The output speed of a hydrostatic unit in a transmission is determined using a pair of variable reluctance sensors, one on a gear driven by the hydrostatic unit output and the other on the carrier of the planetary system. One of the two sensors will always be measuring a relatively high speed from which the hydro output is directly determined or indirectly determined using the current engine speed. Thus the frequency of the speed sensor used to determine the hydrostatic unit output speed is not decreased at slow hydrostatic unit output speeds.

1. Field of the Invention
The present invention relates to a hydro-mechanical transmission having a hydrostatic unit and in particular to a method and means for determining the actual output speed of the hydrostatic unit.
2. Description of Related Art
The controller of a hydro-mechanical transmission commands a given output speed for the hydrostatic unit based on a variety of input factors. For proper control it is necessary to have a feedback to the controller of the actual output speed of the hydrostatic unit. This has been provided in the past by the use of a directional Hall effect sensor and a magnetic ring carried on the hydro unit output shaft or on a gear driven by the hydro unit output shaft. One drawback of this approach is that the directional Hall effect sensors and the magnetic ring are relatively expensive. Another drawback is that when the hydrostatic unit is at near zero stroke, the hydro unit output speed is low and the frequency of the speed pulses is also low. Therefore the update rate for measuring the hydro unit output speed is slow.
It is therefore an object of the present invention to overcome the above drawbacks associated with the use of a directional Hall effect speed sensor.
The transmission of the present invention uses two, non-directional, relatively inexpensive variable reluctance speed sensors on different gears in the transmission to accurately determine the speed and direction of the hydrostatic unit output. One sensor is on the hydro unit output of the hydrostatic unit and measures the hydro unit output speed directly. The other sensor is on the transmission planetary carrier and measures the hydro unit output speed indirectly. The hydro unit output speed must be calculated based on the current engine speed and the known transmission gear ratios. When the hydrostatic unit is stopped or turning at a slow speed, the carrier is turning at a relatively fast speed. Furthermore, when the carrier is stopped or turning at a slow speed, the hydrostatic unit output shaft is turning at a relatively fast speed. The sensor that is measuring the faster actual speed is the sensor that is used to determine the hydro unit output speed. There is a transition period during which the two measured speeds are relatively close to one another. In the transition period, the hydro unit output speeds determined by the two sensors are averaged and the average value used by the controller as the hydro unit output speed.
By using the sensor with the highest actual speed measurement, the frequency of the speed measurement is always greater than or equal to 250 Hz. As a result, a new and accurate speed can be measured every 4 ms for closed loop speed control. The variable reluctance sensors are inexpensive and can measure existing gears in the transmission without the need for a pressed-on magnetic ring. Furthermore, having two sensors to measure the hydrostatic unit speed allows for error checking and onboard diagnostics by the controller.

Apparatus and method for determining the output speed of a hydrostatic unit in a hydro-mechanical transmission


Provided are a heat sink capable of suppressing overcooling of an electronic component which should not be overcooled and highly efficiently cooling only an electronic component which should be cooled, and a circuit device including the same. A heat sink includes a pipe and a cooling block. At least one projection is formed in the cooling block. The pipe is in contact with the projection. The pipe is arranged with a spacing from a portion of the cooling block other than the projection.

Conventionally, there has been provided a heat sink for cooling an electronic component, including a pipe through which a cooled fluid flows and a cooling block made of a thermally conductive material. Such a heat sink is disclosed for example in Japanese Patent Laying-Open No. 2013-232526 (PTL 1). The heat sink disclosed in Japanese Patent Laying-Open No. 2013-232526 has a configuration that a groove is formed in an upper surface of the cooling block and the pipe through which the cooled fluid flows is fitted in the groove. In Japanese Patent Laying-Open No. 2013-232526, the cooling block is cooled by the cooled fluid flowing through the pipe fitted in the groove. Thereby, a power module provided to be in contact with the cooling block is cooled.


A headrest for a seat assembly includes a central main body having a first side and a second side that is opposite from the first side. A first lateral stabilizer is moveably coupled to the first side of the central main body. The first lateral stabilizer is distinct from the central main body. A second lateral stabilizer is moveably coupled to the second side of the central main body. The second lateral stabilizer is distinct from the central main body. The first lateral stabilizer and the second lateral stabilizer are movable between retracted positions and stabilizing positions.

