , or interleukin - 2 ; and pharmaceutical delivery methods which include a transdominant negative integrase gene alone or combined with agents useful for gene therapy inhibition of hiv , antiviral agents , or interleukin - 2 .

in accordance with the flowchart shown in fig1 , the supplied and still unsorted rapeseed a . a is first sorted in a preparation step a such that the rape grains a . e to be further processed have largely the same size . they are then introduced into a device s for dehulling and are thereby separated into a husk fraction s . g and a kernel fraction s . e a pressing of the husks is possible ; however , here only the pressing p of the kernels s . e is drawn in fig2 and said kernels are then further supplied to a fine milling device k . in this process , both oil cake milled once p . b and oil cake milled a plurality of times p . d can be subjected to the fine milling . unpressed kernels s . e can also be included in the fine milling . in accordance with the embodiment in accordance with fig1 and 2 , a cryogenic milling is carried out which works with frozen milling material so that the relatively high residual oil fraction in the milling material k . b cannot result in a smudging or sticking together of the machines . alternatively , it is shown in fig3 and 4 that a so - called milling process of the milling material w . a can also be carried out at room temperature while dispensing with a cost - intensive cooling with liquid nitrogen . also , under certain circumstances , a portion of the milling material k . b or w . a can be milled cryogenically and anther portion can be at room temperature . a fine material k . d ( or w . b : fig4 ) is obtained as a result of the fine milling which forms a free - flowing powder having grain sizes of approximately 100 μm to 500 μm in an approximately gaussian distribution . the powder k . d or w . b respectively has a light color due to the use of only the kernels without husks . this powder k . d can then be used directly as or at least as a base material , filler material or additive for a human food . a powder k . d or w . b formed in this manner can in particular also serve as a starting material for a protein extraction ( protein concentration and / or protein isolation ) since it has a very high protein content with a lot of important amino acids and is liberated from disturbing raw fibers . anti - nutritional substances such as chlorophyll , tannin , polyphenols , or phytic acid are therefore considerably reduced . such a substance can also serve as a substitute for mustard in human food . a lot of water can thus also be bound so that in sausage products , for example , the meat amount can be substantially reduced and the nutritional content can nevertheless be increased . a high stability can also be achieved , in foams for example , in protein isolates obtained from the powder k . d or w . b . said foams therefore not only have very good nutritional properties , but likewise very good functional properties such as the addressed light , pleasant appearance and the high mechanical stability which is larger than that of whipped animal protein . in addition , substantially more vegan foods can be created by the substitution of animal products with the product in accordance with the invention and the need for factory farming can be reduced . the powder k . d or w . b can in particular also form base materials , filler materials or additives in spices , spice mixtures , spice preparations or spice sauces . the obtained fine material can also be readily used as a filler material for powdery spices due to its light powder structure and can there replace lactose or dextrose , for example . in contrast to many other oilseeds , rape has a mild spicy aroma and therefore supports the spice aromas . it is equally possible to mix the obtained fine material k . d or w . b as a base material , filler material or additive into sausage products or in other food bodies or to use it in bakery products since , as mentioned above , it has a mild spicy aroma without unpleasant hotness . in detail , in the preparation of the initially unsorted raw rapeseed a . a , a cleaning of the rapeseed is first carried out in the screening machine 1 so that impurities a . c and shriveled grains a . d can be separated out and the cleaned rapeseed a . b can be dried in a seed dryer 2 , for instance in an airflow . the rape grains a . e cleaned and dried and having an approximately standard size in this manner are then supplied to dehulling s where they are first crushed in a double mill 3 in the gap between the rolling mills . the crushed rape s . a arising in this process is supplied to a screening machine 4 in which coarsely crushed material s . c and finely crushed material s . d are separated out and the so - called useful crushed material are transferred onward into a sifter 5 . in said sifter , the husks s . f are separated out and are supplied overall with the coarsely crushed material s . c and the finely crushed material s . d to a silo 6 as a so - called husk fraction s . g and are further processed depending on their purpose . this further processing can , for example , be an admixture to an oil cake of the kernel fraction s . e which is temporarily stored in a parallel silo 7 . the fraction of oil obtained overall can be increased by this admixture and repeat pressing ; however , the oil cake is then charged with the dark husk fractions so that its optical appearance — and thus the possibility of use as a raw material for food — is limited and it is further used , for example , as animal feed . provided that the visual appearance does not play any role , such an oil cake can also be further used in the manner as is described in the following for the kernel fraction s . e . this dehulled kernel fraction s . e is supplied to a single - stage or multi - stage pressing unit p . as is drawn by way of example in fig2 , two screw presses 8 , 9 are provided there . a first pressing of the dehulled rape s . e is carried out in the screw press 8 so that the kernel oil p . a of the first pressing can be obtained . the kernel cake p . b of the first pressing can be subjected to a second pressing in the second press 9 so that the oil yield increases and the kernel oil p . c can be additionally obtained . the kernel cake p . d of the second pressing ( or of a further pressing ) can , like the kernel cake p . b of the first pressing and / or also unmilled rape kernels s . e , be supplied as an individual fraction or as a mixture of these fractions overall to the fine milling k or w . the fine milling k is here a cryogenic fine milling , i . e . the milling material is k . b frozen in a cooler 11 , here a paddle screw cooler , after passing through a metal separator 10 . liquid nitrogen k . a is introduced here into this cooler 11 so that the oil fraction still contained in the milling material ( typically around 10 % for the second pressing and 22 % for the first pressing ) does not smudge or stick together the milling device . the frozen milling material k . c is beaten in a pin disk mill 12 and is thereby converted into the desired fine material k . d of fine grain in the order of magnitude of 100 μm to 500 μm and is introduced into a collection tank 13 . the separation gas k . e is removed from the fine material k . d via a filter 14 and a fan 15 . the nitrogen k . f can be used in a circuit again for cooling . the further milling process does not necessarily have to include a cryogenic milling process , but can additionally or alternatively also include a further oil separation before the milling of the supplied milling material , in particular by extraction . alternatively , a hot milling w without nitrogen cooling is also shown in fig3 and 4 in which a pin disk mill 17 is likewise provided for milling the milling material w . a and in which a powder w . b is likewise obtained at the end . since only kernel fractions of the rape grains are supplied to the further milling process without the addition of husk fractions , the obtained fine milling material k . d , w . b also remains light yellow and without the fractions which are under certain circumstances unwanted for foods and are contained in the husk fractions . a use of an oil cake p . b , p . d obtained in the processing of rape grains a . a and containing kernel portions s . e of the rape grains as a base material for human food is shown for the first time by the invention . the value creation of the rapeseed is substantially increased since not only just the oil , but also the oil cake is utilized as a high - quality material for food production . the powder k . d obtained in this manner is in this respect usable in a varied manner , for instance as a base material in particular for spices , spice mixtures , spice preparations or spice sauces , for sausage products or bakery products or for other food bodies or as a base material for a protein extraction for creating very high protein human foods . a heating or a chemical modification of this powder k . d , w . b is not necessary in this respect , and nor is an injection of fungi or other additives ; it is rather usable directly as a base food product or as an addition product . the powder k . d , w . b can , however , also be further processed in different manners , in particular also the food formed by the powder can , for example , also be heated or deep frozen .

a method for processing rapeseed includes dehulling and separating the rapeseed into kernel fractions and husk fractions . the kernel fractions are subjected to one or more pressings so as to obtain oil and an oil cake , the oil cake having solid content and oil content . the oil cake is subjected to at least one further milling process so as to provide an output that is a base material , filler material or additive for human foods .

in the embodiment shown in fig1 - 6 , the mattress 10 is supported on a substructure 20 which includes a plurality of vertical support members 30 , 32 , 34 and 36 . three longitudinal vertical support members 30 are identical and are spaced parallel and at uniform distances . these members 30 form the longitudinal supports for the substructure . vertically interlocked with and normal to the longitudinal members 30 is the central transverse vertical support member 32 which is of the same height as the longitudinal members 30 and intersects them at their midpoints . two medial transverse support members 34 are symmetrically located on opposite sides of the central support members 32 . the supports 34 interlock with the longitudinal support members 30 at a distance from their centers of somewhat less than a quarter the length of the latter . two symmetrically located external transverse support members 36 also intersect the support members 30 , near their ends . the support members 36 interlock with support members 30 close to their ends . the heights of the support members 34 and 36 are chosen so that their top edges lie in planes extending from the top edge of support members 31 and inclined at an angle of about 15 ° from the horizontal , as shown in fig4 . the transverse support members 32 , 34 , and 36 are each slotted with slots 38 in their lower edges at positions to intersect with the longitudinal members 30 which also have slots 40 in their upper edges at corresponding positions . these have total depths sufficient to permit the bottom edges of all these members to be coplanar when rigidly interlocked with each other in the lattice pattern shown in fig2 . the slots are of depths slightly greater than half the height of the transverse members . the eight support members described may be made of plywood or other suitable material by a series of straight cuts , including end cuts 42 , 44 , as shown in fig2 . a pair of rigid mattress supporting planar sheets 46 made preferably of a sheet of plywood , each lie with one edge resting on the central transverse vertical support member 32 . each of these planar sheets also rests in an inclined attitude on the transverse support members 34 , 36 on one side of the central members 32 . the two planar sheets 46 form a v - shaped surface with an obtuse angle of about 150 °, in a lengthwise direction , as shown in fig3 . the outer end edges 47 of sheets 46 terminate short of the ends of the longitudinal supports 30 while the outer edges 48 are over the ends of the members 32 , 34 , and 36 . a rectangular frame 50 is formed of side members 51 and end members 52 suitably connected at adjacent ends by brackets or the like in a conventional fashion . the members forming the frame are preferably formed of wood beams having a cross section in the order of 2 × 10 . inches . the frame is dimensioned so that the lower edge of end members 52 rest upon and are supported by the ends of members 30 as illustrated at 54 . a pair of supporting strips 55 are secured lengthwise of each end member 52 intermediate its upper and lower edges . these strips 55 are positioned below and serve to support the end edges 47 of the sheets 46 . the rigidly interconnected side members 51 are also provided with strips 56 that are secured intermediate the upper and lower edges . these strips extend at angles to the length of the members 51 and are positioned to engage the upper side edges of the adjacent sheets 46 to support the frame 50 . the substructure described involves only simply cut wooden pieces which can be assembled in a simple interlocking fashion without hardware for any of the components except the frame 50 . the hardware for these components may comprise screws or simple brackets . the mattress 58 best illustrated in fig6 substantially fills a volume defined by the frame 50 , sheets 46 and the plane extending through the upper edges of the members forming frame 50 . the mattress 58 contains about 35 % less water than a standard rectangular mattress having a uniform depth equal to the maximum depth of mattress 58 . the mattress 58 is formed of an upper fluid impermeable sheet 60 and a lower fluid impermeable sheet 61 . these two flexible fluid impermeable sheets may be made of any suitable plastic material preferably adapted to be thermal plastically heat sealed together . the peripheries of these two sheets may be heat sealed with a butt seam or lap seamed along the peripheral line 66 as shown in fig9 a at 62 and 9b at 64 , respectively . the seam line 66 is normally intermediate the upper edge 67 of the mattress and the lower edge 68 . a suitable top filler valve 69 and air bleeder valve 70 may be integrally formed in the top sheet 60 . the seam 66 is positioned to extend about the side wall of the mattress , which when positioned on the support is adjacent the members forming the frame 50 intermediate the upper and lower edges of the frame . as illustrated in fig6 the filled mattress has a dimension at its transverse center , illustrated by the dotted arrow 72 that is greater than the height of the matress at its ends . in order to attain a shape as illustrated in fig6 the sheets 60 must be initially cut with their side edges bowed or angled from the corners 74 and 75 , on each side , to the center line 72 . the bowing on each sheet 60 must be one half the difference in the effective height of the mattress at the center over the effective height at the end edges . the thickness of the mattress , as illustrated , is greatest along the line transverse of the waterbed assembly . since the greatest weight on a mattress during normal usage is along this center transverse section , the waterbed will function in essentially the same fashion as conventional waterbeds of uniform thickness without sacrificing any of the comforts of such waterbed mattresses . in an alternative embodiment of this invention the thickest section of the mattress may be arranged longitudinally of the waterbed rather than transversely . this arrangement is essentially illustrated in fig7 . in this embodiment , as in the preferred form , the thickest section of the waterbed mattress is designed to underly the section in which the greatest weight of the person using the bed is concentrated . in this embodiment the greatest thickness of the mattress would normally extend under a person lying in the center of the bed .

a lightweight comfortable waterbed assembly comprising a mattress , made of a pair of water impermeable sheets , sealed at their peripheries . an easily assembled supporting substructure of simple geometrically shaped and interlocked components , support the mattress in a non - uniformly thick configuration whereby the maximum thickness of the mattress occurs in areas in which maximum support is required .

the above described drawing figures illustrate the described apparatus and its method of use in at least one of its preferred , best mode embodiment , which is further defined in detail in the following description . those having ordinary skill in the art may be able to make alterations and modifications what is described herein without departing from its spirit and scope . therefore , it must be understood that what is illustrated is set forth only for the purposes of example and that it should not be taken as a limitation in the scope of the present apparatus and method of use . described now in detail , and as best shown in fig1 , is a skate truck assembly apparatus comprising a tubular hanger 10 with left 20 and right 20 ′ collinearly aligned axles engaged with the hanger 10 and extending in opposition therefrom from each side . see common axis 15 in fig2 . the axles 20 and 20 ′ are manufactured as separate elements as is hanger 10 and are then joined using sweat joints , i . e ., the hanger 10 is heated so as to expand receiving apertures 15 ; and the axles 20 and 20 ′ are each chilled so as to compress the shafts 22 . the assembly of shafts 22 into apertures 15 then takes place holding axles 20 , 20 ′ in collinear alignment so that when the several parts are brought to room temperature , true coaxial alignment is attained and retained throughout the useful life of the assembly . this method has been found to be superior in attaining the required alignment tolerance in a highly reliable manner and at low cost . the hanger 10 is further engaged with a pair of suspension bushings 30 and 30 ′ as will be further described below . mounted through the bushings 30 and 30 ′ and hole 16 in the hanger 10 is a kingpin 40 , a bolt , as best shown in fig1 , having a head 41 , shaft 45 with shoulder 42 , and a terminal , reduced diameter threaded portion 44 . a structural base 50 , preferably made of steel , is adapted with mounting holes 52 for mounting the base 50 to the underside of a skateboard ( not shown ) as is well known . the kingpin 40 is engaged with the base 50 as shown in fig3 using threaded portion 44 so that the kingpin 40 is rigidly fixed to base 50 thereby mounting the hanger 20 and the bushings 30 , 30 in position relative to the base 50 as shown in fig2 and 3 . a pivot rod 60 is permanently engaged with the hanger 10 extending therefrom into a rod recess 54 within the base 50 , where the rod recess is positioned distant from the kingpin 40 as shown in the figures . the kingpin 40 and the pivot rod 60 form an acute angle β of between 40 ° and 45 ° and preferably approximately 42 ° between their longitudinal axes as is best shown in fig3 . angular positioning within this angular range has been shown to provide superior dynamic operation of the apparatus . the resultant force vector on the truck when in use is the sum of the rider &# 39 ; s weight vector , see arrow “ a ” and a drag vector represented by arrow “ b ” in fig3 . depending on the relative magnitudes and actual directions of these two vectors bushings 30 and 30 ′ will be compressed and pivot rod 60 will move into compression with pivot bushing 54 ′. therefore , the function of pivot rod 60 and pivot bushing 54 ′ is to provide dynamic resistance to changes in angle 13 so that bushings 30 and 30 ′ do not sustain too much compressive strain . preferably , the pivot bushing 54 ′ is engaged within the recess 54 , the pivot bushing 54 ′ formed in the shape of a cup for receiving a distal end 62 of the pivot rod 60 . the suspension bushings 30 , 30 ′ are axially aligned as shown in fig3 . preferably , a retaining washer 70 is compressively positioned between the kingpin 40 and the upper suspension bushing 30 . the retaining washer preferably has an annular rim 71 or flange to better retain the upper bushing 30 . it should be recognized that the pivot rod 60 is positioned medially between the left and right axles 20 , 20 ′ as shown in fig2 to provide a balanced reactive force to both axles . the base 50 preferably includes a base recess cavity 54 into which insert 54 ′ is preferably pressed and held in place by elastic compression . the upper and the lower suspension bushings 30 , 30 ′ are of a compressible yet extremely hard and durable material such as polyurethane , such that with a neutral compression of the bushings 30 , 30 ′, the pivot rod 60 is in an axially aligned position relative to the base recess cavity 54 , and with compressive forces applied to bushings 30 , 30 ′, pivot rod 60 moves against insert 54 ′ which tends to resist compressively . preferably , the flange of hanger 10 provides at least one bushing recess as shown in fig3 for receiving suspension bushing 30 and 30 ′ on surfaces 12 and 14 respectively . preferably , the kingpin 40 and the base insert 55 are threadedly engaged as shown , but may also be engaged by other means . in use , bushings 30 and 30 ′ of differing hardnesses may be exchanged to accommodate riders of widely differing weight . for instance , a rider of between 200 and 250 pounds will require bushings 30 and 30 ′ to have a durometer of between 97 and 98 , while a rider of between 150 and 200 pounds will require bushings 30 and 30 ′ to have a durometer of between 96 and 97 , and a rider of between 100 and 150 pounds will require bushings 30 and 30 ′ to have a durometer of between 93 and 94 . in this way , “ rebound ” defined as the magnitude of the immediate return response after a compression , and “ elongation ” defined as the total possible elastic range are maintained within desired limits during use . in fig4 and 5 is shown an apparatus very similar to the preferred embodiment shown in fig3 and described above . however , the apparatus of fig4 and 5 uses a kingpin that does not provide shoulder 42 and so is able to move to some extent in the axial direction depending on the direction of load force applied to axles 22 . also , it is common practice among skateboarders to loosen the kingpin to change the stiffness of the suspension . this is not a solution and tends to weaken the assembly and cause excessive wear . the enablements described in detail above are considered novel over the prior art of record and are considered critical to the operation of at least one aspect of the apparatus and its method of use and to the achievement of the above described objectives . the words used in this specification to describe the instant embodiments are to be understood not only in the sense of their commonly defined meanings , but to include by special definition in this specification : structure , material or acts beyond the scope of the commonly defined meanings . thus if an element can be understood in the context of this specification as including more than one meaning , then its use must be understood as being generic to all possible meanings supported by the specification and by the word or words describing the element . the definitions of the words or drawing elements described herein are meant to include not only the combination of elements which are literally set forth , but all equivalent structure , material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result . in this sense it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements described and its various embodiments or that a single element may be substituted for two or more elements in a claim . changes from the claimed subject matter as viewed by a person with ordinary skill in the art , now known or later devised , are expressly contemplated as being equivalents within the scope intended and its various embodiments . therefore , obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements . this disclosure is thus meant to be understood to include what is specifically illustrated and described above , what is conceptually equivalent , what can be obviously substituted , and also what incorporates the essential ideas . the scope of this description is to be interpreted only in conjunction with the appended claims and it is made clear , here , that each named inventor believes that the claimed subject matter is what is intended to be patented .

a skate truck assembly apparatus provides a hanger engaging separate left and right collinearly aligned axles , and at least three pairs of suspension bushings , with one selected pair of said bushings appropriate to a chosen dynamic load , secured by a kingpin ; a base receiving the kingpin in adjustable engagement , thereby mounting the hanger and the at least one suspension bushing in flexible securement on the base ; a pivot rod engaged with the hanger and extending therefrom into a rod recess within the base positionally distant from the kingpin .

referring now to the drawings , the biventricular assist device of the present invention is shown therein and indicated generally by the numeral 10 . the biventricular assist device comprises a generally parabolic - shaped cup 12 having two semi - annular diaphragms 14 disposed adjacent to the inner surface of the cup 12 . the cup 12 is sized to fit over the human heart . the diaphragms 14 are actuated by applying positive and negative pressure to the space between the diaphragms 14 and the cup wall . as the diaphragms 14 inflate or distend , the heart is compressed to empty the right and left ventricles of the heart . when the diaphragms 14 deflate , the heart muscle relaxes allowing blood to flow into the ventricles . the cup 12 is constructed in two components -- a main body section 16 and an end piece 18 . the diaphragms 14 are bonded to the main body section 16 as will be hereinafter described and then the end piece 18 is bonded to the main body section 16 to form the cup 12 . all components are made of a urea - linked polyureathane copolymer . all bonding is done using liquid polymer of the same formulation . after the bonding polymer is applied and allowed to cure , no seams exist since the bonding polymer and the two sections become homogeneous and isotropic upon cure due to identical material formula . the main body section 16 includes a distal end 20 and a proximal end 22 . the main body section 16 should preferably have a shore a hardness in the range of 70 - 82 , and more preferably in the range of 70 - 75 . the distal end 20 defines a cup opening 24 . rounded lobes 26 are formed adjacent both the distal end 20 and the proximal end 22 . each diaphragm 14 is disposed adjacent the inner surface of the main body section 16 of the cup 12 and extends approximately 180 ° around the inner surface of the cup . the ends of the diaphragm 14 are wrapped around the lobes 26 at both ends and then liquid polymer isotropic bonded to the outer surface of the main body section 16 . the side edges of the diaphragms 14 extend through slots 27 a in the main body section 16 and are disposed against the outer surface of the main body section as seen best in fig2 . the common formula bonding agent is applied between the edge portions of the diaphragm 14 and the main body section 16 . an overcoat of the same common formula bonding agent is then applied to seal the edges of the diaphragm 14 . when cured , no physical seams exist due to isotropic bonding . after the diaphragms 14 are bonded to the main body section 16 , the end piece 18 is then bounded to the proximal end 22 of the main body section 16 . the end piece 18 has a shore a hardness of approximately 58 - 60 . a central opening 19 is formed in the center of the end piece 18 . the liquid polymer isotropic bonding agent is applied to the edge of the end piece 18 where it joins the main body section 16 . an overcoat of same liquid polymer is then applied to both sides of the joint between main body section 16 and the end piece 18 . again , no seams exists due to isotropic bonding . a flexible annular flange 27 is finally polymer bonded to the distal end of the cup assembly . this flange , approximately 3 / 8 wide and 0 . 018 &# 34 ; thick , is angled inward at an angle of 15 - 20 °. it functions as a vacuum seal between the heart and the cup 12 , in order to prevent the heart from being ejected during systolic compression . a series of inlet openings 28 are formed in the main body section 16 of the cup 12 . in the disclosed embodiment , six openings are formed a fixed distance from the distal end 20 . these inlet openings 28 communicate with each diaphragm chamber . a series of manifolds 30 are attached to the outer surface of the cup 12 and enclose the inlet openings 28 . the manifolds 30 are connected by pressure lines 32 to a drive connector 34 which is liquid polymer bonded to the base of the end piece 18 . the drive connector 34 is connected to a pressure system for applying positive and negative pressures to actuate the diaphragm 14 . the manifolds 30 have a generally flat profile with smooth mold blended contours . a flange is formed around the perimeter of each manifold 30 to facilitate bonding the manifold 30 to the outer surface of the main body section 16 . the interior of the manifold defines an elongated oval - shaped space which communicates with the inlet openings 28 in the main body section 16 . after the end piece 18 is fixed to the main body section 16 , the manifolds 30 are bonded to the outer surface of the main body section 16 . the bonding agent is applied to the bottom surface of the flanges 32 and the manifolds 30 are pressed against the outer surface of the main body section 16 . an overcoat is then applied to the flange . referring now to fig5 the biventricular drive connector 34 is shown . the drive connector 34 includes an elliptical center tube 36 and an outer housing 38 . the outer housing 38 is divided by a web 46 into two distribution chambers 38a and 38b . the two distribution chambers 38a and 38b function as two , completely independent pressure / vacuum manifolds . these manifolds serve to connect the bi - ventricular cup 12 to the drive lines which independently drive the semi - annular right and left ventricle pumping diaphragms . a flange ( not shown ) extends outwardly from the upper end of the housing 38 for bonding the drive connector 34 to the end piece 18 . two inlet tubes 42 project downwardly from the housing 38 on opposite sides of the center tube 36 . a series of outlet openings 44 are formed in the housing 38 . the connector 34 is bonded to the apex of the end piece 18 such that the center tube 36 communicates with the opening 19 in the center of the end piece 18 . the liquid polymer isotropic bonding agent is applied to the surface of the flange 42 and to the end of the center tube 36 to bond the drive connector 34 to the end piece 18 . the liquid polymer isotropic bonding agent is then applied as an overcoat to the flange 42 to form a smooth transition from the surface of the end piece 18 to the flange 42 . pressure lines 32 connect each manifold 30 to a respective distribution chambers 38a or 38b of the drive connector 34 . the right distribution chamber 38a of the connector 34 is connected by three separate pressure lines 32 to respective manifold parts 30 on the right side of the cup 12 . three additional pressure lines 32 connect the left distribution chamber 38b of the drive connector 34 to the manifold parts 30 on the left side of the cup 12 . the pressure lines 32 extend from the outlet openings 44 in the connector to an inlet opening in the manifolds 30 . the pressure lines 32 are then affixed to the outer surface of the cup 12 by applying the liquid polymer isotropic bonding agent to overcoat the pressure lines 32 . fig6 a and 6b illustrate an optional compensation ring 50 which may be incorporated into the biventricular assist device 10 . the compensation ring 50 comprises an annular membrane fixed to the main body 16 adjacent the distal end 20 . the compensation ring 50 is disposed between the main body 16 and the diaphragm 14 . an opening 52 is fitted with a conventional fill valve 54 . fluid can be injected into the compensation ring 50 through the fill valve 54 to inflate the compensation ring 50 . it will therefore be appreciated that the compensation ring 50 allows the size of the cup opening 24 to be adjusted depending on the size of the patient &# 39 ; s heart . various elastomers , polymers , and plastics have been developed and are readily available for human tissue and organ prothesis . these materials typically include silastic , biomer , pellathane , polysiloxanes , and corothane . various formulations of these materials may be used in the fabrication of the bi - ventricular assist device 10 . a copolymer comprising a urea - linked , cast , block finish , thermostat polyureathane is particularly well suited for the present invention . these polymers comprise a mixture of oligomeric di - mono - amino benzoates prepolymers modified with diphenylmethane di - isocyanate , ( mdi ) polymerizers and chain extenders , and appropriate reaction and material characteristic modifiers . all of these components are widely available from various commercial sources . oligomeric mono - and di - amino benzoates are useful in polyurethane cast elastomers because their reactivity is different from that of other mdi amino formulations commonly used in reaction injection molding ( rim ) applications . conventional approaches to the preparation of cast elastomers involve the reaction of a short chain diamine with a long chain polymer terminated with toluene di - isocyanate . another commonly used system involves reacting diols with resins capped with mdi or methylene di - isocyanate , or methylene - bis - p - phenyl - isocyanate . oligomeric mono and di - amino benzoates reverse the typical arrangement of the reacting agents resulting in the amine functionality being capped onto the ends of the soft segment . chain extension is accomplished by using mdi , modified forms of monomeric mdi , or mdi containing resins as the hard segment . elastomers prepared using these methods were determined as exhibiting the best overall physical properties for practicing the present invention . the formulation of these components to obtain a urea - linked polyureathane co - polymer is governed by the well - principled science of stoichiometric chemistry . stoichiometric chemistry mix requirements for compatible polymer components of various average molecular weight and various nco % content are well known and practiced by those skilled in the science of polymer chemistry . the ventricular actuation cup 12 is actuated by a conventional pulsed - pressure system indicated generally by the numeral 100 . the pulse pressure system includes both a systolic pressure source for applying a positive pressure to the diaphragm 14 and a diastolic vacuum source 120 for applying negative pressure to the diaphragm chamber . the systolic pressure source can be independently regulated to obtain a peak output in the range of 120 to 200 mm of hg . the diastolic vacuum source can be independently regulated to obtain a peak negative pressure of approximately 40 to 100 mm of hg . the pressure system also includes a constant negative pressure system ( not shown ). the constant negative pressure system comprises an independently controllable vacuum source which is connected to the center tube 36 of the drive connector 34 . the vacuum source applies negative pressure to the interior of the ventricular actuation cup 12 to help maintain the heart within the cup 12 . the vacuum source should preferably apply a pressure in the range of 25 mm of hg to 60 mm of hg . fig7 is a schematic diagram of the pulsed pressure system for the biventricular assist device 10 . the drive lines for the biventricular assist device are connected to valves 110 and 120 . the drive lines for the right ventricle is connected to valve 110 while the drive line for the left ventricle is connected to valve 120 . each of the valves 110 and 120 are connected to the positive pressure source and the negative pressure source . valve 110 is connected by positive pressure line 112 to the positive pressure source and by negative pressure line 114 to the negative pressure source . similarly , valve 120 is connected by positive pressure line 122 to the positive pressure source and by negative pressure line 124 to the negative pressure source . pressure regulators 116 and 126 regulate the pressure in lines 112 and 122 respectively . valves 110 and 120 are conventional two position humphrey valves . during operation , the valves 110 and 120 constantly shift position to provide positive and negative pressure pulses to their respective drive lines . a pair of pilot valves 130 are used to shift the position of the valves 110 and 120 . the pilot valves are connected by line 132 to the positive pressure source . a pressure regulator 134 is disposed in line 132 to regulate the pressure . positive pressure is directed through the pilot valves 130 to the valves 110 and 120 . the pilot valves 130 are actuated by mechanical actuators 136 so that each time the pilot valves 130 shift , its corresponding valve 110 or 120 shifts position . the actuators 136 for the pilot valves 130 can be independently controlled so that the timing of the positive and negative pressure pulses for each of the valves 110 and 120 can be independently controlled . in the present invention , the systolic pressure source and the diastolic vacuum source are separate and independent , effectively , eliminating recurrent manual damper valve &# 34 ; tuning &# 34 ; adjustments required for changing cardiac assist needs . the pulsed pressure system permits independent lvad and rvad cardiac support with the desirable feature of independent left and right ventricle systolic and diastolic pressure vacuum profile controls . although &# 34 ; air &# 34 ; has been described as the medium or fluid used for cup actuation , it is to be noted that other &# 34 ; fluids &# 34 ;, e . g . silicone , oil , saline , water or other fluids of suitable properties , can also be employed -- e . g ., a miniature high - rpm electro turbine drive with appropriate fluid path design parameters . the bi - ventricular assist device 10 is used to maintain blood circulation in a patient whose natural heart is in a state of global fibrillation , cardiac arrest , or bi - ventricular failure . the bi - ventricular assist device 10 may also be used to provide cardiac support for a heart which is functioning at less than normal output or pressure . when it is determined that cardiac support is needed , the surgeon selects bi - ventricular assist device 10 of appropriate size as determined by the size and condition of the patient &# 39 ; s heart . the bi - ventricular assist device 10 is inserted over the patient &# 39 ; s heart such that ventricles of the heart are fully contained within the assist device 10 . after the assist device 10 is in place , negative pressure is applied to the interior of the cup 12 by the independent vacuum system to help retain the heart within the cup 12 . next , the diaphragm 14 of the ventricular actuation cup 12 is actuated by selectively switching between the systolic pressure source 110 and the diastolic vacuum source 120 . the appropriate systolic pressure and diastolic vacuums are determined by measuring the pressure in the pulmonary artery and systemic arterial pressures in the patient . the systolic and diastolic pressures are then adjusted to match the pressures measured in the patient . the measurement of pulmonary artery pressure and systemic arterial pressures is normally accomplished through the placement of catheters within the pulmonary artery and the systemic arteries of the patient . during use , the diastolic and systolic pressures actually delivered are monitored by placing pressure transducers within the pressure feed system . the output from these transducers is then fed to a monitor which is used to control the flow regulators 140 . since closed - loop feedback systems of this type are well known to those skilled in the art , further discussion of such systems is not necessary . a significant benefit of the bi - ventricular assist device is that it enables independent right and left ventricular actuation . under normal physiologic conditions , the right ventricle ejects blood under relatively low pressure into the pulmonary artery . in contrast , the left ventricle ejects the same amount of blood into a high - pressure , high - resistance systemic arterial system . thus , the normal left ventricle is designed to function as a high - pressure , high - resistance systemic arterial system . thus , the normal left ventricle is designed to function as a high - pressure pump , while the right ventricle functions as a low - pressure pump . the bi - ventricular assist device 10 can be used to independently control the timing and pressure of the right and left ventricle pumping to optimize forward cardiac output . in contrast , single diaphragm ventricular assist devices , which apply the same person to both the right and left ventricles , cannot achieve optimum cardiac output for both the right and left ventricles . the pressure applied by such devices is , at best , a limiting compromise between right and left ventricular pressures . the bi - ventricular assist device 10 is particularly useful when abnormal physiological conditions of the heart exist . for example , medically refractory congestive heart failure or cardiogenic shock can occur because of primary right ventricular failure , primary left ventricular failure , simultaneous bi - ventricular failure , or incessant ventricular dysrhythmia such as medically refractory ventricular tachycardia or ventricular fibrillation . in patients with primary left ventricular failure , the pulmonary vascular resistance may be normal to moderately elevated . in contrast , patients with left ventricular failure or biventricular failure may have concomitant pulmonary hypertension . in the severest forms of pulmonary hypertension , right - sided pressures are equal to systemic or left - sided pressures . under pathologic conditions , optimal forward cardiac output using the bi - ventricular assist device 10 can be achieved only by controlling independently right and left ventricular systolic actuation as well as diastolic configuration . by incorporating two inflatable chambers within the bi - ventricular assist device 10 , systolic actuation of right and left ventricles can occur at differing time intervals and at different compressing pressures . for example , in patients with severe pulmonary hypertension , both left and right ventricular systolic pressures would be equalized . however , in patients with primary left ventricular failure and normal pulmonary vascular resistance , the right ventricle would be compression during mechanical systolic actuation at a slightly longer time interval under normal pressure in order to allow the right ventricle to remain opposed to the septum during left ventricular systolic actuation . by varying the timing of ventricular actuation and by applying appropriate pressure to each ventricle , the inter - ventricular septum will remain in the midline and will not compromise either left or right ventricular systolic emptying or diastolic filling . the present invention may , of course , be carried out in other specific ways than those herein set forth without parting from the spirit and essential characteristics of the invention . the present embodiments are , therefore , to be considered in all respects as illustrative and not restrictive , and all changes coming within the meaning and equivalency range of the appended claims are intended to be embraced therein .

a direct mechanical bi - ventricular cardiac assist device comprises a ventricular actuation cup having two independently operated diaphragms for independently actuating the right and left ventricle of the patient &# 39 ; s heart . the pressure and timing of each diaphragm can be independently varied to maximize forward cardiac output . the ventricular actuation cup is constructed in two components including a main body section and an end piece . the diaphragm wraps around the ends of the main body section and the edges of the diaphragm are bonded to the outer surface of the main body section . bonding of the diaphragm to the outer surface of the ventricular actuation cup eliminates lifting and tearing vectors which could result in diaphragm failure .

fig3 is a simplified schematic representation of one embodiment of applicants &# 39 ; invention . as with a prior art fryer , applicants &# 39 ; continuous fryer comprises a steam hood 308 which collects the steam produced in situ by product being fried in the hot oil 304 . the product is likewise introduced into the fryer by an infeed conveyor 302 . however , the hood 308 of applicants &# 39 ; invention does not necessarily exhaust the produced steam through exhaust ports 340 located above the frying product , as is illustrated by the exhaust ports 112 in fig1 . in fact , a prior art frying unit can be modified by simply closing off or restricting any such exhaust ports 112 or can maintain one or more such ports 340 ( fig3 ) with an adjustable door or closing means 338 that can restrict the flow of steam through the port 340 . as illustrated in fig3 , applicants &# 39 ; fryer comprises one or more flow inducing devices 310 , 311 , such as a fan 310 , for the purpose of flowing the steam through the hood from an upstream position near the slice infeed 302 to a downstream position near the output conveyor 306 . such one or more fans 310 , 311 can be located in any number of areas in the hood , such as before or after the heat exchanger 324 , provided that the fans induce the flow as will be described herein . for example , and without limitation , a single exhaust fan 311 can be located in the exhaust port 312 at the downstream end of the unit . this exhaust fan 311 can operate alone or in conjunction with one or more other fans 310 located within the hood 308 . likewise , one or more fans 310 located in the hood 308 can drive the steam flow with or without the benefit of an exhaust fan 311 . the location , number and type of fans 310 , 311 used with applicants &# 39 ; invention is dependent on the desired flow characteristics , velocities , and product applications . applicants &# 39 ; invention further consists of a heat exchanger 324 located within the hood . this heat exchanger is located in close proximity to the output conveyor 306 . the heat exchanger 324 is upstream from a flow diversion component 330 that is used to direct steam after it has passed through the heat exchanger 324 towards the product bed located on the output conveyor 306 . the area on the output conveyor 306 that is exposed to the steam flowing through the product bed is referred to by applicants as an oil stripping zone 332 . this oil stripping zone 332 is necessarily located between the heat exchanger 324 and the flow diversion device 330 . the output conveyor 306 is constructed of a porous material or design that allows for the free flow of the steam through the product bed found on the output conveyor 306 and through the output conveyor 306 itself . once the steam is blown through the product bed on the output conveyor 306 the steam is directed out of the fryer by way of the exhaust port 312 which is accessed from an opening 344 downstream of the oil stripping zone . product is removed from the output conveyor by way of a rotary air lock 336 . because of the rotary air lock 336 , steam cannot exit the hood 308 after flowing through the stripping zone 324 by any means other than the exhaust port 312 by way of an opening 344 into said port 312 . the steam flow through the hood 308 from upstream to downstream is illustrated by the flow arrows shown in the hood 308 . in a preferred embodiment , steam is collected in the hood 308 in the temperature range of about 212 ° f . to about 300 ° f . the steam is then passed through the heat exchanger 324 in order to raise the temperature of the steam to preferably in the range of about 280 ° f . to about 320 ° f . or more preferably in the range of about 300 ° f . to about 310 ° f . steam pressure within the unit is maintained at approximately ambient levels . the steam is next directed through the product bed and the output conveyor 306 at the oil stripping zone 332 . the velocity of this steam as it is blown through the oil stripping zone 332 ( passes through the food pieces ) is , in a preferred embodiment , less than 1 , 000 ft ./ min ., and more preferably about 250 ft ./ min . to about 500 ft ./ min . this flow rate corresponds to a product production rate of about 2 , 000 lbs ./ hr . to 40 , 000 lbs ./ hr . and a steam production rate within the hood of about 500 lbs ./ hr . to about 10 , 000 lbs ./ hr . applicants have found that much lower velocities can be used for the stripping steam than has been used in the past in low - oil strippers . this is believed to be a result of not allowing the product to cool prior to stripping . the product bed is subjected to super heated steam as soon as possible after removal from the oil 304 . because the steam is super - heated as it passes through the oil stripping zone 332 , the food pieces on the output conveyor 306 continue to cook , thereby driving moisture out of the food piece . this continuous cooking , without a cool down while the product is in transit to the stripper as occurs in the prior art , inhibits the absorption of further moisture by the food pieces from the contact with the steam and more efficiently drives oil out of the chip , which is then more easily stripped by the steam . importantly , the prior art methods involve an elapsed time of typically 30 to 60 seconds , between the time product is removed from the oil 304 and when it is subject to steam stripping . applicants &# 39 ; invention reduces this elapsed time to 10 seconds or less , because the product is stripped immediately after leaving the oil 304 . in fact , it is preferred that stripping occur within 5 seconds of removal of the product or food pieces from the hot oil 304 by the output conveyor 306 . in order to accomplish this timely stripping , the oil stripping zone 332 must start within a close proximity to the oil 304 , preferably within three feet thereof , and more preferably within two feet thereof . thus , the oil stripping zone 332 starts within three feet of the point where the output conveyor 306 is in communication with the oil 304 . after passing through the oil stripping zone 332 , the steam can be further blown through an oil separator 322 before being exhausted from the frying unit . the recovered oil from the steam is then returned to the frying oil via an oil collection point 334 for further use . alternatively , since virgin steam is being constantly produced in the hood 308 , the steam can be exhausted without passing through an oil separator 332 . the steam temperature and flow rates can be adjusted as well as the product throughput in order to obtain the desired reduction in oil content of a food piece fried with applicants &# 39 ; fryer . the volume of the steam can also be adjusted by a door 338 on an exhaust or relief port 340 ( with its exhaust fan 342 ) located upstream of the heat exchanger . when excess steam collects in the hood 308 , the door 338 is opened on the relief port 340 in order to vent the excess steam prior to the steam passing through the heat exchanger 324 . if necessary , a fan 342 can be activated to draw the excess steam out of the hood 308 . the size of the opening obtained by opening the door 338 and / or the fan 342 speed can be adjusted to ensure the desired amount of steam is removed . in a preferred embodiment , applicants &# 39 ; modified fryer produces potato chips having a finished oil content of about 28 % to about 31 % by weight . these potato chips also have a low moisture level , typically about 1 . 1 % to about 1 . 5 % by weight due to the use of the super - heated steam as previously described . yet , applicants &# 39 ; invention uses less energy to accomplish this stripping . one embodiment of applicants &# 39 ; modified fryer is constructed by modifying existing hooded continuous fryers by sealing off the exhaust ports located above the frying oil , adding an internal heat exchanger and flow inducing device , and constructing the downstream portion of the fryer such that it directs the steam through the oil stripping zone and out an added exhaust port that defines the furthest downstream point of steam within the fryer . in an alternative embodiment of applicants &# 39 ; invention , a hooded continuous fryer is constructed of a hood having no or closeable / adjustable exhaust ports above the frying oil and the same configuration of the downstream heat exchanger , diversion device , and exhaust port as previously described . the foregoing is merely illustrative of the principles of this invention , and various modifications can be made by those skilled in the art without departing from the scope and spirit of the invention . for example , while the invention has been described in the context of a potato chip frying line , it should be understood that the invention and principles involved therein are applicable to the cooking and stripping of any fried food piece , such as fried fruit chips , fried vegetable chips , other fried tuber slices such as sliced sweet potatoes , and fabricated food slices made from sheeted dough as well such as fabricated potato chips , tortilla chips , and corn chips , and other fabricated vegetable and / or fruit based chips . thus , the starting material can be either a raw food piece or a fabricated food piece made from sheeting a dough , any of which results in an end product generically referred to by applicants as a “ chip .” applicants &# 39 ; invention is applicable to all hooded continuous fryers used to cook food pieces of any type .

a continuous oil fryer used to fry food slices , such as potato chips , having an internal oil stripping capability . the fryer accumulates the steam produced by the frying process in a hood and utilizes such steam , after superheating the steam by passing it through a heat exchanger , to strip oil from product immediately upon removal from the hot oil bath by passing the superheated steam through a product bed while on an output conveyor . the superheated steam removes oil from the product on the output conveyor without increasing the moisture level of the product . the fryer therefore accomplishes the same function as a low - oil stripper without increasing the footprint of the frying unit and with less energy .

referring to fig1 basic steps in the method of making the matrix of the present invention are illustrated . in a first step at block 10 , preferably , a pure stock of a milo grain is selected . although there is no specific hybrid of milo which is required for the product and method of the present invention , it is desirable to choose a single pure stock grain because this pure stock grain is advantageous in creating consistency and repeatability of the extrusion process . through testing , it has been found that a few particular hybrids of milo are particularly adapted for extrusion . three hybrid varieties which have shown great success include triumph 65g , asgrow seneca ; and dekalb 5400 . these three hybrid varieties are well known grain stocks for use in animal feed , and are commercially available in the u . s . although these three hybrids are preferred , it shall be understood that there may be a number of other hybrid varieties of milo which are also adapted for consistent and repeatable extrusion . the next step in the process shown at block 12 is to clean and size the milo grain . standard cleaning and sizing equipment may be used to process the grain at this step . for example , air / water streams may be used to clean the grain , and the grain may be passed through various sieves to obtain the desired grain size . in the present invention however , there is no particular grain size required and multiple grain sizes may be used . shown at block 14 is the next step in the process which is an optional destoning operation to remove stones or other similar sized objects which may still remain in the grain after cleaning and sizing . although a destoning operation is shown as a separate optional step , destoning can be incorporated within the cleaning and sizing of the grain at step 12 . the next step in the process is shown at block 16 which is the decortication of the milo grain . anyone of several methods of usual grain decortication may be used to decorticate the milo . two references which disclose methods for decorticating milo and which have been found to be particularly effective are the methods described in the u . s . pat . nos . 5 , 713 , 526 and 5 , 820 , 039 . these two references are incorporated herein by reference for purposes of disclosing basic methods by which milo grain may be decorticated . the next step in the method is shown at block 18 which is an optional step of scouring the grain to remove fatty oils or lipids . in order to enhance the consistency and repeatability of the extrusion process , the fatty endogerm of the milo may be removed because this fatty portion of the grain tends to act as a lubricant through the extrusion die thereby degrading extruder operation . well known grain scouring processes may be used to remove the fatty endogerm from the milo grain . although scouring is discussed as a step in the basic method , it shall be understood that scouring is not necessarily required as it may be desirable to have certain levels of fat within the matrix . additionally , scouring may be eliminated to simplify the overall production process . the next step in the method is shown at block 20 which involves the introduction of a desired anti - fungal / anti - microbial agent to the processed milo . the milo combined with the anti - fungal / anti - microbial agent are referred to as a grain mix . there are a number of anti - fungal / anti - microbial agents which are contemplated within the present invention which may be used for inhibiting mold growth , or inhibiting growth of microbes . many naturally occurring plant products have been identified that possess significant anti - fungal and anti - bacterial activity . for example , the terpenes are isomeric hydrocarbons found primarily in essential oils , resins and balsams that possess strong anti - fungal activity . thus , terpenes and especially y - terpinene , terpinolene , terpinen - 4 - ol , as well as 1 , 8 - cineole , p - cymene and pinene are preferred anti - fungal agents for use in the construction materials of the present invention . additionally , phytoalexins found in sorghum are induced after the plant is exposed to fungal pathogens . the most active phytoalexins include apigeninidin , luteolinidin , a caffeic acid ester of arabinosyl - 5 - o - apigeninidin , and 5 - methoxy - luteolinidin . thus , these natural mold inhibitors are found within the milo grain itself . for example , in red milo , the major pigments found in the hulls of this sorghum are apigeninidin and luteolinidin . therefore , it is also contemplated within the present invention to recover the hulls of the grain which are removed during decortication and then process the hulls to extract the apigeninidin and luteolinidin . these removed pigments can then be added back to the decorticated grain prior to extrusion and used as the anti - fungal agents . calcium propionate is another compound known to have significant anti - fungal activity and is compatible with the naturally occurring plant products listed above . thus , the construction materials of the present invention include an extruded milo matrix incorporating anti - fungal compounds including calcium propionate , at least one terpene and at least one phytoalexin . preferably , the construction material incorporates at least one of calcium propionate , apigeninidin , luteolinidin , a caffeic acid ester of arabinosyl - 5 - o - apigeninidin , 5 - methoxy - luteolinidin , y - terpinene , terpinolene , terpinen - 4 - ol , 1 , 8 - cineole , p - cymene and / or pinene in an extruded milo matrix . depending on the intended use and storage conditions of the construction material each of these individual ingredients may be included in an amount of between about 0 % to about 50 % on a weight / weight basis in the extruded milo matrix . that is , each of the individual ingredients listed above may be absent or may be present in a concentration as high as 50 % w / w of the extruded milo matrix . particularly preferred embodiments of the present invention are described in table 1 which lists the amounts of the active and inactive ingredients in the construction materials . the inactive ingredients represent the extruded milo matrix which includes amylose - pectin starch , calcium , potassium , phosphorus , sulfur , manganese and ash . the water content of the material , if any , is not shown in table 1 . in order to provide an extrudable mixture , it is preferable to maintain the milo at or around 16 % moisture content prior to extrusion . accordingly , an amount of water must be added to the decorticated milo prior to extrusion . depending upon the type of agent which is added to the decorticated milo , a lesser or greater amount of water must be added to bring the moisture content of the milo grain mix to preferably around 16 % moisture . it may be desirable to mechanically mix the grain mix in a bin which will then meter the grain mix into the extrusion machine . mechanical mixing helps to ensure uniform dispersion of the added agent . the next step in the method is illustrated at block 22 which involves extrusion of the milo grain mix . through testing , it has been found that extrusion can be achieved utilizing a bake - type extruder which exposes the grain mix to heat in the range of about 325 ° f . to about 400 ° f . and pressure in the range of between about 1500 and about 2000 psi . the particular shape of the die used in the extruding machine may be adapted to produce a matrix of a desired shape . one example is a die having a round shaped hole with a diameter of approximately 0 . 120 of an inch . the cutting mechanism used in the extruding machine could be adapted for cutting the extrudate to a length of approximately three - quarters of an inch . the resulting extruded product can be of different sizes and densities . for example , if a particularly small enclosed space must be remediated by introduction of the matrix , it may be desirable to provide the matrix in a more dense extrudate . accordingly , the extrudate could have a smaller size and a nugget - like consistency . if the area to be remediated had not yet developed fungal or microbial problems and the purpose of introducing the matrix was primarily for prevention , then it may be adequate to provide the matrix in a larger sized , lighter , puffier extrudate . the amount of the anti - fungal / anti - microbial agent in the denser , nugget - like extrudate would be greater since more matrix is used per piece of extrudate while the amount of the anti - fungal / antimicrobial agent would be more dispersed within the lighter , puffy extrudate . since the concentration of the anti - fungal / antimicrobial agent can vary depending upon the density of the extrudate , the extrudate can be tailored for each application . of course , one could also simply vary the amount of the agent used when it is initially mixed with the decorticated milo to provide the desired concentration of the agent in the matrix . the last step of the method is shown at block 24 which contemplates curing the matrix product to thereby stabilize the product prior to storage and shipping . depending upon the matrix produced , i . e ., one which is either puffed or more dense , a certain amount of curing may be required to allow the matrix to reach equilibrium in terms of moisture content . there are a number of advantages of utilizing a milo matrix as a carrier for an anti - fungal and / or anti - microbial agent . first , the extruded milo is naturally hydrophobic which therefore allows the milo matrix to be used in damp or wet spaces for extended periods of time without substantial decay . milo is a readily available grain source , and is relatively inexpensive compared to man made or artificial compositions . another advantage as mentioned above is the ability to produce a matrix which has a variety of sizes and densities by simply altering the moisture content of the grain mix prior to extrusion . by altering the density , the concentration of the agent may also be adjusted . after extrusion , the milo matrix contains some percentage of carbohydrates ; however , the matrix is very low in nutritional value , and has little odor . the matrix has no detectable amounts of sugars , less than 2 % fat and less than 10 % protein . therefore , the matrix does not attract rodents or insects . the matrix of the present invention is easily deployed within many commercial structures by simply transporting the matrix to a desired location , and spreading the matrix within the desired space to be remediated or for prevention of mold and / or microbial growth . for prevention of mold , it has been found that spreading a layer of 3 - 6 inches of the lighter , puffier , matrix over the targeted area is adequate for preventing mold growth . for remediation of mold , it may be necessary to increase the depth of the spread matrix , and it may also be necessary to increase the density of the matrix at a particular location . as best understood , there are two primary ways in which the agent inhibits mold or microbial growth . the first is physical contact of the matrix with the area to be remediated . the second is production of an off - gas through sublimation of the additive into the atmosphere enclosed by the space to be remediated . for example , with chlorine , a certain amount of the solid chlorine will off - gas producing a vapor which prevents mold growth . of course , the concentration of the chlorine in the milo matrix has to be controlled so that the off gas produced does not reach dangerous levels . it may be necessary over time to add additional amounts of the matrix to the area to be remediated . as the agent continues to sublime or otherwise chemically break down , the concentration of the agent will diminish . the present invention has been described with respect to a preferred embodiment however , other changes and modifications may be made to the invention within the spirit and scope thereof .

the invention provides a composition useful in the construction industry for the prevention or remediation of mold growth in a man made structure . the composition contains an extruded milo matrix incorporating terpenes , phytoalexins . calcium propionate or combinations of these chemicals having antifungal activity . methods of making and using the compositions are also disclosed .

the present invention is illustrated on the basis of the following detailed explanations and exemplary embodiments as well as experimental data , which , however , do not limit the present invention in any way . in the following , a detailed description of the inventive concept is given on the basis of applicant &# 39 ; s studies and investigations , respectively , comprising experimental data which focus on the specific impact of active agents on the basis of inventive trimeric pyrazole compounds on the misfolding of proteins , especially aβ and the respective aggregation thereof . as delineated before , alzheimer &# 39 ; s disease ( ad ) is a steadily increasing threat especially for industrialized countries with a growing percentage of old individuals — today an estimated 5 . 3 million u . s . citizens are suffering from dementia and the number is predicted to quadruple within the next 50 years . research on potential therapies has been going on for several decades now , without producing one single drug which is able to cure alzheimer &# 39 ; s disease . since ad is accompanied by many diverse symptoms , numerous avenues have been exploited in the search for a therapy . antiinflammatory , antihypertensive as well as hypolipidemic agents , passive and active immunization , cholinergic therapies , neuroprotective agents , glutamate receptor antagonists , β - and γ - secretase inhibitors , β - amyloid and tau aggregation inhibitors , metal chelating agents , monoamine oxidase inhibitors , medicinal plants are only a number of the most prominent classes ( review : michael s . wolfe , nat . rev . drug disc . 2002 , 1 , 859 - 866 ). in recent years passive immunization with aβ - specific antibodies held most promise for a breakthrough ; however , the results of phase ii clinical trials revealed only moderate to weak effects with a large percentage of treated patients . as a consequence , the call for small molecules was revived / reinitiated . a plethora of small molecules has been screened in the past 3 decades for their antiaggregation potential against the alzheimer &# 39 ; s peptide ( bisstyrylbenzenes : d . p . flaherty , s . m . walsh , t . kiyota , y . dong , t . ikezu , j . l . vennerstrom , j . med . chem ., 2007 , 50 , 4986 - 4992 ). among these , often colored heterocyclic compounds have been identified , which are in general thought to somehow intercalate between the insoluble cross - β - sheet structure of aβ fibrils ( congo red , rifampicin , melatonin , cucurmin ( yang , f ., lim , g . p ., begum , a . n ., ubeda , o . j ., simmons , m . r ., ambegaokar , s . s ., chen , p . p ., kayed , r ., glabe , c . g ., frautschyj , s . a ., and cole , g . m . ( 2005 ) curcumin inhibits formation of amyloid oligomers and fibrils , binds plaques , and reduces amyloid in vivo , j . biol . chem . 280 , 5892 - 5901 )) ( hydroxyindoles : t . cohen , a . frydman - marom , m . rechter , e . gazit , biochemistry 2006 , 45 , 4727 - 4735 ). zn - and cu - chelating agents were thought to lower the aggregation tendency of monomeric aβ strands ( clioquinol ) ( zn and cu chelators : cherny r a , atwood c s , xilinas m e , gray d n , jones w d , mclean c a , barnham k j , volitakis i , fraser f w , and kim y , neuron 2001 , 30 , 665 - 676 ). another prevailing class of compounds are peptides , in some cases taken directly from putative nucleation sites within the aβ molecule ( klvff derivatives : a ) tjernberg , l . o ., naslund , j ., lindqvist , f ., johansson , j ., karlstrom , a . r ., thyberg , j ., terenius , l ., and nordstedt , c . ( 1996 ) arrest of β - amyloid fibril formation by a pentapeptide ligand , j . biol . chem . 271 , 8545 - 8548 ; b ) b . m . austen , k . e . paleologou , s . a . e . ali , m . m . qureshi , d . allsop , o . m . a . el - agnaf , biochemistry , 2008 , 47 , 1984 - 1992 ; c ) klvff aggregation and gelation : m . j . krysmann , v . castelletto , a . kelarakis , i . w . hamley , r . a . hule , d . j . pochan , biochemistry , 2008 , 47 , 4597 - 4605 ); however only very few of these compounds stem from rational design with a known structural motif in their complexes with aβ monomers , oligomers or fibrils . soto presented the β - sheet breaker lpffd ( iabeta5 ) ( soto , c ., sigurdsson , e . m ., morelli , l ., kumar , r . a ., castaño , e . m ., and frangione , b . ( 1998 ) β - sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis : implications for alzheimer &# 39 ; s therapy , nat . med . 4 , 822 - 826 ), which retained the high affinity towards the self - complementary lvffa region , but impaired its β - sheet forming propensity by introducing a proline - kink ; the d - peptide mehn - lvffl - nh 2 ( ppi - 1019 ) essentially interferes with the aggregation of β - amyloid in the brain and may help promote its clearance ( praecis ). murphy and kiessling synthesized hybrid peptides built from klvff and a highly charged kkkkk or eeeee terminus ( ghanta , j ., shen , c . l ., kiessling , l . l ., and murphy , r . m . ( 1996 ); a strategy for designing inhibitors of β - amyloid toxicity , j . biol . chem . 271 , 29525 - 29528 ; t . j . gibson , r . m . murphy , biochemistry 2005 , 44 , 8898 - 8907 ). aggregation of toxic aβ oligomers is promoted because of increased surface tension . another prominent class are alternating n - methylated and nonmethylated peptide amides or esters , presented by meredith , hughes and kapurniotu ( gordon , d . j ., and meredith , s . c . ( 2003 ) probing the role of backbone hydrogen bonding in β - amyloid fibrils with inhibitor peptides containing ester bonds at alternate positions , biochemistry 42 , 475 - 485 ; hughes , e ., burke , r . m ., and doig , a . j . ( 2000 ) inhibition of toxicity in the β - amyloid peptide fragment β -( 25 - 35 ) using n - methylated derivatives — a general strategy to prevent amyloid formation , j . biol . chem . 275 , 25109 - 25115 ; kapurniotu , a ., schmauder , a ., and tenidis , k . ( 2002 ) structurebased design and study of nonamyloidogenic , double n - methylated iapp amyloid core sequences as inhibitors of iapp amyloid formation and cytotoxicity , j . mol . biol . 315 , 339 - 350 ). these are able to cap growing β - sheets , without the ability of crosslinking because their back is blocked for hydrogen bonding due to the sterically demanding n - methyl groups or ester oxygens . they have recently been optimized with respect to their antiaggregatory capacity by introduction of 3 cyclohexylglycine units and reached nanomolar ic 50 values . the so far most potent compound is also thought to accelerate aβ self - assembly and thereby deplete the level of neurotoxic aβ - oligomers ( n . kokkoni , k . stott , h . amijee , j . m . mason , a . j . doig , biochemistry 2006 , 45 , 9906 - 9918 ). other examples comprise the small molecule homotaurin , which disrupts complexes between aβ and glucosaminoglycans . scyllo - inositol appears to bind oligomers of aβ42 , preventing them from damaging synapses . oligomer - specific aβ antibodies indicated that scyllo - inositol appears to increase the number of monomers and trimers while reducing the amount of larger oligomeric species , such as 40 mers ( a ) mclaurin , j ., goloumb , r ., jurewicz , a ., antel , j . p . & amp ; fraser , p . e . inositol stereoisomers stabilize an oligomeric aggregate of alzheimer amyloid beta peptide and inhibit a β - induced toxicity . j . biol . chem . 2000 , 275 , 18495 - 18502 ; b ) j . mclaurin , m . e . kierstead , m . e . brown , c . a . hawkes , m . h . l . lambermon , a . l . phinney , a . a . darabie , j . e . cousins , j . e . french , m . f . lan , f . chen , s . s . n . wong , h . t . j . mount , p . e . fraser , d . westaway , p . st . george - hyslop ; nat . med . 2006 , 12 , 801 - 808 ). a recent approach comes from willboldt et al ., who selected potent aβ binders from d - peptide libraries by phage display ( d - peptides by phage display : k . wiesehan , k . buder , r . p . linke , s . patt , m . stoldt , e . unger , b . schmitt , e . bucci , d . willbold , selection of d - amino - acid peptides that bind to alzheimer &# 39 ; s disease amyloid peptide abeta ( 1 - 42 ) by mirror image phage display , chembiochem 2003 , 4 , 748 - 753 ). surprisingly little knowledge / information , however , is available on the exact mechanism of action for most aβ complexing agents , even less on structural details . to the best of applicant &# 39 ; s knowledge , the only case is sato &# 39 ; s concept of β - sheet packing : peptide inhibitors based on a gxfxgxf framework disrupt sheet - to - sheet packing and inhibit the formation of mature aβ fibrils ( sato , t , kienlen - campard , p ., ahmed , m ., liu , w , li , h . l ., elliott , j . i ., aimoto , s ., constantinescu , s . n ., octave , j . n , and smith , s . o . ( 2006 ) inhibitors of amyloid toxicity based on β - sheet packing of a β ( 1 - 40 ) and a β ( 1 - 42 ), biochemistry 45 , 5503 - 5516 ). this strategy was developed from inspection of solid state nmr structures of amyloid fibrils and confirmed by 13 c nmr spectroscopy for the best candidate peptide in its direct complex with aβ1 - 40 . in this context , work by bitan is also interesting , who identified met - 35 as a structural switch in aβ aggregation ( bitan , g ., tarus , b ., vollers , s . s ., lashuel , h . a ., condron , m . m ., straub , j . e ., and teplow , d . b . ( 2003 ) a molecular switch in amyloid assembly : met ( 35 ) and amyloid β - protein oligomerization , j . am . chem . soc . 125 , 15359 - 15365 ). a new aspect comes from recent observations , that many small molecules which form colloids inhibit pathological peptide aggregation ( colloidal inhibition : b . y . feng , b . h . toyama , h . wille , d . w . colby , s . r . collins , b . c . h . may , s . b . prusiner , j . weissman , b . k . shoichet , nat . chem . biol . 2008 , 4 , 2 - 3 ). aminopyrazoles are rationally designed β - sheet ligands with a specific dad - sequence of hydrogen bond donors and acceptors , complementary to that of a β - sheet ( t . schrader , c . kirsten , j . chem . soc ., chem . commun . 1996 , 2089 ; t . schrader , c . n . kirsten , j . am . chem . soc . 1997 , 119 , 12061 - 12068 ). derivatives were synthesized and also evaluated on the solid phase ( a ) p . rzepecki , m . wehner , o . molt , r . zadmard , t . schrader , synthesis 2003 , 1815 - 1826 ; b ) kate { hacek over ( r )} ina { hacek over ( c )} ernovskà , miriam kemter , hans - christoph gallmeier , petra rzepecki , thomas schrader and burkhard könig , org . biomol . chem . 2004 , 2 , 1603 - 1611 ; c ) p . rzepecki , h . gallmeier , n . geib , katarina cernovska , b . könig , t . schrader , j . org . chem . 2004 , 69 , 5168 - 5178 ; d ) p . rzepecki , n . geib , m . peifer , f . biesemeier , t . schrader , j . org . chem . 2007 , 72 , 3614 - 3624 ). direct interaction of dimeric and trimeric aminopyrazole derivatives with the mouse prion protein as well as with aβ ( 1 - 42 ) was shown and characterized by sds - page , fcs , auc , density gradient centrifugation as well as hrms . β - sheet recognition as well as the individual strength of all hydrogen bonds involved were studied in great detail by r2pi spectroscopy on a cooled argon jet stream ( a ) p . rzepecki , l . nagel - steger , s . feuerstein , u . linne , o . molt , r . zadmard , k . aschermann , m . wehner , t . schrader , d . riesner , j . biol . chem . 2004 , 279 , 47479 - 47505 ; b ) h . fricke , a . funk , t . schrader , m . gerhards , j . am chem . soc . 2008 , 130 , 4692 - 4698 ; c ) h . fricke , a . gerlach , c . unterberg , m . wehner , t . schrader , m . gerhards , angew . chem . 2009 , 48 , 900 - 904 ). in a misfolded extended peptide strand , amino acid sidechains protrude horizontally ( orthogonal to ) from the vertical peptidic backbone β - sheet ; complexed β - sheet ligands will therefore automatically place their recognition sites close to the typical functional groups found in proteinogenic amino acid residues . it was therefore attempted to match the main classes of amino acids with complementary recognition sites on the complexing aminopyrazole trimers , and to vary sizes and distances from their attachment point . scheme 1 shows an overview about all synthesized derivatives and their classification : 1 . lysine and arginine binders contain carboxylate anions , at varying distances from the heterocyclic core . 2 . aspartate and glutamate binders were introduced as ammonium cations , placed remote and close to the aminopyrazoles ; the pentavalent derivatives are probes for a potential complexation of the glutamate - 22 ladder found in the all solid state nmr structures . 3 . polar residues with xh - groups such as serine and tyrosine are able to form multiple hydrogen bonds with ethyleneglycol moieties ; the teg ( triethyleneglycol ) unit also serves as a water - soluble linker for remote recognition events . 4 . unpolar residues are matched by flexible branched hydrocarbons as found in cyclohexylglycine , already introduced by the stott group ( n . kokkoni , k . stott , h . amijee , j . m . mason , a . j . doig , biochemistry 2006 , 45 , 9906 - 9918 ). 5 . characteristic peptide fragments within the aβ molecule known for efficient self - recognition were finally introduced as peptidic address labels . the trimeric aminopyrazole core structure was elongated with a variety of additional binding sites . to this end , its c - terminal carboxylic acid was connected to the respective amines by way of a peptide bond . conventional coupling reagents comprised edc / hobt , hctu / cl — hobt and mukaiyama &# 39 ; s reagent , which produced the hybrid compounds in high yields . in an economic fashion , all protecting groups of the tether were finally cleaved by tfa together with all pmb - moieties on the aminopyrazole nuclei . peptidic tethers were first synthesized by manual solid phase peptide synthesis ( spps ) on a wang resin , followed by covalent attachment at the aminopyrazole trimer ( hbtu , diea ). final deblocking of all acid - labile protecting groups at 70 ° c . for ˜ 3 hrs furnished , after precipitation and recrystallization from ether , analytically pure final products 3a - z . all these new trimeric aminopyrazoles are soluble in dmso , the most polar even in water . they are listed in table 1 , together with absolute yields and their solubilities . fig1 a and 1b display lewis structures of unprotected aminopyrazole trimer derivatives with appendices z . left : small neutral , anionic and cationic moieties , as well as unpolar and teg - spacered groups . right : peptidic attachments . fig1 c shows a synthetic access to the new c - terminally modified aminopyrazole trimers via peptide coupling of various amines onto the pmb - protected trimer and final total deprotection . the influence of the new β - sheet ligands , based on the aminopyrazole - trimer , on the aβ self - assembly process was first studied kinetically . reference curves were obtained independently for both aβ ( 1 - 40 ) and aβ ( 1 - 42 ). in a typical experiment , one third ( ⅓ ) equivalent of thioflavine t was added to a solution of monomeric aβ in pbs buffer , prepared in hfip . the increase in tht fluorescence was monitored over time , as a measure of the total amount of accumulating aggregates . as expected aβ ( 1 - 42 ) commenced immediately after dilution with fibril formation , as opposed to aβ ( 1 - 40 ), which showed the well - known lag phase of ˜ 24 hrs . both peptides reached a plateau after ˜ 3 days , which was set as standard time period for all consecutive aggregation assays . care was taken to eliminate fluorescence changes induced by any other events than the aggregation process ; thus each ligand was separately shown to be non - fluorescent and not to alter tht fluorescence in mixtures . controls with pure aβ were identical in peptide concentration as well as buffer and solvent composition . aβ ( 1 - 40 ): representative kinetic curves are shown in fig2 . interestingly , no ligand changes the 24 h lag phase , but instead proceeds with distinctly different velocity before it reaches the aggregation maximum , the trimer prototype being the slowest . aβ ( 1 - 42 ): much more impressive is the inhibitory influence of the trimeric ligands on the aggregation kinetics of the full - length aβ ( 1 - 42 ). the trimer itself is outperformed in its aggregation decelerating effect by the corresponding derivative with a distant lysine , whereas the related compound with a proximal lysine goes to the other extreme and greatly expedites the aβ aggregation process . obviously , the location of a single lysine residue on the aminopyrazole ligand has a profound effect on complex formation with and subsequent misfolding of the alzheimer &# 39 ; s peptide . fig2 a and 2b show the kinetics of aβ aggregation in pbs buffer ( ph 7 . 3 ) in the absence and presence of selected trimeric pyrazole inhibitors ; fig2 a : aβ ( 1 - 40 ), fig2 b : aβ ( 1 - 42 ). applicant discovered that the parent trimeric aminopyrazole does not only bind to growing aβ ensembles , but also strongly interacts with preformed aβ fibrils , and leads to their disassembly . the kinetics of this interesting process reveal a two - phase event , with a rapid disaggregation during the first few minutes , and a slow dissolution within the next 5 days , until the overall equilibrium is reached ( fig3 ). in combination with sedimentation analyses , applicant proposes that the first disaggregation phase involves release of protofibrils from mature fibrils , whereas the second slower disassembly may be characterized by further conformational changes with loss of the well - ordered β - sheets . fig3 discloses the kinetics of aβ disaggregation effected by addition of a 6 - fold excess of trimeric aminopyrazole inhibitors to preformed fibrillar aggregates ( 33 μm in pbs ). after 72 h , the aggregation process has reached a maximum in the absence or presence of any trimeric ligand , even for the slow aβ ( 1 - 40 ) peptide . the respective equilibrium concentration is then indicated by the relative fluorescence intensity reached at the end point . the full series of new aminopyrazole trimer derivatives was subjected to tht inhibition experiments and the final equilibrium was analyzed by comparison of the respective fluorescence intensities of intercalated dye at 482 nm ( exc . at 442 nm ). fig4 reveals a significant structure - activity relation for aβ ( 1 - 42 ): structurally related compounds in general display comparable inhibition properties . two classes of the modified derivatives surpass the original trimer activity : trimer - che / trimer - lys - che / trimer - lpffd with attached extended lipophilic groups and trimer - teg - lys / trimer - kkkkg with a distant or multiple lysine residues . their proposed mechanism of action is discussed within the next chapters together with all the other biophysical , biochemical as well as modeling data . starting from preformed fibrils , the disassembly process was also monitored with the full series of modified trimeric aminopyrazoles . surprisingly , the inhibition pattern ( left ) looks quite similar to the disaggregation pattern ( right ), in several cases , that total percentage of tht rest fluorescence is identical . in other words , little difference is observed between the end points of aggregation assays , in which the ligand inhibits de novo aggregation starting from monomeric aβ molecules , and those experiments , which require disaggregation of preformed fibrils by externally added ligand . experimental evidence is thus provided for the fact , that aminopyrazole ligands operate in a fully reversible fashion , and reach an open equilibrium when the thermodynamically most favorable complex is formed . fig4 a and 4b show the equilibrium of 33 μm aβ42 aggregation ( fig4 a ) vs . disaggregation ( fig4 b ) in the absence or presence of trimeric aminopyrazole inhibitors ( each at 198 μm ); fig4 a shows the inhibition of aggregation and fig4 b the disaggregation ( 10 mm pbs , ph 7 . 3 ). for each bar , 6 measurements were averaged . in the past , detailed conformational nmr analyses between aminopyrazole ligands and the model peptide klvff , a putative nucleation site in aβ , furnished strong hints for direct hydrogen bonds between ligand and peptidic backbone ( p . rzepecki , t . schrader , j . am . chem . soc . 2005 , 127 , 3016 - 3025 ). in addition , upfield shifts of aromatic protons in both phenylalanines indicated π - stacking interactions . energy - minimizations and subsequent monte - carlo simulations in water converged on a complex structure with two consecutive phenylalanines sandwiching an aminopyrazole nucleus , which effectively shielded it from the aqueous solvent . recent md simulations between the trimeric aminopyrazole and an aβ monomer residing in its folded fibril conformation ( solid state structure ) demonstrated the klvff sequence to be superior over all other complexation sites . it was therefore attempted to correlate altered complexation behavior and influence on aggregation of the above - mentioned new series of modified aminopyrazole trimers with specific additional noncovalent interactions predicted from docking experiments of these β - sheet ligands onto the aβ fibril . since klvff ( residues 16 - 20 ) represents the starting point of the well ordered part of the aβ sequence , covalently attached c - terminal appendices of the aminopyrazole trimer will be able to exploit the maximum contact area of the fibril &# 39 ; s top face . cd measurements of all water - soluble trimeric ligands in 1 : 1 - mixtures with aβ ( 1 - 42 ) reveal that in most cases , a new cd band evolves at 260 - 320 nm with a positive maximum at 280 nm , typical for complexes of aromatic moieties ( phe : 260 - 270 nm ; tyr 270 - 280 nm ; trp : 290 - 300 nm ). since at this wavelength aminopyrazole ligands are cd - silent , applicant attributes the new band to tight complex formation between aromatic units in aβ and ligand , most likely between the two consecutive phenylalanines and the pyrazole nuclei . this structural motif offers a unique opportunity for docking experiments , which were hence performed on the hydrogen - bonded complex between aggregated aβ ( lührs structure ) and ligand . both were involved in backbone recognition , starting from the phe - phe pair which locks the first aminopyrazole in a sandwich arrangement . intriguingly , several additional favorable interactions were found , which were typical for each major class of trimer tethers . they will be discussed along with all biophysical experiments conducted for each group of trimers . in force - field calculations , the trimer itself forms the characteristic dad pattern of multiple hydrogen bonds towards the solvent - exposed top face of the klvff backbone and simultaneously stacks its pyrazole nuclei with both phenylalanine units in form of a hydrophobic cleft ( trimer - ome , trimer - oh , fig5 ). fig5 displays amd simulation of the complex between aβ and the parent aminopyrazole trimer ( 10 ns ). the trimeric aminopyrazole skeleton is able to reduce the total amount of aβ aggregates ( 30 μm ) to ˜ 40 % at a 6 - fold excess , but to & lt ; 20 % at a 10 : 1 ratio ( inhibition 17 %, disaggregation : 25 %). this corresponds to an estimated dissociation constant of the complex in the low micromolar range ( 2 μm k d in pbs buffer ). interaction of the new trimeric lead structure and monomeric as well as polymeric aβ was further studied with fluorescence correlation spectroscopy ( fcs ), sedimentation analysis ( sa , based on analytical ultracentrifugation ) and transmission electron microscopy ( tem ). in a standard fcs experiment a 5 nm oregon - green - labeled aβ solution was prepared in pbs buffer with ˜ 3 % dmso . trimer - ome was added at 100 nm and reduced the peaks x height value to ˜ 25 % of the control . since the number of peaks remained unchanged , their molecular weight was greatly reduced . independent confirmation came from sedimentation analyses with oregon - green - labeled aβ : coefficients for pure aβ were above 50 s , whereas those for its complex with trimer - oh continuously decreased in a dose - dependant manner down to 25 s , corresponding to a 50 % molecular weight reduction ( fig6 ). it should be noted , that trimer - oh itself also tends to self - associate ; its sharp radial distribution suggests formation of micelles of ˜ 10 s size . this is not surprising , because it comprises a flat arrangement of unpolar aromatics adorned with polar groups for extensive hydrogen bonding . finally , tem pictures were obtained from mature aβ fibrils (& gt ; 600 nm ) as well as globular particles ( 3 - 30 nm ) grown in the absence of aminopyrazole ligands . while the diameter of the twisted ribbons from pure aβ corresponds to 10 nm , thin filaments were produced in the presence of the trimeric ligand ( 5 nm ), and the number of mature fibrils was greatly reduced ( fig7 ). applicant concludes that the trimer seems to break the mature fibrils into protofilaments by a combination of backbone recognition and hydrophobic interactions . in a preliminary cell culture assay with pc - 12 cells , inhibition of aβ ( 1 - 42 )- induced toxicity was very moderate (& lt ; 10 % viability increase , fig1 ). since trimer - oh / ome contain only the trimeric aminopyrazole core unit , their interaction profile sets the standard for all other modified derivatives of this investigation . fig6 a to 6f show the results of sedimentation velocity centrifugation : s - value - distributions of aβ samples in the presence of trimer - oh ( fig6 a , fig6 b , fig6 c ) vs . trim - teg - oet ( fig6 d , fig6 e , fig6 f ). fig6 a , fig6 d : van - holde - weischet distribution plots , g ( s ), for aggregation mixtures of aβ ( 1 - 42 )/ aβ42 - og ( 17 . 5 nm / 3 . 5 μm ) in 10 mm nap i , ph 7 . 4 , 4 % dmso with 0 μm ( control , circles ), 66 μm ( triangles ), 133 μm ( squares ), and 200 μm trimer derivative ( diamonds ). samples were incubated slightly agitated at rt for 5 d prior centrifugation at 20 , 000 rpm , 20 ° c . fig6 b , fig6 e : s - value distributions of the control experiments as determined by 2d - sa and monte carlo analysis . fig6 c , fig6 f : s - value distributions of experiments with 200 μm trimer derivative after 5 d of incubation as determined by 2d - sa and monte carlo analysis . small charged extensions at the trimer &# 39 ; s c - terminus are too short for specific interactions with other amino acid residues in the neighborhood / vicinity and hardly change the trimer &# 39 ; s effect ( trimer - ethylenediamine , trimer - gaba - oh , trimer - gaba - ome ). the strong solvation of the tethered ionic group close to the aminopyrazole &# 39 ; s hydrogen bonding unit may even hinder its approach to the aβ peptide backbone . consequently , all tht values for inhibition as well as disaggregation lie above the trimer standard . ( both gaba derivatives , however , produce a significant viability increase of up to 30 % in the lesion assay ; it may be related to the biological response of gaba receptors .) fig7 shows tem pictures . a : aβ ( 1 - 42 ) fibrils . b - f : aβ ( 1 - 42 ) mixtures ( 20 μm ) with aminopyrazole trimer derivatives ( 100 μm ). b : trim - ome ; c : trim - oh , d : trim - che ; e : trim - lys - ome ; f : trim - teg - lys - ome ; g : trim - teg - oet ; h : trim - teg - oh . by contrast , extended or cyclic unpolar groups align with nonpolar side chains and undergo hydrophobic as well as dispersive interactions ( trimer - chg - che , trimer lys - che , trimer - teg - che , trimer - teg - dd ). likewise nonpolar peptide fragments derived from aβ itself and attached to the trimer , may display their well - known self - complementarity and recognize their counterparts in the fibril ( trimer - lpffd , trimer - klvff ). this is especially pronounced if the unpolar appendix is placed at a distance of more than one amino acid from the trimer - c - terminus , pushing the tht rest fluorescence to values below 30 %. according to a conformational search , unpolar binding sites on the ligand prefer the cluster of hydrophobic residues from ile - 31 to ile - 36 . a teg spacer in trim - teg - dd allows the attached dodecyl tail to explore the entire met - 35 ladder during md simulations for extended van - der waals interactions on the back of the pentameric lührs fibril . cd spectra of trim - lys - che , trim - klvff and trim - teg - dd all feature / display an almost doubled β - sheet band intensity and the total loss of the aromatic signal at 280 nm . a straightforward interpretation suggests a remarkable stabilization of the cross - β - sheet with concomitant withdrawal of the aminopyrazole from its phe - phe cleft , resulting in a tight nonpolar lid covering the solvent - exposed unpolar aggregate face ( fig8 ). the related trim - che , which forms thin filaments by itself , displays a remarkable fibril morphology in its complex with aβ ( 1 - 42 ): very thick screwed fibrils ( up to 70 nm ) are produced , with a length of at least 600 nm . it thus seems , that fibrillogenesis is not prevented but rather shifted to a much more compact form , which does not accommodate well - ordered fluorescent tht molecules . remarkably , three of the eight best candidates in the cell lesion assays contain extended unpolar appendices , either as lpffd or cyclohexylglycine peptide fragments . fig8 displays md simulations ( 5 ns ) of the complex between aβ and an aminopyrazole trimer with attached nonpolar binding site ; left trim - chg - che ; center trim - lys - che ; right trim - teg - dodecyl . a single c - terminal lysine on the trimer seems to be an exception . after aminopyrazole docking to the klvff site , lysine &# 39 ; s ε - ammonium ion remains freely solvated during an entire 10 ns md simulation run ( fig9 left ). in this state it could easily form a saltbridge to glu - 22 / asp - 23 of an opposing strand , which would according to tycko support the connection two u strands via their polar interfaces to a fibril ( trimer - lys - ome ). contrary to almost all other trimer derivatives , this aminopyrazole accelerates aβ aggregation ( cf . kinetics ). the corresponding cd spectrum is also exceptional , because it exhibits the typical additional cotton effect at the wavelength of aromatic amino acids , but retains the β - sheet . applicant concludes that docking of the aminopyrazole onto the phe - phe motif leads to formation of an intra - or intermolecular salt bridge , which brings two protofibrils in close proximity the exceptionally high aggregation propensity is also well documented in sedimentations , featuring the total loss of amyloid β - peptide during rotor acceleration . tem pictures of mixtures with aβ show very thin fibrils ( 5 - 10 nm ) of 800 nm length , whereas this soluble aminopyrazole does not aggregate by itself . in sharp contrast to trim - lys , a single lysine separated from the trimeric aminopyrazole core unit by the teg spacer , leads to the most efficient suppression of aβ fibril formation of all tested derivatives ( 20 % tht fluorescence ). this structurally closely related pair of aminopyrazole trimers is a striking example for the fact , how strongly the exact placement of binding sites influences the degree and path of aβ aggregation . modeling studies reveal a preference for internal ion pair formation with glu - 22 , confirmed by extended md simulations ( fig9 right ). ultracentrifugation and tem experiments indicate a moderate tendency of the pure compounds to self - assemble into thin filaments , whereas the aggregation process of aβ is redirected to unstructured material and thin bent filaments — completely different from aβ fibrils ( tem pictures ). in the cell culture experiments , trim - teg - lys provides the most efficient rescue of pc - 12 cells from aβ toxicity (& gt ; 40 %). fig9 displays md simulations of the complexes between aβ and trimer - lys vs . trim - teg - lys . the polar triethyleneglycol spacer smoothly intercalates between both peptide strands of the top u and similarly undergoes weak dispersive interactions with amino acids in the vicinity of the β - turn ( trimer - teg - oet , trimer - teg - oh ). in extended md simulations , the neutral methyl ester ( replaced by the related methyl amide ) could be observed to intrude into the water - filled canal formed by the stacked β - turns in the solid state structure ( fig1 a ). it serves as a linker to remote additional binding sites such as lipophilic or charged peptide fragments . for a better understanding of its influence on the pathologic aβ self - assembly process , it was independently examined . compared to the pure trimer prototype , the teg - elongated aminopyrazole trimer ( which is unremarkable / inconspicuous in tht experiments ), does not significantly change the medium aggregate size of aggregated aβ , but instead produces a moderate amount of very small oligomers ( monomers - pentamers ), as evidenced by sedimentation analysis ( fig6 a - 6f ). for the trimer standard as well as for both teg - extensions sedimentation assays prove direct complex formation between the natural and the artificial peptide molecules . at nanomolar aβ concentrations ( as in the human brain ) fcs even witnesses the uniform transition to very small oligomers within all aβ aggregates ( fig1 b ). no filaments are formed from pure trim - teg - oh or — ome solutions ; in the presence of aβ , very thin , delicate structures evolve , which show no helical twist . pc - 12 cell protection is only very modest , comparable to the trimer standard . thus , the teg spacer could serve a dual purpose : it brings recognition units close to the u - turn auf the fibril and simultaneously protrudes itself into the interior of the two parallel aβ strands , facilitating further destabilization of the fibrillar structure . fig1 a shows a md simulation of the complex between aβ and trimer - teg - oet ; fig1 b shows fcs ( fluorescence correlation spectroscopy ) measurements at 5 nm aβ with trimer - oh in comparison to trim - teg - oh / oet ( each at 10 μm ). remarkably , multiple lysines attached directly or by way of the teg spacer to the aminopyrazole trimer , in principle allow the formation of multiple chelate complexes with the glu - ladder beneath the fibril in molecular mechanics calculations ( trimer - kkkkkg , trimer - teg - kkkkkg ). the modeling picture displays beautiful mutual chelate structures between the multiple glutamate carboxylates and bridging lysine ammonium functionalities . this complexation mode may lead to a significant destabilization of the u - turn structure and eventually dissolve the β - sheet . together with trimer - teg - lys the above - mentioned are indeed the most potent of all synthesized aminopyrazole derivatives and deplete the tht fluorescence level down to 20 % in inhibition and disaggregation experiments ( fig4 ). the corresponding cd spectrum features the additional cd band at ˜ 280 nm , typical for aromatic amino acids ; however , in this case , the β - sheet band almost completely disappears with time , indicating dissolution of the secondary peptide structure ( fig1 a to 11c ). fig1 a to 11c show typical cd spectra recorded for aggregated aβ ( 1 - 42 ) alone ( curve 5 in fig1 a - 11c ) and after addition of aminopyrazole ligand ( type a : trimer - lys : fig1 a ; type b : trimer - kkkkkg : fig1 b ; type c : trimer - lys - che : fig1 c ). time progresses in the direction of the embedded arrows , indicated by lighter colors ( 0 h , 1 h , 1 d , 2 d ). test solutions contained 10 μm aβ ( 1 - 42 ), 5 μm potassium phosphate buffer ( ph = 7 . 3 ), 2 % hfip and 10 μm of the respective aminopyrazole trimer derivative . subsequent md simulations , however , resulted in successive detachment of the pentalysine tail from the glutamate ladder , until finally all alkylammonium groups pointed into the free solvent and towards the opposite side of the peptide strand . such an arrangement may also result in far - reaching conformational effects , indicated already be widening of the upper u - turn ; these are now proposed to destroy the existing β - sheet ( fig1 ). the high positive charge of all five lysine residues requires the use of pbs with its high ionic strength for sedimentation experiments . here the positively charged aminopyrazoles alone displayed a considerable self - association , reaching s - values of up to 40 in the absence of a teg spacer . admittedly , their structures are somewhat reminiscent of the amphiphilic hybrid peptides ( e . g ., klvff - eeeee ) presented in the nineties for aggregation prevention by surface tension increase . in fact , a similar mechanism could also be functioning in the case of applicant &# 39 ; s amphiphilic aminopyrazole - pentalysines . fig1 displays a md simulation of the complex between aβ and trimer - kkkkg . initially , all compounds were screened for any toxic effect they might have by adding each compound at 100 μm and measuring the effect on cell viability using the 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ( mtt ) reduction assay ( datki , z . ; juhasz , a . ; galli , m . ; soos , k . ; papp , r . ; zadori , d . ; penke , b . brain res . bull . 2003 , 62 , 223 - 229 ) in differentiated rat pheochromocytoma ( pc - 12 ) cells ( shearman , m . s . methods enzymol . 1999 , 309 , 716 - 723 ). encouragingly , none of the compounds was toxic to the cells at this concentration . next , to examine whether the aminopyrazole trimers could protect cell from aβ42 - induced neurotoxicity , cells were treated for 24 h with 10 μm aβ ( 1 - 42 ), a concentration that produces 30 to 40 % decrease in cell viability , in the absence or presence of 100 μm of each compound . the viability of the cells then was assessed using the mtt assay . in both series ( with and without teg spacers ) several candidates were found to rescue cell viability significantly . intriguingly , the most efficient inhibition of aβ toxicity was achieved with 3 lipophilic extensions and trimer - teg - lys - ome , which were also superior in tht and related assays . the two gaba derivatives are a surprise — they might potentially interact with gaba receptors and not with the aβ peptide itself . the above - delineated findings demonstrate that trimeric aminopyrazoles are indeed active against aβ - induced toxicity in living cells ; they also provide experimental evidence for their low toxicity at relatively high doses of 0 . 1 mm , in spite of , e . g ., the presence of an n - terminal nitro group . fig1 a and 13b display viability assays of pc - 12 cells with trimeric aminopyrazoles ( 100 μm ). fig1 a shows aβ lesion control at ˜ 70 %, fig1 b at ˜ 80 % viability . based on this initial screen , applicant evaluated the ic 50 value of compounds that increased the viability of pc - 12 cells to ≧ 90 %. the data are summarized in table 3 . to determine the ic 50 value of each of the compounds , dose - dependence mtt experiments were conducted with the aminopyrazole trimers , at a fixed aβ42 concentration of 10 mm and increasing concentrations of β - sheet ligand ( 0 . 3 , 1 , 3 , 10 , 30 and 100 μm ). ic 50 in this respect is defined as the concentration of the β - sheet ligand ( aminopyrazole trimer derivative ), at which the inhibition of aβ toxicity just reaches 50 % ( fig1 ). fig1 shows a dose - response curve for the inhibition of aβ - induced toxicity in pc - 12 cells by trimer - lpffd ( ic 50 = 3 . 1 mm ). table 3 shows the ic 50 values of the most potent inhibitors of aβ - induced toxicity . with respect to ic 50 values , the two non - polar lpffd - derivatives were found to be the most effective . since the aβ42 concentration was always kept constant at 10 μm , it should be emphasized , that substoichiometric ic 50 values such as that of trim - lpffd - oh indicate very high affinity towards the target peptide , even if a 1 : 1 complex is assumed . it should be kept in mind that , in the brain , aβ concentrations are in the low nanomolar range , similar to the situation in enzyme assays . only in such a scenario , ic 50 values can be expected to drop to nanomolar concentrations . applicant &# 39 ; s investigation provided experimental evidence for the fact that small structural changes in β - sheet ligands have a profound influence on the aggregation behavior of misfolding proteins . moreover , a common anchor point has been identified for the inventive aminopyrazole trimer derivatives , allowing to perform docking experiments and subsequent md simulations . intriguingly , various different types of suitably arranged binding sites correlate well with various kinds of modulated aβaggregation behavior . cd measurements , on the one hand , as well as tht aggregation assays , on the other hand , display pronounced continuous changes within more than two hours , which may involve conformational changes which are not yet visible even during extended modeling experiments . a structure activity relation can therefore be suggested , evolving from a synopsis of different biophysical and biochemical and “ in silico ”- experiments . two major binding motifs could thus be discovered , which greatly improve the β - sheet breaker ability of the aminopyrazole trimer : remote lipophilic moieties for dispersive interactions with the unpolar cluster of amino acids between ile - 31 to ile - 36 , and distant cationic peptide fragments which destabilize aβ &# 39 ; s u - turn . only the latter , however , effectively destroys the cross - β - sheet . applicant has confirmed these structure motifs postulated from modeling and aggregation experiments . direct evidence has been gained from cocrystals of these complexes as well as from 2d solid state nmr experiments . the n -( p - methoxybenzyl )- pyrazolecarboxylic acid methyl ester derivative was dissolved in a mixture of meoh ( 50 ml ) and thf ( 50 ml ). then , aq . lithium hydroxide ( 2 . 50 equiv . in 10 ml ) was added to the solution and the mixture was stirred at room temperature until the starting material disappeared on the tlc plate . the solvent was removed under reduced pressure . the residue was dissolved in water and acidified with aq 1 m hcl . the precipitate was filtered , washed with aq 1 m hcl and dried in vacuo . general procedure b ( trimer - oh coupling to c - terminal amine extension with mukaiyama &# 39 ; s reagent ) in an argon atmosphere , the n - terminal and pmb - protected pyrazole carboxylic acid compound ( 1 . 10 equiv ) was suspended in dcm . to this suspension diisopropylethylamine ( 3 . 50 equiv ) and 2 - chloro - 1 - methylpyridinium iodide ( mukaiyama &# 39 ; s reagent , 1 . 50 equiv ) were added . then the c - terminally and / or side chain - protected amino acid ( 1 . 00 equiv ) or another coupling partner ( 1 . 00 equiv ) was added to the reaction mixture . if the c - terminal protected compound was applied as an ammonium salt , another equivalent of diisopropylethylamine ( 1 . 00 equiv ) was added before for neutralization . the resulting mixture was stirred overnight at room temperature . subsequently , the organic layer was washed twice with aq 1 m hcl , sat . aq nahco 3 and sat . aq nacl . after drying over mgso 4 , the solvent was evaporated in vacuo . the crude product was purified by chromatography on silica gel ( the eluent is described for each compound in the following detailed procedures ). general procedure c ( trimer - oh coupling to c - terminal amine extension with hctu ) under an inert atmosphere , the n - terminal and pmb - protected pyrazole carboxylic acid compound ( 1 . 10 equiv ) was dissolved in dcm / dmf ( 3 : 1 ). cl — hobt ( 2 . 50 equiv ), hctu ( 1 . 10 equiv ) and 2 , 6 - lutidine ( 3 . 00 equiv ) were added and stirred for 10 min at 0 ° c . the c - terminally and / or side chain - protected amino acid ( 1 . 00 equiv ) or another coupling partner ( 1 . 00 equiv ) was dissolved in dcm / dmf ( 3 : 1 ) and added to the reaction mixture . if the c - terminal protected compound was applied as an ammonium salt , 2 , 6 - lutidine ( 1 . 00 equiv ) was added to this solution before for neutralization . the reaction mixture was stirred overnight at room temperature . the mixture was extracted twice with aq 1 m hcl , sat . aq nahco 3 and sat . aq nacl and dried over mgso 4 . after filtration , the solvent was evaporated until it was dry and the residue was purified by chromatography on a silica column . general procedure d ( trimer - oh coupling to c - terminal amine extension with edc ) in an argon atmosphere , the n - terminal and pmb - protected pyrazole carboxylic acid compound ( 1 . 00 equiv ) was suspended in dcm and cooled to 0 ° c . to this suspension hobt ( 3 . 00 equiv ) and after ten minutes edc - hcl ( 3 . 00 equiv ) were added . the reaction mixture was stirred for another ten minutes and then , the c - terminally protected amine coupling partner was added to the suspension . the mixture was gradually warmed to room temperature and stirred for two more days . then , the organic layer was washed twice with 1m aq . hcl , sat . aq nahco 3 and sat . aq nacl and dried over mgso 4 . the solvent was evaporated in vacuo and the crude product was purified by chromatography on silica . in an argon atmosphere the pmb - protected pyrazole compound was heated in anhydrous tfa ( 2 . 50 ml / 50 μmol ) to 70 ° c . for 5 h . subsequently , the solution was cooled to 0 ° c . and treated with ice - cold diethyl ether . the precipitating solid was centrifuged off and washed five times with diethyl ether . afterwards , the residue was dissolved in dcm and the solvent was removed quickly in vacuo . this procedure was repeated five times and the product was dried in vacuo . to a solution of the respective nitro precursor ( 273 mg , 364 μmol ) in thf ( 15 ml ) was added methanol ( 5 ml ) and pd / c ( 10 mol %). the flask was evacuated and filled with h 2 ( general procedure a ). the reaction mixture was stirred for 16 h and the catalyst was removed by filtration over celite . the solution was concentrated in vacuo and the product was crystallized over night at 8 ° c . yield : 215 mg ( 299 μmol , 82 %); colorless solid . 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 3 . 70 - 3 . 72 ( 3s , 9h , ch 3 - pmb ), 3 . 85 ( s , 3h , ooch 3 ), 4 . 85 ( s , 2h , nh 2 ), 5 . 44 ( s , 2h , ch 2 - pmb ), 5 . 58 ( s , 2h , ch 2 - pmb ), 5 . 63 ( s , 2h , ch 2 - pmb ), 6 . 36 ( s , 1h , ch - pyrazole ), 6 . 83 - 6 . 90 ( m , 6h , ch - arom . ), 7 . 11 - 7 . 22 ( m , 7h , ch - arom ., ch - pyrazole ), 7 . 65 ( s , 1h , ch - pyrazole ), 10 . 90 ( s , 1h , nh - amide ), 11 . 40 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 52 . 1 , 52 . 2 , 53 . 0 , 53 . 2 , 54 . 9 , 55 . 0 , 94 . 8 , 101 . 0 , 102 . 9 , 113 . 5 , 113 . 7 , 113 . 8 , 128 . 5 , 128 . 7 , 129 . 0 , 129 . 6 , 130 . 6 , 131 . 1 , 133 . 8 , 134 . 0 , 145 . 4 , 154 . 1 , 157 . 4 , 158 . 3 , 158 . 6 , 158 . 7 , 159 . 3 . mp . : 182 . 3 - 183 . 1 ° c . r f : 0 . 07 n - pentane / ethyl acetate ( 1 : 1 ). hrms ( esi ): calcd for c 37 h 37 n 9 o 7 h : 720 . 2889 . found : 720 . 2901 ; calcd for c 37 h 37 n 9 o 7 na : 742 . 2708 . found : 742 . 2727 . a portion of 61 mg ( 85 μmol , 1 . 00 equiv ) of pmb - protected aminopyrazole trimer synthesized above was treated with hot tfa according to general procedure e to yield the aminotrimer - ome as a colorless solid . yield : 24 mg ( 51 μmol , 60 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 3 . 85 ( s , 3h , ooch 3 ), 7 . 11 ( s , 1h , ch - pyrazole ), 7 . 55 ( brs , 2h ), 11 . 20 ( brs , 1h ), 11 . 25 ( brs , 1h ), 12 . 18 ( brs , 1h ), 13 . 45 ( brs , 1h , nh - pyrazole ), 13 . 67 ( brs , 1h , nh - pyrazole ), 13 . 76 ( brs , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 51 . 9 , 98 . 4 , 100 . 2 , 114 . 5 , 116 . 8 , 132 . 8 , 136 . 6 , 145 . 0 , 147 . 2 , 153 . 9 , 154 . 2 , 156 . 2 , 159 . 2 . mp : decomposition at 272 ° c . hrms ( esi ): calcd for c 13 h 13 n 9 o 4 h : 360 . 1163 . found : 360 . 1160 ; calcd for c 13 h 13 n 9 o 4 na : 382 . 0983 . found : 382 . 0988 . a 1 . 00 g ( 1 . 33 mmol , 1 . 00 equiv ) amount of 1 -( 4 - methoxybenzyl )- 3 -( 1 -( 4 - methoxybenzyl )- 3 -( 1 -( 4 - methoxybenzyl )- 3 - nitro - 1h - pyrazole - 5 - carboxamido )- 1h - pyrazole - 5 - carboxamido )- 1h - pyrazole - 5 - carboxylic acid methyl ester [ o 2 n - pz ( pmb )- pz ( pmb )- pz ( pmb )- ome ] and 81 mg of lithium hydroxide ( 3 . 38 mmol , 2 . 54 equiv ) were stirred in a mixture of methanol / thf / water ( 5 : 5 : 1 ) for 18 h . the crude product is prepared according to general procedure a to yield the compound as a colorless solid . yield : 0 . 92 g ( 1 . 25 mmol , 94 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 3 . 70 - 3 . 71 ( 3s , 9h , ch 3 - pmb ), 5 . 60 ( s , 2h , ch 2 - pmb ), 5 . 66 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 86 - 6 . 91 ( m , 6h , ch - arom . ), 7 . 14 - 7 . 20 ( m , 5h , ch - arom ., ch - pyrazole ), 7 . 25 - 7 . 30 ( m , 2h , ch - arom . ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 99 ( s , 1h , ch - pyrazole ), 11 . 39 ( brs , 1h , nh - amide ), 11 . 53 ( brs , 1h , nh - amide ). 13 c - nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 55 . 0 , 98 . 9 , 103 . 0 , 105 . 0 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 7 , 128 . 8 , 129 . 3 , 129 . 5 , 134 . 2 , 136 . 7 , 143 . 6 , 144 . 8 , 145 . 4 , 153 . 5 , 155 . 4 , 157 . 0 , 158 . 7 , 159 . 0 , 160 . 3 . mp : 258 . 1 - 260 . 2 ° c . hrms ( esi ): calcd for c 36 h 32 n 9 o 9 : 734 . 2328 ; found : 734 . 2323 . 51 mg of compound pmb - protected trimer precursor ( 69 μmol , 1 . 00 equiv ) was dissolved in 3 ml trifluoroacetic acid according to general procedure d to yield trimer - oh as a colorless solid . yield : 23 mg ( 64 μmol , 93 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 7 . 02 ( brs , 1h , ch - pyrazole ), 7 . 56 ( s , 1h , ch - pyrazole ), 7 . 94 ( s , 1h , ch - pyrazole ), 11 . 17 ( brs , 1h , nh - amide ), 11 . 42 ( s , 1h , nh - amide ), 13 . 51 ( brs , 2h , nh - pyrazole ), 14 . 97 ( s , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 98 . 1 , 98 . 3 , 99 . 9 , 102 . 2 , 138 . 6 , 155 . 0 , 155 . 8 , 156 . 6 , 160 . 4 . mp : decomposition at 313 . 4 ° c . hrms ( esi ): calcd for c 12 h 8 n 9 o 6 : 374 . 0592 ; found : 374 . 0611 . a portion of 200 mg ( 0 . 27 mmol , 1 . 10 eq ) of pmb - protected trimer - oh and 73 mg ( 0 . 24 μmol , 1 . 00 equiv ) of n - amino - n ε -( tert - butyloxycarbonyl )-( s )- lysine - carboxylic acid methyl ester hydrochloride were reacted with 95 mg ( 0 . 37 mmol , 1 . 50 equiv ) of mukaiyama &# 39 ; s reagent and 0 . 19 ml ( 1 . 11 mmol , 4 . 50 equiv ) of diisopropylethylamine according to general procedure b . the residue was purified by column chromatography on silica gel using n - pentane / ethyl acetate ( 2 : 1 ) to yield the coupling product as a colorless solid . yield : 153 mg ( 0 . 16 μmol , 63 %). 1 h nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 1 . 37 - 1 . 54 ( m , 13h , ch 2 - lys , ( ch 3 ) 3 ), 1 . 71 - 1 . 83 ( m , 1h , ch 2 - lys ), 1 . 88 - 1 . 99 ( m , 1h , ch 2 - lys ), 3 . 05 - 3 . 14 ( m , 2h , ch 2 - lys ), 3 . 75 - 3 . 76 ( 2s , 9h , ch 3 - pmb ), 3 . 80 ( s , 3h , ooch 3 ), 4 . 55 ( brs , 1h , nh - amide ), 4 . 67 - 4 . 75 ( m , 1h , α - ch - lys ), 5 . 54 ( d , 2h , 3 j = 4 . 3 hz , ch 2 - pmb ), 5 . 61 ( d , 1h , 3 j = 7 . 5 hz , ch 2 - pmb ), 5 . 75 ( d , 1h , 3 j = 7 . 5 hz , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 80 - 6 . 85 ( m , 7h , ch - arom ., nh - amide ), 7 . 10 ( s , 1h , ch - arom ., ch - pyrazole ), 7 . 20 - 7 . 26 ( m , 5h , ch - pyrazole ), 7 . 33 ( brs , 1h , ch - pyrazole ), 7 . 37 - 7 . 41 ( m , 2h , ch - arom . ), 8 . 40 ( brs , 1h , nh - amide ), 8 . 75 ( brs , 1h , nh - amide ). 13 c nmr ( 125 mhz , cdcl 3 ): δ [ ppm ]= 13 . 7 , 14 . 2 , 19 . 1 , 21 . 0 , 22 . 7 , 28 . 4 , 29 . 6 , 30 . 6 , 32 . 0 , 40 . 1 , 52 . 2 , 52 . 8 , 53 . 8 , 54 . 1 , 55 . 2 , 56 . 0 , 64 . 4 , 98 . 2 , 98 . 8 , 103 . 6 , 113 . 9 , 114 . 1 , 127 . 1 , 130 . 1 , 134 . 6 , 135 . 0 , 136 . 0 , 144 . 7 , 154 . 1 , 156 . 1 , 159 . 2 , 159 . 3 , 159 . 4 , 159 . 8 , 172 . 8 . mp : 94 . 4 ° c . r f : 0 . 10 n - pentane / ethyl acetate ( 2 : 1 ). hrms ( esi ): calcd for c 48 h 55 n 11 o 12 h : 978 . 4104 . found : 978 . 4144 ; calcd for c 48 h 55 n 11 o 12 na : 1000 . 3924 . found : 1000 . 3942 . a portion of 50 mg ( 51 μmol , 1 . 00 equiv ) of the pmb - protected trimer - lys - ome was treated with hot tfa according to general procedure e to yield the free trimer - lys - ome as a colorless solid . yield : 37 mg ( 49 μmol , 96 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 38 - 1 . 42 ( m , 2h , ch 2 - lys ), 1 . 53 - 1 . 59 ( m , 2h , ch 2 - lys ), 1 . 81 - 1 . 84 ( m , 2h , ch 2 - lys ), 2 . 78 - 2 . 82 ( m , 2h , ch 2 - lys ), 3 . 67 ( s , 3h , ooch 3 ), 4 . 42 - 4 . 45 ( m , 1h , α - ch - lys ), 7 . 41 ( s , 1h , ch - pyrazole ), 7 . 61 ( s , 1h , ch - pyrazole ), 7 . 65 ( bs , 3h , h - 8 ), 7 . 95 ( s , 1h , ch - pyrazole ), 8 . 89 ( d , 3 j = 6 . 9 hz , 1h , nh - amide ), 11 . 16 ( s , 1h , nh - amide ), 11 . 42 ( s , 1h , nh - amide ), 13 . 28 ( s , 1h , nh - pyrazole ), 13 . 45 ( s , 1h , nh - pyrazole ), 14 . 97 ( s , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): β [ ppm ]= 22 . 3 , 26 . 3 , 29 . 6 , 51 . 8 , 97 . 5 , 98 . 1 , 102 . 0 , 102 . 5 , 154 . 8 , 172 . 2 . mp : decomposition at 198 ° c . hrms ( esi ): calcd for c 19 h 23 n 11 o 2 h : 518 . 1855 . found : 518 . 1860 . a 143 mg ( 146 μmol , 1 . 00 equiv ) amount of 2 -( 1 -( 4 - methoxybenzyl )- 3 -( 1 -( 4 - methoxybenzyl )- 3 -( 1 -( 4 - methoxybenzyl )- 3 - nitro - 1h - pyrazole - 5 - carboxamido )- 1h - pyrazole - 5 - carboxamido )- 1h - pyrazole - 5 - carboxamido - 6 -( tert - butoxycarbonyl )- lysine methyl ester and 9 mg lithium hydroxide ( 376 μmol , 2 . 57 equiv ) were stirred in a mixture of methanol / thf / water ( 5 : 5 : 1 ) for 16 h at 65 ° c . workup and purification were conducted according to general procedure a to yield the free carboxylic acid as a colorless solid . yield : 111 mg ( 115 μmol , 79 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 21 - 1 . 41 ( m , 13h , ch 2 - lys , ( ch 3 ) 3 ), 1 . 67 - 1 . 86 ( m , 2h , ch 2 - lys ), 2 . 87 - 2 . 91 ( m , 2h , ch 2 - lys ), 3 . 70 - 3 . 71 ( 3s , 9h , ch 3 - pmb ), 4 . 25 ( brs , 1h , α - ch - lys ), 5 . 59 ( s , 2h , ch 2 - pmb ), 5 . 68 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 77 ( t , 3 j = 5 . 3 hz , 1h , nh ), 6 . 85 - 6 . 92 ( m , 6h , ch - arom . ), 7 . 17 - 7 . 21 ( m , 4h , ch - arom . ), 7 . 26 - 7 . 29 ( m , 2h , ch - arom . ), 7 . 38 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 78 ( d , 3 j = 6 . 0 hz , 1h , nh - amide ), 11 . 34 ( s , 1h , nh - amide ), 11 . 50 ( brs , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 28 . 1 , 52 . 6 , 54 . 9 , 55 . 0 , 77 . 2 , 100 . 9 , 105 . 0 , 105 . 1 , 105 . 3 , 113 . 7 , 113 . 8 , 113 . 9 , 127 . 9 , 128 . 7 , 129 . 0 , 129 . 3 , 129 . 5 , 129 . 6 , 134 . 3 , 136 . 7 , 144 . 8 , 145 . 2 , 153 . 5 , 158 . 6 , 159 . 0 . mp : 177 . 6 - 180 . 0 ° c . hrms ( esi ): calcd for c 47 h 53 n 11 o 12 na : 986 . 3767 . found : 986 . 3760 ; calcd for c 47 h 52 n 11 o 12 : 962 . 3802 ; found : 962 . 3839 . a 85 mg ( 0 . 88 mmol , 1 . 10 equiv ) amount of pmb - protected trimer - lys - oh and 11 . 76 μl ( 0 . 80 mmol , 1 . 00 equiv ) of cyclohexylethylamine were reacted with 34 mg ( 0 . 20 mmol , 2 . 51 equiv ) of cl — hobt , 36 . 41 mg ( 0 . 88 mmol , 1 . 10 equiv ) of hctu and 28 μl ( 1 . 20 mmol , 3 . 00 equiv ) 2 , 6 - lutidine according to general procedure c . the crude product was purified by column chromatography on silica gel using dichloromethane / ethyl acetate ( 3 : 1 ) to yield compound x as a colorless solid . yield : 76 mg ( 71 μmol , 88 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 87 - 0 . 92 ( m , 2h , ch 2 - cyclohexyl ), 1 . 00 - 1 . 02 ( d , 3h , 3 j = 6 . 8 hz , ch 3 ), 1 . 05 - 1 . 17 ( m , 3h , ch - cyclohexyl , ch 2 - cyclohexyl ), 1 . 24 - 1 . 39 ( m , 14h , ch 2 - lys , ( ch 3 ) 3 ), 1 . 52 - 1 . 69 ( m , 7h , ch 2 - cyclohexyl , ch 2 - lys ), 2 . 87 - 2 . 91 ( m , 2h , ch 2 - lys ), 3 . 59 - 3 . 64 ( m , 1h , ch ), 4 . 33 - 4 . 39 ( m , 1h , α - ch - lys ), 5 . 53 - 5 . 63 ( m , 2h , ch 2 - pmb ), 5 . 68 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 75 ( t , 1h , 3 j = 5 . 5 hz , nh ), 6 . 83 - 6 . 92 ( m , 6h , ch - arom . ), 7 . 17 - 7 . 20 ( m , 4h , ch - arom . ), 7 . 26 - 7 . 29 ( m , 2h , ch - arom . ), 7 . 44 ( s , 1h , ch - pyrazole ), 7 . 68 ( d , 1h , 3 j = 8 . 7 hz , nh ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 58 ( d , 1h , 3 j = 8 . 1 hz , nh - amide ), 11 . 33 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 13 . 5 , 17 . 6 , 18 . 5 , 23 . 0 , 25 . 6 , 25 . 9 , 28 . 2 , 28 . 6 , 28 . 7 , 29 . 1 , 30 . 1 , 33 . 6 , 42 . 3 , 48 . 5 , 55 . 0 , 63 . 4 , 77 . 2 , 99 . 9 , 100 . 8 , 105 . 0 , 113 . 6 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 7 , 129 . 0 , 129 . 3 , 129 . 5 , 129 . 7 , 134 . 3 , 134 . 7 , 136 . 7 , 144 . 8 , 145 . 1 , 153 . 5 , 155 . 4 , 155 . 5 , 156 . 8 , 158 . 6 , 159 . 0 , 170 . 5 . mp : 154 . 2 - 155 . 7 ° c . r f : 0 . 45 dichlormethane / ethyl acetate ( 3 : 1 ). hrms ( esi ): calcd for c 55 h 68 n 12 o 11 h : 1073 . 5203 . found : 1073 . 5226 ; calcd for c 55 h 68 n 12 o 11 na : 1095 . 5023 . found : 1095 . 5008 . a portion of 54 mg ( 50 μmol , 1 . 00 equiv ) of the pmb - protected trimer - lys - che was treated with hot tfa according to the general procedure e to yield the free pyrazole trimer as a light - yellow solid . yield : 24 mg ( 33 μmol , 66 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 85 - 1 . 02 ( m , 5h , ch 3 ( d , 3 j = 6 . 8 hz ), ch 2 ), 1 . 06 - 1 . 17 ( m , 3h , ch , ch 2 ), 1 . 23 - 1 . 40 ( m , 3h , ch , ch 2 ), 1 . 53 - 1 . 73 ( m , 9h , ch 2 , ch ), 2 . 73 - 2 . 81 ( m , 2h , ch 2 - lys ), 3 . 58 - 3 . 65 ( m , 1h , ch ), 4 . 38 - 4 . 45 ( m , 1h , α - ch - lys ), 7 . 38 ( bs , 1h , nh - amide ), 7 . 59 ( bs , 1h , ch - pyrazole ), 7 . 66 ( bs , 3h , nh 2 ), 7 . 79 ( bs , 1h , nh - amide ), 7 . 95 ( bs , 1h , ch - pyrazole ), 8 . 54 ( bs , 1h , ch - pyrazole ), 11 . 14 ( s , 1h , nh - amide ), 11 . 45 ( s , 1h , nh - amide ), 13 . 24 ( bs , 1h , nh - pyrazole ), 13 . 49 ( bs , 1h , nh - pyrazole ), 14 . 98 ( bs , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 17 . 6 , 17 . 7 , 22 . 5 , 25 . 6 , 25 . 9 , 26 . 6 , 28 . 6 , 28 . 7 , 42 . 3 , 48 . 5 , 52 . 5 , 98 . 1 , 102 . 2 , 138 . 6 , 146 . 4 , 155 . 0 , 155 . 8 , 157 . 7 , 157 . 9 , 170 . 5 . mp : decomposition at 211 ° c . hrms ( esi ): calcd for c 26 h 36 n 12 o 6 h : 613 . 2954 . found : 613 . 2971 ; calcd for c 26 h 35 n 12 o 6 : 611 . 2808 ; found : 611 . 2804 . a portion of 150 mg ( 204 μmol , 1 . 09 equiv ) of pmb - protected trimer - oh and 27 . 70 μl ( 186 μmol , 1 . 00 equiv ) of cyclohexylethylamine were reacted with 57 mg ( 223 μmol , 1 . 20 equiv ) of mukaiyama &# 39 ; s reagent and 0 . 10 ml ( 574 μmol , 3 . 08 equiv ) of diisopropylethylamine according to general procedure b . the crude product was purified by column chromatography on silica gel using n - pentane / ethyl acetate ( 2 : 1 ) to yield the pmb - protected trimer - che as a colorless solid . yield : 131 mg ( 155 μmol , 83 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 85 - 0 . 97 ( m , 2h , ch 2 - cyclohexyl ), 1 . 09 ( d , 3 j = 6 . 8 hz , 3h , ch 3 ), 1 . 13 - 1 . 19 ( m , 2h , ch 2 - cyclohexyl ), 1 . 34 - 1 . 41 ( m , 1h , ch ), 1 . 59 - 1 . 74 ( m , 4h , ch 2 - cyclohexyl ), 3 . 70 - 3 . 71 ( 3s , 9h , ch 3 - pmb ), 3 . 76 - 3 . 84 ( m , 1h , ch ), 5 . 55 - 5 . 63 ( dd , 3 j = 9 . 0 hz , 3 j = 14 . 5 hz , 2h , ch 2 - pmb ), 5 . 68 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 85 - 6 . 91 ( m , 6h , ch - arom . ), 7 . 15 - 7 . 19 ( m , 4h , ch - arom . ), 7 . 25 - 7 . 28 ( m , 2h , ch - arom . ), 7 . 31 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 35 ( d , 3 j = 8 . 8 hz , 1h , nh - amide ), 11 . 33 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , cdcl 3 ): δ [ ppm ]= 17 . 5 , 25 . 6 , 25 . 9 , 28 . 9 , 29 . 1 , 42 . 2 , 48 . 8 , 52 . 7 , 53 . 0 , 54 . 9 , 55 . 0 , 99 . 4 , 100 . 9 , 105 . 0 , 113 . 6 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 6 , 128 . 9 , 129 . 3 , 129 . 5 , 129 . 8 , 134 . 4 , 135 . 4 , 136 . 7 , 144 . 8 , 145 . 0 , 153 . 5 , 155 . 4 , 156 . 8 , 158 . 4 , 158 . 6 , 159 . 0 . mp : 178 ° c . r f : 0 . 42 n - pentane / ethyl acetate ( 2 : 1 ). hrms ( esi ): calcd for c 44 h 49 n 10 o 8 h : 845 . 3729 . found : 845 . 3723 ; calcd for c 44 h 49 n 10 o 8 na : 867 . 3549 . found : 867 . 3552 . a portion of 49 mg ( 58 μmol , 1 . 00 equiv ) of pmb - protected trimer - che was treated with hot tfa according to the general procedure e to yield the free pyrazole trimer as a colorless solid . yield : 23 mg ( 47 μmol , 82 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 90 - 1 . 22 ( m , 8h , ch 3 , ch 2 - cyclohexyl ), 1 . 37 - 1 . 42 ( m , 1h , ch ), 1 . 59 - 1 . 75 ( m , 5h , ch 2 - cyclohexyl ), 3 . 78 - 3 . 84 ( m , 1h , ch ), 7 . 33 ( s , 1h , ch - pyrazole ), 7 . 60 ( s , 1h , ch - pyrazole ), 7 . 95 ( s , 1h , ch - pyrazole ), 8 . 26 ( bs , 1h , nh - amide ), 11 . 12 ( s , 1h , nh - amide ), 11 . 43 ( s , 1h , nh - amide ), 13 . 15 ( s , 1h , nh - pyrazole ), 13 . 46 ( s , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 15 . 1 , 17 . 6 , 25 . 6 , 25 . 9 , 28 . 9 , 29 . 1 , 42 . 3 , 48 . 7 , 64 . 8 , 96 . 8 , 98 . 1 , 102 . 2 , 138 . 6 , 155 . 0 , 155 . 8 , 156 . 4 , 158 . 1 . mp : decomposition at 265 . 6 ° c . hrms ( esi ): calcd for c 20 h 25 n 10 o 5 h : 485 . 2004 . found : 485 . 1966 . a portion of 300 mg ( 0 . 41 mmol , 1 . 00 equiv ) of pmb - protected trimer - oh and 63 mg ( 0 . 41 μmol , 1 . 00 equiv ) of γ - aminobutanoic acid methyl ester hydrochloride were reacted with 156 mg ( 0 . 61 mmol , 1 . 50 equiv ) of mukaiyama &# 39 ; s reagent and 0 . 32 ml ( 1 . 83 mmol , 4 . 50 equiv ) of diisopropylethylamine according to general procedure b . the residue was purified by column chromatography on silica gel using n - pentane / ethyl acetate ( 2 : 1 ) to yield pmb - protected trimer - gaba - ome as a colorless solid . yield : 193 mg ( 0 . 23 mmol , 57 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 74 - 1 . 79 ( quin , 3 j = 7 . 1 hz , 2h , ch 2 ), 2 . 34 ( t , 3 j = 7 . 4 hz , 2h , ch 2 ), 3 . 22 - 3 . 26 ( q , 3 j = 6 . 0 hz , 3 j = 6 . 6 hz , 2h , ch 2 ), 3 . 59 ( s , 3h , ooch 3 ), 3 . 70 - 3 . 71 ( 3s , 9h , ch 3 - pmb ), 5 . 61 ( s , 2h , ch 2 - pmb ), 5 . 67 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 86 - 6 . 91 ( m , 6h , ch - arom . ), 7 . 16 - 7 . 19 ( m , 4h , ch - arom . ), 7 . 25 - 7 . 28 ( m , 2h , ch - arom . ), 7 . 31 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 66 ( t , 3 j = 5 . 5 hz , 1h , nh - amide ), 11 . 34 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 24 . 1 , 30 . 6 , 37 . 9 , 51 . 2 , 52 . 6 , 53 . 1 , 54 . 9 , 55 . 0 , 59 . 6 , 99 . 4 , 100 . 8 , 105 . 0 , 113 . 7 , 113 . 8 , 113 . 9 , 127 . 9 , 128 . 6 , 128 . 9 , 129 . 3 , 129 . 5 , 129 . 7 , 134 . 3 , 134 . 9 , 136 . 7 , 144 . 8 , 145 . 1 , 153 . 5 , 155 . 4 , 156 . 8 , 158 . 6 , 159 . 0 , 173 . 0 . mp : 198 . 8 - 201 . 7 ° c . r f : 0 . 08 n - pentane / ethyl acetate ( 2 : 1 ). hrms ( esi ): calcd for c 41 h 42 n 10 o 10 h : 835 . 3158 . found : 835 . 3187 ; calcd for c 41 h 42 n 10 o 10 na : 857 . 2978 . found : 857 . 3001 ; calcd for c 41 h 42 n 10 o 10 k : 873 . 2717 . found : 873 . 2751 ; calcd for c 41 h 41 n 10 o 10 : 833 . 3013 ; found : 833 . 2999 . a portion of 60 mg ( 72 μmol , 1 . 00 equiv ) of pmb - protected trimer - gaba - ome was treated with hot tfa according to the general procedure e to yield the free aminopyrazole as a colorless solid . yield : 26 mg ( 55 μmol , 76 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 72 - 1 . 83 ( quin , 3 j = 7 . 1 hz , 2h , ch 2 ), 2 . 37 ( t , 3 j = 7 . 4 hz , 2h , ch 2 ), 3 . 23 - 3 . 29 ( q , 3 j = 6 . 0 hz , 3 j = 6 . 9 hz , 2h , ch 2 ), 3 . 59 ( s , 3h , ch 3 ), 7 . 16 ( bs , 1h , ch - pyrazole ), 7 . 53 ( bs , 1h , ch - pyrazole ), 7 . 94 ( s , 1h , ch - pyrazole ), 8 . 53 ( t , 3 j = 5 . 4 hz , 1h , nh ), 11 . 08 ( bs , 1h , nh - amide ), 11 . 44 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 24 . 3 , 24 . 4 , 30 . 6 , 31 . 0 , 37 . 8 , 51 . 2 , 87 . 4 , 96 . 6 , 102 . 2 , 155 . 0 , 155 . 8 , 173 . 0 , 174 . 1 . mp : decomposition at 242 ° c . hrms ( esi ): calcd for c 17 h 17 n 10 o 7 : 473 . 1287 ; found : 473 . 1317 . a 70 mg ( 84 μmol , 1 . 00 equiv ) amount of pmb - protected trimer - gaba - ome and 10 mg lithium hydroxide ( 418 μmol , 4 . 98 equiv ) were stirred in a mixture of methanol / thf / water ( 5 : 5 : 1 ) for two days at room temperature . the pure product was prepared according to general procedure a as a colorless solid . yield : 57 mg ( 69 μmol , 83 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 71 - 1 . 77 ( quin , 3 j = 7 . 1 hz , 2h , ch 2 ), 2 . 34 ( t , 3 j = 7 . 4 hz , 2h , ch 2 ), 3 . 22 - 3 . 26 ( q , 3 j = 5 . 8 hz , 3 j = 6 . 5 hz , 2h , ch 2 ), 3 . 70 - 3 . 71 ( 3s , 9h , ch 3 - pmb ), 5 . 61 ( s , 2h , ch 2 - pmb ), 5 . 67 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 86 - 6 . 91 ( m , 6h , ch - arom . ), 7 . 16 - 7 . 20 ( m , 4h , ch - arom . ), 7 . 25 - 7 . 28 ( m , 2h , ch - arom . ), 7 . 32 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 66 ( t , 3 j = 5 . 7 hz , 1h , nh - amide ), 11 . 33 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 24 . 2 , 30 . 9 , 38 . 1 , 52 . 6 , 53 . 1 , 54 . 9 , 55 . 0 , 60 . 1 , 72 . 2 , 99 . 4 , 100 . 8 , 105 . 0 , 113 . 7 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 7 , 128 . 9 , 129 . 3 , 129 . 5 , 129 . 7 , 134 . 3 , 135 . 0 , 136 . 7 , 144 . 8 , 145 . 1 , 153 . 5 , 155 . 4 , 156 . 8 , 158 . 6 , 159 . 0 , 174 . 1 . mp : 209 . 3 - 211 ° c . hrms ( esi ): calcd for c 40 h 41 n 10 o 10 na : 843 . 2821 . found : 843 . 2849 . a portion of 50 mg ( 61 μmol , 1 . 00 equiv ) of pmb - protected trimer - gaba - oh was treated with hot tfa according to general procedure e to yield the free aminopyrazole trimer as a beige solid . yield : 22 mg ( 48 μmol , 78 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 72 - 1 . 78 ( quin , 3 j = 7 . 1 hz , 2h , ch 2 ), 2 . 28 ( t , 3 j = 7 . 4 hz , 2h , ch 2 ), 3 . 24 - 3 . 28 ( q , 3 j = 6 . 0 hz , 3 j = 6 . 9 hz , 2h , ch 2 ), 7 . 20 ( bs , 1h , ch - pyrazole ), 7 . 58 ( bs , 1h , ch - pyrazole ), 7 . 94 ( s , 1h , ch - pyrazole ), 8 . 53 ( bs , 1h , h - 6 ), 11 . 11 ( brs , 1h , nh - amide ), 11 . 43 ( s , 1h , nh - amide ), 13 . 20 ( brs , 1h , nh - pyrazole ), 13 . 49 ( brs , 1h , nh - pyrazole ), 14 . 98 ( s , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 24 . 4 , 31 . 0 , 37 . 9 , 96 . 7 , 98 . 1 , 102 . 2 , 138 . 6 , 155 . 0 , 155 . 8 , 174 . 1 . mp : decomposition at 231 ° c . hrms ( esi ): calcd for c 16 h 15 n 10 o 7 : 459 . 1120 ; found : 459 . 1143 . a 146 mg ( 198 μmol , 1 . 00 equiv ) amount of pmb - protected trimer - oh was dissolved in 20 ml dichlormethane and cooled to 0 ° c . to this suspension 80 mg hobt ( 592 μmol , 2 . 98 equiv ), 114 mg edc - hcl ( 595 μmol , 3 . 00 equiv ) and 64 mg ( 399 μmol , 2 . 01 equiv ) tert - butyl - 2 - aminoethylcarbamate were added according to general procedure d . after workup , the crude product was purified by column chromatography on silica gel using n - pentane / ethyl acetate ( 2 : 1 ) to yield the coupled product as a light yellow solid . yield : 142 mg ( 162 μmol , 82 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 37 ( s , 9h , ( ch 3 ) 3 ), 3 . 06 - 3 . 12 ( m , 2h , ch 2 ), 3 . 23 - 3 . 28 ( m , 2h , ch 2 ), 3 . 70 - 3 . 71 ( 2s , 9h , ch 3 - pmb ), 5 . 61 ( s , 2h , ch 2 - pmb ), 5 . 67 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 86 - 6 . 91 ( m , 7h , h - 4 , ch - arom . ), 7 . 16 - 7 . 21 ( m , 4h , ch - arom . ), 7 . 26 - 7 . 29 ( m , 2h , ch - arom . ), 7 . 32 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 63 ( t , 3 j = 5 . 7 hz , 1h , nh - amide ), 11 . 34 ( s , 1h , nh - amide ), 11 . 51 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 18 . 5 , 20 . 6 , 28 . 1 , 30 . 1 , 52 . 6 , 53 . 1 , 54 . 9 , 55 . 0 , 63 . 4 , 77 . 6 , 99 . 5 , 100 . 9 , 105 . 0 , 113 . 7 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 7 , 129 . 0 , 129 . 3 , 129 . 5 , 129 . 7 , 134 . 3 , 134 . 9 , 136 . 7 , 144 . 8 , 145 . 2 , 153 . 5 , 155 . 4 , 155 . 6 , 156 . 8 , 158 . 6 , 159 . 0 , 159 . 1 , 170 . 3 , 171 . 9 . mp : 117 . 8 ° c . r f : 0 . 06 n - pentane / ethyl acetate ( 2 : 1 ). hrms ( esi ): calcd for c 43 h 47 n 11 o 10 h : 878 . 3580 . found : 878 . 3596 ; calcd for c 43 h 47 n 11 o 10 na : 900 . 3400 . found : 900 . 3420 . a portion of 52 mg ( 59 μmol , 1 . 00 equiv ) of pmb - protected trimer - diamine was treated with hot tfa according to general procedure e to yield the free aminopyrazole trimer as a colorless solid . yield : 16 mg ( 30 μmol , 51 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 2 . 99 ( bs , 2h , ch 2 ), 3 . 48 ( bs , 2h , ch 2 ), 7 . 28 ( bs , 1h , ch - pyrazole ), 7 . 61 ( brs , 1h , ch - pyrazole ), 7 . 78 ( bs , 1h , nh 2 ), 7 . 95 ( bs , 1h , ch - pyrazole ), 8 . 68 ( bs , 1h , nh - amide ), 11 . 18 ( bs , 1h , nh - amide ), 11 . 42 ( bs , 1h , nh - amide ), 13 . 31 ( bs , 1h , nh - pyrazole ), 13 . 47 ( bs , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 36 . 5 , 102 . 3 , 136 . 4 , 136 . 5 , 138 . 6 , 155 . 0 , 156 . 3 , 159 . 2 . mp : decomposition at 256 ° c . hrms ( esi ): calcd for c 14 h 15 n 11 o 5 na : 440 . 1150 . found : 440 . 1188 . to a solution of { 2 -[ 2 -( 2 - azido - ethoxy )- ethoxy ]- ethoxy }- acetic acid ethyl ester ( 0 . 30 g , 1 . 15 mmol , 1 eq ) in ethanol ( 7 ml ) was added 1m hcl ( 2 . 30 ml , 2 . 30 mmol , 2 eq ) and 30 . 0 mg of pd / c ( 10 %). the flask was then evacuated and filled with h 2 . the mixture was stirred under h 2 atmosphere at room temperature until the starting material disappeared on the tlc plate and in mass spectra . the solution was filtered through celite and concentrated in vacuo to give a pale yellow syrup . the obtained 2 -[ 2 -( 2 - ethoxycarbonylmethoxy - ethoxy )- ethoxy ]- ethyl - ammonium chloride can be stored at − 18 ° c . for several months . work - up to get the free amine should only be performed immediately before the next step . to obtain the free amine 350 mg ( 1 . 29 mmol ) of the respective hydrochloride were dissolved in chloroform . the organic layer was washed with sat . aq k 2 co 3 and h 2 o , and the solvent was evaporated in vacuo at room temperature to give a colorless oil . yield : 210 mg ( 0 . 89 mmol , 69 %). 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 1 . 28 ( t , 3h , ch 3 ), 1 . 85 ( brs , 2h , nh 2 ), 2 . 88 ( t , 2h , ch 2 ), 3 . 53 ( t , 2h , ch 2 ), 3 . 61 - 3 . 76 ( m , 8h , ch 2 ), 4 . 15 ( s , 2h , ch 2 ), 4 . 21 ( q , 2h , ch 2 ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 14 . 3 , 41 . 8 , 60 . 9 , 68 . 8 , 70 . 4 , 70 . 6 , 70 . 7 , 71 . 0 , 73 . 2 , 170 . 6 . hrms ( esi ): m / z calcd for c 10 h 22 no 5 : 236 . 1492 ; found : 236 . 1511 , calcd for c 10 h 21 nnao 5 : 258 . 1312 ; found : 258 . 1325 . a 200 mg ( 272 μmol , 1 . 00 equiv ) amount of compound pmb - protected trimer - oh was dissolved in 20 ml dichlormethane and cooled to 0 ° c . to this suspension 97 mg hobt ( 828 μmol , 3 . 05 equiv ), 156 mg edc - hcl ( 816 μmol , 3 . 00 equiv ) and 128 mg ( 544 μmol , 2 . 00 equiv ) ethyl - 2 -{ 2 -[ 2 -( aminoethoxy ) ethoxy ]- ethoxy } acetate were added according to the general procedure d . after workup , the crude product was purified by column chromatography on silica gel using dichlormethane / methanol ( 70 : 1 ) to yield the pure coupling product as a colorless solid . yield : 207 mg ( 218 μmol , 80 %). 1 h nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 1 . 24 ( t , 3 j = 7 . 1 hz , 3h , ch 3 ), 3 . 58 - 3 . 74 ( m , 12h , ch 2 ), 3 . 76 - 3 . 77 ( 2s , 9h , ch 3 - pmb ), 4 . 11 ( s , 2h , ch 2 ), 4 . 13 - 4 . 21 ( q , 3 j = 7 . 1 hz , 2h , ch 2 ), 5 . 63 ( s , 4h ch 2 - pmb ), 5 . 80 ( s , 2h , ch 2 - pmb ), 6 . 79 - 6 . 89 ( m , 7h , h - 11 , ch - arom . ), 7 . 11 ( s , 1h , ch - pyrazole ), 7 . 24 - 7 . 30 ( m , 6h , ch - pyrazole , ch - arom . ), 7 . 37 - 7 . 41 ( m , 2h , ch - arom . ), 8 . 40 ( s , 1h , nh - amide ), 8 . 43 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , cdcl 3 ): δ [ ppm ]= 14 . 1 , 39 . 5 , 53 . 7 , 53 . 9 , 55 . 2 , 55 . 9 , 60 . 9 , 68 . 6 , 69 . 5 , 70 . 3 , 70 . 4 , 70 . 5 , 70 . 8 , 98 . 1 , 98 . 9 , 103 . 7 , 113 . 9 , 114 . 1 , 127 . 1 , 128 . 7 , 129 . 2 , 130 . 0 , 134 . 7 , 135 . 7 , 136 . 1 , 144 . 7 , 154 . 1 , 155 . 1 , 156 . 2 , 159 . 2 , 159 . 3 , 159 . 5 , 159 . 7 , 170 . 5 . mp : 78 . 6 ° c . r f : 0 . 18 dichlormethane / methanol ( 70 : 1 ). hrms ( esi ): calcd for c 46 h 52 n 10 o 13 h : 953 . 3788 . found : 953 . 3766 ; calcd for c 43 h 47 n 11 o 10 na : 975 . 3608 . found : 975 . 3591 . a portion of 49 mg ( 52 μmol , 1 . 00 equiv ) of pmb - protected trimer - teg - oet was treated with hot tfa according to general procedure e to yield the pure aminopyrazole trimer as a colorless solid . yield : 30 mg ( 51 μmol , 98 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 18 ( t , 3 j = 7 . 1 hz , 3h , ch 3 ), 3 . 38 - 3 . 42 ( m , 2h , ch 2 ), 3 . 53 - 3 . 59 ( m , 10h , ch 2 ), 4 . 08 - 4 . 12 ( m , 4h , ch 2 ), 7 . 27 ( bs , 1h , ch - pyrazole ), 7 . 59 ( s , 1h , ch - pyrazole ), 7 . 95 ( s , 1h , ch - pyrazole ), 8 . 40 ( s , 1h , nh - amide ), 11 . 12 ( bs , 1h , nh - amide ), 11 . 43 ( bs , 1h , nh - amide ), 13 . 22 ( bs , 1h , nh - pyrazole ), 13 . 48 ( bs , 1h , nh - pyrazole ), 14 . 98 ( bs , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 14 . 0 , 60 . 0 , 67 . 6 , 68 . 7 , 69 . 5 , 69 . 6 , 69 . 9 , 98 . 2 , 102 . 2 , 138 . 6 , 146 . 4 , 146 . 5 , 155 . 0 , 155 . 8 , 156 . 3 , 170 . 0 . mp : decomposition at 264 . 3 ° c . hrms ( esi ): calcd for c 22 h 28 n 10 o 10 h : 593 . 2063 . found : 593 . 2071 ; calcd for c 22 h 28 n 10 o 10 na : 615 . 1882 . found : 615 . 1899 . a 153 mg ( 161 μmol , 1 . 00 equiv ) amount of pmb - protected trimer - teg - oet and 14 mg lithium hydroxide ( 585 μmol , 3 . 64 equiv ) were stirred in a mixture of methanol / thf / water ( 5 : 5 : 1 ) for two days at room temperature . the pure product was prepared according to general procedure a to yield the free carboxylic acid as a colorless solid . yield : 137 mg ( 148 μmol , 92 %). 1 h nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 3 . 36 - 3 . 40 ( m , 2h , ch 2 ), 3 . 51 - 3 . 58 ( m , 10h , ch 2 ), 3 . 70 - 3 . 71 ( 2s , 9h , ch 3 - pmb ), 4 . 00 ( s , 2h , ch 2 ), 5 . 61 ( s , 2h , ch 2 - pmb ), 5 . 67 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 86 - 6 . 91 ( m , 6h , ch - arom . ), 7 . 16 - 7 . 19 ( m , 4h , ch - arom . ), 7 . 26 - 7 . 28 ( m , 6h , ch - arom . ), 7 . 33 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 98 ( s , 1h , ch - pyrazole ), 8 . 71 ( t , 3 j = 5 . 5 hz , 1h , nh ), 11 . 33 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ), 12 . 55 ( bs , 1h , h - 1 ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 52 . 7 , 53 . 1 , 55 . 0 , 67 . 5 , 68 . 5 , 69 . 4 , 69 . 6 , 69 . 7 , 99 . 5 , 100 . 8 , 105 . 0 , 113 . 7 , 113 . 8 , 113 . 9 , 127 . 9 , 128 . 7 , 128 . 9 , 129 . 3 , 129 . 5 , 129 . 7 , 134 . 3 , 134 . 8 , 136 . 7 , 144 . 8 , 145 . 1 , 153 . 5 , 155 . 4 , 156 . 8 , 158 . 5 , 158 . 6 , 159 . 0 , 159 . 1 , 171 . 5 . mp : 88 ° c . hrms ( esi ): calcd for c 44 h 48 n 10 o 13 h : 925 . 3475 . found : 925 . 3445 ; calcd for c 44 h 48 n 10 o 13 na : 947 . 3295 . found : 947 . 3251 . a portion of 53 . 0 mg ( 57 . 4 μmol ) of trimer ( pmb )- teg - oh ome was treated with hot tfa according to general procedure e to yield trimer - teg - oh as a colorless solid . yield : 30 mg ( 53 . 2 μmol , 94 %). 1 h - nmr ( 500 mhz , dmso ): δ [ ppm ]= 3 . 39 - 3 . 40 ( m , 2h , ch 2 ), 3 . 52 - 3 . 57 ( m , 10h , ch 2 ), 4 . 01 ( s , 2h , ch 2 ), 7 . 16 ( brs , 1h , nh - amide ), 7 . 57 ( s , 1h , ch - pyrazole ), 7 . 94 ( s , 1h , ch - pyrazole ), 8 . 55 ( s , 1h , ch - pyrazole ), 11 . 09 ( s , 1h , nh - amide ), 11 . 43 ( brs , 1h , nh - amide ), 12 . 75 ( s , 1h , nh - pyrazole ), 13 . 09 ( s , 1h , nh - pyrazole ), 13 . 51 ( brs , 1h , co 2 h ), 14 . 98 ( s , 1h , nh - pyrazole ). 13 c - nmr ( 500 mhz , dmso ): δ [ ppm ]= 39 . 5 , 68 . 4 , 69 . 7 , 70 . 5 , 70 . 56 , 70 . 6 , 70 . 7 , 103 . 2 , 139 . 6 , 155 . 9 , 156 . 8 , 172 . 5 . mp : decomposition at 349 ° c . hrms ( esi ): m / z calcd for c 20 h 24 n 10 nao 10 : 587 . 1569 ; found : 587 . 1553 ; for c 20 h 23 n 10 na 2 o 10 : 609 . 1389 , found : 609 . 1388 . a portion of 110 mg ( 119 μmol , 1 . 09 equiv ) of compound pmb - protected trimer - teg - oh and 16 μl ( 109 μmol , 1 . 00 equiv ) of cyclohexylethylamine were reacted with 41 mg ( 161 μmol , 1 . 47 equiv ) of mukaiyama &# 39 ; s reagent and 56 . 50 μl ( 324 μmol , 2 . 98 equiv ) of diisopropylethylamine according to general procedure b . the residue was purified by column chromatography on silica gel using dichlormethane / methanol ( 70 : 1 ) to yield the coupled product as a colorless solid . yield : 84 mg ( 81 μmol , 75 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 81 - 0 . 92 ( m , 2h , ch 2 ), 1 . 00 ( d , 3 j = 6 . 7 hz , 3h , ch 3 ), 1 . 04 - 1 . 07 ( m , 3h , ch , ch 2 ), 1 . 23 - 1 . 28 ( m , 1h , ch ), 1 . 55 - 1 . 66 ( m , 5h , ch , ch 2 ), 3 . 55 - 3 . 71 ( m , 21h , ch 2 , ch 3 - pmb ), 4 . 85 ( s , 2h , ch 2 ), 5 . 61 ( s , 2h , ch 2 - pmb ), 5 . 66 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 86 - 6 . 91 ( m , 6h , ch - arom . ), 7 . 16 - 7 . 19 ( m , 4h , ch - arom . ), 7 . 24 - 7 . 33 ( m , 4h , h - 7 , ch - pyrazole , ch - arom . ), 7 . 70 ( s , 1h , ch - pyrazole ), 7 . 97 ( s , 1h , ch - pyrazole ), 8 . 70 ( t , 3 j = 5 . 2 hz , 1h , nh ), 11 . 33 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 17 . 6 , 25 . 6 , 25 . 9 , 28 . 8 , 38 . 6 , 42 . 2 , 48 . 1 , 52 . 7 , 53 . 1 , 55 . 0 , 55 . 1 , 68 . 6 , 69 . 5 , 69 . 7 , 70 . 2 , 99 . 6 , 100 . 9 , 105 . 0 , 113 . 7 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 7 , 128 . 9 , 129 . 3 , 129 . 5 , 129 . 7 , 134 . 3 , 134 . 9 , 136 . 7 , 144 . 8 , 145 . 2 , 153 . 5 , 155 . 4 , 158 . 6 , 159 . 0 , 159 . 1 , 168 . 3 . mp : 189 . 9 - 191 . 2 ° c . r f : 0 . 35 dichlormethane / methanol ( 70 : 1 ). hrms ( esi ): calcd for c 52 h 63 n 11 o 12 h : 1034 . 4730 . found : 1034 . 4757 ; calcd for c 52 h 63 n 11 o 12 na : 1056 . 4550 . found : 1056 . 4588 . a portion of 42 mg ( 41 μmol , 1 . 00 equiv ) of pmb - protected trimer - teg - che was treated according to general procedure e to yield the free aminopyrazole as a colorless solid . yield : 20 mg ( 30 μmol , 72 %). 1 h nmr ( 500 mhz , dmdo - d 6 ): δ [ ppm ]= 0 . 83 - 1 . 33 ( m , 9h , ch 3 , ch 2 - cyclohexyl ), 1 . 56 - 1 . 67 ( m , 5h , ch - cyclohexyl , ch 2 - cyclohexyl ), 3 . 39 - 3 . 39 ( m , 13h , ch , ch 2 ), 3 . 86 ( s , 2h , ch 2 ), 7 . 26 - 7 . 29 ( bs , 2h , ch - pyrazole , nh - amide ), 7 . 59 ( bs , 1h , ch - pyrazole ), 7 . 95 ( s , 1h , ch - pyrazole ), 8 . 64 ( bs , 1h , nh - amide ), 11 . 14 ( bs , 1h , nh - amide ), 11 . 44 ( bs , 1h , nh - amide ), 13 . 22 ( bs , 1h , nh - pyrazole ), 13 . 48 ( bs , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 17 . 6 , 25 . 6 , 25 . 9 , 28 . 7 , 28 . 8 , 38 . 4 , 42 . 1 , 48 . 1 , 51 . 0 , 59 . 9 , 60 . 1 , 68 . 7 , 69 . 5 , 69 . 7 , 70 . 2 , 80 . 5 , 102 . 2 , 138 . 6 , 155 . 0 , 155 . 8 , 168 . 2 . mp : decomposition at 153 ° c . hrms ( esi ): calcd for c 28 h 39 n 11 o 9 na : 696 . 2824 . found : 696 . 2808 ; calcd for c 28 h 38 n 11 o 9 na : 672 . 2859 . found : 672 . 2874 . a portion of 200 mg ( 0 . 27 mmol , 1 . 00 equiv ) of pmb - protected trimer - oh and 103 mg ( 0 . 27 mmol , 1 . 00 equiv ) of 2 - amino - 2 - cyclohexyl - n -( 1 - cyclohexylethyl ) acetamide - trifluoroacetate were reacted with 104 mg ( 0 . 41 mmol , 1 . 50 equiv ) of mukaiyama &# 39 ; s reagent and 0 . 21 ml ( 1 . 21 mmol , 4 . 45 equiv ) of diisopropylethylamine according to general procedure b . the crude product was purified by column chromatography on silica gel using dichlormethane / ethyl acetate ( 7 : 1 ) to yield the coupled product as a colorless solid . yield : 128 mg ( 0 . 13 mmol , 48 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 89 - 1 . 18 ( m , 13h , ch 3 , ch 2 ), 1 . 26 - 1 . 32 ( m , 1h , ch ), 1 . 56 - 1 . 80 ( m , 11h , ch , ch 2 ), 3 . 59 - 3 . 63 ( m , 1h , ch ), 3 . 70 - 3 . 71 ( 2s , 9h , ch 3 - pmb ), 4 . 28 ( t , 3 j = 8 . 6 hz , 1h , ch ), 5 . 53 - 5 . 60 ( dd , 3 j = 14 . 5 hz , 3 j = 5 . 7 hz , 2h , ch 2 - pmb ), 5 . 67 ( s , 2h , ch 2 - pmb ), 5 . 81 ( s , 2h , ch 2 - pmb ), 6 . 82 - 6 . 80 ( m , 6h , ch - arom . ), 7 . 16 - 7 . 18 ( m , 4h , ch - arom . ), 7 . 26 - 7 . 28 ( m , 2h , ch - arom . ), 7 . 40 ( s , 1h , ch - pyrazole ), 7 . 71 ( s , 1h , ch - pyrazole ), 7 . 79 ( d , 3 j = 8 . 5 hz , 1h , nh - amide ), 7 . 97 ( s , 1h , ch - pyrazole ), 8 . 46 ( d , 3 j = 8 . 8 hz , 1h , nh - amide ), 11 . 32 ( s , 1h , nh - amide ), 11 . 50 ( s , 1h , nh - amide ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 17 . 3 , 25 . 6 , 25 . 7 , 28 . 5 , 28 . 6 , 28 . 7 , 42 . 0 , 55 . 0 , 68 . 2 , 100 . 8 , 113 . 6 , 113 . 8 , 114 . 0 , 127 . 9 , 128 . 7 , 128 . 9 , 129 . 3 , 129 . 5 , 129 . 6 , 134 . 8 , 136 . 7 , 156 . 8 , 158 . 6 , 158 . 9 , 159 . 0 , 169 . 2 , 169 . 5 . mp : 216 ° c . r f : 0 . 40 dichlormethane / ethyl acetate ( 7 : 1 ). hrms ( esi ): calcd for c 52 h 61 n 11 o 9 h : 984 . 4726 . found : 984 . 4737 ; calcd for c 52 h 61 n 11 o 9 na : 1006 . 4546 . found : 1006 . 4492 . a portion of 30 mg ( 30 μmol , 1 . 00 equiv ) of pmb - protected trimer - chg - che was treated according to general procedure e to yield the free aminopyrazole trimer as a colorless solid . yield : 17 mg ( 27 μmol , 89 %). 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 89 - 1 . 21 ( m , 13h , ooch 3 , ch 2 - cyclohexyl ), 1 . 27 - 1 . 33 ( m , 1h , ch - cyclohexyl ), 1 . 59 - 1 . 79 ( m , 11h , ch - cyclohexyl , ch 2 - cyclohexyl ), 3 . 60 - 3 . 66 ( m , 1h , ch ), 4 . 33 ( bs , 1h , ch ), 7 . 39 ( bs , 1h , ch - pyrazole ), 7 . 60 ( bs , 1h , ch - pyrazole ), 7 . 86 ( bs , 1h , h - 7 ), 7 . 96 ( s , 1h , ch - pyrazole ), 8 . 35 ( bs , 1h , nh ), 11 . 11 ( bs , 1h , nh - amide ), 11 . 42 ( bs , 1h , nh - amide ), 13 . 23 ( bs , 1h , nh - pyrazole ), 13 . 47 ( bs , 1h , nh - pyrazole ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 17 . 2 , 25 . 3 , 25 . 4 , 25 . 6 , 25 . 9 , 28 . 4 , 28 . 5 , 28 . 7 , 29 . 1 , 30 . 3 , 42 . 0 , 48 . 6 , 57 . 6 , 98 . 0 , 98 . 2 , 102 . 2 , 136 . 4 , 136 . 5 , 138 . 6 , 146 . 5 , 146 . 4 , 146 . 6 , 155 . 0 , 155 . 2 , 155 . 8 , 169 . 6 . mp : decomposition at 248 . 6 ° c . hrms ( esi ): calcd for c 28 h 36 n 11 o 6 : 622 . 2856 ; found : 622 . 2878 . in an argon atmosphere 105 mg ( 0 . 11 mmol , 1 eq ) of pmb - protected trimer - teg - oh , 39 μl ( 35 mg , 0 . 34 mmol , 3 eq ) of pybop , 39 μl ( 35 mg , 0 . 34 mmol , 3 eq ) of n - methylmorpholine ( nmm ) and 60 mg ( 0 . 20 mmol , 1 . 8 eq ) n - ε - tert .- butyloxycarbonyl -( s )- lysine methyl ester were dissolved in dry dichloromethane ( 30 ml ) and the solution was heated to 40 ° c . for 4 days . dichloromethane was evaporated and the remaining residue was purified over a silica gel column , eluting with dichloromethane / methanol ( 50 : 1 ) to yield the product as a colorless solid . yield 108 mg ( 82 %, 0 . 11 mmol ). 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 1 . 25 - 1 . 41 ( m , 13h , ch 2 , ch 3 - boc ), 1 . 58 - 1 . 83 ( m , 2h , ch 2 ), 3 . 00 ( brs , 2h , ch 2 ), 3 . 56 - 3 . 58 ( m , 2h , ch 2 ), 3 . 61 - 3 . 67 ( m , 13h , ch 2 , ch 3 ), 3 . 72 - 3 . 76 ( 3s , 9h , ch 3 - pmb ), 4 . 02 ( s , 2h , ch 2 ), 4 . 61 - 4 . 65 ( m , 1h , ch ), 5 . 60 - 5 . 79 ( 2s , 6h , ch 2 - pmb ), 6 . 76 - 6 . 81 ( m , 6h , ch - arom ), 7 . 09 - 7 . 40 ( m , 11h , ch - arom , ch - pyrazole , nh - amide ), 8 . 68 ( s , 1h , nh - amide ), 9 . 25 ( s , 1h , nh - amide ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 22 . 8 , 28 . 6 , 29 . 6 , 32 . 2 , 39 . 6 , 40 . 3 , 51 . 5 , 52 . 5 , 53 . 9 , 54 . 0 , 55 . 4 , 56 . 1 , 69 . 7 , 70 . 3 , 70 . 4 , 70 . 5 , 70 . 6 , 71 . 0 , 98 . 4 , 99 . 3 , 104 . 0 , 114 . 0 , 114 . 1 , 114 . 2 , 127 . 4 , 129 . 0 , 129 . 3 , 129 . 4 , 129 . 5 , 130 . 2 , 134 . 9 , 135 . 8 , 136 . 4 , 114 . 9 , 154 . 3 , 155 . 4 , 156 . 2 , 156 . 5 , 159 . 3 , 159 . 4 , 159 . 7 , 159 . 9 , 170 . 3 , 172 . 9 . rf : 0 . 16 in dichlormethane / methanol ( 50 : 1 ). mp : 79 ° c . hrms ( esi ): m / z calcd for c 56 h 71 n 12 nao 16 : 1167 . 5106 ; found : 1167 . 5169 ; calcd for c 56 h 20 n 12 nao 16 : 1189 . 4925 , found : 1189 . 4979 . in an argon atmosphere 50 . 0 mg ( 42 . 9 μmol ) of trimer ( pmb ) teg - lys ( boc )- ome were heated in anhydrous tfa ( 3 ml ) to 70 ° c . for 5 h . after adding cold et 2 o , the product precipitated . the precipitate was filtered , washed with et 2 o and dried in vacuo ; yield : 32 . 0 mg ( 39 . 0 μmol , 91 %), colorless solid . 1 h - nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 30 - 1 . 36 ( m , 2h , ch 2 ), 1 . 50 - 1 . 57 ( m , 2h , ch 2 ), 1 . 62 - 1 . 80 ( m , 2h , ch 2 ), 2 . 77 ( brs , 2h , ch 2 ), 3 . 40 - 3 . 44 ( m , 2h , ch 2 ), 3 . 54 - 3 . 60 ( m , 10h , ch 2 ), 3 . 64 ( s , 3h , ch 3 ), 3 . 95 ( s , 2h , ch 2 ), 4 . 31 - 4 . 34 ( m , 1h , ch ), 7 . 28 ( s , 1h , h — ch - pyrazole ), 7 . 60 - 7 . 63 ( m , 4h , h - 33 , ch - pyrazole ), 7 . 95 - 7 . 98 ( m , 2h , h - 27 , ch - pyrazole ), 8 . 64 ( brs , 1h , nh - amide ), 11 . 13 ( s , 1h , n — nh - amide ), 11 . 41 ( s , 1h , nh - amide ), 13 . 24 ( s , 1h , nhpyrazole ), 13 . 47 ( s , 1h , nhpyrazole ), 14 . 97 ( s , 1h , nhpyrazole ). 13 c - nmr ( 125 . 7 mhz , dmso - d 6 ): δ [ ppm ]= 22 . 3 , 26 . 5 , 30 . 2 , 38 . 6 , 51 . 1 , 52 . 0 , 68 . 8 , 69 . 5 , 69 . 7 , 70 . 2 , 97 . 2 , 98 . 4 , 102 . 2 , 146 . 7 , 158 . 6 , 169 . 6 , 172 . 2 . mp : decomposition at 360 ° c . hrms ( esi ): calcd for c 27 h 39 n 12 h 11 : 707 . 2856 ; found : 707 . 2851 ; calcd for c 27 h 38 n 12 nao 11 : 729 . 2675 ; found : 729 . 2670 . a 50 . 0 mg ( 54 . 1 μmol , 1 . 00 equiv ) amount of tri ( pmb )- teg - oh and 20 . 0 mg ( 0 . 11 mmol , 2 . 00 equiv ) of dodecylamine were reacted with 19 . 0 mg ( 0 . 16 mmol , 3 . 00 equiv ) of hobt and 31 . 0 mg ( 0 . 16 mmol , 3 . 00 equiv ) of edc * hcl according to general procedure d . the residue was purified by column chromatography on silica gel using dichloromethane / methanol ( 50 : 1 ). yield : 44 . 3 mg ( 40 . 6 μmol , 75 %), pale yellow solid . 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 0 . 86 ( t , 3h , ch 3 ), 1 . 22 ( brs , 18h , ch 2 ), 1 . 42 - 1 . 50 ( m , 2h , ch 2 ), 3 . 20 - 3 . 26 ( m , 2h , ch 2 ), 3 . 56 - 3 . 64 ( m , 10h , ch 2 ), 3 . 72 - 3 . 75 ( 3s , 9h , ch 3 - pmb ), 4 . 00 ( s , 2h , ch 2 ), 5 . 59 - 5 . 78 ( 2s , 6h , ch 2 - pmb ), 6 . 75 - 6 . 81 ( m , 6h , ch - arom ), 6 . 88 ( t , 1h , nh - amide ), 6 . 97 ( t , 1h , nh - amide ), 7 . 11 ( s , 1h , ch - pyrazole ), 7 . 17 - 7 . 26 ( m , 5h , ch - arom , ch - pyrazole ), 7 . 34 - 7 . 38 ( m , 3h , ch - arom , ch - pyrazole ), 8 . 62 ( s , 1h , nh - amide ), 9 . 13 ( s , 1h , nh - amide ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 14 . 2 , 22 . 8 , 27 . 9 , 29 . 4 , 29 . 5 , 29 . 6 , 29 . 7 , 29 . 8 , 29 . 9 , 32 . 0 , 39 . 1 , 39 . 6 , 53 . 9 , 54 . 0 , 55 . 4 , 56 . 1 , 69 . 8 , 70 . 4 , 70 . 5 , 70 . 6 , 70 . 7 , 70 . 8 , 98 . 2 , 99 . 1 , 103 . 9 , 114 . 0 , 114 . 1 , 114 . 2 , 127 . 3 , 128 . 9 , 129 . 3 , 129 . 4 , 129 . 5 , 130 . 2 , 134 . 8 , 135 . 8 , 136 . 4 , 144 . 9 , 154 . 2 , 155 . 3 , 156 . 5 , 159 . 3 , 159 . 5 , 159 . 6 , 159 . 9 , 170 . 1 . mp : 105 ° c . r f : 0 . 27 in dichloromethane / methanol ( 50 : 1 ). hrms ( esi ): m / z calcd for c 56 h 74 n 11 o 12 : 1092 . 5513 ; found : 1092 . 5521 ; calcd for c 56 h 73 n 11 nao 12 : 1114 . 5332 ; found : 1114 . 5345 . in an argon atmosphere 20 . 0 mg ( 18 . 3 μmol ) of tri ( pmb )- teg - dodecyl were heated in anhydrous tfa ( 2 ml ) to 70 ° c . for 5 h . after adding cold et 2 o , the product precipitated . the precipitate was filtered , washed with et 2 o and dried in vacuo ; yield : 9 . 50 mg ( 12 . 7 μmol , 70 %), colorless solid . 1 h - nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 83 ( t , 3h , ch 3 ), 1 . 21 ( brs , 18h , ch 2 ), 1 . 39 ( m , 2h , ch 2 ), 3 . 05 - 3 . 09 ( m , 2h , ch 2 ), 3 . 31 - 3 . 43 ( brs , 2h , ch 2 ), 3 . 56 ( brs , 10h , ch 2 ), 3 . 85 ( s , 2h , ch 2 ), 7 . 26 ( brs , 1h , ch - pyrazole , nh - amide ), 7 . 59 - 7 . 63 ( m , 2h , ch - pyrazole , nh - amide ), 7 . 95 ( s , 1h , ch - pyrazole ), 8 . 62 ( brs , 1h , ch - pyrazol , nh - amide ), 11 . 12 ( brs , 1h , nh - amide ), 11 . 43 ( brs , 1h , nh - amide ), 13 . 22 ( brs , 1h , nh - pyrazole ), 13 . 47 ( brs , 1h , nh - pyrazole ). 13 c - nmr ( 125 . 7 mhz , dmso - d 6 ): δ [ ppm ]= 13 . 9 , 22 . 1 , 26 . 4 , 28 . 7 , 29 . 0 , 29 . 1 , 31 . 3 , 38 . 1 , 68 . 8 , 69 . 5 , 69 . 6 , 69 . 7 , 69 . 9 , 70 . 2 , 98 . 2 , 102 . 3 , 155 . 1 , 156 . 0 , 169 . 1 . mp : decomposition at 348 ° c . hrms ( esi ): m / z calcd for c 32 h 49 n 11 nao 9 : 754 . 3607 ; found : 754 . 3646 ; calcd for c 32 h 48 n 11 na 2 o 9 : 776 . 3426 ; found : 776 . 3449 . in an argon atmosphere 0 . 50 g ( 1 . 31 mol , 1 . 00 eq ) of z - lys ( boc )- oh ), 32 . 0 mg ( 0 . 26 mmol , 0 . 20 eq ) of 4 - dimethylaminopyridine ( dmap ), 250 mg ( 307 μl , 1 . 97 mmol , 1 . 5 eq ) of diisopropylcarbodiimide ( dic ) and 72 mg ( 72 μl , 0 . 33 mmol , 0 . 25 eq ) of 4 , 7 , 10 - trioxa - 1 , 13 - tridecandiamine were dissolved in dry dichloromethane ( 15 ml ) and the solution was stirred at room temperature for 24 h . after filtration of the precipitated urea , dichloromethane was evaporated and the remaining residue was purified over silica gel column , eluting with dichloromethane / methanol ( 30 : 1 ) to yield the product as a colorless oil . yield 250 mg ( 0 . 26 mmol , 79 %). 1 h - nmr ( 300 mhz , cdcl 3 ): δ [ ppm ]= 1 . 31 - 1 . 49 ( m , 13h , ch 3 , ch 2 ), 1 . 59 - 1 . 85 ( m , 4h , ch 2 ), 3 . 07 ( brs , 2h , ch 2 ), 3 . 26 - 3 . 40 ( m , 2h , ch 2 ), 3 . 52 - 3 . 61 ( m , 6h , ch 2 ), 4 . 11 - 4 . 16 ( m , 1h , ch ), 4 . 74 ( brs , 1h , nh ), 5 . 08 ( s , 2h , ch 2 ), 5 . 77 ( brs , 1h , nh ), 6 . 89 ( brs , 1h , nh ), 7 . 28 - 7 . 34 ( m , 5h , ch - arom ). r f : 0 . 07 in dichloromethan / methanol 30 : 1 . hrms ( esi ): m / z calcd for c 48 h 77 n 6 o 13 : 945 . 5612 ; found : 945 . 5612 ; calcd for c 48 h 76 n 6 nao 13 : 967 . 5363 ; found : 967 . 5431 . to a solution of bis ( n - benzyloxycarbonyl - n ε - tert - butyloxycarbonyl -( s )- lysinyl )- 4 , 7 , 10 - trioxa - 1 , 13 - tridecandiamine ( 250 mg , 0 . 26 mmol ) in thf ( 50 ml ) was added 30 mg of pd — c ( 10 %). the resulting solution was stirred vigorously under h 2 atmosphere at room temperature until the starting material disappeared on the tlc plate and in mass spectra . the solution was filtered through celite and concentrated in vacuo to give a pale yellow oil . yield : 166 mg ( 0 . 25 mmol , 96 %). 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 1 . 33 - 1 . 55 ( m , 13h , ch 2 , ch 3 ), 1 . 77 - 1 . 80 ( m , 6h , nh 2 , ch 2 ), 3 . 09 - 2 . 12 ( m , 2h , ch 2 ), 3 . 29 - 3 . 38 ( m , 3h , ch , ch 2 ), 3 . 52 - 3 . 64 ( m , 6h , ch 2 ), 4 . 71 ( brs , 1h , nh ), 7 . 54 ( brs , 1h , nh ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 23 . 1 , 28 . 6 , 29 . 4 , 30 . 0 , 30 . 5 , 34 . 5 , 34 . 9 , 37 . 3 , 40 . 3 , 55 . 3 , 62 . 6 , 69 . 9 , 70 . 4 , 70 . 7 , 79 . 2 , 156 . 3 , 175 . 3 . hrms ( esi ): m / z calcd for c 32 h 65 n 6 o 9 : 677 . 4808 ; found : 677 . 4797 ; calcd for c 32 h 64 n 6 nao 9 : 699 . 4627 ; found : 699 . 4616 . in an inert atmosphere 26 . 0 mg ( 85 . 2 μmol , 2 . 50 eq ) of pmb - protected trimer - oh , 59 . 0 mg ( 114 μmol , 3 . 00 eq ) of pybop , 46 . 0 mg , 50 . 0 μl ( 0 . 46 mmol , 12 . 0 eq ) of n - methylmorpholine , and 26 . 0 mg ( 38 . 1 μmol , 1 . 00 eq ) of bis ( amino - n ε - tert - butyloxycarbonyl -( s )- lysinyl )- 4 , 7 , 10 - trioxa - 1 , 13 - tridecanediamine were dissolved in dry dichloromethane ( 20 ml ) and the solution was heated to 40 ° c . for 4 days . dichloromethane was evaporated and the remaining residue was purified over silica gel column , eluting with dichloromethane / methanol ( 30 : 1 ) to yield the product as a colorless solid . yield : 42 . 0 mg ( 19 . 9 μmol , 52 %). 1 h - nmr ( 500 mhz , cdcl 3 , 333 k ): δ [ ppm ]= 1 . 33 - 1 . 42 ( m , 13h , ch 3 , ch 2 ), 1 . 75 - 1 . 93 ( m , 4h , ch 2 ), 3 . 00 - 3 . 05 ( m , 2h , ch 2 ), 3 . 32 - 3 . 49 ( m , 2h , ch 2 ), 3 . 54 - 3 . 65 ( m , 6h , ch 2 ), 3 . 68 - 3 . 71 ( 3s , 9h , ch 3 - pmb ), 4 . 47 - 4 . 51 ( m , 1h , ch ), 4 . 67 ( brs , 1h , nh ), 5 . 39 - 5 . 87 ( m , 6h , ch2 - pmb ), 6 . 71 - 6 . 80 ( m , 6h , ch - arom ), 6 . 90 ( brs , 2h , nh , ch - pyrazole ), 7 . 10 - 7 . 17 ( m , 4h , ch - arom ), 7 . 25 ( s , 1h , ch - pyrazole ), 7 . 33 - 7 . 53 ( m , 2h , ch - arom ), 7 . 49 - 7 . 53 ( brs , 2h , nh , ch - pyrazole ), 8 . 48 ( s , 1h , nh ), 9 . 73 ( s , 1h , nh ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 23 . 4 , 28 . 8 , 29 . 4 , 30 . 1 , 32 . 7 , 38 . 7 , 42 . 7 , 54 . 0 , 54 . 6 , 55 . 6 , 56 . 4 , 70 . 1 , 70 . 6 , 70 . 8 , 98 . 9 , 99 . 9 , 104 . 7 , 114 . 4 , 114 . 5 , 114 . 6 , 127 . 9 , 129 . 4 , 129 . 5 , 129 . 6 , 130 . 3 , 135 . 3 , 135 . 8 , 136 . 8 , 145 . 2 , 145 . 7 , 154 . 6 , 156 . 2 , 156 . 5 , 159 . 7 , 159 . 8 , 160 . 1 , 160 . 2 , 172 . 2 . rf : 0 . 20 in dichloromethan / methanol ( 30 : 1 ). mp : 157 . 3 ° c . hrms ( esi ): m / z calcd for c 104 h 126 n 24 nao 25 : 2134 . 9248 ; found : 2134 . 9258 . a portion of 40 . 0 mg ( 18 . 9 μmol , 1 . 00 eq ) of pmb - protected ( trimer - lys ( boc )) 2 - tegda ome was treated with hot tfa according to general procedure e to yield ( trimer - lys ) 2 - tegda as a colorless solid . yield : 26 . 0 mg ( 18 . 3 μmol , 97 %). 1 h - nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 41 - 1 . 48 ( m , 2h , ch 2 ), 1 . 62 - 1 . 88 ( m , 6h , ch 2 ), 2 . 84 ( t , 2h , ch 2 ), 3 . 18 . 3 . 22 ( m , 2h , ch 2 ), 3 . 46 - 3 . 59 ( m , 6h , ch 2 ), 4 . 44 - 4 . 48 ( m , 1h , ch ), 6 . 96 ( brs , 1h , ch - pyrazole ), 7 . 21 ( brs , 1h , ch - pyrazole ), 7 . 54 - 7 . 56 ( brs , 1h , h - 21 ), 7 . 77 ( s , 1h , ch - pyrazole ), 7 . 88 ( brs , 1h , nh ), 10 . 45 ( brs , 1h , nh ), 10 . 98 ( brs , 1h , nh ). 13 c - nmr ( 125 . 7 mhz , dmso - d 6 ): δ [ ppm ]= 22 . 6 , 26 . 7 , 27 . 1 , 29 . 3 , 31 . 2 , 35 . 9 , 36 . 8 , 38 . 7 , 52 . 6 , 67 . 3 , 68 . 0 , 69 . 4 , 69 . 5 , 69 . 6 , 69 . 7 , 102 . 3 , 138 . 6 , 155 . 1 , 155 . 9 , 157 . 8 , 158 . 1 , 171 . 3 . mp : 200 ° c . hrms ( esi ): m / z calcd for c 46 h 63 n 24 o 15 : 1191 . 4899 ; found : 1191 . 4879 ; calcd for c 46 h 62 n 24 nao 15 : 1213 . 4719 ; found : 1213 . 4693 . a wang - resin , preloaded with fmoc - glycine and an average loading of 0 . 78 mmol / g , was used as a polymeric carrier . prior to the first coupling step , the resin was swollen in dmf for 80 min . the coupling of fmoc - protected amino acids was accomplished by using hbtu and diisopropylethylamine according to the following method : for each coupling step , fmoc - lys ( boc )- oh ( 8 . 00 equiv ), hbtu ( 7 . 62 equiv ) and diisopropyletylamine ( 16 . 00 equiv ) were used in a dmf solution . removal of the fmoc - protecting group was carried out with 20 % piperidine in dmf ( 1 × 3 min , 1 × 7 min ) each coupling and deprotecting step was followed by washing the resin with dmf . the completeness of each coupling step was checked with nf31 - and kaiser - test . [ x ] the fourth coupling was repeated . after five cycles , the resin was coupled with the pmb - protected trimer - oh ( 3 . 00 equiv ), hbtu ( 3 . 30 equiv ) and diisopropyletylamine ( 6 . 00 equiv ) in dmf solution for 6 h . the pyrazole - peptide compound was cleaved off the resin concomitant with deprotection of lysine &# 39 ; s ε - amino - boc groups by means of an acidic cleavage cocktail ( 93 % tfa , 5 % tis and 2 % water ) during 3 h . the solution was then cooled to 0 ° c . and the pmb - protected pyrazole - peptide was precipitated and washed with cold diethyl ether . the colorless solid was dried in vacuo . to cleave the pmb - protecting groups on the pyrazole nucleus , the colorless solid was heated under argon in dry tfa for 5 h to 70 ° c . the solution was again cooled to 0 ° c . and treated according to general procedure e to yield the pure trimer - peptide . 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 1 . 23 - 1 . 33 ( m , 12h ), 1 . 51 - 1 . 56 ( m , 14h ), 1 . 63 - 1 . 74 ( m , 6h ), 2 . 75 ( bs , 11h ), 4 . 20 - 4 . 31 ( m , 4h ), 4 . 41 - 4 . 45 ( m , 1h ), 7 . 76 ( bs , 16h ), 7 . 94 - 7 . 99 ( m , 2h ), 8 . 02 - 8 . 18 ( m , 3h ), 8 . 26 - 8 . 28 ( m , 1h ), 11 . 47 ( bs , 1h ), 14 . 97 ( bs , 1h ). 13 c nmr ( 125 mhz , cd 3 od ): δ [ ppm ]= 22 . 0 , 22 . 2 , 26 . 4 , 30 . 6 , 39 . 2 , 53 . 6 , 53 . 7 , 115 . 3 , 117 . 7 , 120 . 0 , 162 . 6 , 163 . 1 , 163 . 4 , 173 . 3 , 173 . 5 , 174 . 0 . mp : decomposition at 138 ° c . hrms ( esi ): calcd for c 44 h 72 n 20 o 12 : 1073 . 5711 ; found : 1073 . 5747 , calcd for ( ½ m ) 2 + : 537 . 2913 ; found : 537 . 2910 , calcd for ( ⅓ m ) 3 + : 358 . 5302 ; found : 358 . 5303 . trimer - teg - kkkkkg - oh was synthesized using the same procedure as the previous ( trimer - lpffd - oh ). trimer - teg - oh ( 3 . 00 equiv ) was used instead of trimer - oh in this case . 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 1 . 31 ( brs , 10h , ch 2 ), 1 . 49 - 1 . 65 ( m , 20h , ch 2 ), 2 . 76 ( brs , 10h , h - 29 ), 3 . 39 - 3 . 42 ( m , 2h , ch 2 ), 3 . 52 - 3 . 61 ( m , 10h , ch 2 ), 3 . 69 - 3 . 84 ( m , 2h , ch 2 ), 3 . 93 ( s , 2h , ch 2 ), 4 . 20 - 4 . 33 ( m , 5h , ch ), 7 . 58 ( brs , 15h ), 7 . 93 - 8 . 01 ( m , 4h ), 8 . 11 ( d , 1h , 3 j = 7 . 26 hz ), 8 . 26 ( t , 1h , 3 j = 7 . 26 hz ), 8 . 68 ( brs , 1h ), 11 . 14 ( s , 1h ), 11 . 44 ( s , 1h ), 12 . 77 ( brs , 1h ), 13 . 19 ( brs , 1h ), 13 . 50 ( brs , 1h ), 14 . 96 ( brs , 1h ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 22 . 0 , 22 . 1 , 22 . 2 , 22 . 3 , 26 . 5 , 26 . 6 , 26 . 7 , 31 . 3 , 31 . 4 , 31 . 5 , 38 . 6 , 38 . 7 , 51 . 8 , 52 . 1 , 52 . 2 , 52 . 3 , 68 . 8 , 69 . 5 , 69 . 6 , 69 . 7 , 70 . 2 , 102 . 4 , 116 . 0 , 118 . 4 , 157 . 8 , 158 . 1 , 158 . 3 , 158 . 6 , 169 . 4 , 171 . 1 , 171 . 2 , 171 . 3 , 171 . 4 , 171 . 5 , 171 . 7 . hrms ( esi ): [ m + 2h ] 2 + = m / z calcd for c 52 h 89 n 21 o 16 : 631 . 8393 ; found : 631 . 8493 , [ m + 3h ] 3 + = m / z calcd for c 52 h 90 n 21 o 16 : 421 . 5619 ; found : 421 . 5656 . a wang - resin was used as a polymer support , preloaded with fmoc - asp ( o t bu ) and an average loading of 0 . 65 mmol / g . prior to the first coupling step , the resin was swollen in dmf for 80 min . the coupling of fmoc - protected amino acids was accomplished by using hbtu and diisopropyletylamine according to the following method : for each coupling step , 9 - fluorenyl - methoxycarbonylamino acid ( 8 . 00 equiv ), hbtu ( 7 . 62 equiv ) and diisopropyletylamine ( 16 . 00 equiv ) were used in a dmf solution . removal of the fmoc - protecting group was carried out with 20 % piperidine in dmf ( 1 × 3 min , 1 × 7 min ). each coupling and deprotecting step was followed by washing the resin with dmf . the completeness of each coupling step was checked with nf31 - and kaiser - test and the fmoc - protected amino acid proline with the chloranil - test . [ x ] after four cycles , the resin was coupled with pmb - protected trimer - oh ( 6 . 00 equiv ), hbtu ( 6 . 60 equiv ) and diisopropyletylamine ( 12 . 00 equiv ) in dmf solution for 16 h . the pyrazole - peptide compound was cleaved off the resin concomitant with deprotection of the tert - butyl group by means of an acidic cleavage cocktail ( 93 % tfa , 5 % tis and 2 % water ) for 3 h . the solution was then cooled to 0 ° c . and the pmb - protected pyrazole - peptide was precipitated and washed with cold diethyl ether . the colorless solid was dried in vacuo . to cleave the pmb - protecting groups on the pyrazole nucleus , the colorless solid was heated under argon in dry tfa for 5 h to 70 ° c . the solution was cooled to 0 ° c . and treated according to general procedure e to yield the pure trimer - peptide . 1 h nmr ( 500 mhz , dmso - d 6 ): δ [ ppm ]= 0 . 83 - 0 . 92 ( m , 7h ), 1 . 23 ( s , 1h ), 1 . 40 - 1 . 45 ( m , 1h ), 1 . 65 - 1 . 95 ( m , 6h ), 2 . 56 - 2 . 61 ( m , 1h ), 2 . 68 - 2 . 84 ( m , 3h ), 2 . 93 - 3 . 06 ( m , 2h ), 3 . 48 - 3 . 52 ( m , 1h ), 3 . 68 - 3 . 72 ( m , 1h ), 4 . 32 - 4 . 43 ( m , 2h ), 4 . 53 - 4 . 58 ( m , 2h ), 4 . 68 - 4 . 73 ( m , 1h ), 7 . 15 - 7 . 29 ( m , 12h ), 7 . 54 ( bs , 1h ), 7 . 78 ( d , 1h ), 7 . 94 ( s , 1h ), 8 . 03 ( d , 1h ), 8 . 36 ( d , 1h ), 8 . 64 ( bs , 1h ), 11 . 07 ( bs , 1h ), 11 . 43 ( s , 1h ), 14 . 98 ( s , 1h ). 13 c nmr ( 125 mhz , dmso - d 6 ): δ [ ppm ]= 21 . 2 , 23 . 1 , 24 . 1 , 24 . 3 , 28 . 6 , 35 . 9 , 37 . 2 , 37 . 5 , 46 . 6 , 48 . 5 , 48 . 8 , 56 . 4 , 53 . 6 , 59 . 2 , 102 . 2 , 126 . 0 , 126 . 1 , 127 . 9 , 129 . 1 , 129 . 2 , 137 . 5 , 138 . 6 , 155 . 0 , 170 . 4 , 170 . 5 , 107 . 6 , 171 . 0 , 171 . 5 , 172 . 1 . mp : decomposition at 198 ° c . hrms ( esi , neg . ): calcd for c 45 h 49 n 14 o 13 : 993 . 3609 ; found : 993 . 3588 , ( ½ m ) 2 − : calcd for c 45 h 49 n 14 o 13 : 496 . 1762 ; found : 496 . 1767 , ( ⅓ m ) 3 − : calcd for c 45 h 49 n 14 o 13 : 330 . 4482 ; found : 330 . 4488 . trimer - teg - lpffd - oh was synthesized using the same procedure as the previous ( trimer - lpffd - oh ). trimer - teg - oh ( 3 . 00 equiv ) was used instead of trimer - oh in this case . 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 0 . 85 - 0 . 88 ( m , 6h ), 1 . 34 - 1 . 93 ( m , 7h ), 2 . 54 - 3 . 07 ( m , 6h ), 3 . 37 - 3 . 42 ( m , 4h ), 3 . 51 - 3 . 59 ( m , 10h ), 3 . 90 ( s , 2h ), 4 . 30 - 4 . 32 ( m , 1h ), 4 . 37 - 4 . 42 ( m , 1h ), 4 . 52 - 4 . 62 ( m , 2h ), 7 . 16 - 7 . 24 , 7 . 53 ( brs , 1h ), 7 . 65 ( d , 1h ), 7 . 77 ( d , 1h ), 7 . 93 ( s , 1h ), 8 . 00 ( d , 1h ), 8 . 35 ( d , 1h ), 8 . 52 ( brs , 1h ), 11 . 07 ( s , 1h ), 11 . 43 ( s , 1h ), 12 . 81 ( brs , 2h ), 13 . 48 ( brs , 1h ), 14 . 98 ( s , 1h ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 21 . 3 , 23 . 2 , 23 . 3 , 24 . 0 , 24 . 2 , 28 . 7 , 36 . 0 , 37 . 2 , 37 . 6 , 38 . 5 , 40 . 3 , 46 . 6 , 48 . 0 , 48 . 6 , 53 . 4 , 53 . 8 , 59 . 2 , 68 . 7 , 69 . 5 , 69 . 7 , 70 . 2 , 94 . 6 , 96 . 7 , 98 . 1 , 102 . 3 , 126 . 1 , 126 . 2 , 127 . 8 , 127 . 9 , 129 . 1 , 129 . 2 , 137 . 4 , 137 . 5 , 138 . 6 , 155 . 0 , 155 . 8 , 168 . 9 , 170 . 2 , 170 . 5 , 170 . 7 , 171 . 1 , 171 . 6 , 172 . 1 . hrms ( esi ): [ m - h ] − = m / z calcd for c 53 h 63 n 15 o 17 : 590 . 7269 ; found : 590 . 7397 . a wang - resin was used as a polymer support , preloaded with fmoc - phe and an average loading of 0 . 65 mmol / g . prior to the first coupling step , the resin was swollen in dmf for 80 min . the coupling of fmoc - protected amino acids was accomplished by using hbtu and diisopropyletylamine according to the following method : for each coupling step , 9 - fluorenyl - methoxycarbonylamino acid ( 8 . 00 equiv ), hbtu ( 7 . 62 equiv ) and diisopropyletylamine ( 16 . 00 equiv ) were used in a dmf solution . removal of the fmoc - protecting group was carried out with 20 % piperidine in dmf ( 1 × 3 min , 1 × 7 min ). each coupling and deprotecting step was followed by washing the resin with dmf . the completeness of each coupling step was checked with nf31 - and kaiser - test . after four cycles , the resin was coupled with pmb - protected trimer - teg - oh ( 3 . 00 equiv ), hbtu ( 3 . 30 equiv ) and diisopropyletylamine ( 6 . 00 equiv ) in dmf solution for 16 h . the pyrazole - teg - peptide compound was cleaved off the resin concomitant with deprotection of the tert - butyl group by means of an acidic cleavage cocktail ( 93 % tfa , 5 % tis and 2 % water ) for 3 h . the solution was then cooled to 0 ° c . and the pmb - protected pyrazole - peptide was precipitated and washed with cold diethyl ether . the colorless solid was dried in vacuo . to cleave the pmb - protecting groups on the pyrazole nucleus , the colorless solid was heated under argon in dry tfa for 5 h to 70 ° c . the solution was cooled to 0 ° c . and treated according to general procedure e to yield the pure trimer - teg - peptide . 1 h - nmr ( 500 mhz , cdcl 3 ): δ [ ppm ]= 0 . 69 - 0 . 70 ( m , 6h ), 0 . 79 - 0 . 85 ( m , 6h ), 1 . 23 - 1 . 68 ( m , 9h ), 1 . 82 - 1 . 89 ( m , 1h ), 2 . 68 - 3 . 09 ( m , 6h ), 3 . 51 - 3 . 59 ( m , 12h ), 3 . 91 ( s , 2h ), 4 . 07 - 4 . 10 ( m , 1h ), 4 . 29 - 4 . 38 ( m , 2h ), 4 . 42 - 4 . 47 ( m , 1h ), 4 . 54 - 4 . 58 ( m , 1h ), 7 . 14 - 7 . 27 ( m , 10h ), 7 . 62 - 7 . 63 ( m , 4h ), 7 . 69 - 7 . 70 ( d , 1h ), 7 . 92 - 7 . 93 ( brs , 2h ), 8 . 1 - 8 . 12 ( d , 1h ), 8 . 23 - 8 . 8 . 24 ( d , 1h ), 8 . 55 ( brs , 1h ), 11 . 10 ( brs , 1h ), 11 . 34 ( s , 1h ), 13 . 21 ( brs , 1h ), 13 . 49 (( brs , 1h ), 14 . 98 ( brs , 1h ). 13 c - nmr ( 125 . 7 mhz , cdcl 3 ): δ [ ppm ]= 18 . 0 , 19 . 2 , 21 . 6 , 22 . 0 , 23 . 1 , 24 . 2 , 26 . 7 , 30 . 8 , 31 . 9 , 36 . 7 , 37 . 6 , 38 . 6 , 38 . 8 , 51 . 0 , 51 . 4 , 53 . 3 , 53 . 4 , 57 . 5 , 68 . 8 , 69 . 6 , 69 . 8 , 70 . 3 , 102 . 3 , 126 . 2 , 126 . 5 , 128 . 0 , 128 . 2 , 129 . 1 , 137 . 3 , 137 . 5 , 155 . 1 , 155 . 9 , 169 . 0 , 170 . 4 , 170 . 9 , 171 . 0 , 171 . 6 , 172 . 6 . the aβ ( 1 - 40 ) peptide ( bachem , bubendorf , germany ) was dissolved in dmso and stored as ( 4 μl )- aliquots at − 20 ° c . until use . aβ ( 1 - 42 )- peptide ( bachem , bubendorf , germany ) was prepared in hfip ( hexafluoroisopropanol ), lyophilized , redissolved in dmso and stored as ( 4 μl )- aliquots at − 20 ° c . the ligands were dissolved in 100 % dmso as 4 . 95 mm stock solutions and were stored at − 20 ° c . thioflavin t ( tht ) measurements were carried out in a 384 - well plate ( nunc gmbh , wiesbaden , germany ) in an infinite 200 plate reader ( tecan gmbh , crailsheim , germany ). fluorescence intensity was measured at 37 ° c ., 446 nm excitation wavelength ( bandwidth 9 nm ) and 490 nm emission wavelength with a bandwidth of 20 nm . each data point was averaged over 40 lamp flashes . each measurement cycle was started by shaking the sample carrier orbitally for 30 s at medium intensity to avoid settling of larger aggregates . the 384 - well plate was covered with a transparent and dmso - stable film ( nunc gmbh , wiesbaden , germany ). each single sample was composed of 33 μm aβ ( 1 - 40 ) or rather aβ ( 1 - 42 ) in 10 mm pbs ( phosphate buffered saline ), 10 . 7 % dmso , 10 μm tht and 198 μm of the test compound . for graph representation emission values of fourfold samples were averaged . each test compound was measured separately , both in 10 mm pbs and 10 mm pbs with tht to exclude any potential interactions between ligand and tht . to an aliquot of 4 μl aβ ( 1 - 42 )- peptide ( 495 μm stock solution ) was first added 2 . 4 μl of the test compound ( 4 . 95 mm stock solution ). then , a mixture of 9 . 5 μl tht ( 62 . 7 μm stock solution ), 6 μl pbs and 38 . 1 μl water ( bidest .) was pipetted . afterwards the mixture was vortexed and briefly centrifugated . sixty μl of aggregation mixtures were pipetted in a 384 - well plate and the fluorescence intensity ( exc . at 446 nm , em . at 490 nm ) was measured every hour at 37 ° c . the 384 - well sample carrier was agitated 30 s before each measurement . each point is the average of quadruplication . a mixture of 4 μl aβ ( 1 - 42 )- peptide ( 495 μm stock solution ), 9 . 5 μl tht ( 62 . 7 μm stock solution ), 6 μl pbs and 38 . 1 μl water ( bidest .) was incubated for 24 h in a 384 - well plate at 37 ° c . the fluorescence intensity was measured every hour and the 384 - well sample carrier was agitated 30 s before each measurement . after 24 h , 2 . 4 μl of the test compound ( 4 . 95 mm stock solution ) was added to the solution . the fluorescence measurements were observed / monitored every hour within 5 days and each measurement cycle was started by shaking the sample carrier orbitally for 30 s . for graph representation emission values of fourfold samples were averaged . a mixture of 4 μl aβ ( 1 - 42 )- peptide ( 495 μm stock solution ), 2 . 4 μl of the test compound ( 4 . 95 mm stock solution ), 9 . 5 μl tht ( 62 . 7 μm stock solution ), 6 μl pbs and 38 . 1 μl water ( bidest .) was incubated in a thermo mixer ( 600 rpm ) at 37 ° c . for 72 h . the tht assay solution was briefly centrifugated and it was pipetted in a 384 - well plate . the tht fluorescence was measured at λ ex = 446 nm and λ em = 490 nm . each point is the average of quadruplication . to obtain preformed fibrils , a mixture of 4 μl aβ ( 1 - 42 )- peptide ( 495 μm stock solution ), 6 μl pbs and 38 . 1 μl water ( bidest .) was incubated in a thermo mixer ( 600 rpm ) at 37 ° c . for 72 h . then , the test compound ( 2 . 4 μl of a 4 . 95 mm stock solution ) was added and the solution was incubated for further five days . after that , 9 . 5 μl tht ( 62 . 7 μm stock solution ) was pipetted and the assay solution was briefly centrifugated . the tht fluorescence was measured at λ ex = 446 nm and λ em = 490 nm . for graph representation emission values of fourfold samples were averaged . aβ ( 1 - 42 )- peptide ( bachem , bubendorf , germany ) was prepared in hfip ( hexafluoroisopropanol ), lyophilized , dissolved in dmso and stored at − 20 ° c . aβ ( 1 - 42 ) was dissolved in hfip to a concentration of 500 μm . this solution was diluted with 5 μm potassium phosphate buffer ( ph 7 . 3 ) to a final peptide concentration of 10 μm . the single sample was composed of 10 μm aβ ( 1 - 42 ), 5 μm potassium phosphate buffer ( ph 7 . 3 ), 2 % hfip and 10 μm of the test compound . the samples were transferred to a 10 mm pathlength cuvette immediately after mixing and circular dichroism spectra were recorded on a j - 810 spectropolarimeter ( jasco ). measurement range : 190 nm - 400 nm . data pitch : 1 nm . response : 1 s . sensitivity : standard . scanning speed : 100 nm / min . accumulation : 1 . temperature : 22 ° c . a confocor i instrument ( zeiss , evotec ) was equipped with an argon ion laser . a 24 well sample carrier was covered with tesafilm to avoid evaporation . experiments were carried out at ambient temperature . rhodamine 6g calibration was ensured before each measurement . measurement time was 30 s , in a 20 μl total volume . data evaluation involved determination of the number and height of peaks measured above a threshold given by 5 times the standard deviation of the fluorescence fluctuation . all solutions were sterile filtered before use through 0 . 22 μm filters . measurements were performed with the confocor i instrument ( zeiss , jena , evotec , hamburg , germany ) equipped with an argon laser . the pinhole diameter was 45 μm , and the focus was set 200 μm above the cover glass . adjustment of diffusion times was achieved by comparing with rhodamine 6g . measurements were made on lab - tek chambered borosilicate cover glasses ( nalge nunc int . corp ., naperville , ill .) used as sample carriers . the fluorescent probe aβ ( 1 - 42 ) was synthesized in solid phase using fmoc chemistry and labeled directly at the n - terminus with oregongreen ™ ( molecular probes , leiden , the netherlands ). the peptide was purified by reverse - phase hplc . purity was & gt ; 95 % as estimated by reversed phase hplc and mass spectrometric analysis ( dr . p . henklein , institute of biochemistry , charité berlin , germany ). the stock solution contained 500 nm labeled peptide in 5 % water - free dmso , 10 mm sodium phosphate , ph 7 . 2 , and was filtered through 0 . 45 μm pore nylon filters . although originally chosen for combination with unlabeled aβ ( 1 - 42 ) it proved to be more advantageous to use this probe with the less aggressively aggregating aβ ( 1 - 40 ). the unlabeled aβ ( 1 - 40 ) ( sigma ) was dissolved at 500 μm in 100 % water - free dmso . comparative measurements with different ligands were performed with trifluoroacetate salts of the ligands , which rendered the sample preparation more convenient because of their higher solubility . the ligands were dissolved at a concentration of 5 . 4 mm in 100 % dmso . the final incubation assay contained 20 μm aβ ( 1 - 40 ), 10 nm oregongreen ™- labeled aβ ( 1 - 42 ), with or without 100 μm ligand in 10 mm sodium phosphate and 6 % dmso in a 50 μl final volume . all solutions were sterile filtered except the aβ ( 1 - 40 ) stock solution . for each sample the fluorescence intensities were recorded 10 times for 60 s directly after mixing and again after 1 day of incubation at room temperature . it should be noted that the sample holder of the instrument is not thermostated , so experiments were performed at ambient temperature . the concentration dependence was analyzed by repeated measurement cycles beginning after 2 h of incubation at room temperature and lasting for 8 h . in each cycle fluorescence fluctuations for each sample position were measured 20 times for 30 s with a resolution of 16 . 7 data points / s . all samples contained 10 mm sodium phosphate , ph 7 . 2 , 50 mm nacl , 33 μm aβ ( 1 - 40 ) ( bachem biochemica , heidelberg , germany ), 8 % dmso , and 5 . 6 nm oregongreen ™- labeled aβ ( 1 - 42 ). the concentration of the ligand varied from 1 . 35 to 108 μm . sedimentation velocity centrifugation was performed in an xla ( beckmancoulter , palo alto , usa ) equipped with absorption optics and a four hole titanium rotor . prior to the centrifugation the solutions were incubated slightly agitated at room temperature for different incubation times . sample volumes ranging from 300 to 400 μl were filled into standard double sector aluminum center pieces and spun at 20 , 000 rpm , 20 ° c . after thermal calibration . radial scans were recorded at a resolution of 0 . 002 cm . detection wavelength was chosen at 493 nm to observe endlabeled fitc or oregon green ™ and to avoid background absorbance from the test compound . sedimentation data were analyzed with ultrascan 9 . 4 ( http :// www . ultrascan . uthscsa . edu ). after timeinvariant noise subtraction , s - value distributions were determined model independently using the enhanced van holdeweischet method in the ultrascan software ( demeler and van holde 2004 , van holde and weischet 1978 ). molecular weight and frictional ratios were determined with two - dimensional spectrum analysis ( brookes et al . 2006 ) and the genetic algorithm optimization method ( brookes and demeler 2006 , 2007 ). hydrodynamic corrections for buffer conditions were made according to data published by laue et al . ( 1992 ) as implemented in ultrascan . the partial specific volume of the aβ42 , v = 0 . 7377 cm 3 / g was calculated on the basis of its amino acid content by a routine implemented in ultrascan . experimental intensity data were timeinvariant noise corrected using the 2dsa analysis . the van holdeweischet analysis was used to initialize the svalue range in the 2dsa from 1150 s . the frictional ratio range was initialized between 110 . 2dsa analyses were performed with 24 grid movings with a 10 point resolution in both dimensions , resulting in a final svalue resolution of 0 . 625 s and 0 . 042 f / f 0 units . the 2dsa results were used to initialize the ga analysis , and parsimoniously regularized ga distributions were used to initialize the ga monte carlo analysis . data were analyzed on the bioinformatics core facility cluster ( university of texas , health science center , san antonio , tex ., usa ) and on the lonestar cluster at the texas advanced computing center ( austin , tex ., usa ). the hydrodynamic behavior of a molecule sedimenting in a sector shaped cell is fully described by the lamm equation ( lamm 1929 ). in the case of polydisperse samples the shape of the sedimentation boundary and its evolution over time contains information about size , shape and partial concentration of the sedimenting species . to extract the information a linear combination of solutions of the lamm equation is fitted to the experimental data . the simulated solutes represented in the linear combination of lamm equations covers both the sedimentation coefficient range as well as the frictional ratio range of solutes present in the experimental data . tem experiments were performed with a phillips cm 200 feg instrument . after absorbing 5 μl of a tenfold diluted sample of the solution used for analytical ultracentrifugation to the holey carbon film coated copper grids ( plano , wetzlar , germany ) the samples were washed twice with 0 . 1 and 0 . 01 mm ammonium acetate and then negatively stained with 2 % ( w / v ) ammonium molybdate solution for 90 s . mtt viability assays . cell viability assays were performed as described in fradinger et al . ( fradinger et al ., pnas , 2008 ). rat pheochromocytoma ( pc - 12 ) cells were maintained in f - 12 nutrient mixture with kaighn &# 39 ; s modification ( f - 12k ) ( gibco brl , carlsbad , calif .) with 15 % heat - inactivated horse serum and 2 . 5 % fbs at 37 ° c . in an atmosphere of 5 % co 2 . for cell viability assays , cells were plated in 96 - well plates at a density of 25 , 000 cells per well in differentiation media ( f - 12k , 0 . 5 % fbs , 100 mm nerve growth factor ) and maintained for 48 h . aβ42 was solubilized in a minimal amount of dmso ( sigma ) and then diluted in the f - 12k media in the absence or presence of the compounds and then added to cells and incubated for 48 h at 37 ° c . the final aβ42 concentration was always kept constant at 10 μm . the stock solutions of the compounds were prepared at 10 mm in dmso and diluted in the f - 12k media at the required concentration . negative controls included dmso at the same concentration as in the peptide solutions and media alone . a positive control was 1 mm staurosporine as lethal dose which represented 100 % reduction in cell viability , based on which the percentage viability of all of the experimental conditions was calculated . cell viability was assessed quantitatively by the celltiter 96 non - radioactive cell proliferation assay ( promega ). briefly , 15 μl of 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetra - zolium bromide ( mtt ) dye solution was incubated with the cells for 3 h . then 100 μl of solubilization / stop solution was added and the plates were incubated overnight in the dark to ensure complete solubilization . plates were read by using a synergy ht microplate reader ( biotek ), and the absorbance at 570 nm ( formazan product ) minus the absorbance at 630 nm ( background ) was recorded . corrected absorbance was used to calculate the percent cell viability from the experimental change ( amedia - aexperimental ) over the dynamic range ( amedia - astaurosporine ). at least three independent experiments with six replicates ( n ≧ 18 ) were carried out , and the results were averaged . to determine the ic 50 value of each of the compounds , dose - dependence mtt experiments with the compounds were conducted . aβ42 was used at 10 μm and the compounds were used at 100 , 30 , 10 , 3 , 1 and 0 . 3 μm . three independent experiments with six replicates ( n ≧ 18 ) were carried out , and results were averaged . the data for each compound was fitted to the following equation to get the ic50 values . top : the y value at which the top of the sigmoidal curve becomes parallel to the x - axis ; bottom : the y value at which the bottom of the sigmoidal curve becomes parallel to the x - axis . ic 50 in this respect is defined as the concentration of the β - sheet ligand ( aminopyrazole trimer derivative ), at which the inhibition of aβ toxicity just reaches 50 %. fig1 shows dose - response curves for the inhibition of aβ - induced toxicity in pc - 12 cells by aminopyrazole trimer derivatives . also , mtt viability assays were run with differentiated pc - 12 cells . healthy cells ( viability 100 %) were lesioned on day 1 with 10 μm aβ ( 1 - 42 ) and simultaneously protected by 100 μm solutions of aminopyrazoles . after 8 days , the living cells were counted and compared to the untreated control ( 70 %/ 80 %). in both series ( with and without teg spacers ) several candidates rescued cell viability significantly , the most impressive results stemming from the teg - spacered derivatives ( fig1 a and 13b ). intriguingly , the most efficient inhibition of aβ toxicity was achieved with 3 lipophilic extensions and trimer - teg - lys , which were also superior in tht and related assays . the two gaba derivatives are a surprise — they might potentially interact with gaba receptors and not with the aβ peptide itself . the above - delineated findings demonstrate , that trimeric aminopyrazoles are indeed active against aβ - induced toxicity in living cells ; they also provide experimental evidence for their low toxicity at relatively high doses of 0 . 1 mm , in spite of , e . g ., the presence of an n - terminal nitro group .

the present invention relates to the field of protein misfolding diseases and thus to diseases which are associated with or induced by abnormal or pathogenic three - dimensional folding of proteins and / or peptides or which are linked to pathogenic conformational changes of proteins and / or peptides , such as alzheimer &# 39 ; s disease . particularly , the present invention provides novel trimeric pyrazole compounds , which exhibit a therapeutic effectiveness in regard to the aforementioned protein misfolding diseases , and refers to their use for the treatment of such protein misfolding diseases , especially neurodegenerative diseases as well as to medicaments or pharmaceutical compositions comprising these compounds .

referring to appended drawings , the multiple tubes combination structure of the present invention is illustrated . in the following , one embodiment of the present invention will be described . referring to the appended drawings , the combinational structure 1 of multiple tubes includes a base 2 , a buckle seat 3 , a first connecting plate 4 , a tube assembly 5 , a second connecting plate 6 , a toggle 7 , and an outer buckle 8 . one lateral side of the base 2 is used to connect an air valve of an air supply pump . another lateral side thereof is connected to the buckle seat 3 . one side of the base has a plurality of tracks 22 . the base has a plurality of penetrating tube bodies 21 . one of the tubes is a positioning tube body 211 which has a special shape . the buckle seat 3 is a hollow ring . a plurality of buckling plates 32 are arranged around an outer edge of the buckle seat 3 . the number of the buckling plate 32 is equal to that of the tracks 22 . the buckling plate 32 can be buckled in the track 22 . thereby , the buckling seat 3 can be combined to the base 2 . a plurality of locking holes 63 are formed on the buckling seat 3 . the first connecting plate 4 is a round plate corresponding to the buckle seat 3 . a plurality of through holes 41 are formed on the first connecting plate 4 . the arrangement and number of the first opening 41 are identical to those of the tube bodies 21 . one of the plurality of through holes 411 is a positioning through hole 411 having a predetermined shape for being inserted by the positioning tube body 211 . one side of the first connecting plate 4 has a plurality of posts 42 . a top of each post 42 has a locking hole 43 . the tube assembly 5 has a plurality of tubes 51 . one of the tubes 51 is a positioning tube 50 . the shape of the positioning tube 50 is like that of the positioning through hole 411 . the upper and lower ends of each tube body 51 are installed with an upper buckling portion 511 and a lower buckling portion 512 , respectively . the upper buckling portion 511 can be inserted into the opening 41 of the first connecting plate 4 . the second connecting plate 6 is a round plate approximately identical to that of the first connecting plate 4 . a plurality of openings 61 corresponding to the openings 41 are formed on the second connecting plate 6 . a positioning opening 611 having a predetermined shape is installed in the opening 61 . the positioning tube 50 in the tube assembly 5 can be inserted into the positioning opening 611 . a plurality of posts 62 are installed at one side of the second connecting plate 6 . the top of each post 62 is installed with a locking hole 63 . a toggle 7 is a hollow tube . the toggle 7 can enclose the tube assembly 5 . the outer periphery of the toggle 7 has a plurality of locking holes 71 . the positions and number of the locking holes 71 are identical to those of the locking holes 31 . the outer buckle 8 has a shape and a structure approximately identical to those of the first connecting plate 4 and second connecting plate 6 . a plurality of openings 81 are formed on the outer buckle 8 . one of the openings 81 is a positioning opening 811 with a predetermined shape . moreover , the outer buckle 8 has a plurality of locking holes 82 the number of which is equal to that of the locking holes 63 . in assembly , the tube assembly 5 can be buckled between the first connecting plate 4 and second connecting plate 6 . especially , the positioning tube 50 can be inserted between the positioning openings 411 and 611 . then the first connecting plate 4 and second connecting plate 6 are locked by screwing a plurality of screws into the locking holes 43 . then , the toggle 7 encloses the tube assembly 5 . then , screws 33 screws through the locking holes 31 so that the buckle seat 3 is locked to the toggle 7 . finally , the tube assembly 5 protruding from the first connecting plate 4 is buckled to the tube bodies 21 of the base 2 . the buckling plates 32 are buckled to the tracks 22 . thereby , the assembly of the multiple tubes combination structure is complete . 1 . the plurality of tube bodies 51 are cylinders and modulized . when it is desired to install the tube bodies 51 with the tube bodies 21 of the base 2 . it is only necessary to assure the configurations of the positioning tubes 50 and 211 . no error occurs , while conventionally , the tubes are assembled one by one . thereby , the multiple tubes combination structure of the present invention has a beautiful outlook . 2 . referring to fig6 when it is desired to combine the air tubes 9 to the present invention , the air tubes 9 are inserted to the protruding ends of the tube assembly 5 . then , the buckle 8 is assembled . by screwing the screws 83 through the locking holes 82 , the buckle 8 is locked to the second connecting plate 6 . by tightening the opening 81 with the buckling portions 512 of the tube body 51 , the air tubes can be tightly engaged . obviously , the assembly of the present invention is very easy . 3 . since the positioning tube 211 , positioning openings 411 , 611 and 811 all having special shapes are installed , each component can be assembled correctly . therefore , a correct modulized structure can be obtained . although the present invention has been described with reference to the preferred embodiments , it will be understood that the invention is not limited to the details described thereof . various substitutions and modifications have been suggested in the foregoing description , and others will occur to those of ordinary skill in the art . therefore , all such substitutions and modifications are intended to be embraced within the scope of the invention as defined in the appended claims .

a multiple tubes combination structure for being assembled with air tubes of an airbed is disclosed , wherein a plurality of tubes are assembled in a combinational structure . each individual component of the combinational structure has a specific element having a predetermined configuration . thereby , when it is desired to assemble the combinational structure , it is only necessary to assure the configurations of elements . no error occurs . thereby , the multiple tubes combination structure has a beautiful outlook .

as used in the present specification , the singular forms “ a ”, “ an ” and “ the ” include plural aspects unless the context clearly dictates otherwise . thus , for example , reference to a whey protein includes one or more whey proteins . also , as used herein , “ and / or ” refers to and encompasses any and all possible combinations of one or more of the associated listed items . furthermore , the term “ about ,” as used herein when referring to a measurable value such as an amount of a compound , dose , time , temperature , and the like , is meant to encompass variations of 20 %, 10 %, 5 %, 1 %, 0 . 5 %, or even 0 . 1 % of the specified amount . unless otherwise defined , all terms , including technical and scientific terms used in the description , have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . all publications , patent applications , patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented . the present inventors have examined the biological activities provided by various orally administered milk fractions as set forth herein . in particular , it has been discovered that whey protein isolate ( wpi ), a milk fraction that contains whey proteins and that may be further obtained from a variety of sources , including cheese whey and acid / casein whey , possesses an anti - inflammatory activity as identified by an in vitro assay of tnfα expression inhibition . it has further been discovered that the hydrolysis of wpi unexpectedly results in an increase in this anti - inflammatory activity . hydrolysis of whey protein also enhanced the ability of whey protein to stimulate the growth of fibroblasts in vitro . the present inventors have further identified that the administration of the enzyme hydrolysate of wpi is able to attenuate symptoms of muscle damage and promote the recovery of muscle function in subjects after muscle - damaging exercise . this activity is greater than the activity possessed by the corresponding non - hydrolyzed form of wpi . the hydrolysate of wpi was also able to enhance the muscle force generating ability in subjects subjected to muscle - damaging exercise . according to particular embodiments of the present invention , a biological assay used to determine activity is used to validate efficacy . “ validating ” or “ validation ” as used herein refers to the confirmation of a property possessed or proposed to be possessed by a sample . “ efficacy ” as used herein refers to the ability of the sample to provide the desired amount of a desired effect . a “ biological assay ” includes any cellular assay as described herein and as understood those by those skilled in the art to provide assessment of a selected parameter ( s ). the term “ biological activity ” as used herein refers to any activity of the sample on cells or tissues and includes , but is not limited to , physiological , chemical and mechanical activity as such relates to biological processes . the term “ sample ” as used herein refers to a portion of a diary or milk - containing product . in particular embodiments , a sample refers to a milk fraction . the sample may be taken from an end product of the production process for the product , or may be an intermediate . the sample may also be a stored product , wherein the sample is tested to see if the product has maintained activity . the validation process may be used to determine the shelf life of the product , the effect of temperature and further processing steps , for example lyophilization , encapsulation , etc . the present invention is particularly applicable to validating the efficacy of nutraceuticals , particularly those derived from milk . however , the present invention may be extrapolated to any product whose activity is determined using a cellular assay and whose production is not 100 % guaranteed , giving the possibility that a sample of the product may not have the desired activity . this may be particularly the case if the product is produced by an enzyme or under stringent conditions . milk and its fractions have been proposed to have many activities , as tested by biological assays . for example , a milk fraction was described in u . s . patent application publication no . 2007110818 as having cox - 2 inhibitory activity as tested by assaying for inhibition of prostaglandin e2 production from huv - ec - c cells ( a permanent endothelial cell line derived from the vein of a normal human umbilical cord ; atcc crl1730 ; m . miralpeix , m . camacho et al ., brit . j . pharmacol . 121 ( 1997 ), 171 - 180 ). australian patent application no . 200690303232 describes milk fractions that improve muscle function or recovery as tested by assaying for tnfα inhibition or stimulation of fibroblast cell division in vitro . wo 2007 / 028211 describes that wgfe decreases post - exercise inflammatory responses in muscle as tested by assaying for reduced tnfα expression in raw cells . wo 2007 / 028210 describes that wgfe and wpi increase muscle strength as tested by assaying for increased myoblast cell growth and fibroblast proliferation in vitro . in particular embodiments of the present invention , the biological assays are cell - based assays . other biological assays may include , but are not limited to , differential gene expression and biomarker analysis , motility , chemotaxis , contraction , relaxation , biosynthesis , secretion of signaling molecules , depolarization , repolarization , degranulation , adhesion , aggregation , change in metabolic rate , and immediate cellular responses and other assays known in the art . other biological activities for protein fractions from milk or other sources or whole protein extracts will be known to those skilled in the art , as will assays for evaluating such biological function . in particular embodiments , the sample is a milk fraction . throughout the specification the term “ milk fraction ” refers to a composition which is ultimately derived from milk and which is at least enriched in one or more constituents found in whole milk . a “ milk fraction ” may be one that contains non - casein proteins found in milk . whey or “ milk plasma ” is a common milk fraction which remains after the process of “ curdling ” has removed much of the casein and milk fat component from whole milk or skim milk . “ milk fraction ” includes fractions that have been enriched for specific components or combinations of components of milk . the milk fraction “ whey protein isolate ” ( wpi ), for instance , is one in which the non - casein protein components of milk have been enriched when compared with whole milk . “ whey protein ” includes one or more protein ( s ) which are found in whey and which , when hydrolyzed , possesses the desired biological activity described herein . different sources of whey protein are contemplated . in particular , whey protein originating from sweet whey or from acid whey have both been demonstrated to possess similar activity . there are , for example , numerous methods for the production of whey , for instance , as by - products arising during the production of different forms of cheese or as a by - product of the casein making process , and each of these will produce whey with a somewhat different composition . the principal proteins found in whey are α - lactalbumin and β - lactoglobulin and caseinoglycomacropeptide ( cgmp ), the latter forming about 25 % of protein present in cheese whey wpi . milk fractions that contain one or more of these proteins are also contemplated . the milk may be from cows , or due to the relatively similar composition of milk possessed by domestic species , it is contemplated that milk from other animals including sheep , goats , horses and buffalo will be suitable . there may also be advantages in using whey protein of human origin , for instance in the preparation of compositions for administration to newborn babies . the methods of the present invention are particularly useful for validating the efficacy of nutraceuticals . a “ nutraceutical ” as defined herein represents an edible product isolated or purified from food , which is demonstrated to have a physiological benefit or to provide protection or attenuation of an acute or chronic disease or injury when orally administered . the nutraceutical may thus be presented in the form of a dietary supplement , either alone or admixed with edible foods or drinks . the nutraceutical composition may be in any suitable form . for example , the nutritional composition may be in the form of a soluble powder , a liquid or a ready - to - drink formulation . alternatively , the nutritional composition may be in solid form ; for example , in the form of a ready - to - eat bar , breakfast cereal or cookie , as a powder , or capsules or other form . various flavors , fibers , sweeteners , and other additives may also be present . it will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding , various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification . the present invention will now be described with reference to the following , non limiting examples : the aim of the wpi process is to enrich whey proteins by removing other whey components , such as water , lactose , fat , and ash ( which comprises the mineral component of milk such as phosphorous , sodium , potassium , calcium , magnesium , and other metals ), until the remaining material is greater than 90 % whey proteins ( sample basis ). processes that are commonly used commercially to produce wpi include steps of anion exchange chromatographic separation , ultrafiltration ( uf ) and spray drying . the wpi production process works on the principle of anion exchange chromatography , with a large diameter resin that allows for a high flow rates with viscous materials . the starting material may be sweet whey produced by rennet coagulation or acid whey , which results from the removal of casein by adding an acid . whey produced by other methods , such as ultracentrifugation , microfiltration or ethanol precipitation may also be suitable . ideally , the starting material for wpi production is wpc35 ( whey protein concentrate 35 % w protein / w solids ), which is a generic product produced by the ultrafiltration of raw whey to remove ash and lactose . this process is widely known to those in the dairy industry . a very similar product is also produced by using skim milk instead of whey . the starting material is introduced onto anion exchange columns ( gibcocel cr201 ) to load the resin with predominantly negatively charged ( at the ph of whey of 6 . 5 ) whey components . the columns are rinsed with water to remove unbound materials , and the bound whey components are eluted and the columns regenerated with a mixture containing 0 . 75 m sodium chloride and 0 . 75 m potassium chloride , after which the columns are rinsed to remove residual chloride . the whey components eluted from the csep are desalted and concentrated by diafiltration through low temperature , low molecular weight , spiral ultrafiltration membranes . this step retains proteins , but removes salt , ash components and lactose . during this step , total solids rise from 4 % to 25 % and the protein concentration rises from 50 % of total solids to greater than 90 % of total solids . the purpose of the dryer is to remove the majority of the remaining water in the product until a maximum of 5 % water remains . the dryer does this by atomizing the wpi concentrate in a chamber filled with hot air . as the resultant wpi powder is subsequently reconstituted in water as it is prepared for the hydrolysis , it may be possible to eliminate the drying step from this process . the inventors have examined hydrolysates of wpi produced from cheese whey and from acid whey . both contain similar bioactivity on enzyme digestion , and so it is likely that the type of wpi will not materially alter the resultant biological activity produced by the wpi hydrolysate . wpi from each of sweet whey and acid whey wpi were used for the manufacture of the hydrolysates tested in vitro , but only sweet whey wpi hydrolysates were tested in vivo . the hydrolysates produced from sweet whey wpi and from acid whey wpi demonstrated very little difference in the in vitro assays , and therefore it is expected that the results for sweet whey wpi hydrolysates in vivo may be extended to acid whey hydrolysates . the protease solution used in this example is a commercial product “ neutrase ”® ( novozymes ). the target ph for the hydrolysis reaction was ph 6 . 5 . the ph change during hydrolysis was limited , so it was practical to commence hydrolysis at ph 6 . 6 and not readjust the ph during the reaction . the final ph was around 6 . 4 . three kilograms of wpi as prepared according to example 1 was reconstituted in 271 water to make up 301 10 % ( w / v ) solids solution . the ph was adjusted to 6 . 6 with 4m naoh prior to heating to 50 ° c . once heating had commenced , the solution was stirred continuously . 4 . 5 g of neutrase ® 1 . 5mg ( novozyme ) was dissolved in 45 ml water to prepare a 10 % solution , which was then added to the wpi solution . the ph was continually monitored and adjusted only if ph fell below 6 . 4 . the hydrolysis process can be monitored in real time by the decrease in ph . the actual amount of hydrolysis that has taken place can be determined afterwards by measuring the “ degree of hydrolysis ” using a method based on o - phthalaldehyde ( for example lee et al ., 1978 ; supra ). the actual amount of hydrolysis taking place under the conditions described above is not very high , with an observed net degree of hydrolysis (%) between 0 . 3 and 3 . 0 . after 60 min hydrolysis , the solution was adjusted to ph 4 . 0 with 4m hcl and the temperature maintained at 50 ° c . for 30 min to deactivate the neutrase ®. the resulting hydrolysate was cooled to 25 ° c . and the ph readjusted ≧ ph 6 . 5 , and ideally to ph 7 . 0 . the hydrolysate was then dried , ideally by freeze - drying at 35 ° c . hydrolysates of wpi or other milk fractions , which contain whey protein are produced using other proteinase enzymes , and their activity in inhibiting the expression of tnfα in macrophages or stimulating fibroblast cell growth in the in vitro methods described herein in example 3 were screened . these hydrolysates are also screened for their activity in attenuating symptoms of muscle damage and in enhancing muscle contractile force in subjects using the methods described below . modulation of the expression of tnfα in macrophages and stimulation of fibroblast cell division in vitro raw264 . 7 macrophages were seeded into 96 - well plates at a density of 2 × 10 4 cells / well in dmem culture medium containing 10 % heat - inactivated fetal bovine serum ( fbs ). cells were then maintained in culture for 48 h at 37 ° c . upon reaching the optimal cell density , the serum - containing medium was removed and cells stimulated under serum - free conditions for 6 h at 37 ° c . with 50 ng / ml bacterial lipopolysaccharide ( escherichia coli 055 : b5 ) in the presence of either vehicle control ( 0 . 9 % saline ) or test dairy sample at 2 mg / ml . all samples contained sweetener and flavoring agent ; the placebo sample contained no other compounds , the wpi sample contained wpi obtained according to the method described in example 1 , the hydrolyzed wpi samples were taken from two different neutrase ® hydrolysis batches produced according to the method described in example 2 , and the casein sample contained commercially available casein ( acid casein , murray goulburn co - operative ). following the 6 h stimulation period , levels of tnfα present in the cell - conditioned medium were measured using a highly specific tnfα sandwich elisa and data expressed as % inhibition of tnfα release ( relative to cells pre - treated with vehicle alone ). cell viability was assessed by alamarblue staining . balbc3t3 fibroblasts were seeded into 96 - well plates at a density of 0 . 8 × 10 4 cells / well in dmem culture medium containing 10 % fetal bovine serum ( fbs ) and maintained in culture overnight at 37 ° c . following the overnight culture , the serum - containing medium was removed and cells stimulated in serum - free dmem medium containing either vehicle control ( 0 . 9 % saline ) or test sample at 2 mg / ml . all test samples contained sweetener and flavouring agent ; the placebo sample contained no other compounds , the wpi sample contained wpi produced according to the method of example 1 and the hydrolysed wpi samples were taken from two different batches of neutrase ® hydrolysis of wpi according to the method of example 2 . cells were maintained in culture for an additional 48 h , after which time the culture medium was aspirated and cell growth quantitated by alamarblue staining . data was expressed as % growth ( above cells treated with vehicle control ). the results of these experiments are presented in fig1 and 2 . of all the samples tested , the neutrase ® hydrolyzed wpi possessed the greatest activity both in inhibiting the expression of tnfα by lps stimulated macrophages and in stimulating the growth of fibroblasts . subsequent clinical trials showed that the neutrase ® hydrolyzed wpi was able to promote recovery from muscle damage after exercise . neutrase ® hydrolyzed wpi was prepared as described in examples 1 and 2 and test samples validated using the assays described in example 3 . during the optimization of process for the production of the hydrolysate , two thirds of the samples tested for activity were found not to have the desired activity and were discarded . now that the process has been optimized , 90 % of the samples tested have the required efficacy ( results not shown ).

the present invention provides a process for validating the efficacy of a sample having a known activity determined using a biological assay . the process includes subjecting the sample to a biological assay capable of testing for the activity . the process may optionally include an initial step of determining a biological assay for the desired activity . the present invention is particularly applicable to samples from milk .

the felling head 1 of the present invention , as shown in fig1 has upright frame 3 . a pair of curved , tree - gripping arms 5 are mounted on frame 3 near its upper end 7 by vertical pivot pins 9 . hydraulic actuators 11 are pivotally connected between the arms 5 and frame 3 for moving the arms 5 generally horizontally about their pivot pins 9 to grip or release a tree to be harvested . two locating arms 13 may be provided on the frame 3 adjacent its upper end 7 . the arms 13 diverge outwardly from frame 3 and help locate the tree relative to the frame 3 . a tree cutting mechanism 15 is mounted on the bottom of frame 3 . the tree cutting mechanism 15 is movable relative to the frame 3 . in more detail , as shown in fig1 and 4 , the tree cutting mechanism 15 of the present invention includes two rotary cutting devices 21 , 23 . each cutting device 21 , 23 preferably is a circular saw , the two saws 21 , 23 being the same diameter . one saw 21 is mounted directly above the other 23 , and spaced a short distance therefrom . the saws 21 , 23 are rotatably mounted near one end 24 of an elongated support 25 . the support 25 has top and bottom walls 27 , 29 and side walls 31 , 33 . a vertical shaft 35 is rotatably mounted in the top and bottom walls 27 , 29 with bearings 37 as shown in fig5 . the shaft 35 is located adjacent the one end of the support 25 and has threaded top and bottom projecting end portions 39 , 41 . the top circular saw 21 is mounted on the top end portion 39 of shaft 35 . a circular , concentric flange 43 on the bottom face of saw 21 spaces the saw from the top wall 27 of support 25 . the end portion 39 of shaft 35 passes through a central bore 45 in saw 21 . the upper end of bore 45 is counterbored as shown at 47 . a nut 49 is fastened to end portion 39 of shaft 35 in counterbore 47 to fix the saw 21 to shaft 35 . the nut 49 and shaft 35 do not project above the top face of saw 21 . the bottom circular saw 23 is similarly mounted on the bottom end portion 41 of shaft 35 . a circular , concentric flange 51 on the top face of saw 23 spaces the saw from the bottom wall 29 of support 25 . the end portion 41 of shaft 35 passes through a central bore 53 in saw 23 . the bottom end of bore 53 is counterbored as shown at 55 . a nut 57 is fastened to end portion 41 of shaft 35 in counterbore 55 to fix saw 23 to shaft 35 . the nut 57 and shaft 35 do not project below the bottom face of saw 23 . the tree cutting mechanism 15 includes means to rotate the circular saws 21 , 23 . the rotating means , as shown in fig4 to 6 , include a drive motor 63 mounted on the support 25 near its other end 65 . the shaft 67 of the drive motor 63 extends into support 25 through a hole in the top wall 27 of the support 25 . the shaft 67 of drive motor 63 is parallel to the saw shaft 35 . a drive sprocket 69 is mounted on drive shaft 67 and a driven sprocket 71 is mounted on saw shaft 35 within support 25 . a chain 73 , as shown by dotted lines , connects sprockets 69 , 71 together . operation of motor 63 will , through the chain and sprocket drive , rotate the saws 21 , 23 in the same direction . the tree cutting mechanism 15 includes means for mounting it on the bottom of frame 3 and moving the circular saws 21 , 23 forwardly and rearwardly relative to frame 3 . a mounting frame 81 is provided , as shown in fig2 and 3 , consisting of a cross - bar 83 and two guide arms 85 , 87 projecting forwardly from the ends of cross - bar 83 . the guide arms 85 , 87 are parallel to each other . the rear of support 25 is fixed onto the center of cross - bar 83 of frame 81 and extends forwardly therefrom , midway between arms 85 , 87 and parallel to them . the main frame 3 of the felling head 1 has a bottom transverse frame member 91 as shown in fig1 . a pair of guide frame members 93 , 95 extend forwardly from the ends of transverse frame member 91 . guide frame members 93 , 95 are parallel to each other and hollow . their rear ends 97 , 99 are open as shown in fig2 and 3 and the cross - sectional area of their hollow interior is sized to just receive the guide arms 85 , 87 of the mounting frame 81 of the tree cutting mechanism 15 . hydraulic actuators 101 , 103 are mounted at one end to frame members 93 , 95 respectively , and at their other end to the ends of cross - bar 83 of mounting frame 81 . operation of actuators 101 , 103 will move mounting frame 81 forwardly relative to main frame 3 , thus moving saws 21 , 23 forwardly from a position just behind main frame 3 to a position forwardly of frame 3 . the saws 21 , 23 pass just under main frame 3 and bottom frame member 91 . in moving forward , the saws 21 , 23 are rotated by drive motor 63 and cut through a tree &# 34 ; t &# 34 ; as shown in fig2 and 3 , held by the gripping arms 5 . in accordance with the present invention , means are provided on the tree cutting mechanism 15 to permit the saws 21 , 23 to cut completely through the tree &# 34 ; t &# 34 ;. these means operate to move the portion of the cut tree between the saws 21 , 23 in a manner to permit continued forward movement of the saws . the tree portion moving means comprises a wedge 107 mounted on the one end of support 25 and projecting forwardly . preferably wedge 107 is fixed to support 25 . forward movement of support 25 and saws 21 , 23 by actuators 101 , 103 will cause wedge 107 to split the cut portion of the tree between saws 21 , 23 into pieces &# 34 ; p &# 34 ; as shown in fig3 and to move these pieces outwardly to provide space for continued forward movement of the leading end of support 25 . forward movement of the saws 21 , 23 is continued until tree &# 34 ; t &# 34 ; is completely cut through . as shown in fig1 the felling head 1 is mounted by pivot means 111 to the free end 113 of a boom 115 carried by a vehicle ( not shown ). the pivot means 111 connect the boom 115 to the frame 3 below the gripping arms 5 . a hydraulic actuator 119 can be pivotally connected between the boom 115 and frame 3 above pivot means 111 to rotate the felling head 1 about pivot means 111 . the boom 115 is operated from the vehicle to position the felling head 1 adjacent the bottom end of a tree &# 34 ; t &# 34 ; to be harvested . once the felling head 1 is in position , the gripping arms 5 are operated to securely grip the tree &# 34 ; t &# 34 ;. the drive motor 63 is then operated to actuate the saws 21 , 23 and mounting frame 21 is moved forwardly by actuators 101 , 103 to have the rotating saws 21 , 23 cut through the tree &# 34 ; t &# 34 ;. as the saws 21 , 23 cut through the tree , the wedge 107 splits pieces of the cut tree portion between the saws outwardly allowing continued forward movement of the saw . the saws 21 , 23 need only be slightly larger in diameter than the diameter of the largest trees to be cut . thus a great saving in initial saw expense , and the power needed to run the saws , is effected .

an improved tree cutting mechanism for a tree harvester . the mechanism employs two stacked circular saws which are rotated and moved forwardly to cut through a tree . a wedge between the saws moves pieces of the tree being cut between the saws out of the way of the support for the saws .