Commercial aircraft transport passengers between locations. During a flight, passengers within an aircraft are seated. A typical seat assembly within an internal cabin includes a headrest. A passenger may decide to rest and/or sleep during a flight. When passengers rest their heads on the headrest in an upright, seated position, the headrest may not be capable of maintaining the head in a stable position. For example, a passenger's head may slump to a side, which may awaken the passenger, who is trying to sleep.
Certain headrests on seats of a commercial aircraft include side flaps. However, the side flaps typically do not remain in position. As such, a head of a passenger in a seated position trying to rest may slide off or otherwise disengage from the headrest as the side flap moves to an undesirable position. For example, side flaps may be moved into a desired position by a passenger. However, as a head of a passenger leans on a side flap, the side flap typically flattens, which may cause a passenger's neck to kink and jar the passenger awake. In general, finding a comfortable resting position during a flight may prove a challenge to many individuals.


Aqueous formulations suitable for intranasal administration comprise buprenorphine or a physiologically acceptable salt or ester thereof and (a) a pectin having a degree of esterification of less than 50%, (b) chitosan and a polyoxyethylene-polyoxypropylene copolymer (poloxamer) or (c) chitosan and hydroxypropylmethylcellulose. Such formulations can induce rapid and prolonged analgesia when delivered intranasally to a patient. The buprenorphine or buprenorphine salt or ester may be delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration of buprenorphine, Cther, of 0.2 ng/ml or greater which is maintained for a duration Tmaint of at least 2 hours.

The term opioid (or opiate) defines drugs with morphine-like properties. Opioids can be sub-classified on the basis of their receptor specificity. Mu-agonist opioids provide intense analgesia. These opioids can be long-acting (e.g. methadone) or short-acting (e.g. remifentanil).
Mixed agonist/antagonist opioids (e.g. butorphanol and buprenorphine) are partial agonists (the former at mu and kappa receptors and the latter at the mu receptor) and can produce good quality analgesia. They produce less respiratory depression and constipation than high efficacy mu agonists.
Buprenorphine (CAS RN 52485-79-7; [5α,7α(S)-17-(Cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol) has the formula:

The hydrochloride is also active (CAS RN 53152-21-9).
Buprenorphine is a highly lipophilic derivative of thebaine. It is a partial mu agonist and mediates analgesia at the mu opioid receptor. Buprenorphine produces a similar maximum analgesic effect to full mu agonists such as morphine in animal models of pain and, although it may have a ceiling effect in certain pain types in man, it has been shown to produce good quality analgesia of similar efficacy to morphine in most clinical situations including severe pain. An unusual property of buprenorphine observed in in vitro studies is its very slow rate of dissociation from its receptor.
As a class, opioids are associated with a number of undesirable side-effects, including respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention and hypotension. The development of tolerance and the risk of chemical dependence and abuse are further problems. Buprenorphine, however, is unusual in exhibiting a low maximum effect for respiratory depression and also a bell-shaped dose response curve where the effect first increases with larger doses, reaches a ceiling and then diminishes as the dosage is further increased, which makes it a safer drug than morphine, where respiratory depression will ultimately lead to death. Buprenorphine has also been shown to have a lower incidence of other side-effects like constipation in man, and it has a lower abuse potential than full mu agonists.
Buprenorphine has previously been administered via the intravenous, intramuscular and sublingual routes to human subjects. There are limited reports of nasal administration. Eriksen et al, J. Pharm. Pharmacol. 41, 803-805, 1989 report administration to human volunteers of a nasal spray. The spray consisted of 2 mg/ml of buprenorphine hydrochloride dissolved in 5% dextrose and the pH of the solution was adjusted to pH 5.
WO 90/09870 describes a composition for administration to mucosa comprising a pharmacologically active compound and a polycationic substance such as DEAE-dextran or chitosan. WO 98/47535 discloses a single component liquid pharmaceutical composition for administration to a mucosal surface. The composition comprises a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier that gels or can be adapted to gel at the site of application. Neither WO 90/09780 nor WO 98/47535 mentions buprenorphine.

This patent is subject to a terminal disclaimer.

Buprenorphine formulations for intranasal delivery


A saw skid plate shield including a shield plate body defining a leading edge and a trailing edge and a mechanism such as edge rails for attaching the shield plate body to the skid plate. Both the leading and trailing edges of the skid plate body are beveled and/or rounded to divert debris.

The skid plate of a concrete or other saw performs three primary functions: it supports the saw as the skid plate skids across the surface to be cut, it acts as a blade guide, and it helps ensure a quality cut by the blade. When the skid plate wears, the quality of the cut made by the saw blade degrades.
Thus, U.S. Pat. No. 6,736,126, incorporated herein by this reference, proposes a glide plate assembly with a specially designed plate and a plastic overlay for the plate. The skid plate of the saw is removed and the new glide plate/overlay combination is installed on the saw. The primary focus of the '126 patent is minimizing the gap between the saw blade and the slot ultimately formed in the plastic overlay. In all embodiments, the overlay includes mounting flanges and at least a contoured leading mounting portion which conforms to the leading rounded mounting portion of the glide plate. Thus, although in one embodiment the overlay can be slid onto the specially designed glide plate, it cannot be clipped onto it. Moreover, the need for a specially designed replacement glide plate adds to the cost of the system. Finally, the leading edge of the overlay is straight which can result in debris between the overlay and the surface being cut and also marring or scratching of the surface.