for the purposes of promoting an understanding of the principles of the present disclosure , reference will now be made to the embodiments illustrated in the drawings , and specific language will be used to describe the same . it is nevertheless understood that no limitation to the scope of the disclosure is intended . any alterations and further modifications to the described devices , systems , and methods , and any further application of the principles of the present disclosure are fully contemplated and included within the present disclosure as would normally occur to one skilled in the art to which the disclosure relates . in particular , it is fully contemplated that the features , components , and / or steps described with respect to one embodiment may be combined with the features , components , and / or steps described with respect to other embodiments of the present disclosure . for the sake of brevity , however , the numerous iterations of these combinations will not be described separately . as used herein , “ flexible elongate member ” or “ elongate flexible member ” includes at least any thin , long , flexible structure that can be inserted into the vasculature of a patient . while the illustrated embodiments of the “ flexible elongate members ” of the present disclosure have a cylindrical profile with a circular cross - sectional profile that defines an outer diameter of the flexible elongate member , in other instances all or a portion of the flexible elongate members may have other geometric cross - sectional profiles ( e . g ., oval , rectangular , square , elliptical , etc .) or non - geometric cross - sectional profiles . flexible elongate members include , for example , guidewires and catheters . in that regard , catheters may or may not include a lumen extending along its length for receiving and / or guiding other instruments . if the catheter includes a lumen , the lumen may be centered or offset with respect to the cross - sectional profile of the device . in most embodiments , the flexible elongate members of the present disclosure include one or more electronic , optical , or electro - optical components . for example , without limitation , a flexible elongate member may include one or more of the following types of components : a pressure sensor , a temperature sensor , an imaging element , an optical fiber , an ultrasound transducer , a reflector , a minor , a prism , an ablation element , an rf electrode , a conductor , and / or combinations thereof . generally , these components are configured to obtain data related to a vessel or other portion of the anatomy in which the flexible elongate member is disposed . often the components are also configured to communicate the data to an external device for processing and / or display . in some aspects , embodiments of the present disclosure include imaging devices for imaging within the lumen of a vessel , including both medical and non - medical applications . however , some embodiments of the present disclosure are particularly suited for use in the context of human vasculature . imaging of the intravascular space , particularly the interior walls of human vasculature can be accomplished by a number of different techniques , including ultrasound ( often referred to as intravascular ultrasound (“ ivus ”) and intracardiac echocardiography (“ ice ”)) and optical coherence tomography (“ oct ”). in other instances , infrared , thermal , or other imaging modalities are utilized . the electronic , optical , and / or electro - optical components of the present disclosure are often disposed within a distal portion of the flexible elongate member . as used herein , “ distal portion ” of the flexible elongate member includes any portion of the flexible elongate member from the mid - point to the distal tip . as flexible elongate members can be solid , some embodiments of the present disclosure will include a housing portion at the distal portion for receiving the electronic components . such housing portions can be tubular structures attached to the distal portion of the elongate member . some flexible elongate members are tubular and have one or more lumens in which the electronic components can be positioned within the distal portion . the electronic , optical , and / or electro - optical components and the associated communication lines are sized and shaped to allow for the diameter of the flexible elongate member to be very small . for example , the outside diameter of the elongate member , such as a guidewire or catheter , containing one or more electronic , optical , and / or electro - optical components as described herein are between about 0 . 0007 ″ ( 0 . 0178 mm ) and about 0 . 118 ″ ( 3 . 0 mm ), with some particular embodiments having outer diameters of approximately 0 . 014 ″ ( 0 . 3556 mm ) and approximately 0 . 018 ″ ( 0 . 4572 mm )). as such , the flexible elongate members incorporating the electronic , optical , and / or electro - optical component ( s ) of the present application are suitable for use in a wide variety of lumens within a human patient besides those that are part or immediately surround the heart , including veins and arteries of the extremities , renal arteries , blood vessels in and around the brain , and other lumens . “ connected ” and variations thereof as used herein includes direct connections , such as being glued or otherwise fastened directly to , on , within , etc . another element , as well as indirect connections where one or more elements are disposed between the connected elements . “ secured ” and variations thereof as used herein includes methods by which an element is directly secured to another element , such as being glued or otherwise fastened directly to , on , within , etc . another element , as well as indirect techniques of securing two elements together where one or more elements are disposed between the secured elements . reference will now be made to a particular embodiments of the concepts incorporated into an intravascular ultrasound system . however , the illustrated embodiments and uses thereof are provided as examples only . without limitation on other systems and uses , such as but without limitation , imaging within any vessel , artery , vein , lumen , passage , tissue or organ within the body . while the following embodiments may refer to a blood vessel and a blood vessel wall for illustrative purposes , any other tissue structure may be envisioned to be imaged according to methods disclosed herein . more generally , any volume within a patient &# 39 ; s body may be imaged according to embodiments disclosed herein , the volume including vessels , cavities , lumens , and any other tissue structures , as one of ordinary skill may recognize . referring now to fig1 , a rotational probe 100 for insertion into a patient for diagnostic imaging is shown . in some embodiments , the rotational probe 100 is an intravascular ultrasound ( ivus ) probe . the probe 100 comprises a catheter 101 having a catheter body 102 and an elongate drive shaft or shaft 104 . the catheter body 102 is flexible and has both a proximal portion 106 and a distal portion 108 . the catheter body 102 is a sheath surrounding the shaft 104 . for explanatory purposes , the catheter body 102 in fig1 is illustrated as visually transparent such that the shaft 104 disposed therein can be seen , although it will be appreciated that the catheter body 102 may or may not be visually transparent . the shaft 104 is flushed with a sterile fluid , such as saline , within the catheter body 102 . the fluid serves to eliminate the presence of air pockets around the shaft 104 that adversely affect image quality . the fluid can also act as a lubricant . the shaft 104 has a proximal portion 110 disposed within the proximal portion 106 of the catheter body 102 and a distal portion 112 disposed within the distal portion 108 of the catheter body 102 . the distal portion 108 of the catheter body 102 and the distal portion 112 of the shaft 104 are inserted into a patient during the operation of the probe 100 . the usable length of the probe 100 ( the portion that can be inserted into a patient ) can be any suitable length and can be varied depending upon the application . the distal portion 112 of the shaft 104 includes a work element 118 . the proximal portion 106 of the catheter body 102 and the proximal portion 110 of the shaft 104 are connected to an interface module 114 ( sometimes referred to as a patient interface module or pim ). the proximal portions 106 , 110 are fitted with a catheter hub 116 that is removably connected to the interface module 114 . in some embodiments , the interface module 114 couples the probe 100 to a control system and / or a monitor ( not shown ) for direct user control and image viewing . the rotation of the shaft 104 within the catheter body 102 is controlled by the interface module 114 , which provides a plurality of user interface controls that can be manipulated by a user . the interface module 114 also communicates with the work element 118 by sending to and receiving signals from the work element 118 via conductors within the shaft 104 . in some embodiments , the signals to and from the work element 118 are electrical signals and the conductors within the shaft 104 are electrical conductors such as metal wires . in some embodiments , the signals to and from the work element 118 are optical signals and the conductors within the shaft 104 are optical fibers . the interface module 114 can receive , analyze , and / or display information received through the shaft 104 . it will be appreciated that any suitable functionality , controls , information processing and analysis , and display can be incorporated into the interface module 114 . the shaft 104 includes a work element 118 , a housing 120 , and a drive cable 122 . the work element 118 is coupled to the housing 120 . the housing 120 is attached to the drive cable 122 at the distal portion 112 of the shaft 104 . the drive cable 122 is rotated within the catheter body 102 via the interface module 114 and it in turn rotates the housing 120 and the work element 118 . the work element 118 can be of any suitable type , including but not limited to one or more transducer technologies such as pmut or cmut . the work element 118 can include either a single transducer or an array . in some embodiments , the work element 118 includes sensor components or optical lens , such as those used in an oct system . fig2 shows a diagrammatic view of the proximal portion of the probe 100 and the interior of the interface module 114 , in accordance with an embodiment . as shown , the catheter hub 116 includes a stationary exterior housing 224 , a dog 226 , and a connector 228 . the connector 228 is represented with four conductive lines , such as 254 , shown in this embodiment . it will be appreciated , however , that any suitable number of conductive lines and any type of conductive media can be utilized . for example , an optical coupler , a coaxial cable , or six electrically conductive lines can be utilized in various embodiments . as shown , the interior of the interface module 114 includes a motor 236 , a motor shaft 238 , a main printed circuit board ( pcb ) 240 , a spinning element 232 , and any other suitable components for the operation of the probe 100 . the motor 236 is connected to the motor shaft 238 to rotate the spinning element 232 . the main printed circuit board 240 can have any suitable number and type of electronic components 242 including but not limited to the transmitter and the receiver for the work element 118 ( fig1 ). the spinning element 232 has a complimentary connector 244 for mating with the connector 228 on the catheter hub 116 . the connector 244 can have conductive lines , such as 255 , that contact the conductive lines , such as 254 , on the connector 228 . as shown , the spinning element 232 is coupled to a rotary portion 248 of a rotary transformer 246 . the rotary portion 248 of the transformer 246 passes signals to and from the stationary portion 250 of the transformer 246 using a set of windings 251 and 252 . the stationary portion 250 of the transformer 246 is electrically connected to the printed circuit board 240 . it will be appreciated that any suitable number of windings may be used to transmit any suitable number of signals across the transformer 246 . also as shown , the spinning element 232 includes printed circuit boards 256 , 257 comprising a plurality of circuit components . it will be appreciated that fig2 is merely an example and is not intended to limit the present disclosure . for example , a pullback mechanism may be employed to pull the shaft 122 proximally within the catheter 102 to generate a longitudinal image of a vessel . more examples of the proximal portion of the probe 100 and the interior of the interface module 114 can be found in u . s . pat . no . 8 , 403 , 856 entitled “ rotational intravascular ultrasound probe with an active spinning element ,” the contents of which are hereby incorporated by reference in their entirety . fig3 a shows a cross - sectional side view of a distal portion of the catheter 101 according to an embodiment of the present disclosure . in particular , fig3 a shows an expanded view of aspects of the distal portion of the shaft 104 . in this exemplary embodiment , the shaft 104 is terminated at its distal tip by a housing 120 fabricated from stainless steel and provided with a rounded nose 326 and a cutout 328 for the ultrasound beam 330 to emerge from the housing 120 . the drive cable 122 of the shaft 104 includes a torque transmission core 332 and one or more electrical cables 334 secured thereon by a polymer jacket 336 . in some embodiments , the electrical cables 334 are secured to the torque transmission core 332 by a plurality of polymer bands instead of a polymer jacket . in some embodiments , the torque transmission core 332 is composed of two or more layers of counter wound stainless steel wires , welded , or otherwise secured to the housing 120 such that rotation of the drive cable 122 also imparts rotation on the housing 120 . in the illustrated embodiment , the work element 118 includes a pmut microelectromechanical system ( mems ) 338 and an application specific integrated circuit ( asic ) 344 mounted thereon . the pmut mems 338 includes a spherically focused transducer 342 . the work element 118 is mounted within the housing 120 . as shown in fig3 a , one of the electrical cables 334 with an optional shield 333 is attached to the work element 118 with a solder 340 . the electrical cables 334 extends through an outer portion of the drive cable 122 to the proximal portion of the shaft 104 where it is terminated to the electrical connector 228 ( fig2 ). in the illustrated embodiment , the work element 118 is secured in place relative to the housing 120 by an epoxy 348 or other bonding agent . the epoxy 348 also serves as an acoustic backing material to absorb acoustic reverberations propagating within the housing 120 and as a strain relief for the electrical cable 334 where it is soldered to the work element 118 . it will be appreciated that fig3 a is merely an example and is not intended to limit the present disclosure . more examples of the distal portion of the shaft 104 and the work element 118 can be found in u . s . patent application publication no . 2013 / 0303919 on nov . 14 , 2013 , now u . s . pat . no . 8 , 864 , 674 , entitled “ circuit architectures and electrical interfaces for rotational intravascular ultrasound ( ivus ) devices ,” the contents of which are hereby incorporated by reference in their entirety . fig3 b shows additional aspects of the pmut mems component 338 of the work element 118 . the mems component 338 in the embodiment of fig3 b is a paddle - shaped silicon component with the piezoelectric polymer transducer 342 located in the widened portion 349 of the substrate located at the distal portion of the mems component 338 . the narrow portion of the substrate positioned proximal of the widened portion 349 is where the asic 344 is mounted to the mems component 338 . in that regard , the mems component 338 includes ten bond pads , with bond pads 350 , 351 , 352 , 354 , 356 , and 358 configured to match up respectively with bond pads on the asic 344 for mounting the asic 344 thereon , and bond pads 362 , 364 , 366 , and 368 serving as terminations for the four electrical cables 334 of the drive cable 122 . in that regard , the four electrical cables 334 of the drive cable 122 are exposed at a distal portion of the drive cable 122 , and are soldered or otherwise fixedly attached to bond pads 362 , 364 , 366 , and 368 , which are electrically coupled with the bond pads 352 , 354 , 356 , and 358 by conductive traces included on the mems substrate . other embodiments of connecting the electrical cables 334 to the work element 118 are possible , such as those disclosed in u . s . patent application publication no . 2013 / 0303919 on nov . 14 , 2013 , now u . s . pat . no . 8 , 864 , 674 , entitled “ circuit architectures and electrical interfaces for rotational intravascular ultrasound ( ivus ) devices .” fig4 a shows a diagrammatic schematic view of the drive cable 122 , according to various aspects of the present disclosure . referring to fig4 a , the drive cable 122 includes a torque transmission core 402 , an optional electrical insulating layer 404 , one or more conductors 406 , and a polymer jacket 408 . the torque transmission core 402 possesses a certain torsional stiffness in order to adequately deliver rotational force along the relatively long path traversed by the drive cable 122 . at the same time , the torque transmission core 402 is sufficiently flexible to bend around the tight turns presented by the vascular system while maintaining the ability to rotate and to axially translate through the catheter 101 ( fig1 ). the torque transmission core 402 can be made of any suitable material . in an embodiment , the torque transmission core 402 is made of stainless steel , such as two or more layers of counter wound stainless steel wires or braided wires . in an embodiment , the torque transmission core 402 is an optical fiber . the conductors 406 are electrical conductors in some embodiments . in that regard , the conductors 406 may be optionally shielded . in various embodiments , the conductors 406 may be wire ( cu , etc . ), carbon nanotube fiber conductors , conductive ink , conductive polymer , conductive film , and / or combinations thereof . in some embodiments , the conductors 406 are optical pathways , such as optical fibers used in oct systems . in some embodiments , the drive cable 122 includes both electrical conductors 406 and optical conductors 406 in one cable . in some embodiments , the insulating layer 404 serves to electrically isolate the conductors 406 from the torque transmission core 402 . the insulating layer 404 may be formed of any suitable material . in some implementations , the insulating layer 404 is a parylene layer . the polymer jacket 408 secures the conductors 406 and the optional electrical insulating layer 404 over the torque transmission core 402 . in some embodiments , such as those will be described with reference to fig4 c , the polymer jacket 408 can serve as insulating layer for the conductors 406 . furthermore , the polymer jacket 408 also serves to protect the various components of the drive cable 122 from the fluid filled inside the catheter 101 . the polymer jacket 408 may be of any polymeric , insulating , and / or dielectric material , such as polyvinyl chloride ( pvc ), kapton ™ polyimide film from dupont , ethylene tetrafluoroethylene ( etfe ), nylon , or similar polyimide films . in some embodiments , the polymer jacket 408 is an elongate piece , such as a continuous layer in the drive cable 122 . in some embodiments , the polymer jacket 408 comprises a plurality of polymer bands that may be separate or be alternatively joined or fused . in yet another embodiment , the polymer jacket 408 is a spiral wrap . in various embodiments , the polymer jacket 408 can be coated , extruded , or shrunk over the torque transmission core 402 . an advantage of the drive cable 122 of fig4 a over conventional drive cables is that it is easier to manufacture because the conductors 406 are placed outside the torque transmission core 402 , rather than having to be threaded therein as is the case in the conventional drive cables . furthermore , since there is no need to thread conductors through the torque transmission core 402 , the dimensions and tolerance of the drive cable 122 can be reduced , allowing for more space for additional components for the ivus system . a smaller drive cable 122 also allows for a bigger space between the drive cable and the inside surface of the catheter lumen for easier flushing or injection operations . in addition or alternatively , the drive cable 122 can be made stronger , allowing for more reliable operation and longer usable life . fig4 b shows a cross - sectional view of the drive cable 122 of fig4 a , in accordance with an embodiment . referring to fig4 b , in this embodiment , the torque transmission core 402 is shown as a solid core . in alternative embodiments , the torque transmission core 402 is a helical winding having an inner lumen , potentially much smaller than that of existing drive cables . also shown in fig4 b , there are four conductors 406 spaced evenly around the electrical insulating layer 404 . in other embodiments , any number of conductors 406 is possible and different arrangement of the conductors 406 is also possible . the polymer jacket 408 wraps around and secures the conductors 406 to the insulating layer 404 . in an embodiment , the polymer jacket 408 is a heat shrinkable elongate jacket with a large lumen through which a subassembly of the conductors 406 , the insulating layer 404 and the torque transmission core 402 is threaded . the polymer jacket 408 is subsequently heated so as to securely wrap around the subassembly . also shown in fig4 b with dashed lines 412 , portions of the polymer jacket 408 are removed at the proximal and / or distal portion of the drive cable 122 to expose the conductors 406 . this makes it easier for downstream manufacturing of the rotational probe 100 ( fig1 ), e . g ., when the drive cable 122 is to be coupled with the work element 118 ( fig3 b ) or to be terminated with the connector 228 of the catheter hub 116 ( fig2 ). fig4 c shows a cross - sectional view of the drive cable 122 of fig4 a , in accordance with another embodiment . many respects of this embodiment are similar to those of the drive cable 122 of fig4 b . however , in this embodiment , the polymer jacket 408 has the conductors 406 embedded therein . the polymer jacket 408 is secured around the insulating layer 404 and the torque transmission core 402 by , e . g ., a heat shrink process or any other processes . having the polymer jacket 408 with the conductors 406 embedded therein further simplifies the manufacturing of the drive cable 122 and the rotational probe 100 ( fig1 ). in this embodiment , the polymer jacket 408 itself may offer sufficient insulation between the torque transmission core 402 and the conductors 406 , and therefore , the insulating layer 404 may be unnecessary in some instances . fig4 d shows a diagrammatic schematic view of the drive cable 122 , in accordance with an embodiment . referring to fig4 d , in this embodiment , the torque transmission core 402 , the conductors 406 , and the polymer jacket 408 are formed as one piece . for example , the conductors 406 and the polymer jacket 408 can be co - extruded over the torque transmission core 402 during a manufacturing process . fig5 shows a method 500 of manufacturing a catheter for a rotational probe for insertion into a vessel , such as the catheter 101 ( fig1 ), according to various aspects of the present disclosure . the method 500 is merely an example , and is not intended to limit the present disclosure beyond what is explicitly recited in the claims . additional operations can be provided before , during , and after the method 500 , and some operations described can be replaced , eliminated , or moved around for additional embodiments of the method 500 . various operations of fig5 will be described below in conjunction with fig1 - 4d discussed above . operation 510 includes providing an elongate torque transmission core , such as the torque transmission core 402 of fig4 a . the torque transmission core has desired length and dimension for the catheter to be manufactured . in some embodiments , the torque transmission core is electrically conductive , such as counter wound stainless steel wires . in some embodiments , the torque transmission core is not electrically conductive , such as an optical fiber . operation 512 includes optionally forming an electrical insulating layer over the torque transmission core . this is usually the case when the torque transmission core is electrically conductive and the conductors to be assembled onto the torque transmission core are also electrically conductive and are not shielded . operation 514 includes securing at least one conductor to the elongate torque transmission core . the number of conductors depends on the intended function of the catheter . for example , an advanced pmut transducer catheter may need to have four or six conductors . some catheters may require only one or two conductors . in addition , the conductors are suitable for conducting energy for the intended catheter . in that regard , the conductors may be electrical conductors , waveguides such as optical fibers , or a combination thereof . the at least one conductor may be secured to the torque transmission core by gluing , electrically printing ( micro - dispense , aero - jet , ink - jet , transfer , gravure , etc . ), or plating a conductive material over the insulating layer , or by helically wrapping the conductor around the torque transmission core . operation 516 includes securing a polymer jacket over both the at least one conductor and the elongate torque transmission core . in an embodiment , securing the polymer jacket includes wrapping the polymer jacket over the at least one conductor and the elongate torque transmission core . in an embodiment , securing the polymer jacket includes sliding the polymer jacket over the at least one conductor and the elongate torque transmission core . in an embodiment , securing the polymer jacket further includes heating the polymer jacket so as to axially shrink its dimension . in some embodiments , the polymer jacket has the requisite conductors embedded therein . in such cases , operations 514 and 516 are combined into one operation . in some embodiments , operation 516 secures a plurality of polymer jacket bands over both the at least one conductor and the elongate torque transmission core . operation 518 includes coupling a distal portion of the at least one conductor to a work element , such as shown in fig3 b . in that regard , a distal portion of the polymer jacket are removed so as to expose the at least one conductor . subsequently , the conductors are coupled to the work element through appropriate methods , such as soldering . operation 520 includes coupling a distal portion of the torque transmission core to a housing that holds the work element , such as shown in fig3 a . in some instances , some steps may be performed before operation 520 , such as applying epoxy so as to secure the work element and the conductors in the housing . the torque transmission core can be secured to the housing by a suitable method , such as welding . fig6 shows a cross - sectional side view of a distal portion of the catheter 101 according to another embodiment of the present disclosure . many respects of this embodiment are the same as or similar to those of the embodiment shown in fig3 a . therefore , they are labeled with the same reference numerals for the sake of brevity . however , this embodiment has some distinct features . for example , the drive cable , labeled as 122 a and also called data cable in this embodiment , has a different construction than the drive cable 122 in fig3 a . referring to fig6 , the drive cable 122 a includes one or more conductors 632 , a dielectric insulating layer 634 , a shield 636 , and an outer sheath 638 . the conductors 632 are attached to the work element 118 with solders 640 in the distal portion . they also extend through an inner cavity of the drive cable 122 a to the proximal portion of the shaft 104 where they are terminated to the electrical connector 228 ( fig2 ). in various embodiments , the drive cable 122 a is made strong enough to carry torque needed for the operations of the catheter 101 without a need for a separate torque transmission core thereby achieving a one - piece design with both data transmission and torque transmission capabilities . fig7 shows a diagrammatic cross - sectional view of an embodiment of the drive cable 122 a . referring to fig7 , shown therein are four conductors 632 in a cavity 631 inside the dielectric insulating layer 634 . each of the conductors 632 may be individually shielded . in an embodiment , the conductors 632 are similar to the inner conductors found in coaxial cables . in an embodiment , the conductors 632 are made of copper , solid or stranded . although fig7 shows four conductors 632 in the drive cable 122 a , this is not intended to be limiting . in various embodiments , a different number of conductors are possible depending on the application . for example , there may be two conductors or six conductors . in an embodiment , there are at least two conductors 632 . the conductors 632 may be threaded through the cavity 631 . alternatively , the dielectric insulating layer 634 may be extruded over the conductors 632 . the dielectric insulating layer 634 may be made of various materials , such as fluorinated ethylene propylene ( fep ), poly tetrafluoroethylene ( ptfe ), or materials similar to those found in coaxial cables &# 39 ; dielectric layer . in the present embodiment , the dielectric insulating layer 634 is made strong enough to transmit torque , for example , by having a relatively large dimension . in the illustrated embodiment , the insulating layer 634 is also a torque transmission layer that substantially files the volume within shield 636 and has a cross - sectional area greater than the cross - sectional area of the conductors 632 . the dielectric insulating layer 634 is reinforced by the shield 636 and the outer sheath 638 . the shield 636 may be braided or woven , and may be made of copper , aluminum , or other materials . in an embodiment , the shield 636 is grounded in the proximal portion and serves as an electrical shield for the conductors 632 . the outer sheath 638 may be made of pvc , tetrafluoroethylene ( tfe ), fep , or a material similar to that of the polymer jacket 408 discussed above . in various embodiments , one or more of the dielectric insulating layer 634 , the shield 636 , and the outer sheath 638 are made strong enough for transmitting torque . accordingly , various embodiments of the drive cable 122 a provide a one - piece design for both data signal transmission and torque transmission , eliminating the need for a separate torque transmission core . fig8 shows a diagrammatic cross - sectional view of another embodiment of the drive cable 122 a . referring to fig8 , this embodiment includes a strengthening layer 633 embedded in the dielectric insulating layer 634 ( or 634 a / 634 b ). in an embodiment , the dielectric insulating layer 634 includes two insulating layers 634 a and 634 b , and the strengthening layer 633 is woven or braided over the insulating layer 634 a and is then covered by the insulating layer 634 b . in an embodiment , the strengthening layer 633 is made of a conductive material , such as copper , aluminum , or the like . to further this embodiment , the strengthening layer 633 can be made an electrical shield by grounding it in the proximal portion . non - conductive materials can also be used for the strengthening layer 633 , for example , when the shield 636 provides sufficient electrical shield for the conductors 632 . similar to the embodiment shown in fig7 , the drive cable 122 a in fig8 also provides a one - piece design for both data signal transmission and torque transmission , eliminating the need for a separate torque transmission core . the foregoing outlines features of several embodiments so that those of ordinary skill in the art may better understand the aspects of the present disclosure . persons having ordinary skill in the art will also recognize that the apparatus , systems , and methods described above can be modified in various ways . accordingly , persons having ordinary skill in the art will appreciate that the embodiments encompassed by the present disclosure are not limited to the particular exemplary embodiments described above . in that regard , although illustrative embodiments have been shown and described , a wide range of modification , change , and substitution is contemplated in the foregoing disclosure . it is understood that such variations may be made to the foregoing without departing from the scope of the present disclosure . accordingly , it is appropriate that the appended claims be construed broadly and in a manner consistent with the present disclosure .

a compact and efficient drive shaft for an in vivo imaging system and a method of making the same is provided by the present disclosure . in one aspect , the drive shaft includes a plurality of conductors secured to the exterior of a flexible elongate core . the conductors connect an imaging element at the distal end to a connection assembly near the proximal end of the drive shaft .

the stent of the present invention is employed to support or otherwise treat a targeted site within the vasculature . such stent is introduced into the vasculature , advanced therethrough to the deployment site and expanded using conventional techniques and delivery systems . once in position and subject to the continuous flow of blood therethrough , it gradually degrades , substantially without the risk inherent in previously known biodegradable stents or stents with biodegradable coatings of breaking up into or releasing sizeable particles that may be swept downstream and cause emboli . the stent may be wholly constructed of the biodegradable polymer . the material employed in the manufacture of the stent of the present invention is a polymer that is simultaneously hydrophobic and has water labile linkages interconnecting its monomers that are further fortified by ester or imide bonds . the hydrophobic nature of the polymer precludes the incursion of water into its interior while the water - labile bonds that are exposed on its surface nonetheless cause the polymer to degrade . degradation thereby exclusively progresses from the material &# 39 ; s surface inwardly to yield a much more uniform degradation rate and to preclude bulk erosion . the incorporation of the imide ester bonds serves to impart sufficient strength to the material to enable it to provide the support that is required of the stent . alternatively , if the material is used as stent coating , the incorporation of the imide or ester bonds impart sufficient strength to the material to prevent it from flaking off or otherwise becoming detached as the underlying stent undergoes the distortion attendant its being expanded by for example the inflation of a balloon . many of the stent &# 39 ; s ultimate performance characteristics are controllable by the appropriate selection of the various dimensional parameters of the stent . increasing the dimensions of various structural elements of the stent will generally serve to increase strength and decrease flexibility . such effect would result from both an increase in the width or in the wall thickness of the stent &# 39 ; s structural elements . the time period in which the stent would become totally degraded or absorbed is a function of the wall thickness of the various elements while the degradation rate is a function of the total area exposed to contact with the blood . by for example selecting a stent configuration which employs a large number of relatively narrow spine and strut elements to achieve a particular level of strength , the time in which the stent degrades when subjected to the blood flow can be substantially accelerated . conversely , a stent configuration in which a relatively few , wide structural elements are employed causes the degradation rate to be somewhat retarded . the stent &# 39 ; s ultimate performance characteristics are of course also controllable by the appropriate selection of chemical variables . for example , the number of imide or ester bonds that are incorporated in the polymer material not only affects the ultimate strength and flexibility characteristics of the stent , but also has an effect on the rate at which the material degrades when subjected to blood flow . an increased bond content enhances strength , decreases flexibility and increases degradation time . the specific requirements of a particular application will ultimately determine the optimal combination of the stent configuration , wall thickness and ester or imide bond content . polymers that satisfy the above - described requirements include polyanhydrides and polyorthoesters . representative examples of polyanhydride polymers suitable for use in the construction of a stent or formulation of a stent coating in accordance with the present invention include anhydride - co - imide ter polymers containing trimellitylimido - l - tyrosine , sebacic acid ( sa ) and 1 , 3 bis ( carboxyphenoxy ) propane . other examples of suitable polyanhydrides include poly ( fatty acid — sebacic acid ) synthesized from erucic acid and sebacic anhydride p ( ead : sa ) and poly ( l - lactic acid - co - l - aspartic acid ). representative examples of polyorthoester polymers suitable for use in the construction of a stent or formulation of a stent coating in accordance with the present invention include poly ( 4 - hydroxy - l - proline ester ), poly ( 1 , 10 decanediol - 1 , 10 decanediol dilactide ) and poly ( 1 , 2 , 6 hexanetriol - trimethylorthoacetate ). an ester or imide content of 20 %- 40 % has been found to be effective to provide sufficient strength for a stent application . the process for forming a polymer stent is well known in the art . a stent of the present invention is formed by first causing the appropriate reagents to react to form the desired polyanhydride or polyorthoester composition . during copolymer synthesis , the imide content of such composition is increased by incorporating higher imide containing monomers like trimellitylimido - l - tyrosine . increasing imide content results in higher strength material . flexibility of polyanhydrides like p ( ead : sa ) can be increased by increasing the percentage of erucic acid dimer ( ead ) during polymer synthesis . the ester content of such composition is increased by incorporating higher ester containing monomers such as l - proline ester or trimethyl orthoacetate . selected pharmacological agents can be added to the reagents so as to incorporate such materials throughout the polymer to thereby provide for the gradual dispensation of the drug over the service life of the stent . the blending may be accomplished either in solution or in a melt state . drugs such as for example heparin or other proteins can readily be added to the reactants before or during the polymerization process . alternatively , some drugs may be infused throughout the polymer after polymerization is completed . if desired , the drug may be applied to the surface of the cured polymer to cause the entire dosage to be released shortly after implantation . the stent may be formed by any of a number of well known methods including the extrusion of the polymer into the shape of a tube . preselected patterns of voids are then formed into the tube in order to define a plurality of spines and struts that impart a degree of flexibility and expandability to the tube . alternatively , the drug loaded polymer may be applied to the selected surfaces of a stent formed of for example stainless steel or nitinol . in order to coat all of the surfaces of the stent , the stent is immersed in the molten polymer . alternatively , the polymer may be extruded in the form of a tube which is then codrawn with a tube of stainless steel or nitinol . by codrawing two tubes of the polymer with the metal tube , one positioned about the exterior of the metal tube and another positioned within such metal tube , a tube having multi - layered walls is formed . subsequent perforation of the tube walls to define a preselected pattern of spines and struts imparts the desired flexibility and expandability to the tube to create a stent . while a particular form of the invention has been illustrated and described , it will also be apparent to those skilled in the art that various modifications can be made without departing from the spirit and scope of the invention . accordingly , it is not intended that the invention be limited except by the appended claims .

a stent is fabricated utilizing a polymer that is selected for its tendency to degrade from the surface inwardly rather than undergo bulk erosion so as to substantially reduce the risk of large particles becoming detached and being swept downstream . such polymer is hydrophobic yet has water - labile linkages interconnecting the monomers . ester or imide bonds are incorporated in the polymer to render the surface degrading materials suitable for use in stent applications . the stent may be coated with such polymer or may be wholly formed therefrom .

fig1 shows a preferred embodiment of an air velocity indicator and control device 10 employed on a pneumatic distribution system 5 of an air seeder ( not shown ). although no specific air seeder is illustrated , it is well understood that air velocity indicator and control device 10 can be incorporated into any of a variety of suitable air seeders and air seeder components , e . g . air carts and tillage implements , such as various ones manufactured by cnh america llc . suitable air carts include case ih models adx2230 , adx3380 , adx3430 air carts , and others . suitable tillage implements include case ih models atx400 and atx700 air hoe drills . notwithstanding , air velocity indicator and control device 10 can be used with yet other known and available air seeders . known , readily available , air seeders typically include an air cart and a tilling implement , towed in tandem behind a tractor , for pneumatically distributing seed or other particulates or granular product such as fertilizer , herbicide , or other product . the air cart includes one or more frame - mounted product tanks for holding the granular product and each of the product tanks is connected to a product metering device which feeds the product into a pneumatic distribution system 5 in a controlled manner . typically various components within the product metering devices and / or pneumatic distribution systems 5 are controlled , at least in part , by any of a variety of suitable electronic controls , e . g ., an air seeder electronic control system . conventional pneumatic distribution systems 5 intake granular product from the metering device , and by way of a primary distribution manifold 6 , mix , suspend , or entrain the product into an airflow that is produced and delivered by a centrifugal blower or fan . controlling the rotational speed of the centrifugal fan , as well as mechanically controlling the orifice size through which the centrifugal fan delivers its airflow , influences a resultant airflow velocity within the pneumatic distribution system . typical air seeder pneumatic distribution systems 5 include multiple air cart air lines 7 , connected to and extending between the primary distribution manifold ( s ) 6 and a series of secondary distribution manifolds , commonly referred to as “ headers ,” illustrated as headers 8 . the headers 8 further divide and distribute the airflow and entrained product through multiple tilling implement distribution air lines , to multiple ground openers or planting units for seed singulation on the tilling implement . referring now to fig1 - 3 , air velocity indicator and control device 10 can be incorporated anywhere within the pneumatic distribution system 5 of an air seeder . however , it is preferable mounted downstream of a primary distribution manifold . for implementations of air velocity indicator and control device 10 that are retrofitted to existing air seeders , the device 10 is mounted with the pneumatic distribution system 5 at a location which is easily accessible , requires relatively little disassembly of the air seeder components , assemblies , or subassemblies , and thus facilitates simple installation . such locations are where the existing air seeder has accessible mechanical linkages or couplers joining the various components of the pneumatic distribution system 5 , e . g ., between the ( i ) primary distribution manifold 6 and air cart air lines 7 , ( ii ) air cart air lines 7 and headers 8 , ( iii ) headers 8 and tilling implement distribution air lines , ( iv ) tilling implement distribution air lines and seed tubes or planting units , and / or ( v ) elsewhere as desired . air velocity indicator and control device 10 includes a body 20 and indicator assembly 100 that is mounted at least partially with the body 20 . body 20 is an assemblage of an inlet 25 , an inlet transition segment 30 , a tubular deflector housing 35 , an outlet transition segment 40 , and an outlet 45 . inlet 25 is an elongate hollow member that provides an incoming conduit for the air velocity indicator and control device 10 . the particular size , shape , and configuration of inlet 25 corresponds to the component it interfaces with , whereby inlet 25 is configured based at least in part on where in the pneumatic distribution system 5 it is located . accordingly , for the implementations mounted between air cart air lines 7 and headers 8 , such as those seen in fig1 - 3 , the inlet 25 is round in cross - section and sized and configured to suitably couple to , e . g ., a 2 . 5 inch or other air cart air line by a conventional mechanical coupler . the end of inlet 25 that is proximate the remainder of air velocity indicator and control device 10 connects to an inlet transition segment 30 . inlet transition segment 30 has a first end 31 that is joined to inlet 25 and correspondingly approximates the dimensional attributes of the end of inlet 25 . multiple sidewalls 32 , optionally a single circumferential sidewall 32 , extend longitudinally from the first end 31 . in some implementations , the sidewalls laterally diverge from the first end 31 , defining an outwardly flared configuration . in any event , the sidewalls 32 are joined to each other at respective lateral edges , whereby they , in combination , suitably covert the configuration of inlet 25 and first end 31 to join with the tubular deflector housing 35 , by way of second end 33 . second end 33 is defined at the portion of inlet transition segment 30 which is distal inlet 25 . accordingly , the second end 33 interfaces with first end 36 of tubular deflector housing 35 . first end 36 of tubular deflector housing 35 , in some implementations , appears square or rectangular as viewed in a front elevation . the particular perimeter shape of first end 36 of tubular deflector housing 35 is selected to correspond to the cross - sectional configuration of the medial portion of tubular deflector housing 35 , characterized by a perimeter of combination of multiple sidewalls 37 . the cross - sectional configuration of tubular deflector housing 35 , defined by the multiple sidewalls 37 , can be any of a variety of arcuate or polygonal configurations , as desired . it is noted , however , that the perimeter defined about the outer surfaces of sidewalls 37 , and thus the cross - sectional configuration of deflector house 35 corresponds to the particular configurations of various components of indicator assembly 100 , explained in greater detail hereinafter . the sidewalls 37 terminate at their intersection with a second end 38 of tubular deflector housing 35 . the second end 38 provides the interface between the tubular deflector housing 35 and the second transition segment 40 , namely , the first end 41 of outlet transition segment 40 . still referring to fig1 - 3 , in implementations of tubular deflector housing 35 that have a generally constant cross - sectional configuration along its length , the first end 41 of the outlet transition segment 40 corresponds in size , shape , and configuration to the second end 33 of the inlet transition segment 30 . in other words , when the ends 36 , 38 of tubular deflector housing 35 are analogous , so too are the ends of the inlet and outlet transition segments 30 , 40 , namely , second end 33 and first end 41 , respectively . multiple sidewalls 42 , optionally a single circumferential sidewall 42 , extend longitudinally from the first end 41 . in some implementations , the sidewalls 42 laterally converge toward each other from the first end 41 , defining an inwardly tapered configuration . sidewalls 42 are joined to each other at respective lateral edges , whereby they , in combination , serve as the joining mechanism that connects the tubular deflector housing 35 with the outlet 45 . stated another way , second end 43 is defined at the portion of outlet transition segment 40 which is distal the tubular deflector housing 35 , and attaches to outlet 45 . outlet 45 is an elongate hollow member that provides an outgoing conduit for the air velocity indicator and control device 10 . like inlet 25 , the particular size , shape , and configuration of inlet 45 corresponds to the particular component it interfaces with , within the pneumatic distribution system 5 . for example , in implementations having the air velocity indicator and control device 10 mounted between air cart air lines 7 and headers 8 , such as those seen in fig1 - 3 , the outlet 45 is round in cross - section and sized and configured to suitably couple to a 2 . 5 inch or other header by a conventional mechanical coupler . the airflow velocity and thus the velocity of the entrained product within the pneumatic distribution system 5 , e . g ., between the air cart air line 7 and header 8 as seen in fig1 - 3 , is determined by way of an indicator assembly 100 . indictor assembly 100 includes a deflection plate assembly 110 a and a gauge assembly 125 . deflection plate assembly 110 a includes a deflectable plate 111 pivotably housed between the inwardly facing surfaces of tubular deflector housing sidewalls 37 , namely , within a void space 39 . referring now to fig3 , deflectable plate 111 is a planar , damper - type structure that defines a width dimension between opposing lateral edges 112 , 113 . this width dimension corresponds closely to the width dimension of the tubular deflector housing 35 void space , and thus , in some implementations , occupies a substantial portion of void space 39 with relatively small clearances between the lateral edges 112 , 113 and the respective tubular deflector housing sidewalls 37 . referring to fig3 , deflectable plate 111 defines a length dimension between an upper edge 114 and a lower edge 115 . in a resting state , the lower edge 115 can sit upon , e . g ., an upwardly facing surface of the lowermost sidewall 34 . preferably the length dimension of the deflectable plate 111 is greater in magnitude than the height dimension of the void space 39 . in this configuration , the deflection extends angularly between an opposing pair of sidewalls 37 on opposite sides of the void space 39 . in some implementations , the deflectable plate 111 extends angularly and downwardly from the uppermost sidewall 37 to the lowermost sidewall . upper edge 114 is attached to a pivot pin 116 that extends parallel to , but is spaced downwardly from , the uppermost sidewall 37 . pivot pin 116 defines an axis of pivotation about which the deflectable plate 111 articulates while the air seeder is being used . in some implementations , the deflectable plate 111 and pivot pin 116 are fixedly attached to each other , whereby they pivot or rotate in unison . such configuration permits the pivot pin 116 to serve as the interface between the deflection plate assembly 110 a and gauge assembly 125 . gauge assembly 125 includes indicator arm 128 , indicator scale 130 , and can further include wiper arm 135 , resistor 140 , and conductors 145 , as desired . indicator arm 128 is fixedly mounted to an end of pivot pin 116 , whereby it pivots or rotates in unison with both the pivot pin 116 and the deflectable plate 111 . in other words , indicator arm 128 is a needle - type member that extends radially from the pivot pin 116 . it is configured to be visually conspicuous against a scale indicating , e . g ., airflow velocity , such as indicator scale 130 . accordingly , in combination , indicator arm 128 and indicator scale 130 provide a visual representation of the airflow velocity through air velocity indicator and control device 10 and thus through a respective segment of pneumatic distribution system 5 . as desired and / or as required for suitable operation and functionality , the gauge assembly 125 can further include a spring or other resilient member ( not illustrated ) to biasingly urge the deflectable plate 111 , pivot pin 116 , and indicator arm 128 toward their resting state positions . for example , a spring or other resilient member can be required when the mass of deflectable plate 111 is small enough , and the airflow velocity is great enough , that the indicator arm 128 is held against the indicia indicating a maximum value on the indicator scale 130 . in some implementations , it is desired to electronically monitor or determine the airflow velocities within the airflow velocity indicator assembly 100 . in such implementations , various other components are provided to suitably sense or determine the position of deflectable plate 111 , pivot pin 116 , indicator arm 128 , and / or other components of airflow velocity indicator assembly 100 . this enables such mechanical positional information to be sensed , detected , or determined , and to also be conveyed to the air seeder electronic control system or other suitable controller or electronic control module . in such implementations , the gauge assembly 125 can further include , e . g ., wiper arm 135 , resistor 140 , and conductors 145 . the wiper arm 135 is mounted to pivot pin 116 or attached directly to indicator arm 128 , but in any event moves in unison with the indicator arm 128 . resistor 140 is attached to and extends along the length of the backside of indicator scale 130 . while moving , wiper arm 135 is always in mechanical contact with the resistor such that the particular location of wiper arm 135 along the length of resistor 140 varies according to the position of indicator arm 128 and indicator scale 130 . when the wiper arm 135 and resistor 140 are energized , the resultant output voltage output across them changes , based on where the wiper arm 135 contacts the resistor 140 along its length . in other words , the wiper arm 135 and resistor 140 are configured as , e . g ., a potentiometer or rheostat to provide a variable output voltage signal which the air seeder electronic control system interprets to determine the position of wiper arm 135 along resistor 140 , indicator arm 128 along indicator scale 130 , deflectable plate 111 within void space 39 , and thus the velocity of the airflow flowing through air velocity indicator and control device 10 . regardless of the particular monitoring methods , manually or electronically monitored or observed , the airflow entrained with product provides a force which deflects respective ones of the deflectable plates 111 and indicator arms 128 . correspondingly , the differential velocities will cause resulting deflection variances that are observable or can be monitored . based on this information , in other words the variance or differential information , the airflow can be controlled manually or automatically to reduce the magnitude of the velocity differentials . referring now to fig4 , as desired , multiple air velocity indicator and control devices 10 or components thereof can be joined , ganged , banked , or otherwise linked together . such configuration can be useful when the air velocity indicator and control devices 10 are mounted in relatively space - constricted areas , for example , at locations within pneumatic distribution system 5 where multiple air lines , such as air cart air lines 7 , are in close proximity to each other , and / or for automatic regulation . accordingly , multiple joined air velocity indicator and control devices 10 are well - suited for placement between primary distribution manifold 6 and air lines 7 , or elsewhere as desired . regardless of the particular placement location within pneumatic distribution system 5 , some implementations of joined air velocity indicator and control devices 10 are adapted and configured to automatically and passively self - regulate the volumes and velocities of airflow passing therethrough . this can be done by introducing analogous mechanical airflow restrictions , by way of deflectable plates 111 positioned at the same angle ( s ) of deflection , into airflows having differing velocities . since the airflows have different velocities , analogous mechanical airflow restrictions correspondingly produce differing effects on such differing airflows . air velocity indicator and control devices 10 exploit such tendencies of the analogously positioned deflectable plates 111 to produce differing effects in differing airflows to redirect or shunt portions of relatively high velocity airflows into relatively low velocity airflows . this is typically done by modifying the relative flow resistances defined through different bodies 20 , which shunt or redirect portions of the upstream airflow through respective branches of pneumatic distribution system 5 , whereby the lines 7 correspondingly define airflows that have relatively more similar velocities . still referring to fig4 , in some implementations , the air velocity indicator and control device 10 has multiple bodies 20 and a ganged deflection plate assembly 110 b . namely , the ganged deflection plate assembly 110 b has a single , common pivot pin 116 which extends through all of the parallel adjacent bodies 20 effectively ganging all of the deflectable plates 111 together . in this configuration , all of the deflectable plates 111 are fixed to a common pivot pin 116 , whereby the deflectable plates 111 must pivot or rotate in unison with each other . thus , at a given point in time , the pivotal or rotational position of the deflectable plates 111 is a function of all forces applied to the ganged deflectable plate assembly 110 b . correspondingly , the position of a deflectable plate within its respective body 20 is determined not only by operating conditions and characteristics within any single body 20 , but is also influenced by the operating conditions and characteristics within all other bodies 20 . in other words , since the deflectable plates 111 pivot or rotate in unison with each other , pivoting a single deflectable plate 111 correspondingly changes the relative opening dimensions within all bodies 20 simultaneously . in this regard , pivoting , rotating , or otherwise actuating the ganged deflectable plate assembly 1110 b dynamically changes the opening dimensions and air flow characteristics of all bodies 20 simultaneously . although the deflectable plates 111 pivot or rotate in unison with each other , they need not be provided at the same , or constant , relative angular orientations upon the pivot pin 116 . preferably , each of the deflectable plates 111 is independently and adjustably fixed or mounted to the pivot pin 116 , by way of e . g ., setscrew ( s ), grub screw ( s ), locking collar ( s ), and / or other suitable temporary fixation hardware or devices . as desired , the deflectable plates 111 can be in coplanar alignment with each other , while enabling the user to later adjust each of the deflectable plates 111 to intersect with the pivot pin 116 at a different angle ( s ) with respect to the outer circumferential surface of the pivot pin 116 . this permits the user to adjust the default or resting state opening dimensions of the bodies 20 , enabling airflow characteristic tuning to enhance the self - regulatory functionality of air velocity indicator and control device 10 . since the entire volume of air flowing through the air velocity indicator and control device 10 originates from a single centrifugal fan , blower , or other source , airflow pressures , velocities , and volumes in each of the bodies 20 and air lines 7 are intimately related to those within all other bodies 20 and air lines 7 . differences in the values of pressures , volumes , and velocities between individual air lines 7 typically correspond to differences in airflow resistance values of the air lines 7 . generally , air lines 7 with low resistances have relatively high airflow velocities and air lines 7 with high resistances have relatively low airflow velocities , whereby pneumatic distribution systems 5 having differing airflow resistance values through different parallel components define airflow velocity differentials . still referring to fig4 , ganged deflectable plate assembly 110 b mitigates the magnitudes of velocity differentials by applying an inversely resistive relationship to the low and high resistance air lines 7 moving the values of the differing airflow velocities toward a common value . namely , within the air velocity indicator and control device 10 , ganged deflectable plate assembly 110 b introduces a relatively low resistance to the high resistance ( low velocity ) air lines 7 and a relatively high resistance to the low resistance ( high velocity ) air lines 7 . in this regard , the ganged deflectable plate assembly 110 b inversely influences or offsets the relative velocity status of the air lines 7 , whereby the low velocity air lines 7 perceive a relatively small resistance and the high velocity air lines 7 perceive a relatively large resistance to mitigate the velocity differential . airflows passing through the high velocity lines thus lose energy and relative velocity by urging the ganged deflectable plate assembly 1110 b further open . the low velocity lines 7 realize an opposite effect since the other , high velocity airflows increase the sizes of the opening within the bodies 20 . namely , airflows passing through the low velocity lines 7 increase their relative velocities by ( i ) losing velocity to a lesser rate or extent as compared to those flowing through the high velocity lines 7 , or ( ii ) gaining actual velocity , since the high velocity airflows relieve some of the resistive burden from the low velocity lines 7 by urging the ganged deflectable plate assembly 110 b further open . in this regard , the air velocity indicator and control device 10 influences each of the distinct airflows passing therethrough , whereby the resultant airflow velocities are closer to each other in magnitude , as compared to when the air velocity indicator and control device 10 is not utilized . in this manner , deviations from a velocity equilibrium of each of the airflows are attenuated or otherwise reduced , and , accordingly , so is the velocity differential . still referring to fig4 , it is apparent that during use , suitably consistent airflow velocities between the various airlines 7 are achieved by the automatic , passive , and mechanical self - regulation which is influenced , at least in part , by ( i ) the fluid dynamic characteristics of the individual airflows traversing the individual bodies 20 , ( ii ) the relationships between the individual airflows traversing the individual bodies 20 , ( iii ) the airflow induced mechanical reactive tendencies of the deflectable plates 111 within its respective body 20 , and ( iv ) the cumulative effect ( s ) of such mechanical reactive tendencies of the deflectable plates 111 upon each of the airflows through the respective bodies 20 and the overall position of the ganged deflection plate assembly 110 b . referring again to fig1 - 4 , it is apparent that the air velocity indicator and control device 10 provides a simple , cost effective , primarily mechanical device and method for determining airflow velocity in various portions of a pneumatic distribution system 5 of an air seeder . this is because the air velocity indicator and control devices 10 can be easily mounted into existing joints or coupling sites of pneumatic distribution system 5 , where mechanical fasteners or couplers are typically located . furthermore , the air velocity indicator and control device 10 is devoid of sophisticated electronics and function primarily by way of simple , inexpensive , and reliable mechanical components . in other words , air velocity indicator and control device 10 enables monitoring and control of airflow velocities without having to determine particle velocity , which typically requires sensitive and sophisticated sensors and corresponding devices . in light of the above , during use , the air velocity indicator and control devices 10 are either installed by the user at existing joints or points of intersection of the pneumatic distribution system 5 components , or are previously installed by the air seeder manufacturer . providing an air velocity indicator and control devices 10 at each of the relevant pneumatic distribution system 5 components , such as at each air cart air line and / or header 8 , the user can easily determine the relative velocities between the various air cart air lines 7 or headers 8 . based on this information , the user can manually reduce the velocity differential between respective ones of the various air cart air lines 7 or headers 8 . for example , the user can observe the position of each of the indicator arms 128 upon indicator scale 130 , thereby using indicator assembly 100 to quantify or evaluate the airflow velocity in each of the air cart air lines 7 or headers 8 . if one or more of the velocities is greater than the desired velocity , which might correspond , e . g ., to the lowest observed velocity , the user can perform the needed upstream or downstream adjustments to effectuate the desired change in airflow velocity to manually reduce the velocity differential . in other words , the user can adjust the rotational speed of the centrifugal fan at the air cart , or actuate various baffles to widen or restrict various openings , or utilize other suitable known louvers or adjustable internal airflow resistors , within the relevant portion of the pneumatic distribution system 5 , until the desired airflow velocity is achieved and the velocity differential attains an acceptably low value . referring again to fig4 , ganging the deflectable plates 111 to provide ganged deflectable plate assembly 110 b enables the air velocity indicator and control device 10 to automatically and passively self - regulate the airflow velocities so that the velocity differentials are suitably small so that the air seeder operates acceptably without requiring a substantial capital investment from the user . in some implementations , the air velocity indicator and control device 10 obviates the need for indicator assembly 100 ( fig1 - 3 ) or electronic sensors , feedback mechanisms , and / or controls , as desired . this regulation of airflow velocities in air lines 7 of seeders at a substantially lower cost as compared to sophisticated electronically controlled devices and systems . while the invention has been shown and described with respect to particular embodiments , it is understood that alternatives and modifications are possible and are contemplated as being within the scope of the present invention . a wide variety of air seeders ( e . g ., conventional air seeders and respective air carts and tilling implements ) can employ the air velocity indicator and control devices 10 of the present invention . in addition , it should be understood that the number of air velocity indicator and control devices 10 on the air seeder is not limiting on the invention . many changes and modifications could be made to the invention without departing from the spirit thereof . the scope of these changes will become apparent from the appended claims .

an air velocity indicator and control device is provided for use with pneumatic distribution systems used in air seeders that pneumatically discharge agricultural product to the ground , seedbed , or furrow . the air velocity indicator and control device includes a tubular housing , extending between an inlet and an outlet , and pivotally housing a deflectable plate that actuates in response to encountering an airflow entrained with agricultural product . a magnitude of deflection of the deflectable plate , corresponding to airflow velocity , can be displayed through an indicator assembly . this enables a user to identify velocity variances and differentials within the air seeder and make corrective adjustments . in some implementations , multiple air velocity indicator and control devices are ganged together with deflectable plates that pivot in unison with each other . the relative angle of fixation of the deflectable plates , upon the pivot pin , can be adjusted to permit airflow tuning as needed .

in accordance with one aspect of the present invention there is provided a kit , 100 shown in fig1 , containing ingredients for a 1 st and 2 nd stage treatment of the skin , and in particular breast tissue . the chemical composition for first stage of the treatment contains water , witch - hazel and up to about 3 vol . % essential oils and an emulsifying agent . a preferred chemical composition for the first stage of treatment is provided in table i . in this preferred compositions the essential oil components comprise rose otto essential oil and lavender essential oil . the grapefruit seed extract is present in small quantities for its anti - septic properties . in preparing the phase i composition , the coconut emulsifier and essential oil must be mixed together first before putting into the distilled water . to the extent that the compositions is varied , that is increasing or decreasing the total concentration of essential oil , the emulsifier concentration should be likewise adjusted such that 2 parts of emulsifier are mixed with 1 part of essential oil or the mixture of essential oils . thereafter , the oil / emulsifier mixture is added to the water , or the mixture of water and witch hazel , and the composition is shaken , stirred or otherwise well mixed to homogenize the ingredients . table i phase i composition phase i component vol . % distilled water 87 . 38 % witch hazel 12 . 48 % rose otto 0 . 029 % essential oil lavender 0 . 014 % essential oil coconut 0 . 086 % emulsifier grapefruit seed 0 . 003 % extract witch hazel is an astringent produced from the leaves and bark of the north american shrub witch - hazel . witch hazel has been used externally on sores , bruises and swelling . the principal components of the extract are tannin , gallic acid , catechins , proanthocyanins , flavonoids ( kaempferol , quercitin ), essential oil ( carvacol , eugenol , hexaenol ), choline , saponins , and bitters . distilled witch hazel , which contains no tannin , but may contain circa 14 % alcohol may be used , as well as alcohol free distillates of witch hazels known as “ hydrosols ”. it should be appreciated that as witch hazel is a natural product its odor may vary from batch to batch . accordingly , depending on the olfactory quality of the witch hazel its percentage in the formulation may be varied accordingly , along with that of the essential oils to provide a consistently pleasing odor . generally , the witch hazel should not exceed about ⅓ of the total volume , due to its astringent properties . the chemical composition for second stage of the treatment contains one or more vegetable oils and up to about 3 volume ( vol .) % essential oils . a preferred chemical composition for the second stage of treatment is provided in table ii . an alternative chemical composition for the second stage of treatment is provided in table iii . table ii phase ii composition as vol . % of as vol . % of phase ii component vol . % carrier oil essential oil grapeseed oil 77 . 016 % 77 % olive oil 10 . 809 % 11 % sweet almond oil 10 . 809 % 11 % jojoba oil 1 . 351 % 1 % grapefruit seed extract 0 . 001 % less than 1 % geranium essential oil 0 . 004 % 31 % cypress essential oil 0 . 004 % 31 % lemon grass essential 0 . 002 % 13 % oil carrot seed essential 0 . 002 % 13 % oil clary sage essential oil 0 . 002 % 12 % % of carrier oil 99 . 986 % % of essential oil 0 . 0141 % the essential oils in the preferred embodiment of the phase ii composition include cypress , geranium rose , lemongrass , carrot seed , clary - sage , rose otto and true angustifolia . however , the phase ii compositions in table ii and iii contain less than a total of 0 . 02 vol . % of essential oils , with the balance of the composition being the carrier oil . while the proportions of components of the carrier oil can vary , in the preferred embodiments of table ii and iii it comprises about 77 % by volume grapeseed oil , about 11 % by volume oil , about 11 % by volume sweet almond oil and about 1 % by volume jojoba oil . another aspect of the invention is using the compositions listed in table i and ii or iii . in the first step in the process the phase 1 composition , is sprayed on the skin to be treated . accordingly , another aspect of the invention is providing a treatment kit 100 in which the phase 1 composition is contained in a bottle 110 having an attached spraying dispenser head 115 . the container 110 holding the phase i composition should be shaken or otherwise agitated prior to use . the process of treatment and using the treatment kit 100 comprises a second step of applying the phase ii composition on the same area of skin tissue subject to the first treatment step and gently rubbing or messaging the thus combined compositions into the skin . the phase ii composition is intended to be applied immediately after using the phase i composition , while skin is still damp from its application . preferably , the phase ii composition is also sprayed on the skin . accordingly , another aspect of the invention is providing within the treatment kit 100 the phase ii composition in a bottle 120 with a spraying dispenser head 125 attached . whatever container holds the phase ii composition it is preferably shaken or otherwise agitated prior to use . it has been discovered that the phase i and phase ii compositions work with each other to optimize the moisturizing and toning effects on the skin tissue . not wishing to not be bound by theory , it is currently believed that the benefits of the 2 - step process accrue because the combined treatment aids in the retention of the toning components of the phase i compositions . it is also believed that the treatment with the phase i composition makes the skin tissue more receptive to incorporating both the moisturizing oil components and the essential oil of the phase ii composition . as a further aspect of the invention it has been discovered that the combination of the phase i treatment , which provides a moist base , in combination with the carrier oil ( s ) in the phase ii composition lubricates the fingers to further aid in breast examination during the third stage in the application process . again , not wishing to be bound by theory , it is also believed that the beneficial viscosity and lubricity of the skin in the phase ii process is caused in part by the aqueous nature of the phase i treatment . specifically , as the phase i composition contain an emulsifying agent ( coconut emulsifier ) the phase ii composition being an oil base will gradually emulsify with the phase i composition during the messaging action . this also extends the time before evaporation of absorption of the various components to allow examination of the entire breast under approximately the same conditions of lubricity . it is further believed that the immediate softening effects on the skin tissue aids in the detection of breast abnormalities . although the essential oil combination in the preferred embodiment of the phase i compositions includes the essential oil of rose otto and true angustifolia , other essential oils that may be used or combined . these include oil of bitter almond , benzoin , rosewood , camomile , carrot , cedar , lemon , cypress , eucalyptus , clove , hyssop , lavender , lime , mace , nutmeg , bitter orange , oregano , palmarosa , patchouli , rosemary , sandalwood , sage . whatever the combination of essential oils it is preferable that they be present in a concentration range from about 0 . 01 to 3 vol . %. thus , it should be appreciated that the carrier oils in the phase ii compositions are not merely inert ingredients , but also contribute to the immediate skin softening and provide the level of lubricity that aids in breast examination . in particular , the grape seed oil renders the phase ii combination non - greasy because it is readily absorbed into the skin . further , as the grape seed oil has no odor , it dilutes odor of the more pungent carrier oils . providing a non - greasy composition is important so that the user can dress immediately after the final application and messaging of their skin . it should be noted that sweet almond has no odor , but is known to add moisture to and lubricate the skin . the olive oil is highly desired for its benefits to the skin conditioning process , while the grapefruit seed oil is desirable for its antiseptic properties . the quantity of olive oil is generally kept below about 15 % because the strong odor may be objectionable to some consumers . however , to the extent that the selection of essential oils compliment or mask this strong odor , the concentration of olive oil can be increased upwards , so long as the viscosity and skin absorption properties are not radically changed from the preferred compositions . as for alternative embodiments of the phase ii composition , it should be appreciated that the mixture and percentage of the carrier oil can be varied . for example , it may contain from about 70 to 95 vol . % grapeseed oil ; from about 5 to 20 % vol . olive oil ( but preferably below 15 vol . %); from about 0 to 15 % vol . sweet almond oil and from about 0 . 5 to about 5 % vol . jojoba oil or a derivative thereof it may also include other vegetable oils that are readily absorbed by the skin . whatever the combination of essential oils , it is preferable that they be present in a concentration range from about 0 . 01 to 3 vol . %. as the carrot seed and clary sage essential oils are very strong , they should not together generally exceed about 0 . 005 vol . % of the total phase ii composition . alternatives to the essential oil combination in the preferred embodiment of the phase ii compositions include oil of bitter almond , benzoin , rosewood , camomile , cedar , lemon , cypress , eucalyptus , clove , hyssop , lavender , lime , mace , nutmeg , bitter orange , oregano , palmarosa , patchouli , rosemary , sandalwood , sage . while the invention has been described in connection with a preferred embodiment , it is not intended to limit the scope of the invention to the particular form set forth , but on the contrary , it is intended to cover such alternatives , modifications , and equivalents as may be within the spirit and scope of the invention as defined by the appended claims .

a process of skin treatment to soften the skin and minimize wrinkles utilizes in the first step the spray application of a mist to the skin . this first step is followed by the application of a mixture of beneficial vegetable oils that with essential oils . the first step of the treatment facilitates the absorption of the beneficial oils in the second step . as the composition and process also provides for the firming and toning of breast tissue , it promotes a daily regimen of efficient examination critical in the early self - discovery of abnormal tissue , which may be malignant . the preferred compositions are optimized to facilitate the breast self - examination process , providing an appropriate level of lubricity for an extended time without an oily residue .

referring to the drawings wherein like reference numerals designate similar parts throughout , there is illustrated a typical gondola 10 including a back panel 12 extending vertically upwardly from the rear side of a bottom shelf 14 . briefly , as illustrated in fig1 a canopy 16 is adapted to be mounted on the top marginal edge of the back panel 12 by a universal mounting means 18 . in addition to the mounting means 18 , the canopy 16 generally includes a header assembly 20 supported by a pair of rear vertical mounting studs 22 and 22a and a pair of front posts 24 and 24a extending between the header assembly 20 and the top surface 14a of the bottom shelf 14 . referring particularly to fig2 and 3 , the universal mounting means 18 consists of a sheet metal strip generally l - shaped in cross - section having one flange portion 18a provided in which at least a pair of spaced apertures 26 and 26a may be produced and the other flange portion 18b having two pair of spaced threaded stud fasteners 28 and 28a projecting outwardly therefrom . the stud fasteners 28 and 28a are fixedly secured to the flange portion 18b as by tack welds ( not shown ). the flange portion 18a may be secured to the top marginal edge of the back panel 12 by sheet metal screws ( not shown ) or double face tape . it will be noted in fig2 that the flange 18a is set on the top marginal edge of the back panel 12 so that the flange 18b overlaps the surface 12a of the back panel 12 . in fig3 it will be noted that the flange 18a is set on the top marginal edge of the back panel 12 so that the flange 18b of the mounting means 18 projects upwardly from the top marginal edge of the back panel 12 thus providing more usable surface area of the back panel 12 . briefly , the header assemblage 20 includes right - and left - hand end panels 30 and 30a , respectively , which are mirror images of each other , a rear cover panel 32 and a front cover panel 34 all are interconnected to form a ring - like structure . more particularly , each end panel 30 and 30a comprises a front flange section 36 and a rear telescoping flange section 38 . the front section 36 includes upper and lower inwardly facing parallel flanges 36a and 36b , each being provided with a row of apertures 36c . preferably , the outer front front edge of the front panel 36 is downwardly inclined and provided with an inwardly flange 36d . it will be noted that the lower flange 36b of the front section 36 is spaced from the flange 36d for receiving the post 24 or 24a . the post 24 or 24a is secured to the inside surface of the front section 36 by a flange clamping bracket 40 which may be secured to the front section as by tack welding . the clamping bracket 40 generally comprises a u - shaped bracket 40a having flanged ends 40b and includes a strap 42 which may be secured thereto as by wing nuts ( not shown ). the telescoping rear section 38 is provided with upper and lower inwardly facing flanges 38a and and 38b with each flange being provided with a row of apertures 38c aligned with the apertures 36c of the flanges 36a and 36b of the front section 36 . the vertically extending rear edge of the rear section 38 is provided with an inwardly facing flange 38d also having a row of apertures 38c , the purpose of which will be described hereinafter . the upper and lower flanges of the front and rear sections 36 and 38 of each end panel 30 and 30a are secured together in a desired depth relationship by conventional machine bolts ( not shown ). it will be noted that the lower flanges 38b of each rear section 38 is spaced from the flange 38d for receiving the rear mounting stud 22 and 22a extending upwardly from the back panel 12 . the rear cover panel 32 generally comprises an elongate panel 32a formed of sheet metal or the like , having an outwardly extending upper flange 32b provided with a depending lip 32c and a lower inwardly facing flange 32d . the upper flange 32b and its lip 32c are adapted to hang on the top marginal edges of the flange 38d of the rear sections 38 . the front cover panel 34 , also formed of sheet metal or the like , generally comprises a center pane 34a having an upper , downwardly folded lip 34b and a lower , upwardly folded lip 34c for receiving display ads . each open end of the lips 34b and 34c is adapted to engage the top and bottom portions of the flanges 36d of the front panels 36 of the end panels 30 and 30a . the studs 22 and 22a each is an elongated member , angle shaped in cross section , wherein one flange 22b is provided with a row of apertures 22c , the apertures 22c being aligned with the apertures 38c in the flanges 38d of the rear panels 38 of the end panels 30 and 30a and with the studs 28a and 28b projecting from the mounting strip 18 . the bottom end of each front post 24 and 24a is provided with a pair of depending pins 24b , as illustrated in fig1 which extend into cooperating apertures 14b provided in the top surface 14a of the shelf 14 . in assemblying the canopy 16 on the gondola 10 , the mounting means 18 or 18 &# 39 ; is preferably placed on the top marginal edge of the panel 12 as illustrated in fig2 and 5 , and secured thereto at each end by sheet metal screws ( not shown ) or by double face tape . if multiple units , as illustrated in fig4 are employed , then the mounting means 18 or 18 &# 39 ; are butted end - to - end when installed on the top marginal edge of the back panels . in this case one or more center panels 44 is employed . the center panel 44 includes a flange front section 46 and a rear flange section 48 . these sections 46 and 48 are substantially similar to the corresponding end panel sections 32 and 34 , except that vertically extending flanges extend from each side of the panels . more specifically , the front edge of the section 46 is provided with oppositely extending flanges 46a and 46b . likewise , vertically extending flanges 48a and 48b extend from opposite sides of the rear edge of the section 48 . otherwise , the center panel 44 includes the same structural elements as previously described for the end panels 30 and 30a . each end of the flange portion 18b &# 39 ; of the l - shaped mounting means 18 &# 39 ; includes an outwardly flanged channel member 50 which is attached , as by tack welding , to the front face of the flange portion 18b &# 39 ; in an upstanding position to extend above the flange portion 18a . the portion of the channel members 50 extending above the mounting means flange 18a &# 39 ; is provided with a weld nut 52 and bolt 54 , the purpose of which will be described hereinafter . the mounting means 18 &# 39 ; may be attached to the back panel 12 as previously described . the header assemblage 20 &# 39 ;, in this embodiment of the invention , includes right - and left - hand end panels 56 and 56a ( not shown ), respectively , which are mirror images of each other , a rear cover panel 58 and a front cover panel ( not shown ) substantially the same as the previously described front cover panel 34 . more particularly , each end panel 56 and 56a comprises a front flange section 60 and a rear telescoping flange section 62 . the front section 60 includes upper and lower inwardly facing parallel lip type flanges 60a and 60b , respectively , the upper flange 60a being provided with a row of apertures 60c . preferably , the outer front edge of the front panel 60 is downwardly inclined and provided with an inwardly facing flange 60d . it will be noted that the lower flange 60b of the front section 60 is spaced from the flange 60d for receiving the post 24 or 24a . the post 24 or 24a is secured to the inside surface of the front section 60 by an upright flange strip bracket 64 which may be secured to the front section 60 as by tack welding . the strip bracket 64 includes at least two longitudinally spaced locking tabs 64a formed to project over the opening provided in the lower flange 60b for cooperating with complementary opening provided in the side of the adjacent post 24 or 24a . the telescoping rear section 62 is provided with complementary upper and lower inwardly facing lip type flanges 62a and 62b , with the upper flange 62a being provided with a row of apertures 62c aligned with the apertures 60c of the flange 60a of the front section 60 . the vertically extending rear edge of the rear section 62 is provided with an inwardly facing flange channel member 66 ( see fig7 ), the purpose of which will be described hereinafter . a spring loaded lever 68 , one end of which has a locking tab 68a that is adapted to project into aligned apertures of the complementary upper flanges 60a and 62a has its other end affixed as by tack welding to the flange 62a . the lever 68 locks the front and rear sections 60 and 62 in a desired depth relation . the rear cover panel 58 generally comprises an elongate panel 58a formed of sheet metal or the like , having an inwardly extending upper flange 58b and a lower inwardly facing flange 58c . the vertically extending edge of the panel 58a is provided with a rolled flange 58d for cooperating with a complementary flange member 70 affixed to the side of the channel member 66 . the lower flange 58c is spaced from the rolled flange 58d while the upper flange 58b overlaps the rolled flange 58d , thus permitting the rear cover panel 58 to be connected to the rear panel section 62 of the end panel 56 . an inwardly flanged channel member 72 whose flanges are complementary to and cooperate with the flanges of the channel members 50 and 66 ( see fig6 and 7 ) supports and connects the header assemblage 20 &# 39 ; to the mounting means 18 &# 39 ;. referring to fig6 and 7 , a weld nut 52a is affixed to the outer face of the channel member 66 and cooperates with an opening 72a provided in one end of the channel member 72 for receiving a bolt 74 for securing the members 66 and 72 to each other . in all other aspects , the members employed in this embodiment of the invention are the same as those employed in the previously described embodiment . when the header assemblage 20 is used , the rear studs 22 and 22a are attached to the studs 28 and 28a by nuts ( not shown ). it should be noted that the header assemblage 20 may be mounted directly on the mounting means 18 without the studs 22 and 22a that is , if the back panel 12 of the gondola 10 is of an appropriate height . the end panels 30 and 30a and the center panel or panels 44 are then attached to the studs 22 and 22a by machine nuts and bolts ( not shown ) extending through the apertures 38c aligned with the aperture 22c of the studs extending inside the flange portions 38d , 48a and 48b . as previously mentioned , the flange portions 38d , 48a and 48b may be attached directly to the mounting strips 28 and 28a . when the header assemblage 20 &# 39 ; is used , one end of the channel member 72 is telescoped over the channel member 50 as illustrated in fig6 and the bolt 54 is rotated in a direction to clamp the flanges thereof against the complementary flanges of the channel member 50 . the other end of the channel member 72 is telescoped within the channel member 66 of the rear panel section 62 of the end panel 56 and may be secured thereto by the bolt 74 being rotated in a direction to force the complementary flanges thereof against the complementary flanges of the channel member 66 . on the other hand , bolt 74 can be inserted through an aperture provided in the channel member 72 to cooperate with the weld nut 52a provided on the channel member 66 to securely fasten the channel member 72 to the channel member 66 . the posts 24 and 24a are then either assembled in the clamp 40 as illustrated in fig2 by wing bolts ( not shown ) or to the locking tabs 64a illustrated in fig5 with the pins 24b of the posts inserted into the apertures 14b of the shelf 14 . in the embodiment shown in fig2 the back panel 32 is assembled by hooking the flange 32b over the top edges of the flanges 38d and / or the flanges 48a and 48b of the end panels 30 , 30a and / or 44 . corner braces 46 and 46a ( see fig2 ) may be secured to the top , marginal corner edges of the end panels 30 , 30a and the adjacent portion of the flanges 32b for rigidly strengthening the canopy assembly . in the embodiment of the invention shown in fig5 the rear cover panel 58 is assembled to the end panel 56 by sliding the flange portion 58d over the complementary flange of the member 70 until the upper flange 58b rests on the top marginal edge of the member 70 . the front side panel 34 is then assembled by sliding the open end of the lips 34b and 34c over the adjacent end portions of the flanges 36d . the header 20 is then adjusted so that all panels are level and the wing nuts are tightened . desired ads are then installed in the front panel . if desired , appropriate lighting fixtures may be mounted within the header assemblages 20 and 20 &# 39 ; for illuminating and causing attention to be focused on the displayed products . it will be appreciated from the foregoing description that the invention has resulted in a canopy for enhancing product displays which is comprised of a minimum number of components when the components can be installed quickly , economically and without the requirements of any particular expertise or tools or fasteners . also , the canopy is one which can be easily removed and installed on other gondolas with the same ease as the initial installation . in accordance with the patent statues , the principle and mode of operation of the invention has been explained and what is considered to represent its preferred embodiment has been illustrated and described . it should , however , be understood that the invention may be practiced otherwise than as specifically illustrated and described without departing from its spirit and scope .

a canopy structure adapted to be disposed over a conventional display gondola and having a universal mounting device attachable to the top marginal edge of the gondola . the canopy includes a header assembly having adjustable panels , a rear panel and a front sign panel . the rear edge of the header is attached to the mounting device and the opposite edge is supported by posts extending upwardly from the bottom shelf of the gondola . the end panels each include a flange attached to a rear edge thereof for connection to one end of a vertically extending stud which is connected at its other end to the universal mounting device . in one embodiment , the stud and the flange both have apertures formed therein and fastening means are utilized to connect the stud to the flange while the stud is connected at its other end to stud bolts extending from the universal mounting device . in another embodiment , the studs are formed as inwardly flanged channel members attached at one end to the flange formed on the end panels . outwardly extending channel members are attached to the universal mounting device and cooperate with the studs and a stud bolt . in both embodiments , the height of the header assembly can be adjusted by the positioning of the studs with respect to the universal mounting device .

according to this invention , ethyllinoleate and triethylcitrate can be contained in a composition each in a quantity in weight from between 0 . 1 to 99 . 9 %, preferably in equal quantities from between 1 . 00 and 40 % each , based on the final weight of the composition . furthermore , the composition based on ethyllinoleate and triethylcitrate can also contain various active ingredients , which for descriptive simplicity will be defined as synergists . the synergists can be chosen from between acetic acid , lactic acid , salicylic acid , tartaric acid , glycolic acid , clindamycin , eritromycin , metronidazole , amoxycillin , triclosan , capryloyl glcine , azelaic acid , zinc hydroxide , zinc chloride , trans - retinoic acid , resorcinol , hyaluronic acid , gentamicin , meclocycline , phenol , ascorbic acid , tocopherol , lipoic acid , phosphatidylcholine , phosphatidylserine , chlorhexidine , irgasan , adapalene , phospholipids in general , in all the dextrorotary , levorotary forms , recemic mixtures , cis forms , trans forms and relative salts , esters and amides and formulated together with particular additives and excipients for external use . these synergists may be present in the composition , individually or combined , in two or more , together with ethyllinoleate and triethylcitrate . these synergists may be contained in variable weight quantities from between 0 . 001 to 70 %, preferably from 0 . 5 to 15 % based on the final formulation when the proportions of ethyllinoleate and triethylcitrate are each from between 0 . 5 to 90 . 5 % in weight . the clinical efficacy and safety of use are the consequence of an original mechanism of action characterised by the fact that both ethyllinoleate and triethylcitrate , which in themselves behave as inert substances , are transformed into active principles once in contact with the skin . this transformation , from an inert substance into an active principle is a result of the hydrolysis , which takes place through specific cutaneous enzymes or bacteria ( lipase and esterase ) capable of releasing ethyl alcohol and respectively linolenic acid , diethyl citrate then monoethyl citrate and finally citric acid . the action mechanism of the composition of the invention can be described more in detail as follows . ethyllinoleate and triethylcitrate synergically are able to reduce seborrhoea and hyper keratinisation of the pilosebaceous duct ; this action is achieved through the release of the respective acid forms , through hydrolysis of the esters by the action of the lipase bacteria . in this invention it has been proven that hydrolysis of ethyllinoleate and triethylcitrate carried out by lipase bacteria is to be preferred to hydrolysis of the triglycerides ( lipid component of sebum ) carried out by the same lipase bacteria , consequently avoiding an irritative condition due to the release of fatty acids achieved through hydrolysis of the triglycerides . in relation to hyper keratinisation of the pilosebaceous duct , the combined action of ethyllinoleate and triethylcitrate is innovative in that the former prevents hyper - keratinisation whereas the latter cures it , behaving as a keratolytic . this combined action results in higher efficacy compared with the effect of the two components taken individually . in relation to seborrhoea the combined action of ethyllinoleate and triethylcitrate is innovative in that it results in a decrease in the sebum levels achieved by inhibiting the 5 - alpha reductase enzyme , an enzyme which as stated above is the cause of the reduction of testosterone to dihydrotestosterone whose action is capable of increasing the production of sebum . once ethyllinoleate is hydrolysed into linoleic acid , it is able to inhibit the activity of 5 - alpha reductase by a direct mechanism , whereas triethylcitrate , once hydrolysed into citric acid , acts in an indirect way , creating an environment where the activity of the aforementioned enzyme is obstructed . in other words , lipase bacteria recognise the ethyllinoleate and triethylcitrate mixture as the preferential substratum rather than the triglycerides of the sebum and so do not interfere with the structure of these triglycerides , thus reducing the inflammatory pathologies of seborrhoea and acne . effects of the invention in relation to tests reserved on samples based on the present invention , tests were carried out to evaluate experimentally the action of two products , a lotion and a cream , for the treatment of acne through a clinical test using a sebumetric measuring device . the test is able to evaluate if the products being tested are a valid help in the treatment against acne and if they are able to mitigate reddening due to the presence of acne focus . five female volunteers from between 15 and 28 years of age with greasy skin and suffering from acne . the samples must be applied , on the basis of their use characteristics , as they are . the samples must be applied uniformly on specific parts of the face , according to the indications given on the description card handed to the volunteer . the lotion on the right side of the face ; the cream on the left side of the face . after finding the volunteers for the test , the following instrumental evaluations are carried out : basic sebum measurement using an authorized sebumetric device in compliance with eec regulations ( skin lab ®) basic hydration using an authorized instrument in compliance with eec regulations ( skin lab ®) basic tewl using an authorized instrument in compliance with eec regulations ( tewameter ®)— only on the left side of the face acquisition of micro photographs using a video camera with polarised light — videocap — with 20 × enlargements and , when possible , 200 ×. the micro images are necessary to visualise in depth the slight blemishes due to acne and to highlight any improvements during the treatment under examination . acquisition of macro photographs with mini dv . the photographs are useful in defining the general start situation and to document any macroscopic improvements during the use of the products . furthermore the volunteers are supplied with a card on which to register daily observations about the cosmetic agreeable nature of the products and their performance . each volunteer is given a card describing how she must apply the various products being tested . to facilitate the task , the first application is carried out on the premises . the following controls are carried out after seven days ( t7 ), fourteen days ( t14 ), twenty one days ( t21 ) and twenty eight days ( t28 ) of treatment with a lotion and a cream . following the above experiment , the difference between the sebumetric , keratic and tewl values measured before and after the application of the products using the polarised light video camera and with the mini dv the variations of the furuncles and acne pustules was evaluated . the sebumetric , keratic and tewl values are registered , elaborated and graphically presented together with the results in the following tables . here following are some examples of formulations according to the present invention . [ 0051 ] n ° description % w / w 01 ethyllinoleate 20 . 00 02 triethylcitrate 80 . 00 [ 0053 ] n ° description % w / w 01 ethyllinoleate 20 . 00 02 triethylcitrate 20 . 00 03 salicyclic acid 2 . 00 04 ethyl acid 58 . 00 method of preparation : dissolve 03 in 04 ; to the solution mix 01 + 02 [ 0055 ] n ° description % w / w phase a 01 ethyllinoleate 5 . 00 02 triethylcitrate 5 . 00 03 ascorbil palmitate 1 . 50 04 ppg - 15 stearyl ether 10 . 00 05 capryloyl glycine 4 . 00 06 steareth - 2 3 . 00 07 steareth - 21 2 . 00 phase b 08 preservatives as req . 09 glycerol 3 . 0 10 water as req . method of preparation : phase a , mix 01 + 02 + 03 + 04 + 05 + 06 + 07 and heat to 75 ° c . ; phase b , mix 08 + 09 + 10 and heat the pre - mix to + 75 % c ., then add under agitation the phase b to phase a . cool to room temperature always agitating . [ 0057 ] n ° description % w / w 01 ethyllinoleate 20 . 00 02 triethylcitrate 20 . 00 03 erythromycin 10 . 00 04 ethyl acid 50 . 00 method of preparation : dissolve 03 in 04 , mix 01 + 02 in the solution [ 0059 ] n ° description % w / w 01 trans - retinoic 0 . 025 02 ethyllinoleate 5 . 00 03 triethylcitrate 20 . 00 04 ethyl acid as . req . [ 0061 ] n ° description % w / w 01 clindamycin 1 . 00 02 ethyllinoleate 5 . 00 03 triethylcitrate 20 . 00 04 ethyl acid as req . it has therefore been proved that the action of ethyllinoleate and triethylcitrate , described in the treatment of acne , greasy skin and seborrhoea , in consideration of the particular biological , pharmacological , physiological and biochemical action mechanism , has been found to be wider and is addressed to the treatment of several other cutaneous pathologies such as for example atopic dermatitis , dermatitis seborrheica , exfoliative dermatitis , stasis dermatitis , neurodermatitis , acne , acne rosacea , alopecia areata , scarring alopecia , female alopecia , anagen effluviam , hippocratic alopecia , psoriasis , lichen , ichthyosis , xerodermia , keratosis pilaris , decubital ulcer , trophic ulcer , torpid sores , angioma nevus or vascular bundle , hemangioma , granuloma telangiectaticum , keratosis seborrhoea , etc . the use of ethyllinoleate and triethylcitrate , also combined with opportune synergists , due to its particular action mechanism on the skin is innovative even as regards to its cosmetic use , such as : anti - aging composition aimed at improving the aesthetic conditions of the skin and to prevent signs of cutaneous aging ; anti - wrinkle ; moisturiser ; the treatment of cutaneous hyper - pigmentation ; cosmetic treatment of seborrhoea with tendency to develop into acne .

the present invention relates to a composition for topical use for treating and improving the aesthetic conditions of the skin , which comprises , as an active ingredient , a mixture of ethyllinoleate and triethylcitrate . this composition is active in the treatment of seborrhea and acne .

compounds of the present invention can be made according to the schematic procedure shown or other methods using commercially available starting materials , intermediates and reagents . starting materials , reagents and solvents can be obtained from chemical suppliers such as aldrich , baker and eastman chemical companies , or they may be prepared by techniques known in the art . ## str3 ## wherein r is as above described and nicl 2 ( dppp ) represents [ 1 , 3 - bis ( diphenylphosphino ) propane ] nickel ( ii ) chloride . the following examples will further illustrate the compounds of the present invention . 1 - bromohexane ( 1 ml ) was added to a stirred mixture of magnesium turnings ( 5 . 88 g , 242 mmol ) in dry ether ( 25 ml ) under a nitrogen atmosphere at room temperature . a crystal of iodine was added and the mixture was heated to reflux until the color faded . a solution of the remaining 1 - bromohexane ( 33 ml , 234 . 8 mmol ) in ether ( 100 ml ) was added at a rate to maintain reflux . after stirring at reflux for 2 hrs , the solution was transferred by cannula to a solution of trichlorobenzene ( 14 . 2 g , 77 . 4 mmol ) in ether ( 200 ml ) containing [ 1 , 3 - bis ( diphenylphosphino ) propane ] nickel ( ii ) chloride ( nicl 2 , dppp , 0 . 32 g , 0 . 25 mol %). the solution was refluxed gently for several hours whereupon a solid began to precipitate from solution . the reaction mixture was poured into 2000 ml of cold 1n aqueous hcl and the layers were separated . the aqueous solution was extracted with additional ether and the ether extracts were combined . the organic layer was dried over magnesium sulfate , filtered and evaporated to give 23 g of a brown oil which was then filtered through a pad of silica gel ( hexanes eluent ). the crude product was then pumped out under high vacuum with heating to give 19 . 3 g ( 75 %) of 1 , 3 , 5 - trihexylbenzene as a mobile oil . the 1 h - nmr ( 300 mhz ) spectral data were consistent with the desired material and the product was used in the subsequent step without further purification . a mixture of 1 , 3 , 5 - trihexylbenzene ( 19 . 3 g , 58 . 5 mmol ), iodine ( 22 . 3 g , 87 . 8 mmol ) and [ bis ( trifluoroacetoxy ) iodo ] benzene ( 40 . 3 g , 93 . 6 mmol ) in 200 ml of carbon tetrachloride was stirred at room temperature overnight . the solvent was evaporated and 200 ml of 10 % aqueous sodium thiosulfate was added to the residue . dichloromethane was added and the layers were separated . the organic layer was dried over magnesium sulfate and concentrated to give an oil / solid residue mixture which was then flash chromatographed over silica gel ( hexanes ). the crude product was dissolved in hexanes and chilled ; the precipitated solid ( 1 , 4 - diiodobenzene ) was removed . this crystallization procedure was repeated several times followed by silica gel chromatography ( heptane elution ) of the oily residue to give 4 . 5 g ( 11 %) of 1 , 3 , 5 - trihexyl - 2 , 4 , 6 - triiodobenzene as a mobile oil , after concentration and warming under high vacuum . title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 24 h 39 i 3 : c , 40 . 70 ; h , 5 . 55 ; i , 53 . 75 ; found : c , 40 . 88 ; h , 5 . 33 ; i , 53 . 78 . using the procedure described for the preparation of 1 , 3 , 5 - tri - n - hexyl - 2 , 4 , 6 - triiodobenzene , 1 , 3 , 5 - triethyl - 2 , 4 , 6 - triiodobenzene was prepared in 56 % yield from triethylbenzene ( 5 . 0 g , 31 . 4 mmol ), [ bis ( trifluoroacetoxy ) iodo ] benzene ( 21 . 2 g , 49 . 2 mmol ), and iodine ( 12 . 5 g , 47 . 2 mmol ) in 50 ml of ccl 4 . recrystallization from cyclohexane gave 9 . 5 g of pure material . title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 12 h 15 i 3 : c , 26 . 69 ; h , 2 . 80 ; i , 70 . 51 ; found : c , 26 . 84 ; h , 2 . 54 ; i , 70 . 39 . 1 , 3 , 5 - tri - n - butylbenzene was prepared in 92 % yield from n - butylbromide ( 15 ml , 140 mmol ), magnesium ( 3 . 35 g , 140 mmol ), trichlorobenzene ( 8 . 11 g , 44 . 8 mmol ) and nicl 2 ( dppp ) ( 0 . 2 g ) in 200 ml of ether as described for the preparation of 1 , 3 , 5 - tri - n - hexylbenzene . the product ( 10 . 1 g ), an oil , was used directly in the next reaction without further purification . the 1 h - nmr ( 300 mhz ) spectral data were consistent with the desired material . using the procedure described for the preparation of tri - n - heptyltriiodobenzene , the tri - n - butyl derivative was prepared ( 0 . 2 g , 8 % yield ) from the tri - n - butyl - triiodobenzene ( 1 g , 4 . 1 mmol ), [ bis -( trifluoroacetoxy ) iodo ] benzene ( 3 . 5 g , 8 . 2 mmol ) and iodine ( 1 . 9 g , 7 . 38 mmol ) in 10 ml of ccl 4 . recrystallization from ethanol afforded the analytically pure product ( mp . 92 °- 93 ° c .). title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 18 h 27 i 3 : c , 34 . 64 ; h , 4 . 36 ; i , 61 . 00 ; found : c , 34 . 67 ; h , 4 . 35 ; i , 60 . 80 . using the procedure described for the preparation of 1 , 3 , 5 - tri - n - hexyl - 2 , 4 , 6 - triiodobenzene , 1 , 3 , 5 - tri -( 4 - methylpentyl ) benzene was prepared in 28 % yield by the reaction of isohexylbromide ( 10 g , 6 . 06 mmol ), magnesium ( 1 . 5 g , 6 . 06 mmol ), trichlorobenzene ( 3 . 52 g , 1 . 9 mmol ) and nicl 2 ( dppp ) ( 0 . 1 g ) in 150 ml of ether . the 1 h - nmr ( 300 mhz ) spectral data for the oily product ( 5 . 5 g ) were consistent with the desired material which was used directly in the next step . using the procedure described for the preparation of 1 , 3 , 5 - tri - n - butyl - 2 , 4 , 6 - triiodobenzene , the triisohexyl derivative was prepared in 31 % yield as a crystalline solid after recrystallization from ethanol and drying under vacuum ( mp . 87 °- 89 ° c ). title compound : 1h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 24 h 39 i 3 : c , 40 . 70 ; h , 5 . 55 ; i , 53 . 75 ; found : c , 40 . 81 ; h , 5 . 42 ; i , 53 . 69 . using the procedures described for the preparation of 1 , 3 , 5 - tri - n - hexylbenzene , 1 , 3 , 5 - tri - n - pentylbenzene was prepared in 94 % yield from n - bromopentane ( 20 ml , 161 mmol ), magnesium ( 3 . 9 g , 161 mmol ), trichlorobenzene ( 9 . 37 g , 51 . 5 mmol ) and 0 . 25 g of nicl 2 ( dppp ) in ether ( 200 ml ). the product ( 13 . 8 g ) was an oil and was used directly in the next step . the 1 h - nmr ( 300 mhz ) spectral data were consistent with the desired material . a mixture of tri - n - pentyl - triiodobenzene ( 5 g , 17 . 4 mmol ), [ bis ( trifluoroacetoxy ) iodo ] benzene ( 14 . 9 g , 34 . 8 mmol ) and iodine ( 7 . 9 g , 31 . 3 mmol ) in 100 ml of carbon tetrachloride was stirred at room temperature overnight in a flask protected from light . the solvent was removed under vacuum and the residue was taken up in dichloromethane and washed with 10 % aqueous sodium thiosulfate . the organic layer was dried over magnesium sulfate and then filtered through a short column of silica gel . the filtrate was evaporated to give a solid . the solid residue was triturated with acetonitrile and the solid material was collected . the collected solid , which contained the desired product , was then purified by column chromatography ( hexanes ) to give 4 . 7 g ( 40 %) of the desired product ( mp . 71 °- 72 ° c .). title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 21 h 33 i 3 : c , 37 . 86 ; h , 4 . 99 ; i , 57 . 15 ; found : c , 37 . 91 ; h , 5 . 00 ; i , 56 . 90 . using the procedure described for the preparation of 1 , 3 , 5 - tri - n - hexylbenzene , the 1 , 3 , 5 - tri -( 3 - methylbutyl ) derivative was prepared from isopentylbromide ( 20 ml , 167 mmol ), magnesium ( 4 . 0 g , 167 mmol ), trichlorobenzene ( 9 . 7 g , 53 . 4 mmol ) and 0 . 3 g nicl 2 ( 0 . 25 mol %) in ether ( 200 ml ). the desired product ( 10 . 5 g ) was obtained in 22 % yield as an oil after silica gel chromatography ( hexanes ). the 1 h - nmr ( 300 mhz ) spectral data were consistent with the desired product . using the procedure described for the preparation of 1 , 3 , 5 - tri - n - butyl - 2 , 4 , 6 - triiodobenzene , the triisopentyl - triiodo derivative was prepared ( 1 % yield ) as a crystalline solid after recrystallization from ethanol ( top 86 °- 87 ° c .). title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 21 h 33 i 3 : c , 37 . 86 ; h , 4 . 99 ; i , 57 . 15 ; found : c , 38 . 05 ; h , 5 . 03 ; i , 57 . 10 . 1 , 3 , 5 - tri - n - propylbenzene was prepared ( 5 . 78 g , 81 %) as previously described for tri - n - hexylbenzene , from propyl bromide ( 10 ml , 110 . 1 mmol ), magnesium ( 2 . 67 g , 110 . 1 mmol ), trichlorobenzene ( 6 . 39 g , 35 . 2 mmol ) and nicl 2 ( dppp ) ( 0 . 15 g ) in 50 ml of dry ether . the 1 h - nmr spectral data were consistent with the desired material and the product , an oil , was used directly without further purification . using the procedure described for the preparation of tri - n - hexyltriiodobenzene , the desired product was prepared ( 1 % yield ) from tri - n - propylbenzene ( 4 . 1 g , 20 . 1 mmol ), iodine ( 10 . 2 g , 40 . 2 mmol ) and [ bis ( trifluoroacetoxy ) iodo ] benzene ( 18 . 2 g , 42 . 3 mmol ) in 20 ml of ccl 4 . recrystallization of the crude product from cyclohexane and then ethanol gave analytically pure material ( mp . 95 °- 96 ° c .). title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 15 h 21 i 3 : c , 30 . 95 ; h , 3 . 63 ; i , 65 . 41 ; found : c , 31 . 03 ; h , 3 . 52 ; i , 65 . 24 . using the procedure described for the preparation of 1 , 3 , 5 - trihexylbenzene , 1 , 3 , 5 - tri - n - heptylbenzene ( 14 g ) was prepared in 93 % yield as a clear oil from 1 - bromoheptane ( 20 ml , 127 mmol ) and 0 . 25 g of nicl 2 ( dppp ) in dry ether ( 150 ml ). the 1 h - nmr ( 300 mhz ) spectral data were consistent with the desired product which was used without further purification . to a stirred solution of 1 , 3 , 5 - triheptylbenzene ( 7 . 0 g , 18 . 8 mmol ) in carbon tetrachloride ( 50 ml ) was added sequentially , iodine ( 8 . 6 g , 33 . 8 mmol ) and [ bis ( trifluoroacetoxy ) iodo ] benzene ( 16 . 2 g , 37 . 6 mmol ) and the mixture was stirred at room temperature overnight ( reaction flask was covered with aluminum foil ). the solvent was recovered and the residue was taken up in dichloromethane . the organic layer was washed with 10 % aqueous sodium thiosulfate , dried over magnesium sulfate and evaporated to give an oil . the oil was dissolved in hexanes and washed with acetonitrile to remove the bulk of the 1 , 4 ,- diiodobenzene present in the crude product . the product was then subjected to silica gel chromatography ( hexanes ) to give 4 . 5 g ( 32 %) of pure tri - n - heptyltriiodobenzene and an additional 5 g of impure product . this reaction was repeated again with tri - heptylbenzene ( 6 . 32 g , 16 . 9 mmol ), iodine ( 7 . 7 g , 30 . 4 mmol ) and [ bis ( trifluoroacetoxy ) iodo ] benzene ( 14 . 6 g , 33 . 8 mmol ) in carbon tetrachloride ( 50 ml ) and the crude product was isolated as described above to give an oil which was combined with the product from the previous run . repeated silica gel chromatography ( hexanes ) and warming the residue under high vacuum afforded 9 . 5 g , ( 35 %) of the desired product . title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . calculated for c 27 h 45 i 3 : c , 43 . 22 ; h , 6 . 04 ; i , 50 . 74 ; found : c , 43 . 54 ; h , 6 . 08 ; i , 50 . 38 . a suspension of 30 . 09 g ( 68 . 2 mmol ) of n - heptyl - triphenylphosphonium bromide in 68 ml of dry thf was placed under nitrogen . the suspension was cooled to 0 ° c . and a 2 . 38m solution of n - buli in hexane ( 27 . 7 ml , 65 . 9 mmol ) was added dropwise via syringe . the resulting deep red solution was stirred 30 min . at 0 ° c . before a solution of 12 . 00 g ( 45 . 5 mmol ) of 4 - iodoacetophenone in 45 ml of dry thf was added dropwise . the resulting solution was allowed to warm to room temperature at which time an orange suspension formed . the suspension was stirred at room temperature for 72 hrs and was cooled to 0 ° c . a solution of saturated nh 4 cl in water was added dropwise until the suspension was colorless . the mixture was partitioned between 300 ml of water and 250 ml of ethyl acetate . the ethyl acetate layer was then washed with brine ( 50 ml ), dried over na 2 so 4 and concentrated in vacuo to yield an oily tan solid . the solid was washed with hexane ( 200 ml ), filtered and the filtrate was concentrated in vacuo to yield 12 . 26 g of yellow oil . the oil was purified by flash chromatography on 367 g of silica gel with 2 . 5 % ethyl acetate / hexane as eluent . the first 525 ml to elute contained nothing while the pure product eluted with the next 500 ml . concentration in vacuo afforded 9 . 98 g ( 67 %) of product isomers as a slightly yellow tinted oil . 1 h - nmr ( 300 mhz ) spectral data were consistent with the desired structure . a mixture of 12 . 50 g ( 38 . 08 mmol ) of 2 -( 4 - iodophenyl )- 2 - nonene and 6 . 42 g ( 55 . 2 mmol ) of triethylsilane was cooled to 0 ° c . trifluoroacetic acid ( 13 . 03 g , 114 . 2 mmol ) was added dropwise and the resulting mixture was stirred at room temperature for 22 hrs before it was heated to reflux for 30 min . the mixture was cooled and partitioned between 200 ml hexanes and 100 ml of 10 % k 2 co 3 in water . the hexane layer was washed with brine ( 50 ml ) and dried over na 2 so 4 . the colorless solution was concentrated in vacuo to 12 . 31 g of a colorless oil . the oil was purified by flash chromatography on 370 g of silica gel with hexane as the eluent . concentration in vacuo afforded 11 . 45 g ( 91 %) of product as a mobile colorless oil . title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . fab / ms : m + 330 . calculated for c 15 h 23 i : c , 54 . 55 ; h , 7 . 02 . found : c , 55 . 00 , h , 7 . 02 . a 50 ml round bottom flask was charged with 213 mg ( 30 . 7 mmol ) of freshly - cut lithium wire and 3 . 99 g ( 31 . 1 mmol ) of naphthalene . dry thf ( 15 ml ) was added , and the resulting dark green mixture was stirred at room temperature for 2 hrs . a solution of 2 . 09 g ( 15 . 3 mmol ) of zncl 2 in 15 ml thf was then added over 15 min ., and the resulting suspension of active zinc was stirred an additional 15 min . the p - diiodobenzene ( 3 . 37 g , 10 . 2 mmol ) was then added in one portion , and the mixture was allowed to stir at room temperature for 18 hrs . stirring was stopped , and after the excess zinc had settled , the dark brown supernatent solution was transferred via cannula to a 100 ml round bottom flask and cooled to - 20 ° c . a solution of 910 mg ( 21 . 4 mmol ) of licl and 950 mg ( 10 . 6 mmol ) of cucn in 15 ml thf was added over 3 min . and , after stirring an additional 5 min ., the mixture was warmed to 0 ° c . for 20 min . and re - cooled to - 20 ° c . ethyl 11 - bromo - 9 - undecenoate ( 2 . 33 g , 8 . 01 mmol ) was added dropwise and after stirring for 20 min ., the reaction mixture was placed in an ice bath and was allowed to warm to room temperature as stirring was continued for 18 hrs . the reaction mixture was then poured into 20 ml saturated nh 4 cl solution , and 50 ml of ether was added . the layers were separated and the aqueous phase was extracted with ether , decanting the organic layers away from the brown residue which forms . water ( 100 ml ) was added to the combined organic phases and , after removing the white precipitate by filtration , the layers were separated and the organic phase was dried ( mgso 4 ) and concentrated to a yellow oil . the crude product was chromatographed on silica gel using hexanes to elute the naphthalene , then 10 % ethyl acetate / hexanes to afford 2 . 70 g ( 81 %) of a pale yellow oil which was shown by gc and nmr spectral analysis to be a 3 : 2 mixture of a : b , plus an undetermined amount ( 40 %) of des - iodo products . the latter were removed by distillation ( bp 80 °- 145 ° c ., 0 . 25 mm hg ). analytical samples of a and b were obtained by chromatographing a portion of the pot residue on silica gel impregnated with 10 % agno 3 using gradient elution ( 2 %- 5 % ethyl acetate / hexanes ). title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure . ms : mh + 415 . calculated : c , 55 . 08 ; h , 6 . 57 ; i , 30 . 63 . found for c 19 h 27 io 2 : c , 55 . 16 ; h , 6 . 43 , i , 30 . 25 . title compound : 1 h ( 300 mhz ) and 13 c ( 75 mhz ) nmr spectra were consistent with the desired structure ; however , the compound is unstable and will decompose within 30 days . ms : mh + 415 . calculated for c 19 h 27 io 2 : c , 55 . 08 ; h , 6 . 57 , i , 30 . 63 . found : c , 54 . 14 ; h , 6 . 48 ; i , 28 . 45 . the contrast agents may be formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art . the compounds with the addition of pharmaceutically acceptable aids ( such as surfactants and emulsifiers ) and excipients may be suspended or partially dissolved in an aqueous medium resulting in a dispersion , solution or suspension . however , the oily contrast agents are preferably made into emulsions . compositions of the present invention comprise the following pharmaceutically acceptable components based on % w / v : ______________________________________ broad more mostingredients range preferred range preferred range______________________________________contrast agent 30 - 200 40 - 160 85 - 120 ( mg i / ml oftotalsuspension ) cellulose 0 . 05 - 10 0 . 1 - 4 0 . 2 - 1derivative (% w / v ) oily vehicle 0 . 0 - 55 0 . 1 - 25 7 - 15 (% w / v ) surfactant 0 . 0 - 20 0 . 1 - 10 3 - 7 (% w / v ) viscosity 0 . 0 - 15 0 . 001 - 4 0 . 05 - 1modifyingexcipients (% w / v ) water - q . s . to 100 % by volume______________________________________ when the composition is used for ct imaging of the gi tract , the concentration of the x - ray contrast agent should be in the range of from 0 . 01 to 40 mg i / ml , more preferably of from 0 . 25 to 25 mg i / ml and most preferably of from 4 - 12 mg i / ml . the preferred cellulose derivative utilized in the present invention is avicel ® rc - 591 , which is a mixture of about 89 parts microcrystalline cellulose and about 11 parts of sodium carboxymethylcellulose . in further reference to the components used in the compositions of the present invention the following should be noted . the x - ray contrast agent present in concentrations lower than the above - stated minimum in formulations does not provide good quality x - ray or ct images , while concentrations above the maximum concentration render the gi tract too radiopaque and do not allow sufficient delineation of the gi tract . in practicing the present invention an oil - in - water emulsion is preferred over a water - in - oil emulsion , suspension and dispersion . oily materials , the density of which approximate the density of the aqueous phase impart stability to emulsions . for that reason low density oils , such as mineral oils , are desirable in preparing the emulsions . when the x - ray contrast agents are oily substances at room temperature , the presence of an additional oily vehicle is not always necessary . above about 55 % w / v of oil the emulsion is no longer an oil - in - water emulsion but shifts to a water - in - oil emulsion . compositions without the presence of surfactants still provide excellent x - ray images , however , without surfactants the compositions are very difficult to emulsify and only suspensions / dispersions are produced which are less desirable for coating the gi tract and are also less stable on shelf - life . for reason of toxicity it is desirable to keep the concentration of certain surfactants as low as possible ; above about 20 % w / v the risk of toxicity rapidly increases . while the alkylbenzenes of the present invention in formulations with a pharmaceutically acceptable vehicle provide good quality x - ray images , the addition of a cellulose derivative to the formulations greatly increases the quality of the x - ray images . at the low extreme of the concentration range there is little or no benefit gained , while above the higher extreme of the concentration range the emulsion is too viscous for administration . depending on the form and amount of cellulose derivative used , additions of viscosity modifying agents may not be necessary ; at higher levels than about 15 % w / v the viscosity is too high and gels will tend to form . ______________________________________components amounts in % w / v______________________________________1 , 3 , 5 - tri - n - hexyl - 2 , 4 , 6 - triiodobenzene 17 . 50light mineral oil , nf 12 . 50polysorbate 80 ( tween 80 ) 3 . 37sorbitan mono - oleate ( span 80 ) 1 . 64avicel ® rc - 591 0 . 50q . s . with water to 100 % by volume______________________________________ ______________________________________components amounts in % w / v______________________________________1 , 3 , 5 - triethyl - 2 , 4 , 6 - triiodobenzene 25 . 00 ( oil at room temperature ) polysorbate 80 ( tween 80 ) 5 . 00avicel ® rc - 591 6 . 50q . s . with water to 100 % by volume______________________________________ ______________________________________components amounts in % w / v______________________________________1 , 3 , 5 - tri - n - butyl - 2 , 4 , 6 - triiodobenzene 20 . 00light mineral oil , nf 5 . 00polysorbate 20 ( tween 20 ) 2 . 50sorbitan mono - laurate ( span 20 ) 2 . 50avicel ® rc - 591 0 . 50q . s . with water to 100 % by volume______________________________________ ______________________________________components amounts in % w / v______________________________________2 ,( 4 - iodophenyl ) nonane 25 . 00polysorbate 20 ( tween 20 ) 2 . 50sorbitan mono - laurate ( span 20 ) 2 . 50avicel ® rc - 591 0 . 75q . s . with water to 100 % by volume______________________________________ as known by those skilled in the art , surfactants or emulsifiers can reduce the interfacial tension between two immiscible phases , i . e ., oil - in - aqueous medium . these agents can be used alone or in combination with other emulsifying agents and surfactants . for example , dow corning medical antifoam af , which is a composition of 30 % w / v polydimethylsiloxane ( simethicone ) and silica aerogel , 14 % w / v stearate emulsifiers and 0 . 075 % w / v sorbic acid , the balance being water , may be used by itself . intralipid , which is an emulsion of fatty acids needs the presence of a suspending agent for it to form an acceptable emulsion with contrast agents of the present invention . the amount of such surfactants may be in the range of from 0 . 01 to 15 % w / v of the aqueous formulations , although the amount , in general , is kept as low as possible , preferably in the range of 0 . 05 to 5 % w / v . the surface active agents may be cationic , anionic , nonionic , zwitterionic or a mixture of two or more of these agents . suitable cationic surfactants include cetyl trimethyl ammonium bromide . suitable anionic agents include sodium lauryl sulphate , sodium heptadecyl sulphate , alkyl benzenesulphonic acids and salts thereof , sodium butylnapthalene sulfonate , and sulphosuccinates . zwitterionic surface active agents are substances that when dissolved in water they behave as diprotic acids and , as they ionize , they behave both as a weak base and a weak acid . since the two charges on the molecule balance each other out the molecules act as neutral molecules . the ph at which the zwitterion concentration is maximum is known as the isoelectric point . compounds , such as certain amino acids having an isoelectric point at the desired ph of the formulations of the present invention are useful in practicing the present invention . in preparing the formulations of the present invention we prefer to use nonionic emulsifiers or surface active agents which , similarly to the nonionic contrast agents , possess a superior toxicological profile to that of anionic , cationic or zwitterionic agents . in the nonionic emulsifying agents the proportions of hydrophilic and hydrophobic groups are about evenly balanced . they differ from anionic and cationic surfactants by the absence of charge on the molecule and , for that reason , are generally less of an irritant than the cationic or anionic surfactants . nonionic surfactants include carboxylic esters , carboxylic amides , ethoxylated alkylphenols and ethoxylated aliphatic alcohols . one particular type of carboxylic ester nonionic surface active agents are the partial , for example , mono - esters formed by the reaction of fatty and resin acids , for example of about 8 to about 18 carbon atoms , with polyhydric alcohols , for example glycerol , glycols such as mono -, di -, tetra - and hexaethylene glycol , sorbitan , and the like ; and similar compounds formed by the direct addition of varying molar ratios of ethylene oxide to the hydroxy group of fatty acids . another type of carboxylic esters is the condensation products of fatty and resin partial acids , for example , mono - esters of ethylene oxide , such as fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol , for example polyoxyethylene sorbitan . these may contain , for example , from about 3 to about 80 oxyethylene units per molecule and fatty or resin acid groups of from about 8 to about 18 carbon atoms . examples of naturally occurring fatty add mixtures which may be used are those from coconut oil and tallow while examples of single fatty acids are dodecanoic acid and oleic acid . carboxylic amide nonionic surface active agents are the ammonia , monoethylamine and diethylamine amides of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms . the ethoxylated alkylphenol nonionic surface active agents include various polyethylene oxide condensates of alkylphenols , especially the condensation products of monoalkylphenols or dialkylphenols wherein the alkyl group contains about 6 to about 12 carbon atoms in either branched chain or particularly straight chain configuration , for example , octyl cresol , octyl phenol or nonyl phenol , with ethylene oxide , said ethylene oxide being present in amounts equal to from about 5 to about 25 moles of ethylene oxide per mole of alkylphenol . ethoxylated aliphatic alcohol nonionic surface active agents include the condensation products of aliphatic alcohols having from about 8 to 18 carbon atoms in either straight chain or branched chain configuration , for example oleyl or cetyl alcohol , with ethylene oxide , said ethylene oxide being present in equal amounts from about 30 to about 60 moles of ethylene oxide per mole of alcohol . preferred nonionic surface active agents include : sorbitan esters ( sold under the trade name span ) having the formula : ## str14 ## wherein r 1 ═ r 2 ═ oh , r 3 ═ r for sorbitan monoesters , where r ═( c 11 h 23 ) coo for laurate , ( c 17 h 33 ) coo for oleate , ( c 15 h 31 ) coo for palmitate , ( c 17 h 35 ) coo for stearate . where ( x + 1 ) is the number of carbon atoms in the alkyl chain , typically : and y is the number of ethylene oxide groups in the hydrophilic chain , typically 10 - 60 . polyoxyethylene sorbitan fatty add esters ( polysorbates 20 , 40 , 60 , 65 , 80 & amp ; 85 ) sold under the trade names of tweens , crillers , sorlares and monitans , having the formulas ( 1 ) and ( 2 ) ## str15 ## wherein w + x + y + z = 20 ( polysorbate 20 , 40 , 60 , 65 , 80 and 85 ) the dosages of the contrast agent used according to the method of the present invention will vary according to the precise nature of the contrast agent used . preferably , however , the dosage should be kept as low as is consistent with achieving contrast enhanced imaging . by employing as small amount of contrast agent as possible , toxicity potential is minimized . for most contrast agents of the present invention dosages will be in the range of from about 0 . 1 to about 16 . 0 g iodine / kg body weight , preferably in the range of from about 0 . 5 to about 6 . 0 g iodine / kg of body weight , and most preferably , in the range of from about 0 . 8 to about 2 . 0 g iodine / kg body weight for regular x - ray visualization of the gi tract . for ct scanning , the contrast agents of the present invention will be in the range of from about 1 to about 600 mg iodine / kg body weight , preferably in the range of from about 20 to about 200 mg iodine / kg body weight , and most preferably in the range of from about 40 to about 80 mg iodine / kg body weight . the concentration of the contrast agent should be in the range of from about 0 . 001 % w / v to about 75 % w / v of the formulation , preferably from about 0 . 05 % w / v to about 50 % w / v and most preferably of from about 0 . 1 % w / v to about 20 % w / v . the invention having been fully described , it will be apparent to one skilled in the art that changes and modifications can be made thereto without departing from the spirit and scope thereof .

disclosed are x - ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising an x - ray producing agent of the formula or a pharmaceutically acceptable salt thereof ## str1 ## wherein r is methyl , ethyl , n - propyl , c 4 - c 25 alkyl , cycloalkyl , unsaturated allyl or halo - lower - alkyl , each of which may be optionally substituted with halo , fluoro - lower - alkyl , aryl , lower - alkoxy , hydroxy , carboxy or lower - alkoxy carbonyl ; p -- m q , or p -- c . tbd . c -- q ; r 1 , r 2 , r 3 and r 4 are independently h , lower - alkyl , optionally substituted with halo ; n is 2 - 5 ; m is 2 - 5 ; p is 1 - 10 ; and q is h , lower - alkyl , lower - alkenyl , lower - alkynyl , lower - alkylene , aryl , or aryl - lower alkyl ; in a pharmaceutically acceptable carrier comprising a cellulose derivative .

a block diagram of a preferred embodiment of the invention in use during an orthopedic surgical procedure is depicted in fig1 . internal tourniquet 2 supplies clear pressurized fluid to joint capsule 4 to permit a surgical procedure to be performed within the region 6 enclosed by the joint capsule 4 . joint capsule 4 is a substantially fluid - tight sac - like envelope that encloses the cavity of a synovial joint by attaching to the circumference of the articular end of each involved bone 8 and 10 . to visualize the bones and tissues within the joint the operating surgeon inserts a scope 12 into the joint capsule 4 . scope 12 includes a cannulated sheath that provides a fluid passageway from internal tourniquet 2 to the interior region 6 of joint capsule 4 , as shown in fig1 . scope 12 is typical of commonly used scopes and contains fiber optic fibers coupled to a light source for transmitting light into joint capsule 4 and magnifying lenses coupled to a color video camera for visualizing the interior of region 6 of joint capsule 4 . video signals from the camera of scope 12 are transmitted to video display 14 for viewing by the operating surgeon and to internal tourniquet 2 for analysis as described below . pressurized fluid from internal tourniquet 2 is supplied to scope 12 via flexible plastic tubing 16 . surgical instruments may be inserted into the joint capsule 4 via instrument portal 18 . instrument portal 18 forms a substantially fluid - tight seal around the body of a surgical instrument as it is inserted through the portal , the fluid - tight seal of instrument portal 18 may be adapted to accommodate surgical instruments of various diameters and shapes . instrument portal 18 includes retaining elements 20 as shown in fig1 . retaining elements 20 form a fluid - tight seal between the body of instrument portal 18 and joint capsule 4 , thereby preventing fluid loss from the capsule and extravasation of fluid into surrounding tissues . retaining elements 20 also provide robust fixation of the portal for the duration of the surgical procedure and improve retention of the portal while surgical staff insert , manipulate and remove surgical instruments . during the time period of a surgical procedure bleeding may occur from tissues and bones within region 6 of joint capsule 4 and from the tissues surrounding joint capsule 4 where openings into the capsule have been made . the presence of blood within the region can impede the ability of the operating surgeon to clearly visualize both the interior of the joint and any surgical instruments that may be present within the region ; this may result in unnecessary delays , an increase in the risk of patient injury and a decrease in the precision of the surgical procedure . internal tourniquet 2 acts to help improve visualization of the interior of joint capsule 4 by maintaining hemostasis within region 6 of joint capsule 4 . internal tourniquet 2 supplies pressurized fluid to the joint capsule via scope 12 , and controls the pressure of the fluid within the joint capsule and rate of fluid flow through the joint capsule . as described further below , internal tourniquet 2 maintains hemostasis within joint capsule 4 by actively adjusting the fluid pressure and flow within the joint capsule in response to changes in the amount of blood detected within the fluid both within the joint capsule and exiting the joint capsule . to reduce extravasation , internal tourniquet 2 acts to maintain the fluid pressure near the lowest pressure necessary to maintain hemostasis over a time period suitably long for the performance of a surgical procedure . as shown in fig1 , internal tourniquet 2 consists of the following functional modules : user interface and display 22 , flow and pressure control module 24 , hemostasis control module 26 , blood detection module 28 and video blood sensor 30 . internal tourniquet 2 is supplied with fluid from fluid reservoir 32 via flexible plastic tubing 34 . fluid reservoir 32 contains sterile normal saline solution , lactated ringers solution or other clear and sterile fluid suitable for the pressurization of joint capsule 4 . user interface and display 22 includes a lcd panel for the display of : pressure values , flow rate values , sensed blood concentration values and alarm conditions . hemostasis control parameters are also displayed ; these include minimum and maximum pressure limits , minimum and maximum flow limits and the operating modes of hemostasis control module 26 . a membrane key pad forms part of user interface and display 22 for the adjustment of hemostasis control parameters and operating modes . user interface and display 22 also includes an audio transducer for alerting the operator to alarm conditions . flow and pressure control module 24 within internal tourniquet 2 includes a pump that pressurizes fluid from fluid reservoir 32 ; the pressurized fluid is supplied to joint capsule 4 via tubing 16 and scope 12 . flow and pressure control module 24 responds to a fluid flow rate reference signal and a fluid pressure reference signal from hemostasis control module 26 . flow and pressure control module 24 acts to maintain the pressure within joint capsule 4 near the pressure level set by the fluid pressure reference signal and acts to maintain the fluid flow rate to joint capsule 4 near the rate set by the fluid flow rate reference signal . pressure transducer 36 generates a pressure signal . the level of the pressure signal is representative of the pressure of fluid sensed within region 6 of joint capsule 4 . the pressure signal is communicated to flow and pressure control module 24 . for clarity in fig1 , pressure transducer 36 is shown as a separate device extending into joint capsule 4 ; it will be apparent that pressure transducer 36 could be combined with scope 12 , instrument portal 18 or other apparatus in direct communication with the fluid - filled region 6 of joint capsule 4 . the fluid supplied to joint capsule 4 by flow and pressure control module 24 is removed from joint capsule 4 through fluid outlet portal 38 and flexible plastic tubing 40 . an outlet control valve 42 acts upon tubing 40 to control the rate at which fluid leaves joint capsule 4 . in the preferred embodiment outlet control valve 42 is a servo controlled pinch valve which acts upon tubing 40 in response to an outlet control signal from flow and pressure control module 24 . fluid supplied to joint capsule 4 may also leave the joint capsule through extravasation , through instrument portal 18 , and through surgical incisions extending into joint capsule 4 . by varying the degree of restriction in tubing 40 and the rate at which fluid is supplied to joint capsule 4 , flow and pressure control module 24 acts to maintain the pressure level within joint capsule 4 and the fluid flow rate through joint capsule 4 near the levels set by hemostasis control module 26 . in the preferred embodiment , fluid pressure and flow within joint capsule 4 are maintained near set levels with a controllable fluid pump and a variable outlet restriction , it will be apparent that other means may be used to maintain fluid flow through the capsule and pressure within the capsule near desired levels . for example , two pumps may be used , one supplying fluid to the capsule the other acting as a variable restriction or suction source to remove fluid from the capsule ; as another example , fluid from a pressurized source could be supplied to the capsule through a controlled restricting valve and removed from the capsule via a controlled restricting valve or pump . flow and pressure control module 24 communicates the pressure signal and a flow rate signal representative of the rate of fluid flowing into the joint capsule 4 to hemostasis control module 26 and to user interface and display 22 for display to the user . the flow rate signal may be obtained by any suitable flow sensor or meter associated with the flow and pressure control module 24 . blood detection module 28 receives and processes blood concentration signals from blood sensors 44 and 46 and video blood sensor 30 . blood sensors 44 and 46 are optical calorimetric sensors sensitive to the absorption spectra of hemoglobin , a hemoprotein composed of globin and heme that gives red blood cells their characteristic red color ;. blood sensors 44 and 46 transmit light with predetermined wavelengths through a volume of fluid to a photodetector to produce signals indicative of the light absorption , hence the amount of hemoglobin detected within the fluid , which is representative of the concentration of blood present within the fluid . blood sensor 44 ( bld - 6 . 0 , edgewood , n . y .) is shown in fig1 applied to tubing 40 that is external to the joint capsule 4 . this sensor detects the amount of hemoglobin present in a predetermined sample volume of fluid exiting the joint capsule through outlet portal 38 and tubing 40 . blood sensor 46 operates on similar principles to sensor 44 and is inserted directly into the joint capsule . it also produces a signal indicative of the amount of hemoglobin present within a predetermined sample volume of fluid within joint capsule 4 . for clarity in fig1 , blood sensor 46 is shown as a separate device extending into joint capsule 4 ; it will be apparent that blood sensor 46 could form part of scope 12 , instrument portal 18 or other apparatus in direct communication with the fluid - filled region 6 of joint capsule 4 . video blood sensor 30 receives video signals from the color video camera that forms part of scope 12 and analyses these video signals to determine the concentration of blood present in the fluid within the visual field of the scope . video blood sensor 30 produces a video blood concentration signal indicative of the amount of blood sensed within the visual field of the scope that is communicated to blood detection module 28 . video blood detector contains a computer processor with software algorithms that digitize and analyze in real time the video signals from the video camera of scope 12 . the video analysis algorithms identify red colored regions of the visual field . the probability that a region contains a concentration of blood is computed based on : the detected features present within the region , a comparison with surrounding regions ; and a comparison with regions in previous video frames . identified regions with a computed probability that exceed a predetermined minimum probability threshold are then quantified to determine the level of the video blood concentration signal communicated to blood detection module 28 . blood detection module 28 receives inputs from blood sensors 44 , 46 and video blood sensor 20 . blood detection module contains algorithms to prioritize , compare and assign weighting values to the blood concentration signals from the sensors and produces a detected blood concentration signal ; the level of this signal is indicative of the amount of blood present within joint capsule 4 . this detected blood concentration signal is communicated to hemostasis control module 26 and user interface and display 22 . although three different blood sensors are shown and described in the preferred embodiment it will be apparent that blood detection module 28 may be adapted to produce a detected blood concentration signal from a lesser or greater number of blood sensors and may be adapted to accept signals from blood sensors based on other measurement principles . the hemostasis control module 26 of internal tourniquet 2 receives the detected blood concentration signal from blood detection module 28 and receives hemostasis control parameters from user interface and display 22 . hemostasis control module 26 also receives the pressure and flow rate signals from flow and pressure control module 24 . hemostasis control module 26 produces the fluid pressure reference signal and the fluid flow rate reference signal which are communicated to flow and pressure control module 24 . as described above , the levels of these signals control the fluid pressure and the flow rate that fluid control module 24 will maintain in region 6 of joint capsule 4 . hemostasis control module 26 acts to maintain a bloodless surgical field by automatically adjusting the levels of the fluid pressure and fluid flow rate reference signals in response to changes in the level of the detected blood concentration signal . hemostasis control module 26 adjusts the level of the fluid pressure reference signal so that the pressure signal is maintained at a level between the minimum pressure limit and the maximum pressure limit . hemostasis control module 26 also adjusts the level of the fluid flow rate reference signal so that the flow rate signal is maintained at a level between the minimum flow rate limit and the maximum flow rate limit . the values of the minimum and maximum pressure and flow limits may be set individually by an operator of internal tourniquet 2 via user interface and display 22 or be set automatically to predetermined values by hemostasis control module 26 . if for any reason , hemostasis control module 26 and fluid and pressure control module 24 cannot maintain the pressure signal at a level that is within the pressure tolerance window formed by the minimum and maximum pressure limits an alarm signal is generated when the pressure signal is outside the tolerance window . for example if the minimum pressure limit is set at 10 mmhg and the maximum pressure limit is set at 50 mmhg , the alarm signal will be generated if the fluid pressure is less that 10 mmhg or greater than 50 mmhg . the alarm condition is indicated to the operator by user interface and display 22 . similarly , if the level of the flow rate signal cannot be maintained within the flow tolerance window formed by the minimum and maximum flow rate limits an alarm signal is also generated to alert the user that that internal tourniquet 2 cannot maintain the desired pressures or flows . examples of some conditions that may cause alarms are : the occlusion of outlet portal 38 or tubing 40 by surgical debris ; substantial fluid leaks from joint capsule 4 ; occlusion of tubing 16 or the fluid pathway within scope 12 , and failure of capsule pressure sensor 36 . hemostasis control module 26 has two operating modes : pressure - preferred mode and flow - preferred mode . the operating mode of hemostasis control module 26 may be set by the operator via user interface and display 22 or may be set automatically by hemostasis control module 26 in response to predetermined fluid pressure levels , fluid flow rates and region blood concentrations . when operating in pressure - preferred mode , hemostasis control module 26 maintains the fluid pressure reference signal at a constant level and responds to an increase in the amount of blood present within region 6 , as indicated by the level of the detected blood concentration signal , by proportionally increasing the level of the fluid flow rate reference signal . this causes an increase in fluid flow through joint capsule 4 which acts to clear blood from the capsule and restore a clear operating field . when the concentration of blood detected in the capsule decreases , the fluid flow rate reference signal is also decreased by hemostasis control module 26 until the level of the flow rate signal is near the minimum flow rate limit , this acts to conserve the fluid in fluid reservoir 32 . when adjusting the fluid flow rate reference signal , hemostasis control module 26 maintains the level of the flow rate signal within the minimum and maximum fluid flow rate limits . if , while adjusting the fluid flow rate reference signal to control bleeding within the region 6 , hemostasis control module 26 increases the fluid flow rate reference level to the maximum flow rate limit and the level of the detected blood concentration signal exceeds a predetermined minimum level , an alarm signal is generated to indicate to surgical staff that internal tourniquet 2 cannot adequately control the bleeding within the region 6 . when operating in flow - preferred mode , hemostasis control module 26 maintains the fluid flow rate reference signal at a constant level and responds to an increase in the amount of blood present within region 6 , as indicated by the level of the detected blood concentration signal , by increasing the level of the fluid pressure reference signal . this causes an increase in fluid pressure within joint capsule 4 which acts to prevent blood from entering the capsule and obscuring the operating field . when adjusting the fluid pressure reference signal hemostasis control module 26 maintains the level of the fluid pressure signal within the minimum and maximum fluid pressure limits . if while adjusting the fluid pressure reference signal to control bleeding within the region 6 , hemostasis control module 26 increases the fluid pressure reference level to the maximum pressure limit and the level of the detected blood concentration signal exceeds a predetermined minimum level an alarm signal is generated to indicate to a user that internal tourniquet 2 cannot control the bleeding within the region 6 . to continuously maintain a bloodless surgical field for the duration of a surgical procedure , hemostasis control module 26 may be adapted to automatically change operating modes and vary the minimum pressure and flow limits , in response to changes in the level of the detected blood concentration signal and pressure and flow rate signals . in fig1 an external non - invasive blood pressure ( nibp ) monitor 48 is shown in communication with hemostasis control module 26 . nibp monitor 48 is an external device that non - invasively measures the blood pressure ( bp ) of the surgical patient . for example , the nibp monitor may measure bp intermittently using an oscillometric technique , or may measure bp continuously using pulse wave transit time . nibp monitor 48 produces a bp signal indicative of the value of the patient &# 39 ; s systolic blood pressure which is communicated to hemostasis control module 26 . in response to hemostasis control parameters set by an operator via user interface and display 22 , hemostasis control module 26 may operate to make adjustments in the level of the fluid pressure reference signal in response to changes in the patient &# 39 ; s blood pressure . for example , if the patient &# 39 ; s blood pressure rises hemostasis control module 26 can increase the fluid pressure within the window formed by the minimum and maximum fluid pressure limits . similarly , if the patient &# 39 ; s blood pressure decreases hemostasis control module 26 can decrease the fluid pressure . by acting in response to changes in the bp signal to adjust the fluid pressure within region 6 , hemostasis control module 26 can better maintain a bloodless surgical field . it will be apparent that other devices and methods could be used to determine the systolic blood pressure and that hemostasis control module 26 could similarly respond to systolic blood pressure signals produced by other external devices . it will also be apparent that an nibp monitor could be incorporated within internal tourniquet 2 to eliminate the need for a separate device . for clarity the preferred embodiment described above has been shown controlling hemostasis within the region enclosed by the substantially fluid - tight capsule of an articulating joint . the embodiment described may be adapted to help control hemostasis during other minimally invasive surgical procedures within a partially open or open region near a joint or bone where a bloodless surgical field must be maintained . the embodiment illustrated is not intended to be exhaustive or limit the invention to the precise form disclosed . it is chosen and described in order to explain the principles of the invention and its application and practical use , and thereby enable others skilled in the art to utilize the invention .

an internal tourniquet for establishing hemostasis within a portion of a limb to facilitate surgery controls flow of a fluid into a capsule surrounding substantially all of a human joint . blood concentration in the capsule is sensed ; and pressure in the capsule is controlled to maintain a fluid pressure in the capsule within a predetermined pressure tolerance window . the concentration of blood in the capsule is maintained below a predetermined maximum concentration while the fluid pressure is within the pressure tolerance window .

with the foregoing and other objects in view , while taking the aforementioned boundary conditions into consideration , there is provided , in accordance with the invention , a device for treating an acute urinary outflow system obstruction comprising a catheter having a flexible tubular body including a plurality of openings for connection to the tissues , preferably placed at its median and distal portion , at least an elastic sealing device , and an internal ridge , said catheter being internally provided with an electrode having a proximal insulated portion and a distal uninsulated portion . said catheter has a distal portion proximate to its tip , which in use protrudes within the bladder wall , a median portion which in use is located along the urethra and a proximal portion proximate to its inlet and which in use is placed outside the body cavity . according to an embodiment of the present invention said elastic sealing device is arranged circumferentially around the catheter tubular body and preferably comprises a first retaining balloon , more preferably of 3 - 10 ml , placed between the median and distal portions of the catheter . according to another embodiment of the invention a second retaining balloon is provided , being preferably of 2 - 4 ml and circumferentially mounted between the proximal and median portions of the catheter . in accordance with a further feature of the invention said internal ridge is placed between the median and distal portions of the catheter , preferably in juxtaposition of the first retaining balloon , in order to be positioned during use at the bladder neck . according to another aspect of the present invention , the electrode is provided at its uninsulated tip with a non - conductive disc , preferably of diameter approximating the internal diameter of the catheter , in order to abut against the catheter ridge to form a loose seal . in accordance with a further embodiment of the invention , the electrode within the tubular body ( i . e . the hollow part ) of the catheter is bifurcated in a tubular core portion and in an uninsulated spiral arm . the tubular core portion has a proximal insulated portion and a distal uninsulated portion . the first portion extends insulated up to the level of said internal ridge , and thereafter continues in the uninsulated portion along the catheter distal portion . the uninsulated spiral arm is placed within the median portion of the catheter , ends at level of the catheter internal ridge and preferably has a diameter which is approximately equal to the internal diameter of the catheter . preferably , said distal uninsulated portion of the tubular electrode , with particular reference to the bifurcated type , is made of shaped metal alloys ( sma ) and more preferably consists in an copper - zinc - aluminum - nickel ( czan ) alloy . the shaped metal alloys are alloys that can be so fabricated that they are very malleable and flexible prior to reaching a specified temperature , but once this temperature is attained they will assume specified shapes , or angles in the case of tubular structures . these alloys are malleable prior to reaching body temperature and once inserted into the body cavity they assume specified ( predetermined ) angles . in particular , in order to treat an enlarged median lobe the uninsulated tubular portion of the electrode is made of a sma ( for example a nickel - titanium alloy ) which is able to resume preferably an angle of 45 ° to its axis within the bladder cavity ( 37 . 5 ° c . ), whereas in order to treat areas associated with the bladder neck and a protruding transitional zone adenoma , a catheter is used which is able to resume within bladder cavity an angle preferably of 135 - 145 ° to its axis . according to another aspect , the device of the present invention provides a method of treating acute urinary outflow obstruction , due to pathology of the prostate gland , by localised electromotive drug administration comprising : inserting a catheter portion respectively along an urethra and inside a bladder cavity , said catheter portion comprising a plurality of openings , at least an elastic sealing device and an internal ridge ; inserting an electrode connected to an external electrical power source inside said catheter , said electrode comprising a proximal insulated portion extending from said external power source to a point located within said catheter and a distal uninsulated portion extending within the catheter ; infusing via said catheter an electrically - conductive drug solution for treating prostate diseases ; placing in contact with a suitable skin location a secondary electrode also connected to said external power source ; infusion of a drug ( s ) solution into the catheter of the invention results in this solution passing through the catheter holes into the prostatic urethra . application of electric current of appropriate polarity accentuates administration of the drug ( s ) through the urothelium and the prostatic capsule , at level of the obstruction of the urinary system . accordingly , a high drug concentration to the targeted tissues is achieved , avoiding general side - effects due to the systemic administration . while performing the therapeutic method of the invention , drug ( s ) are administered for treating prostate diseases selected from the group comprising analgesic , anti - inflammatory , antibiotics , α adrenergic blocking , antiandrogen , anticancer , hemostatic , detrusor muscle stimulating drugs and mixtures thereof . according to one aspect of the invention , the intensity of the electric current supplied from the power source to the electrodes is preferably of 10 to 40 ma , preferably supplied for time periods ranging from 5 to 60 minutes . the method of treatment and the device for performing it , according to the present invention , together with additional objects and advantages thereof , will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings , wherein : fig1 is a cross - sectional view of the catheter for performing the method of the invention , containing a prostatic urethral electrode and having elastic sealing means . fig2 is a cross - sectional view of a further embodiment of the catheter of the invention containing a bifurcated electrode and having elastic sealing means . fig3 is a schematic side view of a prostate gland and bladder , showing a catheter inserted along the prostatic urethra and bladder to perform the method of the present invention . fig4 is a schematic cross - sectional view of another embodiment of the catheter of the invention , positioned within the bladder . fig1 illustrates an embodiment for application of the method of the present invention to patients whose acute urinary obstruction is due to prostatic obstruction . catheter 1 has a tubular shape with a flexible structure , and a blunt soft tip 5 , which in use protrudes inside the bladder cavity of the patient to be treated . said catheter is made of a soft , flexible , non - irritant , non - conductive material , preferably consisting of silicon , and has an external diameter of 5 mm and an internal diameter of 3 mm . at its proximal end 6 the catheter 1 has a connector with a plurality of inlets of a known type and thus not shown . along the wall 4 of the catheter 1 there is a plurality of openings 7 placed at its middle portion 2 and proximate to its distal portion 3 . circumferentially mounted retaining balloons 8 and 9 are applied in a traverse section of the tubular body of the electrode 1 both at the beginning of its middle portion 2 and at the beginning of its distal portion 3 . balloons 8 and 9 illustrated in their inflated state , are positioned in the present method , respectively at the level of the distal end of the prostatic urethra and at the level of the bladder neck ( as shown in fig3 ) of the patient to be treated , in order to seal the portion of the urinary outflow system which is obstructed . an internal ridge 11 extends around the full circumference of the internal wall 4 of the catheter 1 , said ridge 11 functioning both as a guard and a seal for the electrode 7 . a stem - like electrode 10 passes inside the catheter . said electrode 10 has an insulated portion 10a extending from the power source ( not shown ) to the middle portion 2 of the catheter 1 and an uninsulated ( core ) portion 10b which continues from the insulated portion 10a to the internal ridge 11 . the uninsulated portion 10b is provided , at its distal end , with a thin , slightly flexible , non - conductive plastic disc 13 having a diameter approximating the internal diameter of the catheter and which abuts against the catheter ridge 11 to form a loose seal . referring to fig2 an alternative embodiment is illustrated for application of the method of the present invention to treat prostatic intrusions into the bladder cavity which obstruct urine outflow . catheter 1 is similar to the type referred to in fig1 has a tubular form , is made of a soft , flexible , non - conductive material , such as silicon , and has a balloon control channel of a known type and thus not shown . this channel is separated from the main hollow part of the tubular catheter 1 and is used to control both the balloon 8 , depicted in its inflated state , and the balloon 9 , depicted in its deflated state . a plurality of openings is located only at the level of the distal portion of the catheter 1 , in order to perform the electromotive administration of drug solution to the target tissue . the tip 5 of the catheter 1 is rounded in order to pass easily through the bladder neck without causing damage to the urethral tissues . a specific bifurcated urethral - bladder electrode 12 is inserted into the hollow part of the catheter 1 . said electrode has a tubular core portion 12a extending from the external power source to the tip 5 of the catheter . the length of said tubular core portion extending from the power source to the level of the ridge 9 is sheathed in an insulating plastic material ; the length 12b of the electrode portion extending from the catheter ridge to the tip of the catheter 9 is uninsulated and is made of an sma composed of copper , zinc , nickel , coated with a thin layer , preferably of 3 microns , consisting of silver or gold . the memory metal section of the uninsulated portion 12b is made to resume specific angles of either 45 ° or 135 ° to the axis of the electrode at temperatures of ≧ 35 °. this result can be achieved by inserting a catheter containing a cool malleable electrode followed by infusion of warm fluid ≧ 36 ° c . or more simply by drainage of urine at body temperature ( i . e . 37 ° c .). an uninsulated spiral component 12c , the diameter whereof approximates the internal diameter of the catheter , branches from the sheathed core section of the elctrode 12 and travels the full length of the middle portion 2 of the catheter , terminating at the catheter ridge 11 . the material of this uninsulated spiral section consists of copper . fig3 illustrates the embodiment of fig1 as it may be used in the practical execution of the method of the present invention . the depicted prostate gland 14 has an enlarged transitional zone 15 , a normal central zone 16 and an enlarged median lobe 17 . in the enlarged transitional zone 15 , an adenoma ( not shown ) compresses and obstructs the urinary outflow system , with particular reference to the prostatic urethra . the present figure furthermore shows the rectal wall 26 and a seminal vesicle 18 located above the rectal wall , with its ejaculatory duct 19 leading to the level of the verumontanum region 20 . the use of the present embodiment of the invention provides for the insertion of the catheter 1 in the urinary outflow system of a patient in need of the treatment , in a conventional manner until its distal portion 2 reaches the inside of the bladder 22 . conventionally , the direction towards and within the bladder is termed &# 34 ; proximal &# 34 ;, whereas the one along the urethra towards the tip of the penis is termed &# 34 ; distal &# 34 ;. during the use of the device according to the invention , the catheter 1 has its middle portion 2 placed along the prostatic urethra 21 and its distal portion 3 within the bladder cavity 22 . a balloon 9 fixed proximate to the bladder neck 23 is inflated to delimit and isolate the bladder cavity 22 . a plurality of openings 7 is located both in the distal portion 3 and in the middle portion 2 of the catheter 1 . the plurality of openings 7 of the middle portion 2 of the catheter 1 is placed at the enlarged transitional zone 15 of the prostate gland 1 , wherein there is an adenoma which represents the target tissue in need of the therapeutic treatment . a retaining inflated balloon 8 is placed at the distal end of the prostatic urethra , in order to close the distal passage section of the urethra during the performance of the method of the present invention . a stem - like electrode 10 passes inside the hollow tubular body of the catheter 1 and is divided into an uninsulated distal portion having at its end a non - conductive disc 13 , and into a proximal insulated portion 10a connected to the external power source 24 . the uninsulated portion 10b of the electrode extends along the catheter middle portion 2 wherein openings are provided , in order to realize an appropriate current flow at the transitional zone 15 of the prostate gland 14 which needs to be treated . the external power source 24 is also connected to a secondary dispersive electrode 25 placed on some convenient area of the skin of the patient ( for example upon the abdominal wall 26 ) to be treated with the method of the invention . the treatment method of the invention provides for drainage of the bladder urinary contents , by means of the openings 7 placed in the distal portion 3 of the catheter 1 , and for insertion along the hollow cavity of the catheter 1 of the above mentioned electrode to the level of the bladder neck where said electrode terminates in a disc of electrically non - conductive material which abuts against the catheter ridge . an electrically - conductive drug solution is then instilled into the prostatic section of the urethra via said catheter 1 , the electric power source 24 is switched on , activating the ions contained in the drug solution , thereby producing the therapeutic effect in the target tract of the urinary outflow system wherein the obstruction is localised . the depicted power source 24 is of the current - controlled type , preferably a battery - powered source . the current waveform incorporates constant dc , pulsed dc and preferably a timing device ( not shown ) to allow reversal of polarity with a frequency of 5 - 20 minutes . the envisaged electric currents have an intensity of 5 - 10 ma . fig4 refers to a further embodiment of the method of the present invention . catheter 1 of the device of the invention is depicted both placed in a correct position 27 , in juxtaposition to a pathological middle lobe 28 of a prostate gland , as compared to a normal bladder wall , and in an incorrect position 28 ( broken lines ). catheter 1 is depicted with four openings placed at the level of its distal portion 3 and a plurality of openings in the middle section to permit both the drainage of the urinary content and the electromotive administration of drug ( s ). a retaining balloon 9 in its deflated state is fixed on the external wall 4 of the catheter 1 , at level of the bladder neck 23 . catheter 1 is provided with a ridge 11 of height 0 . 5 mm and width 0 . 5 mm extending around the full circumference of the internal wall 4 and located at the level of the proximal end 29 of the prostatic urethra just distal to the retaining balloon 9 . said ( bifurcated ) electrode 12 extending from the external power source ( not shown ) to the tip 5 of the catheter 1 , positioned inside the bladder cavity 22 , is inserted within the tubular body of the catheter 1 . the core length 12a of the electrode extending from the power source to the level of the catheter ridge 11 is sheathed in an insulating plastic material , whereas the spiral arm 12c is uninsulated . the conductive material of the tubular core section of the insulated portion 12b of the electrode and of the spiral arm 12c consists of copper . the spiral arm 12c of the electrode ( 12 ) is properly positioned so as to treat a pathological transitional zone ( not shown ). the distal portion 3 of the catheter 1 is placed within the bladder cavity 22 in a specific position in order to treat the enlarged median lobe 28 which can obstruct the urinary outflow system , otherwise the great proportion of electric current may be misdirected therapeutically . the catheter - electrode is illustrated angled at 45 ° to its axis which offers the best chance of success for treating by emda an enlarged median lobe of the prostate . the material of which the uninsulated electrode extending from the catheter ridge 11 to the tip of the catheter is made is an sma composed of copper , zinc , aluminium , nickel and advantageously it is also coated with a thin layer ( 3 microns ) of silver or gold . this material is fabricated in order to resume a specific angle of either 45 ° or 135 ° to the axis of the electrode at temperatures ≧ 35 °. in the present embodiment , this objective is achieved during the initial phase of the method consisting in the drainage of urine at body temperature ( 37 ° c .) by means of the openings 7 placed along the distal portion of the catheter . during this initial phase , electrode 12b resumes a specific angle of approx . 45 ° to the axis of the insulated portion 12a and is then positioned within the bladder cavity under ultrasound control in the correct position as illustrated , in order to permit the performing of the electromotive drug administration to both the transitional zone and the enlarged median lobe 28 of the prostate gland , which causes the obstruction 30 of the urinary system , at the level of the bladder neck 23 . the current flow applied to the bifurcated electrode 12 is preferably of 20 - 30 ma . by the electromotive drug administration of the present invention , a specific ion flow is directed to the target sites , providing for a high drug concentration only in proximity of the pathological tissues . the method and device of the present invention provide numerous advantages . by utilizing the urethral catheter of the invention , specific internal locations of a patient may be targeted for treatment with a particular medication . furthermore , the permeation of the medication into the body pathological tissue avoids an excessive concentration of medication to the patient . the analgesic drugs useful in the present method are preferably local anaesthetic agents , more preferably selected from the group comprising lidocaine , mepivacaine , bupivacine , ropivacaine and mixtures thereof , preferably administered in concentrations ranging 0 . 3 - 1 % by weight . these agents can be administered in mixture with epinephrine , to a concentration ranging 1 / 200 , 000 - 1 / 50 , 000 , in order to achieve a prolonged effect . the anti - inflammatory drugs ( both steroidal and non - steroidal drugs ) useful in the present method are preferably selected from the group comprising dexamethasone , betamethasone , ketorolac , diclofenac and mixtures thereof . in order to achieve an high anti - inflammatory effect , the steroidal drugs are administered in concentrations preferably ranging 0 . 08 %- 0 . 3 % by weight , whereas the non - steroidal drugs are administered in concentrations preferably ranging 0 . 15 %- 1 . 0 % by weight . the α adrenergic blocking agents , useful in the practice of the invention , are preferably selected from the group comprising phenoxybenzamine , phentolamine , prazosin , terazosin , doxazosin , trimazosin , alfuzosin and mixtures thereof . these agents are of particular value in causing profound relaxation of the internal sphincter and related muscular tissue , in particular when administered at a concentration of 0 . 025 %- 0 . 1 % by weight , preferably in a physiological electrolyte solution of osmolarity of 150 - 310 mosm . said α blocking agents can also be infused as citrate salt solution , preferably having a concentration ranging from 1 to 3 % by weight . the performing of the method of the invention allows the local administration of a readily available amount of antibacterial agents preferably selected from the group comprising ampicillin , cephalothin , cephapyrin , cephazolin , cephalexin , gentamycin , netilmicin , norfloxacin , ciprofloxacin , trimethoprim - sulfamethoxazole , ciclopirox and mixtures thereof . the local administration by emda of antimicrobial agents is very useful in destroying micro - organisms sheltered in privileged sites . this effect is particularly benefical in case of infective prostatitis where systemic antimicrobial therapy is not satisfactory . in particular , the method of the invention is performed by infusing a solution containing at least one among ampicillin , cephalothin , cephapyrin , cephazolin , cephalexin and ciclopirox , at concentrations preferably of 0 . 1 - 3 % by weight , using an electrode of negative polarity . according to another embodiment , at least one drug selected among gentamycin , tobramycin , netilmycin , norfloxacin , ciprofloxacin and trimethoprim / sulphamethoxazole is administered . said drugs are administered preferably at concentrations ranging 1 - 3 % by weight and using an electrode of positive polarity . according to a further embodiment , specific antimicrobial combinations consisting of a mixture of either ampicillin , cephalothin , cephalexin , cephapyrin , cephazolin and either gentamycin , tobramycin , netilmycin , are administered by supplying an alternating current of frequency of preferably 1 / 5 - 20 min . according to yet another aspect , the method of the present invention allows the local administration of antiandrogen agents , advantageously selected from the group comprising cyproterone acetate , flutamide , finazteride and mixtures thereof . said antiandrogen agents are administered by using an electrode of positive polarity , preferably solubilised to a 0 . 5 - 2 % solution in ethanol , said ethanol solution of drug being admixed in an aqueous electrolyte solution , preferably in a 1 / 10 ratio . said electrolyte solution preferably consists of a physiological electrolyte solution of osmolarity 150 - 310 mosm , or of a citrate salt solution of concentration of 1 to 3 % by weight . the method of the present invention furthermore allows the treatment of cancerous forms located at the prostate gland , which can obstruct the urinary outflow system . in fact , since the urothelium tolerates emda of anticancer drugs , high localised levels are achievable without systemic side - effects . preferably said anticancer drugs are selected from the group comprising doxorubicin , epirubicin , mitoxantrone , bleomycin , mitomycin c and mixtures thereof , advantageously administered at a concentration of 0 . 01 - 0 . 1 % by weight , in a physiological electrolyte solution or a citrate salt solution , using an electrode of positive polarity . according to a further aspect , the present invention provides the local administration of hemostatic agents in order to treat hemorrhages which can occur from a long standing distended bladder wall . preferred hemostatic agents are desmopressin , phytadione , conjugated estrogen , aminocaproic acid , aprotinin and thrombin . these agents are preferably administered in concentrations ranging from 1 mcg / ml - 1 g / 100 ml , except aprotinin and thrombin which are preferably administered in concentrations ranging from 10 iu / 100 ml - 10 , 000 iu / 100 ml . according to another aspect , the present method provides the administration of cholinergic agents , preferably selected from the group comprising methacoline , carbachol , bethanecol and mixture thereof . said drugs are very useful in assisting an attenuated bladder containing a volume of drug solution to contract . if the first catheter balloon is deflated , the contracting bladder will force the drug solution contained in its cavity into the prostatic urethra and emda of the drugs into the prostatic urethra is achieved with the bladder acting as a drug reservoir . to maintain these desirably high tissue levels over therapeutic periods of time there are several options , which depend upon the individual patient &# 39 ; s general response to a particular drug and the pharmacokinetics of the drug ( s ) used : repeated emda therapies alone which is the only possible option with local anaesthetic drugs , with anticancer drugs and the only desirable option with hemostatic and anti - inflammatory drugs ; repeated emda therapies , each lasting 20 - 60 minutes , combined with low dose systemic therapies which is a logical choice for many antibiotics and α adrenergic blocking agents ; repeated emda therapies with moderate dosage systemic therapy , which is the best option for anti - androgen drugs . finally it must be noted that the quantity of drug recommended for each emda treatment never exceeds the total daily dose of that drug were it to be administered systemically . the reason is that , although enma per se results in far less than these quantities being administered into tissues ( faraday &# 39 ; s law ), untoward events are always possible : rupture of the bladder or a major vein can result in absorption of most of the infused fluids and drugs contained therein . thus , although electromotively disadvantageous with the low concentration of some drugs , this rule is a good safety precaution for patients . all salts of local anaesthetic drugs ( e . g . lidocaine hydrochloride ) and epinephrine are positively charged and the concentrations used are sufficient to allow efficient conduction of at least a 30 ma electric current . salts of corticosteroids and nsaid &# 39 ; s ( non - steroidal anti inflammatory drug ) are negatively charged but , as shown by petelenz et al ., it is possible to administer these agents electromotively in combination with local anaesthetic drugs against their coulombic gradients . the α adrenergic blocking agents are available as positively charged salts , but the low concentrations required for safety reasons make it desirable to infuse these drugs in either a physiological electrolyte solution or a citrate salt ( sodium or potassium citrate ) solution . the aforementioned anticancer agents are available as positively charged salts and are administered electromotively using an electrode of positive polarity . among the antimicrobial agents selected , the β lactam antibiotics and ciclopirox are negatively charged . the aminoglycosides and quinolones are positively charged . with the exception of ciclopirox , all can be infused in sufficiently high concentrations to conduct 30 ma current efficiently , and ciclopirox itself will always be infused in conjunction with a β lactam antibiotic . the antiandrogen drugs pose a problem in that their solubility in water is very low . they are , however , readily soluble in ethanol and , so solubilised , they can be infused in an electrolyte or citrate salt solution and then administered by electrophoresis . the hemostatic drugs selected display a very wide range in their molecular size and so the concentrations infused , preferably ranging from 10 to 10000 iu , are listed as both in m / v and international units / volume ( iu / v ). the following example is only illustrative of the present invention . several modifications and alternatives may be devised by those skilled in the art without departing from the spirit and the scope of the present invention . seven male patients age 61 - 77 years afflicted with multiple tumors of the bladder and a modest degree of prostatic obstruction were treated with emda of the local anaesthetic drug , lidocaine , and the vasoconstrictor , epinephrine . a specially fabricated catheter with perforations extending from the intravesical tip approximately to the distal end of the prostatic urethra and a 3 ml bladder neck balloon , according to the invention , was selected . there was inserted into the catheter an electrode of an insulated tubular configuration extending from the external power source and then terminating in 8 cm of uninsulated spiral which is the approximate distance from the centre of the bladder ( where the catheter tip is sited ) to the distal end of the prostatic urethra . the catheter was inserted , balloon inflated , the bladder was drained and 150 ml of lidocaine 2 % with 1 / 100 , 000 epinephrine was infused intravesically through the catheter . electric current of 15 - 20 ma intensity was applied through the catheter - electrode . after 11 minutes the catheter balloon was deflated , bladder contents drained out the catheter at 3 - 4 ml / min and current was maintained at 15 - 20 ma for a further 4 minutes . after 15 minutes of treatment the current ceased , the bladder was drained and the whole process was repeated . by performing the above treatment method two objectives have been achieved : to render the bladder wall analgesic and to render the prostatic urethra and surrounding structures ( prostatic capsule and gland ) analgesic . all patients easily tolerated transurethral resection ( tur ) of a plurality of bladder tumors with diathermy and cautery , a procedure normally performed under general or regional anaesthesia , and a bladder neck incision ( bni ). a bni , as the name implies , is a surgical incision about 1 - 2 cm deep through the bladder neck and running the length of the prostatic urethra . it is a rapid , minimally invasive technique for relief of minor obstruction at the bladder neck when spasm of smooth muscle plays an important role . three important objectives were achieved : analgesia of the required regions ; an anti - inflammatory effect ( epinephrine ) as noted by the pallor visualised though the endoscopes and on the video screen ; the bladder acting as a reservoir and supplying drug solution to the prostatic urethra when the catheter balloon was deflated . nevertheless , the clinical situations were over - simplified in that the prostate glands were only modestly enlarged and there was no acute obstruction associated with edema , inflammation , infection or cancer .

a method of treating acute urinary outflow system obstruction caused by disease of the prostate gland by localised electromotive drug administration . the treatment comprises insertion within the prostatic urethra and within the bladder cavity of a urethral catheter which incorporates a specific electrode and is adapted to perform the electromotive administration of a drug or drug mixture into diseased prostatic tissues thereby resolving the pathologies without resorting to surgery .

the invention provides an isotonic drink which is especially formulated for children . the drink has a taste and image which encourages children to drink but which provides the electrolytes and carbohydrates necessary to keep children hydrated . the drink is based upon water ; electrolytes ; and a carbohydrate source which includes fruit juice . a calcium source and vitamin c are also included . the carbohydrate source may be any suitable carbohydrate source ; particularly a combination of fruit juice and other saccharides . the fruit juice is preferably in the form of a concentrate and may be of any flavor . for example , the fruit juice may be apple juice concentrate , orange juice concentrate , pear juice concentrate , cranberry juice concentrate and the like . the other saccharides may be any saccharides suitable for inclusion in drinks . suitable examples include sucrose , glucose , fructose , high fructose corn syrup , and maltodextrin . the fruit juice is preferably present in an amount that it provides at least about 7 % by weight of the drink ; more preferably about 8 % to about 12 % by weight . for example , the fruit juice may provide about 10 % by weight of the drink . the total carbohydrate content of the drink , including that provided by the fruit juice , is preferably less than about 8 % by weight . at carbohydrate concentrations more than about 8 % by weight , fluid absorption becomes reduced . preferably , the drink contains about 5 % to about 7 . 5 % by weight of carbohydrate . if the carbohydrate source does not provide sufficient sweetness , artificial sweeteners such as saccharin , cyclamates and aspartame may be added in an amount sufficient to provide a sweet flavor . the drink contains the electrolytes sodium and potassium . the sodium and potassium may be provided by suitable sodium and potassium salts such as sodium chloride , sodium citrate , and potassium citrate . the drink preferably contains about 60 mg / l to about 250 mg / l of sodium ; more preferably about 80 mg / l to about 125 mg / l . for example , the drink may contain about 105 mg / l of sodium . the drink preferably contains about 60 mg / l to about 150 mg / l of potassium ; more preferably about 190 mg / l to about 230 mg / l . for example , the drink may contain about 210 mg / l of potassium . the drink contains a source of dietary calcium . the calcium source may be any suitable food - grade calcium salt of organic and inorganic compounds . the calcium source should be capable of being solubilized such that a clear solution at a ph of about 4 . 5 and below may be obtained . calcium sources which adversely affect flavor , calcium absorption or biological functions are to be avoided . suitable inorganic calcium sources include the oxide , hydroxide , carbonate , and orthophosphate ( s ) ( mono -, di - and tricalcium phosphate ). suitable organic calcium sources include calcium lactate , calcium gluconate , calcium citrate , calcium acetate , calcium ascorbate , calcium tartarate , calcium malate and the like . calcium lactate is preferred . the calcium source is preferably present in an amount such that at least about 20 % of the recommended daily value for calcium is provided per liter ; more preferably about 30 % to about 60 % of the recommended daily value for calcium . for example , the drink may contain about 40 % of the recommended daily value for calcium per liter . the drink also contains vitamin c . preferably sufficient vitamin c is provided such that the drink contains at least 300 % of the recommended daily value for vitamin c per liter ; more preferably about 350 % to about 500 % of the recommended daily value for vitamin c per liter . the drink preferably contains an acid to provide a ph in the range of about 3 to about 4 . 5 . any food grade acid may be utilized to adjust the ph of the drink . for example , citric acid , phosphoric acid , fumaric acid , adipic and malic acid may be used without developing off taste . hydrochloric acid is less preferred as the chlorine ion can be nutritionally disadvantageous . preferably , the acid used for acidification is citric acid . the ph is more preferably in the range of about 3 . 5 to about 4 . 2 ; for example about 3 . 7 to about 3 . 9 . the drink has an osmolality of about 300 mosm / kg to about 380 mosm / kg ; more preferably about 340 mosm / kg to about 370 mosm / kg . for example , the drink may have an osmolality of about 360 mosm / kg . osmolalities in this range are better suited to the needs of children . the drink may also include other ingredients normally found in soft drinks such as clouding agents , natural or artificial coloring , preservatives and the like . however , preservatives are not necessary and in fact may be undesirable . the provision of the clear drink allows for the controlled clouding and coloring of the drink . can be added as desired . the drinks may also include other vitamins and minerals as desired . the drink may be manufactured by mixing the calcium source with any other dry ingredients to form a dry mix . water and the fruit juice may then be added to the dry mix and the ingredients dispersed . after dispersion , the ph is adjusted as desired with acids . any additional ingredients may then be added as desired . the volume is adjusted to the appropriate level and the drink bottled and pasteurized according to good manufacturing techniques . the drink is preferably bottled in pet containers under hot filling conditions . a drink is prepared from water , high fructose corn syrup , sucrose , apple juice concentrate , maltodextrin , calcium lactate , citric acid , vitamin c , potassium citrate , sodium chloride , flavors and colors . the drink has the following properties : solids content 8 . 1 % by weight carbohydrate content 7 . 4 % by weight calcium content / liter 42 % of rda vitamin c content / liter 420 % of rda ph 3 . 7 to 3 . 9 osmolality 359 mosm / kg the drink has a pleasant , sweet , citrus - like taste and is readily consumed by young children .

an isotonic drink that is especially designed for children between the ages of 6 and 12 years . the drink contains water , carbohydrates including fruit juice , a calcium source and vitamin c . the drink has an osmolality of about 300 to about 380 mosm / kg and a ph of between about 3 and about 4 . 5 . the drink improves hydration compliance when consumed by children .

a first embodiment assembly according to the present invention is described with respect to fig1 - 4 . an implant assembly ( 10 ) according to the present invention comprises an upper part ( 12 ), a lower part ( 14 ), and a center core ( 16 ). the upper part ( 12 ) comprises a vertical section front face ( 18 ), a vertical section rear face ( 20 ), a horizontal section top face ( 22 ), and a horizontal section bottom face ( 24 ). the lower part ( 14 ) comprises a vertical section front face ( 26 ), a vertical section rear face ( 28 ), a horizontal section top face ( 30 ), and a horizontal section bottom face ( 32 ). each of the vertical sections of the upper part ( 12 ) and the lower part ( 14 ) comprise at least one fastener hole ( 34 , 36 ). each hole ( 34 , 36 ) is adapted to receive a fastener ( 38 , 40 ) such as a bone screw . the horizontal top face ( 22 ) of the upper part ( 12 ) and the horizontal bottom face ( 32 ) of the lower part ( 14 ) are each preferably convex in shape to match the anatomical shape of the end faces of adjacent vertebrae ( 42 , 44 ) for optimal load distribution . one or more teeth ( 46 , 48 ) or similar protrusions are provided to enhance grip of to bite into the end faces of the vertebrae . the opposite sides of the horizontal sections , namely the horizontal bottom face ( 24 ) of the upper part ( 12 ) and the horizontal top face ( 30 ) of the lower part ( 14 ), face each other and are generally concave shaped to privotally engage a center core ( 16 ) that is convex on upper and lower surfaces and , as such , may be generally spherically shaped . depending on the specific dimensions of the concave and convex portions , as well as on any raised circumferential rims ( not shown ) that may be provided on the faces ( 24 , 30 ) or a flange ( not shown ) that may be provided on the center core ( 16 ), pivotal movement may be controlled to a certain degree . similarly , predetermined sliding movement of the center core ( 16 ) relative to the upper and lower parts ( 12 , 14 ) may be introduced if desired by adjusting such dimensions and flange or rim features . the bone screws ( 38 , 40 ) or fasteners may be of a known type having heads that are sized to adequately hold the parts ( 12 , 14 ) to adjacent vertebrae but that allow predetermined sliding movement within the holes ( 34 , 36 ) and / or that allow relative pivoting within the holes ( 34 , 36 ). these features allow predetermined movement or dynamization of an assembled vertebral section using the present invention system . as shown in the preferred embodiment , the holes ( 34 , 36 ) are oversized relative to the screw shafts to allow sliding and pivoting , and the screws ( 38 , 40 ) have semi - spherical heads . by selecting hole size and / or head shape , one or both of sliding and pivoting movement can be controlled or eliminated if desired . as shown in fig4 , more than two adjacent vertebrae ( 42 , 44 , 50 ) may receive adjacent assemblies ( 52 , 54 ) according to the present invention . this in because the offset allows a single vertebra to receive two assembly parts , thereby enabling the present invention assemblies to bridge adjacent vertebral spaces separated by only one vertebra . this is attributable to the offset or asymmetrical characteristic of positioning a vertical portion ( 56 ) offset from a vertical centerline of the assembly to have its vertical portion ( 56 ) be nested relative to the recessed portion ( 58 ). this is a significant advantage over known designs which do not leave adequate space to attach adjacent assemblies to a sequence of adjacent vertebrae . such known designs cannot be installed to bridge successive vertebral spaces separated only one vertebra . implant assemblies according to the present invention are installed using procedural steps and techniques that are similar to current procedures and techniques used in implanting known cervical plates . thus , an advantage of the present invention is that spine surgeons are already familiar with and skilled in the procedures and techniques needed to install the present invention system . the center core ( 16 ) can be made available in a variety of sizes and geometries that can be used with one or a few standard size upper and lower parts ( 12 , 14 ) thereby enabling the present invention to be presented as a modular system and minimizing inventory requirements . this provides advantages of versatility and cost efficiency not attained by known devices . a second embodiment of the present invention assembly ( 100 ) is shown in fig5 having an upper part ( 102 ) and a lower part ( 104 ) in which respective fastener holes ( 106 , 108 ) are elongated . such elongation of the holes ( 106 , 108 ) may b e used for relieving stress by allowing relative movement of the upper or lower part ( 102 , 104 ) with respect to a fastener ( not shown ) which attaches the assembly ( 100 ) to bone structures . the elongated holes ( 106 , 108 ) may also provide versatility in positioning with respect to limited fastener positions during installation . it is understood that such elongated or slotted holes ( 106 , 108 ) may be provided on one or on both parts ( 104 , 106 ) in any of the preferred embodiments described herein . another embodiment of the invention , shown in fig6 , is directed to an assembly ( 200 ) having an upper part ( 202 ) and a lower part ( 204 ). the upper part ( 202 ) is generally similar to the upper part ( 12 ) in the first preferred embodiment . the lower part ( 204 ) is comprised of a vertical front face ( 206 ), a vertical rear face ( 208 ), a horizontal lower face ( 210 ), and a horizontal upper face ( 212 ). the horizontal upper face ( 212 ) has a convex or dome portion ( 214 ) which , effectively , combines the lower part ( 14 ) and center core ( 16 ) of the first embodiment . the upper part ( 202 ), the lower part ( 204 ), or both , may be of various sizes , preferably interchangeable for compatibility with a variety of other parts , to allow versatility in mating parts . another embodiment of the present invention , shown in fig7 , is directed to an assembly ( 300 ) having upper and lower parts ( 302 , 304 ) generally similar to the upper and lower parts described in the earlier embodiments , but with flat , horizontal , opposing surfaces ( 306 , 308 ). the flat surfaces ( 306 , 308 ) are adapted to receive in a fixed manner inserts ( 310 , 312 ) which cooperate to form a moveable joint . for example , the upper insert ( 310 ) has a concave surface for receiving a dome ( 312 ) portion of the lower insert ( 312 ). variations of the specific insert geometries are contemplated . in each embodiment of the present invention described herein , while the upper are lower parts are presented as identical in the above embodiments , except for one having a concave surface adapted to mate with a corresponding concave surface , it is conceivable that in some circumstances , such as those described below , non - like upper and lower parts can be utilized together in a system . thus , with respect to fig8 - 9 , another preferred embodiment is described herein and a component is referred to as a “ first part ” which could be used in a system with an identical “ second part ” or a non - like second part . either part could be the upper or lower part depending on preference and conditions . thus , referring to fig8 - 9 ( 9 a and 9 b ), a first part ( 400 ) has a generally vertical outward facing surface ( 402 ), a generally vertical inward facing surface ( 404 ), a generally horizontal interior surface ( 406 ), a generally horizontal exterior surface ( 408 ), a fastener hole ( 410 ), an approximately ninety degree bend region ( 412 ), an anterior side ( 414 ), a posterior side ( 416 ), a keel ( 418 ), and a sliding part ( 420 ). in the embodiment of fig8 - 9 , the first part ( 400 ) is installed as part of a spinal implant assembly in a manner such as that described above with respect to the upper and lower parts of the preferred embodiments previously described . the horizontal surfaces ( 406 , 408 ) are positioned in and intervertebral space and the vertical inward facing surface ( 404 ) contacts the anterior side of a vertebra . a bone faster or bone screw ( 422 ) passes through the hole ( 410 ) to secure the part ( 400 ) to the vertebra . preferably , the bone screw ( 422 ) has a back - out prevention feature of any known type or of the type shown in fig9 where a captive ring ( 424 ) resides in the hole ( 410 ) and is adapted to receive the head ( 426 ) of the bone screw ( 426 ) in a manner that causes the bone screw ( 424 ) to be held therein by an interference fit . the hole ( 410 ) may be slotted as shown in fig8 to allow adjustment or to allow dynamic movement . the hole ( 410 ) and the screw head ( 426 ) may , as preferred , be provided with features ( generally known ) that enable pivotal movement or that restrict pivotal movement , depending on the desired application . the horizontal interior surface ( 406 ) may be provided with a keel ( 418 ) having a sharp edge ( 428 ) adapted to cut into the surface of a vertebral end face for stability . in the horizontal exterior surface ( 408 ), a sliding part ( 420 ) is provided . the sliding part ( 420 ) is one of a complementing pair of concave and convex surfaces . for illustration , in fig8 there is shown a concave surface ( 430 ) which would slidingly and rotatably engage a complementing convex surface ( not shown ) on a second part ( not shown ) adapted to be mounted in the same intervertebral space and in contact with the opposing vertebra . fig1 is a view of a part ( 500 ) of the type that could be used in combination with the first part ( 400 ) of fig8 - 9 . the part ( 500 ) is like first part ( 400 ) in all respects except that it has as its sliding part ( 520 ) a convex surface ( 532 ) adapted to slidingly and rotatably engage the concave surface ( 430 ) of first part ( 400 ). below when reference to a feature is made as “ not visible in fig1 ” it means , in this context , that a different view than fig1 is needed to see that feature . since the part is the same as that illustrated in fig8 - 9 but for the “ sliding part ( 520 )”, additional views are not shown because they would be redundant . the part ( 500 ) has a generally vertical outward facing surface ( 502 ), a generally vertical inward facing surface ( not visible in fig1 ), a generally horizontal interior surface ( not visible in fig1 ), a generally horizontal exterior surface ( 508 ), a fastener hole ( shown in dotted lines as 410 , but otherwise not visible in fig1 ), an approximately ninety degree bend region ( 512 ), an anterior side ( 514 ), a posterior side ( 516 ), a keel ( not visible in fig1 ), and a sliding part ( 520 ). when selecting mating parts such as first part ( 400 ) and part ( 500 ) to be used together it would be preferable to select them with the vertical parts ( i . e ., 402 and 502 ) being offset to the same side so that they can nest as shown in and described with respect to fig4 . another preferred embodiment is shown in fig1 a - 11b , fig1 a is shown in cross - section . in this embodiment , an assembly ( 600 ) of the type and for the purpose as described above with respect to preceding embodiments , has a first part ( 600 ) having a generally vertical outward facing surface ( 602 ), a generally vertical inward facing surface ( 604 ), a generally horizontal interior surface ( 606 ), a generally horizontal exterior surface ( 608 ), a fastener hole ( 610 ), an approximately ninety degree bend region ( 612 ), an anterior side ( 614 ), a posterior side ( 416 ), a keel ( 618 ), and a sliding part ( 620 ). a second part ( 601 ) has a generally vertical outward facing surface ( 603 ), a generally vertical inward facing surface ( 605 ), a generally horizontal interior surface ( 607 ), a generally horizontal exterior surface ( 609 ), a fastener hole ( 611 ), an approximately ninety degree bend region ( 613 ), an anterior side ( 615 ), a posterior side ( 617 ), a keel ( 619 ), and a sliding part ( 621 ). the first part &# 39 ; s sliding part ( 620 ) has a concave surface ( 622 ) adapted to slidingly and rotatably mate with a convex surface ( 621 ) on the second part ( 601 ). the first part &# 39 ; s sliding part ( 620 ) has an angled sidewall first portion ( 624 ) and an angled sidewall second portion ( 626 ) providing a geometry that blocks over - rotation among the first part ( 600 ) and second part ( 601 ) relative to each other , but that allows more freedom of rotation in the posterior direction than in the anterior direction , in accordance with natural movements of a patient &# 39 ; s spinal column , particularly in the cervical region . fig1 illustrates , schematically , how a first part ( 700 ) intervertebral implant component according to present invention , can be used in cooperation with a non - like intervertebral component ( 702 ) of any type generally known that engages or cooperates with the first part ( 700 ) in a desirable and sufficient manner . for example , when two intervertebral assemblies ( 714 , 716 ) are applied to adjacent intervertebral spaces defined by three successive vertebrae ( 708 , 710 , 712 ), a first part ( 700 ) according to any one of the above - described present invention embodiments is paired with a non - like intervertebral component ( 702 ) such as one generally known or one that does not have a vertical component ( 718 , 720 ) of the type according to the present invention . this could be for any of a variety of reasons as determined by a surgeon . likewise , a third part ( 704 ) according to the present invention is paired with a non - like fourth part ( 706 ). due to the novel , offset vertical components ( 718 , 720 ) of the present invention parts ( 700 , 704 ), the vertical components nest as described with respect to the embodiment of fig4 , thereby making optimal use of limited space on the anterior face ( 722 ) of the vertebra ( 710 ) in the middle of the three - vertebrae sequence . the upper parts , lower parts and center core from any of the above - identified embodiments may be made from any one of or a combination of known materials of sufficient strength and surgical compatibility for surgical implants . these materials include , but are not limited to , titanium , steel , ceramic , teflon ®, nylon , polyethylene , and cobalt chromium moly . while the preferred embodiments of the present invention have been described , various modifications can be made without departing from the scope of the invention .

a system of reconstruction for a spinal joint is directed to a modular implant assembly that includes an upper part and a lower part . the upper and lower parts each comprise a unitary body having an approximately ninety degree bend defining vertical and horizontal components . each vertical component has a fastener hole for attaching it to a bone segment using a bone fastener . the horizontal sections each have a complementary contact surfaces in order to transmit compressive load therebetween and to accommodate sliding and pivoting relative movement therebetween . the vertical sections of each of the upper and lower part are offset with respect to a vertical centerline so that successive assemblies bridging more than one adjacent vertebral space can have an upper part and a lower part according to the present invention coexist on a single vertebra in a space - efficient manner wherein the vertical sections nest spatially .

other objectives , advantages and novel features of the invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings . in this study a total of 160 golden syrian hamsters aged 3 weeks , weighing 80 to 90 g and 20 albino guinea pigs 2 to 3 weeks of age were used for experiments . all animals were kept in a 12 - hour light / dark cycle . all procedures were approved by the institutional animal care and use committee of china medical university and were conducted in accordance with the guidelines of the use of animals in ophthalmic and vision research . hamsters were raised with right eyelid fusion for 21 days . myopia was induced in guinea pigs by covering the right eye with a cloth attached to the skin at a distance of at least 1 cm from the eye . mfd was induced in the right eye ( with the left eye serving as a control ) of animals randomly assigned to treatment or control groups ( n = 10 animals each ) receiving daily applications of drug or phosphate - buffered saline ( pbs ), respectively , to both eyes . r28 rat retinal epithelial cells were provided by gail seigel at the ross eye institute ( suny , buffalo , n . y ., usa ). the cells were cultured in dulbecco &# 39 ; s modified eagle &# 39 ; s medium ( dmem ) with 10 % fetal bovine serum ( fbs ) at 37 ° c . and 5 % co 2 , with medium replacement every 3 days to 4 days . sclera were placed in a 60 - mm culture dish in dmem supplemented with 10 % fbs to isolate primary scleral fibroblasts ; those from fewer than three passages were used in experiments . cells were seeded in six - well plates ( 1 × 10 5 cells / well ) and treated with lipopolysaccharide ( lps ) at 100 ng / ml or left untreated for 4 hours , followed by 100 μm atropine for 24 hours . cell lysates were collected for quantitative ( q ) pcr to determine gene expression levels . sclera tissues were obtained from eyes with or without mfd . total rna was isolated using the rneasy mini kit ( purchased from qiagen ). rna integrity and purity were determined with an agilent bioanalyser . a total of five unique total rnas were pooled together ( equal amounts ) for cdna microarray analysis . cdna microarray analysis was performed using affymetrix genechip human genome u133 plus 2 . 0 and the procedures were consistent with the manufacturer &# 39 ; s guidelines . cdna microarrays were scanned using a genearray scanner . the image files (. cel format ) were analyzed using the dna - chip analyser software . genes that exhibited a differential expression greater than 1 . 2 fold between the control and myopic eyes were selected for ingenuity pathway analysis . the re ( i . e ., spherical - component re , which is defined as the mean re in horizontal and vertical meridians ) was measured using a hand - held streak retinoscope . animals were anesthetized with 10 % ether in o 2 . ocular refraction was evaluated at the start and end of the experiment . at the end of the study , animals were sacrificed through co 2 asphyxiation according to the guidelines of the public health service , office of laboratory animal welfare , national institutes of health , and american association of veterinary medicine . eyes were enucleated using a razor blade on an ice plate under a surgical microscope ( topcon , tokyo , japan ) by cutting perpendicularly to the anterior - posterior axis approximately 1 mm posterior to the ora serrata . the iris and ciliary body of the anterior segment of the eye were separated . posterior sclera was excised using a 7 - mm - diameter trephine . the axial lengths were determined through a - scan ultrasonography ( pacscan 300 plus , ny , usa ). the average of 10 unique measurements was used . total rna of sclera tissues were isolated using an rneasy mini kit ( qiagen ) and preceded for pcr array analysis . rna integrity and purity were determined using an agilent bioanalyser . one microgram of total rna in a final volume of 20 - μl was reverse transcribed using the high - capacity cdna reverse transcription kit ( applied biosystems ). the expression of genes involved in myopia progression was determined using a 96 - well rt2 profiler pcr arrays - human autophagy ( qiagen , frederick , md ., usa ) in a lightcycler 480 pcr system ( roche , germany ). primary sclera fibroblast cells plating on cover slides were washed with tris - buffered saline ( tbs ), and subsequently fixed with 4 % paraformaldehyde and washed twice with tbs before blocking with 1 % bsa and 0 . 1 % triton x - 100 for 1 hour . the cells were incubated with anti - mmp2 or anti - col1 for 1 hour before being washed three times with tbs and subsequently incubated with an appropriate secondary antibody and a 4 ′, 6 - diamidino - 2 - phenylindole ( dapi ) dna stain . after being washed three times with tbs , the cells were imaged using fluorescence microscopy . all experiments were performed at least in triplicate . to facilitate subsequent analysis , 1 × 10 6 cells were seeded in 24 - well plates for at least 12 hours . cells were washed with pbs three times and incubated with a culture medium without fbs in the presence or absence of 100 ng / ml of lps or 100 ng / ml of lps + 100 μm atropine or 100 ng / ml of lps + 50 μm diacerein . culture supernatants were collected after 48 hours and mixed with an equal volume loading buffer ( 125 mm tris - hcl , ph 6 . 8 , 3 % sds , 40 % glycerol , and 0 . 02 % bromophenol blue ). to measure the mmp - 2 / mmp - 9 activities , samples were separated using 8 % sds - page containing 0 . 1 % gelatin . arpe - 19 human retinal pigment epithelial cells were obtained from the bioresource collection and research center , hsinchu , taiwan ( bcrc ; bcrc - 60383 ). cells were cultured in dmem with 10 % fbs at 37 ° c . and 5 % co2 , with medium replacement every 3 to 4 days . arpe - 19 cells were treated with pbs ( control ), 100 ng / ml of lps ( sigma ), or lps + 100 μm atropine for 30 minutes . after treatment , 30 μg of total cell lysates was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis ( sds - page ), followed by immunoblot analysis . primary antibodies used included erk ( thr202 / tyr204 ), akt ( ser473 ), pi3k ( p85 [ tyr458 ]/ p55 [ tyr199 ]), nf - κb ( p65 , ser536 ), and c - fos ( ser32 ; cell signaling , beverly , mass ., usa ). antirabbit or antimouse secondary antibody conjugated with horseradish peroxidase was also used . immunoreactive protein bands were detected using an enhanced chemiluminescence kit ( ecl , pierce , thermo fisher scientific , pittsburgh , pa ., usa ). equal loading was confirmed through probing the blots with β - actin antibody ( abcam , cambridge , mass ., usa ) as well as anti - erk , akt , pi3k , nf - κb , and c - fos . total rna was extracted using the rneasy minikit ( qiagen , valencia , calif ., usa ), and 5 μg of rna was reverse - transcribed to cdna by using the superscript first strand synthesis system ( invitrogen , carlsbad , calif ., usa ). primers and probes used for qpcr were selected from the universal probes library ( roche , west sussex , uk ). transcript levels were normalized to those of glyceraldehyde 3 - phosphate dehydrogenase in each sample . eyes were collected from atropine - treated and control animals , embedded in paraffin , and cut at a thickness of 20 μm ; subsequently , the sections were placed on glass slides . antigen retrieval was performed by boiling the slides in citrate buffer ( ph 6 . 0 ); the sections were then stained with antibodies against il - 6 , tnf - α , tgf - β , mmp2 , c - fos , nf - κb , and chrm1 and 3 . the envision system peroxidase kit ( dako , carpentaria , calif ., usa ) was used to visualize immunoreactivity . data source the nhird , maintained by the national health research institute , is population - based and derived from the claims data of the national health insurance program , a mandatory - enrollment , single - payment system created in 1995 , now covering over 99 % of taiwan &# 39 ; s population . the database contains all medical claims and the information of insurants and provided a valuable resource , unique opportunity , and sufficiently large sample size for this study . the high validity of the diagnostic data from the nhird has been previously reported . files for children ( age & lt ; 18 y ) included 50 % of those randomly selected from the children &# 39 ; s registry from 1996 to 2008 . to ensure the accuracy and reliability of the diagnoses , the index of inflammatory diseases , including sle , t1dm , and kawasaki disease ( kd ), was coded based on the international classification of diseases , ninth revision , clinical modification ( icd - 9 - cm ) and the registry for catastrophic illness patient database ( published by the department of health , executive yuan , taiwan ), which includes selected major injuries or illnesses . the degree of urbanization was divided into seven categories based on a previous report , with levels 1 and 7 representing the highest and lowest degrees , respectively . because there were few children in levels 5 to 7 , these were combined with level 4 . because of the personal electronic data privacy regulation , insurants &# 39 ; identities are encrypted before data are released to researchers . this study was approved by the institutional review board of china medical university hospital . study sample children newly diagnosed with sle ( icd - 9 - cm code 710 . 0 ) between 2000 and 2004 formed the sle cohort . the date of sle diagnosis was the baseline . for each child with sle , four non - sle children were randomly selected who were frequency matched by sex , age (± 1 y ), urbanization level , parental occupation , and baseline year . patients diagnosed with myopia ( icd - 9 - cm code 367 . 1 ) before the index date were excluded . the sle and non - sle cohorts were followed up until myopia appeared or were censored because of loss to follow - up , death , or for being otherwise unavailable before dec . 31 , 2008 similar cohort analyses for investigating the occurrence of myopia were performed in t1dm ( icd - 9 - cm codes 250 . x1 and 250 . x3 ) and kd ( icd - 9 - cm code 446 . 1 ) cohorts , each with an appropriate comparison cohort . statistical analysis patients and control groups were compared regarding the distribution of demographic factors , including sex , age , urbanization level , and parental occupation by performing an χ2 test . the incidence rate and hazard ratio of myopia were calculated for sle versus non - sle , t1dm versus non - t1dm , and kd versus non - kd cohorts by using cox proportional hazards regression analysis . 0 . 1141 g resveratrol ( purchased from sigma aldrich co .) powder was dissolved in 6 ml of ethanol to obtain resveratrol liquid . 1 . 46 g β - cyclodextrin ( purchased from sigma aldrich co .) was dissolved in 2 ml of sterile water to obtain a β - cyclodextrin solution ( as a co - solvent ); resveratrol liquid and β cyclodextrin were mixed in mole number of 1 : 2 by slowly adding dropwise β cyclodextrin solution into resveratrol liquid to form a mixture . the mixture was frozen drained , and then 5 ml artificial tears were added ( purchased from alcon company ) to be re - dissolved to obtain 100 mm resveratrol solution . resveratrol solution can be diluted by fetal bovine serum medium or artificial tears for various embodiments . 8 ml artificial tears ( purchased from alcon company ) was added in a 15 ml test tube , then 100 μl tween 80 and 30 mg of castor oil were added into the test tube . 40 mg diacerein ( purchased from sigma - aldrich ) was dissolved by gradually dropping under oscillating condition . finally , 10 ml artificial tears was added to enhance dissolution by oscillator for 30 minutes to obtain final concentration 10 mm diacerein . 30 mg diclofenac sodium was added to 5 ml artificial tears and then fully dissolved to obtain a final concentration 6 mg / ml ( 0 . 6 w / v %) diclofenac solution by oscillator 15 mg diclofenac sodium was added to 5 ml artificial tears and then fully dissolved to obtain a final concentration 3 mg / ml ( 0 . 3 w / v %) diclofenac solution by oscillator according to the mfd animal model of preparation example 1 and physiological measurements of preparation example 4 , the effect of atropine for treating myopia progression can be displayed as in table 1 . as shown in table 1 , the monocular deprivation animal model was used to study the relationship between inflammation and myopia . no difference was observed in refractive power between right and left eyes before mfd . as shown in table 1 and fig1 , after 21 days , the res for the pbs - treated mfd group were 4 . 65 ± 0 . 37 and 7 . 68 ± 0 . 34 d for mfd ( right ) and non - mfd ( left ) eyes , respectively ( p & lt ; 0 . 0001 ). the re increased for both eyes as a function of atropine concentration : at 0 . 125 %, 0 . 5 %, and 1 % atropine , the re values were 6 . 45 ± 0 . 1 d , 6 . 72 ± 0 . 11 d , and 7 . 06 ± 0 . 29 d , respectively , for the mfd eye , and 8 . 32 ± 0 . 16 d , 8 . 58 ± 0 . 12 d , and 10 . 79 ± 0 . 16 d , respectively , for the non - mfd eye . these data suggest that atropine administration inhibits myopia progression . to affirm the induction of myopia in our animal model , we determined the expression levels of tgf - β and mmp2 in the sclera by using quantitative real - time pcr . as shown in table 2 , the expression levels of tgf - β and mmp2 were higher by 1 . 49 - and 1 . 59 - fold , respectively , in mfd eyes ( p & lt ; 0 . 05 ; table 2 ). whereas the expressions of chrm2 , chrm 4 , and chrm 5 were similar between groups , the chrm1 and chrm3 levels were 1 . 54 - and 1 . 68 - fold higher , respectively , in mfd than they were in non - mfd eyes ( p & lt ; 0 . 05 ). as shown in fig1 b , chrm1 and chrm 3 expression levels were higher in the sclera of the mfd than in the non - mfd eyes ; chrm1 and chrm 3 were downregulated in mfd eyes after atropine treatment compared with the levels in pbs - treated mfd eyes . as shown in fig1 c and 1d , treatment with 1 % atropine decreased the mmp2 and increased col1 expression in the sclera of the mfd eye compared with the results obtained for pbs treatment , which was confirmed through immunohistochemistry . furthermore , the tgf - β level was upregulated by mfd in both the retina and sclera , but this effect was suppressed by atropine . these results indicate that the expression of genes that promote myopia progression through tissue remodeling was altered by mfd but corrected by atropine treatment . according to the microarrays of preparation example 3 and the method of preparation example 5 , over 200 genes differentially expressions were identified in the sclera of pbs - treated mfd and non - mfd eyes expressed through microarray analysis . after ingenuity pathway analysis as table 2 showed , c - fos and nuclear factor kappa b ( nf - κb ), two major transcription factors in regulating inflammatory reaction , were overexpressed in mfd eyes . an inflammatory cytokine and receptor pcr array was used to determine the differential expression of genes in the sclera of mfd versus non - mfd eyes . the increases in transcript levels for the transcription factors c - fos and nf - κb were 1 . 25 - and 1 . 52 - fold higher , respectively , in the sclera of mfd than in non - mfd eyes ( p & lt ; 0 . 05 . other various inflammatory cytokines including interleukin - 6 ( il - 6 ) was 2 . 05 - fold , tnf - α was 1 . 54 - fold , tgf - β was 1 . 49 - fold , and il - 1β was 1 . 87 - fold ( p & lt ; 0 . 05 ). by contrast , the expression of the anti - inflammatory cytokine il - 10 was 0 . 58 - fold lower in mfd than in non - mfd eyes ( p & lt ; 0 . 05 ). since atropine affects both the sclera and retina , the expression of differentially expressed genes identified through the microarray was examined in rat r28 retinal cells and hamster primary scleral fibroblasts in which inflammation was induced by lps . the expression of chrm1 and 3 , c - fos , il - 6 and - 1β , tgf - β , tnf - α , and nf - κb was upregulated by lps treatment , but the effect was suppressed in both cell types in the presence of atropine ( p & lt ; 0 . 05 ). by contrast , il - 10 expression was suppressed by lps and enhanced by atropine ( p & lt ; 0 . 05 ). these results suggest that the inflammatory response is linked to myopia progression . to determine whether decreased inflammation inhibits myopia progression , the immunosuppressive agent cyclosporine a ( csa ) was applied to the eyes of hamsters and the re was measured on day 21 . as shown in table 3 and fig2 a , the res for the pbs - treated group were 7 . 92 ± 0 . 54 d and 10 . 15 ± 0 . 25 d for the mfd and non - mfd eyes , respectively ( p & lt ; 0 . 0001 ). these values changed on treatment with 3 % csa to 9 . 25 ± 0 . 63 d and 9 . 90 ± 0 . 53 d , respectively , indicating that the progression of myopia was blocked . as shown in fig2 b , this was underscored by the concomitant decreases in mmp2 and tgf - β expression that were observed . to test whether increased inflammation enhanced the progression of myopia , lps and 500 ng / ml peptidoglycan ( pgn ), inducers of inflammation originating from gram - negative and - positive bacterial cell walls , respectively , were applied to the eyes of mfd mice every second day for 21 days . as shown in table 4 and fig3 a , the re for pbs - treated animals was 7 . 67 ± 0 . 74 d and 9 . 25 ± 0 . 48 d for mfd and non - mfd eyes , respectively ( p & lt ; 0 . 0001 ); however , these values decreased to 6 . 44 ± 0 . 18 d and 7 . 79 ± 0 . 88 d , respectively , on lps treatment , and to 6 . 47 ± 0 . 39 d and 6 . 78 ± 0 . 63 d , respectively , on pgn treatment . as shown in fig3 b , the decrease in re was accompanied by an upregulation of mmp2 and tgf - β . as shown in fig3 a , myopia was induced in the non - mfd eye through lps and pgn but not through pbs treatment ( p & lt ; 0 . 01 ), suggesting a direct link between inflammation and myopia progression . to further test this possibility , lps and pgn were applied to the eyes of hamsters without mfd . as shown in table 5 and fig3 c , after 21 days , the re for the pbs - treated group was 12 . 5 ± 0 . 18 d and 12 . 21 ± 0 . 29 d for right and left eyes , respectively . these values decreased to 8 . 56 ± 0 . 42 d and 8 . 33 ± 0 . 96 d , respectively , on lps treatment , and 9 . 14 ± 1 . 21 d and 8 . 67 ± 0 . 63 d , respectively , in pgn - treated eyes , representing statistically significant differences with respect to the pbs - treated group ( p & lt ; 0 . 001 ). as shown in fig3 d , these changes occurred concurrently with the upregulation of tgf - β and mmp2 expression . the expression of inflammatory molecules was evaluated through immunohistochemistry . as shown in fig4 a , the expression of c - fos and nf - κb in the retinas of mfd eyes was higher than that in non - mfd eyes but was suppressed through treatment with 1 % atropine . as shown in fig4 b and 4c , csa lowered the c - fos and nf - κb expression that was stimulated by lps or pgn . as shown in fig4 d , il - 6 and tnf - α immunoreactivity in the retina was elevated in mfd eyes , but the expression of these factors was reduced through application of 1 % atropine . by contrast , the il - 10 expression was elevated following atropine treatment . as shown in fig4 e , il - 10 and tnf - α levels , which were increased through lps or pgn treatment . as shown in fig4 f , il - 6 and tnf - α levels were lowered by csa , but il - 10 level was increased after csa treatment . taken together , these results indicate that induced inflammation caused acceleration of myopia , and this acceleration could be reversed through application of anti - inflammatory agents . we observed a similar increase in inflammatory response in hamsters as we did in a guinea pig model of mfd . as shown in fig5 a , mfd was induced in guinea pigs by covering the right eye with a cloth attached to the skin at a distance of at least 1 cm from the eye . 1 % atropine was applied to the eyes of guinea pigs and the res and axial lengths were measured on day 21 . as shown in table 3 , the res for the pbs - treated group were − 9 . 22 ± 0 . 93 d and − 0 . 42 ± 1 . 38 d for mfd and non - mfd eyes , respectively . these values changed on treatment with atropine to − 6 . 79 ± 1 . 00 d and − 1 . 50 ± 0 . 82 d , respectively . the axial lengths for the pbs - treated group were 1 . 17 ± 0 . 01 cm and 1 . 08 ± 0 . 00 cm for mfd and non - mfd eyes , respectively . these values changed on treatment with atropine to 1 . 14 ± 0 . 01 cm and 1 . 04 ± 0 . 82 cm , respectively . both res and axial lengths exhibited statistical significance between pbs and atropine treated mfd eyes ( all p & lt ; 0 . 005 ). the expression levels of mmp2 , tgf - β , and c - fos increased in myopic eyes whereas that of col1 decreased . as shown in fig5 b and 5c , atropine treatment reduced mmp2 , tgf - β , and c - fos and increased col1 expression in the sclera or retina of the mfd eye compared to the results obtained for pbs treatment . the il - 10 level was downregulated by mfd , but this effect was suppressed by atropine . these results revealed consistent outcomes when using various mfd methods in different animal species . atropine inhibits phosphatidylinositol 3 - kinase ( pi3k )- akt - nf - κb and extracellular signal - regulated kinase ( erk )- fos pathways to determine the molecular mechanisms of atropine in inhibiting myopia progression , rat primary sclera fibroblast and human retinal pigment epithelial cells arpe - 19 were used . as shown in fig6 a and 6b , atropine inhibited the expression levels of mmp2 and increased col1 in primary sclera fibroblast . as shown in fig6 c and 6d , mmp2 activities increased in cells activated by lps whereas they decreased through application of atropine or diacerein . the results suggested that diacerein can be used as a new agent to inhibit myopia progression . to study the signaling pathways influenced by atropine , human retinal pigment epithelial cells arpe - 19 were treated with lps or lps / atropine for 4 hours . as shown in fig6 e , the activation of erk through lps was inhibited by atropine treatment as well as its downstream signaling molecule c - fos . atropine treatment also inhibited the lps activation of pi3k , akt , and nf - κb . these results indicated that atropine inhibits inflammation through downregulation of erk - c - fos and pi3k - akt - nf - κb pathways . according to the method of preparation example 11 , the retrospective cohort study was conducted using data on children (& lt ; 18 years old ) obtained from the national health insurance research database ( nhird ) to determine whether the inflammatory diseases sle , kd , and t1d are associated with the incidence of myopia . † the urbanization level was categorized by the population density of the residential area into 4 levels , with level 1 as the most urbanized and level 4 as the least urbanized . † the urbanization level was categorized by the population density of the residential area into 4 levels , with level 1 as the most urbanized and level 4 as the least urbanized . † the urbanization level was categorized by the population density of the residential area into 4 levels , with level 1 as the most urbanized and level 4 as the least urbanized . as shown in tables 7 to 9 , from 2000 to 2004 , 1214 sle , 546 kd , and 559 t1d patients were newly diagnosed and randomly matched for age , sex , and index year with patients without sle , kd , or t1d from the general population at a 1 : 4 ratio . as shown in tables 10 to 12 , cohorts were followed until the end of 2008 when the incidence of myopia was assessed . the risk of myopia was 1 . 40 - fold ( 95 % ci = 1 . 18 - 1 . 66 ) higher in the sle cohort , 1 . 26 - fold ( 95 % ci = 1 . 04 - 1 . 53 ) higher in the kd cohort , and 1 . 59 - fold ( 95 % ci = 1 . 31 - 1 . 94 ) higher in the tid cohort , compared with the controls . as shown in fig7 a to 7c , the cumulative incidence of myopia by the end of the follow - up period was 3 . 5 %, 11 . 6 %, and 7 . 9 % higher in the sle , kd , and t1d groups , respectively , than in controls ( p & lt ; 0 . 001 ). these findings provide clinical evidence for the association between inflammatory diseases and the occurrence of myopia . the refractive powers of hamsters were measured before experiment by refractometer ( in china medical university hospital department of ophthalmology ). the hamsters were administered artificial tears ( referred to as control group ) or various concentrations ( 3 mm , 30 mm , 100 mm ) of resveratrol ( experimental group ) for five hamsters each group . the right eyes of the hamsters of each group were stitched ; after 21 days , the stitches were all removed and then the refractive powers of each hamster were measured . as shown in table 13 , the diopter of the right myopic eye of the control group has increased significantly ; after treatment with various concentrations of resveratrol , the diopter was decreasing significantly , especially 100 mm resveratrol . as shown in fig8 , the diopter difference of left eye and right eye were very obvious . after resveratrol administration with various concentration , myopia can be inhibited , wherein 100 mm resveratrol was the most effective . effect of resveratrol for inflammation - related protein induced myopia and myopic related proteins expression the expression of myopia related proteins : collagen i and inflammation - related proteins , such as tgf - β and tumor necrosis factor - α ( tnf - α ) were observed in myopic eyes . as shown in fig9 , the protein expression of collagen i of the right stitched eye is lower than that of the unstitched left eye in the sclera . after 100 mm resveratrol administration , collagen i has been recovered in the sclera . in the control group , tgf - β expression in the retina of the stitched right eye is higher than that of the unstitched left eye , however , tgf - β expression has reduction effect after the administration of 100 mm resveratrol . tnf - α expression in the retina follows the same trend as tgf - β . human retinal pigment epithelial cells were as model cells under lps stimulation for 24 hours to induce inflammation and monocyte chemoattractant protein - 1 ( mcp - 1 ), and then resveratrol was administered to detect the effect of suppressing inflammatory response . as shown in fig1 , 1 μg / ml lps was used to induce inflammation , such that the expression of mcp - 1 was increasing ; while the administration of 50 μm resveratrol and 1 μg / ml lps for 24 hours , the expression of mcp - 1 was decreasing , so that resveratrol has significant inhibitory effect on mcp - 1 . human retinal pigment epithelium was administrated 500 ng / ml lps for 30 minutes to observe the expression of akt and erk . as shown in fig1 and 12 , 500 ng / ml lps can stimulate the expression of phosphorylated akt and erk increasing . whereas 50 μm resveratrol pretreatment and then 500 ng / ml lps stimulation , the expression of phosphorylated akt and erk would decrease . four weeks lewis rats were used in this example . the right eye induced myopia by fdm were divided into three groups : control group ( no administered the drug ) and diclofenac solution prepared from example 14 ( 6 mg / ml and 3 mg / ml ). the refractive error and axial length of right eye were measured by refractometer within three weeks and recorded in table 14 . the two groups administrated with diclofenac solution were all positive two , which means no myopia ; the refractive error of the group without any administration ( control group ) was − 9 . 20 d ( severe myopia ). the long axial length of eye means severe myopia . the results can also be observed that the axial length of the control group was significantly longer than the two groups administrated with diclofenac solution . in summary , diclofenac administration had a significant inhibitory effect on myopia process . in addition , the inhibitory effect on myopia is better in the concentration of 3 mg / ml than in 6 mg / ml . the present invention shows the relevance of inflammation and the development of myopia , wherein atropine , although having side effects ( such as photophobia and cycloplegia ), can inhibit the development of myopia . in addition , the composition of the present invention comprising resveratrol , diacerein or diclofenac ( anti - inflammatory agents ), and a pharmaceutically acceptable carrier at a specific ratio can be used as an alternative of atropine for inhibiting and / or relieving the progression of myopia .

the present invention provides a pharmaceutical composition for treating and / or relieving myopia , the pharmaceutical composition comprises a therapeutically effective amount of an anti - inflammatory agent and a pharmaceutically acceptable carrier ; the pharmaceutical composition of the present invention is safe , and can treat and / or relieve myopia by the anti - inflammatory agent . the pharmaceutically acceptable carrier can effectively encapsulate the anti - inflammatory agent at a specific ratio , and the stability and solubility of the pharmaceutical composition can be enhanced .

in fig1 is shown a part of a hockey rink including a layer of ice 10 , the boards 11 at the ice edge including a top rail 12 and the glass on top of the rails indicated at 13 formed in separate panels and carried in vertical brackets 14 supporting the edges of the panels . the present invention provides a protective device for use on the glass of a hockey rink . this includes a bracket 15 for mounting on the exposed edge 16 of a sheet of glass of the hockey rink where there is an opening 17 in the span of glass around the playing surface , for example at the penalty box or team bench . an upstanding elongate engagement member 18 , which may for example by a flat plate of metal or other substantially rigid material , has a height that lies generally parallel to the bracket 15 and is the same or similar to the height of the glass so as to be supported at a position spaced from the edge of the sheet of glass . a shock absorbing system 19 is located between the bracket 15 and the engagement member 18 allowing movement of the engagement member in a direction toward the edge of the glass . the shock absorbing system includes a plurality of springs 19 a at spaced positions along the height of the engagement member . the springs absorb the impact and compress to a smaller length to allow the distance between the engagement member and the glass to be used to gradually take up the impact forces from a player impacting the engagement member . this movement may typically of the order of 3 to 6 inches , but may be more in the order of 1 to 3 inches , and preferably 1 to 2 inches , in order to keep the overall size and bulk of the device to a minimum . the engagement member 18 is rigid so that it remains straight when impacted and simply moves to one side toward the glass under the impact toward the glass edge . the springs of the shock absorbing system act to return the engagement member to the original position after absorbing the impact to allow the game to continue without pause . there is provided a guide a track 20 extending along the top rail 12 of the boards extending outwardly from the bottom edge of the glass or bottom end of the bracket 15 and a guide member 21 along the top edge of the glass for guiding movement of the engagement member in the horizontal direction parallel to the vertical plane of the glass . in this way the engagement member is maintained in the plane of the glass and is prevented from hinging inwardly under an impact . the engagement member is covered by a layer of padding 22 on its face away from the glass edge and a band 24 of padding is located between the engagement member and the edge of the glass and extends onto the inside of the glass facing the players on the ice . the band of padding slides in front of the glass when the engagement member is impacted to compress the shock absorbing system . the band of padding therefore closes off the space between the glass edge and the engagement member and hides the shock absorbing system . between the engagement member and the edge of the glass on the outside of the glass facing away from the players is partly covered by a lip 23 of the padding 22 . as also shown in fig2 , a guide rod , bar or pipe 19 b having an outer diameter smaller than the inner diameter of the spring &# 39 ; s coils is received within the spring so that the coils thereof wind around the guide 19 b . one end of the guide 19 b is fixed to the engagement member 18 , and the guide 19 b passes through a hole in a portion 15 a of the bracket that lies in a vertical plane perpendicular to the plane of the glass 13 at the edge 16 of the glass 13 . this hole in the bracket 15 is located on an outer side of the plane of the glass 13 . when the spring 19 a is compressed during travel of the engagement member 18 toward the bracket 15 , the free end of the guide 19 b thus travels along the glass on the outside thereof . the guide 19 b prevents the spring 19 a from deflecting significantly from its horizontal longitudinal axis parallel to the plane of the glass 13 . fig2 a shows a first variant of the embodiment of fig1 and 2 where no guides are present inside the springs 19 a , and accordingly the springs need not be offset from the plane of the glass 13 . however , the springs may be more subject to deflection from a horizontal spring axis parallel to the plane of the glass 13 . fig2 b shows a further variant of the first embodiment , where instead of using a guide rod / bar / pipe 19 b to maintain the orientation of the spring axis parallel to the plane of the glass , the bracket 15 defines a channel 15 b that opens toward the engagement member 18 , much like the channel on the other side of the bracket that embraces the edge 16 of the glass 13 , and the extends into this channel 15 b to make the connection to the portion 15 a of the bracket lying perpendicular to the glass 13 at the vertical edge 16 thereof . space is left between the open end of the channel 15 b and the normal spring - biased position of the engagement member to leave room for the displacement thereof under impact by a player , while the vertical side walls of the channel 15 b act to block or limit horizontal deflection of the spring , at least over the portion thereof received between the side walls of the channel . in fig3 is shown a second embodiment in which the shock absorbing system includes gas springs 30 embedded in a block of foam 32 with cylindrical holes 34 cut in the foam to receive the individual spaced - apart springs in a row along the edge of the glass 13 . the springs are embedded in the block of resilient foam or other similar resilient material , which has an elongated vertical dimension matching or closely following the height of the glass . each gas spring is arranged to compress between its ends by collapse of a corrugated peripheral wall 36 along an axis of the spring parallel to the direction of impact . this is controlled by allowing air to escape through an adjustable discharge valve 40 and re - expand by resilience in the peripheral wall of the spring acting to re - inflate the spring and return the expelled air . although the drawings illustrate gas springs with empty interiors , whereby the re - expansion of the spring is provided entirely by the resilience of the corrugated peripheral wall , other embodiments may employ a soft coil spring disposed inside the gas spring body to contribute to a faster return of the gas spring to its normal extended state . in this arrangement the player impacts an outer edge of the foam body , which lies opposite and faces away from the edge of the glass , and the base of the gas springs at or near this outer edge of the foam body so that there is no need for an additional padded engagement member which moves toward the edge of the glass , as the whole construction can compress in the direction of impact . the gas springs enhance or increase the resistance of the foam to compression . the fig3 device has the foam body mounted directly to the edge of the edge of the glass or a bracket or support located at the glass edge . the foam block may feature a vertical slot running along the height of the block in the edge or side thereof facing the edge of the glass to allow receipt of the glass , bracket or support within the slot so that the foam embraces opposite sides of the glass , bracket or support . options for securing the foam block in place include adhesive , velcro ™ hook and loop fasteners , or string , rope , straps or belts tied around the block and through suitable openings cut or otherwise formed in the glass , bracket or support . fig4 and 5 show a variant of the embodiment of fig3 , wherein a cover 42 of flexible material or fabric is added to enclose and protect the rectangular foam block 32 . the illustrated cover 42 defines a generally rectangular interior volume to closely fit the foam block 32 , and features a folding rectangular flap 44 to selectively open and close the cover 42 at the outer side or edge of the foam block 32 for access to the block and the gas springs inside the container for inspection , repair or replacement . a suitable fastening mechanism is provided to allow the closure flap 44 of the cover to be secured in a closed position ( fig5 ) over the foam block when the device is in use . in the illustrated embodiment , a zipper 46 is used for closing the cover 24 through engagement of mating zipper teeth on three matching sides of the closure flap 44 and the cover opening to be closed thereby , as can be seen in fig4 where the closure flap 44 is in the open position . the fig4 variant also differs from fig3 in that the holes 34 ′ in the foam block 32 and the gas springs 30 ′ received in the holes are not of circular cross - section , instead each having an oblong or other vertically - elongated cross - section to span a larger portion of the overall height of the device along the vertical edge of the glass 13 , and so fewer holes and springs are required . this demonstrates the number , size and shape of the gas springs may be varied while still providing the same overall functionality . fig5 shows that the device may incorporate a rigid base plate 48 lying between the foam block 32 and the bracket 15 for use in fastening the device to the bracket 15 at the edge of the glass 13 , for example using threaded fasteners engaged through the two . the base plate 48 is shown inside the cover 42 , but alternatively may be located on the exterior thereof . the illustrated foam - embedded gas springs have the outer faces thereof ( i . e . the ends of the spring opposite the edge of the glass ) situated at positions slightly recessed into the foam block from the outer face thereof so that the compression of the gas spring only comes into play under sufficient impact to drive the outer face of the foam far enough inward to reach the outer ends of the springs . other embodiments may have the spring ends flush with the outer face of the foam block , or have the springs project outward from the foam block to form part or all of the initial impact area . the valves of the gas springs may be situated at either end of the respective holes in the foam block , and may communicate only with the hollow space inside the foam , or suitable airflow passages or conduits may pass through the foam to communicate the gas springs with the ambient environment outside the foam body . the holes in the foam body may be through - holes passing entirely therethrough , or blind - holes passing only partly through the body from one side thereof , whether from the inner edge or side of the foam body nearest the glass or the opposing outer edge or side . in the arrangements described above , the edge of the glass lies in a flat plane containing the glass . however in another arrangement shown in fig6 and 7 , the edge of the glass is curved out of the flat plane of the glass and the bracket is mounted on the convex side of the curved edge . in the arrangements of fig3 to 5 , there is provided a row of gas springs embedded in a foam body along the edge of the glass , whether each spring is circular or of vertically elongated cross section to extend along the bracket at the edge of the glass . the variant of fig6 and 7 differ in that there is provided only a single gas spring 30 ″, which is mounted without any surrounding foam material and which has an elongated cross - sectional shape that is sufficiently long in the vertical direction to span the full , or substantially full , height of the glass 13 ′. the device features a mounting bracket 15 ′ with a flat outer face against which an end of the gas spring 30 ″ is abutted , and an opposing face with a curvature suitable to sit flush against the curved edge portion of the glass 13 ′. the device may be secured to the glass in any suitable manner , for example by adhesive bonding of the bracket 15 ′ to the glass 13 ′, or bolting of the bracket to the glass through alignable holes in the bracket and the glass . alternatively , another embodiment may forgo the mounting bracket 15 ′ an have an inner end of the spring directly fixed or fastened to the glass . fig6 and 7 also illustrate an alternate cover design , where the cover 42 ′ does not fully enclose all sides of the device , instead lacking any closure on the side of the device that is mounted up against the glass 13 . while fig6 and 7 show the device mounted to position the spring axis parallel to the plane of the flat portion of the glass at a short distance outward therefrom , it may alternatively be configured to place the spring nearer to this primary flat plane of the glass , but still parallel thereto , or to angle the spring axis to extend obliquely toward the primary plane of the glass , but preferably without projecting inward therepast toward the playing area bound by the boards . with reference to fig2 and 10 , all embodiments of the present invention may be similarly placed so that no portions of the spring or springs projects past the upright plane of the glass into the playing area of the hockey rink bound by the glass . with reference to fig9 and 10 specifically , the foam body 32 may be positioned to reach and occupy the upright plane of the glass 13 without reaching therepast so as to prevent interference with shooting of the puck along the glass . where visibility is required , the cover may be transparent and the springs likewise formed from a transparent material . while fig6 and 7 illustrated a particular arrangement in which foam is omitted and a single gas spring provides all the resilience of the shock absorbing system , other arrangements may similarly omit foam material while using a row of multiple gas springs which are independent of foam material so that the resilience of the shock absorbing system is provided solely by the compression of one or more of the gas springs . although the term glass is used in the forgoing description to refer to the transparent shielding / viewing panels through which spectators and other observers can view the playing area bound by the boards while being protected from a puck that is raised above the height of the opaque boards during play , it will be appreciated that use of other transparent or substantially transparent materials will not detriment the functionality of the present invention . for example , it has become known to use acrylic panels instead of glass for these panels , and the present invention may likewise be used to protect players from the edge , corner , bracket or stanchion at the end of a panel regardless of its particular material composition . the drawings of the preceding embodiments of based on prototypes of the invention produced from off the shelf components , which resulted in overall structures which may be considered bulky and somewhat obstructive to visibility of the playing area . however , it will be understood the smaller components ( e . g . shorter springs ) projecting shorter distances along and across the lengthwise direction of the boards at the edge of the glass may be used to provide an impact absorbing function with reduced detriment to spectator sight lines . in fig8 is shown another arrangement for use for example with a post of a sporting equipment structure which is located at a position which might be impacted by the player . examples of such applications include football posts , basketball stanchions , soccer goal posts , etc . at multiple heights along it , the device features a hollow cylindrical sleeve of foam material 50 having radial bores 52 extending into the cylindrical hollow interior thereof from spaced locations around the outer circumference of the sleeve . each radial bore 52 receives a respective gas spring 30 , so that the sleeve provides a radial array of the gas springs 30 located wholly or partly around a post 54 about which the sleeve is fitted . the sleeve length is selected to extend along the post to a required height so that up to the whole periphery of the post may be protected from an impact in any direction . in other embodiments , for example where protection in all directions is not required , the foam padding may not necessarily form a fully closed sleeve around the post , and for example may be an arcuate span of foam having one or more radial bores at one or more levels along the height of the body . again , gas springs of various cross - sectional shapes , and accordingly shaped holes in the foam , may be employed , in which case vertically elongated springs may be used to reduce the number of springs required to span a particular height of the foam body . since various modifications can be made in my invention as herein above described , and many apparently widely different embodiments of same made within the spirit and scope of the claims without department from such spirit and scope , it is intended that all matter contained in the accompanying specification shall be interpreted as illustrative only and not in a limiting sense .

safety or protective devices for use in preventing or limiting injury to players impacting against sports equipment use compression coil springs , gas springs , foam or combinations thereof to absorb force during the impact . particular embodiments are configured for use at the edge of a glass viewing and shielding panel disposed atop the boards of a hockey rink , for example such edges typically found at the team bench of a conventional hockey rink . a shock absorbing system of the device is positioned so as not to reach beyond the plane of the glass into the area of play .

fig1 is a perspective view of the preferred embodiment of a packable battering ram 10 that incorporates the limitations of the present invention . the battering ram 10 has a ramming end 12 and a handle end 14 , and further includes a first body member 16 and a second body member 18 that is substantially symmetrical in shape to the first body member 16 . the first and second body members 16 , 18 , which together compose the main body 20 , are connected with a first handle assembly 22 at the handle end 14 and a second handle assembly 24 positioned between the ramming end 12 and the first handle assembly 22 . a ramming head 26 is attached to the first and second body members 16 , 18 at the ramming end 12 . the first body member 16 has a top surface 28 , an outer sidewall 30 , and an inner sidewall 32 . a first side member 34 is integrally formed into the first body member 16 to expose the inner sidewall 32 proximal to the handle end 14 . similarly , the second body member 18 has a top surface 36 , an outer sidewall 38 , an inner sidewall 40 , and a second side member 42 is integrally formed into the second body member 18 to expose the inner sidewall 40 proximal to the handle end 14 . first and second contoured portions 90 , 92 of the sidewalls 30 , 38 narrow the first and second body members 16 , 18 , respectively near proximal to the first hand hole 44 . when assembled , the first and second side members 34 , 42 define a first hand hole 44 bounded on three sides by the inner sidewalls 32 , 40 . the connection of the first body member 16 to the second body member 18 forms a second hand hole 46 across which the second handle assembly 24 spans . the thickness of the first and second body members 16 , 18 , and therefore the corresponding widths of the outer sidewalls 30 , 38 , is greater proximal to the ramming end 12 as compared to the handle end 14 . thus , the first and second body members 16 , 18 are bulkier and heavier proximal to the ramming end 12 as opposed to the handle end 14 , such that the center of mass of the battering ram 10 is preferably located between the ramming head 26 and the second handle assembly 46 ( inclusive ). the location of the center of mass allows the battering ram 10 to transfer more kinetic energy on a target in direction d during use . fig2 is a reverse isometric assembly view of the battering ram 10 described in fig1 . the first handle assembly 22 comprises a cylindrical external handle member 48 and a cylindrical internal handle member 50 sized to fit therein . similarly , the second handle assembly 24 comprises a cylindrical external handle member 49 and a cylindrical internal handle member 51 sized to fit therein . the external handle members 48 , 49 are connected ( either permanently or temporarily with conventional fastening techniques ) to the first body member 16 at the inner sidewall 32 thereof . similarly , the internal handle members 50 , 51 are connected ( either permanently or temporarily with conventional fastening techniques ) to the inner sidewall 40 thereof . each external handle member 48 , 49 has a bore 52 , 53 disposed therethrough for receiving the corresponding internal handle member 50 , 51 . in addition , each internal handle member 50 , 51 is internally threaded ( not shown ) to allow fastening with a wing bolt 54 having a threaded shaft portion 56 . the ramming head 26 comprises a first ramming member 58 attached to the ramming end 12 of the first body member 16 . the first ramming member 58 has an outer ramming surface 58 a , a lateral surface 58 b that is substantially flush with outer sidewall 30 , and a medial surface 58 c that is substantially flush with inner sidewall 32 . the first ramming member 58 extends perpendicularly away from the top surface 28 of first body member 16 , and terminates in a tapered prying member 58 e . similarly , the ramming head 26 comprises a second ramming member 60 attached to the ramming end 12 of the second body member 18 . the second ramming member 60 has an outer ramming surface 60 a , a lateral surface 60 b that is substantially flush with the outer sidewall 38 , and a medial surface 60 c that is substantially flush with inner sidewall 40 . the second ramming member 60 extends perpendicularly away from the top surface 36 of the second body member 18 , and terminates in a tapered prying member 60 e . in the preferred embodiment , the first and second ramming members 58 , 60 are symmetrical , but otherwise identically shaped and sized . to assemble the battering ram 10 , the first body member 12 and second body member 14 are aligned such that the first ramming member 58 and second ramming member 60 are adjacent each other , with one prying member 58 e adjacent to the other prying member 60 e . the internal handle member 50 of the first handle assembly 22 is inserted into the bore 52 of its corresponding external handle member 48 . similarly , the internal handle member 51 of the second handle assembly 24 is inserted into the bore 53 of its corresponding external handle member 49 . the threaded shafts 56 of two wing bolts 54 are disposed through the first body member 16 at a recessed portion 17 thereof and the first side member 34 , and are mated with the internal handle members 50 , 51 . when fully tightened , the wing bolts 54 clamp the first and second body members 16 , 18 together such that the inner sidewalls 32 , 40 are in contact and form the first and second hand holes 44 , 46 . fig3 is a bottom isometric view of the assembled battering ram 10 of the present invention . a bottom surface 58 d of the first ramming member 58 is substantially flush with a first surface 62 of first body member 16 . similarly , a bottom surface 60 d of the second ramming member 60 is substantially flush with a second surface 64 of the second body member 14 . as further shown in fig3 , the first surface 62 and second surface 64 each comprise a concave portion 65 , 67 , and together form a lower surface 69 of the body 20 . the lower surface 69 also comprises a convex portion 71 adjacent the concave portions 65 , 67 and planar first and second strike faces 70 , 72 for receiving a substantially perpendicular blow from a blunt object , such as a hammer . this allows the prying members 58 e , 60 e to penetrate further into a target in anticipation of prying the target apart from a supporting structure . in the preferred embodiment , the concave portions 65 , 67 of the lower surface 69 approximate the normal curvature of a human adult back . fig4 shows the curvature of the battering ram 10 in greater detail by depicting a side elevation of the second body member 18 . as noted with respect to fig3 , the battering ram 10 has a second surface 64 having a concave portion 65 . the convex portion 71 is immediately adjacent the concave portion 65 and the strike face 70 . together the concave portion 65 and convex portion 70 approximate the normal curvature of a human adult back . fig5 depicts the battering ram 10 as packed by an adult male . while fig5 specifically describes transport of the second body member 18 , it should be noted that transport of the first body member 16 ( not shown ) is analogous with respect to the preferred embodiment because of its symmetrical size and shape . because the battering ram 10 can be quickly dissembled , its weight can be distributed approximately equally between two persons , with one carrying the second body portion 18 and attached components and another carrying the first body portion 16 and attached components . at the location to be forcibly entered , the battering ram 10 can be quickly reassembled and used with the full mass of the battering ram 10 again available . it is anticipated , however , that the component parts could be used separately and distinctly as hammering , prying , or ramming tools should the need arise . as shown in fig5 , the concave portion 65 fits to the convex curvature 80 of the back , while the convex portion 71 of the second surface 64 fits to the concave portion 82 of the back ( i . e ., the “ small ” of the back ). the prying member 60 e protrudes away from the person during transport . the battering ram 10 can be secured to the person by straps such that the straps rest on each shoulder of the person . alternatively , any other suitable attaching device may be employed to comfortably attach the second body member 18 to a person . referring again to fig2 and fig3 , the battering ram 10 is most effectively used to ram a target ( not shown ) with the hands of a person placed with the palms facing each other as the first handle assembly 22 and second handle assembly 24 are gripped . ramming surfaces 58 a and 60 a of first ramming member 58 and second ramming member 60 , respectively , are substantially parallel to the target . in operation , the battering ram 10 is swung in a substantial arc or pendulum backwards , and then in direction d to strike the target and transfer the kinetic energy from the battering ram 10 to the target . to chop a target , the battering ram 10 is turned such that prying members 58 e , 60 e are turned toward the target ( not shown ). first and second contoured portions 90 , 92 provide gripping locations to allow a person to grip and swing the battering ram toward the target . the first and second contoured portions 90 , 92 also provide gripping surfaces to allow a person to pull on the battering ram 10 to pry a target ( not shown ). the present invention is described above in terms of a preferred illustrative embodiment of a specifically described packable battering ram . those skilled in the art will recognize that alternative constructions of such an apparatus can be used in carrying out the present invention . other aspects , features , and advantages of the present invention may be obtained from a study of this disclosure and the drawings , along with the appended claims .

a packable battering ram quickly disassembled for transport by two or more persons . in the preferred embodiment , the invention has first and second body members that are symmetrical , but otherwise identically shaped and sized . when assembled , the first and second body members form a lower surface that has a concave portion that approximates the natural curvature of the back of an adult male . the packable battering may be disassembled to distribute the weight between multiple people , yet quickly assembled for use upon arrival at a emergency response location .

with reference to fig1 which illustrates a first embodiment of the cigarette maker according to the invention , and in particular a machine with a single processing line , 1 denotes an infeed portion , in its entirety , of such a machine . the infeed portion 1 comprises a feed unit 2 by which a mass of shredded tobacco is formed into a continuous flow of tobacco particles . the various components making up the feed unit 2 are housed within a vertically extending enclosure 3 delimited uppermost by a horizontal wall 4 and on either side by two vertical walls 5 and 6 . the infeed portion 1 presents an inlet duct 7 extending upward from the horizontal wall 4 , and below the duct , internally of the enclosure 3 , a power driven toothed roller 8 by which the shredded tobacco 9 is directed down into a lower chamber 10 delimited at the bottom by a conveyor belt 11 . the chamber 10 accommodates a carding roller 12 rotatable about an axis 13 transverse to the side walls 5 and 6 , forming part of a carding unit 14 and positioned adjacent to the downstream end of the belt 11 . in addition to the carding roller 12 , the unit 14 comprises a proportioning roller 15 rotatable substantially tangential to the carding roller 12 and in the same direction . with this arrangement , the shredded tobacco 9 is directed by the toothed roller 8 onto the belt 11 and thence toward the carding roller 12 , whereupon a layer of the tobacco 9 substantially equal in thickness to the radial dimension of the carding teeth is transferred by the roller 12 away from the chamber 10 and beyond its position of tangential proximity to the proportioning roller 15 . the infeed portion further comprises an impeller roller 16 rotatable about an axis parallel to the axis 13 aforementioned , of which the function is to pick up the layer of tobacco 9 from the carding roller 12 and project the constituent particles , in the direction denoted f 1 , down into a substantially vertical descent channel or chute 17 delimited by two side walls 18 and 19 extending parallel one with another and with the axis 13 of the carding roller 12 . the bottom end of the chute 17 is positioned facing the periphery of a toothed take - up unit 20 that comprises a take - up roller 21 and an impeller roller 22 combining one with another to transfer the shredded tobacco 9 away from the chute 17 . more exactly , the tobacco 9 is received by the take - up unit 20 in the form of distinct particles and projected onto conveyor means 23 of which the function is to direct the shredded material toward an ascent channel or riser 24 enclosed at the top end by the moving surface of an aspirating belt 25 fashioned from air - permeable material . in accordance with the present invention , the riser 24 is divided into a lower first portion 26 and an upper second portion 27 , of which the top end 28 is enclosed by the aforementioned aspirating belt 25 . the two portions 26 and 27 are separated and interconnected by conveyor means denoted 29 in their entirety , interposed between the outlet 30 of the first portion 26 and the inlet 31 of the second portion 27 . the length of the first portion 26 , as measured along the direction of movement of the belt 25 , is identical to the corresponding length of the second portion 27 , whereas it will be seen from fig1 that the width of the first portion 26 , measured transversely to this same direction , is appreciably greater than that of the second portion 27 . the aforementioned conveyor means 29 could be of any given type , and will be capable of transferring a predetermined quantity of tobacco 9 between the outlet 30 of the first portion 26 and the inlet 31 of the second portion 27 of the riser 24 . in particular , the conveyor means 29 will consist in any suitable conveying device capable of motion along a path that describes an endless loop . in the example illustrated , such means take the form of a toothed roller 32 rotatable clockwise , as viewed in fig1 about an axis 33 parallel to the axis 13 of the carding roller 12 , also to the direction of movement of the aspirating belt 25 , and connected to a source 34 of negatively pressurized fluid in such a way that suction can be generated through the outer surface of the roller 32 . instead of a roller 32 , alternatively , use could be made of a belt looped around a plurality of pulleys with axes parallel to the axis 13 of the carding roller 12 and to the direction of movement of the belt 25 . in the case of the roller 32 , the looped path appears as a circular circumference and includes a first sector 35 , on which a layer 36 of tobacco 9 is formed , and a second sector 37 from which the particles 38 making up the layer 36 of tobacco 9 are released . more exactly , the first sector 35 coincides with the part of the roller 32 extending upward from and along the outlet 30 of the first portion 26 of the riser 24 , whilst the second sector 37 coincides with the part of the roller 32 extending along the inlet 31 of the second portion 27 of the riser 24 . the path described by the toothed roller 32 also presents a third sector 39 interposed between the first and second sectors 35 and 37 , occupied by metering and leveling means 40 which take the form of an equalizing roller 41 offered tangentially to the toothed roller 32 . the roller 41 in question is rotatable counterclockwise , as viewed in fig1 about an axis 42 extending parallel to the axis of the toothed roller 32 , and at a speed marginally different to that of the latter roller 32 . in this way , the equalizing roller 41 is able to ensure a uniform thickness of the aforementioned layer 36 of tobacco by redistributing particles from areas of greater density to areas of lesser density that may have formed in the layer . as discernible in fig1 the aforementioned lower first portion 26 of the riser 24 terminates at the bottom end in a downwardly inclined wall 43 of which the higher part is directed toward the conveyor means 23 bringing the tobacco 9 from the toothed take - up unit 20 . the inclined wall 43 presents a plurality of holes 44 through which to direct a pressurized fluid from a relative source denoted 45 , of which the purpose will be described in due course . the conveyor means 23 take the form of a first vibrating tray 46 such as will slow the rate at which the tobacco advances toward the inlet of the first portion 26 of the riser 24 . also associated with the toothed roller 32 at a point near the inlet of the upper second portion 27 of the riser 24 , coinciding substantially with the second or release sector 37 of the looped path , are means denoted 47 by which to shut off the suction generated by the source 34 of negative pressure , and / or means denoted 48 by which to generate a flow of positively pressurized fluid . such means 48 might consist , by way of example , in a nozzle 49 connected to a source 50 of pressure and angled convergently with the direction of movement of the aspirating belt 25 . the aspirating action of the belt 25 combines with the dislodging flow blown by the nozzle 49 , which includes a component oriented along the feed direction of the belt 25 , to bring about an efficient transfer of the particles 38 of tobacco 9 from the surface of the roller 32 to the belt 25 . thus , the particles 38 cling to the aspirating belt 25 and form progressively into a continuous stream ( not illustrated ), which on emerging from the second portion 27 of the riser 24 will advance on the belt 25 toward successive stations ( not illustrated ) where it is trimmed , shaped and formed ultimately into a continuous cigarette rod . it will be seen that , with the width of the first portion 26 significantly greater than the width of the second portion 27 , which is substantially equal to that of the aspirating belt 25 , and the width of the sector 35 on which the layer 36 of tobacco 9 is formed likewise much greater than the width of the aspirating belt 25 , it becomes possible with only a relatively modest speed of rotation of the toothed roller 32 about its axis 33 and a relatively modest velocity of the particles 38 of tobacco 9 within the riser 24 , for the belt 25 to be supplied with the correct quantity of tobacco 9 even when running at relatively high speed , and in such a manner as to guarantee a substantially uniform stratification of the tobacco 9 on the aspirating surface , both along the direction of movement of the belt 25 and in the vertical dimension , normal to the belt 25 . also , and to advantage , the process of separating the stems and larger scraps of tobacco 9 from the smaller particles occurs internally of a spacious enclosure afforded by the lower first portion 26 , with the tobacco particles substantially detached one from another and progressing at a comparatively gentle rate of motion . the succession of selection jets delivered through the holes 44 also helps to increase the efficiency of the process whereby the stems and heavier scraps of tobacco are separated out . the stems and heavier scraps 54 drop into a collection trough 55 . [ 0039 ] fig2 and 4 illustrate a second embodiment of the infeed portion 1 forming part of a cigarette maker according to the invention , and in particular a machine with two processing lines , that is to say equipped with two aspirating belts 25 on which two identical streams of tobacco are formed . as regards the structure and operation of the risers 24 and the toothed rollers 32 , it will be seen that there is no difference between this and the single line embodiment of fig1 . in particular , as illustrated in fig4 and 5 , the infeed portion 1 of the machine comprises two risers 24 conveying two respective flows of tobacco particles 38 , and two aspirating belts 25 located each above the top outlet end 28 of the relative second portion 27 of a corresponding riser 24 , on which the two flows of particles 38 are formed into respective streams of tobacco 9 . more exactly , the risers 24 and the respective toothed rollers 32 are disposed symmetrically on either side of a vertical plane 51 lying between the two aspirating belts 25 , as discernible in fig4 and 5 , and positioned transversely to the axes of rotation of the carding roller 12 and of the take - up roller 21 , as illustrated in fig5 . in the solution of fig2 to 5 , more exactly , the toothed conveying rollers 32 are centered on respective axes 33 rotated through an angle of 90 ° ( ninety degrees ) relative to the viewing plane of the drawings , as compared to the position of the single roller 32 illustrated in fig1 where the axis 33 of rotation extends parallel to the axis of the carding roller 12 . in the example of fig5 the tobacco 9 is carried from the take - up roller 21 toward the two risers 24 by conveyor means 23 comprising a common first portion 52 and a pair of mutually independent second portions 53 . the two independent portions 53 extend divergently from the common portion 52 and on either side of the vertical plane of symmetry , in such a way that the particles 38 of tobacco 9 are carried toward respective inclined walls 43 presented by the two lower first portions 26 of the corresponding risers 24 . in like manner to the example of fig1 each of the two inclined walls 43 in this embodiment will present a plurality of holes 44 from which to generate a succession of air jets designed to aid the efficient separation of any stems and heavier scraps 54 of tobacco from the lighter particles . here again , the stems and scraps 54 drop into a collection trough 55 . in particular , both the common first portion 52 and the independent second portions 53 consist in respective vibrating trays 56 and 57 . in the example of fig2 the particles 38 of tobacco 9 leaving the take - up roller 21 drop onto a conveyor 58 moving from right to left as viewed in fig2 and angled upward in such a manner that the forwardmost edge will be positioned over the vibrating tray 56 constituting the common first portion 52 . thus , the particles 38 of shredded tobacco 9 are advanced at a suitably measured rate of feed toward the two bottom walls 43 presented by the two first portions 26 of the risers 24 . here , the stems and scraps 54 are separated and the lighter particles are directed upward through the first portions 26 in a continuous flow , entrained in a current of air generated by pneumatic means of familiar embodiment ( not illustrated ). on reaching the first sector 35 of each toothed roller 32 set in rotation about the relative axis 33 , the flow of tobacco particles 38 will thicken progressively and at low speed on the surface of the roller 32 passing momentarily over the outlet 30 of the first portion 26 , forming into a layer 36 . each layer 36 of tobacco is distributed and spread by the relative equalizing roller 41 and advances gradually toward the second sector 37 of the roller 32 . at this point , the suction shut - off means 47 and / or the nozzles 49 are activated , so that the layer 36 of tobacco 9 is caused to detach from the surface of the roller 32 and gather into a new flow of particles 38 . exposed to the combined action of the aspirating belts 25 and of the jets delivered by the relative nozzles 49 , the released particles will cling progressively to the belts 25 and form into a continuous stream of tobacco on each one . finally , it will be seen in the illustration of fig3 that the particles 38 of tobacco 9 are released by the rollers 21 and 22 directly onto the common vibrating tray 56 .

in a cigarette maker , shredded tobacco is directed by a conveyor into a riser and ascends as a flow of distinct particles toward an aspirating belt , placed at the top outlet end of the riser , by which the particles are attracted and gathered progressively to form a stream of tobacco filler . the riser is made up of a lower first portion in receipt of the tobacco from the conveyor , and an upper second portion enclosed by the aspirating belt ; the first portion is embodied separately from the second portion , and the two portions are inter - connected by the revolving surface of a toothed suction roller designed to transfer a uniform layer of tobacco from the first portion to the second .

the present invention provides a monitoring system designed to monitor and record patient parameters in real time . in particular , the system can measure pressure values , in addition to conventionally monitored parameters , over an extended period of time , for example , for days or weeks . the pressure values are gathered from discrete known positions for providing a continuous mapping of a pressure distribution of a bed - ridden patient . rewind and playback functions allow users to rapidly review patient information to diagnose trends and ensure their patients receive the most informed care without the enormous investments of staff time and effort that would be required to compile the information any other way . the patient parameters can include pressure , weight , activity , and position as well as other parameters normally monitored , such as blood pressure and heart rate . the patient monitoring system combines advances in digital and sensor technology with principles of ergonomics and ease of use . the system combines the basic physical functions of patient skin pressure monitoring , including duration and location of unacceptable pressures , of weighing ( which while critical to patient care is neither simple nor easy to achieve in a hospital or clinical setting ) with monitoring of activity level and position . fig1 is a block diagram illustrating an operating environment for a patient monitoring system in accordance with an embodiment of the invention . a sensing system 100 is operably connected with an interface 110 . data is transmitted through the interface 110 to onsite monitoring equipment 120 . data is optionally , or additionally , transmitted from the interface 110 over any suitable network 130 to a remote device . the remote device can include a terminal 140 and / or a handheld device 150 . in the embodiment of fig1 , the onsite monitoring equipment 120 , the remote device ( terminal 140 and the handheld device 150 ) preferably include or are operably connected with monitoring engines 122 , 142 , 152 . further , it should be understood , that the data collected through the sensing system 100 can be transmitted to fewer devices over the network 130 or to a larger number of devices over the network 130 . for example , each staff member attending a patient may have a handheld device 150 that receives data from one or more sensing systems 100 . in operation , the sensing system 100 is placed beneath a patient preferably under the bed linens and does not come in contact with the patient . as will be further described below , the sensing system 100 preferably includes a disposable , waterproof cover for protection . embodiments of the sensing system will be further described below in connection with fig3 a and 3b . other monitoring system components shown in fig1 , such as the remote terminal 130 , the handheld device 150 , and the on site monitoring equipment 120 may include computer hardware and software , to be further described below . the computer hardware and software facilitate display of real - time data and recording . the display can occur on a central nursing station , on a hand - held computer or through another patient monitoring system . data can be transmitted over the internet from a patient &# 39 ; s home to caregivers throughout the world as well . the system is capable of measuring these parameters continuously so multiple patients can be monitored while in their beds , securely and confidentially , from a central nursing station or other location such as a patient &# 39 ; s home , or a remote caregiver location . the system also interfaces to industry standard patient monitoring systems , giving these systems a whole new range of insights into the patients being monitored . the sensor interface 110 may include a snap - on module that rapidly attaches to the sensing system . the interface 110 may include electronics that scan , detect , digitize and wirelessly broadcast the readings gathered from each sensor cell location . in embodiments of the invention , the sensor cells are scanned at a rate of fifteen times per second or more . in one embodiment , the sensor interface 110 connects to a standard usb port . in other embodiments of the invention , the sensor interface is configured to broadcast data wirelessly through any available wireless network . the sensor interface 110 can be powered through the usb port , through a power adapter or long - lasting rechargeable batteries . in embodiments of the invention , the interface processor uses pressure values acquired from the sensor to compute body pressure at various parts of the human subject in real - time . other embodiments of the invention include more than one sensor interface 110 , or a multi - functional sensor interface 110 . for instance , in one embodiment , a sensor interface is implemented for communication with a handheld system that will allow caregivers to go from bed to bed and take readings with maximum efficiency . in another embodiment , a sensor interface plugs into existing bedside patient monitoring systems in order to enhance the power and functions of these systems at a minimum cost . in other embodiments , a sensor interface sends readings wirelessly to central nursing stations so that multiple patients can be monitored simultaneously without requiring visits to the bedside . the electronics in these sensor interfaces may be contained in a small module directly connected to the sensor . the module can be removed from the sensor and reused when replacement of the sensor becomes necessary . fig2 is a block diagram illustrating an operating environment for a patient monitoring system in accordance with another embodiment of the invention . in the embodiment illustrated in fig2 , a remote monitoring system 200 may include a monitoring engine 202 and may be connected over a network 230 with multiple sensing systems 210 , 212 , 214 , through interfaces 220 , 222 , and 224 respectively . the components shown in fig2 include analogous features to those shown in fig1 and 2 above . the components shown in fig1 , 2 , and 4 may be or may include a computer or multiple computers . the components may be described in the general context of computer - executable instructions , such as program modules , being executed by a computer . generally , program modules include routines , programs , objects , components , data structures , etc ., that perform particular tasks or implement particular abstract data types . those skilled in the art will appreciate that the invention may be practiced with various computer system configurations , including hand - held wireless devices such as mobile phones or pdas , multiprocessor systems , microprocessor - based or programmable consumer electronics , minicomputers , mainframe computers , and the like . the invention may also be practiced in distributed computing environments where tasks are performed by remote processing devices that are linked through a communications network . in a distributed computing environment , program modules may be located in both local and remote computer storage media including memory storage devices . the computer system may include a general purpose computing device in the form of a computer including a processing unit , a system memory , and a system bus that couples various system components including the system memory to the processing unit . computers typically include a variety of computer readable media that can form part of the system memory and be read by the processing unit . by way of example , and not limitation , computer readable media may comprise computer storage media and communication media . the system memory may include computer storage media in the form of volatile and / or nonvolatile memory such as read only memory ( rom ) and random access memory ( ram ). a basic input / output system ( bios ), containing the basic routines that help to transfer information between elements , such as during start - up , is typically stored in rom . ram typically contains data and / or program modules that are immediately accessible to and / or presently being operated on by processing unit . the data or program modules may include an operating system , application programs , other program modules , and program data . the operating system may be or include a variety of operating systems such as microsoft windows ® operating system , the unix operating system , the linux operating system , the xenix operating system , the ibm aix ™ operating system , the hewlett packard ux ™ operating system , the novell netware ™ operating system , the sun microsystems solaris ™ operating system , the os / 2 ™ operating system , the beos ™ operating system , the macintosh ™) operating system , the apache ™ operating system , an openstep ™ operating system or another operating system of platform . at a minimum , the memory includes at least one set of instructions that is either permanently or temporarily stored . the processor executes the instructions that are stored in order to process data . the set of instructions may include various instructions that perform a particular task or tasks , such as those shown in the appended flowcharts . such a set of instructions for performing a particular task may be characterized as a program , software program , software , engine , module , component , mechanism , or tool . the patient monitoring system may include a plurality of software processing modules stored in a memory as described above and executed on a processor in the manner described herein . the program modules may be in the form of any suitable programming language , which is converted to machine language or object code to allow the processor or processors to read the instructions . that is , written lines of programming code or source code , in a particular programming language , may be converted to machine language using a compiler , assembler , or interpreter . the machine language may be binary coded machine instructions specific to a particular computer . any suitable programming language may be used in accordance with the various embodiments of the invention . illustratively , the programming language used may include assembly language , ada , apl , basic , c , c ++, cobol , dbase , forth , fortran , java , modula - 2 , pascal , prolog , rexx , and / or javascript for example . further , it is not necessary that a single type of instruction or programming language be utilized in conjunction with the operation of the system and method of the invention . rather , any number of different programming languages may be utilized as is necessary or desirable . also , the instructions and / or data used in the practice of the invention may utilize any compression or encryption technique or algorithm , as may be desired . an encryption module might be used to encrypt data . further , files or other data may be decrypted using a suitable decryption module . the computing environment may also include other removable / nonremovable , volatile / nonvolatile computer storage media . for example , a hard disk drive may read or write to nonremovable , nonvolatile magnetic media . a magnetic disk drive may read from or writes to a removable , nonvolatile magnetic disk , and an optical disk drive may read from or write to a removable , nonvolatile optical disk such as a cd rom or other optical media . other removable / nonremovable , volatile / nonvolatile computer storage media that can be used in the exemplary operating environment include , but are not limited to , magnetic tape cassettes , flash memory cards , digital versatile disks , digital video tape , solid state ram , solid state rom , and the like . the storage media are typically connected to the system bus through a removable or non - removable memory interface . the processing unit that executes commands and instructions may be a general purpose computer , but may utilize any of a wide variety of other technologies including a special purpose computer , a microcomputer , mini - computer , mainframe computer , programmed micro - processor , micro - controller , peripheral integrated circuit element , a csic ( customer specific integrated circuit ), asic ( application specific integrated circuit ), a logic circuit , a digital signal processor , a programmable logic device such as an fpga ( field programmable gate array ), pld ( programmable logic device ), pla ( programmable logic array ), rfid processor , smart chip , or any other device or arrangement of devices that is capable of implementing the steps of the processes of the invention . it should be appreciated that the processors and / or memories of the computer system need not be physically in the same location . each of the processors and each of the memories used by the computer system may be in geographically distinct locations and be connected so as to communicate with each other in any suitable manner . additionally , it is appreciated that each of the processor and / or memory may be composed of different physical pieces of equipment . a user may enter commands and information into the computer through a user interface that includes input devices such as a keyboard and pointing device , commonly referred to as a mouse , trackball or touch pad . other input devices may include a microphone , joystick , game pad , satellite dish , scanner , voice recognition device , keyboard , touch screen , toggle switch , pushbutton , or the like . these and other input devices are often connected to the processing unit through a user input interface that is coupled to the system bus , but may be connected by other interface and bus structures , such as a parallel port , game port or a universal serial bus ( usb ). one or more monitors or display devices may also be connected to the system bus via an interface . in addition to display devices , computers may also include other peripheral output devices , which may be connected through an output peripheral interface . the computers implementing the invention may operate in a networked environment using logical connections to one or more remote computers , the remote computers typically including many or all of the elements described above . various networks may be implemented in accordance with embodiments of the invention , including a wired or wireless local area network ( lan ) and a wide area network ( wan ), wireless personal area network ( pan ) and other types of networks . when used in a lan networking environment , computers may be connected to the lan through a network interface or adapter . when used in a wan networking environment , computers typically include a modem or other communication mechanism . modems may be internal or external , and may be connected to the system bus via the user - input interface , or other appropriate mechanism . computers may be connected over the internet , an intranet , extranet , ethernet , or any other system that provides communications . some suitable communications protocols may include tcp / ip , udp , or osi for example . for wireless communications , communications protocols may include bluetooth , zigbee , irda or other suitable protocol . furthermore , components of the system may communicate through a combination of wired or wireless paths . although many other internal components of the computer are not shown , those of ordinary skill in the art will appreciate that such components and the interconnections are well known . accordingly , additional details concerning the internal construction of the computer need not be disclosed in connection with the present invention . fig3 a is a top plan view illustrating a sensing system 300 in accordance with an embodiment of the invention . the sensing system 300 includes multiple electrodes . in one embodiment , the system 300 includes sets of preferably perpendicularly disposed intersecting electrodes . as illustrated in the embodiment of fig3 a , a set of horizontally disposed electrodes 310 intersects with a set of vertically disposed electrodes 320 , thus creating multiple intersections 330 . this sensing system configuration is merely exemplary , and any suitable sensing configuration , such as those disclosed in u . s . pat . nos . 5 , 033 , 291 , 4 , 856 , 993 , and 4 , 734 , 034 may be implemented . fig3 b is a sectional view illustrating a sensing system in accordance with an embodiment of the invention . outermost layers 301 a and 301 b designate a backing sheet material . the backing sheet material 301 a and 301 b is removable and is preferably positioned adjacent a disposable covering 340 for the sensing system . conducting layers 302 a and 302 b are preferably applied to each of the backing sheets . dielectric layers 303 a and 303 b are disposed adjacent the conducting layers 303 a and 303 b . conductive stripes 304 a and 304 b are disposed adjacent the dielectric layers 303 a and 303 b . stripes of pressure sensitive material 305 a and 305 b are applied adjacent conductive stripes 304 a and 304 b . in one embodiment , the sensing system 300 includes a thin , flexible sensor , which extends the length and width of a standard hospital mattress ( typically the size of a twin bed ). a suitable sensor thickness is employed , as easily determined by one skilled in the art . in one preferred embodiment , the sensor &# 39 ; s thickness is approximately ⅛ inch . this thin and flexible sensing system can cover the surface of a hospital bed and can be placed under the bed - sheets so as not to come into contact with the patient . in alternative embodiments , if desired , the sensor comes into contact with the patient . as illustrated above , the sensor contains sensing elements arranged in rows and columns . their size and spacing are preferably optimized for the measuring of weight , position , pressure and activity . in embodiments of the invention , approximately three hundred sensor cells are distributed over the surface area of the sensing system . these sensors , as large as a twin bed , ⅛ of an inch thick or less and containing about one sensor cell per square inch , combined with the monitoring components described below , are able to continuously monitor patients in their beds for long periods of time . preferably , each sensor cell scans at a rate of about fifteen times per second or more . alternatively , each sensor cell scans at a rate of about twenty five times per second or more . other scanning rates are also possible . preferably , the sensor can be used for multiple patient stays and can be in continuous use for up to two years or more . while long - lasting , the sensors are affordable and easily replaced . in embodiments of the invention implementing a cover , the cover is a waterproof cover that is preferably a disposable plastic sensor cover . other materials may alternatively be implemented to construct the sensor cover . the cover may be implemented to keep the sensor clean , to protect the sensor , and ensure that cross - contamination does not occur . sensor covers are easily placed in the hospital room without tools or the need for training . the disposable sensor covers also eliminate the need for sensor replacement solely due to contamination . in embodiments of the invention , the disposable cover is replaced with each new patient or even during a patient &# 39 ; s stay if required . in one embodiment , the sensor is used for multiple patient stays . it may be in continuous long term use , for example for up to two years . thus , in a preferred embodiment , the sensing system comprises a bed - size sheet that does not come into direct contact with the patient . the system is non - intrusive , requires no adjustment by medical professionals , and can operate for the entirety of a patient &# 39 ; s stay without intervention . fig4 is a block diagram illustrating a monitoring engine 400 in accordance with an embodiment of the invention . the monitoring engine 400 is implemented by a computer processor and may be stored in a computer memory . the monitoring engine 400 is implemented on any and all of the remote terminal , handheld devices and on - site monitoring equipment shown in fig1 and on the remote terminal shown in fig2 . the monitoring engine 400 includes data collection components 440 for receiving data from the sensing system and interface described above . the collected data is processed by parameter calculation components 410 . the parameter calculation components 410 include a pressure calculation component 412 , a weight calculation component 414 , a position calculation component 416 , and an activity calculation component 418 . these calculation or determination components utilize the collected sensor data and transform the data to determine the desired parameters in a manner known to those skilled in the art . for instance , to determine activity , the activity calculation component 418 determines changes in pressure on various sensor cells over time . the position calculation component 416 relates pressure values over various sensor cells . the weight calculation component 414 determines overall pressure measurements as well as increases and decreases in overall pressure over time . in other embodiments of the invention , in addition to patient parameters such as pressure , weight , activity , and position , other patient parameters , such as respiration , temperature , and heart rate may also be monitored . pressure measurements provided by the sensors are particularly useful for prevention of bedsores . a bedsore relates to breakdown in skin due to prolonged application of pressure . based on sensor data , the monitoring engine 400 provides a location of forming bedsores for a bed - bound patient in real time . as will be further described below , pressure values beyond a predetermined threshold may trigger an alarm or other indicator that provides an indication of the forming bedsore . furthermore , based on the data provided to the monitoring engine from the sensing system , the patient monitoring system provides a location of the forming bedsore . the impact of the system for preventive care is therefore considerable in embodiments of the invention , the monitoring engine further includes comparison and analysis components 430 . the comparison and analysis components 430 compare measured or calculated values to stored threshold values or profiles . furthermore , the comparison and analysis components 430 enable creation and comparison of individual patient files . the comparison and analysis components 430 help to create trend graphs . optimally , the trend graphs reveal information such as body weight of various body parts over time . suitable data output formats may be used , including but not limited to , the output of data in excel or other spreadsheet format to allow for off - line analysis . recording and playback components 450 enable recordings to be made and played back to hospital or care - giving personnel . rewind and playback functions allow users to rapidly review patient information to diagnose trends and ensure their patients receive the most informed care without the enormous investments of staff time and effort that would be required to compile the information any other way . user interface components 420 facilitate interpretation of monitored data and preferably include alarm / alert components 422 , graphical components 424 , and data output components 426 . in embodiments of the invention , the user interface components 420 includes pc - based software that allows users to display sensor readings in color and 3d graphical displays in real - time . the user interface components 420 create easy - to - use trend graphs ( of weight for example ) and facilitate the output of data in excel or other spreadsheet format to facilitate off - line analysis . the alarm / alert components 422 are triggered if unacceptable conditions occur . such conditions may include a patient leaving the patient bed , pressures of problematic degree and duration , hyperactivity , etc . for instance , when connected to a wan , one nursing station monitors dozens of sensing systems and display the patients &# 39 ; conditions with intuitive green / yellow / red indicators . for example , these indicators may be used for problem weight trends , excessive pressure , excessive movement , and out - of - bed alarms . in embodiments of the invention , audible and voice - synthesized alarms are also provided . the monitoring engine 400 enables interfacing to standard patient monitoring systems , eliminating the need for a dedicated computer . the monitoring system allows direct connection of the sensor interface to various standard patient monitoring systems , thus reducing the amount of hardware necessary to use the monitoring system for healthcare centers that already own a patient vital signs monitoring system . when a dedicated computer is implemented , such as for a handheld device or remote terminal , embodiments of the invention implement a standard wintel pc , desktop , laptop , pocket pc , or other type of computing device as described above . preferably the components are linked to a color display . in a preferred embodiment of the invention , the monitoring engine 400 supports hipaa - compliant network and internet connections , allowing remote network and internet - based monitoring of patient real - time data , alerts and alarms and pre - recorded results . using this feature , a single computer can monitor multiple , remote sensing systems with a minimum of hardware or staff attention . the monitoring system has been designed to monitor and record patient information over extended periods of time , such as for days or weeks if necessary . in this way , physicians and caregivers receive an unparalleled perspective on their patients &# 39 ; health . fig5 is a flow chart illustrating a method for patient monitoring in accordance with an embodiment of the invention . the method begins at step 500 and a sensing system is put in proximity to the patient 510 . the monitoring engine collects patient data through a sensing system in step 520 . typically this data will be pressure data recorded at different locations and times . the monitoring system then determines parameters 530 . the parameters may include for example , pressure , weight , activity , and position . other parameters may also be monitored . the system may contain stored threshold levels or stored profiles for comparison for these parameters and in step 540 , the monitoring engine may determine if the determined parameters are beyond a predetermined threshold level . if the determined parameters are not beyond the threshold level , the monitoring engine continues with monitoring in step 520 . if the parameters are beyond the threshold level , the monitoring engine displays or sounds an alarm condition in step 550 , and again continues monitoring . in the case of position parameters , instead of a threshold level , the system may store a number of predetermined acceptable and unacceptable positions and compare the determined positions to the stored positions . in the case of weight parameters , the system may detect weight gain or loss and may utilize the most recent weight determination to identify an appropriate dose of medication . the simplicity of the monitoring system makes it convenient for patients to operate and connect to their internet - connect pc &# 39 ; s without professional assistance . this allows doctors and nurses to monitor risk of pressure sores , patient weight , activity levels , restlessness when awake or asleep , frequency of movement and presence in bed anytime and anywhere . in accordance with the aspects of the present invention , the monitoring system is suitable for use by patients with varying conditions . treatment of certain prevalent patient conditions particularly benefits from the features of the monitoring system . these conditions are summarized in the table below . pressure sores , for example , represent 1 million cases per year alone . conditions such as cancer can expose the patient to a high pressure ulcer risk . conditions that are relevant to the present monitoring system include : i ) skin pressure is important or risk of bedsores is high ; and ii ) requires bed - rest or confinement to a bed for significant periods of time . these two conditions do not permit patients to get out of bed to be weighed and expose the patient to complications of restricted activity and bed confinement . other conditions relevant to the present monitoring system include situations in which : iii ) monitoring patient weight is critical ; iv ) monitoring patient in - bed activity level is critical ; v ) monitoring patients &# 39 ; positions in bed is important ; vi ) “ long - term ” ( hours to days ) recording of bed activity or pressures is required ; and vii ) high treatment or consequence cost ( such as bedsores ). one outcome of healthcare &# 39 ; s inability to continuously monitor the physical condition of patients , for example , is the incidence of decubitus ulcers ( bed or pressure sores ). the problem impacts approximately one million patients a year and costs healthcare billions of dollars per year and the disclosed monitoring system can present a solution . in addition to the capability to provide real - time monitoring and recording of patient skin pressure , weight , position , and activity level while in bed , the system offers valuable economic benefits by increasing the number of patients that can receive outstanding and improved care from existing staff . many hospitals and extended care facilities are confronted with the problem of having too few staff members to monitor patients adequately . as a result , many patients each year fall from bed , are injured in bed - related accidents , are misdiagnosed , improperly medicated , suffer pressure sores or otherwise suffer from inadequate monitoring . in accordance with aspects of the present invention , the present monitoring system connects to an existing patient monitoring system . the present software and system modules are available to allow direct connection of the sensor interface to various standard patient monitoring systems . this conveniently reduces the amount of hardware necessary to use the present monitoring system for healthcare centers that already own a patient vital signs monitoring system . in addition , it integrates the sensor - related patient metrics to other monitoring data . the monitoring system disclosed herein is capable of continuously monitoring patients and alerting caregivers when threatening conditions exist . the system also makes long - term recordings for later review . monitoring and recording these parameters can be critical factors in effective patient care . while particular embodiments of the invention have been illustrated and described in detail herein , it should be understood that various changes and modifications might be made to the invention without departing from the scope and intent of the invention . it is also understood that certain features and sub - combinations are of utility and may be employed without reference to other features and sub - combinations . this is contemplated and within the scope of the appended claims .