Disclosed is a decoder circuit including: a redundancy section row decoder for responding a redundancy main word line signal, thereby selecting a redundancy section word line; a normal section row decoder for receiving a redundancy signal and a normal main word line signal applied from a row redundancy address decoder, thereby selecting a section word line; and, a row redundancy address decoder for generating a signal having a pulse width up to before a next cycle following a redundancy cycle as a redundancy signal, thereby providing the signal to the normal section row decoder and providing the redundancy main word line signal to the redundancy section row decoder during the redundancy cycle, in response to a clock transiting in the redundancy cycle.

1. Field of the Invention
The present invention relates to a circuit applicable to a semiconductor memory device, and in particular, to a decoder circuit which is capable of generating a redundancy signal having a short pulse format, and controlled by the generated signal.
2. Description of the Related Art
Conventionally, a volatile semiconductor memory device has a redundancy repairing scheme for disabling a normal word line or a column pass by use of a signal. A word line redundancy repairing scheme controls an enabling operation or a disabling operation of a section word line decoder by applying a redundancy signal to the section word line decoder which receives a main word line signal, and then in turn generates a signal to select a section word line.
In the prior art, however, it is difficult to rapidly perform the enabling operation of the normal word line because of a static transition of the redundancy signal, which increases the signal load and/or slows the transition speed. FIG. 1 showing timing diagram having clock XCK illustrates the redundancy cycle of the prior art. The enabling speed of a cycle 22A proceeded by a redundancy cycle 101 of the normal word line in the prior art is reduced by that proceeding redundancy cycle 101 itself. That is, here, the enabling speed of the normal word line 22A is interrupted via a line path 1. As a result, because of increase of the load or a reduction of a transition speed, the prior art has a disadvantage in that an enabling speed of a normal word line 22A is easily interrupted.
In the prior art as shown in FIG. 2, a row redundancy address decoder 300, more specifically includes a programmable fuse box 301 and lines 10 and 11 for providing a redundancy main word line signal and a redundancy signal respectively. Row redundancy address decoder 300 includes inverters 302 and 303 and node "A" which is transited from the logic "low" level state to the logic "high" level state during redundancy access, that is node "A" is enabled to the "high" level state during the redundancy access.
In the above redundancy repairing scheme, a redundancy word line of an address to be repaired or a redundancy column selection line thereof instead should be rapidly enabled. Simultaneously, a normal word line or a normal column pass should be rapidly enabled by a specific signal. Additionally, in a case where the address to enable the normal word line or the column pass in a next cycle is inputted after the enabled redundancy word line or the redundancy column pass performs its operation, a signal not selecting the normal word line or the column pass in a previous cycle should be rapidly enabled, thereby preventing a cell connected to the normal word line or the column pass from being selected at a low speed. Therefore, what is needed is a redundancy repair scheme which avoids an increase in signal load and does not slow the transition speed.

Decoder circuit using redundancy signal having a short pulse format


A fibrous product is produced by providing a collection of fibrous material, and encapsulating the fibrous material by covering the fibrous material with a film to form an encapsulated blanket of the fibrous material. The encapsulated blanket is then needled to cause entanglement of the fibrous material, thereby producing a needled, encapsulated fibrous product.