the present invention relates to a patient monitoring system for automatically monitoring patient parameters over time while the patient occupies a bed . the patient monitoring system may include a sensing system positioned underneath a patient and separated from the patient by at least one layer of material , the sensing system comprising a plurality of sensor cells , the sensor cells automatically collecting sensor data related to the patient parameters . the patient monitoring system may further include an interface for receiving the collected sensor data from the sensing system and a monitoring engine receiving the collected sensor data from the interface . calculation components may be provided for determining the patient parameters from the collected sensor data .

with reference now to the drawings , and in particular to fig1 through 8 thereof , new magnetic articles of clothing embodying the principles and concepts of the present invention and generally designated by the reference numeral 10 will be described . the present invention , as designated as numeral 10 , includes a pair of pants 12 having a pair of front and rear pockets 14 each situated therein . each of such pockets has an upper peripheral edge stitchedly mounted to a periphery of a slot 16 formed in a front and rear extent of the pants adjacent to a waist thereof . as shown in fig6 & amp ; 7 , the present invention further includes a work apron 18 removably attachable to a waist of the user . during use , the work apron depends downwardly in front of the pants of the user . the work apron is equipped with a plurality of pockets 20 formed therein with a top opening for allowing access thereto . at least one front pocket magnet plate 22 has a smooth inner and outer surface with a periphery formed therebetween . as shown in fig3 the periphery is formed of a linear top edge , a linear rear edge , and an arcuate front and bottom edge together defining a portion of a circle . in the preferred embodiment , the front magnetic plate is bent such that it defines a portion of a vertically oriented cylinder . note fig5 . the arcuate nature of the bottom edge and front edge prevent chaffing of the legs of the user . during use , the front pocket magnet plate is removably situated within one of the front pockets . at least one rear pocket magnet plate 24 has a smooth inner and outer surface with a periphery formed therebetween . the periphery is formed of a linear top edge , a pair of linear side edges , and an arcuate bottom edge defining a portion of a circle . the rear pocket magnet plate is removably situated within one of the rear pockets . similar to the front magnetic plate , the present plate is bent such that it defines a portion of a vertically oriented cylinder . it should be noted that depending on the weight of the tools which are carried by the pocket magnets , the same arc preferably constructed with a certain degree of flexibility for precluding discomfort to the user . finally , at least one apron magnet plate 26 has a smooth inner and outer surface with an elongated rectangular periphery formed therebetween . the apron magnet plate is removably situated within one of the pockets of the apron . as shown , the apron magnet plate preferably is situated adjacent to a bottom edge of the pocket . as an option , each of the magnets of the present invention may be lined with an elastomeric material for precluding discomfort to the user . in an alternate embodiment , the magnet plates each may be mounted within a pouch fixed to an inner surface of the pants between the pants and one of the corresponding pockets thereby constituting an integral portion of the article of clothing . in further alternate embodiments , the magnet plates may be stitchedly coupled within the corresponding pocket of the article of clothing . it should be noted that during use , the magnet plates also preclude the inadvertent removal of items situated within the pocket . as to a further discussion of the manner of usage and operation of the present invention , the same should be apparent from the above description . accordingly , no further discussion relating to the manner of usage and operation will be provided . with respect to the above description then , it is to be realized that the optimum dimensional relationships for the parts of the invention , to include variations in size , materials , shape , form , function and manner of operation , assembly and use , are deemed readily apparent and obvious to one skilled in the art , and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention . therefore , the foregoing is considered as illustrative only of the principles of the invention . further , since numerous modifications and changes will readily occur to those skilled in the art , it is not desired to limit the invention to the exact construction and operation shown and described , and accordingly , all suitable modifications and equivalents may be resorted to , falling within the scope of the invention .

a magnetic outfit system is provided including an article of clothing and a magnet situated within the article of clothing for allowing the selective securement of metallic construction and household items thereto .

fig1 a depicts an anterior / posterior radiograph of an arthritic hip joint and fig1 b depicts a lateral x - ray of an arthritic hip joint . the pelvic bone ( 1 ) represents the superior portion of the hip joint , the femur ( 10 ) represents the inferior portion of the hip joint , and the femoral head ( 20 ) rotates in the acetabulum ( 25 ). fig2 depicts an example of a femoral component ( 27 ) with a collar ( 28 ). the femoral component is also known as a femoral stem or femoral prosthesis . the collar desirably prevents the femoral prosthesis from subsiding down the femoral canal because the collar rests of the calcar osteotomy ( femoral neck cut ) and prevents further translation of the femoral prosthesis once the collar contacts the femoral osteotomy . fig3 a and 3 b depicts ap and lateral radiographs of a typical hip replacement . the acetabular component ( 30 ) has been implanted into the acetabulum . the femoral component or stem ( 50 ) has been implanted down the femoral canal to the desired level . the prosthetic femoral head ( 40 ) has been attached to the femoral component ( 50 ) and articulates with the acetabular component ( 30 ). the femoral stem has a collar ( 60 ), which rest against the femoral calcar bone ( 70 ). fig4 a depicts an ap view of a femoral guide ( 80 ) that references a substantial portion of the proximal femoral bone , such as either the anterior or posterior femoral neck . the guide could be patient specific or generic . as part of a pre - operative plan , the surgeon could use non - invasive imaging data or other information to determine his intended surgical approach to the hip joint , and this intended approach would determine whether the femoral guide would reference predominately the anterior femoral neck or posterior femoral neck . in both situations , the femoral guide could reference a significant portion of the superior and inferior femoral neck and femoral head ( 20 ) as well . the femoral guide ( 80 ) could contain a drill sleeve ( 110 ) that would accept a drill bit ( 130 ) that could form an anterior to posterior ( ap ) hole ( 120 ) in the femoral bone at the intersection of the vertical femoral cut guide ( 90 ) and the calcar femoral cut guide ( 100 ). this ap hole ( 120 ) could later be used to ensure the femoral broach and prosthesis were implanted in the proper location . after the surgeon drilled this ap hole ( 120 ), they could likely leave the drill bit in the bone and then use the vertical cut guide ( 90 ) and the calcar cut guide ( 100 ) in the femoral guide to make the appropriate osteotomy in the femoral bone . the drill bit could ensure that the saw blade did not extend beyond the intended osteotomy site , which could help prevent greater trochanter fractures from the saw blade extended beyond the intended osteotomy . alternatively , the surgeon could drill the ap hole and then remove this femoral guide ( 80 ) and insert a different femoral guide ( not shown ) that had a cylinder that fit inside this ap hole and a saw guide that rested on the surface of the femoral bone to guide a saw blade to make the calcar and vertical cuts . this alternative approach could include features ( not shown ) to create an improved fixation of the saw guide to the bone to prevent the saw guide from moving while the saw cut the bone . this alternative approach could also drill a second hole in the femoral neck or head for the main purpose of provided the saw guide with additional stability . the femoral head ( 20 ) could then be removed from the femur . the femoral guide could include one or more patient specific soft tissue protectors ( such as those disclosed in u . s . utility patent application no . 14 / 059 , 372 , filed on oct . 21 , 2013 , and u . s . provisional patent application no . 61 / 716 , 571 , filed on oct . 21 , 2012 , the disclosures of which are incorporated herein by reference in their entireties ) along the intended path of the calcar osteotomy and superior femoral neck to desirably prevent the saw blade from inadvertently extended beyond the bone and cutting the hip capsule . the saw blade could be allowed to contact the patient specific soft tissue protector once the saw blade left the femoral bone , instead of the soft tissue surrounding the hip joint . fig5 a depicts a view of a femoral guide ( 80 ) superimposed on the radiograph . the femoral guide ( 80 ) is shown referencing a large portion of the anterior femoral neck . the ap drill sleeve ( 110 ) is shown extending away from and attached to the femoral guide ( 80 ). the height of the drill sleeve ( 110 ) could be patient specific such that the length of the drill bit ( 130 ) minus the height of the drill sleeve ( 110 ) would equal the width of the femoral neck . the drill bit ( 130 ) would therefore drill through the femoral neck and desirably stop immediately after the drill bit went through the opposite cortex when the head of the drill bit contacted the drill sleeve . the drill bit could be any diameter , but in various embodiments would likely be around 3 - 5 mm in diameter . fig5 b depicts a view of a proximal femur after the ap hole ( 120 ) has been drilled and the femoral guide removed . the purposed vertical femoral osteotomy or cut ( 90 ) and the calcar femoral osteotomy or cut ( 100 ) are shown with the marked line , but the cuts have not been performed yet . fig6 a and 6 b depict the femoral bone ( 10 ) after the femoral neck osteotomy has been performed and the femoral head removed . the anterior to posterior ( ap ) hole ( 120 ) is shown at the intersection of the calcar osteotomy ( 100 ) and the vertical osteotomy ( 90 ) ( see fig5 b ). this ap hole could be located anywhere along the calcar osteotomy and does not necessarily have to be located at the intersection . in this embodiment , this ap hole ( 120 ) will be utilized , at least in part , to ensure that the surgeon inserts the broach and femoral prosthesis in the correct anteversion , varus / valgus angle , and depth . because the femoral head and neck have been removed , the medial and superior portions of the ap hole have been removed and the ap hole can accept an anterior to posterior ( ap ) bar ( 140 ) of the broach or prosthesis as they are inserted down the femoral canal . the femoral neck osteotomy surface ( 121 ), and the femoral periosteal surface ( 122 ) and the femoral endosteal surface ( 123 ) are depicted at the level of the femoral neck osteotomy . fig7 a depicts an exemplary femoral broach ( 130 ) inserted into the femur ( 10 ) to prepare or machine the bone to accept the femoral prosthesis . if desired , the femoral broach could include an ap bar ( 140 ) that extended a few millimeters in the anterior and posterior direction away from the broach much like a collar . this ap bar is shown in a more lateral position than a traditional collar , but could be located anywhere along the osteotomy . this ap bar would desirably be a similar diameter as the ap hole ( 120 ) and the drill bit ( 130 ). the broach and / or prosthesis would desirably be in the appropriate position when the anterior and posterior portions of the ap bar ( 140 ) aligned with the anterior and posterior portions of the ap hole ( 120 ). if the surgeon tried to change the femoral anteversion , then the ap bar would desirably no longer key into the ap hole ( 120 ). if the surgeon inserted the broach in a varus position , then the ap bar ( 140 ) could be medially to the ap hole ( 120 ); the surgeon could realize this mistake and remove more bone from the lateral proximal femur to get the broach out of a varus position and into the correct position . the ap bar ( 140 ) on the broach could be removable or elevated on the broach handle so that smaller broaches could be impacted further down the femoral canal to prepare for the next larger broach size . broaches smaller than the intended prosthetic size can typically extended down into the femoral canal a few millimeters below the osteotomy level . the ap bar ( 140 ) could be temporarily removed to allow these small broaches to fully prepare the femoral canal . the ap bar could also be removed so that the surgeon could knowingly change the anteversion of the femoral broach ( and calculate the degree of change ) if the intra - operative information suggested a change was needed . fig7 b depicts the broach without an ap bar . in this alternative embodiment , the surgeon could also simply rely on a visual marker ( 145 ) on the broach , without any type of ap bar , to inform the surgeon about whether the implanted broach position corresponded with the intended broach position . this visual marker shown in fig7 b can be a hollow cylinder ( 145 ) in the anterior to posterior direction . when the hollow cylinder lined up with the ap hole ( 120 ), the surgeon would know the broach was in the correct position regarding the anteversion , varus / valgus , and depth . this hollow cylinder could be limited to just the cross sectional area of the broach so that the hollow cylinder would not interfere with the broach extending below the osteotomy level . the broach could therefore be impacted to its desired level based on the contact between the broach and the medullary canal and endosteal surface . the visual marker ( 145 ) would desirably not prevent or interfere with the broach reaching its appropriate and / or desired position . if desired , the hollow cylinder could accept a drill bit so the surgeon could prepare this ap hole for the final prosthesis if there was a difference between the first ap hole preparation and the hollow cylinder of the broach . this preparation might be necessary if the surgeon implanted the broach further down the canal than the pre - operative plan predicted or if the surgeon deliberately or accidentally changed the anteversion or varus / valgus position of the broach relative to the plan . the femoral broach could include various additional support features , including the use of a collar feature having vertical sides that desirably contact the periosteal bone ( 122 ) to ensure that the broach was implanted in the femoral bone in the correct anteversion . the surgeon could also insert a patient specific cap on the femoral neck osteotomy surface ( 121 ) that referenced the ap holes ( 120 ). this patient specific cap could narrow the width of the proximal femoral canal and help guide the broach into the correct anteversion . the broach could also have vertical markings along the anterior and posterior surface of the broach so the surgeon could align these markings with the ap hole ( 120 ) as the broach was inserted into the femoral canal to ensure the implanted femoral anteversion matched the planned femoral anteversion . fig8 a and 8 b depicts an exemplary femoral prosthesis ( 150 ) implanted into the femur ( 10 ) with an additional collar feature ( 160 & amp ; 180 ) extending over the femoral neck osteotomy ( 121 ) and contacting the periosteal surface ( 122 ) of the exterior surface of the femoral neck . the collar feature could be patient specific , modular , or just come in multiple sizes . if the collar feature was patient specific , then the shape and size of the collar could be based off the pre - operative scan and manufactured as a continuous part of the femoral prosthesis to intimately fit the proximal femur . if the collar feature was modular , the surgeon would make a determination during the surgery as to the correct shape and size of the collar based on how the broach fit the bone . the surgeon could then attach a modular collar with the appropriate size to femoral prosthesis before or after it was implanted into the femoral canal . lastly , the device manufacture could offer the implant with multiple different size collars ( i . e . small , medium and large ) and allow the surgeon to select the most appropriate sized collar during the surgery . the collar feature could have a flat horizontal portion ( 160 ) that could contact the femoral neck osteotomy ( 121 ) and vertical portions ( 180 ) that could contact the endosteal ( 123 ) and / or periosteal ( 122 ) surfaces of the femoral calcar and neck . the collar feature could extend over the neck osteotomy ( 121 ) and down the exterior ( 122 ) and interior surfaces ( 123 ) of the anterior and posterior femoral neck . the flat horizontal portion ( 160 ) of the collar feature could intimately contact the neck osteotomy . the axial force from vertical loading of the hip joint could be transmitted across the horizontal portion of the collar to the femoral osteotomy surface ( 121 ). the horizontal portion ( 160 ) could be the same shape as the cross sectional thickness of the proximal bone at the osteotomy to prevent soft tissue impingement from an oversized collar . the vertical portion ( 180 ) of the collar feature could intimately contact the periosteal surface ( 122 ) of the anterior and posterior femoral neck and calcar . the torsion force between the femoral prosthesis and the femoral bone primarily comes from the moment arm of the femoral head being loaded away from the axis of the femoral prosthesis . in various embodiments , this torsion force could be transmitted through the vertical portions of the collar feature to the periosteal and endosteal surfaces of the femoral neck . when torsion stress is applied between the femoral prosthesis and the femoral bone , a traditional prosthesis will typically push on just one side ( anterior or posterior ) of the endosteal bone . the various embodiments disclosed herein , including the various features described herein , provide an improved prosthesis with collar features that can push on the endosteal surface on one side ( i . e . anterior ) and the periosteal surface of the other side ( i . e . posterior ). this improved torsion stability could prevent implant loosening , intra - operative fracture , and postoperative fracture . fig8 c depicts the ap bar ( 170 ) on the femoral prosthesis keying into the ap hole ( 120 ) in the femoral bone to ensure that the femoral prosthesis ( 150 ) was in the correct anteversion , varus / valgus orientation and depth . the ap bar could be modular such that the femoral prosthesis could have a hole or similar attachment device in the prosthesis . the surgeon could select a length for the anterior and posterior portion of the ap bar based on how far the femoral broach was from the anterior and posterior periosteal surfaces of the proximal femur . the surgeon could then screw the 2 bars into the femoral prosthesis . in various alternative embodiments , the femoral prosthesis could just have a single hole so the 2 bars could be placed through the femoral prosthesis and screw into each other . the cross section of the bar and the hole in the femoral prosthesis could be round to allow for rotation , or could be provided in non - round ( i . e ., oval , triangular , square or other configurations — with corresponding unique spacing arrangements ) to prevent and / or inhibit unwanted rotation . the femoral prosthesis could include one or more collar features , one or more collar features in combinations with the ap bar ( fig8 a and 8 b ), or just the ap bar ( fig8 c ). the collar feature could be continuous and connected with the ap bar or could comprise a separate tab that was not connected to the ap bar . if the collar feature did not attach to the ap bar , the ap bar ( 170 ) could have a vertical wall ( 175 ) on each of the anterior and posterior end of the bar that would extend in the inferior direction and contact the periosteal ( 122 ) surface of the anterior and posterior femoral neck . the vertical wall of the collar feature could alternatively start at the anterior bar and extend medially around the calcar and then continue around to the posterior bar as shown in fig8 b . both the vertical and horizontal portions of the collar feature could be continuous around the entire femoral neck osteotomy or just small tabs in certain areas to allow better visualization of the contact between the collar and the femoral bone . traditional non - collared femoral prosthesis load the endosteal surface of the proximal femoral bone and create hoop stresses in the proximal femur when the femoral prosthesis is driven into the bone during implanting the prosthesis or weight bearing . a femoral prosthesis with a generic “ collar ” design loads the endosteal surface ( 123 ) of the proximal femoral bone and the osteotomy surface ( 121 ). the femoral prosthesis described here , in combination with the vertical portion of the collar feature , desirably allows the prosthesis to load the periosteal surface of the proximal femur as well as the endosteal surface and the osteotomy surface . loading the periosteal surface can help counteract and / or negate the hoop stresses that are generated from loading the endosteal bone . this periosteal loading would desirably generate compressive forces in the proximal femur instead of tensile forces ( hoop stresses ). the material properties of bone are much stronger in compression than tension , so loading the periosteal surface could decrease femoral calcar fractures . fig8 a also depicts two suture holes ( 190 ) in the anterior and posterior portion of the collar . these suture holes could vary in number and be used to reattach the posterior or anterior hip capsule back to the femoral bone . these suture holes could also be used to reattach the greater trochanter if a trochanter fracture occurred during the surgery . fig9 a , 9 b , and 9 c depict ap and lateral views of another exemplary collar feature on an exemplary femoral prosthesis . the horizontal portion ( 160 ) and vertical portion ( 180 ) of the collar feature are shown . the ap bar ( 170 ) is shown . fig9 b depicts the exterior vertical collar ( 200 ) that can be positioned to contact the periosteal surface ( 122 ) of the proximal femur and the interior vertical collar ( 210 ) that desirably contacts the endosteal surface ( 123 ) of the proximal femur . the vertical wall in fig9 b is desirably parallel with the axis of the prosthesis . fig9 c depicts an exterior vertical collar ( 215 ) that is divergent to the axis of the prosthesis , which desirably allows for easier insertion of the prosthesis over the femoral neck osteotomy . this divergent wall could also load the periosteum of the proximal femur and neglect the hoop stresses that are typically generated from the normal prosthesis loading of the endosteal surface of the proximal femur . this arrangement also reduces and / or negates the need for a cerclage wire or other reinforcing arrangement on the proximal femur , as surgeons will occasionally place a cerclage wire around the proximal femur to counteract the hoop stresses on the bone associated with implanting the prosthesis in much the same way as this divergent wall could . it should be understood that the collar features could be formed in a wide variety of shapes and / or configurations , including shapes and / or features that match and / or substantially conform , to varying degrees , to the underlying anatomy that they contact . for example , the collar features could comprise a hemispherical dome , an oval - shaped dome , a triangular box , a square or virtually any other shape that accomplished some or all of the features of the present invention . in various embodiments , the bone - contacting surface ( s ) of the collar feature may be non - round and / or irregularly curved and / or otherwise shaped , so as to desirably reduce , prevent and / or inhibit rotation of the implant and / or preferentially load the periosteal bone to varying degrees ( instead of the endosteal side of the bone ). it should also be understood that , where the collar feature and prosthesis are modular and / or separately formed , the collar feature could include a circular , non - circular and / or irregularly shaped opening formed therein to accommodate the femoral prosthesis . fig1 a , 10 b , and 10 c depict cross - sectional views of a standard flat calcar reamer ( 220 ), of a reverse domed - shaped calcar reamer ( 250 ), and of a hemispherical or domed shaped calcar reamer ( 260 ). flat calcar reamers are well known in the art . the male portion ( 230 ) of the femoral broach ( 70 ) slides into the female portion ( 240 ) of the flat calcar reamer . the flat calcar reamer can rotate around the male portion and remove the necessary femoral bone to make a flat osteotomy surface ( 121 ) that maximizes contact between a flat collar and the femoral bone . fig1 b depicts a cross - sectional view of a reverse domed - shaped reamer that could rotate around the male portion of the broach and desirably remove an amount of femoral bone to create a dome shaped osteotomy surface to maximize contact between a reverse dome shaped collar and the femoral bone . if desired , the curvature of the reamer ( i . e ., modifying the proximal femur ) could be slightly flatter than the curvature of the associated collar feature , which could facilitate the collar contacting the outside edge ( i . e ., periosteal edge ) of the bone and loading the bone from the “ outside - in .” fig1 c depicts a cross - sectional view of a hemisphere shaped reamer ( 260 ) that could rotate around the male portion of the broach and remove the necessary femoral bone to create a reverse dome ( i . e ., a hemispherical dome ) shaped osteotomy surface that maximizes contact between a hemispherical shaped collar and the femoral bone . the advantage of a dome shaped or reverse dome shaped osteotomy surface can be that axial compression of the implant and bone will desirably increase the contact between the collar and the bone . the torsion stability of the implant could also be improved by this arrangement . the anterior to posterior and medial to lateral stability of the implant could also be improved . the reverse dome shaped osteotomy in fig1 b with the dome shaped collar could also help minimize hoop stress from the femoral component loading the femoral canal . the dome shaped collar could help transform the tensile forces ( i . e ., hoop stresses ) into compressive forces , and thereby help prevent calcar fractures that can be seen with implanting a standard femoral prosthesis or loading the femoral prosthesis during weight bearing movement . the vertical portion of the patient specific collar could also help minimize hoop stresses in a manner similar to the cerclage wire does when it is wrapped around the proximal femoral bone , but without the need for such an additional adjunct to the surgery . if desired , the transitional spacing between the horizontal and vertical exterior surfaces of the collar could be rounded to prevent soft tissue impingement . the drawings and text above refer to the implantation of a femoral component into a femoral bone for descriptive purposes only . similar principles such as those described above could apply to other joints like the knee , ankle , feet , shoulder , elbow , back and wrist , with various modifications to account for anatomical and loading differences . for example , the sutures holes ( 190 ) in the vertical portions of the collar , shown in fig8 , could be applied to an implant for the shoulder joint to allow for a repair of the rotator cuff tendons ( supraspinatus , subscapularis , and / or anterior capsule ). the entire disclosure of each of the publications , patent documents , and other references referred to herein is incorporated herein by reference in its entirety for all purposes to the same extent as if each individual source were individually denoted as being incorporated by reference . the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof . the foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein . scope of the invention is thus intended to include all changes that come within the meaning and range of equivalency of the descriptions provided herein . many of the aspects and advantages of the present invention may be more clearly understood and appreciated by reference to the accompanying drawings . the accompanying drawings are incorporated herein and form a part of the specification , illustrating embodiments of the present invention and together with the description , disclose the principles of the invention . although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding , it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the disclosure herein .

disclosed are systems , methods , devices and surgical techniques for joint arthroplasty , including implant components that facilitate the position and implantation of a hip replacement using cutting guides and various femoral implant arrangements .

referring now to the drawing , wherein like reference numerals refer to like elements throughout , fig3 - 4 illustrate an exemplary stent delivery system 10 ′ of the present invention , having an exemplary docking pusher 16 ′ and docking catheter tip 20 ′. as shown in fig3 , stent delivery system 10 ′ comprises an outer sheath 12 , central lumen 22 , and central core 23 , similar to delivery systems known in the art . as used herein , the term “ system ” shall encompass both a completed assembly which is capable of deploying a stent or a sub - assembly which is capable of deploying a stent when combined with other components . docking pusher 16 ′ and catheter tip 20 ′, however , comprise docking sections 42 and 42 ′ respectively , each docking section having a pocket 40 and 40 ′, respectively . docking section 42 located at pusher distal end 28 is adapted to hold proximal end 30 of compressed stent 14 , whereas docking section 42 located at catheter tip proximal end 29 is adapted to hold distal end 31 of compressed stent 14 . docking section 42 or 42 ′ may be a discrete section connected to , respectively , pusher 16 ′ or catheter tip 20 ′, as shown in fig3 and 4 with respect to pusher 16 ′, or may be a hollowed section integral to the rest of the pusher or catheter tip , as shown in the figures with respect to catheter tip 20 ′. other docking section configurations or means for engaging the compressed stent end with the pusher or catheter tip may also be used , as described herein later . the term “ pusher ” is used herein throughout , although such device may also be referred to in the art as a “ stabilizer ”, because the method of deploying the stent may not actually comprise “ pushing ” the stent out of the sheath , but rather “ stabilizing ” the stent ( holding it in place and preventing it from moving ) while the outer sheath is retracted . thus , use of the term “ pusher ” herein refers to such a device adapted for any method of deploying known in the art , including as a stabilizer , and the term “ pusher ” is not intended as a limitation thereof . docking pusher 16 ′ and docking catheter tip 20 ′ overcome kinking in the body lumen because a certain amount of compressed stent 14 is actually docked or cradled inside pocket 40 or 40 ′, creating a smooth transition between the stent and the pusher or catheter tip . the pusher and stent and / or catheter tip and stent in such docked configurations thus move together at their respective interface points while navigating the tortuous anatomy of the body lumen , by minimizing any area of weakened rigidity to prevent kinks . in addition , as long as rim 44 of docking section 42 in pusher 16 ′ grips stent 14 , the stent may be “ recaptured ” or “ recovered ” even once it has been partially deployed . for instance , if a medical professional determines that a partially deployed stent 14 needs to be repositioned , pusher 16 ′ may be pulled back within sheath 12 or the sheath advanced to recover the partially deployed stent . then , the deployment process can start over . other embodiments having other means for releasably engaging the stent may offer similar recapture capabilities . also , because of the docked arrangement between stent 14 and pusher 16 ′, the stent may be rotated , pushed , or pulled both before and during deployment , unlike with conventional deployment systems where the pusher can only transmit force in a pushing direction . for example , where the stent architecture has a particular feature intended for alignment with a particular part of the body lumen , such as a particularly flexible portion of the stent to be aligned with a tortuous portion of the body lumen , the stent can be rotated , pushed , or pulled to effect this alignment . additionally , in the configuration shown in fig3 where docking section 42 pinches stent 14 against central core 23 , creating friction , there is less undesired movement of the stent inside the delivery system as compared to non - docked prior configurations . additionally , the use of a docking section in the catheter tip may facilitate placement of the distal end of the stent in a predetermined location . as shown in fig3 , stent 14 is held within pocket 40 of docking section 42 of pusher 16 ′ and pinched inwardly by end rim 44 . when compressed within sheath 12 , docking section 42 has a bottleneck shape created by inward protrusions 48 of end rim 44 that define a neck with a smaller diameter than the remainder of pocket 40 , as shown in fig3 . end rim 44 of docking section 42 thus has a normal radial bias outward that is compressed and confined within the walls of sheath 12 during introduction to the body . as shown in fig4 , once the target zone has been reached , outer sheath 12 is retracted . when sheath 12 is retracted beyond end rim 44 of docking section 42 , rim 44 springs open into an outwardly flared configuration and releases proximal end 30 of stent 14 . accordingly , docking section 42 may comprise any material , such as stainless steel , that provides flared end rim 44 with the requisite “ springiness ” to pinch inward when compressed and to spring open when the sheath is retracted . although illustrated with respect to the pusher docking section 42 in fig4 , this outwardly - flared configuration may also be applicable to catheter tip docking section 42 ′; however , as shown in fig3 , a non - outwardly - biased , cylindrical configuration is preferred , as described below . instead of having a bottleneck shape when compressed within sheath 12 and radially flared and biased outward when not housed within the sheath , end rim 44 ′ of docking section 42 ′ in catheter tip 20 ′ is cylindrical in shape and capable of holding stent 14 within pocket 40 ′ merely by frictional engagement . prior to retraction of sheath 12 to deploy stent 14 , central core 23 and tip 20 ′ attached thereto may , in some cases , need to be advanced distally so that the stent disengages from the pocket 40 ′. such a non - radially - biased pocket may also be provided on docking section 42 of pusher 16 ′. in such case , stent 14 may be partially deployed and anchored into the walls of a body lumen so that the stent has sufficient frictional resistance against the body lumen to enable pusher 16 ′ to be retracted to disengage the stent from within the non - flared pocket without dislocating the stent . the step of advancing catheter tip 20 ′ prior to retraction of sheath 12 may also be performed to facilitate stent delivery even where docking section 42 ′ includes a radially - biased end rim ( not shown ). such a radially - biased end rim on catheter tip 20 ′, however , may present difficulty in preparing delivery system 10 ′ for retraction from the body after deployment unless there is some mechanism to re - compress the end rim back inside sheath 12 . without such re - compression of the radially - biased end rim back inside the sheath , such as is possible with respect to pusher 16 ′ merely by retracting the pusher to pull end rim 44 back inside sheath 12 , the radially - biased end rim may protrude from the streamlined shape of the delivery system at the catheter end during retraction and provide a catching point that may damage the body lumen . thus , a non - radially - biased end rim 44 ′ is preferred for catheter tip 20 ′. docking section 42 may include a radiopaque marker 46 , to provide increased radiographic “ vision ” of the pusher end , and when combined with a similar marker ( not shown ) on the proximal end of stent 14 , to visualize relative movement of pusher and stent as stent 14 disengages from pusher 16 ′. similar markers 46 may also be provided for similar purposes on the catheter tip docking section 42 ′ and on the stent distal end ( not shown ). “ radiopaque marker ” as used herein encompasses any discrete area of different radiopacity as compared to a surrounding area . pusher docking sections , catheter tip docking sections , stent delivery systems , and methods incorporating such pushers and / or catheter tips may take a wide variety of forms other than that described specifically above . a particular stent delivery system may include only a pusher docking section , only a catheter tip docking section , or both . the essence of any such docking section is that it releasably engages an end of the stent over some axial length in a manner whereby that engagement is releasable upon stent deployment . the term “ releasably engaging ” denotes that the engagement between the docking section and the stent is not permanent , but rather is releasable in the sense that the stent is released from the docking section when the outer sheath is retracted or when the pusher or catheter tip is advanced or retracted away from the stent . the pusher docking section is either biased radially outward or defines a pocket in which the portion of the stent proximal end is nested . the length of the stent engaged by the docking section of this invention should be sufficiently long , taking into account the stent diameter and flexibility as well as the tortuosity of the lumen to be traversed during its deployment , to maintain a pushing engagement notwithstanding the tortuosity for which the stent is designed . such pushing engagement enables transmission of a pushing force applied thereto , such as from the pusher to the stent , or from the stent to the catheter tip . the length of the stent engaged by the docking section should be sufficiently short , however , and / or the angle of radial flare a ( as shown in fig4 ) sufficiently great , so as to facilitate reliable release of stent 14 when sheath 12 is retracted . the dimensions and mechanical features of individual docking section designs may be readily determinable by those skilled in the art . in particular , the docking section may comprise an axially - extending engagement surface which extends over a short axial length of the stent either on the interior or exterior thereof . such surface may define the interior of pocket 40 previously described and shown in fig3 and 4 , or an insert adapted to be inserted within the stent end to engage the stent end , as shown in fig6 . as shown in fig6 , docking section 142 ′ of catheter tip 120 is a reduced diameter section ( i . e ., an insert ) of catheter 120 that fits within distal end 31 of compressed stent 14 . docking section 142 of pusher 116 fits within proximal end 30 of compressed stent 14 , and is radially biased outward to firmly hold stent 14 against sheath 12 . such bias outward to radially urge the stent proximal end 29 against the inner surface of the deployment sheath 12 further facilitates pusher 116 and stent 14 moving as one without pulling away from one another . although docking section 142 ′ having merely a reduced diameter section is illustrated in fig6 with respect to catheter tip 120 whereas radially - biased - outward docking section 142 is illustrated with respect to pusher 116 , either configuration is applicable to both the catheter tip and the pusher . as described above , however , a non - biased configuration is generally preferred at the catheter tip for ease of delivery system retraction . in another exemplary embodiment , shown in fig7 a and 7b , docking section 242 of pusher 216 may comprise engagement means in the form of a set of fingers 244 . fingers 244 may define a pocket adapted for surrounding the stent , as shown in fig7 a and 7b . referring now to fig8 a and 8b , in yet another embodiment , docking section 342 of pusher 316 may comprise pocket 340 in the form of an annular pocket between inner wall 341 and outer wall 343 adapted for insertion of the stent proximal end ( not shown ). inner wall 341 may define a hollow or solid cylinder , or may be in the form of fingers that insert within the stent . outer wall 343 may be solid as shown in fig8 a and 8b , or may be in the form of outer fingers . as shown in fig8 c , another embodiment may comprise a plurality of inner fingers 441 and outer fingers 443 that define the inner wall and outer wall , respectively . another embodiment , not shown , may comprise only inner fingers 441 . such inner fingers , outer fingers , or combination thereof may be radially biased outward . although docking sections 242 , 342 , and 442 are described and shown in fig7 a - 8b with respect to pushers , similar docking section configurations may be provided for catheter tips . the invention also comprises a method for pre - loading a stent delivery system , as described below relative to fig3 and 4 . the method comprises loading at least compressed stent 14 and pusher 16 ′ within outer sheath 12 , including releasably engaging a portion of stent proximal end 30 with docking section 42 at pusher 16 ′ distal end 28 , stent distal end 31 with docking section 42 ′ at catheter tip 20 ′ proximal end 29 , or a combination thereof . the method may include disposing a portion of the corresponding stent end 30 or 31 within a pocket 40 in docking section 42 or 42 ′. the invention further comprises a method for deploying a stent in accordance with the flowchart depicted in fig5 and the drawings shown in fig3 and 4 . the method comprises in step 100 , introducing a pre - loaded stent delivery system 10 ′ to a body lumen . delivery system 10 ′ comprises a compressed stent 14 having a proximal end 30 and a distal end 31 , a pusher 16 ′ having a distal end 28 , a catheter tip 20 ′ having a proximal end 29 and attached to a central core 23 slideably disposed within pusher 16 ′. at least one of pusher 16 ′ or catheter tip 20 ′ have a docking section 42 or 42 ′ adapted to releasably engage the stent end over some length thereof , such as with pocket 40 and / or 40 ′ within which the stent end is disposed . outer sheath 12 overlies compressed stent 14 , pusher 16 ′, and each docking section 42 and / or 42 ′. next , in step 105 , the stent delivery system is navigated to a desired location for deploying stent 14 , and finally , in step 110 , outer sheath 12 is retracted to deploy the stent from the outer sheath and from docking 42 and / or 42 ′ into the desired location . where catheter tip 20 ′ has a docking section 42 ′, the method may further comprise advancing central core 23 and the catheter tip 20 ′ attached thereto prior to retracting sheath 12 , to further facilitate release of stent 14 from the docking section . where pocket 40 has an end rim 44 that is radially biased outward and adapted to be inwardly compressed to grip the stent end when loaded within outer sheath 12 , as shown in fig3 and 4 , the method may further comprise the end rim expanding outward during evacuation of the stent from the pocket . where , as is shown in fig6 , docking section 142 and / or 142 ′ comprise a reduced diameter section adapted for inserting within the end of stent 14 , the method may further comprise the stent expanding away from the reduced diameter section . while the present invention has been described with respect to specific embodiments thereof , it is not limited thereto . therefore , the claims that follow are intended to be construed to encompass not only the specific embodiments described but also all modifications and variants thereof which embody the essential teaching thereof .

a delivery system for delivering an endoluminal implant to a distal deployment location inside a body lumen from a proximal access location outside the lumen . the system comprises the implant , a catheter , and a slidable sheath having an advanced position in which the sheath covers the implant and a retracted position in which the implant is exposed . the catheter comprises a stabilizer having a distal end adjacent the implant proximal end and / or a catheter tip attached to a central core slideably disposed relative to the implant and having a proximal end adjacent the implant distal end . the catheter tip proximal end and / or the stabilizer distal end comprises a docking section adapted to releasably engage a portion of the implant . each docking section has an engagement geometry comprising a flared engagement surface that extends inside a short axial length of the implant or a pocket having a bottleneck geometry .

“ defibrillation ” and “ defibrillator ” are the nouns used to refer to the act of and the device which terminates a rapid heart rhythm with a non - synchronized shock . these two terms are , herein , intended to also refer to “ cardioversion ” and “ cardioverter ”, respectively , these latter two terms implying a synchronized shock . 1 ) overview of device function ( fig1 - 5 ) 2 ) example : system with unified adapter and communication device ( fig6 - 9 ) 3 ) example : detailed description of a modified external defibrillator system which may have various embodiments ( fig1 ) 4 ) example : system with unified adapter and cardiac monitoring and treatment device ( fig1 - 13 ) 5 ) example : versions of the system with at least one implantable component ( fig1 a , 14b and 14 c ). fig1 shows an overview of a generalized version of the invention . the main components are cardiac treatment and monitoring ( cmtd ) device 1 and adapter ( ap ) 2 . the broadest overview of the path of informational and command signals between the cmtd and the remotely located mp is as follows : electrocardiogram ( ecg ) signals from a victim of a medical emergency pass from cmtd 1 to ap 2 to communication device ( cd ) 3 to remote station ( rs ) 4 . a medical professional ( mp ) at the rs — in a location remote from the victim — receives the ecg signals , views them , and makes a decision about whether cardiac defibrillation or cardiac pacing is necessary . if either one is necessary , the mp sends one or more control signals via the route rs to cd to ap to cmtd . cmtd 1 is a defibrillating or pacing device which has been modified so that it may communicate with a remotely located mp via an adapter 2 and a communication device 3 . the adapter allows the cmtd to be compatible with the cd . a more detailed overview of the path of informational and command signals between the cmtd and the remotely located mp is as follows : an ecg signal is derived from two or more sensing electrodes 5 . the signal is introduced to cardiac signal circuit 6 via cardiac sensing electrode input 6 a . the signal is amplified and may be further processed , as is known in the art . signal 10 from cardiac signal circuit output 6 b is coupled to data translation device 7 of the adapter . various means of achieving this coupling are possible including : 1 ) a hard - wired electrical signal connection : in this case , each of a ) circuit output 6 b , and b ) the input to 7 , is externalized , i . e . hardwired to a jack or port at the surface of each of 1 and 2 , or to a connector at the end of an external cable ; and 2 ) a wireless connection which may utilize a radiofrequency signal ( rf ), an optical or infrared signal , bluetooth , wifi , or another wireless internet - based connection . 7 provides any further necessary signal conditioning required to render the output of 6 b appropriate as an input for communication device 3 . such conditioning may include amplification , filtering , noise reduction , decoding , encoding , decrypting and encrypting . once accomplished the signal 11 leaves the adapter via output port 8 . adapter 2 communicates with t / r 1 by either a wired or wireless connection . if the connection is wireless it may be rf , optical or infrared signal , bluetooth , wifi , or another wireless internet - based connection . cd and rs , communicate via either a wired or wireless connection or a mixture of the two . if wired , it may utilize the public telephone network or a private carrier . if the connection is wireless it may utilize a public cellular network ; rf communication on a medical band , on a cordless telephone frequency , on a satellite phone or a private carrier . there may be a wired or a wireless connection to the internet . other means of communication will be obvious to those skilled in the art . utilizing one or more of the aforementioned signaling means , ecg information moves from 3 to 4 as signal 12 . after mp decision making , the signal which reflects that decision , 13 , is transmitted back to 3 by any one or more of the aforementioned cd — rs signaling means , and , as signal 14 back to the input port 15 of the adapter . the approach to ap - cd information transfer discussed hereinabove applies to the technique of cd - ap information transfer . the input port feeds information to another data translation device 16 , which provides any necessary signal conditioning required to render the output of 3 appropriate as a control input for the cmtd . such conditioning may include amplification , filtering , noise reduction , decoding , encoding , decrypting and encrypting . once accomplished the signal 17 exits the adapter and enters 1 . any of the routes and modalities discussed in conjunction with outgoing signal 10 are possible routes and modalities for incoming signal 17 , as it traverses the 16 to 18 a route . control input 18 a is the entry point for control signals which determine what treatment circuit 18 does . in one embodiment of the invention , 18 a functions only as a conduit for signals which explicitly control defibrillation and / or pacing ( e . g . a “ deliver shock ” signal ); in another embodiment of the invention ( see below ), 18 a additionally has a switching function , whereby it allows the selection of a source of control , e . g . the treatment circuit or circuits 18 controlled by 18 a may be : the output of the treatment circuit 18 b is applied to two or more defibrillator electrodes 19 . ( in the case of an implanted pacing or defibrillator device , one of these electrodes may be the “ can ” of the implanted device .) when cmtd 1 is an aed which contains both an ecg data output port and a command input port it is referred to hereinbelow as “ maed ”. the maed may be initially built with such ports , or suitably modified post initial manufacturing . the maed will contain logic device 20 , for analysis of ecg signals , which reach 20 along the route 5 to 6 a to 6 to 6 b to 20 . if a shock or pacing is appropriate based on the ecg analysis , the output of 20 will be a command ( to shock or pace ) delivered to treatment circuit control input 18 a . from this point , the command which originates in the logic device has an identical route and effect as the remotely originating command described hereinabove . the cmtd may be a manually controlled defibrillator and / or pacing device , i . e . a device which is used by a medical doctor or emergency medical technician ( each of which , hereinbelow , is referred to as “ local mp ”), and whose use entails the local mp making a shock / no - shock or pace / no - pace decision , and whose use may also involve the selection of shock parameters ( e . g . synchronization , energy ) or pacing parameters ( e . g . pacing rate ). in such an embodiment of the invention , the local mp will have a defibrillation control input 21 if the cmtd is a defibrillating device ; there will be a pacing control input 22 if the cmtd is a pacing device . embodiments of the invention in which 1 performs both functions are possible . the local mp will also require a display device 23 , for displaying the ecg signals , allowing him to make his management decision ( s ). in a device such as that described herein with more than one source of a control , it is advantageous to have a design feature which allows for the selection of a single control source . in such an embodiment of the invention , for example , if the local mp wishes to take control , he would wish to prevent or lock out control by either ( a ) the remote mp or ( b ) the logic device within the aed . this may be accomplished , as shown in fig1 , by having a lockout control 24 which may be inputted by the local mp . in this instance , following local mp input to 24 , a signal is sent to 18 a which causes it to ignore control signals from logic device 20 ( if any ) or signals 17 from a remote mp ( if sent ). in an alternative embodiment of the invention , the remote mp may be allowed to be the source of a lockout command , giving him control priority over either a local mp or the logic device . the remote mp may send such a lockout signal 17 which arrives at control input 18 a and either a ) signals the control input directly , or b ) signals lockout control 24 , or c ) both a ) and b ). in one embodiment of the invention , ( a ) the local mp may lockout the logic device , but may not lockout the remote mp , and ( b ) the remote mp may lockout either or both the local mp and the logic device . in another embodiment of the invention , ( a ) the remote mp may lockout the logic device , but may not lockout the local mp , and ( b ) the local mp may lockout either or both the remote mp and the logic device . besides controlling the parameters of pacing and / or defibrillation via signal ( 17 ), in yet another embodiment of the invention , a remote mp may also control the choice of pacing and / or defibrillation electrodes 19 , if more than two electrodes are available . such control signals 17 traverse the route 16 to 18 a to 18 to 18 b where , in this embodiment , they determine the choice of output electrodes . in yet another embodiment of the invention , a remote mp may also control the choice of sensing electrodes 19 , if more than two electrodes are available . such control signals 25 traverse the route 16 to 6 ( or 16 to 6 a ) where , in this embodiment , they determine the choice of sensing electrodes . embodiments of the invention , described hereinbelow , are possible in which the cmtd is a pacing or pacing / defibrillating device which is implanted in a patient . in this case , adapter 2 , which may be either inside the body or outside the body , allows the implanted pacemaker or pacemaker - defibrillator to use a cd ( such as a cellular telephone ) which is external to the body to communicate with a remotely located mp . embodiments of the invention are also possible in which all three of the cmtd , the ap and the cd are implanted in the body . in order to assure that an unauthorized person does not communicate with the system , data translation device 16 may contain means for confirming the identification of the putative mp , in a preferred embodiment of the invention . one approach is to assign a unique identification ( id ) number to each authorized mp user and store the id numbers in 16 . the remote mp could then be required to present his identification number at the start of a remote session , or , with each command that he sends . if the id number presented by the mp does not match one of the stored id numbers , access to the system is denied . in one embodiment of the invention , the mp would be notified if access is denied ; the connection in fig1 from 16 to 7 indicates that such denial information would be routed from 16 to 7 to 8 to 3 and then to 4 . in another embodiment , the mp could also be notified of acceptance of the id number , by a signal sent along the aforementioned route — from 16 to 7 . . . and on to 4 . additional security could be achieved by requiring additional electronic identification . for example , the mp could also be required to submit a password ; the allowable passwords would be stored in 7 . either an incorrect password or an incorrect id number would result in rejection of access . in one embodiment of the invention , the password would be required for the mp to first gain access , and the correct id number would need to accompany each mp command . b ) one of a number of types of memory of a “ write - once - only - variety ,” i . e . eproms , eeproms , etc . from time to time , these units could be replaced by an on - site maintenance person , who services the adapter , or by having the entire adapter replaced from time to time , the new adapter containing the updated list of id numbers ( and , if used , passwords ) in 7 . in yet another embodiment , the id number and password list could be maintained in a memory that could only be over - written by an on - scene maintenance person . other variations in such memory access restriction methods will be obvious to those skilled in the art . other systems of user identification are possible . id numbers could be changed very frequently — even during the course of a transmission ; an id number master source could supply these on a very frequent basis to known mps and known adapter owners . alternatively , the frequency ( for transmission between cd and rs ) could be shifted on a frequent basis , even during the course of a transmission , following a pattern that would be known only to authorized users . still other user identification methods will be obvious to those skilled in the art . embodiments of the invention in which access denial hardware and / or software is located in the cd ( instead of , or in addition to its being located in the adapter ), are possible . embodiments of the invention in which access denial hardware and / or software is located in the cmtd ( instead of , or in addition to its being located in the adapter ), are also possible . an embodiment of the invention is possible in which access denial hardware and / or software is located in each of the cmtd , the ap and the cd . in order to assure proper functioning in a system with multiple attachable and detachable components , it is desirable to have a system which assures that all components are properly attached , and , in the event of a detachment , allows for one or more of : a ) notifying one or more users , who may remedy a detachment , and / or b ) causing the cmtd to revert to autonomous functioning . signaling methodology which accomplishes these tasks is discussed generally in conjunction with fig2 . apparatus for one version of signaling is discussed in conjunction with fig3 , and further discussed in conjunction with a ) the maed , hereinbelow and b ) a unit in which the ctmd and the ap are combined , also hereinbelow . referring to fig2 , each of elements 1 , 2 , 3 and 4 function as described hereinabove . the broken lines in the figure indicate attachment signals , each of which let the downstream hardware “ know ”— based on receipt of that signal — that the upstream signal source is properly attached . ( hereinbelow , “ downstream ” refers to the 4 to 3 to 2 to 1 direction , i . e . 3 is downstream from 4 . “ upstream ” refers to the opposite direction , so that 4 is considered to be upstream from 3 .) thus the receipt of signal 30 a lets the cmtd know that the ap is properly attached to it , while receipt of signal 30 b lets the ap know that the cmtd is properly attached . if the system uses the detection of a failure of attachment as a trigger for reversion of a cmtd to automatic functioning ( e . g . defibrillation management by logic device 20 ), it requires a means by which a 2 - 3 detachment ( i . e . a detachment of 2 from 3 ) or a 3 - 4 detachment ( i . e . a detachment of 3 from 4 ) is communicated to 1 . various approaches to this will be clear to those skilled in the art . one approach is to detect a detachment upstream ( e . g . at the 2 - 3 link [ the link between 2 and 3 ]), and communicate it downstream ( e . g . from 2 to 1 ). a second approach is to consider complete attachment as requiring all three links ( 1 - 2 , 2 - 3 and 3 - 4 ) to be intact , and therefore design the system so that signals pass from 4 to 3 to 2 to 1 ; in this case , failure to receive a signal at 1 implies an upstream detachment and triggers the automatic functioning of 1 , perhaps until signals from 4 are restored . specifically the aforementioned approach would entail : 1 ) signal 32 a sent from 4 to 3 ; 2 ) receipt of 32 a by 3 triggers 3 to send 31 a to 2 ; 3 ) receipt of 31 a by 2 triggers 2 to send 30 a to 1 . in this case , the arrival of 30 a at 1 indicates an intact connection between each of 1 - 2 , 2 - 3 and 3 - 4 . embodiments of the invention in which a signal repeatedly is sent from 4 , intended to signal cmtd 1 , are possible , so that the failure to receive 30 a indicates that disconnection occurred somewhere upstream in the interval since the previously received signal . embodiments of the invention with more complex downstream signaling are possible , e . g . one in which if 3 ( or 2 ) failed to receive a timely signal from 4 ( or 3 ), it would send a downstream signal indicating the failure , thereby localizing the source of the failure . this information could be useful to a person using the cmtd . it could also be useful to convey attachment information in the upstream direction . all of the same concepts and means for downstream notification of an attachment failure , apply to upstream notification . in short , the sequence would be : 1 ) signal 30 b sent from 1 to 2 ; 2 ) receipt of 30 b by 2 triggers 2 to send 31 b to 3 ; 3 ) receipt of 31 b by 3 triggers 3 to send 32 b to 4 . notification of the remote mp of an attachment failure could trigger one or more of : c ) use of backup communication means , if available , at the remote mp end ; and d ) use of backup communication means , if available , at the cmtd end , which may be activated by either the local user , or electronically by the remote mp . still more complex signaling arrangements are possible . for example , a continuously or semi - continuously circulating signal may traverse the route 4 to 3 to 2 to 1 to 2 to 3 to 4 to 3 to . . . in this embodiment , an initial signal may be sent from 4 which , if it reaches 1 triggers a return signal . if the return signal reaches 4 , it triggers another signal from 4 to 1 . the process continues repeatedly until either the session ends , or a break in communications occurs . because of the circulating feature of the signals , when such a break occurs , both the remote mp and the cmtd ( and / or the cmtd operator ) will be informed of its occurrence . ( the initial signal could also be sent from the cmtd .) still other signaling arrangements would let either 4 ( or the 4 operator ) and / or 1 ( or the 1 operator ) localize the point of detachment : a ) each of 4 , 3 and 2 send their own downstream signals which are coded so that the downstream recipient can identify the signal source . in this arrangement , if 1 receives signals from 2 , and not from 3 and 4 , it indicates a 2 - 3 detachment . b ) each of 1 , 2 and 3 send their own upstream signals which are coded so that the upstream recipient can identify the signal source . in this arrangement , if 4 receives signals from 2 , and not from 1 , it indicates a 1 - 2 detachment . c ) arrangements with a continuously circulating signal in which , in addition to the circulating signal , either the mp or the cmtd may cause either the ap or the cd to echo an incoming signal ; this would let the mp or the cmtd identify the point of detachment . for example , if the remote mp failed to receive the circulating signal , and then sent out an echo signal which successfully traverses the route 4 to 3 to 4 , and then sent out another echo signal which did not successfully traverse the intended route 4 to 3 to 2 to 2 to 4 , it would be clear to the remote mp that the site of the detachment was 2 - 3 . for hardwired connections involving multi - pin connectors , it would be possible to have a communication failure involving some pins , which would not be apparent if the pins carrying the attachment signals were properly connected . methods for detecting such situations include : having multiple connectors between adjacent components ( e . g . 2 and 3 ) at different geometric locations , each carrying an attachment signal ; and having an attachment signal routing routine where the attachment - signal - carrying pins are continuously varied , so that ultimately , any inadequately connected pair of pins would be detected . still other connection confirmation methodologies and routines will be obvious to those skilled in the art . fig3 shows an example of communication confirmation signaling arrangement . test signal means 40 generates a test signal 42 which , in the presence of proper attachment between rs 4 and cd 3 , is communicated to 3 , and , in the presence of proper attachment between cd 3 and ap 2 , is communicated to 2 , and in the presence of proper attachment between ap 2 and cmtd 1 is communicated to communication confirmation means 41 in 1 . in the absence of 42 , 41 signals control input 18 a which transfers control from the remote mp to either the logic device in the cmtd or to a local mp , if present . variations of this embodiment include : a ) one in which the test signal is repeatedly generated and in which 41 indicates a communication failure if a test signal is not received at the expected interval after the last received test signal ; b ) one in which a break in communication is indicated by cmtd indication means 43 . 43 may be a display screen , a tone generating apparatus , an alarm , etc . 41 and the display screen may also be configured to indicate adequate communication status ; and c ) one in which 45 emits signals on a fixed schedule ( i . e . not based on whether it receives any signals ). with this arrangement , in the presence of intact attachments of each upstream pair of components , there would be a repetitive receipt of such signals by 40 ; and a break in the received signals would indicate a detachment ; this approach could be used in addition to sending test signals 42 downstream ; d ) one in which : ( i ) the receipt of 42 by 41 results in the generation of a handshake signal 44 by handshake generating means 45 . the handshake signal traverses the system in the upstream direction . in the presence of proper attachment between each of 1 and 2 , 2 and 3 , and 3 and 4 , the signal arrives at 40 in rs 4 . non - arrival of an expected return signal 44 ( such expectation based on 40 having sent out signal 42 ) triggers a message from 46 at the remote station 4 . optionally , arrival of 44 at 4 triggers a status message on rs indication means 46 ( tone or screen message , etc . ); and ( ii ) at fixed intervals of time thereafter , 40 generates additional test signals , for repeatedly evaluating the integrity of each attachment ; ( i ) the receipt of 42 by 41 results in the generation of a handshake signal 44 by handshake generating means 45 . the handshake signal traverses the system in the upstream direction . in the presence of proper attachment between each of 1 and 2 , 2 and 3 , and 3 and 4 , the signal arrives at 40 in rs 4 . non - arrival of an expected return signal 44 ( such expectation based on 40 having sent out signal 42 ) triggers a message from 46 at the remote station 4 . optionally , arrival of 44 at 4 triggers a status message on rs indication means 46 ( tone or screen message , etc . ); ( ii ) the receipt of 44 by 40 triggers the next test signal , 42 + [ as opposed to the method of ( d ) above , where the next test signal is not triggered by the arrival of 44 , but instead occurs a fixed interval after the previous test signal was emitted ]; ( iii ) the receipt of 42 + by 41 triggers the next handshake signal , 44 +; ( iv ) the receipt of 44 + by 40 triggers still another test signal , 42 ++; ( v ) the process of nth test signal generating the nth handshake signal , and the nth handshake signal generating the ( n + 1 ) th test signal continues until the event for which communication is required has ended , or until there is a break in communication . fig4 shows one possible embodiment of a remote station 4 . it consists of a ) transmitting and receiving apparatus 50 ; and b ) a computer 51 linked to 50 . 50 communicates with cd 3 , as shown in fig1 ( not shown in fig4 ). the communication between 50 and 51 may be ‘ hard - wired ,’ radiofrequency , bluetooth , wifi and infrared / optical signals , through the internet ( via a wired or wireless connection ) or through the public telephone system ( wired or wireless ). 51 contains a processor 53 linked to a ) memory 52 and b ) a display device 54 . not shown in the figure are one or more input devices , a power supply and other items commonly found in a computer , as is well known in the art . the computer 51 allows the mp to input commands , and to store information about : the current event , this victim &# 39 ; s prior events [ if any ] entailing use of the remotely controlled apparatus , this victim &# 39 ; s medical history , medical practice in general , legal aspects of arrest and emergency management , in general advanced legal directives that pertain to this victim , the cmtd which is downstream [ including prior malfunctions ( if any ) of the model of cmtd , and of the particular cmtd in current use ], the ap which is downstream , the cd which is downstream , the competence of a particular local mp who is using 1 , 2 and 3 , the availability of emergency services in the vicinity of the victim , and the availability of other remote mps , should he find himself needing to handle a larger number of simultaneous tasks than is practical . the computer also allows the mp to more carefully analyze a complex or difficult to diagnose electrocardiogram , either by enlarging it , making on - screen measurements , filtering it in different ways , or comparing it to a database . the computer allows the mp to select from a menu of commands to be inputted into the cmtd . these may be as simple as shock vs . no shock , or complex packages of commands ( e . g . perform anti - tachycardia pacing with the computer also allows the mp to select voice prompts , if necessary ( e . g . if available bandwidth for communication with the cmtd is very narrow ) which may be stored in the cmtd . the computer also allows the mp to select a video prompt , e . g . for the delivery of cpr instructions to a bystander at the arrest scene ; the video prompt may be stored in 52 , in the cmtd , or at another location with which 51 can communicate . acknowledgment is made of the concept that , as cellular telephones and personal communication devices become progressively more sophisticated , the distinction between a communication device and a communication device plus computer becomes somewhat arbitrary . we are already at a point where essentially all commercially available communication devices have each of the items in 51 , as well as a power supply and one or more input devices . thus , the combination of 50 and 51 may be a cellular telephone , a blackberry device , etc . form a complete remotely controlled monitoring and treatment device ( rcmtd ). only the addition of a remote station is necessary to assemble the complete system . fig5 a , 5b and 5 c show three ways in which the three aforementioned components may ( or may not ) be assembled . fig5 a , version 1 , shows the linkage of ap 2 and cd 3 within housing 60 . the combined ap and cd is referred to as the ccmtd — indicating communication and control unit of a cardiac monitoring and treatment device . symbolic representations of the aforementioned functional relationships shown in fig5 a , in which the components of the ccmtd include the adapter and the communications device , are : in the case where an aed is being upgraded to a remotely controllable defibrillator , the above symbolic statements would be written as : where crcd refers to the communication and control unit of a remotely controlled defibrillator , the other terms having been defined hereinabove . fig5 b shows another way , version 2 , of distributing the components of the rcmtd . it shows the incorporation of a cmtd 1 and an adapter 2 , each with functionality similar to that described hereinabove , combined within one housing to form a communications device compatible cmtd 61 , “ cdccmtd .” a communications device 3 such as a cell phone may be attached to the cdccmtd to form the complete rcmtd . symbolic representations of the aforementioned functional relationships shown in fig5 b , in which the components of the cdccmtd include the cmtd and the ap , are : in the case where an aed is being upgraded to a remotely controllable defibrillator , the above symbolic statements would be written as : where cdcaed refers a communication device compatible aed , the other terms having been defined hereinabove . fig5 c shows another way , version 3 , of distributing the components of the complete rcmtd . it shows each of the three components of the rcmtd , a symbolic representation of the aforementioned functional relationships shown in fig5 c , in which each of the three components of the rcmtd is separate , is : in the case where an aed is being upgraded to a remotely controllable defibrillator , the above symbolic statement would be written as : fig6 shows a specific example of version one , referred to in fig5 a , in which the cmtd is a modified aed . it illustrates a schematized view of a method and apparatus for adapting automatic external defibrillators so that they may be remotely controlled with minimal modification . the requirements for constructing such a system are : 1 ) an aed design modification which “ externalizes ” ( i ) aed ecg signals and ( ii ) defibrillation control signal circuit and / or command access points , so that they become ( i ) aed telemetry output and ( ii ) aed control input ; units with such modifications are referred to as modified aeds ( maeds ). 2 ) coupling the maed outputs and inputs to a device or devices which allow for electronically extending these inputs and outputs to a remote mp , via a communication system . this may be accomplished by coupling the maed inputs and outputs to either : a single device , a crcd ( as defined hereinabove ) which combines the components and functionality of each of the ap and the cd . referring again to fig6 is a modified automatic external defibrillator . the modification consists of the addition of external access to : 1 ) ecg signals from a victim attached to the maed ; and 2 ) control inputs which allow control of the defibrillator ( and pacing ) circuitry within the maed . as shown in the figure , the ecg and control signals may be coupled to a crcd 102 by cable 104 and schematically shown connector 106 a and 106 b . following the coupling of connectors 106 a and 106 b , remote control of the maed is achieved according to the sequence : 1 ) victim ecg signals from maed 100 to crcd 102 ( via the sequence 100 → 106 b → 106 a → 104 → 102 ); 2 ) ecg signals from crcd to remotely located medical professional ( mp ); 3 ) mp analyzes the ecg signals , and decides on the need for defibrillation , pacing ( in the case of a 100 unit with capability to pace as well as defibrillate ) or neither ; 4 ) if appropriate , mp sends defibrillation or pacing control signals ; 5 ) control signals , if any , traverse the route from crcd 102 to maed 100 ( via the sequence 102 → 104 → 106 a → 106 b → 100 ); and 6 ) depending on whether a defibrillation or pacing signal has been sent , the victim may receive defibrillation or pacing stimulation . although the connectors 106 a and 106 b show one pair of wires and one pair of pins for each of two signals , formats involving a greater or lesser number of channels and a greater or lesser number of pins are possible , as is known in the art . as shown in the example in fig7 , the connection between the maed and the crcd need not be hard - wired . electromagnetic signals such as radiofrequency , bluetooth , wifi and infrared / optical signals may link the maed and the crcd . as shown in the figure , maed 100 may use associated signaling unit 101 a to send signal 101 b which may be rf , microwave , infrared , etc . to the crcd signaling unit 101 c . 101 c is coupled to crcd 102 . signaling in the opposite direction proceeds along the path 102 → 101 c → 101 b → 101 a → 100 . 1 ) maed type i , wherein the modification ( which allows electrical coupling to takes place ) is made post - aed production ; and 2 ) maed type ii , wherein the modification is built in at the time of production . fig8 shows a more detailed view of the components of an embodiment of the maed 100 and their interaction with those of an embodiment of the crcd 102 . victim ecg signals are processed at 200 ( electrode inputs not shown in the figure ), and formatted and optionally displayed at 202 . signals from 200 are also made available for coupling to the crcd at 204 . in the coupling arrangement shown , the ecg signal gets to the crcd via female / male pin arrangement 220 c / 220 d . many other possible connector arrangements will be familiar to those skilled in the art . the ecg signals are optionally further processed at 230 within the crcd . from 230 , they pass to 232 where they are encoded , possibly encrypted and transmitted to a mp . if the mp determines that the victim &# 39 ; s heart rhythm is ventricular fibrillation , or a ventricular tachycardia which requires a shock ( there are non - shock - requiring vts . ), he may send a command signal (“ a button press signal ”) which causes the aed to shock the victim . the button press signal path would be : from mp to receiver and decoder 234 ( decryption here , if necessary ), to optional further signal processing within the crcd at 236 , to the maed via connectors 220 f and thence 220 e ( other connector arrangements possible ), to optional further signal processing within the maed at 206 , to defibrillator circuits 208 . in a preferred embodiment of the invention , the mp would also be able to override a defibrillation command signal which originates in the aed logic device , as discussed hereinabove in conjunction with fig1 . in embodiments of the invention in which the mp also controls the energy of the defibrillator pulse , the mp may send a pulse energy selection signal which traverses the path : 234 → 238 → 220 h → 220 g → 210 → 208 . in embodiments of the invention in which the mp also controls the shock synchronization , the mp may send a synchronization selection signal which traverses the path : 234 → 240 → 220 j → 220 i → 212 → 208 . the mp may send a variety of other commands and signals . these may include : in embodiments in which the mp controls pacing and defibrillation , pacing control would be achieved with a system whose design is analogous to elements 208 + 206 / 210 / 212 , which control defibrillation . 3 ) commands to control a chest compression device ( as discussed in ser . no . 10 / 460 , 458 ; and in ser . no . 11 / 502 , 484 ); 5 ) signals which control the audio output from ( e . g . volume control ) and / or audio input to ( e . g . microphone gain ) the maed ; 8 ) signals which control video prompt ( i . e . video images stored within the maed or crcd ) selection ; 10 ) signals which control the maed video display ( e . g . brightness on maed video screen ) and / or video input to the maed ( e . g . input to a maed videocamera ); 11 ) signals which download new software into the maed ; 12 ) signals which are intended for test purposes — i . e . mp ( or other non - medical personnel ) testing of : 13 ) signals which are intended for teaching purposes during a non - emergency event , which may include : the path of the aforementioned commands are indicated in the figure as traversing the route 234 → 242 → 220 l → 220 k → 214 . from 214 , the command signal would pass to the appropriate target , e . g . to defibrillator circuits 208 in the case of defibrillator controlling commands , and to audio signal processing and amplification circuitry ( not shown in the figure ) in the case of a voice message to the either the victim , or an “ enabler ” who uses the apparatus to aid a victim . signals in addition to ecg signals , i . e . other telemetry signals , which may be sent from maed to crcd and thence to the remotely located mp may include : 2 ) audio signals from either the victim , or an enabler ; 3 ) video signals showing either the victim , or the performance of an enabler ; 4 ) battery voltage for one or more maed batteries ; 5 ) signals indicating the results of testing done to evaluate the integrity / proper function of maed circuitry ; 6 ) signals , if available , indicating victim physiologic parameters which may include : the path of the aforementioned other telemetry signals are indicated in the figure as traversing the route 216 → 220 a → 220 b → 244 → 232 . the telemetry signal reaches 216 , from the appropriate source , e . g . from defibrillator circuits 208 in the case of defibrillator charging and , possibly , shock delivery confirmation signals , and from audio signal processing and amplification circuitry ( not shown in the figure ) in the case of a voice message from the victim or enabler . in one embodiment of the invention , proper linkage and communication between the maed and the crcd may be confirmed on an intermittent or continuous basis by a series of handshake signals . in the event of an interrupted connection , indicated by an interruption in handshake signals , non - mutually exclusive options would include : 1 ) notifying the enabler and / or victim ; 2 ) notifying the mp ; 3 ) returning control of the defibrillator circuits to the aed logic device ( i . e . the aed then functions as a conventional [ v . i . z . autonomous ] aed , with the aed logic circuits controlling all aspects of aed function ); and 4 ) continuing to try to re - establish a proper handshake . referring to fig9 , maed microprocessor 300 generates a handshake signal 302 /( a ) [ the “( a )” of “ 302 /( a )” is intended to indicate the first of a sequence of signals collectively referred to as 302 , with the next one after 302 /( a ) referred to as “ 302 /( b )”, etc .] which , if connection 320 e → 320 f is intact , is passed to crcd microprocessor 310 . receipt of first handshake signal 302 /( a ) by 310 , causes 310 to generate handshake signal 312 /( a ) [ the 312 terminology is the same as the aforementioned 310 terminology ] which , if connection 320 d → 320 c is intact , is passed to maed microprocessor 300 . the handshake cycle continuously repeats , as long as the aforementioned maed - crcd connections are intact . in the event that crcd microprocessor 310 does not receive an expected handshake signal , it may : 1 ) notify the enabler and / or victim by causing a signal to be sent to announcement components 314 . these components may include audio circuitry and a speaker , or a text message associated with an alarm signal ; 2 ) notify the mp by causing a signal to be sent to transmitter 232 via an encoder ; and 3 ) attempt to send a signal 312 /( b *) to the maed microprocessor indicating that the crcd microprocessor did not receive the previous / expected handshake signal from the maed . this 312 /( b *) signal may cause the maed to ( i ) attempt / make a repeat handshake transmission to the crcd ; and / or ( ii ) send a signal to defibrillator circuits 208 to switch to conventional aed function ( i . e . no mp control ). in the event that maed microprocessor 300 does not receive an expected handshake signal , it may : 1 ) notify the enabler and / or victim by causing a signal to be sent to announcement components 304 . these components may include audio circuitry and a speaker , or a text message associated with an alarm signal ; 2 ) send a signal to defibrillator circuits 208 to switch to conventional aed function ( i . e . no mp control ); and 3 ) attempt to send a signal 302 /( b *) to the crcd microprocessor indicating that the maed microprocessor did not receive the previous / expected handshake signal from the crcd . this 302 /( b *) signal may cause the crcd to ( i ) attempt / make a repeat handshake transmission to the maed ; and / or ( ii ) notify the mp by causing a signal to be sent to transmitter 232 via an encoder . handshake signals 312 of fig9 corresponds to signal 30 a of fig2 ; handshake signals 302 of fig9 corresponds to signal 30 b of fig2 . in an embodiment of the invention in which the communication confirmation process extends from the rs to the maed , the signal path would be rs to 234 ( by a signal corresponding to signal 32 a of fig2 ), to 310 , giving rise to signal 312 , to 320 d , to 320 c , to 300 . in an embodiment of the invention in which the communication confirmation process extends from the maed to the rs , the signal path would be 300 , giving rise to signal 302 , to 320 e , to 320 f , to 310 , to 232 , and then to the rs ( by a signal corresponding to 32 b of fig2 ). many additional types of handshake signals and handshake signal formats will be familiar to those skilled in the art . referring again to fig9 , a preferred embodiment of the invention may include an aed identifier signal generator 306 . this would allow the crcd to identify the brand and model of maed to which the crcd has been connected , which would allow the crcd to accommodate such issues as signaling and control formats , voltages , and even pin arrangements particular to certain maed brands and models . the aed identifier signal is sent to the crcd microprocessor along the path : 306 → 320 a → 320 b → 310 . aed model identification may also be passed along to the mp . the transmitter 232 and receiver 234 shown in fig8 and 9 may be long range ( e . g . greater than line - of - sight ), short range ( e . g . approximately line - of - sight ), or very short range ( e . g . bluetooth ). furthermore , the crcd may ( instead of , or in addition to , using a transmitter and receiver ) interface : 1 ) with public telephone carriers ( through either a hard - wired connection or short range transmitter / receiver combination ), with telemetry information and mp commands carried over a public telephone connection ; or 2 ) with the internet , with a connection to the internet ( and ultimately , to the mp ) via either : b ) digital subscriber line or any line which is formed from a combination of individual lines ; or in a preferred embodiment of the invention , the crcd would have its own power supply ; in an alternative embodiment of the invention , the crcd could obtain power from ( or supply power to ) the maed , on a continuous basis or on an as - needed basis . fig6 to 9 and the associated specification regarding the present example could ( as discussed in conjunction with fig1 and the associated specification , hereinabove ), besides applying to a modified aed , also apply to : a modified manually operated external defibrillator , as discussed in conjunction with fig1 , hereinabove ; and a modified external defibrillator which has both an aed mode and a local mp - controlled ( i . e . non - automatic ) mode . example : detailed description of a modified aed system which may have various embodiments fig1 shows a schematic description of each of the components of a remotely controlled defibrillator , or rcd . communications device 500 includes each of the functional sub - units found in commonly available cellular telephones and other communication devices such as the blackberry ®. these include : 500 may optionally include video communication equipment . this may include a video camera 518 and camera - associated circuits ; and may include a screen 520 and associated screen control circuits , for viewing video images . 506 may be a single antenna which serves both 502 and 504 . alternatively , there may be one antenna for each of 502 and 504 . in yet another alternative embodiment , there may be more that one antenna for the transmitter , each optimized for a different frequency . there may also be more that one antenna for the receiver , each optimized for a different frequency . alternatively , there may be multiple antennae , each serving both 502 and 504 , and each optimized for a different frequency . 512 may be a standalone microprocessor , or may consist of multiple microprocessors . alternatively , data processing may occur in each of 502 - 510 and 514 , 516 , 518 ( if present ), and 520 ( if present ). 514 may be the standard 12 key arrangement as is known in the art , and as is present on many current - day cellular telephones . alternatively 514 may consist of a complete alphanumeric arrangement with at least 26 letters and 10 digits . many other keyboard arrangements and contents will be apparent to those skilled in the art . 516 may be a rechargeable cell as is known in the art . there may optionally be additional access to power from the adapter 530 , or from maed 550 via 530 . these outside - the - cd sources of power may : the power supply is electrically connected to each of the power - requiring sections of 500 ( connections not shown in the figure ). a ) signals which are intended for the control of 500 , which may include : 1 ) signals which control the audio output characteristics ( e . g . volume control ) and / or audio input to ( e . g . microphone gain ) of 500 ; and 2 ) signals which control the video output characteristics from ( e . g . brightness , contrast ) and / or video input to ( e . g . iris size , zoom ) of 500 ; b ) audio , video and text signals for communicating information to the enabler / user of the unit ; and in the example shown in the figure , 500 is in electrical communication with adapter 530 via female / male pin pairs 522 a / 522 b and 522 c / 522 d . alternative links between 500 and 530 are possible including : b ) short - range rf or infrared linkage ( e . g . as is described in conjunction with fig7 , and as is known in the art ). unit 530 receives signals from 504 in 500 . the signals arrive at the decoder via the path 506 → 504 → 522 c → 522 d → 532 . the decoder separates out : 1 ) one or more signals which control “ button press ” ( as described in conjunction with fig8 hereiabove , i . e . causing a defibrillator shock ); and which may control one or more of 2 ) shock synchronization ; 3 ) shock energy and / or voltage ; 4 ) shock waveform ; 5 ) shock electrodes ( in a system with more than two electrodes ); 6 ) commands to pacing circuits ( not shown in fig1 but shown and discussed in the aforementioned applications ) including : g ) anti - tachycardia pacing signals , to attempt termination of a ventricular tachycardia ; 7 ) commands to control a chest compression device ( as discussed in ser . no . 10 / 460 , 458 ; and in ser . no . 11 / 502 , 484 ); 8 ) signals which control the video display , if any , of maed 550 ; 9 ) signals which download new software into the maed ; 10 ) signals which are intended for test purposes — i . e . mp ( or other non - medical personnel ) testing of : 11 ) signals which are intended for teaching purposes during a non - emergency event , which may include : a ) setup information for one or more of the maed , the ap , the cd , the crcd and / or the cdcaed ( as defined in conjunction with fig5 b , hereinabove ); and the aforementioned signals may be “ conditioned ” at 534 and then passed to the maed . the purpose of conditioning is to render the signal format and quality that is outputted at 532 suitable for input to the maed . conditioning may include a variety of processing formats including : a ) one in which there is no signal conditioning post decoder ; b ) one in which there is additional signal conditioning pre - decoder ; and from 534 , signals exit ap and enter the maed via pin arrangement 540 a and 540 b . as indicated hereinabove with respect to the electrical linkage of the cd and the ap , the electrical link may consist of : b ) short - range rf or infrared linkage ( e . g . as is described in conjunction with fig7 , and as is known in the art ). adapter 530 also serves to transfer ecg and other data signals ( both physiologic and equipment - related ) from the maed to the cd . signals are passed from the maed to the ap via pin set 542 a and 542 b . as indicated hereinabove with respect to the electrical linkage of the cd and the ap , the electrical link may consist of : b ) short - range rf or infrared linkage ( e . g . as is described in conjunction with fig7 , and as is known in the art ). signals from the maed are encoded by 536 and conditioned at 538 . signal conditioning in the maed to ap to cd route serves the analogous purpose as signal conditioning in the cd to ap to maed route , i . e . to render the signal amplitude and format acceptable to the cd ( and ultimately , to the remotely located mp ). a ) one in which there is no signal conditioning post encoder ; b ) one in which there is additional signal conditioning pre - encoder ; and a ) be within the same housing as the cd , in which case the composite unit is referred to as the crcd . in this case , at the time of use , assembly of the composite defibrillator device — i . e . the device which is capable of communication with the remote station — entails attaching the crcd to the maed ; b ) be within the same housing as the maed , in which case the composite unit is referred to as the cdcaed . in this case , at the time of use , assembly of the composite device entails attaching the cdcaed to the cd ; or c ) may be a stand - alone unit . in this case , at the time of use , assembly of the composite device entails attaching the ap to the maed and attaching the cd to the ap . the maed 550 contains substantially all of the components of an aed , as is known in the art . ecg signals 556 and other telemetry signals ( including physiologic and equipment related telemetry ) 558 , output unit 550 via 542 a / b . the illustration of both outputs going through the same pin is purely schematic ; though it may occur as such , the use of multiple pins , and of non - contact signal transfer arrangements , as is discussed hereinabove , are possible . also externalized is the control of ( i ) the defibrillator circuits 552 ( defibrillation electrodes and sensing input [ if any ] which would be attached to 552 , not shown in the figure ), and ( ii ) other control circuits ( e . g . pacing , screen control [ if any ], troubleshooting and maintenance , etc .). in a preferred embodiment of the invention , the presence of an electrically intact link of both ( i ) the maed to the cd ( via the ap ) and ( ii ) an intact communication link with the mp would , at 554 , disable the connection of the aed logic 560 to 552 . the result would be that a ) the mp would have sole control of shocking ( and pacing , if the pacing feature was present ); and b ) the aed logic / shock decision circuits would be disconnected from the defibrillator charging and shock delivery circuits . the disconnection of the aed logic / shock decision circuits ( contained within 560 ) from the charging and shock delivery circuits 552 could be accomplished by a control signal which either ( i ) originates within 554 or ( ii ) is delivered to 554 when the proper connections have been established . the establishment of the proper connections may be confirmed by a handshaking process which is described hereinabove and hereinbelow , or by other methods which will be obvious to those skilled in the art . embodiments of the invention without the aforementioned disconnect of aed logic from aed shocking circuits are possible . in this instance , either the maed or the remotely located mp could decide to deliver a shock . this might be particularly useful if the maed was operated by a trained person such as a physician or emergency medical technician . embodiments of the invention are possible in which the mp can see what decision the aed logic would have made . in such an embodiment , the aed decision would be a signal which traverses the route 560 → 558 → 542 a → 542 b → etc . fig1 and the associated specification regarding the present example could , besides applying to a modified aed , also apply to a modified manually operated external defibrillator , as discussed in conjunction with fig1 , hereinabove . in such a circumstance , element 560 and its connections would be absent , replaced by a ) a display device for displaying ecg signals for a local medical professional , and b ) local mp control input ( s ) for inputting defibrillation and / or pacing commands — as shown in fig1 . optionally , the remote mp could , by sending a signal to 554 , enable / disable local mp access to defibrillator control . fig1 and the associated specification regarding the present example could also apply to a modified external defibrillator which has both an aed mode and a local mp controlled ( i . e . non - automatic ) mode , as discussed in conjunction with fig1 , hereinabove . in such a circumstance , aed logic device 560 and its connections would be present . in addition ( as shown in fig1 and discussed in the associated specification ), there would be a ) a display device for displaying ecg signals for a local medical professional coupled to 556 , b ) local mp control input ( s ) for inputting defibrillation and / or pacing commands coupled to 554 , and c ) a means for maintaining a hierarchical control structure , i . e . establishing which control source ( among remote mp , local mp and aed logic device ) takes priority . such means could be pre - programmed or pre - wired within 554 , or could be supplied to 554 by a remote mp . fig1 shows additional units and signals to support a handshaking arrangement which may allow the cd to have information about the adequacy of the hookup of : it may also allow the cdcaed or the ap to have information about the adequacy of the hookup of the maed . the purpose of the handshaking is that if the maed receives a signal indicating inadequate hookup , the signal ( arriving at 554 in fig1 ) would restore conventional ( i . e . autonomous ) aed function . it might also cause the maed to attempt to remedy the inadequate connection by electronic means , and / or cause it to notify the enabler of the situation . if the cd receives a signal indicating inadequate hookup , the signal ( arriving at 502 in fig1 ) would be used to notify the mp of the linkage problem . the mp could a ) attempt to remotely repair the problem ; b ) notify the enabler of the problem , suggesting a better attempt at linking the units ; and / or c ) send a signal which attempts to notify the maed of the failed link , thereby causing a change in maed function to that of a conventional ( autonomous ) aed each of a ), b ) and c ) immediately above may also be performed by the cd itself . to facilitate this , a direct signal connection from the ap to 512 ( not shown in the figure ) would be beneficial . referring again to fig1 , the basic handshake loop is from the microprocessor 602 within cd 600 , generating handshake signal 604 ( corresponding to signal 31 a of fig2 ), transmitted to microprocessor 622 in cdcaed or ap 620 via pins 610 a / b ( or additional pins , or wireless arrangement ), generating handshake signal 624 ( corresponding to signal 31 b of fig2 ), transmitted to microprocessor 602 in cd 600 via pins 612 a / b ( or additional pins , or wireless arrangement ). 10 / 460 , 458 describes a variety of alternate handshake signals which may be used to signal a non - received handshake and to signal a restored handshake , one or more of which signals may be used in the present invention . the specification hereinabove , in conjunction with fig2 and 3 gives additional information about approaches to communication confirmation methods and apparatus . in the case of separate maed and ap units , the quality of a maed - ap handshake 626 may be passed along to the cd via 612 a / b . the transmission of a signal indicating a failed ap - maed handshake would have a similar effect as the transmission of a failed ap - cd handshake ( or a failed cdcaed - cd handshake ): 602 would send a signal via transmitter 606 to the mp ; this would be acted on as discussed above . 602 would also cause 606 to send a failed handshake signal ( which , in a preferred embodiment of the invention would indicated the point of failure insofar as it may be known ), in the event that it did not receive a handshake signal within a preset time after sending one . in the case of 622 not receiving a handshake signal in a preset time after sending one , it would issue signal 628 indicating a handshake failure , to the maed . this would initiate , as indicated above , a variety of possible maed actions . furthermore , 628 could be issued if 622 receives a signal indicating that 602 failed to receive a handshake signal . the cdcaed may be manufactured as such at the time of its original build . alternatively , an aed may be modified , post initial production , to have the functionality and components of a cdcaed . in either of the two aforementioned cases , it would be possible to further configure the cdcaed such that the remote control feature could be an option which must be turned on by either a key , another means of identification , a signal , combinations of the aforementioned , or other means as is obvious to those skilled in the art . in the case of a 3 - unit device , although fig1 c and 10 shows a geometry in which the adapter lies physically between the maed and the cd , it would be possible , in another embodiment of the invention , to have : a ) the adapter connect to the maed but not directly to the cd ; and in yet another embodiment of the invention , it would be possible to have : a ) the adapter connect to the cd but not directly to the maed ; and fig1 a shows one possible embodiment of the apparatus which may connect a cd to a cdcaed : cdcaed 700 can accommodates a cd ( e . g . a cellular telephone ) within appropriate shaped cellular telephone receptacle section 702 . within 702 is a multi - pin connector 704 which will functionally perform as 522 b and 522 d of fig1 . fig1 b shows the cell phone 706 in place : 704 has been inserted into a slot within 706 which contains components analogous to 522 a and 522 c of fig1 . additional apparatus to secure the cellular telephone in place may be present . fig1 shows one embodiment of the invention containing apparatus for securing a cd 806 at the end of a maneuverable boom 804 . the boom is part of either the maed or the cdcaed 800 . the purpose of the arrangement would be to let the mp maneuver the cd so that audio and , if present , video communication is optimized . the angular relationships between the cd and the enabler , or between the cd and the victim , may change as the management of the emergency situation progresses , and this feature would be useful in such a circumstance . in the figure , holding apparatus 808 may be an elastic strap which helps fix 806 to a receptacle within 804 . many other arrangements for securing 806 to 804 will be obvious to those skilled in the art . the apparatus shown in fig1 would also be useful in cases where the relationship geometric relationship among cd , enabler and victim does not change ; allowing the mp to do the optimizing of cd position and angulation saves valuable time , i . e . by taking the task away from the enabler . embodiments of the invention in which the boom is either extensible or not extensible are possible . c ) either the mp or the enabler can orient and / or extend the boom , are possible . in embodiments of the invention in which the mp may orient and / or extend the boom , apparatus 802 allows the mp to do so . such apparatus may allow the mp to control the angulation and / or rotation of the boom at one or more points along the shaft , to rotate or tilt the cd at the end of the shaft , to extend or retract the shaft , or combinations of these motions . embodiments of the invention in which one or more of the audio or video interfaces is part of the maed rather than part of the cd are possible . an obvious example would be to use a larger video display screen or louder audio apparatus that may be part of the maed . however , examples in which the microphone and / or the video camera are part of the maed are also possible . embodiments in which one or more of these components is part of the ap are also possible . example : versions of the system with at least one implantable component fig1 a , 14b and 14 c show embodiments of the invention in which the cmtd is implanted inside the body . since the cmtds in each of these three figures could be pacemakers or defibrillator - pacemakers , a logic device — which controls the automatic pacing and sensing function of each respective device — is shown within each . referring to fig1 a , cmtd 902 containing logic device 904 is implanted inside of person 900 . in the embodiment shown by fig1 a , the ap 906 is inside the body , and is linked to 902 by a hard - wired connection . signals 910 link ap 906 and cd 908 . the signals may be any short range wireless signal , e . g . radiofrequency , as is known in the art . the cd communicates with a remote station 911 , using any of the means described hereinabove . thus a remotely located medical professional can control the implanted device , i . e . by a ) receiving signals from intracardiac and / or intrathoracic electrodes ( not shown ) sent from 902 to 906 to 908 to the rs 911 ; and b ) sending control signals from the rs 911 to 908 to 906 to 902 . in one embodiment of the invention , the cd is a cellular telephone in the pocket of person 900 , or elsewhere in the vicinity of 900 . other communication devices are possible for the cd . the cd may also be part of a pacemaker / defibrillator programmer . in such a circumstance , the programmer would also contain : a ) display device 912 for displaying intracardiac and / or intrathoracic electrical activity to a local mp ; and b ) at least one of ( i ) local pacing control device ( s ) 914 and ( ii ) local defibrillator control device ( s ) 916 , each of which lets a local mp assess the current and prior heart rhythm , assess the functioning of cmtd , and change its operating parameters . these local control devices would allow the mp to change the operating parameters : for long term use ( e . g . programming an icd &# 39 ; s parameters for vt detection ), and / or for current use ( e . g . dealing with an episode of vt in progress at the time of local mp use ). the display device may also be part of a touch sensitive screen , which would allow a local mp to input commands , in a manner known in the art . embodiments of the invention are possible in which one , two or three of 912 , 914 and 916 : a ) communicate directly with the cmtd ( shown in the figure by long dashed lines ); b ) communicate with the cmtd via the ap ( not shown in the figure ) by exchanging signals directly with the ap ; c ) communicate with the cmtd via the cd ( shown in the figure by short dashed lines ), along the routes 908 to 906 to 904 , and 904 to 906 to 908 . referring to fig1 b , cmtd 932 containing logic device 934 is implanted inside of person 930 . in this embodiment , the ap 936 which is outside the body , exchanges signals 939 with cmtd 932 by a wireless connection . signals 940 link ap 936 and cd 938 . each of signals 939 and 940 may be any short range wireless signal , e . g . radiofrequency , as is known in the art ; the 936 - 938 connection may also be a hard - wired one . the cd communicates with a remote station 941 , using any of the means described hereinabove . thus a remotely located medical professional can control the implanted device , i . e . by a ) receiving signals from intracardiac and / or intrathoracic electrodes ( not shown ) sent from 932 to 936 to 938 to the rs 941 ; and b ) sending control signals from rs 941 to 938 to 936 to 932 . in one embodiment of the invention , the cd and the adapter are physically linked — as shown for the crcd of fig5 a , and may constitute a communication device carried by person 930 , or be in the vicinity of 930 . the adapter may also be part of a pacemaker / defibrillator programmer . in such a circumstance , the programmer would also contain a ) display device 942 for displaying intracardiac and / or intrathoracic electrical activity to a local mp ; and b ) at least one of ( i ) local pacing control device ( s ) 944 and ( ii ) local defibrillator control device ( s ) 946 , each of which lets a local mp assess the current and prior heart rhythm , assess the functioning of cmtd , and change its operating parameters . these local control devices would allow the mp to change the operating parameters : for long term use ( e . g . programming an icd &# 39 ; s parameters for vt detection ), and / or for current use ( e . g . dealing with an episode of vt in progress at the time of local mp use ). the display device may also be part of a touch sensitive screen , which would allow a local mp to input commands , in a manner known in the art . embodiments of the invention are possible in which one , two or three of 942 , 944 and 946 : a ) communicate directly with the cmtd ( shown in the figure by long dashed lines ); b ) communicate with the cmtd via the ap by directly exchanging signals with the ap ( shown in the figure by short dashed lines ). referring to fig1 c , cmtd 962 containing logic device 964 is implanted inside of person 960 . in the embodiment shown by fig1 c , the ap 966 is inside the body , and is linked to 962 by a hard - wired connection ; cd 968 is also inside the body , and is linked to ap 966 by a hardwired connection . the cd communicates with remote station 970 , using any of the wireless means described hereinabove . thus a remotely located medical professional can control the implanted device , i . e . by a ) receiving signals from intracardiac and / or intrathoracic electrodes ( not shown ) sent from 962 to 966 to 968 to 970 ; and b ) sending control signals from the 970 to 968 to 966 to 962 . in one embodiment of the invention , one or more of the adapter connections ( to 962 and / or 968 ) may be wireless . a pacemaker / defibrillator programmer may be used in conjunction with the implanted hardware . in such a circumstance , the programmer would also contain : a ) display device 972 for displaying intracardiac and / or intrathoracic electrical activity to a local mp ; and b ) at least one of ( i ) local pacing control device ( s ) 974 and ( ii ) local defibrillator control device ( s ) 976 , each of which lets a local mp assess the current and prior heart rhythm , assess the functioning of cmtd , and change its operating parameters . these local control devices would allow the mp to change the operating parameters : for long term use ( e . g . programming an icds parameters for vt detection ), and / or for current use ( e . g . dealing with an episode of vt in progress at the time of local mp use ). the display device may also be part of a touch sensitive screen , which would allow a local mp to input commands , in a manner known in the art . embodiments of the invention are possible in which one , two or three of 972 , 974 and 976 : b ) communicate with the cmtd via the ap ( not shown in the figure ) by exchanging signals directly with the ap ; c ) communicate with the cmtd via the cd ( shown in the figure by short dashed lines ). there is thus described apparatus and methodology which will allow a cell phone or other portable communications device to serve as the communications end of a remotely controlled defibrillator , thereby facilitating the adaption of minimally modified aeds , manually controlled defibrillators and implanted pacemakers and defibrillators to serve as a sub - unit of remotely controlled defibrillators . many other modifications based on similar principles will be obvious to those skilled in the art .

a cardiac monitoring and treatment apparatus allows a victim of a medical emergency access to a medical professional who can monitor , diagnose and treat the victim from a remote site . the apparatus includes a cardiac monitoring and treatment device coupled to an electronic adaptor designed to communicate with a local , first transmitting / receiving device which , in turn , is adapted to electronically communicate with a remote , second transmitting / receiving device used by the mp . the cmpd comprises a cardiac treatment circuit for effecting cardiac pacing and / or defibrillation and a cardiac signal circuit for receiving cardiac signals . the cardiac signals are transmitted from the signal circuit to the second t / r device for evaluation by the mp , the mp may transmit a control signal to the treatment circuit , and , in response thereto , the treatment circuit may generate one or more electrical pulses for treatment of the victim .

fig1 a and 1b illustrate front elevation and back elevation views , respectively , of a backpack 10 that includes support arrangements , which can be deployed to convert the backpack into a resting platform such as a bed or a chaise . backpack 10 includes a sack section 12 usually made of a fabric or the like material . on the side 14 configured for resting against the user &# 39 ; s body ( back side ) are provided at least one , but usually two , shoulder straps 16 . the manner of use of a backpack is well known . therefore , how a backpack is used will not be described here . fig1 a and 1b illustrate the apparatus in a non - use state . thus , the support arrangements are in a stored state . however , pull - out handles 18 are visible in fig1 b . fig2 a and 2b illustrate front and side elevation views , respectively , of backpack 10 . for the sake of clarity , the sack section 12 and the shoulder straps 16 are only illustrated in outline form . a backpack 10 according to the invention includes at least one , but preferably two support arrangements . each support arrangement includes a pull out handle 18 , a compliant and rollable fabric 20 , which , in its stored state , is rolled around a spring loaded roller 22 ( similar to the one disclosed in the related applications discussed in the background section ) and a pair of telescopic arms 11 each coupled to an end of pull out handle 18 . each telescopic arm 11 includes an external extension tube 24 having a first internal diameter , a middle extension tube 26 having a second internal diameter smaller than the first internal diameter , and an internal extension tube ( or rod ) 28 having an outer diameter that is smaller than the first and the second internal diameters . internal extension tube 28 is received inside of middle extension tube 26 and middle extension tube is received inside of external extension tube 24 . thus , internal extension tube 28 may be extracted from the interior of middle extension tube 26 , and middle extension tube 26 may be extracted from the interior of external extension tube , whereby the three bodies can be extended / collapsed in a telescopic fashion . referring to fig3 a - 3d , in order to integrate tubes 24 - 28 , appropriate stoppers may be employed . referring to fig3 a ( identified as region s - 01 in fig2 a ), a pair of extension stoppers 30 are provided at the end of external extension tube 24 . extension stoppers 30 are configured to engage a section of middle extension tube 26 when middle extension tube 26 has been extended out a predetermined distance . thus , for example , each extension stopper 30 may be pivotably mounted about a pin 31 ( see fig3 c ) allowing the stoppers 30 to swing into features defined in internal extension tube 24 . referring to fig3 d , for example , middle extension tube 26 may be provided with stopper catcher 32 recesses at a short distance from an end thereof . when middle extension tube 24 has been pulled out far enough extension stoppers 30 swing into stopper catchers 32 of middle extension tube 26 and prevent its further longitudinal travel . note that the same mechanism is preferably used to stop the internal extension tube 28 from advancing beyond a predetermined point . specifically , extension stoppers 30 are provided at the end of middle extension tube 26 in the same manner as described above , and internal extension tube 28 is provided with stopper catcher 32 recesses ( see fig3 d ) which engage extension stoppers 30 at the end of middle extension tube 26 when internal extension tube 28 has been pulled out far enough . note that the end of internal extension tube 28 is coupled to pull out handle 18 . thus , when pull out handle 18 is pulled away from sack 12 , internal extension tube 28 is extracted causing the telescopic extension of the tubes . further note that external extension tube 24 includes extension stopper 30 ( see fig3 b and 3d ), which pivot about pivot pin ( see fig3 b ), and are received inside respective stopper catch 32 recesses , deployed in a common support tube 33 which houses the telescopic arms . common support tube 33 may be longitudinally aligned with tubes 24 , 26 and 28 , and disposed on or inside sack 12 backpack 10 . one purpose of common support tube 33 is to set how far out external extension tube 24 may be extended outwardly , thereby setting the limit for the length of the telescopic arm 11 in its extended state . referring now back to fig2 a and 2b , while only one telescopic arm 11 has been described , it should be noted that two telescopic arms 11 are used to realize a support arrangement . each telescopic arm 11 is positioned adjacent ( i . e . close to ) a respective side of two opposite sides of sack 12 in order to set the width of the support arrangement . furthermore , while one support arrangement may be employed in a backpack 10 according to the present invention , two support arrangements , each deployable from a respective side of two opposite sides of sack 12 , is preferred . note that the telescopic support arms of each support arrangement may be extended to the same length , or different lengths , or may be configured to be the same or different length when stored . while not shown in the figures , it will be understood that to use the present invention , the user will extend the telescopic arms by pulling out the handle 18 . the rollout fabric 20 , which may be coupled to pull out handle 20 , will be automatically pulled out ( i . e ., rolled out ). once telescopic arms 11 are fully extended , fabric 20 will provide a support for the user in generally the same manner as described in the related applications set forth in the background section . note that , optionally , a rigid plate 19 or the like ( fig3 e ) may be integrated with sack portion 12 between arms 11 at back side of sack 12 to provide further support for the weight of the user . preferably , the rigid plate is coupled to common support tubes 33 , but such coupling is not necessary and the rigid plate may be left uncoupled . fig4 a , 4b , 4c and 4d show front , right , left and back elevation views of a suitcase 34 that includes the same support arrangements as those of backpack 10 . thus , instead of a sack 12 , suitcase 34 includes a suitcase section 36 having one surface 37 which can provide , partial support for the user when the support arrangements are deployed , similar to the suitcases shown in the related applications discussed in the background section . fig5 a and 5b illustrate suitcase 34 . for the sake of clarity the suitcase section 36 is shown in outline form . note that like numerals are used to identify like features as those described above . fig6 a and 6b illustrate suitcase 34 with the support arrangements deployed for use . note that a compartment 38 is provided inside suitcase section 36 to house fabric 20 and its associated roller . such a component is also shown in the related applications discussed in the background section . also , note a pull - out handle support 39 , which is preferably hingedly coupled to handle 18 , may be optionally provided for further support as also illustrated in the related applications described in the background section . fabric 20 is permanently attached to handle 18 ; whereas , in the arrangements shown in the related applications described in the background section , the fabric is detachably attached . fig7 a , 7b and 7c illustrate the stopper catcher arrangements described above in a deployed state . fig8 a , 8b , 8c and 8d show front , left , right and back elevation views , respectively , of a suitcase 40 according to a new variation . suitcase 40 includes a suitcase section 36 having a surface 37 that can be used for partial support of a user . similar to the backpack 10 and suitcase 34 and also similar to the suitcases shown in the related applications described in the background section , suitcase 40 includes support arrangements , which when deployed , convert the suitcase into a bed or a chaise . however , suitcase 40 employs a novel configuration . fig9 a illustrates suitcase 40 with the arrangements deployed . the support arrangements in suitcase 40 include a rollable fabric 20 , a fabric roller 22 , which is disposed in a compartment 38 residing at or inside handle 18 , rather than at or inside suitcase section 36 . fabric 20 is permanently or detachably attached to suitcase section 36 at an edge which is adjacent to surface 37 of suitcase section 36 . note that suitcase 40 preferably includes two support arrangements each residing at one side of two opposite sides of suitcase section 36 , each side being preferably adjacent surface 37 . a support arrangement in suitcase 40 includes a one piece arm ( not a multiple piece telescopic arm 11 ) which resides in and is slidably supported within a support tube 42 . for example , one arm 44 is attached at one end to a handle 18 , and is provided with a rubber stopper 46 at another , opposite end . rubber stopper 46 is disposed on the exterior surface of arm 44 and is sized to make contact with the interior surface of support tube 42 . arm 44 may have a first interior diameter that is larger than the cross - section ( exterior diameter ) of another arm 48 . another arm 48 is coupled at one end to another handle 18 having another component 38 in which a roller 22 and fabric 20 reside ( in a stored state ), and includes another rubber stopper 50 at an opposite end . rubber stopper 50 preferably extends around the exterior surface of arm 48 and is sized so that it makes contact with the interior surface of support tube 42 . note that in the stored state , arm 44 is received inside of support tube 44 until it meets rubber stopper 50 , and arm 48 is moved , relative to rubber stopper 50 and received inside of arm 44 in the stored state . fig9 b , 9c and 9d illustrate arms 44 and 48 in their stored state . note that arm 48 may include a rubber top 52 or the like which is sized to engage the interior of arm 44 so that , in a stored state , arm 48 does not move around and cause rattling . arm 44 is configured to slide relative to stopper 46 , while stopper 46 is preferably fixed relative to support tube 42 and does not exit from support tube 42 when arm 44 is extracted . similarly , arm 48 is configured to slide relative to stopper 50 while stopper 50 is preferably fixed relative to support tube 42 so that rubber stopper 50 does not exit support tube 42 when arm 48 is extended . alternatively , stoppers 46 and 50 may be allowed to slide toward one another inside support tube 42 ; however , the respective ends of support tube 42 may be configured to prevent stoppers 46 , 50 from falling out of support tube 42 . it should be noted that while only support arms 44 and 48 are discussed a each support arrangement , as illustrated in the figures , would include two support arms , each positioned adjacent a respective side of opposite sides of a suitcase section 36 , and each connected at one end to a pull - out handle 18 . thus , one support arrangement would include two arms 44 each connected to a respective end of a pull - out handle 18 and another support arrangement would include a pair of arms 48 each connected at one end to a handle 18 . although the present invention has been described in relation to particular embodiments thereof , many other variations and modifications and other uses will become apparent to those skilled in the art . it is preferred , therefore , that the present invention be limited not by the specific disclosure herein , but only by the appended claim .

a portable apparatus including a storage and a support arrangement that is convertible to a resting platform defined as a back pack or a suitcase .

the xenogeneic articular cartilage heterograft produced in accordance with the method of the invention is substantially non - immunogenic , while generally maintaining the mechanical properties of native articular cartilage . while the articular cartilage may undergo some shrinkage during processing , a xenogeneic articular cartilage heterograft prepared in accordance with the invention will have the general appearance of a native articular cartilage . the xenogeneic articular cartilage heterograft may also be cut into segments , each of which may be implanted into a joint of a recipient as set forth below the invention provides , in one embodiment , a method for preparing or processing a xenogeneic articular cartilage for engraftment into humans . as defined herein , &# 34 ; xenogeneic &# 34 ; means any non - human animal . thus articular cartilage may be harvested from any non - human animal to prepare the heterografts of the invention . articular cartilage from transgenic non - human animals or from genetically altered non - human animals may also be used as heterografts in accordance with the present invention . preferably , bovine , ovine , or porcine knee joints serve as sources of the articular cartilage used to prepare the heterografts . more preferably , immature pig , calf or lamb knee joints are the sources of the articular cartilage , since the cartilage of younger animals may be inherently more elastic and engraftable than that of older animals . most preferably , the age of the source animal is between six and eighteen months at time of slaughter . in the first step of the method of the invention , an intact articular cartilage is removed from a joint of a non - human animal . any joint may serve as the source of articular cartilage . preferably articular cartilage from a corresponding donor joint is used to make the articular cartilage heterograft of the invention . for example , articular cartilage from a femero - tibial ( stifle ) joint is used to make an articular cartilage heterograft for implantation into a knee . similarly , articular cartilage from a donor animal &# 39 ; s hip joint is used to make an articular cartilage heterograft for a human hip joint . the joint which serves as the source of the articular cartilage should be collected from freshly killed animals and preferably immediately placed in a suitable sterile isotonic or other tissue preserving solution . harvesting of the joints should occur as soon as possible after slaughter of the animal and should be performed in the cold , i . e ., in the approximate range 5 - 20 ° c ., to minimize enzymatic and / or bacterial degradation of the articular cartilage tissue . the articular cartilage is harvested from the joints in the cold , under strict sterile technique . in accordance with the invention , a fine peel of articular cartilage with a small layer of subchondral bone is shaved from the donor joint to form the heterograft . the heterograft is then washed in about ten volumes of sterile cold water to remove residual blood proteins and water soluble materials . the heterograft is then immersed in alcohol at room temperature for about five minutes , to sterilize the tissue and to remove non - collagenous materials . in a preferred form of the invention , as heterograft appears as a hyaline tissue supported on a bone substrate , having generally a spherical - shaped principal surface on the top side ( the &# 34 ; superior surface &# 34 ;), with the under surface of bone ( the &# 34 ; inferior surface &# 34 ;) being rough . after alcohol immersion , the heterograft may be directly implanted a prepared site at an articular surface of a human patient . alternatively the heterograft may be subjected to at least one of the treatments set forth below . when more than one treatment is applied to the heterograft , the treatments may occur in any order . in one embodiment of the method of the invention , the heterograft may be treated by exposure to radiation , for example , by being placed in an ultraviolet radiation sterilizer such as the stragene ™ model 2400 , for about fifteen minutes . in another embodiment , the heterograft may be treated by again being placed in an alcohol solution . any alcohol solution may be used to perform this treatment . preferably , the heterograft is placed in a 70 % solution of isopropanol at room temperature . in another embodiment , the heterograft may be subjected to ozonation . in another embodiment , the heterograft may be treated by freeze / thaw cycling . for example , the heterograft may be frozen using any method of freezing , so long as the heterograft is completely frozen , i . e ., no interior warm spots remain which contain unfrozen tissue . preferably , the heterograft is dipped into liquid nitrogen for about five minutes to perform this step of the method . more preferably , the heterograft is frozen slowly by placing it in a freezer . in the next step of the freeze / thaw cycling treatment , the heterograft is thawed by immersion in an isotonic saline bath at room temperature ( about 25 ° c .) for about ten minutes . no external heat or radiation source is used , in order to minimize fiber degradation . the heterograft may optionally be exposed to a chemical agent to tan or crosslink the proteins within the interstitial matrix , to further diminish or reduce the immunogenic determinants present in the heterograft . any tanning or crosslinking agent may be used for this treatment , and more than one crosslinking step may be performed or more than one crosslinking agent may be used in order to ensure complete crosslinking and thus optimally reduce the immunogenicity of the heterograft . for example , aldehydes such as glutaraldehyde , formaldehyde , adipic dialdehyde , and the like , may be used to crosslink the collagen within the interstitial matrix of the heterograft in accordance with the method of the invention . other suitable crosslinking agents include aliphatic and aromatic diamines , carbodiimides , diisocyanates , and the like . when glutaraldehyde is used as the crosslinking agent , for example , the heterograft may be placed in a buffered solution containing about 0 . 05 to about 5 . 0 % glutaraldehyde and having a ph of about 7 . 4 . any suitable buffer may be used , such as phosphate buffered saline or trishydroxymethylaminomethane , and the like , so long as it is possible to maintain control over the ph of the solution for the duration of the crosslinking reaction , which may be from one to fourteen days , and preferably from three to five days . the crosslinking reaction should continue until the immunogenic determinants are substantially removed from the xenogeneic tissue , but the reaction should be terminated prior to significant alterations of the mechanical properties of the heterograft . when diamines are also used as crosslinking agents , the glutaraldehyde crosslinking should occur after the diamine crosslinking , so that any unreacted diamines are capped . after the crosslinking reactions have proceeded to completion as described above , the heterograft should be rinsed to remove residual chemicals , and 0 . 01 - 0 . 05 m glycine may be added to cap any unreacted aldehyde groups which remain . prior to treatment , the outer surface of the heterograft may optionally be pierced to increase permeability to agents used to render the heterograft substantially non - immunogenic . a sterile surgical needle such as an 18 gauge needle may be used to perform this piercing step , or , alternatively a comb - like apparatus containing a plurality of needles may be used . the piercing may be performed with various patterns , and with various pierce - to - pierce spacings , in order to establish a desired access to the interior of the heterograft . piercing may also be performed with a laser . in one form of the invention , one or more straight lines of punctures about three millimeters apart are established in the outer surface of the heterograft . prior to implantation , the articular cartilage heterograft of the invention may be treated with limited digestion by proteolytic enzymes such as ficin or trypsin to increase tissue flexibility , or with glycosidases to remove surface carbohydrate moieties , or coated with anticalcification agents , antithrombotic coatings , antibiotics , growth factors , or other drugs which may enhance the incorporation of the heterograft into the recipient knee joint . the articular cartilage heterograft of the invention may be further sterilized using known methods , for example , with additional glutaraldehyde or formaldehyde treatment , ethylene oxide sterilization , propylene oxide sterilization , or the like . the heterograft may be stored frozen until required for use . the articular cartilage heterograft of the invention , or a segment thereof , may be implanted into damaged human joints by those of skill in the art using known arthroscopic surgical techniques . specific instruments for performing arthroscopic techniques are known to those of skill in the art , which ensure accurate and reproducible placement of articular cartilage implants . the underlying bone bed of the recipient joint is prepared with a bone burr to produce a cancellous bleeding bed . grafting can involve either the entire articular surface or a portion of the articular surface . the substantially non - immunogenic articular cartilage heterograft of the invention is applied to the recipient joint as a cover , which is held in place by one or more suture anchors , absorbable pins , screws , staples , and the like . a fibrin clot may also be used to hold the substantially non - immunogenic articular cartilage heterograft in place . those of skill in the art will recognize that the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof . the presently described embodiments are therefore to be considered in all respects as illustrative and not restrictive , the scope of the invention being indicated by the appended claims rather than by the foregoing description , and all variations of the invention which are encompassed within the meaning and range of equivalency of the claims are therefor intended to be embraced therein .

the invention provides an article of manufacture comprising a substantially non - immunogenic articular cartilage heterograft for implantation into humans . the invention further provides a method for preparing an articular cartilage heterograft by removing at least a portion of an articular cartilage from a non - human animal to provide a heterograft ; washing the heterograft in saline and alcohol ; subjecting the heterograft to at least one treatment selected from the group consisting of exposure to ultraviolet radiation , immersion in alcohol , ozonation , freeze / thaw cycling , and optionally to chemical crosslinking . in accordance with the invention the heterograft has substantially the same mechanical properties as the native xenogeneic articular cartilage .

fig1 shows the apparatus for the basic measurement of plant water status . a sensor surface 1 is placed within the plant 2 and a second electrode 7 is placed in the root environment . a first wire 3 is connected to the sensor surface . a second wire 7 is connected to the second electrode . fig2 shows an expanded view of the sensor surface inside the plant . in this case the location within the plant is the petiole of a leaf . the sensor surface goes into one side of the petiole and out the other side of the petiole . the electrical capacitance between the ends of the two wires is measured . the total sensor surface length 6 within the plant is obtained with a caliper or equivalent . in terms of the measured variables , water content for a cylindrical sensor becomes water ⁢ ⁢ content = electrical ⁢ ⁢ capacitance length ⁢ ⁢ of ⁢ ⁢ the ⁢ ⁢ sensor ⁢ ⁢ surface ⁢ ⁢ within ⁢ ⁢ the ⁢ ⁢ plant ⁢ ( 1 ) the units of water content are farads / meter . in terms of the values commonly encountered under field conditions , the units are nanofards / millimeter . fig3 a and 3b show the sensor surface with clusters of water on the surface under high water content conditions and low water content conditions , respectively . as the water content of the plant increases , the wetted area 12 on the sensor surface 14 increases and vice versa . the question that must be addressed is what relation does electrical capacitance have with these changes in wetted surface area on the sensor surface . how can electrical capacitance give an indication of the change in the extent of wetted area shown in fig3 a and fig3 b ? to answer this question one must examine the characteristics of water on the surface of a noble metal surface . water on the surface of a noble metal contains dissolved oxygen . this oxygen adsorbs and ionizes on the surface of the noble metal sensor ( hoare , 1968 ). ionized oxygen forms one layer of charge of an electrical capacitor . the second layer of charge consists of electrons in the metal . these two opposing charge layers form an electrical capacitor . the magnitude of the capacitor is a function of the wetted surface area of the filament in the tissue , the distance between the charge layers and the dielectric constant of the material between the charge layers . in this case the distance between the charge layers is fixed by virtue of the fact that water resides on the sensor surface . the dielectric is water . as the wetted area changes , the electrical capacitance of the interface changes . in conclusion , the value of interfacial capacitance of the sensor surface - wetted area gives a measure of the extent of this wetted area . this theory can be verified by the following simple experimental procedure . a cup is filled with tap water . a sensor surface ( in this case a filament of noble metal 150 micrometers in diameter ) is suspended above the surface of the water . a second electrode is immersed in a cup . the second electrode is a brass rod , 2 . 42 millimeters in diameter , immersed to a depth of 78 millimeters . the filament is gradually lowered into the water . the capacitance is measured between a first wire attached to the sensor surface and a second wire attached to the second electrode in the same manner as shown in fig1 . this situation matches the situation in the plant except the root environment is totally liquid in this calibration setup and the sensor surface is progressively covered with water . fig4 illustrates the measured capacitance as the sensor surface is immersed deeper and deeper into the water . the increase in wetted area results in a linear increase in capacitance . in other words , as the wetted area of the sensor surface increases , the capacitance measured between the two wires increases . this is because the layers of charge in the water and metal increase in area . a linear least squares fit of the data points yields the relation : where y is the measured capacitance in nanofarads and x is the depth of immersion in millimeters . this equation states that the capacitance increases 199 nanofarads for each increase in one millimeter in the depth of immersion . by extrapolating to zero immersion , the capacitance is 30 nanofarads . this is the intercept on the vertical axis of the straight line fit over the data points . this intercept is the capacitance in the remainder of the circuit pathway from the water in the cup through the water - second electrode interface and back through the second electrode wire . this capacitance is a constant value . the measured capacitance is the total capacitance in the path consisting of this constant value of capacitance plus a variable value of capacitance depending on the water content of the plant . the next question to address is how the ratio on the right side of eqn . 1 can be interpreted in terms of a “ water dipstick .” first substitute eqn 2 in eqn . 1 , water ⁢ ⁢ content = 199 * wetted ⁢ ⁢ length ⁢ ⁢ of ⁢ ⁢ sensor + 30 length ⁢ ⁢ of ⁢ ⁢ the ⁢ ⁢ sensor ⁢ ⁢ surface ⁢ ⁢ within ⁢ ⁢ the ⁢ ⁢ plant ( 3 ) water ⁢ ⁢ content = ( 199 * wetted ⁢ ⁢ length ⁢ ⁢ of ⁢ ⁢ sensor ⁢ ⁢ surface + 30 ) * diameter * ∏ length ⁢ ⁢ of ⁢ ⁢ the ⁢ ⁢ sensor ⁢ ⁢ surface ⁢ ⁢ within ⁢ ⁢ the ⁢ ⁢ plant * diameter * ∏ ( 4 ) water ⁢ ⁢ content = 199 * wetted ⁢ ⁢ area total ⁢ ⁢ sensor ⁢ ⁢ surface ⁢ ⁢ area + 30 * diameter * π total ⁢ ⁢ sensor ⁢ ⁢ surface ⁢ ⁢ area ( 5 ) water ⁢ ⁢ contenet = k 1 * wetted ⁢ ⁢ area ⁢ ⁢ of ⁢ ⁢ the ⁢ ⁢ sensor ⁢ ⁢ surface total ⁢ ⁢ area ⁢ ⁢ of ⁢ ⁢ the ⁢ ⁢ sensor ⁢ ⁢ surface + k 2 ( 6 ) where k 1 is 199 nanofarads / mm and k 2 is 30 / length of the sensor surface within the plant in millimeters . eqn 6 indicates the ratio of the measured capacitance over the measured length of the sensor surface within the plant is proportional to a ratio of the wetted area of the sensor surface to the total area of the sensor surface plus an additive constant . in other words , a water dipstick plus an additive constant . the additive constant is usually neglected . based on field observations at over forty production agriculture sites in the summer of 2003 , the variable value of capacitance per unit length at the sensor surface varies between about 20 to 140 nanofarads / mm . this indicates plants with a very high water content will not reach the maximum level of 199 nanofarads / millimeter . in other words , even at very high water content levels there is a substantial part of the surface area of the sensor surface covered with air . the range of immersion depth in fig4 matches the range of diameters of the stems , petioles and peduncles encountered in normal agricultural practice , that is , from two to six millimeters . further verification of the two charge layer model of the interface between the sensor surface and water can be gained by calculating the distance between the two charge layers based on values in eqn . 2 . for a capacitor consisting of two parallel plates separated by a dielectric material ( boylstad and nashelsky , 1977 , page 51 ) capacitance = area ⁢ ⁢ of ⁢ ⁢ a ⁢ ⁢ plate * dielectric ⁢ ⁢ value ⁢ ⁢ of ⁢ ⁢ the ⁢ ⁢ water distance ⁢ ⁢ between ⁢ ⁢ the ⁢ ⁢ plates 199 * 10 ⁢ e - 9 = ( 1 * 150 * 10 ⁢ e - 6 * 3 . 14 ) * ( 80 * 8 . 85 * 10 ⁢ e - 12 ) distance ⁢ ⁢ between ⁢ ⁢ the ⁢ ⁢ plates ( 7 ) where 80 is the relative permittivity and 8 . 85 * 10e - 12 is the permittivity of air ( bard , 1980 ). the distance between the plates is 1 . 67 nanometers . this indicates the charge layers are separated by atomic dimensions and verifies that the measured changes in capacitance arise at the sensor surface - water interface . in this calibration setup , the second electrode has a constant surface area of 592 millimeters squared , a capacitance of 30 nanometers and a capacitance per unit area of 0 . 05 nanofarads / millimeter squared . by contrast , the sensor surface has a capacitance per unit area of 422 nanofarads / millimeter squared . this is a difference of over 8000 to 1 . this indicates the ratio of the measured capacitance / measured area is essentially the capacitance / unit area of the sensor surface plus an additive constant . in cultural practice , the additive constant can be neglected . the reason for this is that in production agriculture plants with water content levels down so low as to make the additive constant significant would be not suitable for harvest or commercial sale . the water content within a plant can be determined by implanting a sensor surface within a plant and then measuring the total area of the sensor surface and the electrical capacitance . as the water content of the plant increases and decreases , the electrical capacitance increases and decreases . the ratio of electrical capacitance to total length of the sensor surface within the plant functions in the same manner as a water dipstick . this dipstick functions in any gravitational orientation and also in any change in gravitational orientation . the latter would occur as movement of the leaf blade in the wind or growth causes shifts in the orientation of the petiole . both capacitance and length measurements are plant - based . soil and environmental influences are integrated by the plant and yield the resultant level of water content and a resultant ratio . weather conditions such as high temperatures causes dehydration , irrigation causes rehydration . the water content changes accordingly . the water content values can be applied from site to site and from season to season . it is intrinsic to the plant . a merlot wine grapevine with a petiole water content value of 30 nfd / mm at harvest one year can be adjusted to 40 nfd / mm the following year if grape quality dictates a higher level . the apparatus can be applied to any plant type in which a measurement of total area and wetted area of the implanted surface can be made . the total area of the surface within the plant can be measured two ways : by implanting the surface within the plant and them measuring the extent of the implanted surface within the plant . alternately , the total area can be measured before the surface is implanted and then implanting the surface such that this pre - measured total surface lies within the plant . the first method is useful in implants in which the surface enters and exits from the plant such as in petioles . the second method is useful in implants in which the surface enters but does not exit out the other side . this is the preferred method in fruit with skin such that penetration of the fruit through the calyx does not destroy the integrity of the fruit , but exit out the skin would destroy the integrity of the fruit . the sensor surface itself has several embodiments . a cylindrical shape is the simplest form because the entire surface of the sensor is uniformly sensitive , it is mechanically the most rigid shape and is manufactured most readily . in the case of an implant which enters the tissue but does not protrude out of the tissue , the filament can be bent such that a known length is implanted within the tissue . this is required in applications such as implants into grapes wherein puncture of the skin would destroy the integrity of the grape . the second electrode also has many embodiments . its shape , size and material will vary . in order to maintain a large ratio between interfacial capacitance of the sensor surface versus the second electrode , it is best to use a sensor surface material which has a high level of oxygen adsorption and ionization . by contrast , the second electrode material should have a minimal level of oxygen adsorption and ionization . this is not essential , but will yield the maximum resolution and range . it is best to use a second electrode with a large surface area compared to the surface area of the sensor surface . this will minimize any interfacial resistance . while there have been illustrated and described various embodiments of the present invention , it will be apparent to those skilled in the art that modification thereof will occur to those skilled in the art . it is intended in the appended claims to cover all such changes and modifications that fall within the true scope and spirit of the present invention .

this invention is concerned with a method and plant - based apparatus to measure the water content within plants . a metallic surface is implanted in any orientation within the plant . the total area of this surface within the plant is measured with a mechanical caliper or equivalent . the wetted area of this surface is obtained by means of a measurement of electrical capacitance at the interface between the surface and water in the plant . plant water content is equal to the ratio of measured capacitance to measured surface area within the plant . the apparatus functions as a “ water dipstick ” in the same manner as an “ oil dipstick ” in an automobile . the surface is normally implanted in the petiole in the early season and remains there until harvest . water content readings are then used to set irrigation schedules . the full season chronology of water content readings can be extrapolated from site to site and season to season for optimization of agricultural practice .