Conventional fibers are useful in a variety of applications including reinforcements, textiles, and acoustical and thermal insulation materials. The fibers can be formed from organic molten materials, such as polymers, and inorganic materials such as glass, rock, slag, and basalt. Continuous fibers are typically produced via stationary bushings for reinforcement and textile applications. Such fibers are typically coated with a size for protection against abrasion and for enhanced compatibility with resin matrices. The glass fibers are often further processed by combining them into continuous strands, yarns and rovings, or by chopping the glass fibers into preselected lengths defined by the end user. Where chopped, the resulting short, straight fiber segments may be mixed with other materials, wet processed into mats such as are used for shingles, or otherwise treated for use. While stationary bushings have significant operational lifetimes, their throughput is limited relative to rotary fiberizing techniques for producing glass fibers.
Short, straight fibers typical of conventional acoustical and thermal insulation materials are made by rotary fiberizing techniques and are interconnected by binders. In such techniques, molten material is delivered to an orificed centrifuge, commonly referred to as a spinner. Fibers produced by the spinner are drawn downward by a blower. Binder can optionally be sprayed onto the fibers as they are drawn downward. The fibers are then collected and formed into a continuous blanket. The blanket can then be cut into desired lengths called batts.
Fibrous material, in the form of blankets or a collection of fibers, may optionally be encapsulated with a film to form an encapsulated blanket. Typically, the film is wrapped around the fibrous material and sealed together at the edges so that the film completely covers the fibrous material. The film could also be supplied in the form of a bag and then placed over the fibrous material. Encapsulation is particularly desirable when the fibers are loosely entangled or unbonded with each other rather than bound into a sharply defined, compressible product by an organic binder. Encapsulating the fibers provides for easy handling of the loosely entangled fibers for further processing or for supplying the fibers to an end user.
Needlepunching or "needling" is commonly used in the textile industry and the needled fabrics are found in a wide range of products. Needling is accomplished by a needle loom which subjects the fabrics to a needling process in which needles are pushed through the fibers of the fabrics to further entangle the fibers. It is difficult to needle fibers because of their loose entanglement with each other and the difficulty of holding the fibers together as they are fed into a needle loom. To overcome this difficulty, the fibers are frequently subjected to precursor processing steps, such as, carding, blending with other fibers, or lubrication before being needled. Carding aligns the fibers in a generally parallel direction and entangles the fibers because of the curliness of the fibers, giving the fibrous blanket some rigidity or strength. The carding is typically accomplished by the action of opposing, rotating cylinders having thousands of metal teeth which can damage or break the fibers.
It would be desirable to produce a fibrous product having rigidity and stiffness, in which the method of producing the fibrous product does not subject the fibers to excessive damage. It would also be desirable to produce the fibrous product so that a large quantity of fibrous material can be processed and to reduce the costs of manufacturing by eliminating processing steps and reducing the environmental clean up costs.

Owens Corning Fiberglas Technology, Inc.


Apparatuses, methods and systems for controlling lighting, an environment factor, or security of a structure are discloses. A lighting control system includes a plurality of lighting devices, a central server and a switch. The central server communicates with each of the plurality of lighting devices, and controls an operating configuration of each of the lighting devices. The switch communicates with at least some of the plurality of lighting devices, wherein the communication includes information, and wherein the at least some of the plurality of lighting devices respond to the information based on the operating configuration of the at least some of the plurality of lighting devices.

Typical wireless switches that are battery powered have to optimize between battery-life, functionality, flexibility and security. Existing garage door openers, wireless remotes are either paired at the factory with knowledge and shared secrets of the device they are controlling losing flexibility or are generic, thereby compromising security. For example, one remote control wireless switch from the same manufacturer can affect all controlled devices from that manufacturer.
The battery life limits these devices from being turned on all the time. It is desirable to extend the battery life by only waking up (activating) the device (wireless switch) sending control messages and not having to wait for a response before going to sleep to conserve battery power.
Wireless switches that control scenes typically go through extensive pre-configuration and switch customization. The switches store configuration information that is button dependent. These switches also require two-way communication to keep the devices under control synchronized.
It is desirable to have methods, systems and apparatuses for a wireless switch, and control of devices (such as, lighting fixtures) by the wireless switch. It is also desirable to upgrade the firmware on these devices to fix bugs in deployed switches and leverage improved security capabilities as standards and techniques improve.

Configuration free and device behavior unaware wireless switch


A receiver of a radio frequency signal having a pseudo-random noise (PRN) code modulated on a carrier, and techniques of processing such a signal that are especially adapted for ranging applications. Such an application is in a global positioning system (GPS or GLONASS) receiver. Both of the receiver DLL code and PLL carrier loops include a loop component that senses an error in its main loop caused by the presence of a multipath signal. The main loop is continuously adjusted by this sensed error, thereby causing the loop to track more precisely and minimize the effect of the multipath signal. The result is a more accurate range measurement.