compounds of the invention , including n - oxides and salts of the compounds or n - oxides , can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes . the reactions for preparing compounds of the invention can be carried out in suitable solvents , which can be readily selected by one of skill in the art of organic synthesis . suitable solvents can be substantially non - reactive with the starting materials ( reactants ), the intermediates , or products at the temperatures at which the reactions are carried out , e . g ., temperatures which can range from the solvent &# 39 ; s freezing temperature to the solvent &# 39 ; s boiling temperature . a given reaction can be carried out in one solvent or a mixture of more than one solvent . depending on the particular reaction step , suitable solvents for a particular reaction step can be selected by the skilled artisan . preparation of compounds of the invention can involve the protection and deprotection of various chemical groups . the need for protection and deprotection , and the selection of appropriate protecting groups , can be readily determined by one skilled in the art . the chemistry of protecting groups can be found , for example , in t . w . greene and p . g . m . wuts , protective groups in organic synthesis , 3 rd ed ., wiley & amp ; sons , inc ., new york ( 1999 ), which is incorporated herein by reference in its entirety . reactions can be monitored according to any suitable method known in the art . for example , product formation can be monitored by spectroscopic means , such as nuclear magnetic resonance spectroscopy ( e . g ., 1 h or 13 c ), infrared spectroscopy , spectrophotometry ( e . g ., uv - visible ), mass spectrometry , or by chromatographic methods such as high performance liquid chromatography ( hplc ) or thin layer chromatography ( tlc ). compounds of formula i and intermediates thereof may be prepared according to the following reaction schemes and accompanying discussion . unless otherwise indicated , r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , r t1 , r t2 , q 1 , x 1 , and y 1 , and structural formula i in the reaction schemes and discussion that follow are as defined above . in general the compounds of this invention may be made by processes which include processes analogous to those known in the chemical arts , particularly in light of the description contained herein . certain processes for the manufacture of the compounds of this invention and intermediates thereof are provided as further features of the invention and are illustrated by the following reaction schemes . other processes are described in the experimental section . the schemes and examples provided herein ( including the corresponding description ) are for illustration only , and not intended to limit the scope of the present invention . scheme 1 refers to preparation of compounds of formula i . referring to scheme 1 , compounds of formula 1 - 1 [ where lg 1 is a suitable leaving group such as triazolyl or halo ( e . g ., cl or br )] or 1 - 2 [ wherein z 1 is a halogen ( cl , br , or i )] are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 1 - 3 can be prepared by coupling a compound of formula 1 - 1 with a compound of formula 1 - 2 , for example , by heating a mixture of a compound of formula 1 - 1 with a compound of formula 1 - 2 in the presence of a base , such as cs 2 co 3 , in an appropriate solvent , such as dmso at temperatures between 50 ° c . and 120 ° c . for about 20 minutes to 48 hours . alternatively , a metal - catalyzed ( such as a palladium or copper catalyst ) coupling may be employed to accomplish the aforesaid coupling . in this variant of the coupling , a mixture of a compound of formula 1 - 1 and a compound of formula 1 - 2 can be heated at temperatures ranging between 50 ° c . and 120 ° c . in the presence of a base [ such as cs 2 co 3 ], a metal catalyst [ such as a palladium catalyst , e . g ., pd ( oac ) 2 ], and a ligand [ such as binap ] in an appropriate solvent , such as 1 , 4 - dioxane , for about 30 minutes to 48 hours . a compound of formula 1 - 3 can subsequently be reacted with a compound of formula q 1 - z 2 [ wherein z 2 can be br ; b ( oh ) 2 ; b ( or ) 2 wherein each r is independently h or c 1 - 6 alkyl , or wherein two ( or ) groups , together with the b atom to which they are attached , form a 5 - to 10 - membered heterocycloalkyl or heteroaryl optionally substituted with one or more c 1 - 6 alkyl ; a trialkyltin moiety ; or the like ] by a metal - catalyzed ( such as palladium -) coupling reaction to obtain a compound of formula i . compounds of formula q 1 - z 2 are commercially available or can be prepared by methods analogous to those described in the chemical art . alternatively , a compound of formula 1 - 3 can be converted to a compound of formula 1 - 4 [ wherein z 2 is defined as above ]. for example , a compound of formula 1 - 3 ( wherein z 1 is halogen such as br ) can be converted to a compound of formula 1 - 4 [ wherein z 2 is b ( oh ) 2 ; b ( or ) 2 wherein each r is independently h or c 1 - 6 alkyl , or wherein two ( or ) groups , together with the b atom to which they are attached , form a 5 - to 10 - membered heterocycloalkyl or heteroaryl optionally substituted with one or more c 1 - 6 alkyl ] by methods described herein or other methods well known to those skilled in the art . in this example , the reaction can be accomplished , for example , by reacting a compound of formula 1 - 3 ( wherein z 1 is halogen such as br ) with 4 , 4 , 4 ′, 4 ′, 5 , 5 , 5 ′, 5 ′- octamethyl - 2 , 2 ′- bi - 1 , 3 , 2 - dioxaborolane , a suitable base [ such as potassium acetate ], and a palladium catalyst [ such as [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii )] in a suitable solvent such as 1 , 4 - dioxane . in another example , a compound of formula 1 - 3 ( wherein z 1 is halogen such as br ) can be converted to a compound of formula 1 - 4 [ wherein z 2 is a trialkyltin moiety ] by alternate methods described herein or other methods well known to those skilled in the art . in this example , the reaction can be accomplished , for example , by reacting a compound of formula 1 - 3 ( wherein z 1 is halogen such as br ) with a hexaalkyldistannane [ such as hexamethyldistannane ] and a palladium catalyst [ such as tetrakis ( triphenylphosphine ) palladium ( 0 )] in a suitable solvent such as 1 , 4 - dioxane . a compound of formula 1 - 4 can then be reacted with a compound of formula q 1 - z 1 [ wherein z 1 is defined as above ] by a metal - catalyzed ( such as palladium -) coupling reaction to obtain a compound of formula i . compounds of formula q 1 - z 1 are commercially available or can be prepared by methods analogous to those described in the chemical art . the type of reaction employed depends on the selection of z 1 and z 2 . for example , when z 1 is halogen or triflate and the q 1 - z 2 reagent is a boronic acid or boronic ester , a suzuki reaction may be used [ a . suzuki , j . organomet . chem . 1999 , 576 , 147 - 168 ; n . miyaura and a . suzuki , chem . rev . 1995 , 95 , 2457 - 2483 ; a . f . littke et al ., j . am . chem . soc . 2000 , 122 , 4020 - 4028 ]. in some specific embodiments , an aromatic iodide , bromide , or triflate of formula 1 - 3 is combined with 1 to 3 equivalents of an aryl or heteroaryl boronic acid or boronic ester of formula q 1 - z 2 and a suitable base , such as 2 to 5 equivalents of potassium phosphate , in a suitable organic solvent such as thf . a palladium catalyst is added , such as 0 . 01 equivalents of s - phos precatalyst { also known as chloro ( 2 - dicyclohexylphosphino - 2 ′, 6 ′- dimethoxy - 1 , 1 - biphenyl )[ 2 -( 2 - aminoethylphenyl )] palladium ( ii )— tert - butyl methyl ether adduct }, and the reaction mixture is heated to temperatures ranging from 60 to 100 ° c . for 1 to 24 hours . alternatively , when z 1 is halogen or triflate and z 2 is trialkyltin , a stille coupling may be employed [ v . farina et al ., organic reactions 1997 , 50 , 1 - 652 ]. more specifically , a compound of formula 1 - 3 [ wherein z 1 is bromide , iodide , or triflate ] may be combined with 1 . 5 to 3 equivalents of a compound of formula q 1 - z 2 [ wherein the q 1 - z 2 compound is an q 1 stannane compound ] in the presence of a palladium catalyst , such as 0 . 05 equivalents of dichlorobis ( triphenylphosphine ) palladium ( ii ), in a suitable organic solvent such as toluene , and the reaction may be heated to temperatures ranging from 100 ° c . to 130 ° c . for 12 to 36 hours . where z 1 is br , i or , triflate and z 2 is br or i , a negishi coupling may be used [ e . erdik , tetrahedron 1992 , 48 , 9577 - 9648 ]. more specifically , a compound of formula 1 - 3 [ wherein z 1 is bromide , iodide , or triflate ] may be transmetallated by treatment with 1 to 1 . 1 equivalents of an alkyllithium reagent followed by a solution of 1 . 2 to 1 . 4 equivalents of zinc chloride in an appropriate solvent such as tetrahydrofuran at a temperature ranging from − 80 ° c . to − 65 ° c . after warming to a temperature between 10 ° c . and 30 ° c ., the reaction mixture may be treated with a compound of formula q 1 - z 2 ( wherein z 2 is br or i ), and heated at 50 to 70 ° c . with addition of a catalyst such as tetrakis ( triphenylphosphine ) palladium ( 0 ). the reaction may be carried out for times ranging from 1 to 24 hours . none of these reactions are limited to the employment of the solvent , base , or catalyst described above , as many other conditions may be used . scheme 2 also refers to preparation of compounds of formula i . referring to scheme 2 , compounds of formula i may be prepared utilizing analogous chemical transformations to those described in scheme 1 , but with a different ordering of steps . compounds of formula 2 - 1 [ wherein pg is a suitable protecting group such as boc or cbz when y 1 is nh or methyl , or pg is benzyl when y 1 is o ] are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 2 - 1 can be converted to a compound of formula 2 - 2 either directly or after conversion to a compound of formula 2 - 3 using methods analogous to those described in scheme 1 . a compound of formula 2 - 2 may then be deprotected , using appropriate conditions depending on the selection of the pg group , to obtain a compound of formula 2 - 4 , which in turn can be coupled with a compound of formula 1 - 1 in scheme 1 to afford a compound of formula i . the coupling conditions employed may be analogous to those described for the preparation of a compound of formula 1 - 3 in scheme 1 . scheme 3 refers to a preparation of a compound of formula 3 - 3 [ wherein a 1 is either pg as defined above or a moiety of formula a 1a ]. when a 1 is pg , the compound of formula 3 - 3 is an example of a compound of formula 2 - 2 . when a 1 is a la , the compound of formula 3 - 3 is an example of a compound of formula i . referring to scheme 3 , compounds of formula 3 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 3 - 1 can be reacted with 4 - chloro - 3 - nitropyridine and the initial product can be subsequently reduced to obtain a compound of formula 3 - 2 . examples of suitable reaction conditions for the coupling of a compound of formula 3 - 1 with 4 - chloro - 3 - nitropyridine include mixing the two reactants with a suitable base , such as triethylamine , in a suitable reaction solvent such as ethanol , at temperatures typically between 0 ° c . and 100 ° c . for about 20 minutes to 48 hours . the subsequent reduction of the nitro group to afford a compound of formula 3 - 2 can be achieved by , for example , hydrogenation in the presence of a catalyst such as palladium on carbon in a suitable solvent such as methanol under hydrogen pressures typically between 1 atm and 4 atm . a compound of formula 3 - 2 can then be reacted with acetic anhydride and triethyl orthoformate at temperatures between about 100 ° c . and 150 ° c . for about 1 hour to 48 hours to obtain a compound of formula 3 - 3 . a 1 is pg or a moiety of a 1a : scheme 4 refers to a preparation of a compound of formula 4 - 3 [ wherein each r 77 is independently h or r 7 ( such as c 1 - 3 alkyl , for example methyl )]. when a 1 is pg , the compound of formula 4 - 3 is an example of a compound of formula 2 - 2 . when a 1 is a 1a , the compound of formula 4 - 3 is an example of a compound of formula i . referring to scheme 4 , compounds of formula 4 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 4 - 2 can be prepared by reacting an aryl ketone of formula 4 - 1 with n , n - dimethylformamide dimethylacetal ( dmf - dma ) in a suitable solvent such as n , n - dimethylformamide ( dmf , which is also a reagent ), at temperatures typically between 0 ° c . and 160 ° c ., for about 1 hour to 24 hours . a pyrazole of formula 4 - 3 can be prepared by reacting a compound of formula 4 - 2 with a hydrazine of formula r 77 — nh - n h 2 in a suitable solvent such as dmf or 1 , 4 - dioxane , at temperatures typically between 0 ° c . and 100 ° c ., for about 1 hour to 24 hours . scheme 5 refers to a preparation of a compound of formula 5 - 4 or 5 - 5 [ wherein r 77 is h or r 7 ( such as c 1 - 3 alkyl , for example methyl )]. when a 1 is pg , the compound of formula 5 - 4 or 5 - 5 is an example of a compound of formula 2 - 2 . when a 1 is a 1a , the compound of formula 5 - 4 or 5 - 5 is an example of a compound of formula i . referring to scheme 5 , compounds of formula 5 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 5 - 2 can be prepared by reacting an arylketone of formula 5 - 1 with an alkyl nitrite ( e . g ., isoamyl nitrite ) in the presence of an acid ( such as hydrochloric acid ) at at temperatures typically between 0 ° c . and 100 ° c . for about 1 hour to 24 hours . the resulting oxime of formula 5 - 2 can be converted to the diketone of formula 5 - 3 upon treatment with formaldehyde ( or its equivalent such as metaformaldehyde or polyformaldehyde ) in the presence of an acid ( such as an aqueous hydrochloric acid solution ) at temperatures typically between 0 ° c . and 50 ° c . for about 1 hour to 24 hours . diketones of formula 5 - 3 can be reacted with glycinamide or a salt thereof [ such as an acetic acid salt ] in the presence of a base such as sodium hydroxide to obtain pyrazinones of formula 5 - 4 . alkylation of the pyrazinone nitrogen to obtain a compound of formula 5 - 5 can be achieved by treatment of a compound of formula 5 - 4 with a base [ such as lda , lhmds , and the like ] and a compound of the formula of r 7 z 3 ( wherein z 3 is an acceptable leaving group such as cl , br , i , methanesulfonate , and the like ), in a suitable solvent such as dmf , 1 , 4 - dioxane , or thf , at at temperatures typically between 0 ° c . and 50 ° c ., for about 1 hour to 24 hours . scheme 6 refers to a preparation of a compound of formula 6 - 5 [ wherein each r 77 is independently h or r 7 ( such as c 1 - 3 alkyl , for example methyl )]. when a 1 is pg , the compound of formula 4 - 3 is an example of a compound of formula 6 - 5 . when a 1 is a 1a , the compound of formula 6 - 5 is an example of a compound of formula i . referring to scheme 6 , compounds of formula 6 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 6 - 3 can be prepared by coupling a compound of formula 6 - 1 with an enol triflate of formula 6 - 2 . compounds of formula 6 - 2 can be prepared by methods described herein or other methods well known to those skilled in the art . the aforesaid coupling may be accomplished by reacting a compound of formula 6 - 1 with 1 to 3 equivalents of a triflate of formula 6 - 2 in the presence of a suitable base [ such as potassium carbonate ], a suitable catalyst [ such as palladium ( ii ) acetate ], a suitable ligand [ such as tricyclohexylphosphine ], and optionally a suitable phase transfer catalyst such as tetrabutylammonium chloride , in a suitable solvent such as a polar aprotic solvent ( e . g ., 1 , 4 - dioxane or thf ), at temperatures typically between 20 ° c . and 80 ° c ., for about 1 hour to 24 hours . a compound of formula 6 - 3 can be reacted with 1 to 5 equivalents of a suitable base [ such as dbu ] under an oxygen atmosphere to obtain a compound of formula 6 - 4 , in a suitable solvent such as a polar aprotic solvent ( e . g ., dmf , 1 , 4 - dioxane or thf ), at temperatures typically between 20 ° c . and 80 ° c ., for about 12 hours to 48 hours . a compound of formula 6 - 5 can be obtained by reacting a compound of formula 6 - 4 with hydrazine in a suitable solvent such as 1 - butanol , at temperatures typically between 20 ° c . and 120 ° c ., for about 1 hour to 24 hours . scheme 7 refers to a preparation of a compound of formula 7 - 6 [ wherein r 77 is h or r 7 ( such as c 1 - 3 alkyl , e . g ., methyl )]. when a 1 is pg , the compound of formula 7 - 6 is an example of a compound of formula 2 - 2 . when a 1 is a la , the compound of formula 7 - 6 is an example of a compound of formula i . referring to scheme 7 , compounds of formula 7 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 7 - 3 can be prepared by coupling a compound of formula 7 - 1 with a compound of formula 7 - 2 [ wherein pg 3 is a suitable protecting group such as 2 - tetrahydropyranyl ( thp )]. a compound of formula 7 - 2 can be prepared by methods described herein or other methods well known to those skilled in the art . the aforesaid coupling may be accomplished by reacting a compound of formula 7 - 1 with 1 to 3 equivalents of a compound of formula 7 - 2 in the presence of a suitable base [ such as cesium carbonate ] and a suitable catalyst [ such as [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii )], in a suitable solvent such as a polar aprotic solvent ( e . g ., 1 , 4 - dioxane or thf ), at temperatures typically between 50 ° c . and 120 ° c ., for about 1 hour to 24 hours . a compound of formula 7 - 4 can be obtained by removing the protecting pg 3 group , for example , by treating a compound of formula 7 - 3 ( wherein pg 3 is , for example , thp ) with hcl in an alcoholic solvent [ such as 2 - propanol ] at temperatures ranging from 20 ° c . to 80 ° c . treatment of a compound of formula 7 - 4 with phosphorous oxychloride can provide a compound of formula 7 - 5 , at temperatures typically between 50 ° c . and 120 ° c ., for about 20 minutes to 24 hours . a compound of formula 7 - 5 can be a reactive intermediate in numerous chemical transformations to obtain a compound of formula 7 - 6 . for example , a compound of formula 7 - 5 can be reacted with 1 to 3 equivalents of trimethylaluminum and 0 . 05 to 0 . 1 equivalents of a suitable palladium catalyst [ such as tetrakis ( triphenylphosphine ) palladium ( 0 )] in 1 , 4 - dioxane to afford a compound of formula 7 - 6 [ wherein the newly introduced r 7 is methyl ], at temperatures typically between 50 ° c . and 120 ° c ., for about 30 minutes to 12 hours . scheme 8 refers to a preparation of a compound of formula 8 - 4 [ wherein r 77 is h or r 7 ( such as c 1 - 3 alkyl , e . g ., methyl )], which is an example of a compound of formula i . referring to scheme 8 , compounds of formula 8 - 1 can be prepared according to methods described in scheme 1 . a compound of formula 8 - 2 can be prepared by reacting a compound of formula 8 - 1 with boron tribromide at temperatures typically between − 50 ° c . and 50 ° c . for about 1 hour to 24 hours . a compound of formula 8 - 3 can be obtained by treating a compound of formula 8 - 2 with phosphorous oxychloride at temperatures typically from 50 ° c . to 120 ° c . for about 20 minutes to 24 hours . a compound of formula 8 - 3 can be reacted with 1 to 3 equivalents of a suitable amine hnr 14 r 15 , 1 to 5 equivalents of a base [ such as triethylamine , diisopropylethylamine , and the like ] and a catalytic amount of cesium fluoride to obtain a compound of formula 8 - 4 in a suitable solvent such as a polar aprotic solvent ( e . g ., 1 , 4 - dioxane , dmf , or dimethyl sulfoxide ), at temperatures typically between 50 ° c . and 150 ° c ., for about 1 hour to 24 hours . scheme 9 refers to a preparation of a compound of formula 9 - 3 and / or 9 - 4 , which can be used in schemes 1 and / or 2 . for example , when a 1 is pg , the compound of formula 9 - 3 or 9 - 4 is an example of a compound of formula 2 - 1 . when a 1 is a 1a , the compound of formula 9 - 3 or 9 - 4 is an example of a compound of formula 1 - 3 . referring to scheme 9 , compounds of formula 9 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 9 - 2 can be prepared by treating a compound of formula 9 - 1 with a suitable base [ such as lithium diisopropylamide ] and then reacting the resulting anion with n , n - dimethylformamide in a suitable solvent such as a polar aprotic solvent ( e . g ., 1 , 4 - dioxane or thf ), at temperatures typically between − 78 ° c . and 0 ° c . for about 1 hour to 24 hours . a compound of formula 9 - 2 can be reacted with methyl hydrazine to obtain a mixture of compounds of formula 9 - 3 and formula 9 - 4 in a suitable solvent such as 1 , 4 - dioxane at temperatures typically between 50 ° c . and 150 ° c ., for about 1 hour to 24 hours . scheme 10 refers to a preparation of a compound of formula 10 - 3 , which can be used in schemes 1 and / or 2 . for example , when a 1 is pg , the compound of formula 10 - 3 is an example of a compound of formula 2 - 1 . when a 1 is a 1a , the compound of formula 10 - 3 is an example of a compound of formula 1 - 3 . referring to scheme 10 , compounds of formula 10 - 1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art . a compound of formula 10 - 2 can be prepared by treating a compound of formula 10 - 1 with n - bromosuccinimide in a suitable solvent [ such acetonitrile ] at temperatures typically between 0 ° c . and 20 ° c . for about 30 minutes to 6 hours . a compound of formula 10 - 2 can be reacted with diiodomethane and a suitable base [ such as cesium carbonate ] to obtain a compound of formula 10 - 3 . scheme 11 refers to a preparation of a compound of formula 11 - 2 . when a 1 is pg , the compound of formula 11 - 2 is an example of a compound of formula 2 - 2 . when a 1 is a 1a , the compound of formula 11 - 2 is an example of a compound of formula i . referring to scheme 11 , compounds of formula 11 - 1 can be prepared according to methods described in scheme 5 . a compound of formula 11 - 1 can be reacted with 2 - hydrazinyl - 1h - imidazole in a suitable solvent such as dmf to obtain a compound of formula 11 - 2 at temperatures between about 80 ° c . and 120 ° c . scheme 12 refers to a preparation of a compound of formula 12 - 2 [ wherein each r 77 is independently h or r 7 ( such as c 1 - 3 alkyl , for example methyl )], which is an example of a compound of formula i . referring to scheme 12 , a compound of formula 12 - 1 can be prepared by methods described in scheme 1 . a compound of formula 12 - 1 can be reacted with chloroacetaldehyde to obtain a compound of formula 12 - 2 at temperatures typically between 80 ° c . and 120 ° c . for about 1 hour to 24 hours . scheme 13 refers to a preparation of a compound of formula 13 - 3 [ wherein r 77 is h or r 7 ( such as c 1 - 3 alkyl , for example methyl )], which is an example of a compound of formula i . referring to scheme 13 , a compound of formula 13 - 1 can be prepared according to methods described in scheme 7 . a compound of formula 13 - 2 can be prepared by reacting a compound of formula 13 - 1 with hydrazine in a suitable solvent such as ethanol at temperatures typically between 60 ° c . and 100 ° c . for about 12 to 24 hours . a compound of formula 13 - 2 can be reacted with 1 , 1 ′- carbonyldiimidazole in a solvent such as acetonitrile to obtain a compound of formula 13 - 3 . additionally , a compound of formula i may also be prepared by enzymatic modification [ such as a microbial oxidation ] of a related compound of formula i . for example , as shown in scheme 14 , incubation of a compound of formula i [ for example , wherein q 1 is a moiety that can be oxidized such as an optionally substituted pyridazinyl in a compound of formula 14 - 1 ( wherein each r 77 is independently h or r 7 ( such as c 1 - 3 alkyl , for example methyl ))] with pseudomonas putida for a reaction time between 24 and 96 hours in a suitable buffer can provide an alternate compound of formula i ( for example , wherein q 1 is an optionally substituted pyridazinonyl in a compound of formula 14 - 2 ). additional starting materials and intermediates useful for making the compounds of the present invention can be obtained from chemical vendors such as sigma - aldrich or can be made according to methods described in the chemical art . those skilled in the art can recognize that in all of the schemes described herein , if there are functional ( reactive ) groups present on a part of the compound structure such as a substituent group , for example r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , x 1 , y 1 , q 1 , etc ., further modification can be made if appropriate and / or desired , using methods well known to those skilled in the art . for example , a — cn group can be hydrolyzed to afford an amide group ; a carboxylic acid can be converted to an amide ; a carboxylic acid can be converted to an ester , which in turn can be reduced to an alcohol , which in turn can be further modified . for another example , an oh group can be converted into a better leaving group such as a mesylate , which in turn is suitable for nucleophilic substitution , such as by a cyanide ion ( cn − ). for another example , an — s — can be oxidized to — s (═ o )— and / or — s (═ o ) 2 —. for yet another example , an unsaturated bond such as c ═ c or c ≡ c can be reduced to a saturated bond by hydrogenation . in some embodiments , a primary amine or a secondary amine moiety ( present on a substituent group such as r 2 , r 5 , etc .) can be converted to an amide , sulfonamide , urea , or thiourea moiety by reacting it with an appropriate reagent such as an acid chloride , a sulfonyl chloride , an isocyanate , or a thioisocyanate compound . one skilled in the art will recognize further such modifications . thus , a compound of formula i having a substituent that contains a functional group can be converted to another compound of formula i having a different substituent group . similarly , those skilled in the art can also recognize that in all of the schemes described herein , if there are functional ( reactive ) groups present on a substituent group such as r 3 , r 5 , etc ., these functional groups can be protected / deprotected in the course of the synthetic scheme described here , if appropriate and / or desired . for example , an oh group can be protected by a benzyl , methyl , or acetyl group , which can be deprotected and converted back to the oh group in a later stage of the synthetic process . for another example , an nh 2 group can be protected by a benzyloxycarbonyl ( boc ) group , which can be deprotected and converted back to the nh 2 group in a later stage of the synthetic process . as used herein , the term “ reacting ” ( or “ reaction ” or “ reacted ”) refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system . reactions can take place in the presence or absence of solvent . compounds of formula i described herein include compounds of formula i , n - oxides thereof , and salts of the compounds and the n - oxides . compounds of formula i may exist as stereoisomers , such as atropisomers , racemates , enantiomers , or diastereomers . conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using , for example , chiral high pressure liquid chromatography ( hplc ). alternatively , the racemate ( or a racemic precursor ) may be reacted with a suitable optically active compound , for example , an alcohol , or , in the case where the compound contains an acidic or basic moiety , an acid or base such as tartaric acid or 1 - phenylethylamine . the resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer ( s ) by means well known to one skilled in the art . chiral compounds of formula i ( and chiral precursors thereof ) may be obtained in enantiomerically enriched form using chromatography , typically hplc , on an asymmetric resin with a mobile phase consisting of a hydrocarbon , typically heptane or hexane , containing from 0 % to 50 % 2 - propanol , typically from 2 % to 20 %, and from 0 % to 5 % of an alkylamine , typically 0 . 1 % diethylamine . concentration of the eluate affords the enriched mixture . stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art . see , e . g ., stereochemistry of organic compounds by e . l . eliel and s . h . wilen ( wiley , new york , 1994 ), the disclosure of which is incorporated herein by reference in its entirety . suitable stereoselective techniques are well - known to those of ordinary skill in the art . where a compound of formula i contains an alkenyl or alkenylene ( alkylidene ) group , geometric cis / trans ( or z / e ) isomers are possible . cis / trans isomers may be separated by conventional techniques well known to those skilled in the art , for example , chromatography and fractional crystallization . salts of the present invention can be prepared according to methods known to those of skill in the art . the compounds of formula i that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids . although such salts must be pharmaceutically acceptable for administration to animals , it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt . the acid addition salts of the basic compounds of this invention can be prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent , such as methanol or ethanol . upon evaporation of the solvent , the desired solid salt is obtained . the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution . if the inventive compound is a base , the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art , for example , treatment of the free base with an inorganic acid , such as hydrochloric acid , hydrobromic acid , sulfuric acid , nitric acid , phosphoric acid and the like , or with an organic acid , such as acetic acid , maleic acid , succinic acid , mandelic acid , fumaric acid , malonic acid , pyruvic acid , oxalic acid , glycolic acid , salicylic acid , isonicotinic acid , lactic acid , pantothenic acid , bitartric acid , ascorbic acid , 2 , 5 - dihydroxybenzoic acid , gluconic acid , saccharic acid , formic acid , methanesulfonic acid , ethanesulfonic acid , benzenesulfonic acid , p - toluenesulfonic acid , and pamoic [ i . e ., 1 , 1 ′- methylene - bis -( 2 - hydroxy - 3 - naphthoate )] acids , a pyranosidyl acid , such as glucuronic acid or galacturonic acid , an alpha - hydroxy acid , such as citric acid or tartaric acid , an amino acid , such as aspartic acid or glutamic acid , an aromatic acid , such as benzoic acid or cinnamic acid , a sulfonic acid , such as ethanesulfonic acid , or the like . those compounds of formula i that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations . examples of such salts include the alkali metal or alkaline earth metal salts and particularly , the sodium and potassium salts . these salts are all prepared by conventional techniques . the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non - toxic base salts with the acidic compounds of formula i . these salts may be prepared by any suitable method , for example , treatment of the free acid with an inorganic or organic base , such as an amine ( primary , secondary or tertiary ), an alkali metal hydroxide or alkaline earth metal hydroxide , or the like . these salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations , and then evaporating the resulting solution to dryness , for example under reduced pressure . alternatively , they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together , and then evaporating the resulting solution to dryness in the same manner as before . in either case , stoichiometric quantities of reagents are , for example , employed in order to ensure completeness of reaction and maximum yields of the desired final product . pharmaceutically acceptable salts of compounds of formula i ( including compounds of formula la or ib ) may be prepared by one or more of three methods : ( i ) by reacting the compound of formula i with the desired acid or base ; ( ii ) by removing an acid - or base - labile protecting group from a suitable precursor of the compound of formula i or by ring - opening a suitable cyclic precursor , for example , a lactone or lactam , using the desired acid or base ; or ( iii ) by converting one salt of the compound of formula i to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column . all three reactions are typically carried out in solution . the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent . the degree of ionization in the resulting salt may vary from completely ionized to almost non - ionized . polymorphs can be prepared according to techniques well - known to those skilled in the art , for example , by crystallization . when any racemate crystallizes , crystals of two different types are possible . the first type is the racemic compound ( true racemate ) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts . the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer . while both of the crystal forms present in a racemic mixture have identical physical properties , they may have different physical properties compared to the true racemate . racemic mixtures may be separated by conventional techniques known to those skilled in the art — see , for example , stereochemistry of organic compounds by e . l . eliel and s . h . wlen ( wiley , new york , 1994 ). the invention also includes isotopically labeled compounds of formula i wherein one or more atoms is replaced by an atom having the same atomic number , but an atomic mass or mass number different from the atomic mass or mass number usually found in nature . isotopically labeled compounds of formula i ( or pharmaceutically acceptable salts thereof or n - oxide thereof ) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein , using an appropriate isotopically labeled reagent in place of the non - labeled reagent otherwise employed . prodrugs in accordance with the invention can , for example , be produced by replacing appropriate functionalities present in the compounds of formula i with certain moieties known to those skilled in the art as ‘ pro - moieties ’ as described , for example , in design of prodrugs by h . bundgaard ( elsevier , 1985 ). the compounds of formula i should be assessed for their biopharmaceutical properties , such as solubility and solution stability ( across ph ), permeability , etc ., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication . compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products . they may be obtained , for example , as solid plugs , powders , or films by methods such as precipitation , crystallization , freeze drying , spray drying , or evaporative drying . microwave or radio frequency drying may be used for this purpose . they may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs ( or as any combination thereof ). generally , they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients . the term “ excipient ” is used herein to describe any ingredient other than the compound ( s ) of the invention . the choice of excipient will to a large extent depend on factors such as the particular mode of administration , the effect of the excipient on solubility and stability , and the nature of the dosage form . pharmaceutical compositions suitable for the delivery of compounds of the present invention ( or pharmaceutically acceptable salts thereof ) and methods for their preparation will be readily apparent to those skilled in the art . such compositions and methods for their preparation may be found , for example , in remington &# 39 ; s pharmaceutical sciences , 19th edition ( mack publishing company , 1995 ). the compounds of the invention ( or pharmaceutically acceptable salts thereof ) may be administered orally . oral administration may involve swallowing , so that the compound enters the gastrointestinal tract , and / or buccal , lingual , or sublingual administration by which the compound enters the blood stream directly from the mouth . formulations suitable for oral administration include solid , semi - solid and liquid systems such as tablets ; soft or hard capsules containing multi - or nano - particulates , liquids , or powders ; lozenges ( including liquid - filled ); chews ; gels ; fast dispersing dosage forms ; films ; ovules ; sprays ; and buccal / mucoadhesive patches . liquid formulations include suspensions , solutions , syrups and elixirs . such formulations may be employed as fillers in soft or hard capsules ( made , for example , from gelatin or hydroxypropylmethylcellulose ) and typically comprise a carrier , for example , water , ethanol , polyethylene glycol , propylene glycol , methylcellulose , or a suitable oil , and one or more emulsifying agents and / or suspending agents . liquid formulations may also be prepared by the reconstitution of a solid , for example , from a sachet . the compounds of the invention may also be used in fast - dissolving , fast - disintegrating dosage forms such as those described by liang and chen , expert opinion in therapeutic patents 2001 , 11 , 981 - 986 . for tablet dosage forms , depending on dose , the drug may make up from 1 weight % to 80 weight % of the dosage form , more typically from 5 weight % to 60 weight % of the dosage form . in addition to the drug , tablets generally contain a disintegrant . examples of disintegrants include sodium starch glycolate , sodium carboxymethyl cellulose , calcium carboxymethyl cellulose , croscarmellose sodium , crospovidone , polyvinylpyrrolidone , methyl cellulose , microcrystalline cellulose , lower alkyl - substituted hydroxypropyl cellulose , starch , pregelatinized starch and sodium alginate . generally , the disintegrant will comprise from 1 weight % to 25 weight %, for example , from 5 weight % to 20 weight % of the dosage form . binders are generally used to impart cohesive qualities to a tablet formulation . suitable binders include microcrystalline cellulose , gelatin , sugars , polyethylene glycol , natural and synthetic gums , polyvinylpyrrolidone , pregelatinized starch , hydroxypropyl cellulose and hydroxypropyl methylcellulose . tablets may also contain diluents , such as lactose ( monohydrate , spray - dried monohydrate , anhydrous and the like ), mannitol , xylitol , dextrose , sucrose , sorbitol , microcrystalline cellulose , starch and dibasic calcium phosphate dihydrate . tablets may also optionally comprise surface active agents , such as sodium lauryl sulfate and polysorbate 80 , and glidants such as silicon dioxide and talc . when present , surface active agents may comprise from 0 . 2 weight % to 5 weight % of the tablet , and glidants may comprise from 0 . 2 weight % to 1 weight % of the tablet . tablets also generally contain lubricants such as magnesium stearate , calcium stearate , zinc stearate , sodium stearyl fumarate , and mixtures of magnesium stearate with sodium lauryl sulfate . lubricants generally comprise from 0 . 25 weight % to 10 weight %, for example , from 0 . 5 weight % to 3 weight % of the tablet . other possible ingredients include anti - oxidants , colorants , flavoring agents , preservatives and taste - masking agents . exemplary tablets contain up to about 80 % drug , from about 10 weight % to about 90 weight % binder , from about 0 weight % to about 85 weight % diluent , from about 2 weight % to about 10 weight % disintegrant , and from about 0 . 25 weight % to about 10 weight % lubricant . tablet blends may be compressed directly or by roller to form tablets . tablet blends or portions of blends may alternatively be wet -, dry -, or melt - granulated , melt congealed , or extruded before tabletting . the final formulation may comprise one or more layers and may be coated or uncoated ; it may even be encapsulated . the formulation of tablets is discussed in pharmaceutical dosage forms : tablets , vol . 1 , by h . lieberman and l . lachman ( marcel dekker , new york , 1980 ). consumable oral films for human or veterinary use are typically pliable water - soluble or water - swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula i , a film - forming polymer , a binder , a solvent , a humectant , a plasticizer , a stabilizer or emulsifier , a viscosity - modifying agent and a solvent . some components of the formulation may perform more than one function . the compound of formula i ( or pharmaceutically acceptable salts thereof or n - oxide thereof ) may be water - soluble or insoluble . a water - soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes . less soluble compounds may comprise a smaller proportion of the composition , typically up to 30 weight % of the solutes . alternatively , the compound of formula i may be in the form of multiparticulate beads . the film - forming polymer may be selected from natural polysaccharides , proteins , or synthetic hydrocolloids and is typically present in the range 0 . 01 to 99 weight %, more typically in the range 30 to 80 weight %. other possible ingredients include anti - oxidants , colorants , flavorings and flavor enhancers , preservatives , salivary stimulating agents , cooling agents , co - solvents ( including oils ), emollients , bulking agents , anti - foaming agents , surfactants and taste - masking agents . films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper . this may be done in a drying oven or tunnel , typically a combined coater dryer , or by freeze - drying or vacuuming . solid formulations for oral administration may be formulated to be immediate and / or modified release . modified release formulations include delayed -, sustained -, pulsed -, controlled -, targeted and programmed release . suitable modified release formulations for the purposes of the invention are described in u . s . pat . no . 6 , 106 , 864 . details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in verma et al ., pharmaceutical technology on - line , 25 ( 2 ), 1 - 14 ( 2001 ). the use of chewing gum to achieve controlled release is described in wo 00 / 35298 . the compounds of the invention ( or pharmaceutically acceptable salts thereof or n - oxide thereof ) may also be administered directly into the blood stream , into muscle , or into an internal organ . suitable means for parenteral administration include intravenous , intraarterial , intraperitoneal , intrathecal , intraventricular , intraurethral , intrasternal , intracranial , intramuscular , intrasynovial and subcutaneous . suitable devices for parenteral administration include needle ( including microneedle ) injectors , needle - free injectors and infusion techniques . parenteral formulations are typically aqueous solutions which may contain excipients such as salts , carbohydrates and buffering agents ( for example to a ph of from 3 to 9 ), but , for some applications , they may be more suitably formulated as a sterile non - aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile , pyrogen - free water . the preparation of parenteral formulations under sterile conditions , for example , by lyophilization , may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art . the solubility of compounds of formula i used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques , such as the incorporation of solubility - enhancing agents . formulations for parenteral administration may be formulated to be immediate and / or modified release . modified release formulations include delayed -, sustained -, pulsed -, controlled -, targeted and programmed release . thus compounds of the invention may be formulated as a suspension or as a solid , semi - solid , or thixotropic liquid for administration as an implanted depot providing modified release of the active compound . examples of such formulations include drug - coated stents and semi - solids and suspensions comprising drug - loaded poly ( dl - lactic - coglycolic acid ) ( plga ) microspheres . the compounds of the invention ( or pharmaceutically acceptable salts thereof or n - oxide thereof ) may also be administered topically , ( intra ) dermally , or transdermally to the skin or mucosa . typical formulations for this purpose include gels , hydrogels , lotions , solutions , creams , ointments , dusting powders , dressings , foams , films , skin patches , wafers , implants , sponges , fibers , bandages and microemulsions . liposomes may also be used . typical carriers include alcohol , water , mineral oil , liquid petrolatum , white petrolatum , glycerin , polyethylene glycol and propylene glycol . penetration enhancers may be incorporated — see e . g ., finnin and morgan , j . pharm . sci . 1999 , 88 , 955 - 958 . other means of topical administration include delivery by electroporation , iontophoresis , phonophoresis , sonophoresis and microneedle or needle - free ( e . g ., powderject ™, bioject ™, etc .) injection . formulations for topical administration may be formulated to be immediate and / or modified release . modified release formulations include delayed -, sustained -, pulsed -, controlled -, targeted and programmed release . the compounds of the invention ( or pharmaceutically acceptable salts thereof ) can also be administered intranasally or by inhalation , typically in the form of a dry powder ( either alone , as a mixture , for example , in a dry blend with lactose , or as a mixed component particle , for example , mixed with phospholipids , such as phosphatidylcholine ) from a dry powder inhaler , as an aerosol spray from a pressurized container , pump , spray , atomizer ( for example an atomizer using electrohydrodynamics to produce a fine mist ), or nebulizer , with or without the use of a suitable propellant , such as 1 , 1 , 1 , 2 - tetrafluoroethane or 1 , 1 , 1 , 2 , 3 , 3 , 3 - heptafluoropropane , or as nasal drops . for intranasal use , the powder may comprise a bioadhesive agent , for example , chitosan or cyclodextrin . the pressurized container , pump , spray , atomizer , or nebulizer contains a solution or suspension of the compound ( s ) of the invention comprising , for example , ethanol , aqueous ethanol , or a suitable alternative agent for dispersing , solubilizing , or extending release of the active , a propellant ( s ) as solvent and an optional surfactant , such as sorbitan trioleate , oleic acid , or an oligolactic acid . prior to use in a dry powder or suspension formulation , the drug product is micronized to a size suitable for delivery by inhalation ( typically less than 5 microns ). this may be achieved by any appropriate comminuting method , such as spiral jet milling , fluid bed jet milling , supercritical fluid processing to form nanoparticles , high pressure homogenization , or spray drying . capsules ( made , for example , from gelatin or hydroxypropylmethylcellulose ), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention , a suitable powder base such as lactose or starch and a performance modifier such as l - leucine , mannitol , or magnesium stearate . the lactose may be anhydrous or in the form of the monohydrate . other suitable excipients include dextran , glucose , maltose , sorbitol , xylitol , fructose , sucrose and trehalose . a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl . a typical formulation may comprise a compound of formula i or a pharmaceutically acceptable salt thereof , propylene glycol , sterile water , ethanol and sodium chloride . alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol . suitable flavors , such as menthol and levomenthol , or sweeteners , such as saccharin or saccharin sodium , may be added to those formulations of the invention intended for inhaled / intranasal administration . formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using , for example , pgla . modified release formulations include delayed -, sustained -, pulsed -, controlled -, targeted and programmed release . in the case of dry powder inhalers and aerosols , the dosage unit is determined by means of a valve which delivers a metered amount . units in accordance with the invention are typically arranged to administer a metered dose or “ puff ” containing from 0 . 01 to 100 mg of the compound of formula i . the overall daily dose will typically be in the range 1 μg to 200 mg , which may be administered in a single dose or , more usually , as divided doses throughout the day . the compounds of the invention may be administered rectally or vaginally , for example , in the form of a suppository , pessary , or enema . cocoa butter is a traditional suppository base , but various alternatives may be used as appropriate . formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release . modified release formulations include delayed -, sustained -, pulsed -, controlled -, targeted and programmed release . the compounds of the invention may also be administered directly to the eye or ear , typically in the form of drops of a micronized suspension or solution in isotonic , ph - adjusted , sterile saline . other formulations suitable for ocular and aural administration include ointments , gels , biodegradable ( e . g ., absorbable gel sponges , collagen ) and non - biodegradable ( e . g ., silicone ) implants , wafers , lenses and particulate or vesicular systems , such as niosomes or liposomes . a polymer such as crossed - linked polyacrylic acid , polyvinylalcohol , hyaluronic acid , a cellulosic polymer , for example , hydroxypropylmethylcellulose , hydroxyethylcellulose , or methyl cellulose , or a heteropolysaccharide polymer , for example , gelan gum , may be incorporated together with a preservative , such as benzalkonium chloride . such formulations may also be delivered by iontophoresis . formulations for ocular / aural administration may be formulated to be immediate and / or modified release . modified release formulations include delayed -, sustained -, pulsed -, controlled -, targeted , or programmed release . the compounds of the invention may be combined with soluble macromolecular entities , such as cyclodextrin and suitable derivatives thereof or polyethylene glycol - containing polymers , in order to improve their solubility , dissolution rate , taste - masking , bioavailability and / or stability for use in any of the aforementioned modes of administration . drug - cyclodextrin complexes , for example , are found to be generally useful for most dosage forms and administration routes . both inclusion and non - inclusion complexes may be used . as an alternative to direct complexation with the drug , the cyclodextrin may be used as an auxiliary additive , i . e ., as a carrier , diluent , or solubilizer . most commonly used for these purposes are alpha -, beta - and gamma - cyclodextrins , examples of which may be found in international patent applications nos . wo 91 / 11172 , wo 94 / 02518 and wo 98 / 55148 . since the present invention has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients which may be administered separately , the invention also relates to combining separate pharmaceutical compositions in kit form . the kit comprises two separate pharmaceutical compositions : a compound of formula i a prodrug thereof or a salt of such compound or prodrug and a second compound as described above . the kit comprises means for containing the separate compositions such as a container , a divided bottle or a divided foil packet . typically the kit comprises directions for the administration of the separate components . the kit form is particularly advantageous when the separate components are for example administered in different dosage forms ( e . g ., oral and parenteral ), are administered at different dosage intervals , or when titration of the individual components of the combination is desired by the prescribing physician . an example of such a kit is a so - called blister pack . blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms ( tablets , capsules , and the like ). blister packs generally consist of a sheet of relatively stiff material covered with a foil of a transparent plastic material . during the packaging process recesses are formed in the plastic foil . the recesses have the size and shape of the tablets or capsules to be packed . next , the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed . as a result , the tablets or capsules are sealed in the recesses between the plastic foil and the sheet . in some embodiments , the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess . the tablet or capsule can then be removed via said opening . it may be desirable to provide a memory aid on the kit , e . g ., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested . another example of such a memory aid is a calendar printed on the card , e . g ., as follows “ first week , monday , tuesday , etc .... second week , monday , tuesday , . . . ” etc . other variations of memory aids will be readily apparent . a “ daily dose ” can be a single tablet or capsule or several pills or capsules to be taken on a given day . also , a daily dose of formula i compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa . the memory aid should reflect this . in another specific embodiment of the invention , a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided . for example , the dispenser is equipped with a memoryaid , so as to further facilitate compliance with the regimen . an example of such a memoryaid is a mechanical counter which indicates the number of daily doses that has been dispensed . another example of such a memoryaid is a battery - powered micro - chip memory coupled with a liquid crystal readout , or audible reminder signal which , for example , reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken . the invention will be described in greater detail by way of specific examples . the following examples are offered for illustrative purposes , and are not intended to limit the invention in any manner . those of skill in the art will readily recognize a variety of non - critical parameters that can be changed or modified to yield essentially the same results . in the following examples and preparations , “ dmso ” means dimethyl sulfoxide , “ n ” where referring to concentration means normal , “ m ” means molar , “ ml ” means milliliter , “ mmol ” means millimoles , “ pmol ” means micromoles , “ eq .” means equivalent , “° c .” means degrees celsius , “ mhz ” means megahertz , “ hplc ” means high - performance liquid chromatography . experiments were generally carried out under inert atmosphere ( nitrogen or argon ), particularly in cases where oxygen - or moisture - sensitive reagents or intermediates were employed . commercial solvents and reagents were generally used without further purification , including anhydrous solvents where appropriate ( generally sure - seal ™ products from the aldrich chemical company , milwaukee , wis .). products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing . mass spectrometry data is reported from either liquid chromatography - mass spectrometry ( lcms ), atmospheric pressure chemical ionization ( apci ) or gas chromatography - mass spectrometry ( gcms ) instrumentation . chemical shifts for nuclear magnetic resonance ( nmr ) data are expressed in parts per million ( ppm , δ ) referenced to residual peaks from the deuterated solvents employed . in some examples , chiral separations were carried out to separate atropisomers ( or atropenantiomers ) of certain compounds of the invention . the optical rotation of an atropisomer was measured using a polarimeter . according to its observed rotation data ( or its specific rotation data ), an atropisomer ( or atropenantiomer ) with a clockwise rotation was designated as the (+)- atropisomer [ or the (+) atropenantiomer ] and an atropisomer ( or atropenantiomer ) with a counter - clockwise rotation was designated as the (−)- atropisomer [ or the (−) atropenantiomer ]. for syntheses referencing procedures in other examples or methods , reaction conditions ( length of reaction and temperature ) may vary . in general , reactions were followed by thin layer chromatography or mass spectrometry , and subjected to work - up when appropriate . purifications may vary between experiments : in general , solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate r f s or retention times . to a solution of 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 120 g , 781 mmol ) in dimethyl sulfoxide ( 1 . 56 l ) was added cesium carbonate ( 509 g , 1 . 56 mol ) and 4 - bromo - 3 - methylphenol ( 161 g , 861 mmol ), and the reaction was heated to 125 ° c . for 16 hours . at this point , the reaction mixture was cooled to room temperature , poured into water ( 5 l ), and extracted with ethyl acetate ( 2 × 2 . 5 l ). the combined organic extracts were washed with water ( 2 . 5 l ), washed with saturated aqueous sodium chloride solution ( 2 . 5 l ), dried over anhydrous sodium sulfate , filtered and concentrated in vacuo . purification by chromatography on silica gel ( eluent : 2 % ethyl acetate in petroleum ether ) afforded the product as a pale yellow solid . yield : 205 g , 674 mmol , 86 %. lcms m / z 304 . 0 , 306 . 0 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 00 ( d , j = 6 . 2 hz , 1h ), 7 . 64 ( d , j = 2 . 1 hz , 1h ), 7 . 55 ( d , j = 8 . 3 hz , 1h ), 7 . 20 ( dd , j = 5 . 8 , 0 . 8 hz , 1h ), 7 . 12 ( d , j = 2 . 9 hz , 1h ), 6 . 93 ( dd , j = 8 . 5 , 2 . 7 hz , 1h ), 6 . 88 ( dd , j = 2 . 5 , 0 . 8 hz , 1h ), 2 . 41 ( s , 3h ). to a stirred solution of 4 -( 4 - bromo - 3 - methylphenoxy ) furo [ 3 , 2 - c ] pyridine ( c1 ) ( 50 . 0 g , 164 mmol ) in 1 , 4 - dioxane ( 1 . 02 l ) was added 4 , 4 , 4 ′, 4 ′, 5 , 5 , 5 ′, 5 ′- octamethyl - 2 , 2 ′- bi - 1 , 3 , 2 - dioxaborolane ( 41 . 76 g , 164 . 4 mmol ), potassium acetate ( 64 . 6 g , 658 mmol ) and [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( 11 ) ( 6 . 0 g , 8 . 2 mmol ), and the reaction mixture was heated at 85 ° c . for 16 hours . after cooling to room temperature , it was filtered through a pad of celite , and the pad was washed with ethyl acetate . the combined filtrates were concentrated in vacuo and the residue was purified by silica gel chromatography ( eluent : 2 % ethyl acetate in petroleum ether ) to provide the product as a white solid . yield : 40 . 0 g , 114 mmol , 70 %. lcms m / z 352 . 2 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 02 ( d , j = 5 . 8 hz , 1h ), 7 . 84 ( d , j = 7 . 5 hz , 1h ), 7 . 61 ( d , j = 2 . 1 hz , 1h ), 7 . 19 ( d , j = 5 . 8 hz , 1h ), 7 . 00 ( m , 2h ), 6 . 80 ( m , 1h ), 2 . 56 ( s , 3h ), 1 . 34 ( s , 12h ). 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) ( 250 mg , 0 . 712 mmol ), 5 - bromo - 4 , 6 - dimethylpyrimidine ( 160 mg , 0 . 855 mmol ), tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 95 %, 26 . 9 mg , 0 . 142 mmol ), tricyclohexylphosphine ( 79 . 9 mg , 0 . 285 mmol ) and potassium phosphate ( 302 mg , 1 . 42 mmol ) were combined in a 3 : 1 mixture of 1 , 4 - dioxane and water ( 12 ml ), and subjected to irradiation in a microwave reactor at 120 ° c . for 5 hours . the reaction mixture was filtered through celite ; the filtrate was concentrated under reduced pressure , taken up in ethyl acetate , filtered through silica gel ( 1 g ), and concentrated in vacuo . purification via silica gel chromatography ( gradient : 0 % to 100 % ethyl acetate in heptane ) afforded the product as a colorless oil . yield : 123 mg , 0 . 371 mmol , 52 %. lcms m / z 332 . 1 ( m + h ). 1 h nmr ( 500 mhz , cdcl 3 ) δ 8 . 98 ( s , 1h ), 8 . 07 ( d , j = 5 . 9 hz , 1h ), 7 . 67 ( d , j = 2 . 2 hz , 1h ), 7 . 25 - 7 . 27 ( m , 1h , assumed ; partially obscured by solvent peak ), 7 . 24 ( br d , j = 2 . 4 hz , 1h ), 7 . 19 ( br dd , j = 8 . 3 , 2 . 4 hz , 1h ), 7 . 08 ( d , j = 8 . 3 hz , 1h ), 6 . 90 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 27 ( s , 6h ), 2 . 04 ( s , 3h ). 6 - bromo - 5 - methylpyrazin - 2 - amine ( which may be prepared according to the method of n . sato , j . heterocycl . chem . 1980 , 171 , 143 - 147 ) ( 2 . 40 g , 12 . 8 mmol ), 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) ( 4 . 48 g , 12 . 8 mmol ), and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 95 %, 466 mg , 0 . 383 mmol ) were combined in a pressure tube and dissolved in 1 , 4 - dioxane ( 60 ml ) and ethanol ( 20 ml ). a solution of sodium carbonate ( 2 . 0 m in water , 19 . 1 ml , 38 . 2 mmol ) was added , and argon was bubbled through the reaction mixture for 15 minutes . the tube was sealed , and then heated at 140 ° c . for 16 hours . the reaction mixture was combined with a second , identical , reaction mixture for workup . the combined reaction mixtures were filtered ; solids remaining in the reaction vessels were slurried in water and filtered , and the filter cake was washed with ethanol . all of the organic filtrates were passed through a pad of celite , and the celite pad was washed with ethanol . these filtrates were concentrated in vacuo , and the resulting solid was slurried in water , filtered and washed with water . the solid was then slurried in 1 : 1 heptane / diethyl ether , filtered and washed with diethyl ether to afford the product as a light yellow solid . yield : 6 . 774 g , 20 . 38 mmol , 80 %. 1 h nmr ( 500 mhz , dmso - d 6 ) δ 8 . 14 ( d , j = 2 . 2 hz , 1h ), 8 . 01 ( d , j = 5 . 7 hz , 1h ), 7 . 82 ( s , 1h ), 7 . 47 ( dd , j = 5 . 8 , 0 . 9 hz , 1h ), 7 . 21 ( d , j = 8 . 3 hz , 1h ), 7 . 15 ( br d , j = 2 . 4 hz , 1h ), 7 . 09 ( br dd , j = 8 . 2 , 2 . 4 hz , 1h ), 7 . 06 ( dd , j = 2 . 2 , 0 . 7 hz , 1h ), 6 . 18 ( br s , 2h ), 2 . 12 ( s , 3h ), 2 . 07 ( br s , 3h ). n - bromosuccinimide ( 95 %, 609 mg , 3 . 25 mmol ) was added to a solution of 6 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methylpyrazin - 2 - amine ( c3 ) ( 900 mg , 2 . 71 mmol ) in n , n - dimethylformamide ( 15 ml ), and the reaction mixture was heated to 60 ° c . for 45 minutes . the reaction mixture was cooled to room temperature , diluted with ethyl acetate and quenched with a small amount of water . after adsorption onto silica gel , the product was purified via silica gel chromatography ( gradient : 0 % to 50 % ethyl acetate in heptane ). the purified material was taken up in ethyl acetate and washed with 1 : 1 water / saturated aqueous sodium bicarbonate solution , with water , and with saturated aqueous sodium chloride solution to remove residual n , n - dimethylformamide . the organic layer was dried over sodium sulfate and concentrated in vacuo to provide the product as a yellow solid . yield : 700 mg , 1 . 71 mmol , 63 %. lcms m / z 412 . 9 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 14 ( d , j = 2 . 2 hz , 1h ), 8 . 01 ( d , j = 5 . 9 hz , 1h ), 7 . 48 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 26 ( d , j = 8 . 2 hz , 1h ), 7 . 17 ( br d , j = 2 . 3 hz , 1h ), 7 . 11 ( br dd , j = 8 . 3 , 2 . 4 hz , 1h ), 7 . 07 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 6 . 51 ( br s , 2h ), 2 . 13 ( s , 3h ), 2 . 09 ( br s , 3h ). 3 - bromo - 6 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methylpyrazin - 2 - amine ( c4 ) ( 575 mg , 1 . 40 mmol ) was dissolved in a mixture of 2 h 4 - methanol and 2 h 6 - acetone under gentle warming . the solution was allowed to stand for 10 minutes , then was concentrated in vacuo . the residue was dissolved in 1 : 1 tetrahydrofuran / 2 h 4 - methanol ( 30 ml ) and a solution of sodium deuteroxide in 2 h 4 - methanol ( 3 mm , 1 . 5 equivalents ), and hydrogenated under 5 psi 2 h 2 for 2 . 5 hours at room temperature , using 10 % palladium on carbon catalyst ( 5 % load ). the reaction mixture was then filtered to remove catalyst and concentrated under reduced pressure , to provide a yellow solid . this solid was slurried in a small amount of ethyl acetate , filtered and rinsed with ethyl acetate to afford the product as a yellow solid . the filtrate was found to contain additional product via lcms analysis . the filtrate was concentrated in vacuo to afford a yellow solid , which was washed with ethyl acetate ; the resulting white precipitate was removed by filtration and discarded . the filtrate was combined with the initially collected yellow solid , diluted with additional ethyl acetate and washed with water , with saturated aqueous ammonium chloride solution , with saturated aqueous sodium chloride solution , dried over sodium sulfate and filtered . concentration of the filtrate under reduced pressure provided a yellow solid , which was purified by silica gel chromatography ( gradient : 20 % to 100 % ethyl acetate in heptane ). a yellow solid was obtained ; upon attempted dissolution in ethyl acetate , a white solid formed , which was filtered to provide the product as a white solid . yield : 207 mg , 0 . 621 mmol , 44 %. lcms m / z 334 . 1 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 14 ( d , j = 2 . 2 hz , 1h ), 8 . 01 ( d , j = 5 . 9 hz , 1h ), 7 . 47 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 21 ( d , j = 8 . 2 hz , 1h ), 7 . 15 ( br d , j = 2 . 4 hz , 1h ), 7 . 07 - 7 . 11 ( m , 1h ), 7 . 06 ( dd , j = 2 . 2 , 1 . 1 hz , 1h ), 6 . 18 ( br s , 2h ), 2 . 11 ( s , 3h ), 2 . 07 ( br s , 3h ). chloroacetaldehyde ( 55 % solution in water , 1 . 28 ml , 10 . 9 mmol ) was added to a mixture of 6 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methyl -[ 3 - 2 h ]- pyrazin - 2 - amine ( c5 ) ( 182 mg , 0 . 546 mmol ) in water ( 2 . 5 ml ), and the reaction mixture was heated to 100 ° c . for 1 hour . after cooling to room temperature , the reaction mixture was diluted with water ( 15 ml ) and ethyl acetate ( 15 ml ), then treated with saturated aqueous sodium bicarbonate solution ( 5 to 10 ml ). the aqueous layer was extracted with ethyl acetate , and the combined organic layers were washed with water , washed with saturated aqueous sodium chloride solution , dried over sodium sulfate , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 0 % to 5 % methanol in dichloromethane ) afforded the product as a solid . yield : 158 mg , 0 . 442 mmol , 81 %. lcms m / z 358 . 0 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 18 ( d , j = 2 . 2 hz , 1h ), 8 . 08 ( d , j = 5 . 9 hz , 1h ), 7 . 77 ( d , j = 1 . 0 hz , 1h ), 7 . 54 ( dd , j = 5 . 8 , 0 . 9 hz , 1h ), 7 . 46 ( d , j = 8 . 4 hz , 1h ), 7 . 40 ( br d , j = 2 . 4 hz , 1h ), 7 . 30 ( br dd , j = 8 . 3 , 2 . 4 hz , 1h ), 7 . 26 ( d , j = 1 . 0 hz , 1h ), 7 . 12 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 27 ( s , 3h ), 2 . 00 ( br s , 3h ). chiral separation of 5 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 6 - methyl -[ 8 - 2 h ]- imidazo [ 1 , 2 - a ] pyrazine ( 2 ) ( 0 . 158 g ) was carried out using supercritical fluid chromatography ( column : chiralpak ad - h , 5 μm ; eluent : 3 : 1 carbon dioxide / methanol ) to afford 3 [ first - eluting peak , designated as the (+)- atropisomer according to its observed rotation data , 50 mg , 32 %] and 4 [ second - eluting peak , designated as the (−)- atropisomer according to its observed rotation data , 55 mg , 34 %]. compound 3 : 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 09 ( d , j = 5 . 7 hz , 1h ), 7 . 78 - 7 . 86 ( br m , 1h ), 7 . 71 ( d , j = 2 . 4 hz , 1h ), 7 . 35 - 7 . 37 ( m , 1h ), 7 . 29 - 7 . 34 ( m , 3h ), 7 . 23 - 7 . 27 ( m , 1h , assumed ; partially obscured by solvent peak ), 6 . 96 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 44 ( s , 3h ), 2 . 08 ( s , 3h ). compound 4 : 1 h nmr ( 500 mhz , dmso - d 6 ) δ 8 . 18 ( d , j = 2 . 3 hz , 1h ), 8 . 08 ( d , j = 5 . 7 hz , 1h ), 7 . 77 ( d , j = 1 . 0 hz , 1h ), 7 . 53 ( dd , j = 5 . 8 , 0 . 9 hz , 1h ), 7 . 46 ( d , j = 8 . 3 hz , 1h ), 7 . 40 ( d , j = 2 . 4 hz , 1h ), 7 . 30 ( dd , j = 8 . 2 , 2 . 6 hz , 1h ), 7 . 26 ( d , j = 1 . 0 hz , 1h ), 7 . 12 ( dd , j = 2 . 2 , 0 . 8 hz , 1h ), 2 . 27 ( s , 3h ), 2 . 00 ( s , 3h ). a solution of 4 - methoxy - 2 - methylaniline ( 23 . 8 g , 173 mmol ), 4 - chloro - 3 - nitropyridine ( 25 g , 160 mmol ), and triethylamine ( 33 . 0 ml , 237 mmol ) in ethanol ( 250 ml ) was stirred at room temperature for 16 hours , then concentrated under reduced pressure . the residue was dissolved in ethyl acetate ( 200 ml ) and filtered through a thick pad of silica gel ( eluent : ethyl acetate , 1 l ). the filtrate was concentrated in vacuo to provide the product as a purple oil , which solidified on standing . this material was used without further purification . yield : 41 g , 160 mmol , 100 %. lcms m / z 260 . 1 ( m + h ). palladium on carbon ( 10 %, 3 × 2 . 12 g ) was added to each of three batches of n -( 4 - methoxy - 2 - methylphenyl )- 3 - nitropyridin - 4 - amine ( c6 ) ( each approximately 10 g ; total 31 g , 120 mmol ) in methanol ( 3 × 100 ml ). the three suspensions were independently hydrogenated under 45 psi hydrogen at room temperature on a parr shaker for 24 hours . the three reaction mixtures were combined , filtered through a pad of celite , and concentrated in vacuo . purification by silica gel chromatography [ gradient : 2 % to 10 % ( 1 . 7 m ammonia in methanol ) in dichloromethane ] afforded the product as a light brown solid . yield : 24 . 0 g , 105 mmol , 88 %. lcms m / z 230 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 01 ( s , 1h ), 7 . 88 ( d , j = 5 . 5 hz , 1h ), 7 . 08 ( d , j = 8 . 6 hz , 1h ), 6 . 84 ( br d , j = 2 . 8 hz , 1h ), 6 . 78 ( br dd , j = 8 . 6 , 3 . 0 hz , 1h ), 6 . 34 ( d , j = 5 . 5 hz , 1h ), 5 . 66 ( br s , 1h ), 3 . 82 ( s , 3h ), 2 . 20 ( br s , 3h ). a mixture of n 4 -( 4 - methoxy - 2 - methylphenyl ) pyridine - 3 , 4 - diamine ( c7 ) ( 3 . 95 g , 17 . 2 mmol ), acetic anhydride ( 1 . 96 ml , 20 . 7 mmol ), and triethyl orthoacetate ( 99 %, 15 . 9 ml , 86 . 4 mmol ) was heated at 145 ° c . for 1 hour , then at 100 ° c . for 48 hours . after being cooled to room temperature , the reaction mixture was diluted with ethyl acetate ( 100 ml ), washed with saturated aqueous sodium bicarbonate solution ( 30 ml ), washed with water , dried over sodium sulfate , filtered , and concentrated under reduced pressure . purification by silica gel chromatography ( gradient : 2 % to 5 % methanol in dichloromethane ) provided the product as a light pink oil . yield : 4 . 10 g , 16 . 2 mmol , 94 %. lcms m / z 254 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 9 . 07 ( br d , j = 0 . 8 hz , 1h ), 8 . 36 ( d , j = 5 . 5 hz , 1h ), 7 . 15 ( d , j = 8 . 6 hz , 1h ), 6 . 89 - 6 . 97 ( m , 3h ), 3 . 90 ( s , 3h ), 2 . 42 ( s , 3h ), 1 . 94 ( br s , 3h ). boron tribromide ( 1 m solution in dichloromethane , 44 . 1 ml , 44 . 1 mmol ) was added drop - wise to a solution of 1 -( 4 - methoxy - 2 - methylphenyl )- 2 - methyl - 1h - imidazo [ 4 , 5 - c ] pyridine ( c8 ) ( 3 . 72 g , 14 . 7 mmol ) in dichloromethane ( 150 ml ) at − 78 ° c . the reaction mixture was stirred at − 78 ° c . for 15 minutes , then the cooling bath was removed and the reaction mixture was allowed to gradually warm to room temperature . after 20 hours at room temperature , the reaction mixture was recooled to − 78 ° c . and slowly quenched with methanol ( 20 ml ). at this point , the cooling bath was removed ; the mixture was allowed to reach ambient temperature and then stir for 15 minutes . volatiles were removed in vacuo , methanol ( 100 ml ) was added , and the mixture was heated at reflux for 30 minutes . after concentration under reduced pressure , the resulting solid was taken directly to the next step . lcms m / z 240 . 1 ( m + h ). a mixture of 3 - methyl - 4 -( 2 - methyl - 1h - imidazo [ 4 , 5 - c ] pyridin - 1 - yl ) phenol ( c9 ) ( from the preceding step , ≦ 14 . 7 mmol ), 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 2 . 37 g , 15 . 4 mmol ) and cesium carbonate ( 99 %, 19 . 3 g , 58 . 6 mmol ) in dimethyl sulfoxide ( 100 ml ) was heated to 140 ° c . for 16 hours . after cooling to room temperature , the reaction mixture was diluted with ethyl acetate ( 400 ml ) and filtered through a pad of celite . the filtrate was washed with water , with a 1 : 1 mixture of water and saturated aqueous sodium chloride solution ( 4 × 100 ml ), dried over sodium sulfate , filtered , and concentrated in vacuo . the residue was purified by silica gel chromatography ( gradient : 2 % to 10 % methanol in ethyl acetate ) to afford a yellow solid , which was dissolved in tent - butyl methyl ether ( 500 ml ), treated with activated carbon ( 5 g ) and heated to 40 ° c . the mixture was filtered to provide a colorless solution , which was concentrated at reflux until it became cloudy (˜ 150 ml tent - butyl methyl ether remaining ). upon gradual cooling to room temperature , a precipitate formed . filtration and washing with diethyl ether afforded the product as a free - flowing white solid . yield : 2 . 02 g , 5 . 67 mmol , 39 % over 2 steps . lcms m / z 357 . 1 ( m + h ). 1 h nmr ( 500 mhz , cdcl 3 ) δ 9 . 08 ( d , j = 1 . 0 hz , 1h ), 8 . 39 ( d , j = 5 . 5 hz , 1h ), 8 . 08 ( d , j = 5 . 9 hz , 1h ), 7 . 71 ( d , j = 2 . 2 hz , 1h ), 7 . 34 - 7 . 36 ( m , 1h ), 7 . 30 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 28 - 7 . 29 ( m , 2h ), 7 . 00 ( dd , j = 5 . 5 , 1 . 1 hz , 1h ), 6 . 97 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 48 ( s , 3h ), 1 . 99 ( br s , 3h ). 2 - bromo - 3 - methylpyrazine ( 104 mg , 0 . 600 mmol ), tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 95 %, 133 mg , 0 . 109 mmol ) and sodium carbonate ( 175 mg , 1 . 64 mmol ) were combined with 4 -[ 3 - methoxy - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine [ c10 , which was prepared in analogous fashion to 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) in example 1 ] ( 200 mg , 0 . 545 mmol ) in 1 , 4 - dioxane ( 3 ml ) and water ( 1 ml ). the reaction mixture was heated to 130 ° c . in a microwave reactor for 1 hour . the mixture was cooled to room temperature , and the supernatant was decanted into another flask . the remaining solids were washed with ethyl acetate ( 3 × 10 ml ) and the combined organic portions were concentrated in vacuo . purification was carried out twice using silica gel chromatography ( first column : eluent : 2 % methanol in dichloromethane ; second column : gradient : 0 % to 100 % ethyl acetate in heptane ). the colorless fractions were combined and concentrated under reduced pressure to provide the product as a white solid . yield : 85 mg , 0 . 25 mmol , 46 %. lcms m / z 334 . 0 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 47 ( ab quartet , downfield doublet is broadened , j ab = 2 . 5 hz , δv ab = 14 hz , 2h ), 8 . 08 ( d , j = 5 . 9 hz , 1h ), 7 . 66 ( d , j = 2 . 3 hz , 1h ), 7 . 36 ( d , j = 8 . 0 hz , 1h ), 7 . 25 - 7 . 28 ( m , 1h , assumed ; partially obscured by solvent peak ), 6 . 90 - 6 . 96 ( m , 2h ), 6 . 88 ( dd , j = 2 . 2 , 0 . 8 hz , 1h ), 3 . 79 ( s , 3h ), 2 . 50 ( s , 3h ). yellow fractions were repurified to provide additional product : 55 mg , overall yield : 75 %. n , n - dimethylformamide dimethyl acetal ( 94 %, 19 . 0 ml , 134 mmol ) was added to a solution of 1 -[ 4 -( benzyloxy ) phenyl ] ethanone ( 15 . 32 g , 67 . 71 mmol ) in n , n - dimethylformamide ( 30 ml ) and the reaction mixture was heated at reflux for 18 hours . at this point , the reflux condenser was replaced with a distillation head , and distillation was carried out until the temperature of the distillate reached 140 ° c . the material in the reaction pot was cooled to room temperature , treated with methylhydrazine ( 98 %, 7 . 4 ml , 136 mmol ) and heated at 75 ° c . for 3 hours . the reaction mixture was cooled , diluted with ethyl acetate , washed four times with aqueous 5 % sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated in vacuo . purification via silica gel chromatography ( gradient : 2 % to 10 % ethyl acetate in dichloromethane ) afforded the product as a light yellow solid . yield : 13 . 79 g , 52 . 17 mmol , 77 %. lcms m / z 265 . 1 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) characteristic peaks , δ 3 . 81 ( s , 3h ), 5 . 17 ( s , 2h ), 6 . 31 ( d , j = 1 . 5 hz , 1h ), 7 . 12 ( d , j = 8 . 8 hz , 2h ). 5 -[ 4 -( benzyloxy ) phenyl ]- 1 - methyl - 1h - pyrazole ( c11 ) ( 13 . 49 g , 51 . 04 mmol ) was mixed with 10 % palladium on carbon (˜ 50 % in water , 1 . 46 g ) and dissolved in ethanol ( 125 ml ). the reaction mixture was hydrogenated at room temperature and 1 atmosphere hydrogen for 18 hours , then filtered and concentrated in vacuo . the residue was triturated with heptane to afford the product as a colorless solid . yield : 8 . 74 g , 50 . 2 mmol , 98 %. lcms m / z 175 . 1 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 9 . 73 ( br s , 1h ), 7 . 40 ( d , j = 1 . 9 hz , 1h ), 7 . 31 ( br d , j = 8 . 7 hz , 2h ), 6 . 86 ( br d , j = 8 . 7 hz , 2h ), 6 . 26 ( d , j = 1 . 9 hz , 1h ), 3 . 79 ( s , 3h ). 4 -( 1 - methyl - 1h - pyrazol - 5 - yl ) phenol ( c12 ) ( 123 mg , 0 . 706 mmol ) and 4 - chlorothieno [ 3 , 2 - c ] pyridine ( 100 mg , 0 . 590 mmol ) were combined in 1 - methylpyrrolidin - 2 - one ( 2 ml ). cesium carbonate ( 99 %, 388 mg , 1 . 18 mmol ) was added and the reaction mixture was heated to 135 ° c . for 24 hours . after addition of water ( 30 ml ), the layers were separated and the aqueous layer was extracted with 1 : 1 diethyl ether / hexanes ( 4 × 30 ml ). the combined organic layers were washed with aqueous sodium hydroxide solution ( 1 n , 2 × 20 ml ) and with saturated aqueous sodium chloride solution ( 20 ml ), then dried over sodium sulfate . after filtration and concentration under reduced pressure , purification using silica gel chromatography ( eluent : 30 % ethyl acetate in heptane ) provided the product as a white solid . yield : 78 mg , 0 . 25 mmol , 42 %. lcms m / z 308 . 3 ( m + h ). 1 h nmr ( 500 mhz , cd 3 od ) δ 7 . 90 ( d , j = 5 . 6 hz , 1h ), 7 . 74 ( d , j = 5 . 5 hz , 1h ), 7 . 69 ( dd , j = 5 . 7 , 0 . 7 hz , 1h ), 7 . 65 ( dd , j = 5 . 5 , 0 . 8 hz , 1h ), 7 . 55 ( br d , j = 8 . 7 hz , 2h ), 7 . 51 ( d , j = 2 . 0 hz , 1h ), 7 . 32 ( br d , j = 8 . 7 hz , 2h ), 6 . 39 ( d , j = 2 . 0 hz , 1h ), 3 . 91 ( s , 3h ). cesium carbonate ( 99 %, 522 mg , 1 . 59 mmol ) was added to a mixture of 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 146 mg , 0 . 951 mmol ) and 4 - bromobenzenethiol ( 150 mg , 0 . 793 mmol ) in dimethyl sulfoxide ( 3 ml ); the reaction mixture was degassed , and then heated at 80 ° c . for 16 hours . water ( 30 ml ) was added and extraction was carried out with 1 : 1 ethyl acetate / hexanes ( 4 × 30 ml ). the combined organic layers were dried over sodium sulfate , filtered , and concentrated in vacuo . purification via silica gel chromatography ( gradient : 5 % to 10 % ethyl acetate in heptane ) provided a colorless oil ( 220 mg ); this was dissolved in diethyl ether ( 20 ml ) and washed with aqueous sodium hydroxide solution ( 1 n , 3 × 15 ml ). the organic layer was concentrated under reduced pressure to provide the product , determined by 1 h nmr analysis to be contaminated with extraneous furo [ 3 , 2 - c ] pyridyl activity . this was taken to the following step without further purification . lcms m / z 308 . 3 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) product peaks only , δ 8 . 32 ( d , j = 5 . 7 hz , 1h ), 7 . 60 ( d , j = 2 . 2 hz , 1h ), 7 . 47 ( br ab quartet , j ab = 8 . 7 hz , δv ab = 31 . 2 hz , 4h ), 7 . 29 ( dd , j = 5 . 8 , 1 . 0 hz , 1h ), 6 . 58 ( dd , j = 2 . 3 , 1 . 0 hz , 1h ). 4 -[( 4 - bromophenyl ) sulfanyl ] furo [ 3 , 2 - c ] pyridine ( c13 ) ( 210 mg from the previous step ), ( 1 - methyl - 1h - pyrazol - 5 - yl ) boronic acid ( 104 mg , 0 . 826 mmol ), triphenylphosphine ( 21 . 5 mg , 0 . 0819 mmol ) and potassium carbonate ( 190 mg , 1 . 37 mmol ) were combined in n , n - dimethylformamide ( 6 ml ) and water ( 2 ml ), and the mixture was degassed with nitrogen for 20 minutes . palladium ( ii ) acetate ( 98 %, 4 . 8 mg , 0 . 021 mmol ) was added , and the reaction mixture was heated at 80 ° c . for 18 hours . after cooling to room temperature , the reaction mixture was diluted with water ( 15 ml ) and extracted with 1 : 1 ethyl acetate / hexanes ( 3 × 15 ml ). the combined organic layers were dried over sodium sulfate , filtered , and concentrated in vacuo . purification was effected first via silica gel chromatography ( eluent : 80 % ethyl acetate in heptane ), followed by hplc ( column : waters xbridge c18 , 5 μm ; mobile phase a : water with trifluoroacetic acid modifier ; mobile phase b : acetonitrile with trifluoroacetic acid modifier ; gradient : 40 % to 100 % b ), to afford the product as a white solid . yield : 30 mg , 0 . 071 mmol , 9 % over two steps . lcms m / z 308 . 0 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 8 . 29 ( d , j = 5 . 8 hz , 1h ), 7 . 87 ( d , j = 2 . 2 hz , 1h ), 7 . 61 ( br d , j = 8 . 6 hz , 2h ), 7 . 53 ( br d , j = 8 . 7 hz , 2h ), 7 . 51 ( d , j = 2 . 1 hz , 1h ), 7 . 49 ( dd , j = 5 . 8 , 1 . 0 hz , 1h ), 6 . 66 ( dd , j = 2 . 3 , 1 . 1 hz , 1h ), 6 . 42 ( d , j = 2 . 0 hz , 1h ), 3 . 90 ( s , 3h ). 1h - imidazole ( 2 . 14 g , 31 . 4 mmol ) was added portion - wise to a 0 ° c . solution of 2 - bromo - 5 - hydroxybenzonitrile ( 5 . 65 g , 28 . 5 mmol ) and tert - butyldimethylsilyl chloride ( 4 . 52 g , 30 . 0 mmol ) in tetrahydrofuran ( 56 . 5 ml ). the reaction mixture was allowed to stir at room temperature for 2 hours , and was then filtered . the filtrate was washed with water and with saturated aqueous sodium chloride solution . the aqueous layer was extracted with diethyl ether , and the combined organic layers were concentrated in vacuo to afford the product as an orange oil . yield : 8 . 87 g , 28 . 4 mmol , 99 . 6 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 50 ( d , j = 8 . 8 hz , 1h ), 7 . 08 - 7 . 12 ( m , 1h ), 6 . 90 - 6 . 95 ( m , 1h ), 0 . 98 ( s , 9h ), 0 . 22 ( s , 6h ). 2 - bromo - 5 -{[ tert - butyl ( dimethyl ) silyl ] oxy } benzonitrile ( c14 ) ( 8 . 00 g , 25 . 6 mmol ), 4 , 4 , 4 ′, 4 ′, 5 , 5 , 5 ′, 5 ′- octamethyl - 2 , 2 ′- bi - 1 , 3 , 2 - dioxaborolane ( 6 . 83 g , 26 . 9 mmol ) and potassium acetate ( 10 . 06 g , 102 . 5 mmol ) were combined in degassed 1 , 4 - dioxane ( 160 ml ). after addition of [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( 11 ) ( 1 . 05 g , 1 . 28 mmol ), the reaction mixture was heated to 80 ° c . for 4 hours . after cooling , it was filtered through celite , and the filter pad was rinsed with ethyl acetate . the filtrate was concentrated in vacuo and purified via silica gel chromatography ( gradient : 20 % to 50 % ethyl acetate in heptane ) to provide the product as a colorless , viscous oil . yield : 5 . 60 g , 15 . 6 mmol , 61 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 76 ( br d , j = 8 . 3 hz , 1h ), 7 . 15 ( dd , j = 2 . 4 , 0 . 3 hz , 1h ), 7 . 02 ( dd , j = 8 . 3 , 2 . 3 hz , 1h ), 1 . 38 ( s , 12h ), 0 . 98 ( s , 9h ), 0 . 22 ( s , 6h ). 5 -{[ tert - butyl ( dimethyl ) silyl ] oxy }- 2 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) benzonitrile ( c15 ) ( 4 . 05 g , 11 . 3 mmol ) was combined with 5 - bromo - 4 , 6 - dimethylpyrimidine hydrobromide ( 7 . 16 g , 26 . 7 mmol ) and potassium phosphate ( 7 . 03 g , 33 . 1 mmol ) in 2 - methyltetrahydrofuran ( 20 . 2 ml ) and water ( 16 . 2 ml ). [ 2 ′-( azanidyl - κn ) biphenyl - 2 - yl - κc 2 ]( chloro )[ dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl )- λ 5 - phosphanyl ] palladium ( prepared from biphenyl - 2 - amine and dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl ) phosphane ( s - phos ) according to the procedure of s . l . buchwald et al ., j . am . chem . soc . 2010 , 132 , 14073 - 14075 ) ( 0 . 20 g , 0 . 28 mmol ) was added , and the reaction mixture was heated to reflux for 18 hours . it was then cooled to room temperature , and the organic layer was extracted with aqueous hydrochloric acid ( 2 n , 2 × 20 ml ). the combined extracts were adjusted to a ph of roughly 6 - 7 with 2 m aqueous sodium hydroxide solution , and then extracted with ethyl acetate . these combined organic layers were dried over magnesium sulfate , filtered , and concentrated in vacuo . the resulting solids were triturated with hot heptane to afford the product as a tan solid . yield : 1 . 86 g , 8 . 26 mmol , 73 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 10 . 48 ( s , 1h ), 8 . 94 ( s , 1h ), 7 . 36 ( d , j = 8 . 4 hz , 1h ), 7 . 31 ( d , j = 2 . 5 hz , 1h ), 7 . 23 ( dd , j = 8 . 5 , 2 . 6 hz , 1h ), 2 . 18 ( s , 6h ). 2 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 5 - hydroxybenzonitrile ( c16 ) ( 1 . 00 g , 4 . 44 mmol ), 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 750 mg , 4 . 88 mmol ), palladium ( ii ) acetate ( 49 . 8 mg , 0 . 222 mmol ), 1 , 1 ′- binaphthalene - 2 , 2 ′- diylbis ( diphenylphosphane ) ( 96 %, 288 mg , 0 . 444 mmol ) and cesium carbonate ( 99 %, 2 . 92 g , 8 . 87 mmol ) were combined in 1 , 4 - dioxane ( 25 ml ) and nitrogen was bubbled through the mixture for 15 minutes . the reaction mixture was then heated at 100 ° c . for 18 hours , cooled to room temperature and filtered through celite . the filtrate was partitioned between ethyl acetate and water , and the aqueous layer was extracted with ethyl acetate . the combined organic layers were washed with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated in vacuo . purification using silica gel chromatography ( gradient : 75 % to 100 % ethyl acetate in heptane ) provided the product as a viscous yellow oil , which slowly solidified on standing . further purification was effected using supercritical fluid chromatography ( column : princeton 2 - ethylpyridine , 5 μm ; eluent : 4 : 1 carbon dioxide / methanol ). yield : 1 . 5 g , 4 . 4 mmol , 99 %. lcms m / z 343 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 9 . 04 ( s , 1h ), 8 . 06 ( d , j = 5 . 9 hz , 1h ), 7 . 78 ( br d , j = 2 . 5 hz , 1h ), 7 . 72 ( d , j = 2 . 2 hz , 1h ), 7 . 66 ( dd , j = 8 . 4 , 2 . 5 hz , 1h ), 7 . 36 ( dd , j = 8 . 4 , 0 . 4 hz , 1h ), 7 . 33 ( dd , j = 5 . 7 , 1 . 0 hz , 1h ) 6 . 97 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 36 ( s , 6h ). a mixture of 4 , 5 - dichloropyridazin - 3 - ol ( 42 g , 250 mmol ), 3 , 4 - dihydro - 2h - pyran ( 168 g , 2 . 00 mol ) and para - toluenesulfonic acid ( 8 . 8 g , 51 mmol ) in tetrahydrofuran ( 2 l ) was refluxed for 2 days . after cooling to room temperature , the mixture was concentrated under reduced pressure . the residue was purified by chromatography on silica gel ( gradient : 3 % to 5 % ethyl acetate in petroleum ether ) to afford the product as a white solid . yield : 42 g , 170 mmol , 68 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 84 ( s , 1h ), 6 . 01 ( br d , j = 11 hz , 1h ), 4 . 10 - 4 . 16 ( m , 1h ), 3 . 70 - 3 . 79 ( m , 1h ), 1 . 99 - 2 . 19 ( m , 2h ), 1 . 50 - 1 . 80 ( m , 4h ). to a mixture of 4 , 5 - dichloro - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one ( c17 ) ( 40 g , 0 . 16 mol ), methylboronic acid ( 9 . 6 g , 0 . 16 mol ) and cesium carbonate ( 155 g , 0 . 476 mol ) in a mixture of 1 , 4 - dioxane ( 500 ml ) and water ( 50 ml ) was added [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) ( 5 g , 7 mmol ). the reaction mixture was stirred at 110 ° c . for 2 hours , then concentrated under reduced pressure . purification by silica gel chromatography ( gradient : 3 % to 5 % ethyl acetate in petroleum ether ) provided product c18 as a pale yellow solid ( yield : 9 g , 40 mmol , 25 %) and product c19 , also as a pale yellow solid ( yield : 9 . 3 g , 41 mmol , 26 %). c18 : lcms m / z 250 . 8 ( m + na + ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 71 ( s , 1h ), 6 . 07 ( dd , j = 10 . 7 , 2 . 1 hz , 1h ), 4 . 10 - 4 . 18 ( m , 1h ), 3 . 71 - 3 . 81 ( m , 1h ), 2 . 30 ( s , 3h ), 1 . 98 - 2 . 19 ( m , 2h ), 1 . 53 - 1 . 81 ( m , 4h ). c19 : lcms m / z 250 . 7 ( m + na + ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 77 ( s , 1h ), 6 . 02 ( dd , j = 10 . 7 , 2 . 1 hz , 1h ), 4 . 10 - 4 . 17 ( m , 1h ), 3 . 71 - 3 . 79 ( m , 1h ), 2 . 27 ( s , 3h ), 1 . 99 - 2 . 22 ( m , 2h ), 1 . 51 - 1 . 79 ( m , 4h ). a mixture of 4 - chloro - 5 - methyl - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one ( c18 ) ( 457 mg , 2 . 00 mmol ), 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) ( 702 mg , 2 . 00 mmol ) and [ 2 ′-( azanidyl - κn ) biphenyl - 2 - yl - kc 2 ]( chloro )[ dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl )- λ 5 - phosphanyl ] palladium ( 29 mg , 0 . 040 mmol ) was subjected to three rounds of vacuum evacuation followed by introduction of nitrogen . degassed tetrahydrofuran ( 4 ml ) was added , followed by degassed aqueous potassium phosphate solution ( 0 . 5 m , 8 . 0 ml , 4 . 0 mmol ), and the reaction mixture was allowed to stir at room temperature for 23 hours . the reaction mixture was then partitioned between ethyl acetate ( 20 ml ) and water ( 8 ml ); the organic layer was dried over sodium sulfate , filtered , and concentrated in vacuo . purification via silica gel chromatography ( gradient : 20 % to 70 % ethyl acetate in heptane ) afforded the product as a white solid . by nmr , this was determined to consist of a diastereomeric mixture due to the tetrahydropyranyl group . yield : 588 mg , 1 . 41 mmol , 70 %. lcms m / z 418 . 0 ( m + h ). 1 h nmr ( 500 mhz , cdcl 3 ) δ 8 . 06 ( d , j = 5 . 9 hz , 1h ), 7 . 82 ( d , j = 2 . 8 hz , 1h ), 7 . 63 ( d , j = 2 . 3 hz , 1h ), 7 . 23 - 7 . 25 ( m , 1h ), 7 . 16 - 7 . 17 ( m , 1h ), 7 . 06 - 7 . 13 ( m , 2h ), 6 . 79 - 6 . 81 ( m , 1h ), 6 . 10 ( dd , j = 10 . 6 , 2 . 2 hz , 1h ), 4 . 14 - 4 . 20 ( m , 1h ), 3 . 72 - 3 . 80 ( m , 1h ), 2 . 15 - 2 . 25 ( m , 1h , assumed ; partially obscured by methyl group ), 2 . 14 and 2 . 15 ( 2 s , total 3h ), 2 . 01 - 2 . 08 ( m , 1h , assumed ; partially obscured by methyl group ), 2 . 03 and 2 . 04 ( 2 s , total 3h ), 1 . 71 - 1 . 82 ( m , 3h ), 1 . 55 - 1 . 63 ( m , 1h ). 4 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methyl - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one ( c20 ) ( 580 mg , 1 . 39 mmol ) was dissolved in methanol ( 3 ml ), treated with a solution of hydrogen chloride in 1 , 4 - dioxane ( 4 m , 5 . 0 ml , 20 mmol ) and allowed to stir at room temperature for 3 hours . removal of solvent under reduced pressure provided the product as a pale yellow solid , presumed to be the bis - hydrochloride salt . yield : 550 mg , 1 . 35 mmol , 97 %. lcms m / z 334 . 0 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 13 . 01 ( br s , 1h ), 8 . 15 ( d , j = 2 . 3 hz , 1h ), 8 . 02 ( d , j = 5 . 8 hz , 1h ), 7 . 89 ( s , 1h ), 7 . 48 ( dd , j = 5 . 8 , 1 . 1 hz , 1h ), 7 . 16 - 7 . 18 ( m , 1h ), 7 . 08 - 7 . 12 ( m , 3h ), 2 . 06 ( br s , 3h ), 1 . 95 ( s , 3h ). 4 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methylpyridazin - 3 ( 2h )- one , bis - hydrochloride salt ( 10 ) ( 550 mg , 1 . 35 mmol ) was suspended in phosphorus oxychloride ( 6 . 0 ml , 64 mmol ), and the reaction mixture was heated at 90 ° c . for 2 hours . after removal of phosphorus oxychloride under reduced pressure , the residue was partitioned between dichloromethane ( 35 ml ), water ( 10 ml ), and saturated aqueous sodium bicarbonate solution ( 10 ml ). the organic layer was dried over sodium sulfate , filtered , and concentrated in vacuo to afford the product as a foamy , pale amber solid . yield : 465 mg , 1 . 32 mmol , 98 %. lcms m / z 352 . 0 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 9 . 07 ( s , 1h ), 8 . 11 ( d , j = 5 . 8 hz , 1h ), 7 . 69 ( d , j = 2 . 3 hz , 1h ), 7 . 31 ( dd , j = 5 . 9 , 0 . 9 hz , 1h ), 7 . 25 - 7 . 28 ( m , 1h , assumed ; partially obscured by solvent peak ), 7 . 21 - 7 . 24 ( m , 1h ), 7 . 09 ( d , j = 8 . 2 hz , 1h ), 6 . 84 ( dd , j = 2 . 2 , 0 . 8 hz , 1h ), 2 . 19 ( s , 3h ), 2 . 08 ( br s , 3h ). nitrogen was bubbled into a mixture of tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 31 . 0 mg , 0 . 027 mmol ) and 4 -[ 4 -( 3 - chloro - 5 - methylpyridazin - 4 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine ( 11 ) ( 427 mg , 1 . 21 mmol ) in 1 , 4 - dioxane ( 12 ml ) for 10 minutes . a solution of trimethylaluminum in toluene ( 2 m , 1 . 2 ml , 2 . 4 mmol ) was added , and the reaction mixture was heated to 95 ° c . for 90 minutes , then cooled in an ice bath and treated drop - wise with methanol ( 12 ml ) { caution : gas evolution !}. the mixture was filtered through celite and the filter cake was rinsed with additional methanol ( 35 ml ); the filtrate was concentrated in vacuo and purified using silica gel chromatography ( eluent : 2 . 5 % methanol in ethyl acetate ) to provide the product as a solid . yield : 320 mg , 0 . 966 mmol , 80 %. lcms m / z 332 . 1 ( m + h ). 1 h nmr ( 500 mhz , cd 3 od ) δ 9 . 05 ( s , 1h ), 7 . 99 ( d , j = 6 . 0 hz , 1h ), 7 . 90 ( d , j = 2 . 2 hz , 1h ), 7 . 39 ( dd , j = 5 . 9 , 0 . 9 hz , 1h ), 7 . 26 - 7 . 27 ( m , 1h ), 7 . 19 ( br dd , half of abx pattern , j = 8 . 3 , 2 . 1 hz , 1h ), 7 . 15 ( d , half of ab pattern , j = 8 . 3 hz , 1h ), 6 . 94 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 42 ( s , 3h ), 2 . 16 ( s , 3h ), 2 . 03 ( s , 3h ). example 12 ( 4 -[ 4 -( 3 , 5 - dimethylpyridazin - 4 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine ) ( 316 mg ) was separated into its component atropenantiomers using supercritical fluid chromatography ( column : chiralpak as - h , 5 μm ; eluent : 7 : 3 carbon dioxide / ethanol ). both were obtained as solids . first - eluting atropenantiomer : 13 [ designated as the (+) atropenantiomer according to its observed rotation data ], yield : 137 mg , 43 %. lcms m / z 332 . 3 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 9 . 03 ( s , 1h ), 7 . 99 ( d , j = 5 . 8 hz , 1h ), 7 . 89 ( d , j = 2 . 2 hz , 1h ), 7 . 38 ( br d , j = 5 . 8 hz , 1h ), 7 . 24 - 7 . 27 ( m , 1h ), 7 . 19 ( br dd , half of abx pattern , j = 8 . 3 , 2 . 0 hz , 1h ), 7 . 14 ( d , half of ab quartet , j = 8 . 2 hz , 1h ), 6 . 91 - 6 . 94 ( m , 1h ), 2 . 41 ( s , 3h ), 2 . 14 ( s , 3h ), 2 . 02 ( s , 3h ). second - eluting atropenantiomer : 14 [ designated as the (−)- atropenantiomer according to its observed rotation data ], yield : 132 mg , 42 %. lcms m / z 332 . 3 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 9 . 04 ( s , 1h ), 7 . 99 ( d , j = 6 . 0 hz , 1h ), 7 . 89 ( d , j = 2 . 2 hz , 1h ), 7 . 38 ( dd , j = 6 . 0 , 1 . 0 hz , 1h ), 7 . 25 - 7 . 27 ( m , 1h ), 7 . 19 ( br dd , half of abx pattern , j = 8 . 3 , 2 . 2 hz , 1h ), 7 . 15 ( d , half of ab quartet , j = 8 . 2 hz , 1h ), 6 . 93 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 41 ( s , 3h ), 2 . 15 ( s , 3h ), 2 . 02 ( s , 3h ). to a mixture of 1 - methoxy - 3 - methylbenzene ( 12 . 2 g , 100 mmol ) and propanoyl chloride ( 18 . 5 g , 200 mmol ) in dichloromethane ( 200 ml ) was added aluminum chloride ( 26 . 5 g , 199 mmol ) in one portion , and the reaction mixture was stirred at room temperature for 4 hours . the reaction was quenched with aqueous hydrochloric acid ( 1 n , 100 ml ), and the organic layer was dried over magnesium sulfate , filtered , and concentrated in vacuo . the residue was purified by silica gel chromatography to afford the product as a yellow solid . yield : 3 . 87 g , 21 . 7 mmol , 22 %. boron tribromide ( 5 . 57 g , 22 . 2 mmol ) was added to a solution of 1 -( 4 - methoxy - 2 - methylphenyl ) propan - 1 - one ( c21 ) ( 3 . 87 g , 21 . 7 mmol ) in dichloromethane ( 50 ml ), and the reaction mixture was stirred at room temperature for 4 hours . water ( 20 ml ) was added , and the organic layer was separated , dried over magnesium sulfate , and concentrated under reduced pressure to provide the product as a yellow solid , which was used without further purification . yield : 3 . 77 g , & gt ; 100 %. a mixture of 1 -( 4 - hydroxy - 2 - methylphenyl ) propan - 1 - one ( c22 ) ( 1 . 64 g , & lt ; 10 . 0 mmol ), 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 1 . 53 g , 9 . 96 mmol ), and potassium carbonate ( 2 . 76 g , 20 . 0 mmol ) in n , n - dimethylformamide ( 50 ml ) was heated to reflux for 8 hours . the reaction mixture was partitioned between water ( 50 ml ) and ethyl acetate ( 150 ml ); the organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the product as a yellow oil , which was used without additional purification . yield : 2 . 97 g , & gt ; 100 %. 1 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ] propan - 1 - one ( c23 ) ( 2 . 87 g , & lt ; 10 . 7 mmol ) in a mixture of n , n - dimethylformamide dimethyl acetal ( 10 ml ) and n , n - dimethylformamide ( 10 ml ) was heated to reflux for 30 minutes . after removal of solvent under reduced pressure , the residue was washed with ethyl acetate to provide the product as a yellow solid . yield : 1 . 76 g , 5 . 23 mmol , & gt ; 49 %. lcms m / z 337 . 1 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 7 . 94 ( d , j = 6 . 1 hz , 1h ), 7 . 87 ( d , j = 2 . 2 hz , 1h ), 7 . 35 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 14 ( d , j = 8 . 2 hz , 1h ), 7 . 04 - 7 . 07 ( m , 2h ), 7 . 00 ( br dd , j = 8 . 1 , 2 . 4 hz , 1h ), 6 . 90 ( dd , j = 2 . 3 , 1 . 0 hz , 1h ), 3 . 15 ( s , 6h ), 2 . 24 ( s , 3h ), 2 . 14 ( s , 3h ). a solution of 3 -( dimethylamino )- 1 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 2 - methylprop - 2 - en - 1 - one ( c24 ) in ethanol ( 0 . 125 m , 0 . 600 ml , 0 . 075 mmol ) was combined with a solution of tert - butylhydrazine in 0 . 2 m aqueous hydrochloric acid ( 0 . 128 m , 0 . 700 ml , 0 . 090 mmol ). acetic acid ( 0 . 05 ml , 0 . 9 mmol ) was added , and the reaction mixture was shaken at 100 ° c . for 3 hours . solvents were removed in vacuo , and the residue was purified by hplc ( column : phenomenex gemini c18 , 5 μm ; mobile phase a : aqueous ammonium hydroxide , ph 10 ; mobile phase b : acetonitrile ; gradient : 70 % to 90 % b ) to afford the product . lcms m / z 362 ( m + h ). retention time : 3 . 056 min ( column : welch xb - c18 , 2 . 1 × 50 mm , 5 μm ; mobile phase a : 0 . 0375 % trifluoroacetic acid in water ; mobile phase b : 0 . 01875 % trifluoroacetic acid in acetonitrile ; gradient : 25 % b for 0 . 50 minutes , 25 % to 100 % b over 3 . 0 minutes ; flow rate : 0 . 8 ml / minute ). this reaction was carried out in two identical batches . a mixture of 3 - amino - 4 - bromophenol ( 13 g , 69 mmol ), cesium carbonate ( 45 g , 140 mmol ) and 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 7 . 0 g , 46 mmol ) in dimethyl sulfoxide ( 200 ml ) was heated to 130 ° c . for 18 hours . the two batches were cooled to room temperature and combined , and the mixture was poured into ice water ( 800 ml ) and extracted with ethyl acetate ( 5 × 1200 ml ). the combined organic layers were washed with saturated aqueous sodium chloride solution ( 500 ml ), dried over anhydrous sodium sulfate , filtered , and concentrated under reduced pressure . purification using silica gel chromatography ( gradient : 17 % to 25 % ethyl acetate in petroleum ether ) provided the product as a white solid . yield : 25 g , 82 mmol , 89 %. this reaction was carried out in two identical batches . to a solution of 2 - bromo - 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) aniline ( c25 ) ( 10 . 9 g , 35 . 7 mmol ), tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 3 . 3 g , 3 . 6 mmol ), and biphenyl - 2 - yl ( dicyclohexyl ) phosphane ( 1 . 3 g , 3 . 7 mmol ) in toluene ( 250 ml ) was added triethylamine ( 10 . 9 g , 108 mmol ) and 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolane ( 13 . 8 g , 108 mmol ), and the reaction mixture was heated to reflux for 18 hours . the two batches were cooled to room temperature and combined , then filtered and evaporated to dryness . the residue was dissolved in methanol , filtered and concentrated in vacuo . purification via silica gel chromatography ( gradient : 9 % to 25 % ethyl acetate in petroleum ether ) afforded the product as a yellow solid . yield : 13 . 5 g , 38 . 3 mmol , 54 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 10 ( d , j = 2 . 0 hz , 1h ), 8 . 00 ( d , j = 5 . 9 hz , 1h ), 7 . 47 ( dd , j = 5 . 9 , 0 . 8 hz , 1h ), 7 . 40 ( d , j = 8 . 2 hz , 1h ), 6 . 96 ( dd , j = 2 . 4 , 0 . 8 hz , 1h ), 6 . 36 ( d , j = 2 . 0 hz , 1h ), 6 . 28 ( dd , j = 8 . 2 , 2 . 4 hz , 1h ), 5 . 65 ( br s , 2h ), 1 . 29 ( s , 12h ). this reaction was carried out in two identical batches . a mixture of 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) aniline ( c26 ) ( 4 . 5 g , 13 mmol ), potassium phosphate trihydrate ( 9 . 6 g , 36 mmol ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( 11 ) ( 1 . 1 g , 1 . 3 mmol ) and 5 - bromoimidazo [ 1 , 2 - a ] pyridine ( 3 . 8 g , 19 mmol ) in 2 - methyltetrahydrofuran ( 50 ml ) and water ( 10 ml ) was heated to 75 ° c . for 18 hours . the two batches were cooled to room temperature and combined . after filtration , the filter cake was washed with water , and the combined filtrates were extracted with ethyl acetate ( 4 × 100 ml ). the combined organic layers were washed with saturated aqueous sodium chloride solution , dried over sodium sulfate , filtered , and concentrated in vacuo . the residue was combined with the filter cake and purified by silica gel chromatography ( gradient : 2 % to 5 % methanol in dichloromethane ) to provide the product as a yellow solid . yield : 4 . 2 g , 12 mmol , 46 %. lcms m / z 342 . 9 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 14 ( d , j = 2 . 2 hz , 1h ), 8 . 06 ( d , j = 5 . 9 hz , 1h ), 7 . 60 ( br d , j = 9 . 0 hz , 1h ), 7 . 58 ( d , j = 1 . 0 hz , 1h ), 7 . 50 ( dd , j = 5 . 9 , 0 . 8 hz , 1h ), 7 . 33 ( dd , j = 9 . 0 , 6 . 8 hz , 1h ), 7 . 32 ( br s , 1h ), 7 . 19 ( d , j = 8 . 2 hz , 1h ), 7 . 07 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 6 . 89 ( br dd , j = 6 . 8 , 0 . 7 hz , 1h ), 6 . 65 ( d , j = 2 . 4 hz , 1h ), 6 . 50 ( dd , j = 8 . 4 , 2 . 4 hz , 1h ), 5 . 17 ( br s , 2h ). a mixture of 4 , 4 , 5 , 5 - tetramethyl - 2 -( 2 - methyl - 4 - nitrophenyl )- 1 , 3 , 2 - dioxaborolane ( 390 mg , 1 . 48 mmol ), 5 - bromoimidazo [ 1 , 2 - a ] pyridine ( 243 mg , 1 . 23 mmol ), potassium carbonate ( 683 mg , 4 . 94 mmol ) and [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( 11 ) ( 90 mg , 0 . 12 mmol ) in n , n - dimethylformamide ( 10 ml ) was stirred at 120 ° c . for 1 hour . the reaction mixture was filtered and the filtrate was concentrated in vacuo . purification via silica gel chromatography ( eluent : 2 % methanol in dichloromethane ) afforded the product as a yellow oil . yield : 320 mg , 1 . 26 mmol , 100 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 27 ( br s , 1h ), 8 . 22 ( br d , j = 8 . 5 hz , 1h ), 7 . 73 ( d , j = 9 . 0 hz , 1h ), 7 . 66 ( br s , 1h ), 7 . 56 ( d , j = 8 . 0 hz , 1h ), 7 . 31 ( dd , j = 9 . 0 , 7 . 0 hz , 1h ), 7 . 05 ( s , 1h ), 6 . 75 ( d , j = 6 . 5 hz , 1h ), 2 . 23 ( s , 3h ). a mixture of 5 -( 2 - methyl - 4 - nitrophenyl ) imidazo [ 1 , 2 - a ] pyridine ( c27 ) ( 300 mg , 1 . 18 mmol ), iron ( 199 mg , 3 . 56 mmol ) and ammonium chloride ( 253 mg , 4 . 73 mmol ) in ethanol ( 9 ml ) and water ( 3 ml ) was heated at reflux for 1 hour . the mixture was filtered and the filtrate was concentrated in vacuo ; purification via silica gel chromatography ( eluent : 5 % methanol in dichloromethane ) provided the product as a solid . yield : 224 mg , 1 . 00 mmol , 85 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 72 ( br d , j = 9 hz , 1h ), 7 . 61 ( br s , 1h ), 7 . 29 - 7 . 36 ( m , 1h ), 7 . 19 ( br s , 1h ), 7 . 12 ( d , j = 8 . 3 hz , 1h ), 6 . 74 ( br d , j = 6 . 5 hz , 1h ), 6 . 67 - 6 . 69 ( m , 1h ), 6 . 64 ( dd , j = 8 , 2 hz , 1h ), 2 . 01 ( s , 3h ). a mixture of 4 -( imidazo [ 1 , 2 - a ] pyridin - 5 - yl )- 3 - methylaniline ( c28 ) ( 185 mg , 0 . 828 mmol ), 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 127 mg , 0 . 827 mmol ), cesium carbonate ( 810 mg , 2 . 49 mmol ), palladium ( ii ) acetate ( 28 mg , 0 . 12 mmol ) and 4 , 5 - bis ( diphenylphosphino )- 9 , 9 - dimethylxanthene ( xantphos , 72 mg , 0 . 12 mmol ) in 1 , 4 - dioxane ( 8 ml ) was stirred at 120 ° c . for 2 hours . after the reaction mixture was filtered , the filtrate was diluted with ethyl acetate ( 100 ml ), washed with saturated aqueous sodium chloride solution , and concentrated in vacuo . the residue was purified via preparative thin layer chromatography ( eluent : 5 % methanol in dichloromethane ) to afford the product as a yellow solid . yield : 157 mg , 0 . 461 mmol , 56 %. lcms m / z 341 . 3 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 16 ( d , j = 6 . 0 hz , 1h ), 7 . 58 - 7 . 67 ( m , 4h ), 7 . 29 ( d , j = 8 . 0 hz , 1h ), 7 . 25 - 7 . 36 ( br m , 1h , assumed ; partially obscured by solvent peak ), 7 . 21 ( br s , 1h ), 7 . 09 ( br d , j = 6 hz , 1h ), 6 . 92 - 7 . 03 ( br m , 1h ), 6 . 72 - 6 . 80 ( br m , 2h ), 2 . 11 ( s , 3h ). a mixture of 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) ( 4 . 0 g , 11 mmol ), 5 - bromo - 4 - methoxy - 6 - methylpyrimidine ( z . wang et al ., synthesis 2011 , 1529 - 1531 ) ( 2 . 0 g , 10 mmol ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) ( 1 . 1 g , 1 . 4 mmol ) and potassium carbonate ( 4 . 0 g , 29 mmol ) in 1 , 4 - dioxane ( 30 ml ) containing 5 drops of water was heated at 120 ° c . for 2 hours . after filtration and concentration of the filtrate under reduced pressure , the residue was purified by silica gel chromatography ( eluent : 33 % ethyl acetate in petroleum ether ) to give the product as a yellow solid . yield : 1 . 8 g , 5 . 2 mmol , 52 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 72 ( s , 1h ), 8 . 07 ( d , j = 6 . 0 hz , 1h ), 7 . 66 ( d , j = 2 . 3 hz , 1h ), 7 . 25 ( dd , j = 5 . 9 , 0 . 9 hz , 1h ), 7 . 19 - 7 . 21 ( m , 1h ), 7 . 09 - 7 . 16 ( m , 2h ), 6 . 88 ( dd , j = 2 . 3 , 0 . 8 hz , 1h ), 3 . 95 ( s , 3h ), 2 . 29 ( s , 3h ), 2 . 07 ( s , 3h ). boron tribromide ( 20 g , 80 mmol ) was slowly added to a solution of 4 -[ 4 -( 4 - methoxy - 6 - methylpyrimidin - 5 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine ( c29 ) ( 1 . 8 g , 5 . 2 mmol ) in dichloromethane ( 150 ml ) at − 60 ° c . the reaction mixture was allowed to warm to room temperature and stirred for 18 hours . methanol ( 150 ml ) was then added , and the ph was adjusted to 6 via addition of solid sodium bicarbonate . the mixture was filtered and the filtrate was concentrated in vacuo . this residue was mixed with acetone and filtered again ; concentration of the filtrate afforded the product as a yellow solid . yield : 1 . 5 g , 4 . 5 mmol , 87 %. a mixture of 5 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 6 - methylpyrimidin - 4 - ol ( c30 ) ( 1 . 5 g , 4 . 5 mmol ) and phosphorus oxychloride ( 100 g , 65 mmol ) was heated at reflux for 2 hours . after concentration under reduced pressure , the residue was slowly treated with saturated aqueous sodium bicarbonate solution ( 200 ml ). the resulting mixture was extracted with ethyl acetate ( 4 × 100 ml ) and the combined organic layers were dried , filtered and concentrated in vacuo . purification via silica gel chromatography ( eluent : 50 % ethyl acetate in petroleum ether ) provided the product as a yellow solid . yield : 750 mg , 2 . 13 mmol , 47 %. lcms m / z 352 . 1 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 8 . 86 ( s , 1h ), 7 . 99 ( br d , j = 5 . 9 hz , 1h ), 7 . 88 ( d , j = 2 . 3 hz , 1h ), 7 . 38 ( dd , j = 5 . 9 , 0 . 9 hz , 1h ), 7 . 22 - 7 . 25 ( m , 1h ), 7 . 20 ( d , half of ab quartet , j = 8 . 2 hz , 1h ), 7 . 16 ( br dd , half of abx pattern , j = 8 . 3 , 2 . 2 hz , 1h ), 6 . 88 ( dd , j = 2 . 3 , 1 . 0 hz , 1h ), 2 . 35 ( s , 3h ), 2 . 08 ( br s , 3h ). to a mixture of 3 - bromo - 6 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methylpyrazin - 2 - amine ( c4 ) ( 1 . 5 g , 3 . 6 mmol ) in water ( 30 ml ) was added chloroacetaldehyde ( 0 . 57 g , 7 . 3 mmol ), and the reaction mixture was heated at reflux for 18 hours . after basification to ph 8 with solid sodium bicarbonate , the mixture was concentrated in vacuo . purification via silica gel chromatography ( gradient : 2 % to 5 % methanol in dichloromethane ) provided the product as a yellow solid . yield : 255 mg , 0 . 685 mmol , 19 %. lcms m / z 372 . 8 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 7 . 98 ( d , j = 5 . 8 hz , 1h ), 7 . 93 ( d , j = 2 . 3 hz , 1h ), 7 . 46 - 7 . 48 ( m , 1h ), 7 . 43 ( d , j = 8 . 3 hz , 1h ), 7 . 40 ( br d , j = 5 . 8 hz , 1h ), 7 . 31 ( d , j = 2 . 3 hz , 1h ), 7 . 22 ( dd , j = 8 . 3 , 2 . 5 hz , 1h ), 7 . 17 - 7 . 18 ( m , 1h ), 7 . 01 - 7 . 03 ( m , 1h ), 2 . 16 ( s , 3h ), 2 . 07 ( s , 3h ). to a solution of 4 -( 4 - bromo - 3 - methylphenoxy ) furo [ 3 , 2 - c ] pyridine ( c1 ) ( 4 . 00 g , 13 . 2 mmol ) in carbon tetrachloride ( 80 ml ) was added n - bromosuccinimide ( 2 . 34 g , 13 . 2 mmol ) and 2 , 2 ′- azobisisobutyronitrile ( aibn , 108 mg , 0 . 658 mmol ) at room temperature . the reaction mixture was heated to reflux for 3 hours , cooled to room temperature , and treated with water ( 150 ml ). the mixture was extracted with dichloromethane ( 3 × 50 ml ), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude product . yield : 5 . 04 g , 13 . 2 mmol , 100 %. lcms m / z 383 . 7 ( m + h ). to a solution of 4 -[ 4 - bromo - 3 -( bromomethyl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c31 ) ( 5 . 04 g , 13 . 2 mmol ) in n , n - dimethylformamide ( 60 ml ) was added sodium acetate ( 5 . 40 g , 65 . 8 mmol ) at room temperature . the reaction mixture was heated to 80 ° c . for 3 hours , then cooled and partitioned between water ( 150 ml ) and dichloromethane ( 200 ml ). the aqueous layer was separated and extracted with dichloromethane ( 3 × 50 ml ). the combined organic layers were dried over sodium sulfate and concentrated in vacuo ; the resulting residue was dissolved in methanol ( 40 ml ) and treated with aqueous sodium hydroxide solution ( 1 n , 13 . 1 ml , 13 . 1 mmol ). after stirring for 1 hour at room temperature , the reaction mixture was partitioned between water ( 100 ml ) and dichloromethane ( 100 ml ). the aqueous layer was separated and extracted with dichloromethane ( 3 × 50 ml ). the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the crude product . yield : 4 . 2 g , 13 . 1 mmol , 99 %. lcms m / z 321 . 7 ( m + h ). [ 2 - bromo - 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) phenyl ] methanol ( c32 ) ( 230 mg , 0 . 718 mmol ), pyridine ( 170 mg , 2 . 15 mmol ), and acetyl chloride ( 113 mg , 1 . 44 mmol ) were combined in tetrahydrofuran ( 5 ml ) at room temperature . the reaction mixture was subjected to microwave irradiation at 60 ° c . for 40 minutes , then poured into saturated aqueous sodium bicarbonate solution ( 30 ml ). after extraction with dichloromethane ( 3 × 20 ml ), the combined organic layers were dried over sodium sulfate , filtered , and concentrated in vacuo to afford the product . yield : 260 mg , 0 . 718 mmol , 100 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 00 ( d , j = 5 . 8 hz , 1h ), 7 . 67 ( d , j = 2 . 0 hz , 1h ), 7 . 62 ( d , j = 8 . 5 hz , 1h ), 7 . 32 ( d , j = 2 . 5 hz , 1h ), 7 . 23 ( d , j = 6 . 0 hz , 1h ), 7 . 10 ( dd , j = 8 . 6 , 2 . 6 hz , 1h ), 6 . 90 - 6 . 93 ( m , 1h ), 5 . 20 ( s , 2h ), 2 . 14 ( s , 3h ). to 2 - bromo - 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) benzyl acetate ( c33 ) ( 260 mg , 0 . 718 mmol ) in 1 , 4 - dioxane ( 6 ml ) were added 4 , 4 , 4 ′, 4 ′, 5 , 5 , 5 ′, 5 ′- octamethyl - 2 , 2 ′- bi - 1 , 3 , 2 - dioxaborolane ( 237 mg , 0 . 933 mmol ), potassium acetate ( 211 mg , 2 . 15 mmol ) and [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( 11 ) ( 157 mg , 0 . 215 mmol ) at room temperature . the mixture was heated to 80 ° c . and stirred for 3 hours , then cooled and filtered . the filtrate was concentrated in vacuo and purified by silica gel chromatography to provide the product . yield : 164 mg , 0 . 401 mmol , 56 %. 1 h nmr ( 400 mhz , cd 3 od ) δ 7 . 97 ( d , j = 6 . 0 hz , 1h ), 7 . 85 - 7 . 89 ( m , 2h ), 7 . 39 ( d , j = 6 . 0 hz , 1h ), 7 . 20 - 7 . 23 ( m , 1h ), 7 . 11 - 7 . 15 ( m , 1h ), 6 . 82 - 6 . 84 ( m , 1h ), 5 . 36 ( s , 2h ), 2 . 1 ( s , 3h ), 1 . 36 ( s , 12h ). to a solution of 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) benzyl acetate ( c34 ) ( 82 mg , 0 . 20 mmol ) in 1 , 4 - dioxane ( 10 ml ) were added 5 - bromo - 4 , 6 - dimethylpyrimidine ( 41 mg , 0 . 22 mmol ), potassium carbonate ( 83 mg , 0 . 6 mmol ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) ( 44 mg , 0 . 060 mmol ) and water ( 5 drops ) at room temperature . the reaction mixture was degassed with nitrogen for 5 minutes , then subjected to microwave irradiation at 120 ° c . for 50 minutes . after filtration of the reaction mixture , the filtrate was concentrated in vacuo ; purification was carried out by preparative thin layer chromatography to give the product . yield : 28 mg , 0 . 072 mmol , 36 %. lcms m / z 389 . 9 ( m + h ). aqueous sodium hydroxide solution ( 1 n , 0 . 36 ml , 0 . 36 mmol ) was added to a solution of 2 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) benzyl acetate ( c35 ) ( 28 mg , 0 . 072 mmol ) in tetrahydrofuran ( 2 ml ), and the reaction mixture was stirred at room temperature for 18 hours . saturated aqueous sodium chloride solution was added , and the mixture was extracted with tetrahydrofuran ( 3 × 10 ml ). the combined organic layers were concentrated in vacuo and purified by preparative thin layer chromatography on silica gel to give the product . yield : 19 mg , 0 . 055 mmol , 76 %. lcms m / z 347 . 9 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ), characteristic peaks : δ 8 . 96 ( s , 1h ), 8 . 03 ( d , j = 5 . 5 hz , 1h ), 7 . 67 ( br s , 1h ), 7 . 53 ( br s , 1h ), 7 . 21 - 7 . 34 ( m , 2h , assumed ; partially obscured by solvent peak ), 7 . 10 ( d , j = 8 . 0 hz , 1h ), 6 . 90 ( br s , 1h ), 4 . 33 ( s , 2h ), 2 . 26 ( s , 6h ). ( diethylamino ) sulfur trifluoride ( 37 mg , 0 . 23 mmol ) was added to a solution of [ 2 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) phenyl ] methanol ( 20 ) ( 20 mg , 0 . 058 mmol ) in dichloromethane ( 2 ml ) at 0 ° c . the reaction mixture was stirred for 30 minutes at 40 ° c ., then concentrated in vacuo . purification by preparative thin layer chromatography on silica gel afforded the product . yield : 10 mg , 0 . 029 mmol , 50 %. lcms m / z 350 . 0 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 9 . 01 ( s , 1h ), 8 . 07 ( d , j = 5 . 8 hz , 1h ), 7 . 69 ( d , j = 2 . 3 hz , 1h ), 7 . 49 - 7 . 52 ( m , 1h ), 7 . 39 - 7 . 43 ( m , 1h ), 7 . 29 ( dd , j = 5 . 9 , 0 . 6 hz , 1h ), 7 . 18 ( br d , j = 8 . 0 hz , 1h ), 6 . 94 ( dd , j = 2 . 0 , 0 . 7 hz , 1h ), 5 . 04 ( d , j hf = 47 . 4 hz , 2h ), 2 . 28 ( s , 6h ). compound c36 was prepared from 1 - bromo - 4 - methoxy - 2 - methylbenzene according to the general procedure for the synthesis of 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) in example 1 . the product was obtained as a solid . yield : 15 g , 60 mmol , 80 %. the product was prepared from 2 -( 4 - methoxy - 2 - methylphenyl )- 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolane ( c36 ) and 5 - bromo - 4 , 6 - dimethylpyrimidine according to the general procedure described in step 3 of example 1 . the product was obtained as a solid . yield : 3 . 5 g , 15 mmol , 75 %. boron tribromide ( 3 . 8 ml , 40 mmol ) was added drop - wise to a solution of 5 -( 4 - methoxy - 2 - methylphenyl )- 4 , 6 - dimethylpyrimidine ( c37 ) ( 3 . 0 g , 13 mmol ) in dichloromethane ( 150 ml ) at − 70 ° c . the reaction mixture was stirred at room temperature for 16 hours , then adjusted to ph 8 with saturated aqueous sodium bicarbonate solution . the aqueous layer was extracted with dichloromethane ( 3 × 200 ml ), and the combined organic layers were dried over sodium sulfate , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 60 % to 90 % ethyl acetate in petroleum ether ) afforded the product as a yellow solid . yield : 1 . 2 g , 5 . 6 mmol , 43 %. lcms m / z 215 . 0 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 98 ( s , 1h ), 6 . 89 ( d , j = 8 . 0 hz , 1h ), 6 . 86 ( d , j = 2 . 3 hz , 1h ), 6 . 80 ( dd , j = 8 . 3 , 2 . 5 hz , 1h ), 2 . 24 ( s , 6h ), 1 . 96 ( s , 3h ). 3 - bromo - 4 - chlorofuro [ 3 , 2 - c ] pyridine ( c39 , prepared according to the method of y . miyazaki et al ., bioorg . med . chem . lett . 2007 , 17 , 250 - 254 ; 430 mg , 1 . 85 mmol ), 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 3 - methylphenol ( c38 ) ( 396 mg , 1 . 85 mmol ) and cesium carbonate ( 1 . 21 g , 3 . 71 mmol ) were combined in dimethyl sulfoxide ( 8 . 0 ml ) and heated at 120 ° c . for 3 hours . the reaction mixture was filtered through celite , the celite pad was rinsed thoroughly with ethyl acetate , and the combined filtrates were washed twice with a 1 : 1 mixture of water and saturated aqueous sodium chloride solution , then washed twice with 1 n aqueous sodium hydroxide solution . the organic layer was dried over sodium sulfate , filtered , and concentrated in vacuo . silica gel chromatographic purification ( gradient : 50 % to 90 % ethyl acetate in heptane ) afforded the product as a white solid . yield : 404 mg , 0 . 985 mmol , 53 %. lcms m / z 412 . 0 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 98 ( s , 1h ), 8 . 07 ( d , j = 5 . 9 hz , 1h ), 7 . 69 ( s , 1h ), 7 . 26 - 7 . 28 ( m , 1h , assumed ; partially obscured by solvent peak ), 7 . 25 ( d , j = 5 . 9 hz , 1h ), 7 . 21 - 7 . 25 ( m , 1h ), 7 . 09 ( br d , j = 8 . 2 hz , 1h ), 2 . 28 ( s , 6h ), 2 . 05 ( br s , 3h ). 3 - bromo - 4 -[ 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine ( c40 ) ( 89 . 0 mg , 0 . 217 mmol ), methylboronic acid ( 98 %, 27 mg , 0 . 44 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 15 mg , 0 . 013 mmol ) were combined in a mixture of 1 , 4 - dioxane ( 2 . 4 ml ) and ethanol ( 0 . 78 ml ), and the mixture was deoxygenated by bubbling nitrogen through it . aqueous sodium carbonate solution ( 2 m , 0 . 34 ml , 0 . 68 mmol ) was added , and the reaction mixture was subjected to microwave irradiation at 120 ° c . for 2 hours . as starting material was observed at this point by gcms , additional methylboronic acid ( 2 equivalents ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 0 . 06 equivalents ) were added , the reaction mixture was again purged with nitrogen , and then subjected to microwave conditions for an additional 12 hours at 120 ° c . the mixture was filtered through a 0 . 45 μm filter , which was then rinsed with ethyl acetate ; the combined filtrates were concentrated in vacuo and purified by hplc ( column : phenomenex lux cellulose - 2 , 5 μm ; mobile phase a : heptane ; mobile phase b : ethanol ; gradient : 5 % to 100 % b ). the product was obtained as a yellow - orange solid . yield : 10 . 1 mg , 0 . 0292 mmol , 13 %. lcms m / z 345 . 9 ( m + h ). 1 h nmr ( 500 mhz , cdcl 3 ) δ 8 . 98 ( s , 1h ), 8 . 01 ( d , j = 5 . 9 hz , 1h ), 7 . 42 - 7 . 43 ( m , 1h ), 7 . 23 ( br d , j = 2 . 1 hz , 1h ), 7 . 18 ( d , j = 5 . 9 hz , 1h ), 7 . 17 - 7 . 20 ( m , 1h ), 7 . 08 ( d , j = 8 . 2 hz , 1h ), 2 . 44 ( d , j = 1 . 3 hz , 3h ), 2 . 28 ( s , 6h ), 2 . 04 ( s , 3h ). compound c41 was prepared from 4 - bromo - 7 - methoxy - 1h - indole according to the general procedure for the synthesis of 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) in example 1 , except that the reaction solvent employed was 6 % water in 1 , 4 - dioxane . purification in this case was carried out via silica gel chromatography ( gradient : 90 % to 100 % dichloromethane in heptane ), to afford the product as a dark yellow solid . yield : 371 mg , 1 . 36 mmol , 62 %. gcms m / z 273 ( m + ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 70 ( d , j = 8 . 0 hz , 1h ), 7 . 55 ( d , j = 3 . 7 hz , 1h ), 7 . 10 ( d , j = 3 . 5 hz , 1h ), 6 . 81 ( d , j = 8 . 0 hz , 1h ), 3 . 97 ( s , 3h ), 1 . 37 ( s , 12h ). compound c42 was prepared from 7 - methoxy - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl )- 1h - indole ( c41 ) according to the general procedure for the synthesis of 4 -[ 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine ( 1 ) in example 1 , to provide the product as a yellow oil . yield : 70 mg , 0 . 28 mmol , 24 %. gcms m / z 253 ( m + ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 99 ( s , 1h ), 7 . 54 ( d , j = 3 . 7 hz , 1h ), 6 . 94 ( ab quartet , j ab = 8 . 1 hz , δv ab = 24 . 6 hz , 2h ), 6 . 01 ( d , j = 3 . 7 hz , 1h ), 4 . 02 ( s , 3h ), 2 . 23 ( s , 6h ). compound c43 was prepared from 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 7 - methoxy - 1h - indole ( c42 ) according to the general procedure for the synthesis of 3 - methyl - 4 -( 2 - methyl - 1h - imidazo [ 4 , 5 - c ] pyridin - 1 - yl ) phenol ( c9 ) in example 5 . the crude product was triturated with ethyl acetate to afford a mustard - yellow solid containing some impurities . yield : 53 mg , & lt ; 0 . 22 mmol , & lt ; 88 %. lcms m / z 240 . 1 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ), product peaks only : δ 9 . 29 ( s , 1h ), 7 . 29 ( d , j = 3 . 1 hz , 1h ), 6 . 75 ( ab quartet , j ab = 7 . 8 hz , δv ab = 38 . 4 hz , 2h ), 6 . 04 ( d , j = 3 . 1 hz , 1h ), 2 . 49 ( s , 6h ). 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 1h - indol - 7 - ol ( c43 ) ( 50 mg , 0 . 21 mmol ), 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 32 mg , 0 . 21 mmol ) and cesium carbonate ( 136 mg , 0 . 417 mmol ) were combined in dimethyl sulfoxide ( 1 ml ), and the reaction mixture was heated to 120 ° c . for 19 hours . after cooling to room temperature , the mixture was filtered through celite , the filter pad was rinsed with ethyl acetate , and the combined filtrates were washed twice with a 1 : 1 mixture of water and saturated aqueous sodium chloride solution , then washed twice with aqueous 1 n sodium hydroxide solution . the organic layer was dried over sodium sulfate , filtered , and concentrated in vacuo . purification via silica gel chromatography ( gradient : 50 % to 100 % ethyl acetate in heptane ) provided the product as an off - white solid . yield : 3 mg , 0 . 008 mmol , 4 %. lcms m / z 357 . 2 ( m + h ). 1 h nmr ( 500 mhz , cdcl 3 ) δ 9 . 01 ( s , 1h ), 8 . 67 ( br s , 1h ), 8 . 07 ( d , j = 5 . 9 hz , 1h ), 7 . 68 ( d , j = 2 . 2 hz , 1h ), 7 . 29 ( br d , j = 5 . 7 hz , 1h ), 7 . 22 ( dd , j = 2 . 9 , 2 . 7 hz , 1h ), 7 . 17 ( d , j = 7 . 8 hz , 1h ), 6 . 92 ( d , j = 7 . 8 hz , 1h ), 6 . 86 - 6 . 87 ( m , 1h ), 6 . 12 ( dd , j = 2 . 9 , 2 . 2 hz , 1h ), 2 . 31 ( s , 6h ). a solution of potassium hydrogen difluoride ( 124 mg , 1 . 59 mmol ) in water ( 0 . 50 ml ) was added to a mixture of 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) ( 186 mg , 0 . 530 mmol ) in methanol ( 0 . 50 ml ) and acetone ( 0 . 30 ml ). after 1 hour , the volume of the reaction mixture was reduced in vacuo , and the resulting solid was isolated via filtration and rinsed with a small amount of methanol . the product was obtained as a white solid . yield : 110 mg , 0 . 332 mmol , 63 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 13 ( d , j = 2 . 4 hz , 1h ), 7 . 97 ( d , j = 5 . 9 hz , 1h ), 7 . 68 ( d , j = 8 . 2 hz , 1h ), 7 . 47 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 04 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 7 . 03 ( br d , j = 2 . 4 hz , 1h ), 6 . 98 ( br dd , j = 8 . 0 , 2 . 4 hz , 1h ), 2 . 47 ( s , 3h ). 5 - bromo - 4 - chloro - 6 - methylpyrimidine ( 65 mg , 0 . 31 mmol ), potassium trifluoro [ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ] borate ( c44 ) ( 110 mg , 0 . 332 mmol ), potassium carbonate ( 130 mg , 0 . 941 mmol ), palladium ( 11 ) acetate ( 0 . 40 mg , 0 . 0018 mmol ) and dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl ) phosphane ( 1 . 20 mg , 0 . 0029 mmol ) were dissolved in nitrogen - purged ethanol , and the reaction mixture was heated to 85 ° c . for 66 hours . after cooling to room temperature , the reaction mixture was diluted with methanol and ethyl acetate , filtered through celite , and concentrated under reduced pressure . purification via silica gel chromatography ( gradient : 0 % to 70 % ethyl acetate in heptane ) afforded the product as a colorless oil . yield : 24 mg , 0 . 066 mmol , 21 %. lcms m / z 362 . 4 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 67 ( s , 1h ), 8 . 06 ( d , j = 5 . 9 hz , 1h ), 7 . 63 ( d , j = 2 . 0 hz , 1h ), 7 . 23 ( d , j = 5 . 9 hz , 1h ), 7 . 16 - 7 . 19 ( m , 1h ), 7 . 13 ( dd , half of abx pattern , j = 8 . 2 , 2 . 0 hz , 1h ), 7 . 09 ( d , half of ab pattern , j = 8 . 2 hz , 1h ), 6 . 80 - 6 . 84 ( m , 1h ), 4 . 32 - 4 . 52 ( m , 2h ), 2 . 25 ( s , 3h ), 2 . 06 ( s , 3h ), 1 . 28 ( t , j = 7 . 0 hz , 3h ). to a solution of 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) ( 13 . 5 g , 38 . 4 mmol ) in 1 , 4 - dioxane ( 200 ml ) and water ( 10 ml ) were added 5 - bromo - 6 - methylimidazo [ 1 , 2 - a ] pyrazine ( c45 , see a . r . harris et al ., tetrahedron 2011 , 67 , 9063 - 9066 ) ( 8 . 15 g , 38 . 4 mmol ), potassium carbonate ( 15 . 9 g , 115 mmol ) and [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) ( 2 . 8 g , 3 . 8 mmol ) at room temperature . the reaction mixture was degassed with nitrogen for 5 minutes , then stirred for 10 hours at reflux . the mixture was cooled to room temperature and filtered ; the filtrate was concentrated in vacuo and purified via chromatography on silica gel ( gradient : 0 % to 50 % ethyl acetate in petroleum ether ) to afford the product as a yellow solid . yield : 12 . 4 g , 34 . 8 mmol , 91 %. lcms m / z 357 . 0 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 9 . 02 ( s , 1h ), 8 . 00 ( d , j = 6 . 0 hz , 1h ), 7 . 93 ( d , j = 2 . 0 hz , 1h ), 7 . 79 - 7 . 80 ( m , 1h ), 7 . 48 - 7 . 51 ( m , 1h ), 7 . 44 ( d , j = 8 . 5 hz , 1h ), 7 . 41 ( dd , j = 6 . 0 , 1 . 0 hz , 1h ), 7 . 36 ( br d , j = 2 . 0 hz , 1h ), 7 . 28 ( br dd , j = 8 , 2 hz , 1h ), 7 . 02 - 7 . 05 ( m , 1h ), 2 . 38 ( s , 3h ), 2 . 07 ( s , 3h ). 5 -[ 4 -( furo [ 3 , 2 - c ] pyridine - 4 - yloxy )- 2 - methylphenyl ]- 6 - methylimidazo [ 1 , 2 - a ] pyrazine ( c46 ) was separated into its atropenantiomers using supercritical fluid chromatography ( column : chiralpak ad - h , 5 μm ; eluent : 3 : 1 carbon dioxide / methanol ). example 25 [ designated the (+)- atropenantiomer according to its observed rotation data ] was the first - eluting isomer , followed by example 26 . example 26 [ designated the (−)- atropenantiomer according to its observed rotation data ] was examined by vibrational circular dichroism ( vcd ) spectroscopy [ chiral / r ™ vcd spectrometer ( biotools , inc . )], and on the basis of this work , the absolute configuration of example 26 was assigned as ( r ). lcms m / z 357 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 9 . 10 ( s , 1h ), 8 . 08 ( d , j = 5 . 8 hz , 1h ), 7 . 73 ( d , j = 1 . 0 hz , 1h ), 7 . 70 ( d , j = 2 . 2 hz , 1h ), 7 . 31 - 7 . 34 ( m , 2h ), 7 . 26 - 7 . 30 ( m , 2h , assumed ; partially obscured by solvent peak ), 7 . 16 - 7 . 18 ( m , 1h ), 6 . 95 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 2 . 38 ( s , 3h ), 2 . 07 ( br s , 3h ). lcms m / z 357 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 9 . 10 ( s , 1h ), 8 . 09 ( d , j = 5 . 8 hz , 1h ), 7 . 73 ( d , j = 1 . 0 hz , 1h ), 7 . 70 ( d , j = 2 . 3 hz , 1h ), 7 . 31 - 7 . 35 ( m , 2h ), 7 . 26 - 7 . 31 ( m , 2h , assumed ; partially obscured by solvent peak ), 7 . 16 - 7 . 18 ( m , 1h ), 6 . 95 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 2 . 38 ( s , 3h ), 2 . 07 ( br s , 3h ). methylation of ethyl 3 - oxopentanoate ( according to the method of d . kalaitzakis et al ., tetrahedron : asymmetry 2007 , 18 , 2418 - 2426 ) afforded ethyl 2 - methyl - 3 - oxopentanoate ; subsequent treatment with one equivalent of bromine in chloroform provided ethyl 4 - bromo - 2 - methyl - 3 - oxopentanoate . this crude material ( 139 g , 586 mmol ) was slowly added to a 0 ° c . solution of potassium hydroxide ( 98 . 7 g , 1 . 76 mol ) in water ( 700 ml ); the internal reaction temperature rose to 30 ° c . during the addition . the reaction mixture was subjected to vigorous stirring for 4 hours in an ice bath , at which point it was acidified via slow addition of concentrated hydrochloric acid . after extraction with ethyl acetate , the aqueous layer was saturated with solid sodium chloride and extracted three additional times with ethyl acetate . the combined organic layers were washed with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated under reduced pressure to afford a mixture of oil and solid ( 81 . 3 g ). this material was suspended in chloroform ( 200 ml ); solids were filtered , then washed with chloroform ( 2 × 50 ml ). the combined filtrates were concentrated in vacuo and treated with a 3 : 1 mixture of heptane and diethyl ether ( 300 ml ). the mixture was vigorously swirled until some of the oil began to solidify , then concentrated under reduced pressure to afford an oily solid ( 60 . 2 g ). after addition of a 3 : 1 mixture of heptane and diethyl ether ( 300 ml ) and vigorous stirring for 10 minutes , filtration afforded the product as an off - white solid . yield : 28 . 0 g , 219 mmol , 37 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 4 . 84 ( br q , j = 6 . 8 hz , 1h ), 1 . 74 ( br s , 3h ), 1 . 50 ( d , j = 6 . 8 hz , 3h ). trifluoromethanesulfonic anhydride ( 23 . 7 ml , 140 mmol ) was added portion - wise to a solution of 4 - hydroxy - 3 , 5 - dimethylfuran - 2 ( 5h )- one ( c47 ) ( 15 . 0 g , 117 mmol ) and n , n - diisopropylethylamine ( 99 %, 24 . 8 ml , 140 mmol ) in dichloromethane ( 500 ml ) at − 20 ° c ., at a rate that maintained the internal reaction temperature below − 10 ° c . the reaction mixture was stirred at − 20 ° c ., then allowed to warm gradually to 0 ° c . over 5 hours . the reaction mixture was passed through a plug of silica gel , dried over magnesium sulfate , and concentrated in vacuo . the residue was suspended in diethyl ether and filtered ; the filtrate was concentrated under reduced pressure . purification using silica gel chromatography ( gradient : 0 % to 17 % ethyl acetate in heptane ) afforded the product as a pale yellow oil . yield : 21 . 06 g , 80 . 94 mmol , 69 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 5 . 09 - 5 . 16 ( m , 1h ), 1 . 94 - 1 . 96 ( m , 3h ), 1 . 56 ( d , j = 6 . 6 hz , 3h ). compound c49 was synthesized using the method described for 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) in example 1 , except that 4 - bromo - 3 - fluorophenol was used in place of 4 - bromo - 3 - methylphenol . the product was obtained as an off - white solid . yield : 22 . 5 g , 63 . 3 mmol , 39 % over 2 steps . lcms m / z 356 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 04 ( d , j = 5 . 9 hz , 1h ), 7 . 80 ( dd , j = 8 . 2 , 6 . 9 hz , 1h ), 7 . 65 ( d , j = 2 . 3 hz , 1h ), 7 . 25 ( dd , j = 5 . 8 , 0 . 9 hz , 1h ), 7 . 02 ( dd , j = 8 . 3 , 2 . 1 hz , 1h ), 6 . 94 ( dd , j = 10 . 2 , 2 . 1 hz , 1h ), 6 . 85 ( dd , j = 2 . 3 , 1 . 0 hz , 1h ), 1 . 37 ( s , 12h ). a solution of 4 -[ 3 - fluoro - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c49 ) ( 3 . 20 g , 9 . 01 mmol ) and 2 , 4 - dimethyl - 5 - oxo - 2 , 5 - dihydrofuran - 3 - yl trifluoromethanesulfonate ( c48 ) ( 2 . 46 g , 9 . 45 mmol ) in 1 , 4 - dioxane ( 80 ml ) was purged with nitrogen for 5 minutes . a mixture of tetrabutylammonium chloride ( 99 %, 127 mg , 0 . 452 mmol ), tricyclohexylphosphine ( 99 %, 128 mg , 0 . 452 mmol ) and palladium ( ii ) acetate ( 101 mg , 0 . 450 mmol ) was added , followed by an aqueous solution of potassium carbonate ( 3 m , 9 . 0 ml , 27 . 0 mmol ), and the reaction mixture was heated at 50 ° c . for 18 hours . after cooling to room temperature , the reaction mixture was diluted with ethyl acetate , washed three times with water , washed once with saturated aqueous sodium chloride solution , and dried over magnesium sulfate . filtration and removal of solvent under reduced pressure was followed by chromatographic purification on silica gel ( gradient : 15 % to 50 % ethyl acetate in heptane ), affording the product as a tan oil that slowly solidified upon standing . yield : 1 . 55 g , 4 . 57 mmol , 51 %. lcms m / z 340 . 3 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 06 ( d , j = 5 . 9 hz , 1h ), 7 . 70 ( d , j = 2 . 2 hz , 1h ), 7 . 33 - 7 . 38 ( m , 1h ), 7 . 31 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 13 - 7 . 20 ( m , 2h ), 6 . 94 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 5 . 43 - 5 . 51 ( m , 1h ), 1 . 99 - 2 . 01 ( m , 3h ), 1 . 38 ( d , j = 6 . 6 hz , 3h ). a solution of 4 -[ 2 - fluoro - 4 -( furo [ 3 , 2 - c ] pyridine - 4 - yloxy ) phenyl ]- 3 , 5 - dimethylfuran - 2 ( 5h )- one ( c50 ) ( 5 . 0 g , 15 mmol ) in tetrahydrofuran ( 200 ml ) and n , n - dimethylformamide ( 100 ml ) was treated with 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 - ene ( 6 . 61 ml , 44 . 2 mmol ) and purged with oxygen for 10 minutes . a slight positive pressure of oxygen was introduced into the flask and the reaction mixture was heated at 50 ° c . with vigorous stirring for 5 hours . upon heating , a slight additional pressure build - up was noted within the flask via examination of the rubber septum . lcms analysis indicated approximately 6 % of the starting material remaining ; the flask was cooled to room temperature , recharged with oxygen , and heated at 50 ° c . for an additional 18 hours . the reaction was cooled to room temperature , diluted with ethyl acetate ( 300 ml ) and washed sequentially with aqueous hydrochloric acid ( 0 . 25 m , 175 ml ) and water ( 150 ml ). the ph of the combined aqueous layers was adjusted from ph 3 to roughly ph 4 - 5 , and the aqueous layer was extracted with ethyl acetate ( 300 ml ). the combined organic layers were washed with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated in vacuo . purification via silica gel chromatography ( gradient : 0 % to 40 % ethyl acetate in heptane ) afforded the product as a white foam . yield : 4 . 20 g , 11 . 8 mmol , 79 %. lcms m / z 356 . 4 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 07 ( d , j = 5 . 8 hz , 1h ), 7 . 66 - 7 . 71 ( m , 2h ), 7 . 31 ( br d , j = 5 . 8 hz , 1h ), 7 . 11 - 7 . 17 ( m , 2h ), 6 . 93 - 6 . 94 ( m , 1h ), 3 . 95 ( br s , 1h ), 1 . 86 - 1 . 88 ( m , 3h ), 1 . 64 ( s , 3h ). anhydrous hydrazine ( 98 . 5 %, 1 . 88 ml , 59 . 0 mmol ) was added to a solution of 4 -[ 2 - fluoro - 4 -( furo [ 3 , 2 - c ] pyridine - 4 - yloxy ) phenyl ]- 5 - hydroxy - 3 , 5 - dimethylfuran - 2 ( 5h )- one ( c51 ) ( 4 . 20 g , 11 . 8 mmol ) in 1 - butanol ( 75 ml ), and the reaction mixture was heated at 110 ° c . for 2 hours . after cooling to room temperature and stirring at this temperature for 18 hours , the reaction mixture was stored in a refrigerator for 66 hours . the resulting suspension was filtered to afford a gray solid , which was dissolved in hot ethanol ( 150 - 175 ml ) and filtered through a nylon syringe filter . the filtrate was concentrated in vacuo to provide the product as a white solid . yield : 1 . 30 g , 3 . 70 mmol , 31 %. lcms m / z 352 . 2 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 12 . 89 ( br s , 1h ), 8 . 17 ( d , j = 2 . 2 hz , 1h ), 8 . 06 ( d , j = 5 . 8 hz , 1h ), 7 . 54 ( br d , j = 5 . 8 hz , 1h ), 7 . 38 - 7 . 46 ( m , 2h ), 7 . 25 ( br dd , j = 8 . 4 , 2 . 2 hz , 1h ), 7 . 12 - 7 . 14 ( m , 1h ), 1 . 99 ( s , 3h ), 1 . 85 ( s , 3h ). the product was prepared as an off - white solid , via reaction of 2 , 4 - dimethyl - 5 - oxo - 2 , 5 - dihydrofuran - 3 - yltrifluoromethanesulfonate ( c48 ) with 4 -[ 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c52 ) [ this may be prepared in a similar manner to 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) in example 1 ] as described for synthesis of 4 -[ 2 - fluoro - 4 -( furo [ 3 , 2 - c ] pyridine - 4 - yloxy ) phenyl ]- 3 , 5 - dimethylfuran - 2 ( 5h )- one ( c50 ) in example 27 . yield : 760 mg , 2 . 36 mmol , 80 %. lcms m / z 322 . 2 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 04 ( d , j = 5 . 9 hz , 1h ), 7 . 69 ( d , j = 2 . 2 hz , 1h ), 7 . 40 ( br ab quartet , j ab = 8 . 8 hz , δv ab = 27 . 3 hz , 4h ), 7 . 26 - 7 . 29 ( m , 1h , assumed ; partially obscured by solvent peak ), 6 . 93 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 5 . 43 ( qq , j = 6 . 7 , 1 . 8 hz , 1h ), 2 . 09 ( d , j = 1 . 8 hz , 3h ), 1 . 43 ( d , j = 6 . 6 hz , 3h ). 4 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) phenyl ]- 3 , 5 - dimethylfuran - 2 ( 5h )- one ( c53 ) was converted to the product in a similar manner to that described for synthesis of 5 -[ 2 - fluoro - 4 -( furo [ 3 , 2 - c ] pyridine - 4 - yloxy ) phenyl ]- 4 , 6 - dimethylpyridazin - 3 ( 2h )- one ( 27 ) in example 27 . the crude product was subjected to silica gel chromatography ( eluent : 40 % ethyl acetate in dichloromethane ), then recrystallized from ethanol to afford the title product as a white solid . yield : 270 mg , 0 . 810 mmol , 35 % over 2 steps . lcms m / z 334 . 0 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 12 . 79 ( br s , 1h ), 8 . 15 ( d , j = 2 . 4 hz , 1h ), 8 . 03 ( d , j = 5 . 9 hz , 1h ), 7 . 50 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 7 . 31 - 7 . 38 ( m , 4h ), 7 . 09 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 1 . 97 ( s , 3h ), 1 . 83 ( s , 3h ). the product was prepared from 4 -( 4 - bromo - 3 , 5 - dimethylphenoxy ) furo [ 3 , 2 - c ] pyridine [ synthesized via reaction of 4 - bromo - 3 , 5 - dimethylphenol with 4 - chlorofuro [ 3 , 2 - c ] pyridine ] and ( 3 - methylpyridin - 4 - yl ) boronic acid , according to the general procedure for the synthesis of 5 -( 2 - chloro - 4 - methoxyphenyl )- 4 , 6 - dimethylpyrimidine ( c64 ) in preparation p7 . lcms m / z 331 . 1 ( m + h ). 1 h nmr ( 600 mhz , dmso - d 6 ) 6 8 . 57 ( br s , 1h ), 8 . 49 ( br d , j = 4 . 8 hz , 1h ), 8 . 13 ( d , j = 2 . 2 hz , 1h ), 8 . 02 ( d , j = 5 . 9 hz , 1h ), 7 . 47 ( dd , j = 5 . 8 , 1 . 0 hz , 1h ), 7 . 10 ( br d , j = 4 . 8 hz , 1h ), 7 . 05 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 7 . 02 - 7 . 04 ( m , 2h ), 1 . 97 ( s , 3h ), 1 . 89 ( s , 6h ). potassium hydroxide ( 112 mg , 1 . 99 mmol ) and 1 , 4 , 7 , 10 , 13 , 16 - hexaoxacyclooctadecane ( 18 - crown - 6 ; 13 . 3 mg , 0 . 050 mmol ) were added to a solution of 4 -( imidazo [ 1 , 2 - a ] pyridin - 5 - yl ) naphthalen - 1 - ol ( c54 ) [ prepared via suzuki reaction between ( 4 - methoxynaphthalen - 1 - yl ) boronic acid and 5 - bromoimidazo [ 1 , 2 - a ] pyridine as described in example 8 , followed by boron tribromide - mediated methyl ether cleavage ] ( 85 mg , 0 . 25 mmol ) and 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 57 . 3 mg , 0 . 373 mmol ) in xylene ( 3 ml ), and the reaction mixture was heated to 140 ° c . for 24 hours . solvent was removed in vacuo , and the crude material was combined with crude product from a similar reaction carried out on 30 mg of c54 . after the reaction was partitioned between ethyl acetate ( 25 ml ) and water ( 25 ml ), the aqueous layer was extracted with ethyl acetate ( 3 × 30 ml ), and the combined organic layers were dried over sodium sulfate . purification was first effected via silica gel chromatography ( eluent : ethyl acetate ), followed by hplc ( column : xbridge c18 , 5 μm , mobile phase a : water with trifluoroacetic acid modifier ; mobile phase b : acetonitrile with trifluoroacetic acid modifier ; gradient : 30 % to 50 % b ). the product was obtained as a colorless gum . yield : 20 mg , 0 . 041 mmol , 12 %. lcms m / z 378 . 1 ( m + h ). 1 h nmr ( 500 mhz , cd 3 od ) δ 8 . 17 ( dd , half of abx pattern , j = 9 . 0 , 7 . 1 hz , 1h ), 8 . 15 ( br d , j = 8 . 0 hz , 1h ), 8 . 10 ( br d , half of ab pattern , j = 9 hz , 1h ), 7 . 99 - 8 . 01 ( m , 2h ), 7 . 89 ( d , j = 5 . 9 hz , 1h ), 7 . 83 ( d , j = 7 . 8 hz , 1h ), 7 . 70 ( br d , j = 2 hz , 1h ), 7 . 67 ( dd , j = 7 . 1 , 1 . 0 hz , 1h ), 7 . 61 ( ddd , j = 8 . 3 , 6 . 8 , 1 . 2 hz , 1h ), 7 . 56 ( ddd , j = 8 . 3 , 6 . 8 , 1 . 2 hz , 1h ), 7 . 54 ( d , j = 7 . 6 hz , 1h ), 7 . 41 - 7 . 44 ( m , 2h ), 7 . 20 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ). preparations p1 - p15 describe preparations of some starting materials or intermediates used for preparation of certain compounds of the invention . boron tribromide ( 1 . 9 g , 7 . 6 mmol ) was slowly added to a solution of 4 -[ 3 - methoxy - 4 -( 3 - methylpyrazin - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( 6 ) ( 2 . 3 g , 6 . 9 mmol ) in dichloromethane ( 100 ml ) at 0 ° c . the reaction mixture was stirred at 0 ° c . for 1 hour , then quenched with water , stirred and filtered . the filtrate was adjusted to neutral ph with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane ( 3 × 50 ml ). the combined organic layers were dried , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 0 % to 2 % methanol in dichloromethane ) afforded the product . yield : 1 . 2 g , 3 . 8 mmol , 55 %. lcms m / z 320 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 11 . 83 ( s , 1h ), 8 . 48 ( d , j = 2 . 5 hz , 1h ), 8 . 36 ( d , j = 2 . 5 hz , 1h ), 8 . 08 ( d , j = 5 . 8 hz , 1h ), 7 . 68 ( d , j = 8 . 5 hz , 1h ), 7 . 66 ( d , j = 2 . 3 hz , 1h ), 7 . 25 - 7 . 28 ( m , 1h , assumed ; partially obscured by solvent peak ), 6 . 95 ( d , j = 2 . 5 hz , 1h ), 6 . 90 ( dd , j = 2 . 3 , 1 . 0 hz , 1h ), 6 . 86 ( dd , j = 8 . 8 , 2 . 5 hz , 1h ), 2 . 87 ( s , 3h ). the product was prepared from c55 ( a 1 : 1 mixture of 5 - bromo - 6 - methylimidazo [ 1 , 2 - a ] pyridine and 5 - chloro - 6 - methylimidazo [ 1 , 2 - a ] pyridine , see a . r . harris et al ., tetrahedron 2011 , 67 , 9063 - 9066 ) ( 210 mg , 1 . 00 mmol ) and ( 4 - methoxyphenyl ) boronic acid ( 116 mg , 0 . 765 mmol ) using the method of example 6 . silica gel chromatography ( gradient : 0 % to 40 % [ 20 % methanol in dichloromethane ] in dichloromethane ) afforded the product . yield : 159 mg , 0 . 667 mmol , 87 %. 1 h nmr ( 500 mhz , cdcl 3 ) δ 7 . 55 ( d , j = 9 . 3 hz , 1h ), 7 . 50 ( s , 1h ), 7 . 30 ( d , j = 8 . 5 hz , 2h ), 7 . 14 ( d , j = 9 . 3 hz , 1h ), 7 . 12 ( s , 1h ), 7 . 07 ( d , j = 8 . 5 hz , 2h ), 3 . 89 ( s , 3h ), 2 . 13 ( s , 3h ). the product was prepared from 5 -( 4 - methoxyphenyl )- 6 - methylimidazo [ 1 , 2 - a ] pyridine ( c56 ) ( 159 mg , 0 . 667 mmol ) as described for the synthesis of 6 -( 4 - hydroxy - 2 - methylphenyl )- 1 , 5 - dimethylpyrazin - 2 ( 1h )- one ( p8 ) in preparation p8 . in this case , after the second addition of methanol , the mixture was concentrated in vacuo , then azeotroped with heptane to provide the product as a brown solid . yield : 193 mg , 0 . 63 mmol , 95 %. lcms m / z 225 . 0 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 7 . 97 ( d , j = 9 . 2 hz , 1h ), 7 . 91 ( d , j = 2 . 2 hz , 1h ), 7 . 83 ( br d , j = 9 . 4 hz , 1h ), 7 . 54 ( dd , j = 2 . 2 , 0 . 7 hz , 1h ), 7 . 36 ( br d , j = 8 . 6 hz , 2h ), 7 . 08 ( br d , j = 8 . 8 hz , 2h ), 2 . 31 ( s , 3h ). methyl propanoate ( 44 g , 0 . 50 mol ) was reacted with methyl formate ( 55 . 5 g , 0 . 75 mol ) according to the method of f . kido et al ., tetrahedron 1987 , 43 , 5467 - 5474 . purification by distillation ( 70 - 104 ° c .) gave compound c57 as a colorless liquid . yield : 23 g , 0 . 20 mol , 40 %. 1 h nmr ( 400 mhz , cdcl 3 ), roughly 1 : 1 mixture of aldehyde and enol forms : δ 11 . 24 ( d , j = 11 . 5 hz , 1h ), 9 . 78 ( s , 1h ), 6 . 99 ( d , j = 10 . 5 hz , 1h ), 3 . 79 ( s , 6h ), 3 . 41 ( q , j = 7 hz , 1h ), 1 . 68 ( s , 3h ), 1 . 36 ( d , j = 7 hz , 3h ). a solution of methyl 3 - hydroxy - 2 - methylprop - 2 - enoate ( c57 ) ( 95 g , 0 . 82 mol ) and 1h - 1 , 2 , 4 - triazol - 5 - amine ( 100 g , 1 . 19 mol ) in a mixture of ethanol ( 300 ml ) and acetic acid ( 150 ml ) was heated to reflux for 12 hours . the reaction mixture was allowed to cool to ambient temperature and solids were filtered to afford the product as a white solid . yield : 41 g , 27 mmol , 33 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 8 . 18 ( s , 1h ), 7 . 91 ( s , 1h ), 2 . 00 ( s , 3h ). to a stirred suspension of 6 - methyl [ 1 , 2 , 4 ] triazolo [ 1 , 5 - a ] pyrimidin - 7 - ol ( c58 ) ( 105 g , 0 . 699 mol ) in phosphorus oxychloride ( 500 ml ) at room temperature was added drop - wise n , n - diisopropylethylamine ( 100 ml ) and the reaction mixture was heated to reflux for 110 minutes . after the mixture cooled to ambient temperature , it was concentrated to near dryness in vacuo , poured into ice water , and adjusted to ph 9 by addition of potassium carbonate . the resulting solution was extracted three times with dichloromethane ( 800 ml ) and the combined organic phases were washed with saturated aqueous sodium chloride solution , dried over sodium sulfate , and concentrated under reduced pressure . silica gel chromatography ( gradient : 17 % to 33 % ethyl acetate in petroleum ether ) provided the product as a white solid . yield : 55 g , 330 mmol , 47 %. lcms m / z 169 . 2 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 70 ( s , 1h ), 8 . 52 ( s , 1h ), 2 . 54 ( s , 3h ). pyrazin - 2 - amine ( 1 g , 10 mmol ) was dissolved in ethanol ( 15 ml ) and 1 - chloropropan - 2 - one ( 1 . 2 ml , 14 mmol ) was added . the resulting solution was stirred at reflux for 2 hours , cooled to room temperature , and concentrated in vacuo . saturated aqueous sodium bicarbonate solution ( 50 ml ) was added , and the mixture was extracted three times with chloroform ( 20 ml ); the combined organic layers were dried over sodium sulfate , filtered , and concentrated . silica gel chromatography ( gradient : 0 % to 50 % methanol in ethyl acetate ) gave c59 as an orange solid . yield : 122 mg , 0 . 916 mmol , 9 %. lcms m / z 133 . 9 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 98 ( br s , 1h ), 7 . 99 ( dd , j = 4 . 6 , 1 . 5 hz , 1h ), 7 . 83 ( br d , j = 4 . 5 hz , 1h ), 7 . 46 ( br s , 1h ), 2 . 53 ( s , 3h ). 2 - methylimidazo [ 1 , 2 - a ] pyrazine ( c59 ) ( 122 mg , 0 . 916 mmol ) was dissolved in chloroform ( 2 ml ) and treated with n - bromosuccinimide ( 189 mg , 1 . 1 mmol ). the resulting mixture was stirred at ambient temperature for 1 . 5 hours and then concentrated in vacuo . silica gel chromatography ( gradient : 33 % to 100 % ethyl acetate in heptane ) afforded the product , still containing some succinimide . this material was dissolved in dichloromethane ( 25 ml ) and washed with aqueous sodium hydroxide solution ( 0 . 5 m , 3 × 10 ml ). the organic layer was dried over sodium sulfate , filtered , and concentrated in vacuo to afford the product as an off - white solid . yield : 125 mg , 0 . 59 mmol , 64 %. lcms m / z 213 . 9 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 93 ( s , 1h ), 7 . 96 ( br s , 2h ), 2 . 51 ( s , 3h ). 4 -[ 4 - bromo - 3 -( trifluoromethyl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( 3 . 58 g , 10 . 0 mmol ) was reacted with 4 , 4 , 4 ′, 4 ′, 5 , 5 , 5 ′, 5 ′- octamethyl - 2 , 2 ′- bi - 1 , 3 , 2 - dioxaborolane ( 99 %, 3 . 33 g , 13 . 0 mmol ), potassium acetate ( 95 %, 4 . 13 g , 40 . 0 mmol ) and [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) ( 732 mg , 1 . 00 mmol ) in analogous fashion to the synthesis of 4 -[ 3 - methyl - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c2 ) in example 1 . silica gel chromatography ( gradient : 0 % to 20 % ethyl acetate in heptane ) provided the product as a white solid . yield : 2 . 035 g , 5 . 022 mmol , 50 %. lcms m / z 406 . 2 ( m + h ). 1 h nmr ( 500 mhz , cdcl 3 ) δ 8 . 00 ( d , j = 5 . 9 hz , 1h ), 7 . 84 ( br d , j = 8 . 0 hz , 1h ), 7 . 66 ( d , j = 2 . 2 hz , 1h ), 7 . 55 ( br d , j = 2 . 2 hz , 1h ), 7 . 39 ( br dd , j = 8 . 2 , 2 . 3 hz , 1h ), 7 . 25 ( dd , j = 5 . 9 , 1 . 0 hz , 1h ), 6 . 87 ( dd , j = 2 . 2 , 1 . 0 hz , 1h ), 1 . 38 ( s , 12h ). 6 - bromo - 5 - methylpyrazin - 2 - amine ( c60 , see a . r . harris et al ., tetrahedron 2011 , 67 , 9063 - 9066 ; 111 mg , 0 . 590 mmol ), ( 4 - methoxy - 2 , 5 - dimethylphenyl ) boronic acid ( 127 mg , 0 . 708 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 95 %, 40 mg , 0 . 033 mmol ) were combined in a pressure tube and dissolved in 1 , 4 - dioxane ( 2 ml ) and water ( 0 . 6 ml ). an aqueous solution of sodium carbonate ( 2 . 0 m , 0 . 885 ml , 1 . 77 mmol ) was added , and the reaction was conducted in analogous fashion to the synthesis of 6 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methylpyrazin - 2 - amine ( c3 ) in example 2 . silica gel chromatography ( gradient : 0 % to 75 % ethyl acetate in heptane ) afforded the product . yield : 116 mg , 0 . 477 mmol , 81 %. lcms m / z 244 . 1 ( m + h ). 1 h nmr ( 400 mhz , cd 3 cn ) δ 7 . 83 ( s , 1h ), 6 . 90 ( s , 1h ), 6 . 82 ( s , 1h ), 4 . 93 ( br s , 2h ), 3 . 83 ( s , 3h ), 2 . 15 ( br s , 3h ), 2 . 11 ( s , 3h ), 2 . 05 ( br s , 3h ). chloroacetaldehyde ( 55 % solution in water , 0 . 28 ml , 2 . 38 mmol ) was added to a mixture of 6 -( 4 - methoxy - 2 , 5 - dimethylphenyl )- 5 - methylpyrazin - 2 - amine ( c61 ) ( 116 mg , 0 . 477 mmol ) in water ( 3 . 6 ml ). the reaction mixture was heated to 115 ° c . for 2 hours in a microwave reactor and then cooled to room temperature , whereupon the solvent was removed in vacuo . silica gel chromatography ( gradient : 0 % to 10 % methanol in dichloromethane ) afforded the product . yield : 115 mg , 0 . 43 mmol , 90 %. lcms m / z 268 . 1 ( m + h ). 1 h nmr ( 400 mhz , cd 3 cn ) δ 9 . 45 ( s , 1h ), 7 . 99 ( br s , 1h ), 7 . 37 ( br s , 1h ), 7 . 08 ( s , 1h ), 7 . 04 ( s , 1h ), 3 . 91 ( s , 3h ), 2 . 41 ( s , 3h ), 2 . 20 ( br s , 3h ), 2 . 03 ( br s , 3h ). 5 -( 4 - methoxy - 2 , 5 - dimethylphenyl )- 6 - methylimidazo [ 1 , 2 - a ] pyrazine ( c62 ) ( 115 mg , 0 . 43 mmol ) was dissolved in dichloromethane ( 5 ml ) and the reaction mixture was cooled to − 78 ° c . a solution of boron tribromide ( 1 m in dichloromethane , 2 . 58 ml , 2 . 58 mmol ) was added slowly drop - wise , and the resulting mixture was stirred for 15 minutes ; the cooling bath was then removed and the reaction mixture was stirred at room temperature for 18 hours . methanol ( 5 ml ) was added and the resulting mixture was heated to a gentle reflux for 30 minutes . the solvent was removed in vacuo and the resulting yellow residue was triturated three times with ethyl acetate ( 10 ml ) to afford the product . yield : 104 mg , 0 . 410 mmol , 95 %. lcms m / z 254 . 1 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 9 . 40 ( s , 1h ), 8 . 20 ( d , j = 2 . 0 hz , 1h ), 7 . 60 - 7 . 62 ( m , 1h ), 7 . 11 ( s , 1h ), 6 . 91 ( s , 1h ), 2 . 46 ( s , 3h ), 2 . 23 ( br s , 3h ), 1 . 98 ( br s , 3h ). 4 , 6 - dimethyl - 5 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) pyrimidine ( c63 , prepared from 5 - bromo - 4 , 6 - dimethylpyrimidine using the method of example 1 , step 2 ) ( 750 mg , 3 . 2 mmol ) and 1 - bromo - 2 - chloro - 4 - methoxybenzene ( 1 . 46 g , 6 . 41 mmol ) were dissolved in tetrahydrofuran ( 10 ml ), and aqueous potassium phosphate solution ( 0 . 5 m , 12 . 8 ml ) was added . nitrogen was bubbled through the reaction mixture for 10 minutes . [ 2 ′-( azanidyl - κn ) biphenyl - 2 - yl - κc 2 ]( chloro )[ dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl )- λ 5 - phosphanyl ] palladium ( 116 mg , 0 . 161 mmol ) was added , and then nitrogen bubbling was continued for a few minutes . the reaction vessel was sealed and stirred at 70 ° c . for 18 hours . the reaction mixture was cooled to room temperature , diluted with ethyl acetate , washed with water and with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated under reduced pressure . the crude material was purified by chromatography on silica gel ( eluent : 25 % ethyl acetate in heptane ) to afford the product as a light yellow oil , which solidified on standing . yield : 320 mg , 1 . 29 mmol , 40 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 93 ( s , 1h ), 7 . 05 ( d , j = 2 . 5 hz , 1h ), 7 . 02 ( d , j = 8 . 6 hz , 1h ), 6 . 90 ( dd , j = 8 . 6 , 2 . 5 hz , 1h ), 3 . 84 ( s , 3h ), 2 . 21 ( s , 6h ). 5 -( 2 - chloro - 4 - methoxyphenyl )- 4 , 6 - dimethylpyrimidine ( c64 ) ( 310 mg , 1 . 25 mmol ) was converted to the product according to the general procedure for the synthesis of 5 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 6 - methylpyrimidin - 4 - ol ( c30 ) in example 18 . the product was obtained as an orange solid . yield : 280 mg , 1 . 19 mmol , 95 %. 1 h nmr ( 400 mhz , cd 3 od ) δ 8 . 82 ( s , 1h ), 7 . 05 ( d , j = 8 . 4 hz , 1h ), 6 . 98 ( d , j = 2 . 3 hz , 1h ), 6 . 85 ( dd , j = 8 . 4 , 2 . 3 hz , 1h ), 2 . 20 ( s , 6h ). a mixture of 1 - methoxy - 3 - methylbenzene ( 85 . 5 g , 0 . 700 mol ) and aluminum chloride ( 138 . 6 g , 1 . 04 mol ) in dichloromethane ( 2 . 5 l ) was cooled in an ice bath ; propanoyl chloride ( 97 . 1 g , 1 . 05 mol ) was added drop - wise over a period of 30 minutes . the ice bath was removed , and the resulting mixture was stirred at room temperature for 20 minutes , then re - cooled in an ice bath . water ( 150 ml ) was added drop - wise followed by addition of more water ( 500 ml ). the organic phase was separated and concentrated in vacuo . silica gel chromatography ( 3 % ethyl acetate in petroleum ether ) gave the product as a colorless oil , which became a white solid upon standing at room temperature . by nmr , the product was contaminated with a small amount of another isomer . yield : 100 g , 0 . 56 mol , 80 %. 1 h nmr ( 400 mhz , cdcl 3 ), product peaks : δ 7 . 73 ( d , j = 9 . 5 hz , 1h ), 6 . 73 - 6 . 78 ( m , 2h ), 3 . 84 ( s , 3h ), 2 . 91 ( q , j = 7 . 3 hz , 2h ), 2 . 55 ( s , 3h ), 1 . 19 ( t , j = 7 . 3 hz , 3h ). to a mixture of 1 -( 4 - methoxy - 2 - methylphenyl ) propan - 1 - one ( c65 ) ( 100 g , 0 . 56 mol ) in tetrahydrofuran ( 2 . 5 l ) was slowly added isoamyl nitrite ( 131 g , 1 . 12 mol ) and hydrogen chloride ( 4 n in 1 , 4 - dioxane , 200 ml ). the mixture was stirred at room temperature for 24 hours , then concentrated in vacuo . silica gel chromatography ( gradient : 3 % to 10 % ethyl acetate in petroleum ether ) gave crude product ( 120 g ), which was further purified by slurrying in a mixture of petroleum ether ( 1 l ) and ethyl acetate ( 100 ml ) at room temperature for 30 minutes . the mixture was filtered to yield the product as a solid . yield : 75 g , 0 . 36 mol , 64 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 98 - 8 . 12 ( br m , 1h ), 7 . 46 ( d , j = 8 . 3 hz , 1h ), 6 . 72 - 6 . 79 ( m , 2h ), 3 . 84 ( s , 3h ), 2 . 40 ( s , 3h ), 2 . 16 ( s , 3h ). to a mixture of 2 -( hydroxyimino )- 1 -( 4 - methoxy - 2 - methylphenyl ) propan - 1 - one ( c66 ) ( 37 . 5 g , 181 mmol ) in water ( 720 ml ) was slowly added formaldehyde solution ( 450 ml ) and concentrated hydrochloric acid ( 270 ml ). a second batch of the reaction was prepared in the same manner . both mixtures were stirred at room temperature for 18 hours . the two batches were combined and extracted with ethyl acetate ( 3 × 2 l ); the combined organic extracts were concentrated . silica gel chromatography ( 5 % ethyl acetate in petroleum ether ) gave the product as a yellow oil . yield : 60 g , 310 mmol , 86 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 66 ( d , j = 8 . 5 hz , 1h ), 6 . 75 - 6 . 83 ( m , 2h ), 3 . 87 ( s , 3h ), 2 . 60 ( s , 3h ), 2 . 51 ( s , 3h ). 1 -( 4 - methoxy - 2 - methylphenyl ) propane - 1 , 2 - dione ( c67 ) ( 4 . 0 g , 21 mmol ) and glycinamide acetate ( 2 . 79 g , 20 . 8 mmol ) were dissolved in methanol ( 40 ml ) and cooled to − 10 ° c . aqueous sodium hydroxide solution ( 12 n , 3 . 5 ml , 42 mmol ) was added , and the resulting mixture was slowly warmed to room temperature . after stirring for 3 days , the reaction mixture was concentrated in vacuo . the residue was diluted with water , and 1 n aqueous hydrochloric acid was added until the ph was approximately 7 . the aqueous phase was extracted several times with ethyl acetate , and the combined organic extracts were washed with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated under reduced pressure . the resulting residue was slurried with 3 : 1 ethyl acetate / heptane , stirred for 5 minutes , and then filtered . the filtrate was concentrated under reduced pressure . silica gel chromatography ( eluent : ethyl acetate ) gave the product as a tan solid that contained 15 % of an undesired regioisomer ; this material was used without further purification . yield : 2 . 0 g , 8 . 7 mmol , & lt ; 41 %. lcms m / z 231 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ), product peaks : δ 8 . 09 ( s , 1h ), 7 . 14 ( d , j = 8 . 2 hz , 1h ), 6 . 82 - 6 . 87 ( m , 2h ), 3 . 86 ( s , 3h ), 2 . 20 ( s , 3h ), 2 . 11 ( s , 3h ). 6 -( 4 - methoxy - 2 - methylphenyl )- 5 - methylpyrazin - 2 ( 1h )- one ( c68 ) ( from the previous step , 1 . 9 g , & lt ; 8 . 2 mmol ) was dissolved in n , n - dimethylformamide ( 40 ml ). lithium bromide ( 0 . 86 g , 9 . 9 mmol ) and sodium bis ( trimethylsilyl ) amide ( 95 %, 1 . 91 g , 9 . 89 mmol ) were added and the reaction mixture was stirred for 30 minutes . methyl iodide ( 0 . 635 ml , 10 . 2 mmol ) was added and the resulting solution was stirred at room temperature for 18 hours . the reaction mixture was diluted with water and brought to a ph of approximately 7 by slow portion - wise addition of 1 n aqueous hydrochloric acid . the aqueous layer was extracted with ethyl acetate and the combined ethyl acetate layers were washed several times with water , dried over magnesium sulfate , filtered , and concentrated . silica gel chromatography ( gradient : 75 % to 100 % ethyl acetate in heptane ) gave the product as a viscous orange oil . yield : 1 . 67 g , 6 . 84 mmol , 33 % over two steps . lcms m / z 245 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 17 ( s , 1h ), 7 . 03 ( br d , j = 8 hz , 1h ), 6 . 85 - 6 . 90 ( m , 2h ), 3 . 86 ( s , 3h ), 3 . 18 ( s , 3h ), 2 . 08 ( br s , 3h ), 2 . 00 ( s , 3h ). to a cooled (− 78 ° c .) solution of 6 -( 4 - methoxy - 2 - methylphenyl )- 1 , 5 - dimethylpyrazin - 2 ( 1h )- one ( c69 ) ( 1 . 8 g , 7 . 37 mmol ) in dichloromethane was added a solution of boron tribromide in dichloromethane ( 1 m , 22 ml , 22 mmol ). the cooling bath was removed after 30 minutes , and the reaction mixture was allowed to warm to room temperature and stir for 18 hours . the reaction was cooled to − 78 ° c ., and methanol ( 10 ml ) was slowly added ; the resulting mixture was slowly warmed to room temperature . the reaction mixture was concentrated in vacuo , methanol ( 20 ml ) was added , and the mixture was again concentrated under reduced pressure . the residue was diluted with ethyl acetate ( 300 ml ) and water ( 200 ml ) and the resulting aqueous layer was brought to ph 7 via the portion - wise addition of saturated aqueous sodium carbonate solution . the mixture was extracted with ethyl acetate ( 3 × 200 ml ). the combined organic extracts were washed with water and with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated in vacuo to afford the product as a light tan solid . yield : 1 . 4 g , 6 . 0 mmol , 81 %. lcms m / z 231 . 1 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 21 ( s , 1h ), 6 . 98 ( d , j = 8 . 2 hz , 1h ), 6 . 87 - 6 . 89 ( m , 1h ), 6 . 85 ( br dd , j = 8 . 2 , 2 . 5 hz , 1h ), 3 . 22 ( s , 3h ), 2 . 06 ( br s , 3h ), 2 . 03 ( s , 3h ). a mixture of 1 -( 4 - methoxy - 2 - methylphenyl ) propane - 1 , 2 - dione ( c67 ) ( 1 . 0 g , 5 . 2 mmol ) and 2 - hydrazinyl - 1h - imidazole hydrochloride ( 1 . 05 g , 7 . 8 mmol ) in n , n - dimethylformamide ( 8 ml ) was heated to 100 ° c . in a microwave reactor for 20 minutes . after the progress of the reaction had been assessed by thin layer chromatography , the mixture was heated to 120 ° c . for 20 minutes . the solvent was removed in vacuo and the residue was taken up in ethyl acetate ( 30 ml ) and water ( 10 ml ). saturated aqueous sodium bicarbonate solution was added to adjust the ph to roughly 8 . the aqueous layer was extracted with additional ethyl acetate ( 30 ml ) and the combined organic extracts were dried over magnesium sulfate , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 50 % to 100 % ethyl acetate in heptane ) afforded the product as a light yellow solid . yield : 587 mg , 2 . 31 mmol , 44 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 06 ( d , j = 0 . 9 hz , 1h ), 7 . 21 ( d , j = 8 . 2 hz , 1h ), 7 . 15 ( d , j = 1 . 1 hz , 1h ), 6 . 95 - 7 . 00 ( m , 2h ), 3 . 91 ( s , 3h ), 2 . 63 ( s , 3h ), 2 . 03 ( br s , 3h ). 4 -( 4 - methoxy - 2 - methylphenyl )- 3 - methylimidazo [ 2 , 1 - c ][ 1 , 2 , 4 ] triazine ( c70 ) ( 587 mg , 2 . 31 mmol ) in dichloromethane ( 5 ml ) was reacted with boron tribromide ( 1 m in dichloromethane , 13 . 1 ml , 13 . 1 mmol ) as described in preparation p8 . the product was obtained as a tan solid . yield : 543 mg , 2 . 25 mmol , 97 %. lcms m / z 241 . 1 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 9 . 99 ( s , 1h ), 8 . 09 ( d , j = 1 . 0 hz , 1h ), 7 . 43 ( d , j = 1 . 2 hz , 1h ), 7 . 27 ( d , j = 8 . 4 hz , 1h ), 6 . 89 ( br d , j = 2 . 2 hz , 1h ), 6 . 83 ( br dd , j = 8 . 3 , 2 . 4 hz , 1h ), 2 . 49 ( s , 3h ), 1 . 91 ( br s , 3h ). a solution of 4 - bromo - 3 - fluorophenol ( 1 . 22 g , 6 . 39 mmol ), benzyl chloromethyl ether ( 60 %, 2 . 22 ml , 9 . 58 mmol ) and diisopropylethylamine ( 2 . 23 ml , 12 . 8 mmol ) in dichloromethane was heated at reflux for two hours . the reaction mixture was then concentrated in vacuo and purified by silica gel chromatography ( gradient : 15 % to 40 % ethyl acetate in heptane ) to afford the product as a colorless oil . yield : 2 . 35 g , & gt ; 100 %. 1 h nmr ( 400 mhz , cd 3 od ), characteristic peaks : δ 7 . 48 ( dd , j = 8 . 9 , 8 . 1 hz , 1h ), 6 . 95 ( dd , j = 10 . 6 , 2 . 7 hz , 1h ), 6 . 84 ( ddd , j = 8 . 9 , 2 . 8 , 1 . 1 hz , 1h ), 5 . 31 ( s , 2h ), 4 . 70 ( s , 2h ). a solution of 4 -[( benzyloxy ) methoxy ]- 1 - bromo - 2 - fluorobenzene ( c71 ) ( from the previous step , 525 mg , & lt ; 1 . 69 mmol ) in tetrahydrofuran ( 20 ml ) was cooled to − 78 ° c . for 15 minutes . lithium diisopropylamide ( 1 . 60 m , 1 . 58 ml , 2 . 53 mmol ) was then added drop - wise over 15 minutes . after one hour at − 78 ° c ., n , n - dimethylformamide ( 0 . 197 ml , 2 . 53 mmol ) in tetrahydrofuran ( 5 ml ) was added . the reaction mixture was stirred at − 78 ° c . for 30 minutes , quenched with 50 % saturated aqueous sodium chloride solution ( 30 ml ) and then allowed to reach room temperature . the reaction mixture was extracted with ethyl acetate ( 3 × 30 ml ). the combined organic layers were dried over sodium sulfate , filtered , concentrated in vacuo and purified by silica gel chromatography ( gradient : 15 % to 40 % ethyl acetate in heptane ) to afford the product as a light yellow oil . yield : 397 mg , 1 . 17 mmol , 82 % over two steps . 1 h nmr ( 400 mhz , cdcl 3 ) δ 10 . 36 ( d , j = 1 . 4 hz , 1h ), 7 . 66 ( dd , j = 9 . 2 , 7 . 6 hz , 1h ), 7 . 29 - 7 . 38 ( m , 5h ), 7 . 04 ( dd , j = 9 . 1 , 1 . 5 hz , 1h ), 5 . 42 ( s , 2h ), 4 . 75 ( s , 2h ). a mixture of 6 -[( benzyloxy ) methoxy ]- 3 - bromo - 2 - fluorobenzaldehyde ( c72 ) ( 1 . 40 g , 4 . 13 mmol ) and methylhydrazine ( 8 . 69 ml , 165 mmol ) was dissolved in 1 , 4 - dioxane ( 8 ml ) in a pressure vessel and heated at 110 ° c . for 4 hours , then at 120 ° c . for 16 hours . the mixture was submitted to microwave irradiation at 150 ° c . for 90 minutes . the reaction mixture was concentrated in vacuo and purified by silica gel chromatography ( gradient : 15 % to 40 % ethyl acetate in heptane ) to provide c73 as a colorless oil and c74 as a yellow oil . yield : c73 , 801 mg , 2 . 31 mmol , 56 %; c74 , 296 mg , 0 . 852 mmol , 21 %. c73 : 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 05 ( s , 1h ), 7 . 41 ( d , j = 8 . 2 hz , 1h ), 7 . 28 - 7 . 38 ( m , 5h ), 6 . 67 ( d , j = 8 . 2 hz , 1h ), 5 . 44 ( s , 2h ), 4 . 76 ( s , 2h ), 4 . 41 ( s , 3h ). c74 : 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 06 ( br s , 1h ), 7 . 38 ( d , j = 7 . 9 hz , 1h ), 7 . 28 - 7 . 38 ( m , 5h ), 6 . 59 ( d , j = 8 . 0 hz , 1h ), 5 . 42 ( s , 2h ), 4 . 76 ( s , 2h ), 4 . 26 ( br s , 3h ). a mixture of 4 , 6 - dimethyl - 5 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) pyrimidine ( c63 ) ( 152 mg , 0 . 649 mmol ), 4 -[( benzyloxy ) methoxy ]- 7 - bromo - 2 - methyl - 2h - indazole ( c74 ) ( 150 mg , 0 . 432 mmol ), tetrahydrofuran ( 5 ml ), and aqueous potassium phosphate solution ( 0 . 5 m , 2 . 59 ml , 1 . 30 mmol ) was purged with nitrogen for two minutes before adding [ 2 ′-( azanidyl - κn ) biphenyl - 2 - yl - κc 2 ]( chloro )[ dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl )- λ 5 - phosphanyl ] palladium ( 31 mg , 0 . 043 mmol ). the reaction mixture was heated at 70 ° c . for 40 hours , then filtered through a thin layer of celite . the filtrate was concentrated in vacuo and purified by silica gel chromatography ( gradient : 5 % to 10 % methanol in dichloromethane ) to give the product as a dark oil . yield : 63 mg , 0 . 17 mmol , 39 %. lcms m / z 375 . 2 ( m + h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 98 ( s , 1h ), 8 . 06 ( s , 1h ), 7 . 29 - 7 . 41 ( m , 5h ), 6 . 96 ( d , j = 7 . 6 hz , 1h ), 6 . 76 ( d , j = 7 . 6 hz , 1h ), 5 . 50 ( s , 2h ), 4 . 83 ( s , 2h ), 4 . 17 ( s , 3h ), 2 . 31 ( s , 6h ). to a solution of acetyl chloride ( 98 %, 0 . 122 ml , 1 . 68 mmol ) in methanol ( 2 ml ) was added a solution of 4 -[( benzyloxy ) methoxy ]- 7 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 2 - methyl - 2h - indazole ( c75 ) ( 63 mg , 0 . 17 mmol ) in methanol ( 2 ml ). after 16 hours , the reaction mixture was concentrated in vacuo and purified by silica gel chromatography ( gradient : 5 % to 10 % methanol in dichloromethane ) to afford the product as a glassy solid . yield : 37 mg , 0 . 14 mmol , 82 %. lcms m / z 255 . 2 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 8 . 87 ( s , 1h ), 8 . 28 ( s , 1h ), 6 . 97 ( d , j = 7 . 6 hz , 1h ), 6 . 47 ( d , j = 7 . 6 hz , 1h ), 4 . 13 ( s , 3h ), 2 . 25 ( s , 6h ). compound p11 was prepared from 4 -[( benzyloxy ) methoxy ]- 7 - bromo - 1 - methyl - 1h - indazole ( c73 ) according to steps 4 and 5 of the synthesis of 7 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 2 - methyl - 2h - indazol - 4 - ol ( p10 ) in preparation p10 , to provide the product as an off - white solid . yield : 36 mg , 0 . 14 mmol , 64 %. lcms m / z 255 . 2 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ) δ 10 . 40 ( br s , 1h ), 8 . 95 ( s , 1h ), 8 . 09 ( s , 1h ), 6 . 96 ( d , j = 7 . 6 hz , 1h ), 6 . 53 ( d , j = 7 . 8 hz , 1h ), 3 . 38 ( s , 3h ), 2 . 15 ( s , 6h ). to a solution of 2 - bromo - 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) benzonitrile ( prepared from 2 - bromo - 5 - hydroxybenzonitrile and 4 - iodofuro [ 3 , 2 - c ] pyridine by the method of step 3 in example 7 ; 4 - iodofuro [ 3 , 2 - c ] pyridine was synthesized from 4 - chlorofuro [ 3 , 2 - c ] pyridine with acetyl chloride and sodium iodide in acetonitrile ) ( 7 . 0 g , 22 mmol ) in 1 , 4 - dioxane ( 70 ml ) was added hexamethyldistannane ( 21 . 8 g , 66 . 6 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 1 . 28 g , 1 . 11 mmol ). the resulting mixture was heated at 120 ° c . for 18 hours . the reaction mixture was filtered and the filtrate was concentrated to give a crude residue , which was purified by silica gel chromatography ( eluent : 400 : 1 petroleum ether / ethyl acetate ) to provide the product as a white solid . yield : 6 . 0 g , 15 mmol , 67 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 01 ( d , j = 5 . 9 hz , 1h ), 7 . 68 ( d , j = 2 . 2 hz , 1h ), 7 . 62 ( d , j = 8 . 1 hz , 1h ), 7 . 55 - 7 . 58 ( m , 1h ), 7 . 42 ( dd , j = 8 . 0 , 2 . 4 hz , 1h ), 7 . 26 ( dd , j = 5 . 8 , 0 . 9 hz , 1h ), 6 . 93 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 0 . 47 ( s , 9h ). to a solution of 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( trimethylstannyl ) benzonitrile ( c76 ) ( 8 . 3 g , 21 mmol ) in tetrahydrofuran ( 160 ml ) was added 5 - bromoimidazo [ 1 , 2 - a ] pyridine ( 3 . 9 g , 20 mmol ), lithium chloride ( 0 . 67 g , 15 . 8 mmol ), copper ( i ) bromide ( 0 . 57 g , 4 . 0 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 2 . 27 g , 2 . 0 mmol ). the mixture was heated to reflux for 48 hours . the reaction mixture was filtered and the filtrate was concentrated to give crude product , which was purified by silica gel chromatography ( gradient : 7 % to 20 % ethyl acetate in petroleum ether ) to give the product as a brown solid . yield : 5 g , 13 mmol , 68 %. lcms m / z 353 . 0 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od , concentrated hcl ), characteristic peaks : δ 8 . 23 - 8 . 26 ( m , 1h ), 8 . 12 ( br d , half of ab quartet , j = 8 hz , 1h ), 8 . 06 ( br d , half of ab quartet , j = 8 hz , 1h ), 7 . 93 ( br d , j = 6 hz , 1h ), 7 . 77 - 7 . 81 ( m , 1h ). to an aqueous solution of sodium hydroxide ( 15 % w / v , 25 ml ) was added 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( imidazo [ 1 , 2 - a ] pyridine - 5 - yl ) benzonitrile ( c77 ) ( 4 . 35 g , 12 . 3 mmol ) and ethanol ( 25 ml ), and the reaction mixture was heated to reflux for 18 hours . the mixture was cooled to room temperature and extracted with dichloromethane . the aqueous layer was adjusted to ph 7 with 3 n aqueous hydrochloric acid ; the resulting mixture was filtered , and the filter cake was washed with ethyl acetate and dichloromethane , then dried under vacuum to give the product as a yellow solid . yield : 1 . 9 g , 5 . 1 mmol , 42 %. lcms m / z 371 . 9 ( m + h ). 1 h nmr ( 400 mhz , dmso - d 6 ), characteristic peaks : δ 8 . 17 ( d , j = 2 . 4 hz , 1h ), 8 . 04 ( d , j = 5 . 9 hz , 1h ), 7 . 52 ( d , j = 5 . 9 hz , 1h ), 6 . 72 ( br d , j = 6 . 7 hz , 1h ). to a mixture of 3 - methoxybenzene - 1 , 2 - diol ( 578 mg , 4 . 12 mmol ) in acetonitrile ( 10 ml ) at 0 ° c . was slowly added n - bromosuccinimide ( 95 %, 811 mg , 4 . 33 mmol ) in acetonitrile ( 5 ml ). after two hours at 0 ° c ., aqueous sodium thiosulfate solution ( 1 m , 2 ml ) was added . after ten minutes , the reaction mixture was concentrated in vacuo and purified by silica gel chromatography ( gradient : 20 % to 40 % ethyl acetate in heptane ) to give the product as a white solid . yield : 858 mg , 0 . 3 . 92 mmol , 95 %. lcms m / z 216 . 8 ( m − h ). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 00 ( d , j = 9 . 0 hz , 1h ), 6 . 43 ( d , j = 9 . 0 hz , 1h ), 5 . 54 ( s , 1h ), 5 . 48 ( s , 1h ), 3 . 89 ( s , 3h ). to a solution of 3 - bromo - 6 - methoxybenzene - 1 , 2 - diol ( c78 ) ( 420 mg , 1 . 92 mmol ) in n , n - dimethylformamide ( 5 ml ) were added diiodomethane ( 0 . 170 ml , 2 . 11 mmol ) and cesium carbonate ( 690 mg , 2 . 1 mmol ). the reaction mixture was stirred at 100 ° c . for one hour , then cooled to room temperature and diluted with ethyl acetate ( 20 ml ). the solid was removed by filtration and washed with ethyl acetate ( 30 ml ). the filtrate was washed with 50 % saturated aqueous sodium chloride solution ( 4 × 20 ml ), dried over sodium sulfate , filtered , concentrated in vacuo , and purified by silica gel chromatography ( gradient : 20 % to 40 % ethyl acetate in heptane ) to give the product as a white solid . yield : 335 mg , 1 . 45 mmol , 76 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 6 . 92 ( d , j = 9 . 0 hz , 1h ), 6 . 46 ( d , j = 9 . 1 hz , 1h ), 6 . 05 ( s , 2h ), 3 . 90 ( s , 3h ). to a solution of 4 - bromo - 7 - methoxy - 1 , 3 - benzodioxole ( c79 ) ( 186 mg , 0 . 805 mmol ) in acetonitrile ( 5 ml ) was added trimethylsilyl iodide ( 0 . 343 ml , 2 . 42 mmol ). the reaction mixture was heated at 85 ° c . for 18 hours and purified by silica gel chromatography ( gradient : 30 % to 40 % ethyl acetate in heptane ) to give the product as an oil . yield : 59 mg , 0 . 27 mmol , 34 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 6 . 86 ( d , j = 9 . 0 hz , 1h ), 6 . 44 ( d , j = 9 . 0 hz , 1h ), 6 . 05 ( s , 2h ). a mixture of 7 - bromo - 1 , 3 - benzodioxol - 4 - ol ( c80 ) ( 59 mg , 0 . 27 mmol ), 4 - chlorofuro [ 3 , 2 - c ] pyridine ( 62 . 7 mg , 0 . 408 mmol ) and cesium carbonate ( 224 mg , 0 . 687 mmol ) in dimethyl sulfoxide ( 2 ml ) was heated at 140 ° c . for 4 hours . the reaction mixture was cooled to room temperature and combined with a similar reaction carried out on 16 mg of c80 . ethyl acetate was added and the solid was removed by filtration . the filtrate was washed with 50 % saturated aqueous sodium chloride solution ( 3 × 15 ml ), concentrated in vacuo and purified by silica gel chromatography ( gradient : 10 % to 30 % ethyl acetate in heptane ) to afford the product as an oil . yield : 61 mg , 0 . 182 mmol , 53 %. lcms m / z 335 . 9 ( m + h ). a mixture of 4 -[( 7 - bromo - 1 , 3 - benzodioxol - 4 - yl ) oxy ] furo [ 3 , 2 - c ] pyridine ( c81 ) ( 61 mg , 0 . 18 mmol ), 4 , 4 , 4 ′, 4 ′, 5 , 5 , 5 ′, 5 ′- octamethyl - 2 , 2 ′- bi - 1 , 3 , 2 - dioxaborolane ( 99 %, 70 . 3 mg , 0 . 274 mmol ), 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( 11 ) ( 50 %, 26 . 3 mg , 0 . 018 mmol ) and potassium acetate ( 55 mg , 0 . 55 mmol ) were combined in acetonitrile ( 3 ml ). after bubbling nitrogen through the reaction mixture for five minutes , it was heated at 80 ° c . for 18 hours . the reaction mixture was then filtered through a thin layer of celite , washing with ethyl acetate ( 20 ml ). the filtrate was concentrated in vacuo and the residue was partitioned between water ( 15 ml ) and ethyl acetate ( 20 ml ). the aqueous layer was extracted with ethyl acetate ( 3 × 10 ml ); the combined organic layers were dried over sodium sulfate , filtered , and concentrated in vacuo . purification by silica gel chromatography ( gradient : 15 % to 50 % ethyl acetate in heptane ) provided the product as a light yellow gum . yield : 25 mg , 0 . 066 mmol , 37 %. 1 h nmr ( 400 mhz , cdcl 3 ) δ 8 . 00 ( d , j = 5 . 8 hz , 1h ), 7 . 64 ( d , j = 2 . 2 hz , 1h ), 7 . 30 ( d , j = 8 . 4 hz , 1h ), 7 . 21 ( dd , j = 5 . 8 , 1 . 0 hz , 1h ), 6 . 92 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 6 . 80 ( d , j = 8 . 5 hz , 1h ), 6 . 03 ( s , 2h ), 1 . 37 ( s , 12h ). to a solution of 5 - methoxyisoquinoline ( 1 . 48 g , 9 . 30 mmol ) in acetic acid ( 15 ml ) was added a solution of bromine ( 2 . 1 g , 13 mmol ) in acetic acid ( 5 ml ). after three days at room temperature , the reaction mixture was cooled to 0 ° c ., quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane ( 3 × 50 ml ). the combined organic layers were dried over sodium sulfate , filtered , concentrated in vacuo and purified by silica gel chromatography ( gradient : 5 % to 33 % ethyl acetate in petroleum ether ) to give the product as a solid . yield : 1 . 72 g , 7 . 22 mmol , 78 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 9 . 40 ( s , 1h ), 8 . 64 ( d , j = 6 . 0 hz , 1h ), 7 . 99 ( d , j = 5 . 5 hz , 1h ), 7 . 90 ( d , j = 8 . 5 hz , 1h ), 7 . 18 ( d , j = 8 . 5 hz , 1h ), 4 . 00 ( s , 3h ). to a solution of 8 - bromo - 5 - methoxyisoquinoline ( c82 ) ( 1 . 72 g , 7 . 22 mmol ) in 1 , 4 - dioxane ( 75 ml ) and water ( 5 ml ) were added 4 , 6 - dimethyl - 5 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) pyrimidine ( c63 ) ( 2 . 20 g , 9 . 40 mmol ), tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 659 mg , 0 . 72 mmol ), tricyclohexylphosphine ( 403 mg , 1 . 44 mmol ) and potassium phosphate ( 3 . 07 g , 14 . 46 mmol ). the reaction mixture was degassed with nitrogen for five minutes , then stirred for 6 hours at 120 ° c . more 4 , 6 - dimethyl - 5 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) pyrimidine ( c63 ) ( 1 . 1 g , 4 . 7 mmol ) was added . the reaction mixture was stirred for 7 hours at 120 ° c . and then filtered . the filtrate was concentrated in vacuo and purified by silica gel chromatography ( gradient : 0 . 5 % to 2 . 5 % methanol in dichloromethane ) to provide the product as a solid . yield : 1 . 0 g , 3 . 8 mmol , 53 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 9 . 00 ( s , 1h ), 8 . 56 - 8 . 60 ( m , 2h ), 8 . 07 ( dd , j = 5 . 8 , 0 . 8 hz , 1h ), 7 . 51 ( d , j = 7 . 8 hz , 1h ), 7 . 36 ( d , j = 8 . 0 hz , 1h ), 4 . 07 ( s , 3h ), 2 . 08 ( s , 6h ). to a solution of 8 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 5 - methoxyisoquinoline ( c83 ) ( 1 . 0 g , 3 . 8 mmol ) in dichloromethane ( 60 ml ) was slowly added boron tribromide ( 4 . 7 g , 19 mmol ) at − 78 ° c . the mixture was allowed to warm to room temperature and stirred overnight before being quenched at − 20 ° c . with methanol . the reaction mixture was washed with saturated aqueous sodium bicarbonate solution ; the aqueous layer was extracted with dichloromethane ( 5 × 50 ml ) and ethyl acetate ( 5 × 50 ml ). the combined organic layers were dried over sodium sulfate , filtered , concentrated in vacuo and purified by silica gel chromatography ( gradient : 0 . 5 % to 5 % methanol in dichloromethane ) to give the product as a solid . yield : 300 mg , 1 . 19 mmol , 31 %. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 10 . 88 ( br s , 1h ), 8 . 98 ( s , 1h ), 8 . 49 - 8 . 55 ( m , 2h ), 8 . 04 ( br d , j = 6 hz , 1h ), 7 . 36 ( d , j = 7 . 8 hz , 1h ), 7 . 21 ( d , j = 7 . 8 hz , 1h ), 2 . 07 ( s , 6h ). a mixture of 4 - chloro - 5 - methyl - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one ( c18 ) ( 30 g , 130 mmol ), ( 2 , 4 - dimethoxyphenyl ) boronic acid ( 26 g , 140 mmol ), tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 9 . 69 g , 10 . 6 mmol ), tricyclohexylphosphine ( 7 . 5 g , 27 mmol ) and potassium phosphate monohydrate ( 69 g , 300 mmol ) in 1 , 4 - dioxane ( 250 ml ) was heated at reflux for 3 hours and then cooled to room temperature , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 9 % to 17 % ethyl acetate in petroleum ether ) afforded the product as a yellow solid . yield : 40 g , 120 mmol , 92 %. 1 h nmr ( 400 mhz , cdcl 3 ), mixture of diastereomers , characteristic peaks : δ 7 . 76 and 7 . 77 ( 2 s , total 1h ), [ 7 . 10 ( d , j = 8 . 3 hz ) and 7 . 07 ( d , j = 8 . 3 hz ), total 1h ], 6 . 51 - 6 . 59 ( m , 2h ), 6 . 06 - 6 . 12 ( m , 1h ), 4 . 11 - 4 . 20 ( m , 1h ), 3 . 85 ( s , 3h ), 3 . 74 and 3 . 76 ( 2 s , total 3h ), 1 . 99 and 2 . 00 ( 2 s , total 3h ). 4 -( 2 , 4 - dimethoxyphenyl )- 5 - methyl - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one ( c84 ) ( 30 g , 91 mmol ) was dissolved in phosphorus oxychloride ( 158 ml ) and the mixture was heated at reflux for 5 hours , cooled to room temperature , and poured into ice water . careful addition of potassium carbonate to neutralize the reaction was followed by extraction with ethyl acetate ( 3 × 500 ml ). the combined organic extracts were concentrated in vacuo . silica gel chromatography ( gradient : 17 % to 50 % ethyl acetate in petroleum ether ) gave the product as an orange solid . yield : 20 g , 76 mmol , 83 %. lcms m / z 264 . 7 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 8 . 90 ( s , 1h ), 6 . 88 ( d , j = 8 . 3 hz , 1h ), 6 . 60 ( d , j = 2 . 3 hz , 1h ), 6 . 53 ( dd , j = 8 . 2 , 2 . 1 hz , 1h ), 3 . 73 ( s , 3h ), 2 . 36 ( s , 3h ), 2 . 10 ( s , 3h ). a mixture of 3 - chloro - 4 -( 2 , 4 - dimethoxyphenyl )- 5 - methylpyridazine ( c85 ) ( 18 g , 68 mmol ), methylboronic acid ( 17 g , 280 mmol ), [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) ( 5 . 2 g , 70 mmol ), and cesium carbonate ( 46 g , 140 mmol ) in 1 , 4 - dioxane ( 300 ml ) was heated at reflux for 2 . 5 hours and then cooled to room temperature , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 17 % to 50 % ethyl acetate in petroleum ether ) gave the product as an orange solid . yield : 14 g , 57 mmol , 84 %). lcms m / z 245 . 0 ( m + h ). trimethylsilyl iodide ( 58 g , 290 mmol ) was added to a stirred solution of 4 -( 2 , 4 - dimethoxyphenyl )- 3 , 5 - dimethylpyridazine ( c86 ) ( 12 g , 49 mmol ) in acetonitrile ( 100 ml ), and the mixture was heated at reflux for 18 hours . the reaction mixture was cooled to 0 ° c ., slowly diluted with methanol , and concentrated in vacuo . the residue was partitioned between ethyl acetate and saturated aqueous sodium thiosulfate solution . the aqueous layer was extracted with ethyl acetate ( 4 × 150 ml ) and the combined organic extracts were dried over sodium sulfate , filtered , and concentrated in vacuo . silica gel chromatography ( gradient : 50 % to 100 % ethyl acetate in petroleum ether ) provided the product as a yellow solid . yield : 3 . 0 g , 13 mmol , 26 %. lcms m / z 230 . 7 ( m + h ). 1 h nmr ( 400 mhz , cd 3 od ) δ 8 . 90 ( s , 1h ), 6 . 88 ( d , j = 8 . 0 hz , 1h ), 6 . 60 ( d , j = 2 . 0 hz , 1h ), 6 . 53 ( dd , j = 8 . 3 , 2 . 3 hz , 1h ), 3 . 73 ( s , 3h ), 2 . 36 ( s , 3h ), 2 . 10 ( s , 3h ). methods m1 - m7 describe specific methods for preparations of certain compounds of the invention . solutions of the appropriate phenol and 4 - chlorofuro [ 3 , 2 - c ] pyridine were prepared at 0 . 2 m using degassed 1 , 4 - dioxane . a 2 - dram vial was charged with the phenol solution ( 0 . 5 ml , 0 . 1 mmol ) and the 4 - chlorofuro [ 3 , 2 - c ] pyridine solution ( 0 . 5 ml , 0 . 1 mmol ). cesium carbonate ( 100 mg , 0 . 3 mmol ), palladium ( 11 ) acetate ( 2 . 5 mg , 0 . 01 mmol ) and di - tert - butyl [ 3 , 4 , 5 , 6 - tetramethyl - 2 ′, 4 ′, 6 ′- tri ( propan - 2 - yl ) biphenyl - 2 - yl ] phosphane ( 10 mg , 0 . 02 mmol ) were added . the vial was subjected to three rounds of vacuum evacuation followed by nitrogen fill and the resulting mixture was shaken and heated at 100 ° c . for 12 hours . the reaction mixture was cooled to room temperature , partitioned between water ( 1 . 5 ml ) and ethyl acetate ( 2 . 5 ml ), vortexed , and allowed to settle . the organic layer was passed through a solid phase extraction cartridge filled with sodium sulfate ( 1 . 0 g ); this extraction procedure was repeated twice , and the combined filtrates were concentrated in vacuo . the products were generally purified by hplc ( column : waters xbridge c18 , 5 μm ; mobile phase a : 0 . 03 % ammonium hydroxide in water ( v / v ); mobile phase b : 0 . 03 % ammonium hydroxide in acetonitrile ( v / v ); gradient : increasing percentage of b , starting with 10 % or 20 % b ). a solution of the appropriate phenol ( 0 . 050 mmol , 1 . 0 eq ) in anhydrous n , n - dimethylformamide dimethyl acetal or n , n - dimethylformamide ( 0 . 2 ml ) was treated with either cesium carbonate or potassium carbonate ( 0 . 10 mmol , 2 . 0 eq ), sodium iodide ( 0 . 008 mmol , 0 . 2 eq ), and the appropriate bromide or chloride reagent ( 0 . 075 mmol , 1 . 5 eq ). the reaction vial was capped and shaken at 80 ° c . for 16 hours . the reaction mixture was concentrated and the crude residue was purified by reversed phase hplc ( gradient : increasing concentration of either acetonitrile in water containing 0 . 225 % formic acid , or acetonitrile in aqueous ph 10 ammonium hydroxide solution ) to provide the final compound . a solution of 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( imidazo [ 1 , 2 - a ] pyridine - 5 - yl ) benzoic acid ( p12 ) ( 0 . 060 mmol , 1 . 0 eq ) in anhydrous n , n - dimethylformamide ( 0 . 2 ml ) was treated with the appropriate commercially available amine ( 0 . 090 mmol , 1 . 5 eq ), o -( 7 - azabenzotriazol - 1 - yl )- n , n , n ′, n ′- tetramethyluronium hexafluorophosphate ( hatu , 0 . 060 mmol , 1 . 0 eq ), and diisopropylethylamine ( 0 . 240 mmol , 4 . 0 eq ). the reaction vial was capped and shaken at 30 ° c . for 16 hours . the reaction mixture was concentrated and the crude residue was purified by reversed phase hplc ( gradient : increasing concentration of either acetonitrile in water containing 0 . 225 % formic acid , or acetonitrile in aqueous ph 10 ammonium hydroxide solution ) to provide the final compound . a solution of 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( 2 - methylpyridin - 3 - yl ) phenol ( prepared via methyl ether cleavage of example 181 ) ( 0 . 075 mmol , 1 . 0 eq ) in tetrahydrofuran / dichloromethane ( v / v = 1 : 1 , 1 . 0 ml ) was added to a vial containing the appropriate commercially available primary alcohol ( 0 . 120 mmol , 1 . 6 eq ) and polymer - supported triphenylphosphine ( 0 . 225 mmol , 3 . 0 eq ). diisopropyl azodicarboxylate ( diad ; 0 . 150 mmol , 2 . 0 eq ) was added to the reaction vial , which was then capped and shaken at 30 ° c . for 16 hours . the reaction mixture was concentrated and the crude residue was purified by reversed phase hplc ( gradient : increasing concentration of either acetonitrile in water containing 0 . 225 % formic acid , or acetonitrile in aqueous ph 10 ammonium hydroxide solution ) to provide the final compound . a solution of 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( imidazo [ 1 , 2 - a ] pyridine - 5 - yl ) benzaldehyde [ prepared from 4 - bromo - 3 -( 1 , 3 - dioxan - 2 - yl ) phenol ( see f . kaiser et al ., j . org . chem . 2002 , 67 , 9248 - 9256 ) using the procedures of example 1 , followed by deprotection with aqueous hydrochloric acid in tetrahydrofuran ] ( 0 . 094 mmol , 1 . 25 eq ) in dichloromethane ( 1 . 0 ml ) was added to a vial containing the appropriate commercially available amine ( 0 . 075 mmol , 1 . 0 eq ). sodium bicarbonate ( 18 mg , 0 . 225 mmol , 3 . 0 eq ) was added , and the reaction vial was capped and shaken at 30 ° c . for 16 hours . sodium triacetoxyborohydride ( 47 mg , 0 . 225 mmol , 3 . 0 eq ) was added , and the reaction mixture was shaken at 30 ° c . for an additional 5 hours . the reaction mixture was concentrated and the crude residue was purified by reversed phase hplc ( gradient : increasing concentration of acetonitrile in water containing 0 . 1 % trifluoroacetic acid ) to provide the final compound . a solution of 4 -[ 4 -( 4 - chloro - 6 - methylpyrimidin - 5 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine ( example 18 ) ( 0 . 50 mmol , 1 . 0 eq ) in anhydrous dimethyl sulfoxide ( 0 . 5 ml ) was added to a vial containing the appropriate commercially available amine ( 0 . 110 mmol , 2 . 2 eq ). diisopropylethylamine ( 0 . 170 mmol , 3 . 4 eq ) and cesium fluoride ( 15 mg , 0 . 100 mmol , 2 . 0 eq ) were added , and the reaction vial was capped and shaken at 120 ° c . for 16 hours . the reaction mixture was concentrated and the crude residue was purified by reversed phase hplc ( gradient : increasing concentration of acetonitrile in water containing either 0 . 225 % formic acid or 0 . 1 % trifluoroacetic acid ) to provide the final compounds . a frozen seed vial containing pseudomonas putida ( atcc 17453 ) was removed from a − 80 ° c . freezer , thawed and used to inoculate iowa medium ( 1 l ; iowa medium consists of glucose [ 20 g ], sodium chloride [ 5 g ], potassium hydrogenphosphate [ 5 g ], soy flour [ 5 g ] and yeast extract [ 5 g ]; the mixture was adjusted to ph 7 . 0 before sterilization in an autoclave ) in a 3 - liter baffled shake flask ( corning , # 431253 ). the cultures were grown for 2 - 4 days while shaking at 30 ° c . and 160 rpm on an orbital shaker with a 2 inch throw . the cells were harvested by centrifugation ; the cell pellet was frozen at − 80 ° c . cells of pseudomonas putida ( atcc 17453 ) were suspended in aqueous potassium phosphate buffer ( 25 mm , ph 7 . 0 ) at a concentration of 45 g cells per 150 ml buffer . this suspension was added to a 1 liter baffled shake flask ( nalge , 4116 - 1000 ) and a solution of substrate ( 30 mg ) in dimethyl sulfoxide ( 3 ml ) was added to the suspension . the flask was incubated at 30 to 40 ° c . and 300 rpm for 24 - 96 hours on an orbital shaker with a 1 inch throw . the reaction was extracted with ethyl acetate , and the combined organic layers were concentrated in vacuo . the product was isolated using chromatographic techniques . 3 example 16 was n - formylated to provide n -[ 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 -( imidazo [ 1 , 2 - a ] pyridin - 5 - yl ) phenyl ] formamide by heating in methyl formate in the presence of sodium hydride and [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ). reduction with borane - dimethylsulfide complex provided example 38 . 4 in this case , 4 - amino - 3 - chlorophenol was used as starting material , and the phenol was carried through construction of the imidazo [ 4 , 5 - c ] pyridine without protection . 5 hplc conditions . column : waters xbridge c18 , 2 . 1 × 50 mm , 5 μm ; mobile phase a : 0 . 0375 % trifluoroacetic acid in water ; mobile phase b : 0 . 01875 % trifluoroacetic acid in acetonitrile ; gradient : 10 % to 100 % b over 4 . 0 minutes ; flow rate : 0 . 8 ml / minute . 6 hplc conditions . column : waters xbridge c18 , 2 . 1 × 50 mm , 5 μm ; mobile phase a : 0 . 0375 % trifluoroacetic acid in water ; mobile phase b : 0 . 01875 % trifluoroacetic acid in acetonitrile ; gradient : 1 % to 5 % b over 0 . 6 minutes , then 5 % to 100 % b over 3 . 4 minutes ; flow rate : 0 . 8 ml / minute . 7 this example was prepared via reductive amination of example 16 with 1 - methyl - 1h - imidazole - 5 - carbaldehyde . 8 coupling partner 3 - bromo - 4 - methylpyridine - 2 - carbonitrile may be prepared from 3 - bromo - 4 - methylpyridine by generation of the pyridine n - oxide through reaction with hydrogen peroxide , followed by cyanation according to the method of t . sakamoto et al ., chem . pharm . bull . 1985 , 33 , 565 - 571 . 9 hplc conditions . column : waters atlantis dc18 , 4 . 6 × 50 mm , 5 μm ; mobile phase a : 0 . 05 % trifluoroacetic acid in water ( v / v ); mobile phase b : 0 . 05 % trifluoroacetic acid in acetonitrile ( v / v ); gradient : 5 . 0 % to 95 % b over 4 . 0 minutes , linear ; flow rate : 2 ml / minute . 10 example 17 was n - methylated using sodium hydride and methyl iodide . 11 the final step in the synthesis was cleavage of the methyl ether using boron tribromide . 12 hplc conditions . column : waters xbridge c18 , 4 . 6 × 50 mm , 5 μm ; mobile phase a : 0 . 03 % ammonium hydroxide in water ( v / v ); mobile phase b : 0 . 03 % ammonium hydroxide in acetonitrile ( v / v ); 5 . 0 % to 95 % b over 4 . 0 minutes , linear ; flow rate : 2 ml / minute . 13 in this case , the suzuki coupling was carried out using tetrakis ( triphenylphosphine ) palladium ( 0 ) and potassium carbonate or sodium carbonate . 14 the starting material was alkylated using 5 -( chloromethyl )- 3 - cyclopropyl - 1 , 2 , 4 - oxadiazole and cesium carbonate . 16 5 - bromo - 4 - methoxy - 6 - methylpyrimidine was prepared by reaction of 5 - bromo - 4 - chloro - 6 - methylpyrimidine with sodium methoxide . 17 the requisite 5 - bromo - 6 - methyl - 2 -( trifluoromethyl ) imidazo [ 1 , 2 - a ] pyrazine was prepared via reaction of c60 with 3 - bromo - 1 , 1 , 1 - trifluoropropan - 2 - one . 19 the requisite 5 - bromo - 6 - methylpyrimidine - 4 - carbonitrile was prepared via reaction of 5 - bromo - 4 - chloro - 6 - methylpyrimidine with tetra - n - butylammonium cyanide . 20 the product was separated into its component atropenantiomers using supercritical fluid chromatography ( column : chiralpak ad - h , 5 μm ; eluent : 3 : 1 carbon dioxide / propanol ). the first - eluting compound was example 83 and the second - eluting atropenantiomer was example 82 . 21 the requisite 2 - amino - 5 - bromo - 6 - methylpyrimidine - 4 - carbonitrile may be prepared via reaction of 5 - bromo - 4 - chloro - 6 - methylpyrimidin - 2 - amine with tetraethylammonium cyanide and 1 , 4 - diazabicyclo [ 2 . 2 . 2 ] octane in a mixture of acetonitrile and n , n - dimethylformamide . 22 the required 3 - bromo - 2 - cyclopropylpyridine was prepared via reaction of 2 , 3 - dibromopyridine with cyclopropylboronic acid at 100 ° c . in the presence of palladium ( ii ) acetate , tricyclohexylphosphine and potassium phosphate . 23 the requisite 5 - bromo - 1 , 4 - dimethyl - 1h - imidazole may be prepared via methylation of 5 - bromo - 4 - methyl - 1h - imidazole using sodium hydride and methyl iodide . 24 suzuki reaction of ( 4 - methoxy - 2 , 6 - dimethylphenyl ) boronic acid with 5 - bromo - 4 , 6 - dimethylpyrimidine , mediated by tris ( dibenzylideneacetone ) dipalladium ( 0 ) and dicyclohexyl ( 2 ′, 6 ′- dimethoxybiphenyl - 2 - yl ) phosphane , followed by cleavage of the methyl ether , afforded the requisite phenol . 25 obtained from supercritical fluid chromatographic separation of example 19 [ column : chiralcel as , 20 μm ; mobile phase 7 : 3 carbon dioxide /( methanol containing 0 . 2 % diethylamine )]. this example was the second - eluting atropenantiomer from the column . 26 this was the first - eluting atropenantiomer from the separation described in footnote 25 . 27 compound c4 was heated with aqueous chloroacetaldehyde at reflux for 2 hours , affording 8 - bromo - 5 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 6 - methylimidazo [ 1 , 2 - a ] pyrazine . reaction of this intermediate with sodium methoxide in methanol provided example 107 . 28 the 8 - bromo intermediate from footnote 27 was subjected to reaction with trimethylboroxin in the presence of [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) and potassium carbonate to provide example 109 . 29 reaction of chloroacetaldehyde with 2 - amino - 5 - methylpyrimidin - 4 - ol afforded a mixture of 6 - methylimidazo [ 1 , 2 - a ] pyrimidin - 5 - ol and 6 - methylimidazo [ 1 , 2 - a ] pyrimidin - 7 - ol , which was subjected to reaction with phosphorus oxychloride , providing a mixture of 5 - chloro - 6 - methylimidazo [ 1 , 2 - a ] pyrimidine and 7 - chloro - 6 - methylimidazo [ 1 , 2 - a ] pyrimidine . reaction of this mixture with c2 yielded a separable mixture of examples 110 and 111 . the structures of these two compounds were subsequently assigned using noe studies carried out on the separated intermediates 6 - methylimidazo [ 1 , 2 - a ] pyrimidin - 5 - ol and 6 - methylimidazo [ 1 , 2 - a ] pyrimidin - 7 - ol . 30 the 8 - bromo intermediate from footnote 27 was subjected to reaction with tert - butyl carbamate in the presence of palladium ( ii ) acetate , 1 , 1 ′- binaphthalene - 2 , 2 ′- diylbis ( diphenylphosphane ) and cesium carbonate , at 120 ° c . for 2 hours , to afford example 112 . 31 the requisite 4 -( 4 - bromo - 3 , 5 - difluorophenoxy ) furo [ 3 , 2 - c ] pyridine was prepared from 4 - chlorofuro [ 3 , 2 - c ] pyridine and 4 - bromo - 3 , 5 - difluorophenol , using the general method of example 17 , step 3 . 32 example 11 was reacted with hydrazine . the resulting 4 -[ 4 -( 3 - hydrazinyl - 5 - methylpyridazin - 4 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine was cyclized with 1 , 1 ′- carbonyldiimidazole to provide the product . 33 example 117 was isolated as a side product during the synthesis of examples 120 and 121 , derived from an over - methylated contaminant in p8 . 34 the racemic version of example 82 was hydrolyzed with aqueous sodium hydroxide in ethanol to provide the product . 35 the racemic product was separated via supercritical fluid chromatography ( column : chiralcel oj - h , 5 μm ; eluent : 3 : 1 carbon dioxide / methanol ). example 121 eluted first , followed by example 120 . 36 ( 2 - chloro - 5 - methoxyphenyl ) acetonitrile ( see c . pierre and o . baudoin , org . lett . 2011 , 13 , 1816 - 1819 ) may be dimethylated using sodium hydride and methyl iodide to provide 2 -( 2 - chloro - 5 - methoxyphenyl )- 2 - methylpropanenitrile . suzuki reaction with 4 - methyl - 5 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) pyrimidine was followed by cleavage of the methyl ether with the sodium salt of ethanethiol , which afforded the requisite 2 -[ 5 - hydroxy - 2 -( 4 - methylpyrimidin - 5 - yl ) phenyl ]- 2 - methylpropanenitrile . reaction with 4 - chlorofuro [ 3 , 2 - c ] pyridine was mediated by tris ( dibenzylideneacetone ) dipalladium ( 0 ), tricyclohexylphosphine and cesium carbonate . 37 compound c24 was reacted with 1 - methylurea and p - toluenesulfonic acid to provide the product . 38 the protecting group was removed in the final step , with a solution of hydrogen chloride in methanol . 39 hplc conditions : column : acquity hss t3 , 2 . 1 × 50 mm , 1 . 8 μm ; mobile phase a : 0 . 05 % trifluoroacetic acid in water ( v / v ); mobile phase b : 0 . 05 % trifluoroacetic acid in acetonitrile ( v / v ); gradient : 5 . 0 % to 98 % b over 1 . 6 minutes ; flow rate : 1 . 3 ml / minute . 41 in this case , reduction of the nitro group to the aniline was achieved by hydrogenation with pd / c in a 1 : 1 mixture of ethanol and methanol . the final coupling reaction employed tris ( dibenzylideneacetone ) dipalladium ( 0 ) as the palladium source . 42 the crude metabolite mixture was first purified by silica gel chromatography ( eluent : 10 % 2 - propanol in toluene ), then subjected to hplc separation ( column : kromasil c18 , 10 μm ; eluent : 3 : 2 methanol / water ). product fractions were concentrated in vacuo , and the aqueous residue was extracted with ethyl acetate ( 2 × 50 ml ). the combined organic layers were concentrated under reduced pressure to provide the product . 43 the racemic product was separated into atropenantiomers via hplc ( column : phenomenex lux cellulose - 3 , 5 μm ; gradient : 5 % to 95 % ethanol in heptane ). the first - eluting atropenantiomer is the compound of this example . 44 compound c2 was coupled with 4 - chloro - 5 - methoxy - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one , which may be prepared according to b . dyck et al ., j . med . chem . 2006 , 49 , 3753 - 3756 , in the presence of [ 1 , 1 ′- bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( ii ) and cesium carbonate . the resulting 4 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 5 - methoxy - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one was converted to the product using the methods of examples 10 , 11 and 12 . the racemic product was separated into its component atropenantiomers using supercritical fluid chromatography ( column : chiralpak as - h , 5 μm ; eluent : 3 : 1 carbon dioxide / methanol ). example 135 was the first - eluting atropenantiomer . 45 cleavage of the methyl ether of c68 with boron tribromide gave the requisite 6 -( 4 - hydroxy - 2 - methylphenyl )- 5 - methylpyrazin - 2 - ol . 46 reaction of 2 - amino - 6 - bromopyridin - 3 - ol with chloroacetaldehyde , followed by protection with benzyl chloromethyl ether , afforded the requisite 8 -[( benzyloxy ) methoxy ]- 5 - bromoimidazo [ 1 , 2 - a ] pyridine . 47 example 12 was reacted with hydrogen peroxide and maleic anhydride to provide a roughly 1 : 1 mixture of 4 -[ 4 -( 3 , 5 - dimethyl - 2 - oxidopyridazin - 4 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine and 4 -[ 4 -( 3 , 5 - dimethyl - 1 - oxidopyridazin - 4 - yl )- 3 - methylphenoxy ] furo [ 3 , 2 - c ] pyridine . 48 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 2 , 5 - difluorophenol was prepared from ( 2 , 5 - difluoro - 4 - methoxyphenyl ) boronic acid and 5 - bromo - 4 , 6 - dimethylpyrimidine using the general method of example 6 , followed by cleavage of the methyl ether . 49 5 - bromo - 4 , 6 - dimethylpyrimidine was reacted with ( 2 , 3 - difluoro - 4 - methoxyphenyl ) boronic acid according to the general procedure for the synthesis of 1 in example 1 . the resulting 5 -( 2 , 3 - difluoro - 4 - methoxyphenyl )- 4 , 6 - dimethylpyrimidine was deprotected with boron tribromide to yield the requisite 4 -( 4 , 6 - dimethylpyrimidin - 5 - yl )- 2 , 3 - difluorophenol . 50 . the racemic product was separated via supercritical fluid chromatography ( column : chiralpak as - h , 5 μm ; eluent : 4 : 1 carbon dioxide / methanol ). example 143 eluted first , followed by example 142 . 51 starting material 4 - bromo - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one was prepared according to c . aciro et al ., pct int . appl . ( 2010 ) wo 2010131147 a1 20101118 . 52 2 - amino - 5 - methylpyrimidin - 4 - ol was reacted with chloroacetaldehyde to afford 6 - methylimidazo [ 1 , 2 - a ] pyrimidin - 5 - ol ; this was chlorinated with phosphorus oxychloride to provide the requisite 5 - chloro - 6 - methylimidazo [ 1 , 2 - a ] pyrimidine . 53 chiral separation was carried out using supercritical fluid chromatography ( column : chiralpak ad - h , 5 μm ; eluent : 65 : 35 carbon dioxide / ethanol ). 54 on chiralpak ad - h analysis [ 5 μm , supercritical fluid chromatography ; gradient : 5 % to 40 % ( ethanol containing 0 . 05 % diethylamine ) in carbon dioxide ], example 147 eluted first , followed by example 146 . 55 reaction of example 152 with phosphorus oxychloride , followed by displacement with sodium methoxide in methanol , provided this example . 56 example 11 was reacted with dimethylamine and sodium carbonate to provide the product . 57 5 - bromo - 4 , 6 - dimethylpyrimidin - 2 - ol was protected as its triisopropylsilyl ether , and used in the suzuki reaction . 58 in this case , potassium phosphate was used , and the catalyst for the reaction with methylboronic acid was bis ( tri - tert - butylphosphine ) palladium ( 0 ). example 154 resulted from dechlorination of example 11 . 59 the catalyst employed for the suzuki reaction was the same as that used during the synthesis of example 10 , step 3 . 60 the product was synthesized via reaction of example 11 with sodium ethoxide in ethanol . 61 the suzuki reaction was carried out using the conditions of example 10 . coupling partner 8 - chloro - 5 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy ) quinoline was synthesized in the following manner : skraup reaction of 2 - chloro - 5 - methoxyaniline with propane - 1 , 2 , 3 - triol afforded 8 - chloro - 5 - methoxyquinoline , which was demethylated with aqueous hydrobromic acid . the resulting 8 - chloroquinolin - 5 - ol was then reacted with 4 - chlorofuro [ 3 , 2 - c ] pyridine using cesium carbonate in dimethyl sulfoxide . 62 example 134 was reacted with lithium bromide , sodium bis ( trimethylsilyl ) amide and methyl iodide to afford the product . 63 in this case , the first step was carried out using [ 2 ′-( azanidyl - κn ) biphenyl - 2 - yl - κc 2 ]( chloro ){ dicyclohexyl [ 2 ′, 4 ′, 6 ′- tri ( propan - 2 - yl ) biphenyl - 2 - yl ]- λ 5 - phosphanyl } palladium as catalyst . 65 the requisite 5 - bromo - 6 - methoxyisoquinoline may be prepared according to p . chen et al ., bioorg . med . chem . lett . 2003 , 13 , 1345 - 1348 . 66 in this case , c17 was reacted with sodium methoxide , to provide 4 - chloro - 5 - methoxy - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one , prior to the suzuki reaction . 67 hplc conditions . column : waters sunfire c18 , 4 . 6 × 50 mm , 5 μm ; mobile phase a : 0 . 05 % trifluoroacetic acid in water ( v / v ); mobile phase b : 0 . 05 % trifluoroacetic acid in acetonitrile ( v / v ); gradient : 5 . 0 % to 95 % b over 4 . 0 minutes ; flow rate : 2 ml / minute . 68 the requisite 3 - bromo - 4 - methylpyridine - 2 - carbonitrile may be prepared from the n - oxide of 3 - bromo - 4 - methylpyridine via the method of b . elman , tetrahedron 1985 , 41 , 4941 - 4948 . 69 cyclization of c67 with hydrazinecarboxamide , followed by boron tribromide - mediated cleavage of the methyl ether , afforded 5 -( 4 - hydroxy - 2 - methylphenyl )- 6 - methyl - 1 , 2 , 4 - triazin - 3 ( 2h )- one . 70 example 72 was reacted with 2 - bromoethyl methyl ether and cesium carbonate . 71 the requisite 5 - bromo - 4 - ethoxy - 6 - methylpyrimidine was prepared from 5 - bromo - 4 - chloro - 6 - methylpyrimidine via treatment with sodium ethoxide in ethanol . 72 hplc conditions . column : xbridge c18 , 2 . 1 × 50 mm , 5 μm ; mobile phase a : 0 . 05 % ammonium hydroxide in water ; mobile phase b : acetonitrile ; gradient : 5 % to 100 % b over 3 . 4 minutes ; flow rate : 0 . 8 ml / minute . 74 in this case , the final reaction was carried out in methanol . 75 compound c4 was converted to 8 - bromo - 5 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 6 - methylimidazo [ 1 , 2 - a ] pyrazine via reaction with chloroacetaldehyde . subsequent reaction with potassium cyanide and 1 , 4 , 7 , 10 , 13 , 16 - hexaoxacyclooctadecane ( 18 - crown - 6 ) afforded the product . 76 example 16 was converted to the product by reaction with ethoxyacetic acid and 2 - chloro - 1 , 3 - dimethylimidazolinium chloride ( dmc ) in the presence of n , n - diisopropylethylamine . 77 intermediate 4 -[ 3 - chloro - 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine was synthesized by using the method of example 1 , but employing 4 - bromo - 3 - chlorophenol in place of 4 - bromo - 3 - methylphenol . 5 the required 5 -( 4 - hydroxyphenyl )- 4 , 6 - dimethyl - 2 -( tetrahydro - 2h - pyran - 2 - yl ) pyridazin - 3 ( 2h )- one was prepared in the following manner : ( 4 -{[ tert - butyl ( dimethyl ) silyl ] oxy } phenyl ) boronic acid and 2 , 4 - dimethyl - 5 - oxo - 2 , 5 - dihydrofuran - 3 - yl trifluoromethanesulfonate ( c48 ) were reacted according to example 27 to provide 4 -( 4 -{[ tert - butyl ( dimethyl ) silyl ] oxy } phenyl )- 3 , 5 - dimethylfuran - 2 ( 5h )- one . the silyl protecting group was removed with tetrabutylammonium fluoride , and replaced with a benzyl protecting group , yielding 4 -[ 4 - benzyloxy ) phenyl ]- 3 , 5 - dimethylfuran - 2 ( 5h )- one . this was subjected to reaction with oxygen , followed by hydrazine , as described in example 27 , to afford 5 -[ 4 -( benzyloxy ) phenyl ]- 4 , 6 - dimethylpyridazin - 3 ( 2h )- one . nitrogen protection with 3 , 4 - dihydro - 2h - pyran as in example 10 , followed by hydrogenolysis of the benzyl group , provided the requisite phenol . 6 prior to the acidic removal of the tetrahydropyran protecting group in example 211 , the bromine was replaced by a cyano group using copper ( i ) cyanide in n , n - dimethylformamide . removal of the protecting group afforded example 212 . 7 the requisite 6 -( 4 - hydroxy - 2 - methylphenyl )- 1 , 5 - dimethylpyrazin - 2 ( 1h )- one was prepared in the following manner : suzuki reaction between ( 4 - methoxy - 2 - methylphenyl ) boronic acid and 2 - bromo - 3 - methylpyrazine afforded 2 -( 4 - methoxy - 2 - methylphenyl )- 3 - methylpyrazine . after formation of the n - oxide and rearrangement with acetic anhydride ( see a . ohta et al ., j . het . chem . 1985 , 19 , 465 - 473 ), the resulting 6 -( 4 - methoxy - 2 - methylphenyl )- 5 - methylpyrazin - 2 - ol was n - methylated , and then deprotected with boron tribromide . 8 4 -( imidazo [ 1 , 2 - a ] pyridin - 5 - yl ) phenol was prepared from ( 4 - hydroxyphenyl ) boronic acid and 5 - bromoimidazo [ 1 , 2 - a ] pyridine , using the method of example 6 . 9 hplc conditions . column : waters atlantis dc18 , 4 . 6 × 50 mm , 5 μm ; mobile phase a : 0 . 05 % trifluoroacetic acid in water ( v / v ); mobile phase b : 0 . 05 % trifluoroacetic acid in acetonitrile ( v / v ); 15 . 0 % to 95 % b , linear , over 4 . 0 minutes ; flow rate : 2 ml / minute . 10 in this case , the incubation was carried out for 2 . 25 hours rather than 24 - 96 hours . 11 example 124 was separated into its component atropenantiomers via supercritical fluid chromatography ( column : chiralpak ad - h , 5 μm ; eluent : 7 : 3 carbon dioxide / propanol ). the second - eluting enantiomer [(−)- 6 -[ 4 -( furo [ 3 , 2 - c ] pyridin - 4 - yloxy )- 2 - methylphenyl ]- 1 , 5 - dimethylpyrimidin - 2 ( 1h )- one ] was used in the biotransformation . the crude biotransformation product was purified via silica gel chromatography ( eluant : 70 % ethyl acetate in heptane ). 12 supercritical fluid chromatography conditions . column : phenomenex cellulose - 4 , 4 . 6 × 250 mm , 5 μm ; eluent : 55 : 45 carbon dioxide / methanol ; flow rate 2 . 5 ml / minute . 1 - methylurea ( 98 %, 8 . 26 g , 109 mmol ) and ethyl 2 - cyanopropanoate ( 95 %, 13 . 2 ml , 99 . 6 mmol ) were dissolved in methanol ( 75 ml ) and treated with sodium methoxide ( 25 weight percent solution in methanol , 27 ml , 120 mmol ). the resulting mixture was heated at reflux for 18 hours . after cooling to room temperature , the reaction mixture was concentrated under reduced pressure to remove the bulk of the methanol . the solvent was subsequently exchanged by repeated addition of acetonitrile ( 3 × 50 ml ) followed by concentration in vacuo . the resulting solid was dissolved in acetonitrile ( 100 ml ) and water ( 100 ml ), and 6 m aqueous hydrochloric acid was added until the ph reached approximately 2 . during this acidification , a white precipitate formed . after the mixture had stirred for an hour , the solid was collected via filtration and washed with tent - butyl methyl ether , providing the product as a white solid . yield : 15 . 2 g , 79 . 3 mmol , 80 %. lcms m / z 156 . 3 [ m + h ]. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 10 . 37 ( br s , 1h ), 6 . 39 ( br s , 2h ), 3 . 22 ( s , 3h ), 1 . 67 ( s , 3h ). a 1 : 1 mixture of acetonitrile and water ( 60 ml ) was added to a mixture of 6 - amino - 1 , 5 - dimethylpyrimidine - 2 , 4 ( 1h , 3h )- dione , hydrochloride salt ( c87 ) ( 5 . 00 g , 26 . 1 mmol ), sodium nitrite ( 98 %, 2 . 76 g , 39 . 2 mmol ) and copper ( ii ) bromide ( 99 %, 11 . 8 g , 52 . 3 mmol ) { caution : bubbling and slight exotherm observed }, and the reaction mixture was allowed to stir at room temperature for 18 hours . upon dilution with aqueous sulfuric acid ( 1 n , 100 ml ) and ethyl acetate ( 100 ml ), a precipitate formed ; this was isolated via filtration and washed with water and with ethyl acetate to afford the product as a solid ( 3 . 65 g ). the filtrate was concentrated in vacuo to approximately 25 % of its original volume , during which more precipitate was observed . filtration and washing of this solid with water and ethyl acetate afforded additional product ( 0 . 60 g ). total yield : 4 . 25 g , 19 . 4 mmol , 74 %. lcms m / z 219 . 0 , 221 . 0 [ m + h ]. 1 h nmr ( 400 mhz , dmso - d 6 ) δ 11 . 58 ( br s , 1h ), 3 . 45 ( s , 3h ), 1 . 93 ( s , 3h ). 6 - bromo - 1 , 5 - dimethylpyrimidine - 2 , 4 ( 1h , 3h )- dione ( c88 ) ( 78 . 0 mg , 0 . 356 mmol ), 4 -[ 4 -( 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - dioxaborolan - 2 - yl ) phenoxy ] furo [ 3 , 2 - c ] pyridine ( c52 ) ( 60 . 0 mg , 0 . 178 mmol ), potassium carbonate ( 99 %, 74 . 5 mg , 0 . 534 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 99 %, 10 . 5 mg , 0 . 0090 mmol ) were combined in ethanol ( 5 ml ) and heated to 80 ° c . for 18 hours . the reaction mixture was diluted with water , made slightly acidic by addition of 1 . 0 m aqueous hydrochloric acid , and extracted several times with ethyl acetate . the combined organic layers were washed with saturated aqueous sodium chloride solution , dried over magnesium sulfate , filtered , and concentrated in vacuo . purification via silica gel chromatography ( gradient : 75 % to 100 % ethyl acetate in heptane ) followed by reversed - phase hplc ( column : waters sunfire c18 , 5 μm ; mobile phase a : 0 . 05 % trifluoroacetic acid in water ( v / v ); mobile phase b : 0 . 05 % trifluoroacetic acid in acetonitrile ( v / v ); gradient : 20 % to 100 % b ) afforded the product as a solid . yield : 20 mg , 0 . 057 mmol , 32 %. lcms m / z 350 . 0 [ m + h ]. 1 h nmr ( 600 mhz , dmso - d 6 ) δ 8 . 14 ( d , j = 2 . 2 hz , 1h ), 8 . 04 ( d , j = 5 . 9 hz , 1h ), 7 . 51 ( br d , j = 5 . 9 hz , 1h ), 7 . 42 ( br ab quartet , j ab = 8 . 8 hz , δv ab = 16 . 7 hz , 4h ), 7 . 08 ( dd , j = 2 . 2 , 0 . 9 hz , 1h ), 2 . 94 ( s , 3h ), 1 . 55 ( s , 3h ). the affinity of the compounds described herein was determined by competition binding assays similar to those described in ryman - rasmussen et al ., “ differential activation of adenylate cyclase and receptor internalization by novel dopamine d1 receptor agonists ”, molecular pharmacology 68 ( 4 ): 1039 - 1048 ( 2005 ). this radioligand binding assay used [ 3 h ]- sch23390 , a radio d1 ligand , to evaluate the ability of a test compound to compete with the radioligand when binding to a d1 receptor . d1 binding assays were performed using over - expressing ltk human cell lines . to determine basic assay parameters , ligand concentrations were determined from saturation binding studies where the kd for [ 3 h ]— sch23390 was found to be 1 . 3 nm . from tissue concentration curve studies , the optimal amount of tissue was determined to be 1 . 75 mg / ml per 96 well plate using 0 . 5 nm of [ 3 h ]— sch23390 . these ligand and tissue concentrations were used in time course studies to determine linearity and equilibrium conditions for binding . binding was at equilibrium with the specified amount of tissue in 30 minutes at 37 ° c . from these parameters , k i values were determined by homogenizing the specified amount of tissue for each species in 50 mm tris ( ph 7 . 4 at 4 ° c .) containing 2 . 0 mm mgcl 2 using a polytron and spun in a centrifuge at 40 , 000 × g for 10 minutes . the pellet was resuspended in assay buffer ( 50 mm tris ( ph 7 . 4 @ rt ) containing 4 mm mgso 4 and 0 . 5 mm edta ). incubations were initiated by the addition of 200 μl of tissue to 96 - well plates containing test drugs ( 2 . 5 μl ) and 0 . 5 nm [ 3 h ]— sch23390 ( 50 μl ) in a final volume of 250 μl . non - specific binding was determined by radioligand binding in the presence of a saturating concentration of (+)- butaclamol ( 10 μm ), a d1 antagonist . after a 30 minute incubation period at 37 ° c ., assay samples were rapidly filtered through unifilter - 96 gf / b pei - coated filter plates and rinsed with 50 mm tris buffer ( ph 7 . 4 at 4 ° c .). membrane bound [ 3 h ]— sch23390 levels were determined by liquid scintillation counting of the filterplates in ecolume . the ic 50 value ( concentration at which 50 % inhibition of specific binding occurs ) was calculated by linear regression of the concentration - response data in microsoft excel . k i values were calculated according to the cheng - prusoff equation . where [ l ]= concentration of free radioligand and k d = dissociation constant of radioligand for d1 receptor ( 1 . 3 nm for [ 3 h ]— sch23390 ). the d1 camp ( cyclic adenosine monophosphate ) htrf ( homogeneous time - resolved fluorescence ) assay used and described herein is a competitive immunoassay between native camp produced by cells and camp labeled with xl - 665 . this assay was used to determine the ability of a test compound to agonize ( including partially agonize ) d1 . a mab anti - camp labeled cryptate visualizes the tracer . the maximum signal is achieved if the samples do not contain free camp due to the proximity of donor ( eu - cryptate ) and acceptor ( xl665 ) entities . the signal , therefore , is inversely proportional to the concentration of camp in the sample . a time resolved and ratiometric measurement ( em 665 nm / em 620 nm ) minimizes the interference with medium . camp htrf assays are commercially available , for example , from cisbio bioassays , iba group . materials : the camp dynamic kit was obtained from cisbio international ( cisbio 62am4pej ). multidrop combi ( thermo scientific ) was used for assay additions . envision ( perkinelmer ) reader was used to read htrf . cell cuture : a hek293t / hd1 # 1 stable cell line was constructed internally ( pfizer ann arbor ). the cells were grown as adherent cells in nunct 500 flasks in high glucose dmem ( invitrogen 11995 - 065 ), 10 % fetal bovine serum dialyzed ( invitrogen 26400 - 044 ), 1 × mem neaa ( invitrogen 1140 , 25 mm hepes ( invitrogen 15630 ), 1 × pen / strep ( invitrogen 15070 - 063 ) and 500 μg / ml genenticin ( invitrogen 10131 - 035 ) at 37 ° c . and 5 % co 2 . at 72 or 96 hours post growth , cells were rinsed with dpbs and 0 . 25 % trypsin - edta was added to dislodge the cells . media was then added and cells were centrifuged and media removed . the cell pellets were re - suspended in cell culture freezing medium ( invitrogen 12648 - 056 ) at a density of 4e7 cells / ml . one ml aliquots of the cells were made in cryo - vials and frozen at − 80 ° c . for future use in the d1 htrf assay . d1 camp htrf assay procedure : frozen cells were quickly thawed , re - suspended in 50 ml warm media and allowed to sit for 5 min prior to centrifugation ( 1000 rpm ) at room temperature . media was removed and cell pellet was re - suspended in pbs / 0 . 5 μm ibmx generating 2e5 cells / ml . using a multidrop combi , 5 pl cells / well was added to the assay plate ( greiner 784085 ) which already contained 5 pl of a test compound . compound controls [ 5 μm dopamine ( final ) and 0 . 5 % dmso ( final )] were also included on every plate for data analysis . cells and compounds were incubated at room temperature for 30 min . working solutions of camp - d2 and anti - camp - cryptate were prepared according to cisbio instructions . using multidrop , 5 pl camp - d2 working solution was added to the assay plate containing the test compound and cells . using multidrop , 5 μl anti - camp - cryptate working solutions was added to assay plate containing test compound , cells and camp - d2 . assay plate was incubated for 1 hour at room temperature . assay plate was read on envision plate reader using cisbio recommended settings . a camp standard curve was generated using camp stock solution provided in the cisbio kit . data analysis : data analysis was done using computer software . percent effects were calculated from the compound controls . ratio ec 50 was determined using the raw ratio data from the envision reader . the camp standard curve was used in an analysis program to determine camp concentrations from raw ratio data . camp ec 50 was determined using the calculated camp data . fourteen different potential binding site residue mutations of the d1r were made to more precisely determine where the d1 agonists of the present invention were binding . generally , there is very good agreement between the fold - shift values of the d1 agonists of the present invention when compared to those of known catechol derivative full ( or super ) d1 agonists and partial agonists ; however 4 of those 14 residues ( ser188 , ser198 , ser202 , and asp103 ) showed statistically significant deviations and reprentative results are shown herein . human dopamine d1 receptor agonist activity was measured using cisbio dynamic 3 ′- 5 ′- cyclic adenosine monophosphate ( camp ) detection kit ( cisbio international 62am4pej ). camp was measured using a homogeneous time - resolved fluorescence ( htrf ) competitive immunoassay between native camp and camp labeled with the dye d2 . a monoclonal anti - camp antibody labeled cryptate bound the labeled camp . europiumcryptate donor was added , and the transfer of energy to the d2 acceptor was measured . the maximum signal was achieved if the samples did not contain free camp , due to the proximity of eu - cryptate donor and d2 acceptor entities . the signal , therefore , was inversely proportional to the concentration of native camp in the sample . a time resolved and ratiometric measurement ( em 665 nm / em 620 nm ) was obtained , which was then converted to camp concentrations using a standard curve . all camp experiments were performed in the presence of 500 nm ibmx to inhibit phosphodiesterase ( pde ) activity . the camp standard curve was generated using camp provided in the cisbio camp detection kit . preparation of the standard curve is as follows . ( 1 ) prepared 2848 nm camp stock solution in dplbecco &# 39 ; s phosphate buffered saline ( pbs , from sigma , cat # d8537 ), this stock solution was aliquoted ( 40 μl / vial ) and frozen at − 20 ° c . 2 ) on the day of assay , 40p1 pbs was added to two column of a 96 - well compound plate ( costar , cat # 3357 ). 2 ) on the day of assay , 40p1 2848nm camp stock solution was transferred to first well and mixed with 40 μl pbs ( see the figure below ), and then a 16 pt , 2 fold dilution was made by transfer 40 μl from higher conc . to lower conc . ( 3 ) manually transfer 10 μl / well ( in triplicate ) of camp solution to assay plate . stable hek293t cells expressing hd1r ( wild type or a mutant thereof ) were grown in high glucose dmem ( invitrogen 11995 - 065 ), 10 % fetal bovine serum dialyzed ( invitrogen 26400 - 044 ), 1 × mem neaa ( invitrogen 1140 ), 25 mm hepes ( invitrogen 15630 ), 1 × penicillin / streptomycin ( invitrogen 15070 - 063 ) and 500 pg / ml genenticin ( invitrogen 10131 - 035 ) at 37 c and 5 % co2 . at 72 to 96 hours post seeding , cells were rinsed with phosphate buffered saline and 0 . 25 % trypsin - edta was added to dislodge the cells . media was then added and cells were centrifuged and media removed . the cell pellets were re - suspended in cell culture freezing medium ( invitrogen 12648 - 056 ) at a density of 40 million cells / ml . one ml aliquots of the cells were made in cryo - vials and frozen at − 80 ° c . for use in the hd1 ( or a mutant thereof ) htrf camp assay . frozen cells were quickly thawed , re - suspended in warm media and allowed to sit for 5 min prior to centrifugation ( 1000 rpm ) at room temperature . media was removed and the cell pellet was re - suspended in pbs containing 500 nm ibmx . using a multidrop combi ( thermo scientific ), 5 μl cells / well at a cell density of approximately 1000 cells / well were added to the assay plate ( greiner 784085 ) which contained 5 μl of test compound . the exact cell density could vary depending on the camp concentration relative to the standard curve . each plate contained positive controls of 5 um dopamine ( final concentration ) and negative controls of 0 . 5 % dmso ( final concentration ). cells and compounds were incubated at room temperature for 30 min . working solutions of camp - d2 and anti - campcryptate were prepared according to cisbio instructions . using the multidrop combi , 5 μl camp - d2 working solution was added to the assay plate containing the test compound and cells . using the multidrop combi , 5 μl anti - camp - cryptate working solutions was added to assay plate containing test compound , cells and camp - d2 . assay plates were incubated for 1 hour at room temperature , then read using an envision plate reader ( perkin elmer ) using cisbio recommended settings . a camp standard curve was generated using camp stock solution provided in the cisbio kit , which was then used to convert the raw ratio data to camp concentrations . ec 50 values were determined using a logistic 4 parameter fit model . the percent efficacy for each curve was determined by the maximum asymptote of that fitted curve , and expressed as a percent of the maximum response produced by the positive controls ( 5 μm dopamine ) on each plate . wild type 3xha - h d1 expression construct ( in pcdna3 . 1 +) was obtained from missouri s & amp ; t cdna resource center . several mutations were created using mutagenesis methods ( e . g ., stratagene quick change mutagenesis kit ). all mutations were confirmed via sequencing . wild type and mutant ( s ) expressing hek293 cells were generated ( for camp assays ) via transient transfection ( 48 hrs .) in freestyle hek 293f cells ( invitrogen ). the number of cells / paste used per data point was based on relative expression levels as determined via western blot analysis . d1r vvt refers to wild type . several mutants were designed based upon a computational homology model of d1 and mutant numbering is consistent with what has been previously published in the literature . see e . g ., n j pollock , et . al , “ serine mutations in transmembrane v of the dopamine d 1 receptor affect ligand interactions and receptor activation .” j . biol . chem . 1992 , 267 [ 25 ], 17780 - 17786 . mutants are designated by the number corresponding to their position in the primary sequence and the three - letter amino acid code . for example , d103a mutant refers to the amino acid aspartate ( d ) at the 103 rd position in the primary sequence mutated to the amino acid alanine ( a ); s188i mutant refers to the amino acid serine ( s ) at the 188 th position in the primary sequence mutated to the amino acid isoleucine ( 1 ); and s198a mutant refers to the amino acid serine ( s ) at the 198 th position in the primary sequence mutated to the amino acid alanine ( a ). relative 3xha - hd1 mutant expression levels were normalized to wild type hd1 levels by western blot analysis . soluble ripa lysates of transiently transfected hek293f cells were prepared by lysing cells at 4 ° c . for 30 minutes in ripa buffer ( sigma ) with protease and phosphatase inhibitors ( pierce ). equivalent amounts of total soluble ripa lysates ( determined by bca total protein assay , pierce ) were run on sds - page , transferred to nitrocellulose and probed with anti - ha as well as anti - gapdh antibodies ( sigma ). total mutant hd1 ha immunoreactivity was quantitated verses gapdh immunoreactivity ( ha / gapdh ) and finally normalized to wild type 3xha - hd1 ( ha / gapdh ) using licor / odyssey software . based on this relative ha / gapdh ratios as compared to wild type , the relative amount of cell paste or cell number / well was adjusted for each mutants &# 39 ; expression levels . a first run of camp assays was conducted . from the first run , it was determined that the results were at the upper end of linear range ( for agonists ) of the standard curve ( the range is provided by cisbo ), indicating this first run is at a higher density of cells / well . typically , a higher density of cells / well run ( within the linear range ) is suitable for mutants that are either lower expressers or have low activity ; but not as suitable for the higher activity / expressing mutants . table 4 shows ec 50 data in the first run of camp assays . a second run of camp assays was conducted . according to a comparison with the standard curve , this run of assays was at a lower density of cells / well because the results were at the lower end of linear range ( for agonists ) of the standard curve . typically , assays at a lower density of cells / well ( within the liner range ) are more suitable for the higher activity / expressing mutants , but less suitable for those mutants with lower expression / activity . table 5 shows ec 50 data in the second run of camp assays . results from both mutation runs revealed that many of the mutant receptors have weaker activity ( higher ec 50 values ) when compared to the wt d1 , reflecting the loss of interaction between the ligand and the receptor with the mutated side chain . in an attempt to determine the side - chain contribution to activity , quantifications of the shift between the mutant receptor and the wt receptor , i . e ., fold shift data were calculated according to the equation ; fold shift = ec 50 ( mutant )/ ec 50 ( wt ). fold shift data are shown in table 6 . in general , assays with most of the mutant d1 receptors provided values in the “ kit - defined ” linear range with the lower cell / well variant . however , s198a gave poor results for the lower cells / well run . a comparison of the average fold shifts for each tested mutant across both runs revealed that the fold shifts were more pronounced for the lower activity run by a factor of ˜ 2 . 5 . this factor was determined by regressing the average log ( foldshift ) values between runs for all mutants : the intercept value of 0 . 3968 reflects the ˜ 2 . 5 × systematic difference between the runs . dopamine , another catechol - derivative full d1 agonist ( dihydrexidine ), and two other catechol - derivative partial d1 agonist ( skf - 38393 and skf - 77434 ) have fold shift less than about 4 . 0 with respect to s1881 mutant , indicating that they do not interact significantly with the ser188 unit of d1r . in contrast , examples 215 and 27 ( full d1 agonists ) and example 25 ( partial d1 agonist ) have fold shift greater than about 7 . 0 with respect to s188i mutant , indicating that they interact significantly with the ser188 unit of d1r . dopamine and another catechol - derivative d1 full agonist ( dihydrexidine ) have fold shift greater than about 70 with respect to s202a mutant , indicating that they interact significantly with the ser202 unit of d1r . in contrast , examples 215 and 27 ( full d1 agonists ) have fold shift less than about 4 . 0 with respect to s202a mutant , indicating that they do not interact significantly with the ser202 unit of d1r . dopamine and 3 other catechol - derivative d1 agonists , as well as examples 215 and 27 ( full d1 agonists ) and example 25 ( partial d1 agonist ) have fold shift greater than about 7 . 0 with respect to d103a mutant , indicating that they interact significantly with the asp103 unit of d1r . on average , the fold shift for the catechol - derivative agonist ( greater than 100 , 150 , or 180 ) are much greater than those for examples 215 and 27 ( full d1 agonists ) and example 25 ( partial d1 agonist ), indicating the interactions between d1r and non - catechol derivative examples 215 , 27 , and 25 are less strong than thos between d1r and the catechol - derivative agonists . dopamine and 3 other catechol - derivative d1 agonists , as well as examples 215 and 27 ( full d1 agonists ) and example 25 ( partial d1 agonist ) have fold shift greater than about 7 . 0 with respect to s198a mutant , indicating that they interact significantly with the ser198 unit of d1r . however , on average , the fold shift for the catechol - derivative full agonists ( dopamine and dihydrexidine , both are greater than 25 , 30 , or 35 ) are greater than examples 215 and 27 ( full d1 agonists ), indicating the interactions between d1r and non - catechol - derivative full agonist examples 215 , and 27 are less strong than those between d1r and the catechol - derivative full agonists . the % intrinsic activity of each of the test compounds [ i . e ., the maximum percent efficacy ( calculated by maximum camp concentration ) in reference to dopamine ] was determined using camp data from a d1 camp htrf assay as in example bb . a these fold shift value have been transformed using the equation : foldshift = 2 . 234 *( ec 50 — mutant / ec 50 — wt ). this correction was done in order to correct for differences in receptor density between two assay runs shown in tables 4 and 5 . any other foldshift refers to the shift in functional activity as defined : = ec 50 ( mutant )/ ec 50 ( wt ). for all studies of β - arrestin , a stable u2os cell line co - expressing human dopamine dl ( d1a ) receptors and human 3 - arrestin2 - green fluorescent fusion protein ( gfp ) was used . this cell line was obtained and licensed from professor marc g . caron , duke university , durham , n . c ., usa . the stable u2os cell line provides a fluorescent biosensor of β - arrestin2 - gfp that can be used to assess gpcr signaling and gpcr - mediated β - arrestin membrane recruitment using imaging - based methods such as fluorescence microscopy ( u . s . pat . nos . 7 , 572 , 888 and 7 , 138 , 240 )( 9 ); this technology is currently marketed as the transfluor assay ( molecular devices , usa ). the u2os cells were cultured under antibiotic selection in dmem ( invitrogen ) containing 25 mm glucose and 4 mm l - glutamine supplemented with 10 % dialyzed fetal bovine serum , 200 mg / ml geneticin , 100 mg / ml zeocin , and 100 u / ml penicillin / streptomycin ( all from invitrogen ) and incubated at 37 ° c . in 5 % carbon dioxide . cells from passage four through ten were used in these experiments . cells were grown in 35 mm glass bottomed imaging dishes ( mattek corp ). cells were incubated for 1h in serum free media ( sfm ) and subsequently treated for 10 minutes at 37 ° c . with 0 . 01 % dmso ( control ) or 1 μm of all test compounds dissolved in sfm followed by immediate fixation on ice with a 4 % paraformaldehyde / 1 × phosphate buffered saline solution . total internal reflection fluorescence microscopy ( tirfm ) was used . tirfm is a microscopy technique that enables visualization of the plasma membrane and a narrow region just inside the cell , providing a meansto visualize proteins at the plasma membrane of cells such as d1 receptors and recruited β - arrestin - gfp ( see yudowski g a , von zastrow m . “ investigating g protein - coupled receptor endocytosis and trafficking by tir - fm ”; methods in molecular biology . 2011 ; 756 : 325 - 32 .). all images were captured using a zeiss ps . 1 elyra superresoution fluorescence microscope equipped with tirf module . images of cells were obtained using tirf and a 100 × oil immersion objective and dedicated 488 nm excitation laser . optimal exposure time and laser power was determined using dopamine treated cells which exhibited maximal β - arrestin - gfp membrane signal and identical acquisition parameters were used for all cells and conditions . to quantify β - arrestin - gfp membrane recruitment , individual cells in microscopy images were identified and a polygon region of interest was traced for each cell using imagej , imaging analysis software ( schneider c a , rasband w s , eliceiri k w . “ nih image to imagej : 25 years of image analysis ”. nature methods . 2012 ; 9 ( 7 ): 671 - 5 ). an intensity - based threshold was established by evaluating dopamine treated cells which exhibited the maximal plasma membrane signal of β - arrestin - gfp . a range of values , 10 , 30 , 60 , 90 , etc . were tested and the lowest possible threshold , in this case 60 , capable of identifying the individual β - arrestin - gfp puncta was selected for continued analysis . sub - images were generated for all identified cells , and the total number of membrane β - arrestin - gfp puncta / cell , integrated intensity / cell , and total area / cell was established . individual objects were filtered based on size . a minimum of 60 cells for each condition were analyzed across three independent cell preparations and experiments . the mean membrane β - arrestin - gfp intensity / cell and puncta area / cell were determined and statistical differences compared by a one - way anova with dunnett &# 39 ; s post - test analysis using graphpad prism 5 . 02 . u2os cells stably expressing human d1 receptors and human β - arrestin - gfp proteins were treated for 10 minutes with 0 . 01 % dmso in serum free media ( control ) or with 1μm of a test compound ). test compounds include dopamine , dihydrexidine , skf - 81297 , skf - 38393 , skf - 77434 , example 5 ( partial agonist , 70 % intrinsic activity at human d1r v . dopamine ), example 9 ( full agonist , 92 % intrinsic activity at human d1r v . dopamine ), example 13 ( partial agonist , 58 % intrinsic activity at human d1r v . dopamine ), and example 25 ( full agonist , 88 % intrinsic activity at human d1r v . dopamine ). the % intrinsic activity of each of the test compounds [ i . e ., the maximum percent efficacy ( calculated by maximum camp concentration ) in reference to dopamine ] was determined using camp data from a d1 camp htrf assay as in example bb . cells were immediately fixed and β - arrestin - gfp located at the plasma membrane of cells was determined using total internal reflection fluorescence microscopy ( tirfm ). tables 7 and 8 list quantification of β - arrestin - gfp signal at the plasma membrane of cells using tirfm to assess total intensity / cell and total area / cell ; non - catechol - derivative d1 receptor agonists ( examples 5 , 9 , 13 and 25 ) showed significantly reduced plasma membrane β - arrestin - gfp total intensity and total area relative to dopamine . all results are the mean ± standard error averaged from 60 cells / condition obtained across three independent experiments ( n = 3 ). a , p & lt ; 0 . 05 versus control ; b , p & lt ; 0 . 05 versus dopamine . as shown in tables 7 and 8 , dopamine and two catechol - derivative full d1 agonists ( dihydrexidine and skf - 81297 ) recruited greater than about 95 % β - arrestin - gfp to the plasma membrane relative to dopamine ( the result can also be observed qualitatively from representative tirfm images of cells treated with these agonists ). in contrast , either of examples 9 and 25 ( full non - catechol - derivative d1 agonists ) recruited less than 70 % ( or 60 % or 50 %, or 40 %, or 35 %, or 30 % or 25 %) of β - arrestin - gfp to the plasma membrane relative to dopamine . each of the partial d1 agonists tested ( skf - 38393 , skf - 77434 , and examples 5 and 13 ) recruited less than 70 % ( or 60 % or 50 %, or 40 %, or 35 %, or 30 % or 25 %) of β - arrestin - gfp to the plasma membrane relative to dopamine . primary striatal neurons were obtained from embryonic day 18 ( e18 ) rats by standard neuronal isolation procedures and plated at a density of 35 , 000 cells / well in poly - ornithine / laminin coated 96 well plates ( bd falcon ). striatal neurons were chosen because they express endogenous d1 - like receptors and are a physiologically relevant tissue for examining neurotransmitter receptor desensitization in vitro . neurons were cultured in neurobasal media supplemented with b27 , 1 × glutamax and penicillin / streptomycin ( 100 u / ml ) ( all from invitrogen ) and incubated at 37 ° c . in 5 % carbon dioxide for 14 - 16 days prior to assay . to assess d1r desensitization , neurons in wells were pretreated for 120 minutes with 0 . 1 % dmso in serum free media ( control / sfm ) or 10 μm of a test compound dissolved in serum free neurobasal media . after the pretreatment , cells were washed twice at 5 minute intervals with 250 μl / well fresh neurobasal media . the ability of d1 - like receptors to signal was then examined by treating cells for 30 minutes with 1μm skf - 81297 , a catechol derivative d1 - like selective full agonist , in the presence of 500μm isobutylmethylxanthine . the concentration of camp accumulated in each well was determined using the cisbio htrf camp dynamic range assay kit ( cisbio ) according to the manufacturers &# 39 ; suggested protocol . the concentration of camp ( nm ) from treated wells was interpolated from a camp standard curve by non - linear regression least squares analysis using graphpad prism 5 . 02 . the mean ± standard error of the camp concentrations were calculated from results obtained across three independent experiments ( n = 3 ) each assayed in quadruplicate . the % desensitization was calculated as the percent decrease in camp relative to control . statistical differences were compared by a one - way anova with dunnett &# 39 ; s post - test analysis using graphpad prism 5 . 02 . all results are the mean ± standard error from three independent experiments assayed in quadruplicate ( n = 3 ). *, p & lt ; 0 . 05 versus control . as shown in table 9 , pretreatment of neurons with dopamine , two catechol derivative full d1 agonists ( dihydrexidine and skf - 81297 ), and two catechol derivative partial d1 agonists ( skf - 38393 and skf - 77434 ) significantly decreased d1r - mediated camp signaling . in contrast , pretreatments with non - catechol derivative d1 full agonists ( examples 9 and 25 ) and non - catechol derivative d1 partial agonists ( examples 5 and 13 ) did not significantly decrease d1r - mediated camp signaling ( closer to control ). as shown in table 10 , dopamine , two catechol derivative full d1 agonists ( dihydrexidine and skf - 81297 ), and two catechol derivative partial d1 agonists ( skf - 38393 and skf - 77434 ) significantly desensitized d1r receptors ( decreased greater than about 30 %, 40 %, or 50 % v . control ). in contrast , non - catechol derivative d1 full agonists ( examples 9 and 25 ) and non - catechol derivative d1 partial agonists ( examples 5 and 13 ) show decreased desensitization ( only decreased less than about 25 %, 20 %, 18 %, or 15 % v . control ). various modifications of the invention , in addition to those described herein , will be apparent to those skilled in the art from the foregoing description . such modifications are also intended to fall within the scope of the appendant claims . each reference ( including all patents , patent applications , journal articles , books , and any other publications ) cited in the present application is hereby incorporated by reference in its entirety .

the present invention provides , in part , compounds of formula i : and pharmaceutically acceptable salts thereof and n - oxides thereof ; processes for the preparation of ; intermediates used in the preparation of ; and compositions containing such compounds and the uses of such compounds for the treatment of d1 - mediated disorders including cognitive and motivational impairments and negative symptoms associated with illnesses such as schizophrenia , depression , bipolar disorder , parkinson &# 39 ; s disease , mild cognitive impairment , alzheimer &# 39 ; s disease , lupus , huntington &# 39 ; s disease , parkinson &# 39 ; s , dyskinesia , adhd , post - traumatic stress disorder , autism spectrum disorder , treatment - resistant depression , major depressive disorder , drug dependence , tourette &# 39 ; s syndrome , tardive dyskinesias as well as impairments associated with age , chronic stress , sleep deprivation , combat , chronic fatigue ; endocrine or metabolic diseases such as hyperglycemia , dislipidemia , diabetes , obesity , and sepsis ; and cardiovascular disorder such as hypertension . the present invention further provides a d1 agonist with reduced d1r desensitization , a d1 agonist with a reduced β - arrestin recruitment activity relative to dopamine , a d1 agonist interacting significantly with the ser188 but not significantly with the ser202 of a d1r when binding to the d1r , a d1 agonist interacting less strongly the asp103 and interacting less strongly with the ser198 of a d1r when binding to the d1r , and their uses .

the diphenylethylene is prepared by condensation of 3 , 5 - dimethoxybenzaldehyde and p - hydroxyphenyl acetic acid , followed by decarboxylation . the diphenylethylene compound according to the present invention may be combined with a physiologically acceptable vehicle in pharmaceutical composition , such as , a lyophilized powder in the form of tablets or capsules which also includes various fillers and binders . the effective dosages of the compound in a composition will be selected by those of ordinary skill in the art and may empirically be determined . the compound of the present invention are useful for the treatment of diseases such as diabetes characterized by the presence of elevated blood glucose levels , that is , hyperglycemic disorders such as diabetes melitus , including both type i and ii diabetes as well as other hyperglycemic related disorders such as obesity , increased cholesterol , kidney related disorders , and the like . by “ treatment ”, it is meant that the compound is administered at least to reduce the blood glucose level in the patient suffering from the hyperglycemic disorder . the compound is administered in an amount sufficient to reduce blood glucose level to an acceptable range , wherein an acceptable range means ± 10 %, usually ± 8 % and usually ± 5 % of the normal average blood glucose level for the subject . a variety of subjects may be treated with the compounds to reduce blood glucose levels , such as livestock , valuable or rare animals , pets , as well as humans . the compound may be administered to the subject suffering from the hyperglycemic disorder using a convenient administration technique , including intravenous , intradermal , intramuscular subcutaneous , oral and the like . the dosage delivered to the host will necessarily depend upon the route by which the compound is delivered , but generally ranges from 5 to 500 mg / 70 kg human body weight or typically from about 50 to 200 mg / 70 kg human body weight . of particular interest are methods of treating human hyperglycemic disorder such as diabetes , including both type i and ii , where the compound is administered to the human suffering from the hyperglycemic disorder to at least reduce the blood glucose level of the subject to about the normal blood glucose range for a human . the following examples are offered by way of illustration and not intended to limit the invention in any way . to a mixture of 3 , 5 - dimethoxybenzaldehyde ( 30 mm ) and p - hydroxphenyl acetic acid ( 30 mm ) was added to 5 ml acetic anhydride and 2 . 5 ml of triethylamine ( tea ). after being stirred at 130 - 140 ° c . for 24 hr , the mixture was cooled to room temperature and quenched with 25 ml concentrated hcl and extracted with ch 2 cl 2 . the organic extract was further extracted with in naoh , then the naoh extract was washed with water , the aqueous layer was acidified with conc . hcl and washed with water to obtain the crude product . crude product was recrystallized from ethanol / water . to 1 g of this product under n 2 , 3 g of cu power and 30 ml of quinoline was added , the mixture was refluxing with stirring for 4 hr . the reaction mixture was filtered , diluted with water and extracted with ch 2 cl 2 . organic layer was dried and concentrated , product was purified by flash chromatography . streptozotocin ( stz ) induced diabetic rats were made by injecting stz ( 40 mg / kg / bw ) intravenously . following verification of blood glucose levels after 72 hours , diabetic rats showing fasting blood glucose levels above 200 mg / dl were divided into two groups . the diphenylethylene was administered to one group in a dose of 20 mg / kg / bw in propyleneglycol . the control group received only propyleneglycol . soon after the administration of the compound , glucose tolerance testing was conducted by a glucose load of 2 g / kg / bw and blood glucose levels were monitored at zero , 30 , 60 , 120 and 180 minutes by milking the tail of the rats . the results are shown in fig1 . in the group treated with the pterostilbene it can be seen that after about 30 minutes , the blood glucose levels begin to fall and stayed consistently below the blood glucose levels in the control group until the end of the test . the same test was conducted on stz induced diabetic rats comparing the diphenylethylene with the commercial product metformin . the diphenylethylene was administered at a dose of 20 mg / kg and metformin was administered at the dosage of 30 mg / kg . the results are shown below in table 1 . it can be seen by the glucose levels obtained by the administration of the diphenylethylene are equivalent to those obtained by the commercial product . six spontaneously diabetic ( db / db ) mice were divided into two groups of three each . one test group receives the diphenylethylene ( 20 mg / kg / bw / ip ) in propyleneglycol . the control group received an equal volume of propyleneglycol . soon after the administration of the test materials , blood glucose levels were monitored at 1 hour ( see fig2 a ) and 24 hours ( see fig2 b ) after treatment . the diphenylethylene reduced the blood glucose level by over 50 percent within 24 hours , thus establishing its antihyperglycemic effect .

a diphenylethylene pterocarpus marsupium is provided which is administered orally to decrease blood glucose levels in rats . the compound is an effective anti - diabetic agent that can reduce abnormality of glucose metabolism in diabetes .

one aspect of the invention relates to the synthesis and use of molecular nanofibers as a anticancer nanomedicines . while conventional drug delivery systems require a polymer matrix , and the degradation of the polymer matrix usually cause side effects , the molecular nanofibers disclosed herein allow for self - delivery ; that is , because the self - assembled drug molecules form their own gel they eliminate the need for a polymer matrix . in certain embodiments the invention relates to the use of an enzymatic reaction to initiate the self - assembly of a derivative of a pharmaceutical agent to form nanofibers that result in a supramolecular hydrogel . enzymes , as a class of highly efficient and specific catalysts , dictate a myriad of reactions that constitute various cascades in biological systems . the expression and distribution of enzymes differ by the types and states of cells , tissues , and organs , thus leading to diverse extracellular and intracellular environments . using an enzymatic reaction to convert pharmaceutical agent - containing precursors into amphiphilic molecules ( referred to herein as gelators ) that self - assemble into nanofibers in water , one can control the cellular responses to molecular nanofiber according to a specific biological condition or environment , thus providing an accessible route to create sophisticated nanomaterials for biomedicine . in certain embodiments the pharmaceutical agent - containing precursor comprises an antineoplastic agent such as paclitaxel . paclitaxel is a well - established antineoplastic agent that binds specifically to the β - tubulin subunit of microtubules ( mt ) to arrest mitosis and result in programmed cell death ( i . e ., apoptosis ) and has shown remarkable activity in the treatment of breast , lung , ovarian , bladder and head and neck cancers . while the invention will often be described herein with paclitaxel as the pharmaceutical agent , this is not intended in any way to limit the scope of the invention to paclitaxel . rather , other aspects of the invention relate to the self - assembly of derivatives of other neoplastic agents , such as doxorubicin , daunorubicin , vinblastine , or vincristine , as well as other biologically active compounds , such as hydrophobic drugs , to form nanofibers that result in a supramolecular hydrogel . to connect paclitaxel covalently with a motif that tends to self - assemble and a group that is cleavable by an enzyme , a precursor for producing a paclitaxel hydrogel was designed and synthesized . as illustrated in fig1 ( top ), upon the action of an enzyme , the precursor ( 5a ) transforms into a hydrogelator ( 5b ), which self - assembles into nanofibers and affords a supramolecular hydrogel of paclitaxel . the hydrogel can slowly releases the hydrogelator ( 5b ) into an aqueous medium . besides representing the first example of enzyme - instructed self - assembly and hydrogelation of complex , bioactive small molecules , this result demonstrates a new , facile way to formulate highly hydrophobic drugs , such as paclitaxel , into an aqueous form ( e . g ., hydrogel ) without comprising their activities , and promises a general methodology to create therapeutic molecules that have a dual role as the delivery vehicle and the drug itself . fig1 ( bottom ) shows the synthetic route and the structure of the precursor ( 5a ), which consists of a self - assembly motif , an enzyme - cleavable group , a linker , and a paclitaxel molecule . yang , z . m . ; gu , h . w . ; fu , d . g . ; gao , p . ; lam , j . k . ; xu , b . adv . mater . 2004 , 16 , 1440 ; and yang , z . m . ; liang , g . l . ; wang , l . ; bing , x . j . am . chem . soc . 2006 , 128 , 3038 . based on the study of the structure - activity of paclitaxel derivatives , a linker ( succinic acid ) was connected to the c2 ′ hydroxyl group of paclitaxel ( 1 ) to provide an intermediate ( 2 ), which was activated by n - hydroxysuccinimide ( nhs ) to afford 3 . guerittevoegelein , f . ; guenard , d . ; lavelle , f . ; legoff , m . t . ; mangatal , l . ; potier , p . j . med . chem . 1991 , 34 , 992 ; swindell , c . s . ; krauss , n . e . ; horwitz , s . b . ; ringel , i . j . med . chem . 1991 , 34 , 1176 ; and dosio , f . ; brusa , p . ; crosasso , p . ; arpicco , s . ; cattel , l . j . control . rel . 1997 , 47 , 293 . the reaction of 3 with a phosphatase substrate ( napffkyp , 4 ) that consists of the self - assembly motif and the enzyme - cleavable group affords the precursor ( 5a ) in an overall yield of 37 . 1 %. additional details are provided below . compared to paclitaxel and the pyridinium paclitaxel prodrug , the precursor ( 5a ) exhibits much better solubility ( 7 . 6 mg / ml or 4 . 26 mm in a 100 mm phosphate buffered saline ( pbs ) solution ) and has the distribution coefficient ( octanol / water ) of 0 . 61 . nicolaou , k . c . ; guy , r . k . ; pitsinos , e . n . ; wrasidlo , w . angew . chem . intl . ed . 1994 , 33 , 1583 ; u . s . pat . no . 6 , 271 , 384 to nicolaou et al . ; and pct application no . pct / us95 / 00538 to nicolaou et al . in addition , the precursor ( 5a ) has excellent stability in water and shows hardly any dephosphorylation over months without a phosphatase . after dissolving 10 mg of the precursor ( 5a ) into 1 ml of water at a ph of about 7 . 3 with the aid of sonication ( fig2 a ), 5 μl of alkaline phosphatase ( 10 u / μl ) was added into the solution . the solution becomes slightly turbid ( fig2 b ) 5 minutes after the addition of the enzyme and turns into a translucent hydrogel ( gel 5b , fig2 c ) overnight . lc - ms and hplc traces confirmed the complete conversion of 5a to 5b in the hydrogel . moreover , mass spectroscopic ( ms ) analysis indicates that 5b is stable in gel state over weeks , an important prerequisite for the sustained release of 5b from its own hydrogel ( vide infra ). as shown in the tem image ( fig2 d ), the solution of 5a gives featureless aggregates after cryo - drying . according to the tem in fig2 e , five minutes after the addition of the enzyme , the mixture already contains the nanofibers with a width of 20 nm besides particle aggregates . apparently , the nanofibers stretch out of the amorphous area , suggesting that the nanofibers grow from the enzymes . this is consistent with the enzyme - catalyzed self - assembly process . while the scanning electron micrograph ( sem ) shows lamellar microstructures , the cryo - dried gel 5b exhibits well - dispersed nanofiber networks with the uniform fiber width of 29 nm ( fig2 f ). these results confirm the self - assembly and formation of the nanofibers upon enzyme catalysis . circular dichroism ( cd ) spectra of the solution of 5a and the corresponding gel 5b further help elucidate the molecular arrangement of 5b in gel phase . the spectrum of gel 5b exhibits a positive band near 192 nm ( ππ * transition of the amide bonds ) and a broad negative band near 216 nm ( nπ * transition of the amide bonds and ππ * of the naphthyl aromatics ), coinciding with the cd of napffegy 17 and indicating the existence of β - sheet like features . moreover , the intensity of the peak at 298 nm , a characteristic peak of paclitaxel , decreases dramatically in the cd spectrum of gel 5b in comparison with that of the solution of 5a , indicating that the 5b nanofibers might align in such a way to force the intrinsic dipole transition moments of the paclitaxels to opposite directions to reduce each other . this observation is consistent with traditional antiparallel arrangements in a β - sheet like secondary structures . to evaluate the activity of 5a , it was used to treat hela cells ; paclitaxel ( 1 ) was used as the control . as shown in fig3 a , after 48 h of incubation with hela cells , 5a exhibits an ic 50 value of 9 . 97 ± 2 . 05 nm , about five times lower than that of 1 ( 47 . 3 ± 2 . 99 nm ). further examination shows the phosphatase substrate ( 4 ), is essentially biocompatible ( ic 50 greater than about 500 μm ). 5b itself exhibits ic 50 of 51 . 4 ± 7 . 69 nm , which is comparable to that of 1 . these results indicate that the activity of paclitaxel is conserved successfully in the precursor and the hydrogelator . one possible explanation for the higher activity of 5a than that of 5b in the cell assay might be the improved solubility of 5a . the poor solubility of 5b ( 21 . 6 μg / ml or 12 . 66 μm ) in water , unfortunately , prevents it from forming a hydrogel directly from 5b by changing temperature or ph . however , it is easy to generate hydrogels that consist of or contain 5b by enzymatic dephosphorylation of 5a , which allows one to evaluate the release of 5b from the hydrogels . fig3 b shows the release profiles of 5b from two kinds of gels : gel 5b resulted from treating the solution of 5a ( 0 . 8 wt %) with alkaline phosphatase ; and a mixed gel made by adding alkaline phosphatase into the solution of 5a ( 0 . 6 wt %) and 4 ( 0 . 6 wt %). when contacted with a fresh pbs buffer solution , gel 5b and the mixed gel release 5b at the rates of 0 . 05 % and 0 . 016 % per hour , respectively . this experiment demonstrates the sustained release of 5b from its own gel and shows a way for the release rate control via the concentration of 5b in the mixed gel . one aspect of the invention relates to a compound represented by formula i : provided that the sum of p and q is 2 , 3 , 4 , 5 , 6 , 7 or 8 ; and at least one instance of r is — oh or — opo 3 h 2 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 0 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 2 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 3 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 4 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 5 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 6 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 7 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein p is 8 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 0 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 2 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 3 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 4 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 5 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 6 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 7 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein q is 8 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein only one instance of r is — opo 3 h 2 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein only one instance of r is — opo 3 h 2 ; and all other instances of r are — h . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein only one instance of r is — oh . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein only one instance of r is — oh ; and all other instances of r are — h . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein one r 1 is and the remaining instances of r 1 , if any , and r 2 , if any , are in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein one r 2 is and the remaining instances of r 2 , if any , and r 1 , if any , are in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein one r 1 is and the remaining instances of r 1 , if any , and r 2 , if any , are in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein one r 2 is and the remaining instances of r 2 , if any , and r 1 , if any , are in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r 1 is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r 1 is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r 2 is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r 3 is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r 3 is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein w is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein w is — ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein x is o . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein y is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein y is — ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein m is 0 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is an antineoplastic agent . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is paclitaxel , doxorubicin , daunorubicin , vinblastine , vincristine , cisplatin or 5 - fluorouracil . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is r 2 ′ is — ph or — otbu ; and r 3 ′ is — h or — c (— o ) ch 3 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is another aspect of the invention relates to a compound of formula ii : in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — oh . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — opo 2 h 3 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein w is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein w is — ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein x is o . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein y is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein y is — ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein m is 0 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is an antineoplastic agent . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is paclitaxel , doxorubicin , daunorubicin , vinblastine , vincristine , cisplatin or 5 - fluorouracil . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is r 2 ′ is — ph or — otbu ; and r 3 ′ is — h or — c (═ o ) ch 3 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — oh ; x is o ; and m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — opo 2 h 3 ; x is o ; and m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — oh ; w is — ch 2 ch 2 ch 2 ch 2 —; x is o ; y is — ch 2 ch 2 —; and m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — opo 2 h 3 ; w is — ch 2 ch 2 ch 2 ch 2 —; x is o ; y is — ch 2 ch 2 —; and m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — oh ; w is — ch 2 ch 2 ch 2 ch 2 —; x is o ; y is — ch 2 ch 2 —; m is 1 ; and z is in certain embodiments , the present invention relates to any one of the aforementioned compounds , wherein r is — opo 2 h 3 ; w is — ch 2 ch 2 ch 2 ch 2 —; x is o ; y is — ch 2 ch 2 —; m is 1 ; and z is certain compounds of the invention which have acidic substituents may exist as salts with pharmaceutically acceptable bases . the present invention includes such salts . examples of such salts include sodium salts , potassium salts , lysine salts and arginine salts . these salts may be prepared by methods known to those skilled in the art . certain compounds of the invention and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof . certain compounds of the invention and their salts may also exist in the form of solvates , for example hydrates , and the present invention includes each solvate and mixtures thereof . certain compounds of the invention may contain one or more chiral centers , and exist in different optically active forms . when compounds of the invention contain one chiral center , the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers , such as racemic mixtures . the enantiomers may be resolved by methods known to those skilled in the art , for example by formation of diastereoisomeric salts which may be separated , for example , by crystallization ; formation of diastereoisomeric derivatives or complexes which may be separated , for example , by crystallization , gas - liquid or liquid chromatography ; selective reaction of one enantiomer with an enantiomer - specific reagent , for example enzymatic esterification ; or gas - liquid or liquid chromatography in a chiral environment , for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent . it will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above , a further step may be used to liberate the desired enantiomeric form . alternatively , specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents , substrates , catalysts or solvents , or by converting one enantiomer into the other by asymmetric transformation . when a compound of the invention contains more than one chiral center , it may exist in diastereoisomeric forms . the diastereoisomeric compounds may be separated by methods known to those skilled in the art , for example chromatography or crystallization and the individual enantiomers may be separated as described above . the present invention includes each diastereoisomer of compounds of the invention and mixtures thereof . certain compounds of the invention may exist in different tautomeric forms or as different geometric isomers , and the present invention includes each tautomer and / or geometric isomer of compounds of the invention and mixtures thereof . certain compounds of the invention may exist in different stable conformational forms which may be separable . torsional asymmetry due to restricted rotation about an asymmetric single bond , for example because of steric hindrance or ring strain , may permit separation of different conformers . the present invention includes each conformational isomer of compounds of the invention and mixtures thereof . certain compounds of the invention may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of the invention and mixtures thereof . another aspect of the invention relates to a self - assembled molecular nanofiber , comprising a plurality of any one of the aforementioned compounds , wherein at least one instance of r is — oh . another aspect of the invention relates to a self - assembled molecular nanofiber consisting essentially of a plurality any one of the aforementioned compounds wherein at least one instance of r is — oh . another aspect of the invention relates to a self - assembled molecular nanofiber , comprising a plurality of any one of the aforementioned compounds , wherein at least one instance of r is — oh ; and a plurality of napffky . another aspect of the invention relates to a self - assembled molecular nanofiber , consisting essentially of a plurality of any one of the aforementioned compounds , wherein at least one instance of r is — oh ; and a plurality of napffky . another aspect of the invention relates to a supramolecular hydrogel comprising any one of the aforementioned self - assembled molecular nanofibers . another aspect of the invention relates to a supramolecular hydrogel consisting essentially of any one of the aforementioned self - assembled molecular nanofibers . in certain embodiments , the present invention relates to any one of the aforementioned compounds or supramolecular hydrogels for use in the treatment of cancer , tumors , malignancies , neoplasms , or other dysproliferative diseases . in certain embodiments , the present invention relates to any one of the aforementioned compounds or supramolecular hydrogels for use in the manufacture of a medicament for treating cancer , tumors , malignancies , neoplasms , or other dysproliferative diseases . examples of cancers , tumors , malignancies , neoplasms , and other dysproliferative diseases that can be treated according to the invention include leukemias , such as myeloid and lymphocytic leukemias , lymphomas , myeloproliferative diseases , and solid tumors , such as but not limited to sarcomas and carcinomas such as fibrosarcoma , myxosarcoma , liposarcoma , chondrosarcoma , osteogenic sarcoma , chordoma , angiosarcoma , endotheliosarcoma , lymphangiosarcoma , lymphangioendotheliosarcoma , synovioma , mesothelioma , ewing &# 39 ; s tumor , leiomyosarcoma , rhabdomyosarcoma , colon carcinoma , pancreatic cancer , breast cancer , ovarian cancer , prostate cancer , squamous cell carcinoma , basal cell carcinoma , adenocarcinoma , sweat gland carcinoma , sebaceous gland carcinoma , papillary carcinoma , papillary adenocarcinomas , cystadenocarcinoma , medullary carcinoma , bronchogenic carcinoma , renal cell carcinoma , hepatoma , bile duct carcinoma , choriocarcinoma , seminoma , embryonal carcinoma , wilms &# 39 ; tumor , cervical cancer , testicular tumor , lung carcinoma , small cell lung carcinoma , bladder carcinoma , epithelial carcinoma , glioma , astrocytoma , medulloblastoma , craniopharyngioma , ependymoma , pinealoma , hemangioblastoma , acoustic neuroma , oligodendroglioma , meningioma , melanoma , neuroblastoma , and retinoblastoma . one or more compounds of this invention can be administered to a human patient alone or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient ( s ) at doses to treat or ameliorate a disease or condition as described herein . mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions . for example , one aspect of the invention relates to pharmaceutical composition comprising a therapeutically effective dose of a compound of formula i or ii , a nanofiber or gel prepared therefrom , or a pharmaceutically acceptable salt , biologically active metabolite , solvate , hydrate , prodrug , enantiomer or stereoisomer thereof ; and a pharmaceutically acceptable diluent or carrier . as used herein , a therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein . techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art , such as “ remington &# 39 ; s pharmaceutical sciences ,” mack publishing co ., easton , pa ., latest edition . suitable routes of administration may , for example , include oral , eyedrop , rectal , transmucosal , topical , or intestinal administration ; parenteral delivery , including intramuscular , subcutaneous , intramedullary injections , as well as intrathecal , direct intraventricular , intravenous , intraperitoneal , intranasal , or intraocular injections . alternatively , one may administer the compound in a local rather than a systemic manner , for example , via injection of the compound directly into an edematous site . furthermore , one may administer the drug in a targeted drug delivery system , for example , in a liposome coated with endothelial cell - specific antibody . the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known , e . g ., by means of conventional mixing , dissolving , granulating , dragee - making , levigating , emulsifying , encapsulating , entrapping or lyophilizing processes . pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically . proper formulation is dependent upon the route of administration chosen . for injection , the agents of the invention may be formulated in aqueous solutions , preferably in physiologically compatible buffers such as hanks &# 39 ; solution , ringer &# 39 ; s solution , or physiological saline buffer . for transmucosal administration , penetrants appropriate to the barrier to be permeated are used in the formulation . such penetrants are generally known in the art . for oral administration , the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art . such carriers enable the compounds of the invention to be formulated as tablets , pills , dragees , capsules , liquids , gels , syrups , slurries , suspensions and the like , for oral ingestion by a patient to be treated . pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient , optionally grinding a resulting mixture , and processing the mixture of granules , after adding suitable auxiliaries , if desired , to obtain tablets or dragee cores . suitable excipients are , in particular , fillers such as sugars , including lactose , sucrose , mannitol , or sorbitol ; cellulose preparations such as , for example , maize starch , wheat starch , rice starch , potato starch , gelatin , gum tragacanth , methyl cellulose , hydroxypropylmethyl - cellulose , sodium carboxymethylcellulose , and / or polyvinylpyrrolidone ( pvp ). if desired , disintegrating agents may be added , such as the cross - linked polyvinyl pyrrolidone , agar , or alginic acid or a salt thereof such as sodium alginate . dragee cores are provided with suitable coatings . for this purpose , concentrated sugar solutions may be used , which may optionally contain gum arabic , talc , polyvinyl pyrrolidone , carbopol gel , polyethylene glycol , and / or titanium dioxide , lacquer solutions , and suitable organic solvents or solvent mixtures . dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses . pharmaceutical preparations which can be used orally include push - fit capsules made of gelatin , as well as soft , sealed capsules made of gelatin and a plasticizer , such as glycerol or sorbitol . the push - fit capsules can contain the active ingredients in admixture with filler such as lactose , binders such as starches , and / or lubricants such as talc or magnesium stearate and , optionally , stabilizers . in soft capsules , the active compounds may be dissolved or suspended in suitable liquids , such as fatty oils , liquid paraffin , or liquid polyethylene glycols . in addition , stabilizers may be added . all formulations for oral administration should be in dosages suitable for such administration . for buccal administration , the compositions may take the form of tablets or lozenges formulated in conventional manner . for administration by inhalation , the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser , with the use of a suitable propellant , e . g ., dichlorodifluoromethane , trichlorofluoromethane , dichlorotetrafluoroethane , carbon dioxide or other suitable gas . in the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount . capsules and cartridges of , e . g ., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch . the compounds can be formulated for parenteral administration by injection , e . g ., bolus injection or continuous infusion . formulations for injection may be presented in unit dosage form , e . g ., in ampoules or in multi - dose containers , with an added preservative . the compositions may take such forms as suspensions , solutions or emulsions in oily or aqueous vehicles , and may contain formulatory agents such as suspending , stabilizing and / or dispersing agents . pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water - soluble form . additionally , suspensions of the active compounds may be prepared as appropriate oily injection suspensions . suitable lipophilic solvents or vehicles include fatty oils such as sesame oil , or synthetic fatty acid esters , such as ethyl oleate or triglycerides , or liposomes . aqueous injection suspensions may contain substances which increase the viscosity of the suspension , such as sodium carboxymethyl cellulose , sorbitol , or dextran . optionally , the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions . alternatively , the active ingredient may be in powder form for constitution with a suitable vehicle , e . g ., sterile pyrogen - free water , before use . the compounds may also be formulated in rectal compositions such as suppositories or retention enemas , e . g ., containing conventional suppository bases such as cocoa butter or other glycerides . in addition to the formulations described previously , the compounds may also be formulated as a depot preparation . such long acting formulations may be administered by implantation ( for example subcutaneously or intramuscularly or by intramuscular injection ). thus , for example , the compounds may be formulated with suitable polymeric or hydrophobic materials ( for example as an emulsion in an acceptable oil ) or ion exchange resins , or as sparingly soluble derivatives , for example , as a sparingly soluble salt . alternatively , other delivery systems for hydrophobic pharmaceutical compounds may be employed . liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs . certain organic solvents such as dimethysulfoxide also may be employed , although usually at the cost of greater toxicity . additionally , the compounds may be delivered using a sustained - release system , such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent . various sustained - release materials have been established and are well known by those skilled in the art . sustained - release capsules may , depending on their chemical nature , release the compounds for a few weeks up to over 100 days . depending on the chemical nature and the biological stability of the therapeutic reagent , additional strategies for protein stabilization may be employed . the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients . examples of such carriers or excipients include but are not limited to calcium carbonate , calcium phosphate , various sugars , starches , cellulose derivatives , gelatin , and polymers such as polyethylene glycols . many one of the compounds of the invention may be provided as salts with pharmaceutically compatible counterions ( i . e ., pharmaceutically acceptable salts ). a “ pharmaceutically acceptable salt ” means any non - toxic salt that , upon administration to a recipient , is capable of providing , either directly or indirectly , a compound or a prodrug of a compound of this invention . a “ pharmaceutically acceptable counterion ” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient . pharmaceutically compatible salts may be formed with many acids , including but not limited to hydrochloric , sulfuric , acetic , lactic , tartaric , malic , succinic , etc . salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms . acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide , hydrochloric , hydrobromic , hydroiodic , sulfuric and phosphoric acid , as well as organic acids such as para - toluenesulfonic , salicylic , tartaric , bitartaric , ascorbic , maleic , besylic , fumaric , gluconic , glucuronic , formic , glutamic , methanesulfonic , ethanesulfonic , benzenesulfonic , lactic , oxalic , para - bromophenylsulfonic , carbonic , succinic , citric , benzoic and acetic acid , and related inorganic and organic acids . such pharmaceutically acceptable salts thus include sulfate , pyrosulfate , bisulfate , sulfite , bisulfite , phosphate , monohydrogenphosphate , dihydrogenphosphate , metaphosphate , pyrophosphate , chloride , bromide , iodide , acetate , propionate , decanoate , caprylate , acrylate , formate , isobutyrate , caprate , heptanoate , propiolate , oxalate , malonate , succinate , suberate , sebacate , fumarate , maleate , butyne - 1 , 4 - dioate , hexyne - 1 , 6 - dioate , benzoate , chlorobenzoate , methylbenzoate , dinitrobenzoate , hydroxybenzoate , methoxybenzoate , phthalate , terephathalate , sulfonate , xylenesulfonate , phenylacetate , phenylpropionate , phenylbutyrate , citrate , lactate , . beta .- hydroxybutyrate , glycolate , maleate , tartrate , methanesulfonate , propanesulfonate , naphthalene - 1 - sulfonate , naphthalene - 2 - sulfonate , mandelate and the like salts . preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid , and especially those formed with organic acids such as maleic acid . suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include , but are not limited to , hydroxides of alkali metals such as sodium , potassium , and lithium ; hydroxides of alkaline earth metal such as calcium and magnesium ; hydroxides of other metals , such as aluminum and zinc ; ammonia , and organic amines , such as unsubstituted or hydroxy - substituted mono -, di -, or trialkylamines ; dicyclohexylamine ; tributyl amine ; pyridine ; n - methyl , n - ethylamine ; diethylamine ; triethylamine ; mono -, bis -, or tris -( 2 - hydroxy - lower alkyl amines ), such as mono -, bis -, or tris -( 2 - hydroxyethyl ) amine , 2 - hydroxy - tert - butylamine , or tris -( hydroxymethyl ) methylamine , n , n - di alkyl - n -( hydroxy alkyl )- amines , such as n , n - dimethyl - n -( 2 - hydroxyethyl ) amine , or tri -( 2 - hydroxyethyl ) amine ; n - methyl - d - glucamine ; and amino acids such as arginine , lysine , and the like . pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose . more specifically , a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated . determination of the effective amounts is well within the capability of those skilled in the art . one aspect of the invention relates to a method of treating cancer , tumors , malignancies , neoplasms , or other dysproliferative diseases , comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula i : provided that the sum of p and q is 2 , 3 , 4 , 5 , 6 , 7 or 8 ; and at least one instance of r is — opo 3 h 2 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 0 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 1 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 2 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 3 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 4 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 5 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 6 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 7 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein p is 8 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 0 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 1 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 2 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 3 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 4 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 5 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 6 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 7 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein q is 8 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein only one instance of r is — opo 3 h 2 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein only one instance of r is — opo 3 h 2 ; and all other instances of r are — h . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein one r 1 is and the remaining instances of r 1 , if any , and r 2 , if any , are in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein one r 2 is and the remaining instances of r 2 , if any , and r 1 , if any , are in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r 1 is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r 2 is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r 3 is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r 3 is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein w is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein w is — ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein x is o . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein y is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein y is — ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein m is 0 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is an antineoplastic agent . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is paclitaxel , doxorubicin , daunorubicin , vinblastine , vincristine , cisplatin or 5 - fluorouracil . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is r 2 ′ is — ph or — otbu ; and r 3 ′ is — h or — c (═ o ) ch 3 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is another aspect of the invention relates to a method of treating cancer , tumors , malignancies , neoplasms , or other dysproliferative diseases , comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula ii : in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein w is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein w is — ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein x is o . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein y is — ch 2 —, — ch 2 ch 2 —, — ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 —, — ch 2 ch 2 ch 2 ch 2 ch 2 — or — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein y is — ch 2 ch 2 —. in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein m is 0 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is an antineoplastic agent . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is paclitaxel , doxorubicin , daunorubicin , vinblastine , vincristine , cisplatin or 5 - fluorouracil . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein — c (═ o )— z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is r 2 ′ is — ph or — otbu ; and r 3 ′ is — h or — c (═ o ) ch 3 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein z is in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r is — opo 2 h 3 ; x is o ; and m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r is — opo 2 h 3 ; w is — ch 2 ch 2 ch 2 ch 2 —; x is o ; y is — ch 2 ch 2 —; and m is 1 . in certain embodiments , the present invention relates to any one of the aforementioned methods , wherein r is — opo 2 h 3 ; w is — ch 2 ch 2 ch 2 ch 2 —; x is o ; y is — ch 2 ch 2 —; m is 1 ; and z is examples of cancers , tumors , malignancies , neoplasms , and other dysproliferative diseases that can be treated according to the invention include leukemias , such as myeloid and lymphocytic leukemias , lymphomas , myeloproliferative diseases , and solid tumors , such as but not limited to sarcomas and carcinomas such as fibrosarcoma , myxosarcoma , liposarcoma , chondrosarcoma , osteogenic sarcoma , chordoma , angiosarcoma , endotheliosarcoma , lymphangiosarcoma , lymphangioendotheliosarcoma , synovioma , mesothelioma , ewing &# 39 ; s tumor , leiomyosarcoma , rhabdomyosarcoma , colon carcinoma , pancreatic cancer , breast cancer , ovarian cancer , prostate cancer , squamous cell carcinoma , basal cell carcinoma , adenocarcinoma , sweat gland carcinoma , sebaceous gland carcinoma , papillary carcinoma , papillary adenocarcinomas , cystadenocarcinoma , medullary carcinoma , bronchogenic carcinoma , renal cell carcinoma , hepatoma , bile duct carcinoma , choriocarcinoma , seminoma , embryonal carcinoma , wilms &# 39 ; tumor , cervical cancer , testicular tumor , lung carcinoma , small cell lung carcinoma , bladder carcinoma , epithelial carcinoma , glioma , astrocytoma , medulloblastoma , craniopharyngioma , ependymoma , pinealoma , hemangioblastoma , acoustic neuroma , oligodendroglioma , meningioma , melanoma , neuroblastoma , and retinoblastoma . the systemic delivery of anticancer agents has been widely investigated but localized delivery may offer a safer and more effective delivery approach . the supramolecular hydrogels described above can be used to locally deliver antineoplastic agents . one aspect of the invention relates to a method of treating cancer , tumors , malignancies , neoplasms , or other dysproliferative diseases by administering to a patient in need thereof any one of the aforementioned supramolecular hydrogels . in one embodiment , the present invention relates to the use of any one of the aforementioned compounds , supramolecular hydrogels , or pharmaceutical compositions , or pharmaceutically acceptable salts or solvates of any of them , in the manufacture of a medicament for the treatment of cancers , tumors , malignancies , neoplasms , or other dysproliferative diseases . examples of cancers , tumors , malignancies , neoplasms , and other dysproliferative diseases that can be treated according to the invention include leukemias , such as myeloid and lymphocytic leukemias , lymphomas , myeloproliferative diseases , and solid tumors , such as but not limited to sarcomas and carcinomas such as fibrosarcoma , myxosarcoma , liposarcoma , chondrosarcoma , osteogenic sarcoma , chordoma , angiosarcoma , endotheliosarcoma , lymphangiosarcoma , lymphangioendotheliosarcoma , synovioma , mesothelioma , ewing &# 39 ; s tumor , leiomyosarcoma , rhabdomyosarcoma , colon carcinoma , pancreatic cancer , breast cancer , ovarian cancer , prostate cancer , squamous cell carcinoma , basal cell carcinoma , adenocarcinoma , sweat gland carcinoma , sebaceous gland carcinoma , papillary carcinoma , papillary adenocarcinomas , cystadenocarcinoma , medullary carcinoma , bronchogenic carcinoma , renal cell carcinoma , hepatoma , bile duct carcinoma , choriocarcinoma , seminoma , embryonal carcinoma , wilms &# 39 ; tumor , cervical cancer , testicular tumor , lung carcinoma , small cell lung carcinoma , bladder carcinoma , epithelial carcinoma , glioma , astrocytoma , medulloblastoma , craniopharyngioma , ependymoma , pinealoma , hemangioblastoma , acoustic neuroma , oligodendroglioma , meningioma , melanoma , neuroblastoma , and retinoblastoma . in one aspect of the invention , a compound of the invention , or a pharmaceutically acceptable salt thereof , can be used alone or in combination with another therapeutic agent to treat diseases such as cancer . it should be understood that the compounds of the invention can be used alone or in combination with an additional agent , e . g ., a therapeutic agent , said additional agent being selected by the skilled artisan for its intended purpose . for example , the additional agent can be a therapeutic agent that is art - recognized as being useful to treat the disease or condition being treated by the compound of the present invention . the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e . g ., an agent that affects the viscosity of the composition . the combination therapy contemplated by the invention includes , for example , administration of a compound of the invention , or a pharmaceutically acceptable salt thereof , and additional agent ( s ) in a single pharmaceutical formulation as well as administration of a compound of the invention , or a pharmaceutically acceptable salt thereof , and additional agent ( s ) in separate pharmaceutical formulations . in other words , co - administration shall mean the administration of at least two agents to a subject so as to provide the beneficial effects of the combination of both agents . for example , the agents may be administered simultaneously or sequentially over a period of time . it should further be understood that the combinations included within the invention are those combinations useful for their intended purpose . the combination can also include more than one additional agent , e . g ., two or three additional agents if the combination is such that the formed composition can perform its intended function . as used herein , a “ therapeutically effective amount ” or “ therapeutically effective dose ” is an amount of a compound of the invention or a combination of two or more such compounds , which inhibits , totally or partially , the progression of the condition or alleviates , at least partially , one or more symptoms of the condition . a therapeutically effective amount can also be an amount which is prophylactically effective . the amount which is therapeutically effective will depend upon the patient &# 39 ; s size and gender , the condition to be treated , the severity of the condition and the result sought . for a given patient , a therapeutically effective amount can be determined by methods known to those of skill in the art . for any compound used in a method of the present invention , the therapeutically effective dose can be estimated initially from cellular assays . for example , a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the ic 50 as determined in cellular assays ( i . e ., the concentration of the test compound which achieves a half - maximal inhibition ). in some cases it is appropriate to determine the ic 50 in the presence of 3 to 5 % serum albumin since such a determination approximates the binding effects of plasma protein on the compound . such information can be used to more accurately determine useful doses in humans . a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient . toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals , e . g ., for determining the maximum tolerated dose ( mtd ) and the ed 50 ( effective dose for 50 % maximal response ). the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between mtd and ed 50 . the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans . the dosage of such compounds lies preferably within a range of circulating concentrations that include the ed 50 with little or no toxicity . the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized . the exact formulation , route of administration and dosage can be chosen by the individual physician in view of the patient &# 39 ; s condition . ( see e . g ., fingl et al ., 1975 , in “ the pharmacological basis of therapeutics ”, ch . 1 p 1 ). in the treatment of crises , the administration of an acute bolus or an infusion approaching the mtd may be required to obtain a rapid response . dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects , or minimal effective concentration ( mec ). the mec will vary for each compound but can be estimated from in vitro data . dosages necessary to achieve the mec will depend on individual characteristics and route of administration . however , hplc assays or bioassays can be used to determine plasma concentrations . dosage intervals can also be determined using the mec value . compounds should be administered using a regimen which maintains plasma levels above the mec for 10 - 90 % of the time , preferably between 30 - 90 % and most preferably between 50 - 90 % until the desired amelioration of symptoms is achieved . in cases of local administration or selective uptake , the effective local concentration of the drug may not be related to plasma concentration . the amount of composition administered will , of course , be dependent on the subject being treated , on the subject &# 39 ; s weight , the severity of the affliction , the manner of administration and the judgment of the prescribing physician . the compositions may , if desired , be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient . the pack may for example comprise metal or plastic foil , such as a blister pack . the pack or dispenser device may be accompanied by instructions for administration . compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared , placed in an appropriate container , and labeled for treatment of an indicated condition . all definitions , as defined and used herein , should be understood to control over dictionary definitions , definitions in documents incorporated by reference , and / or ordinary meanings of the defined terms . the indefinite articles “ a ” and “ an ,” as used herein in the specification and in the claims , unless clearly indicated to the contrary , should be understood to mean “ at least one .” the phrase “ and / or ,” as used herein in the specification and in the claims , should be understood to mean “ either or both ” of the elements so conjoined , i . e ., elements that are conjunctively present in some cases and disjunctively present in other cases . multiple elements listed with “ and / or ” should be construed in the same fashion , i . e ., “ one or more ” of the elements so conjoined . other elements may optionally be present other than the elements specifically identified by the “ and / or ” clause , whether related or unrelated to those elements specifically identified . thus , as a non - limiting example , a reference to “ a and / or b ”, when used in conjunction with open - ended language such as “ comprising ” can refer , in one embodiment , to a only ( optionally including elements other than b ); in another embodiment , to b only ( optionally including elements other than a ); in yet another embodiment , to both a and b ( optionally including other elements ); etc . as used herein in the specification and in the claims , “ or ” should be understood to have the same meaning as “ and / or ” as defined above . for example , when separating items in a list , “ or ” or “ and / or ” shall be interpreted as being inclusive , i . e ., the inclusion of at least one , but also including more than one , of a number or list of elements , and , optionally , additional unlisted items . only terms clearly indicated to the contrary , such as “ only one of ” or “ exactly one of ,” or , when used in the claims , “ consisting of ,” will refer to the inclusion of exactly one element of a number or list of elements . in general , the term “ or ” as used herein shall only be interpreted as indicating exclusive alternatives ( i . e ., “ one or the other but not both ”) when preceded by terms of exclusivity , such as “ either ,” “ one of ,” “ only one of ,” or “ exactly one of ” “ consisting essentially of ,” when used in the claims , shall have its ordinary meaning as used in the field of patent law . as used herein in the specification and in the claims , the phrase “ at least one ,” in reference to a list of one or more elements , should be understood to mean at least one element selected from any one or more of the elements in the list of elements , but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements . this definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “ at least one ” refers , whether related or unrelated to those elements specifically identified . thus , as a non - limiting example , “ at least one of a and b ” ( or , equivalently , “ at least one of a or b ,” or , equivalently “ at least one of a and / or b ”) can refer , in one embodiment , to at least one , optionally including more than one , a , with no b present ( and optionally including elements other than b ); in another embodiment , to at least one , optionally including more than one , b , with no a present ( and optionally including elements other than a ); in yet another embodiment , to at least one , optionally including more than one , a , and at least one , optionally including more than one , b ( and optionally including other elements ); etc . it should also be understood that , unless clearly indicated to the contrary , in any methods claimed herein that include more than one step or act , the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited . in the claims , as well as in the specification above , all transitional phrases such as “ comprising ,” “ including ,” “ carrying ,” “ having ,” “ containing ,” “ involving ,” “ holding ,” “ composed of ,” and the like are to be understood to be open - ended , i . e ., to mean including but not limited to . only the transitional phrases “ consisting of ” and “ consisting essentially of ” shall be closed or semi - closed transitional phrases , respectively , as set forth in the united states patent office manual of patent examining procedures . for purposes of this invention , the chemical elements are identified in accordance with the periodic table of the elements , cas version , handbook of chemistry and physics , 67th ed ., 1986 - 87 , inside cover . the term “ amino acid ” is intended to embrace all compounds , whether natural or synthetic , which include both an amino functionality and an acid functionality , including amino acid analogues and derivatives . in certain embodiments , the amino acids contemplated in the present invention are those naturally occurring amino acids found in proteins , or the naturally occurring anabolic or catabolic products of such amino acids , which contain amino and carboxyl groups . naturally occurring amino acids are identified throughout by the conventional three - letter and / or one - letter abbreviations , corresponding to the trivial name of the amino acid , in accordance with the following list : alanine ( ala ), arginine ( arg ), asparagine ( asn ), aspartic acid ( asp ), cysteine ( cys ), glutamic acid ( glu ), glutamine ( gln ), glycine ( gly ), histidine ( his ), isoleucine ( ile ), leucine ( leu ), lysine ( lys ), methionine ( met ), phenylalanine ( phe ), proline ( pro ), serine ( ser ), threonine ( thr ), tryptophan ( trp ), tyrosine ( tyr ), and valine ( val ). the abbreviations are accepted in the peptide art and are recommended by the iupac - iub commission in biochemical nomenclature . for example , the abbreviation “ napffkyp ” refers to the following compound : the term “ amino acid ” further includes analogues , derivatives , and congeners of any specific amino acid referred to herein , as well as c - terminal or n - terminal protected amino acid derivatives ( e . g ., modified with an n - terminal or c - terminal protecting group ). the term “ gelling ” or “ gelation ” means a thickening of the medium that may result in a gelatinous consistency and even in a solid , rigid consistency that does not flow under its own weight . a “ gelator ” is defined herein to include a non - polymeric organic compound whose molecules can establish , between themselves , at least one physical interaction leading to a self - assembly of the molecules in a carrier fluid to form a gel . the gel may result from the formation of a network of molecular nanofibers due to the stacking or aggregation of gelator molecules . a “ molecular nanofiber ” is defined as a fiber with a diameter on the order of about 100 nanometers , or about 10 nanometers , or about 1 nanometer . a “ small molecule ” refers to a molecule which has a molecular weight of less than about 5000 amu , or less than 2000 amu , or less than about 1000 amu , and less than about 500 amu . a “ bioactive small molecule ” refers to a small molecule that has a biological activity ( e . g . clinically used drugs ). “ treating ” is used herein to refer to any treatment of , or prevention of , or inhibition of a disorder or disease in a subject and includes by way of example : ( a ) preventing the disease or disorder from occurring in a subject that may be predisposed to the disease or disorder , but has not yet been diagnosed as having it ; ( b ) inhibiting the disease or disorder , i . e ., arresting its progression ; or ( c ) relieving or ameliorating the disease or disorder , i . e ., causing regression . the term “ alkyl ” means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms . representative examples of alkyl include , but are not limited to , methyl , ethyl , n - propyl , iso - propyl , n - butyl , sec - butyl , iso - butyl , tert - butyl , n - pentyl , isopentyl , neopentyl , and n - hexyl . the term “ alkylene ” pertains to a bidentate ( diradical ) moiety obtained by removing two hydrogen atoms , either both from the same carbon atom , or one from each of two different carbon atoms , of a hydrocarbon compound , which may be aliphatic or alicyclic , or a combination thereof , and which may be saturated , partially unsaturated , or fully unsaturated . examples of linear saturated c 1 - 10 alkylene groups include , but are not limited to , —( ch 2 ) n — where n is an integer from 1 to 10 , for example , — ch 2 — ( methylene ), — ch 2 ch 2 — ( ethylene ), — ch 2 ch 2 ch 2 — ( propylene ), — ch 2 ch 2 ch 2 ch 2 — ( butylene ), — ch 2 ch 2 ch 2 ch 2 ch 2 — ( pentylene ) and — ch 2 ch 2 ch 2 ch 2 ch 2 ch 2 — ( hexylene ). examples of branched saturated c 1 - 10 alkylene groups include , but are not limited to , — ch ( ch 3 )—, — ch ( ch 3 ) ch 2 —, — ch ( ch 3 ) ch 2 ch 2 —, — ch ( ch 3 ) ch 2 ch 2 ch 2 —, — ch 2 ch ( ch 3 ) ch 2 —, — ch 2 ch ( ch 3 ) ch 2 ch 2 —, — ch ( ch 2 ch 3 )—, — ch ( ch 2 ch 3 ) ch 2 —, and — ch 2 ch ( ch 2 ch 3 ) ch 2 —. examples of linear partially unsaturated c 1 - 10 alkylene groups include , but are not limited to , — ch ═ ch — ( vinylene ), — ch ═ ch — ch 2 —, — ch ═ ch — ch 2 — ch 2 —, — ch ═ ch — ch 2 — ch 2 — ch 2 —, — ch ═ ch — ch ═ ch —, — ch ═ ch — ch ═ ch — ch 2 —, — ch ═ ch — ch ═ ch — ch 2 — ch 2 —, — ch ═ ch — ch 2 — ch ═ ch —, and — ch ═ ch — ch 2 — ch 2 — ch ═ ch —. examples of branched partially unsaturated c 1 - 10 alkylene groups include , but are not limited to , — c ( ch 3 )═ ch —, — c ( ch 3 )═ ch — ch 2 —, and — ch ═ ch — ch ( ch 3 )—. examples of alicyclic saturated c 1 - 10 alkylene groups include , but are not limited to , cyclopentylene ( e . g ., cyclopent - 1 , 3 - ylene ), and cyclohexylene ( e . g ., cyclohex - 1 , 4 - ylene ). examples of alicyclic partially unsaturated c 1 - 10 alkylene groups include , but are not limited to , cyclopentenylene ( e . g ., 4 - cyclopenten - 1 , 3 - ylene ), and cyclohexenylene ( e . g ., 2 - cyclohexen - 1 , 4 - ylene , 3 - cyclohexen - 1 , 2 - ylene , and 2 , 5 - cyclohexadien - 1 , 4 - ylene ). the term “ aryl ,” as used herein , means a phenyl group or a naphthyl group . the aryl groups of the present invention can be optionally substituted with one , two , three , four , or five substituents independently selected from the group consisting of alkenyl , alkoxy , alkoxycarbonyl , alkoxysulfonyl , alkyl , alkylcarbonyl , alkylcarbonyloxy , alkylsulfonyl , alkylthio , alkynyl , amido , amino , carboxy , cyano , formyl , halo , haloalkoxy , haloalkyl , hydroxyl , hydroxyalkyl , mercapto , nitro , silyl and silyloxy . the term “ arylalkyl ” or “ aralkyl ” as used herein , means an aryl group , as defined herein , appended to the parent molecular moiety through an alkyl group , as defined herein . representative examples of arylalkyl include , but are not limited to , benzyl , 2 - phenylethyl , 3 - phenylpropyl , and 2 - naphth - 2 - ylethyl . the term “ heteroaryl ” as used herein , include aromatic ring systems , including , but not limited to , monocyclic , bicyclic and tricyclic rings , and have 3 to 12 atoms including at least one heteroatom , such as nitrogen , oxygen , or sulfur . for purposes of exemplification , which should not be construed as limiting the scope of this invention : azaindolyl , benzo ( b ) thienyl , benzimidazolyl , benzofuranyl , benzoxazolyl , benzothiazolyl , benzothiadiazolyl , benzotriazolyl , benzoxadiazolyl , furanyl , imidazolyl , imidazopyridinyl , indolyl , indolinyl , indazolyl , isoindolinyl , isoxazolyl , isothiazolyl , isoquinolinyl , oxadiazolyl , oxazolyl , purinyl , pyranyl , pyrazinyl , pyrazolyl , pyridinyl , pyrimidinyl , pyrrolyl , pyrrolo [ 2 , 3 - d ] pyrimidinyl , pyrazolo [ 3 , 4 - d ] pyrimidinyl , quinolinyl , quinazolinyl , triazolyl , thiazolyl , thiophenyl , tetrahydroindolyl , tetrazolyl , thiadiazolyl , thienyl , thiomorpholinyl , triazolyl or tropanyl . the heteroaryl groups of the invention are substituted with 0 , 1 , 2 , or 3 substituents independently selected from alkenyl , alkoxy , alkoxycarbonyl , alkoxysulfonyl , alkyl , alkylcarbonyl , alkylcarbonyloxy , alkylsulfonyl , alkylthio , alkynyl , amido , amino , carboxy , cyano , formyl , halo , haloalkoxy , haloalkyl , hydroxyl , hydroxyalkyl , mercapto , nitro , silyl and silyloxy . the term “ heteroarylalkyl ” or “ heteroaralkyl ” as used herein , means a heteroaryl , as defined herein , appended to the parent molecular moiety through an alkyl group , as defined herein . representative examples of heteroarylalkyl include , but are not limited to , pyridin - 3 - ylmethyl and 2 -( thien - 2 - yl ) ethyl . the invention will be more readily understood by reference to the following examples , which are included merely for purposes of illustration of certain aspects and embodiments of the present invention , and are not intended to limit the invention . [ a ] synthesis of 2 : paclitaxel ( 1 , 170 . 6 mg , 0 . 2 mmol ) was added to succinic anhydride ( 70 mg , 0 . 7 mmol ) in the presence of 4 - dimethylamino - pyridine ( 41 mg , 0 . 33 mmol ) which was previously dried under vacuum for 2 h . then , 5 ml of dry pyridine were added and the solution was stirred for 3 h at room temperature . dosio , f . ; brusa , p . ; crosasso , p . ; arpicco , s . ; cattel , l . j . control . rel . 1997 , 47 , 293 - 304 . the 2 ′- succinyl - paclitaxel ( 2 ) was purified by extraction according to following procedure : after 20 ml of dry dichloromethane ( dcm ) were added into the reaction mixture , the organic phase was washed using 1 m hcl solution ( 20 ml × 3 ) and water ( 20 ml × 3 ). water phase was extracted by dcm ( 10 ml × 3 ). the organic phase was combined and washed by brine ( 10 ml × 3 ) and dried over na 2 so 4 . the filtrate was concentrated on rotary evaporator and the crude product was used without further purification . [ b ] synthesis of 3 : compound 2 ( 190 . 6 mg , 0 . 2 mmol ) was mixed with n - hydroxysuccinimide ( 23 . 0 mg , 0 . 2 mmol ); then , 10 ml of chcl 3 were added to obtain a well - dispersed solution . after n , n ′- dicylcohexylcarbodiimide ( 41 . 2 mg , 0 . 2 mmol ) was added into the mixture , the solution was stirred for 4 h at room temperature . the 2 ′- nhs - succinyl - paclitaxel ( 3 ) was purified by chromatography with chloroform - methanol as the eluent ( 19 : 1 ). [ c ] synthesis of 5a : compound 4 ( 48 . 6 mg , 0 . 057 mmol ) was dissolved in 5 ml of water , and the ph of the solution was adjusted to 8 . 5 with sodium carbonate . compound 3 ( 50 mg , 0 . 0476 mmol ) was dissolved in 3 ml of acetone , and then added into the water solution dropwise . the ratio of water / acetone was adjusted to keep the reaction mixture clear . the mixture was stirred at room temperature for 12 h . the reaction mixture was subjected to hplc purification . compound 5a was purified with water - methanol eluent ( from 7 : 3 to 1 : 9 ). the experimental procedure used to determine drug release was as follows . to the solution of 0 . 25 ml of water containing 2 mg of 5a at ph of about 7 . 3 , alkaline phosphatase ( 5 u , 1 μl ) was added to form the sample ‘ gel 5b ’ in fig3 b . 0 . 25 ml of fresh pbs buffer solution ( 100 mm ) were added onto the top of the gel . at the end of every hour , the pbs buffer was taken out for analysis , and another 0 . 25 - ml aliquot of fresh pbs buffer ( 100 mm ) was added onto the top of the hydrogel . to the solution of 0 . 5 ml of water containing 3 mg of 4 and 3 mg of 5a at ph = 7 . 3 , alkaline phosphatase ( 5 u , 1 μl ) was added to form the sample ‘ mixed gel ’ in fig3 b . 0 . 5 ml of fresh pbs buffer solution ( 100 mm ) were added onto the top of the gel . at the end of every hour , the pbs buffer was taken out for analysis , and another 0 . 5 - ml aliquot of fresh pbs buffer ( 100 mm ) was added onto the hydrogels . the samples of the pbs solutions that were taken out by hplc were analyzed , and table 1 ( below ) shows the result of the analysis . ( the integration of 0 . 56 mg of 5b ( standard ) is 20761595 μv * sec . the detection wavelength is 220 nm .) the data suggest that the release of 5b was almost linear at a rate of 0 . 05 %/ hr in ‘ gel 5b ’ and 0 . 016 %/ hr in ‘ mixed gel ’. fig4 depicts the cytotoxicity of 4 against hela cells ; fig5 depicts the cytotoxicity test of ( a ) 1 , ( b ) 5a and ( c ) 5b against hela cells . the ic 50 of 4 ( at 48 h ) is higher than the highest concentration ( 500 μm ) tested . the result shows that 4 has very limited toxicity . all of the u . s . patents and u . s . patent application publications cited herein are hereby incorporated by reference . those skilled in the art will recognize , or be able to ascertain using no more than routine experimentation , many equivalents to the specific embodiments of the invention described herein . such equivalents are intended to be encompassed by this disclosure .

disclosed is a general methodology to create nano fibers of therapeutic molecules that have a dual role , as both the delivery vehicle and the drug itself . it is shown that with proper molecular design , the integration of enzymatic reaction and self - assembly provides a powerful method to create molecular hydrogels of clinically - used therapeutics without compromising their bioactivities . in addition , the results disclosed herein demonstrate enzyme - instructed self - assembly as a facile strategy for generating the supramolecular hydrogels of molecules that inherently have poor solubility in water . for example , by covalently connecting paclitaxel with a motif that is prone to self - assemble , a hydrogel of paclitaxel can be formed without compromising the activity of the paclitaxel .

the present invention describes animal and human dietary food supplement compositions and methods for preparing the compositions . preparation of the supplement using the methods of the invention minimizes chemical changes in chemically reactive molecules , particularly in the unsaturated carbon - carbon double bonds of hydrocarbon chains in fatty acids of plant and / or animal constituents . the components of the food supplement compositions of the present invention for humans and animals consist of about 10 major ingredients , which will be termed &# 34 ; macro ingredients &# 34 ;, and about nine minor ingredients , which will be termed &# 34 ; micro ingredients &# 34 ;. these macro and micro ingredients are combined in different combinations to produce supplements for humans , dogs , cats , horses , rodents , ferrets , fox , mink , rabbits , hamsters , gerbils , reptiles , birds and pocket pets . pocket pets include , but are not limited to , mice , rats , and guinea pigs . the various supplements contain different percentages by weight of the ingredients , and some contain ingredients that are not included in other supplements . for example , vegetarian supplements do not include ingredients of animal origins . ( 1 ) a seed product selected from the group consisting of flax , hemp , buckwheat , sunflower and sesame , and mixtures thereof ; ( 2 ) a coating selected from the group consisting of viscous liquids or spray - dried viscous liquids such as molasses , honey , glycerin , other viscous liquids and mixtures thereof ; ( 5 ) other nutrients deemed essential for the specific application under consideration ; and ( 6 ) equisetum or other herbs deemed beneficial to the application under consideration . all ingredients are of a quality which is fit for human consumption . the coating materials are molasses , honey , glycerin , other suitable viscous liquid or combinations thereof . in a preferred embodiment the viscous liquid coating is spray - dried and added to the other components in the dry , rather than the liquid , form . these coating liquids inhibit reactions of desirable molecules , in the food , resulting from exposure to light and / or oxygen . the coating aids in the preservation of naturally occurring antioxidants found in the supplement components . the natural antioxidant include tocopherols , carotenes , quinones , sterols , terpenes , bioflavonoids , polyphenols , polycyclic anthraquinones and antioxidant pigments and are in the components of the supplements . prooxidant metals are also excluded from the supplements to minimize oxidation of the components of the supplement . the percentage by weight of the macro ingredients is best defined by considering the seeds , coating material and remaining ingredients separately . grains and seeds typically comprise 30 % to 90 %, preferably 60 % to 80 %, and most preferably 70 % to 75 % of a particular supplement blended for a human or specific animal . unless other wise stated all percentages used are by weight . the coating material ( molasses , honey , or glycerine , liquid or spray dried ) typically comprises 3 % to 16 %, preferably 6 % to 12 %, and most preferably 7 % to 10 % of a particular supplement blended for a human or specific animal . the &# 34 ; remaining ingredients &# 34 ; typically comprise 7 % to 38 %, preferably 15 % to 25 %, but most preferably 18 % to 22 %, depending on the specific animal or human for which the supplement is intended , and on palatability considerations . rice bran , yeast and liver typically comprise the larger percentages of the &# 34 ; remaining ingredients &# 34 ;, preferably 8 % to 18 %, but most preferably between 14 % and 16 %. alfalfa , carrot , apple , bone meal , and fish meal typically comprise 1 % to 12 %, preferably 2 % to 7 %, but most preferable between 4 % and 6 %, depending on if the supplement is formulated for a human or a specific animal and on palatability considerations . formulations can vary greatly , depending on the species . effective , and palatable , examples of supplements for dogs , cats , horses , foxes / minks , rabbits and humans are shown in table i . table i__________________________________________________________________________typical formulations for some animals and humansingredientdog cat horse fox / mink rabbit human__________________________________________________________________________macroflax 71 %. sup . 1 / 73 . sup . 2 71 %/ 73 % 71 %/ 73 % 71 %/ 73 % 71 %/ 73 % 71 %/ 73 % molasses9 . 5 %/ 7 . 5 % 9 . 5 %/ 7 . 5 % 9 . 5 %/ 7 . 5 % 9 . 5 % 17 .% 9 . 5 %/ 7 . 5 % 9 . 5 %/ 7 . 5 % yeast5 % 5 % 4 % 5 % 5 % 5 % rice / bran5 % 5 % 6 % 5 % 6 % 6 % liver4 % 4 % 1 % 4 % 1 % 2 % alfalfa2 % 2 % 3 . 5 % 2 % 3 . 5 % 2 % bone 1 . 5 % 1 % 0 . 5 % 1 % 0 . 5 % 1 % carrot1 % 1 % 2 . 5 % 1 % 2 . 5 % 2 % fish meal0 . 5 % 1 % 0 % 0 . 10 % 0 % 0 % apple0 % 0 % 1 . 5 % 0 % 0 . 5 % 2 % microoyster0 . 1 % 0 . 2 % 0 % 0 . 1 % 0 % 0 % kelp 0 . 1 % 0 . 15 % 0 . 02 % 0 . 1 % 0 . 2 % 0 . 07 % lecithin0 . 05 % 0 . 05 % 0 . 03 % 0 . 03 % 0 . 03 % 0 . 01 % garlic0 . 01 % 0 . 01 % 0 . 01 % 0 . 01 % 0 . 01 % 0 . 01 % taurine0 % 0 . 05 % 0 % 0 . 02 % 0 % 0 . 02 % equisetum0 % 0 % 0 % 0 % 0 % 0 . 01 % herbcarnitine0 % 0 % 0 % 0 % 0 % 0 . 01 % __________________________________________________________________________ . sup . 1 percent by weight . sup . 2 liquid / dry the micro ingredients typically comprise from 0 . 2 % to 4 % of a particular supplement , primarily depending on the type of animal . preferably , these ingredients to comprise 0 . 5 % to 2 . 5 % and most preferably 1 % to 2 % of a particular supplement . the amount of each specific micro ingredient is strongly related to the animal type . for example , fish and oyster are not usually part of the horse supplement and kelp is higher in the cat supplement than either dog or , particularly , horse supplement . table i also shows examples of most preferable combinations of the micro ingredients . in order that the invention described herein may be more fully understood , the following examples are set forth as illustrations of the invention . it should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the scope of this invention in any manner . the method of this example involves the use of coating liquids ( molasses , honey , glycerin , or other comparable liquids ). according to this method , the grains and seed are first reduced in size by grinding . the grinding process is most preferably done under dark room conditions . all other ingredients are weighed out prior to the grinding step . this is done to keep the time from grinding to packaging and sealing to a minimum . suitable methods of grinding can be determined by those skilled in the art , but , by way of example , include roller mill or similar grinder or cutter equipment . it should be noted that most preferably the temperature during size reduction should not exceed 100 ° f . ( 37 . 8 ° c .). typically , the grains and seeds are ground to an extent that results in 5 % to 35 % of a representative sample passing through a # 30 u . s . standard screen . preferably , the amount passing through the # 30 screen is 8 % to 25 %, and most preferably 10 % to 20 %. examples of screen analysis for size reduction are shown in table ii . table ii__________________________________________________________________________test 1ground through a coffee bean plate - type test 2grinder ground in a rollermillstandard gauge % passing through standard gauge % passing throughsize screen size screen__________________________________________________________________________ + 10 u . s . 0 . 7 % + 10 u . s . 3 . 3 %+ 16 u . s . 46 . 4 % + 16 u . s . 52 . 5 %+ 20 u . s . 23 . 2 % + 20 u . s . 24 . 2 %+ 30 u . s . 10 . 2 % + 30 u . s . 9 . 2 %- 30 u . s . 19 . 6 % - 30 u . s . 10 . 8 % __________________________________________________________________________ the next step in example 1 is a mixing process . the ground grains and seeds are immediately transferred to the bowl of a mixer , such as a hobart mixer ( other types of mixers are also suitable ). most preferably , the coating liquid is added and allowed to blend with the ground seed until the particles are coated ( about 1 to 2 minutes ). the premixed macro ingredients and micro ingredients are then added . these are first prepared by blending the micro ingredients with an appropriate blender , such as a crossley economy mdl ee type blender with intensifier bar . the blended micro ingredients are then combined with the macro ingredients using , for example , a hobart mixer or a &# 34 ; v &# 34 ; type blender . with all ingredients combined with the coated grain component in the mixer , a blending period of 10 minutes is typically used , but more preferably 8 minutes and most preferably 5 minutes . the thoroughly blended supplement is transferred to an automatic weigher / filler , such as an all fill type machine that dispenses the desired amount of product into the package . the above details of this example 1 are in the way of an example of a batch type process . other equipment and equipment combinations , such as continuous processing , can readily be determined by those skilled in the art of process and production engineering . this method of preparing the present invention , including packaging and sealing in opaque , oxygen impermeable containers typically is accomplished in 16 to 20 minutes , but preferably in 12 to 16 minutes , and most preferably in 8 to 12 minutes , under dark room conditions and with no stage of the process raising the temperature above 100 ° f . ( 37 . 8 ° c .). while not wanting to be bound by any particular explanation , it is believed that the preparation of the food supplement of the present invention by this method results unexpectedly in general and specific improvements in human and in animal health due to preservation of the component ingredients in their natural state by the action of : 1 ) the coating of the ingredient particles with the appropriate liquid ( molasses , honey , or glycerin ); 5 ) the minimizing of the time lapsed between size reduction and sealing in an opaque , oxygen barrier container ; 8 ) the presence of the antioxidant properties of other fiber ingredients included in the formulation ( for example , rice bran ). this method of producing this present invention requires the use of a high speed cutting process using the &# 34 ; comminutor &# 34 ; principle of size reduction / blending of the ingredients . more particularly , this method incorporates the unique concept of simultaneous size reduction and intimate blending of the premixed supplement ingredients , including whole , unground grains and seeds and powdered ( dry ) additional ingredients , using an arrangement of equipment to rapidly move the ingredients into opaque , oxygen barrier packaging in under 5 minutes , most preferably in under 2 minutes . specifically , the concept of , and the equipment for , accomplishing a one step process of premixed ingredients through a high speed size reduction / blending and thence directly into opaque , oxygen barrier packaging is unique . the premix of all the formula ingredients including the whole , unground oil seed , with the use of powdered forms of molasses , honey or glycerin , allows for staged and inventoried material . this material is stable until further processing and is ready , in the quantities desired , for the comminutor process . the high speed , simultaneous size reduction and intimate blending releases the natural oils , essential fatty acids and naturally occurring antioxidants which then coat the other ingredients . this gives the supplement formulation an effective temporary stabilization against oxidation and free radical chemical reactions . the addition of special packaging and handling of the product when opened extends the period of stabilization for at lease 90 days from the date of production . the process was developed in cooperation with urschel laboratories , inc ., using their comitrol processor model 1700 . research in cooperation with urschel in which the concept of this present invention of using the proper combination of impellers , cutterhead design , cutterhead knife spacing and machine &# 34 ; rpm &# 34 ; to simultaneously and intimately reduce in size and blend the formula ingredients is unique . the ability to produce a dry product by this method was a surprising and expected result as it was expected that the dry products would : plug or jam the machine ; raise the processing temperature above 100 ° f . ( 37 . 8 ° c . ); not be accomplished at satisfactory &# 34 ; production &# 34 ; rates ; or leave grains and seeds uncut or unsatisfactorily cut and poorly blended with the other ingredients . urschel equipment is size reduction equipment , not thought to be used in a simultaneous size reduction / blending process at low temperatures ( under 100 ° f . ; 37 . 8 ° c .). preferably , the urschel 1700 comitrol processor is fitted with a 15 to 45 horsepower motor , either a 30 blade impeller or straight impeller , a type &# 34 ; b &# 34 ;, three inch high slicing head or cutting head with 0 . 010 thousandths of an inch horizontal thickness of separators , and 0 . 010 to 0 . 080 thousandths of an inch opening between horizontal separators , operating at 2 , 200 to 6 , 000 rpms . more preferably , the urschel model 1700 comitrol processor is fitted with a 30 horsepower motor , straight impeller , a type &# 34 ; b &# 34 ;, 3 inch high cutting head with 0 . 010 thousandths of an inch horizontal thickness of separators , and 0 . 020 to 0 . 060 thousandths of an inch opening between horizontal separators , operating between 2 , 500 and 5 , 800 rpm &# 39 ; s . most preferably , the urschel 1700 comitrol processor is fitted with a 30 horsepower motor , straight impeller , type &# 34 ; b &# 34 ;, 3 inch high cutting head with 0 . 010 thousandths of an inch thickness of separators , and 0 . 040 thousandths of an inch opening between horizontal separators , operating between 3 , 600 and 5 , 650 rpm &# 39 ; s . the steps in this method , then , are mixing of all ingredients , including a spray - dried form of blackstrap molasses and whole , unground grains and seeds , in a &# 34 ; v &# 34 ; blender of a size appropriate for the production capacity desired . this mixing process only requires that a thorough blending of the ingredients take place and can be accomplished in a variety of mixer or blender types familiar to those skilled in the art of blending equipment . this premix of ingredients is ready for the comitrol processor and can be inventoried ( stored or staged ) in mini bulk bags , barrels , or other suitable containers until said processing step is initiated . operating production rates for the comitrol process are between 2 , 000 and 3 , 000 pounds per hour depending on the rpm selected and how fine a grind is desired . typically , a coarser blend is produced at 3 , 600 rpm and production feed rates of 2 , 000 pounds per hour ( see a , table iii ). most preferably , a finer blend is produced at 5 , 634 rpm and production feed rates of 2 , 700 pounds per hour ( see b , table iii ). table iii__________________________________________________________________________test a test b3 , 600 rpm , 2 , 000 lb / hr . 5 , 634 rpm , 2 , 700 lb / hr . standard gauge % passing through standard gauge % passing throughsize screen size screen__________________________________________________________________________ + 10 trace + 10 0 %+ 16 9 % + 16 4 %+ 20 22 % + 20 17 %+ 30 19 % + 30 19 %- 30 50 % - 30 60 % __________________________________________________________________________ other equipment that uses the &# 34 ; comminutor &# 34 ; principle of size reduction may be appropriate to accomplish the results found using the urshel model 1700 . for example , the model 194 or 197 comitrol made by quadro engineering , with proper impellers and cutting screens . the quadro equipment is preferred for small production rates . once the material exits the size reduction / blending step , it is directed into automatic weigher / dispenser machines ( such as all fill automatic weigher / dispensers ). a special component was developed to divide and direct the exiting material to several automatic weigher / dispensers , as production demands . the key factor is to set the rate the material exits the comitrol to the rate the container lines are running . the container production line can be of any degree of sophistication to accomplish the production requirements and is readily determinable by one skilled in the art of production line engineering . the exiting supplement blend must be dispensed into and sealed in either opaque , oxygen impermeable pouches or into inert gas flushed , oxygen impermeable containers to which an oxygen absorber packet has been added , preferably in under 5 minutes , but most preferably in under 2 minutes . in addition to the process being performed rapidly , the process is performed at a temperature under 100 ° f . ( 37 . 8 ° c .) and in the absence of white light ( i . e . under dark room conditions ). while not wanting to be bound by any particular explanation , it is believed that by this one step process the supplement blend , when consistently fed to humans and / or animals over time , results in general and specific improvements in health due to preservation of the ingredients in their natural state by the action of : 1 ) an intimate blending and dispersing of the naturally occurring antioxidants over the particles ; 2 ) the minimization of exposure to oxygen due to the one step processing technique ; 3 ) the minimization of exposure to light due to the one step processing technique ; 5 ) the minimizing of lapsed time from exiting the comitrol to sealing the supplement blend in opaque , oxygen barrier containers due to the one step processing to technique ; 6 ) the coating action of naturally occurring antioxidants and other related compounds ( see &# 34 ; 1 )&# 34 ;, above ) caused by the action of the premixed ingredients being guided to the center of a high speed , rotating impeller in which the centrifugal force moves product outward to the impeller tips which carry it past the cutting edges of the stationary reduction head of the comitrol processor ; 8 ) the antioxidant properties of other ingredients included in the formulation ( such as rice bran ). a rapid method of preparing the food supplement using dry ingredients the following ingredients , suitable for use as a supplement from dogs are weighed in the following proportions and mixed 72 % flax , 8 % spray - dried molasses , 5 % yeast , 5 % rice bran , 4 % liver , 2 % alfalfa , 1 . 5 % bone , 1 % carrot , 0 . 5 % fish meal , 0 . 1 % oyster , 0 . 1 % kelp , 0 . 05 % lecithin and 0 . 01 % garlic . the mixture is then stored until required . when required the mixture is cut in a high speed cutting process , as described in example 2 , operating at 5 , 634 rpm and production feed rates of 2 , 700 pounds per hour . after the cutting is completed the cut mixture is immediately packed into opaque , oxygen barrier packaging . the packages are then evacuated to remove oxygen and sealed . the process , from the commencement of cutting to sealing the cut ingredients in the packaging is completed in about 2 minutes . the process , from the commencement of cutting to sealing the cut ingredients in the packaging is conducted under &# 34 ; dark room conditions &# 34 ; as described above and at a temperature which does not exceed 100 ° f . ( 37 . 8 ° c .). food supplements specifically formulated for dogs were prepared according to the process of example 3 and fed to a total of 540 dogs for 60 days . veterinarians then monitored the animals for changes in a variety of conditions . the results of the feeding trials are shown in table iv . the dogs showed remarkable improvements in a variety of conditions . for example , a number of conditions relating to skin and hair improved after animals were fed the diet . hair shedding decreased in 385 of 385 dogs examined , and dandruff conditions similarly improved in 214 of 214 dogs examined . energy levels for dogs older than eight years of age were increased in 197 of 270 dogs examined . the food supplements also improved conditions related to digestion , immune function , and energy levels in the dogs . additional anecdotal evidence was noted for improvements in additional skin , hair , thyroid , digestive ( including stool texture ), immune conditions , arthritic conditions , respiratory diseases , renal disease , muscle pain , or in healing time following in jury or surgery for canine , equine , and feline animals . the results of the feeding trials for dogs is summarized in table iv . table iv__________________________________________________________________________results of feeding trials with dogs positive # of dogs / % of no some response / condition 540 dogs worse effect effect cured total__________________________________________________________________________doggy odor 70 13 % 0 7 3 60 63 / 70wet , red , inflamed 127 25 % 0 14 88 30 113 / 127eyesdry , flaky , dandruff 214 40 % 0 0 47 167 214 / 214skinhot spots , eczema , 138 26 % 0 26 55 57 112 / 138inflamed skinoily , seborrhea skin 31 6 % 0 9 13 9 22 / 31dry , coarse hair 283 32 % 0 0 68 215 283 / 283brittle , dull , lusterless 232 43 % 0 7 47 178 225 / 232hairshedding hair 385 71 % 0 27 127 231 385 / 385flea allergy 97 18 % 0 13 84 0 84 / 97other allergies ( incl . 97 18 % 0 57 28 12 40 / 97dermatitis ) auto - immune 59 11 % 0 21 36 2 38 / 59stool texture ( including 97 18 % 0 0 42 55 97 / 97constipation ) megacolon 5 1 % 0 1 3 4 / 5smelly stool 108 20 % 0 17 11 80 91 / 108stiffness , arthritis ( 8 + 216 40 % 0 52 118 46 164 / 216years ) low energy ( 8 + years ) 270 30 % 0 73 106 91 197 / 270low energy ( 1 - 8 years ) 108 20 % 0 51 32 25 57 / 108__________________________________________________________________________ food supplements specifically formulated for cats were prepared according to the invention and fed to a total of 300 cats for 60 days . veterinarians then monitored the animals for changes in a variety of conditions . the results of the feeding trials are shown in table v . the cats showed remarkable improvements in a variety of conditions . for example , a number of conditions relating to skin and hair improved after animals were fed the diet . hair balls where reduced in 188 of 195 cats examined , and dandruff conditions similarly improved in 99 of 114 cats examined . energy levels for older cats were increased in 84 of 238 cats examined . table v__________________________________________________________________________results of feeding trials with cats positive # of cats / % of no some response / condition 300 cats worse effect effect cured total__________________________________________________________________________hair balls , long - 90 30 % 0 4 0 86 86 / 90haired catshair - balls , short - 105 35 % 0 3 0 102 102 / 105haired catsfeline acne 15 5 % 0 0 0 15 15 / 15dry , flaky 114 38 % 0 15 11 88 99 / 114dandruff skinhot spots , 18 6 % 0 3 6 9 15 / 18eczema , inflamedskinoily , seborrhea 3 1 % 0 0 2 1 3 / 3skindry , coarse hair 90 30 % 0 0 14 76 90 / 90brittle , dull 123 41 % 0 0 9 114 123 / 123lusterless hairshedding hair 258 86 % 0 18 22 218 240 / 258flea allergy 30 10 % 0 7 19 4 23 / 30other allergies 24 8 % 0 0 22 2 24 / 24 ( incl . derinatitis ) stool texture ( incl . 9 3 % 0 0 2 7 9 / 9constipation ) diarrhea 8 3 % 0 2 2 4 6 / 8fetid , smelly stool 6 2 % 0 0 0 6 6 / 6stiffness , arthritis 54 18 % 0 5 41 8 49 / 54low energy ( older 238 46 % 0 54 63 21 84 / 238cats ) __________________________________________________________________________ while this describes what are at present to be the preferred embodiments of the invention , it will be clear to those skilled in the art that various changes and modifications may be made without departing from the invention . the invention is to be determined solely in terms of the following claims .

a composition and method for preparing a food supplement . the composition consisting essentially of at least 70 % by weight of an oil seed constituent , at least 8 % by weight of an additional plant constituent and at least 4 % by weight of yeast wherein oil seed constituent , additional plant constituent and yeast are prepared by blending and cutting for less than about 20 minutes at a temperature of less than about 100 ° f . and in the presence of light of a wavelength not greater than that of red light and of an intensity not greater than that of a darkroom light to thereby inhibit oxidation of the components of the composition . the method comprising combining at least 70 % by weight of an oil seed constituent , at least 8 % by weight of an additional plant constituent , and at least 4 % by weight of yeast wherein oil seed constituent seed with a liquid coating solution , cutting and blending the constituents , packaging the cut and blended constituents in an opaque , oxygen impermeable pouch , expelling oxygen from the pouch and sealing the pouch .