This invention relates to digital radio receivers which are used for navigation systems and other ranging applications, wherein the received signals are encoded with a pseudo-random noise (PRN) type code. This invention deals specially with environments where the multipath fading is severe.
The United States government has placed into orbit a number of satellites as part of a global positioning system (GPS). A GPS receiver receives signals from several such satellites and can determine very accurate parameters, such as position, velocity, and time. There are both military and commercial uses. A primary military use is for a receiver in an aircraft or ship to constantly determine the position and velocity of the plane or ship. An example of a commercial use includes surveying and the accurate determination of the location of a fixed point or a distance between two fixed points, with a high degree of accuracy. Another example is the generation of a high accuracy timing reference.
In order to accomplish this, each satellite continually transmits two L-band signals. A receiver simultaneously detects the signals from several satellites and processes them to extract information from the signals in order to calculate the desired parameters, such as position, velocity or time. The United States government has adopted standards for these satellite transmissions so that others may utilize the satellite signals by building receivers for specific purposes. The satellite transmission standards are set forth in detail by an "Interface Control Document" of Rockwell International Corporation, entitled "Navstar GPS Space Segment/Navigation User Interfaces", dated Sep. 26, 1984, as revised Dec. 19, 1986.
Briefly, each satellite transmits an L1 signal on a 1575.42 Mhz carrier, usually expressed as 1540 f.sub.0, where f.sub.0 =1.023 Mhz. A second, L2 signal transmitted by each satellite, has a carrier frequency of 1227.6 Mhz, or 1200 f.sub.0. Each of these signals is modulated in the satellite by at least one pseudo-random signal function that is unique to that satellite. This results in developing a spread spectrum signal that resists radio frequency noise or intentional jamming. It also allows the L-band signals from a number of satellites to be individually identified and separated in a receiver. One such pseudo-random function is a precision code ("P-code") that modulates both of the L1 and L2 carriers in the satellite. The P-code has a 10.23 Mhz clock rate and thus causes the L1 and L2 signals to have a 20.46 Mhz bandwidth. The length of the code is seven days; that is, the P-code pattern is begun again every seven days. In addition, the L1 signal of each satellite is modulated by a second pseudo-random function, or a unique clear acquisition code ("C/A code"), having a 1.023 Mhz clock rate and repeating its pattern every one millisecond, thus containing 1023 bits. Further, the L1 carrier is also modulated by a 50 bit-per-second navigational data stream that provides certain information of satellite identification, status and the like.
In a receiver, in the process of demodulating those satellite signals, signals corresponding to the known pseudo-random functions are generated and aligned in phase with those modulated onto the satellite signals. The phase of the carriers from each satellite being tracked is measured from the results of correlating each satellite signal with a locally generated pseudo-random function. The relative phase of carrier signals from a number of satellites is a measurement that is used by a receiver to calculate the desired end quantities of distance, velocity, time, etc. Since the P-code encrypted functions (Y-code) are to be classified by the United States government so that they can be used for military purposes only, commercial users of the GPS must work directly only with the C/A code pseudo-random function.
The government of the former USSR has placed into orbit a similar satellite positioning system called GLONASS; more information on its standard can be found in the "Global Satellite Navigation System GLONASS-Interface Control Document" of the RTCA Paper No. 518-91/SC159-317, approved by the Glavkosmos Institute of Space Device Engineering, the official former USSR GLONASS responsible organization. Although the present invention is described herein for use with the United States GPS system, it can be applied to a receiver designed to acquire the GLONASS signals or any radio frequency system using pseudo-random noise sequences for ranging.
One of the major factors influencing the final accuracy of a distance, velocity, etc., measurement being made is the accuracy with which the signal phase measurements are made. In turn, this phase measurement precision is altered if, in addition to the direct line-of-sight propagation signal, a multipath fading signal is also received. The phase of the C/A code, for example, is determined by use of a delay locked loop (DLL) correlator, wherein the phase of the internally generated C/A PRN code sequence is adjusted in a control loop to minimize an error signal. The DLL uses early and late versions of the internally generated code in a signal correlator that is part of it. Many such receivers use a time spacing between the early and late versions of one PRN code chip. (A "chip" is the time during which the code remains at a plus or minus one.) Operation of the DLL within such receivers is affected by any multipath signal present, thus causing a tracking error. The phase locked condition of the DLL is not only controlled by the line-of-sight signal, as is desired in order to eliminate a cause of phase measurement errors, but is also affected by the multipath signals as well.
Errors caused by multipath distortion in the out-of-phase condition can be reduced by narrowing the delay spacing between the early and late correlators in the DLL. Although this technique reduces the effect of the received multipath signals somewhat by reducing the loop gain to the weaker multipath signals, inaccuracies still result. It has not been found to be possible to completely eliminate the tracking error by simply narrowing the early-late delay spacing.
The Prior Application identified above describes use of a correlator having a zero loop gain over a majority of a range of relative phase difference between the locally generated PRN code and that encoded in the radio frequency signal being received from a satellite or other source, while, at the same time, providing a finite magnitude of loop gain in an operating phase difference region positioned about a zero phase difference. This significantly reduces, and even, in some cases, eliminates phase measurement errors that result when one or more multipath versions of a PRN encoded signal are present. However, as the desired level of measurement precision has increased, a phase measurement accuracy even greater than that provided by the techniques described in the Prior Application has been sought.
Therefore, it is a primary and general object of the present invention to provide a receiver signal processing technique that substantially eliminates phase measurement errors resulting from the presence of one or more multipath signals being received along with the desired line-of-sight signal.

Signal correlation technique for a receiver of a spread spectrum signal including a pseudo-random noise code that reduces errors when a multipath signal is present


A sensitive method for measurement of telomeric DNA content in human tissue, based upon the ratio of telomeric to centromeric DNA present in the tissue.

Telomeres, nucleoprotein complexes at the ends of eukaryotic chromosomes, are 10-12 Kbp in length in somatic cells, but as small as 1-2 Kbp in rapidly growing cancer cells. Recent studies have correlated telomere length with the aggressiveness and genetic variability of tumors, making telomere length a potentially informative prognostic factor. Southern blot analysis is currently the standard method for the measurement of telomere length. However, accurate determinations are not possible when DNA is broken or scant, precluding the analysis of many samples, including fixed tissues embedded in paraffin. To avoid these problems, a slot-blot assay that quantitates the relative content, instead of length, of telomere DNA was developed. The relative contents of telomere DNA determined by this slot-blot assay were directly proportional to the relative lengths of telomere DNA determined in parallel by Southern blot analysis in several samples. Relative telomere DNA content could be measured in samples containing as little as 15 ng of total DNA by the slot-blot assay. Relative telomere DNA content, but not length, also was unaffected by breakage of DNA into fragments 1 Kbp or less in length.

Sensitive method for measurement of telomeric DNA content in human tissues


A method and apparatus provide for stable signal demodulation in a communication system. The method and apparatus includes including detecting an erroneous demodulation value based on backward-demodulation of received signals, using a difference between a received signal to be demodulated and a preceding signal of the received signals and correcting the error demodulation value. Alternatively, backward-demodulation is used to confirm received signals.

1. Field
The following description relates to a method and apparatus for stable signal demodulation in a communication system.
2. Description of Related Art
Use of a sensor network to gather information is rapidly becoming widespread based on the fast improvement and commercialization of wireless network technology. Technological standardization of protocols that are used for wireless communication is also being actively conducted by entities such as the Institute of Electrical and Electronics Engineers (IEEE). In particular, standardization of wireless communication protocols such as Bluetooth, IEEE 802.15.4 and ZigBee is being performed. Such standardization helps devices to communicate with one another because in order for successful communication to occur between devices, it is necessary for the devices to agree on ways to transmit information using wireless signals and subsequently obtain the information from the signals.
A wireless sensor device may be used in various fields for many potential applications. For example, wireless sensor devices may be used in fields including home security, medicine, mobile healthcare, chemical and biological defect monitoring, breakdown and damage diagnosis for machinery, environmental monitoring, sensing information associated with natural disasters, intelligent logistics management, real-time security, remote observation, and the like. A wireless sensor is able to use sensor technology to gather information, and then use wireless communications technology to transmit the gathered information to be analyzed and interpreted.
Various wireless sensor networks and local area networks (LANs) require compact-sized sensors. For example, limited physical space may be available for sensors, and hence it may be necessary to use sensors that require minimal space. Also, for practical operation of a number of sensors, meeting low power and low complexity requirements is necessary. For example, sensors may have limited access to power, such as if they use a battery as a power source, and hence the sensors may need to ensure that they use a controlled amount of power to ensure that the power stored in the battery is not depleted too quickly. Similarly, if the sensors are too complicated, the infrastructure needed to support them may not be practical.
In particular, a sensor to be attached to or mounted on a human body needs to meet the low power and low complexity requirements as discussed above in a wireless body area network (WBAN), in which communication with an adjacent mobile device or a sensor of another human body is performed wirelessly.
To meet low power and low complexity requirements, a super-low power radio frequency (RF) structure may be used in lieu of a high power RF structure. However, the use of a super-low power radio frequency (RF) structure may lead to problems when trying to perform stable demodulation of a received signal.

Method and apparatus for stable signal demodulation in communication system


A balloon kite is formed with a plurality of sized sheets of gas impervious sheet material that form one or more fillable interior chambers. The balloon kite is capable of being flown and deployed in the presence or absence of a critical level of wind. When the critical level of wind is present a balloon kite lifts and assumes an aloft position with the interior chamber or chambers filled with air. If the wind is below the critical level of wind, the balloon kite may be filled with a lighter-than-air gas and flown with a minimal amount of wind, and by an individual having minimal training. The balloon kite is structured with extended and folded portions that provide a simple and low cost reinforced attaching arrangement for securing a bridle and kite flying line to the balloon kite. One or more of the sized sheet is formed with a coiled tail portion. Each coiled tail portion is extendable when uncoiled and useful for stabilizing a balloon kite when in an aloft position.

The present invention relates to inflatable toys and amusement devices. More particularly, the invention relates to an inflatable balloon kite structured with aerodynamic surfaces and employable as a toy and or training kite when the balloon kite is inflated with a volume of lighter-than-air gas. The lighter-than-air gas (e.g., helium) provides a buoyancy such that the balloon kite will lift and fly, even when the wind is below a critical level of wind, wherein a kite would not normally fly.
A large variety of toys, amusement devices, and recreational items are available in the art. One simple and well known example is a common balloon. Balloons may be filled with air, water, etc., or alternately filled with a volume of a lighter-than-air gas and made buoyant. When considering this later buoyant version, young children can be amused and entertainedxe2x80x94at least for a short period of time. Further, decorative markings are often disposed upon surfaces of balloons to enhance their appearance and or provide a message or image appropriate for an occasion.
A relatively recent development in the art of balloons is the use of mylar sheeting materials to provide a balloon of fixed dimensions that may be embodied with a variety of decoratively covered surfaces. These mylar balloons provide a tough surface that is also difficult to puncture and pop when they come in contact with sharp or pointed objects. However, balloons are truly a simple toy. Indeed, most children will quickly become bored with this type of toy or amusement device.
Another group of amusement and hobby devices includes hobby items are common kites. Although a large variety of kites are available, many are structured with a frame made of interconnected rods suitably arranged to support a covering that aids in establishing one or more aerodynamic surfaces. It is the interaction of these aerodynamic surfaces with moving air masses, such as those available on a windy day, that enable an individual to fly and operate such a kite.
A major problem that arises when attempting to fly a kite is experienced during calm periods, wherein a low wind is present. Short of running to create a relative or artificial wind, it is simply not possible to get a kite in an aloft position and maintain it there. As a result, during low wind situations, attempts at flying and controlling a kite may prove difficult, frustrating, and possibly even upsetting.
Accordingly, it would be most desirable to have a kite or kite-like toy that would be easy for children and young individuals to fly and use. Skilled individuals will understand a need for improved, easy to fly kite-like toys that are simply structured, durable, and structured for use and operating by young children with little of no previous experience with flying kites. A number of characteristics, advantages, and associated novel features of the present invention, will become clear from the description and figures provided herein. Attention is called to the fact, however, that the drawings are illustrative only. Variations are contemplated as being part of the invention, limited only by the scope of the appended claims.
In accordance with the present invention, a balloon kite is formed of a plurality of sized sheets, with each sheet preferably provided by a gas impervious sheet material. Each sized sheet includes edge portions and non-edge portions, which are bonded to other portions (including other edge portions) to form at least one gas-tight and fillable envelope. When these envelopes are inflated one or more aerodynamic surfaces are established. Each fillable envelope includes one or more interior chambers configured with a filling means for filling and inflating the chamber. Filling means may be provided by items such as filling ports, filling stems, etc., each of which are well understood in the art. Accordingly, it is to be understood that filling means are included to enable the filling of interior chamber(s) of the balloon kite with a selected volume of gas, as will be fully addressed further below. Once filled, the sized sheets are arranged to provide aerodynamic surfaces without additional support members or structures.
The balloon kite of the invention is intended to be used in the presence or absence of a critical level of wind. A critical level of wind is a level of wind resulting from a motion of a surrounding air mass relative to the balloon kite of the invention. It is important to understand that the terms xe2x80x98critical windxe2x80x99 or xe2x80x98critical level of windxe2x80x99 may actually be realized by a natural wind, which is present when the individual flying the balloon kite is substantially stationary, or by an artificial wind created by the relative movement (e.g., running) of the individual with respect to surrounding/proximate air masses. Of course, a critical level of wind may also be provided by a combination of a natural wind and an artificial wind. Accordingly, when a wind is at or above the critical level of wind, if the interior chambers of the balloon kite are filled with air, the balloon kite will lift and assume an aloft position. An operator of the balloon kite may be said to be flying the balloon kite. In this situation, the kite flies due to an interaction between the wind and the aerodynamic surfaces of the balloon kite, much like a conventional kite.
Alternately, when the wind is below the critical level of wind, if the interior chambers of the balloon kite are filled with air, the balloon kite will not lift and assume an aloft position. It is in these situations, in accordance with the invention, that the interior chambers formed within the envelope(s) of the balloon kite will most preferably be filled with a lighter-than-air gas, for example, such as helium. When the interior chambers are filled with a lighter-than-air gas, the balloon kite will exhibit a buoyancy, and may be said to xe2x80x98flyingxe2x80x99, even when the wind is below the critical level of wind and the kite could not normally be flown. As fully appreciated by skilled persons, an actual critical level of wind required for a respective balloon kite, say in miles per hour, will vary according to the specific design, aerodynamics, and materials employed to construct and fly a respective embodiment of the invention. Minimal critical levels of wind may typically be somewhere in a range of 2 to 10 miles an hour, or higher.
It is contemplated that the level of entertainment and amusement experienced when flying the balloon kite may be increased, especially for younger users, with the disposing of one or more decorative graphical images upon an outer surface of at least one sheet material forming the envelopes of the balloon kite. The graphical images may be provided in the form of abstract designs, cartoon characters, reproduced personal photographic images, advertisements, business and marketing slogans, trademarks, etc.
The balloon kite in accordance with the invention is further arranged with one or more sized sheets having extended portions. Each extended portion is arranged having at least one foldable tab formed thereupon. The tabs are structured for folding over, so as to superpose an adjacent portion of the extended portion, forming a reinforced multi-layer attaching location. The attaching locations are arranged for having fixed thereto ends of a bridle, which may then have a line fixed thereto for use in controlling and flying the balloon kite. It may be noted that by employing a small amount of additional material of a sized sheet, a reinforced securing and attaching means may be readily provided with no additional items or hardware required. Further, it is to be understood that a plurality of sized sheets and extended portions may be provided by a single monolithic sheet material. For example, the embodiment of FIGS. 1, 2A and 2B, may be formed of a single sheet possibly having two substantially equivalently shaped portions that may be folded over upon each other and suitably bonded to form the desired interior chambers.


This invention relates to a method of inhibiting tumor cell adhesion, pain, and inflammation at a wound during a surgical procedure by delivering an irrigation solution containing a tumor cell anti-adhesion agent and a plurality of additional agents to an operative site during the surgical procedure. In addition, methods of inhibiting tumor cell attachment and implantation during a surgical procedure as well as inhibiting tumor metastasis during a surgical procedure are also provided.

The present invention relates to methods of inhibiting tumor cell adhesion and/or invasion and/or local tumor cell metastasis while simultaneously treating pain, and/or inflammation, and/or smooth muscle spasm and/or restenosis during surgical procedures using perioperative, local delivery of a combination of therapeutic agents.
Endooscopy is a surgical procedure in which a camera, attached to a remote light source and video monitor, is inserted into a body cavity (e.g., joint, peritoneal cavity, bladder, thorax, etc.) through a small portal incision in the overlying skin and body wall. Through similar portal incisions, surgical instruments may be placed in a body cavity, their use guided by arthroscopic visualization. As endoscopists"" skills have improved, an increasing number of operative procedures, once performed by xe2x80x9copenxe2x80x9d surgical technique, now can be accomplished endoscopically. Such procedures include, for example, appendectomies, cholecystectomies and cardiac surgery. As a result of widening surgical indications and the development of small diameter endoscopes, pediatric endoscopy has become routine.
Throughout each endoscopic procedure, physiologic irrigation fluid (e.g., normal saline or lactated Ringer""s) is flushed continuously through the joint, distending the body cavity removing operative debris, thereby providing clearer visualization. U.S. Pat. No. 4,504,493 to Marshall discloses an isomolar solution of glycerol in water for a non-conductive and optically clear irrigation solution for arthroscopy.
Irrigation is also used in other procedures, such as cardiovascular and general vascular diagnostic and therapeutic procedures, urologic procedures and the treatment of burns and any operative wounds. In each case, a physiologic fluid is used to irrigate a wound or body cavity or passage. Conventional physiologic irrigation fluids do not inhibit tumor cell adhesion and/or invasion and/or local tumor cell metastasis, nor do they provide analgesic, anti-inflammatory, anti-spasm and anti-restenotic effects.
Cell adhesion molecules are important in cell-cell interaction and interactions between cells and components of the extracellular matrix. While these adhesion molecules are fundamental to diverse biological processes and regulate intracellular signaling events, these molecules are particularly important in the earliest stages of tumor metastasis that require adhesion and/or invasion of tumor cells. Specific cell adhesion molecules and proteinases have been associated with the attachment and implantation of free tumor cells which occur during metastasis in a wide variety of human malignancies, including breast, prostate, liver, ovarian and bladder cancer. The diverse adhesion molecules, which mediate the adhesion interactions, are comprised of cellular surface receptor-ligand pairs. The cellular surface receptors constitute a group of transmembrane proteins that can be classified as members of related biological families or superfamilies based upon homologous structure and shared functional characteristics. Adhesion of cancer cells at secondary sites is known to be regulated by several families of adhesion proteins, including the CD44 proteoglycans, integrins and selecting. The primary functions of these receptors are to mediate cellular binding to the specific structural proteins that comprise the extracellular matrix (ECM) and to recognize membrane bound ligands mediating cell-cell adhesion. Cellular adhesion and invasion can also be facilitated by proteinases, such as the metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs).
Surgical trauma has been found to increase the frequency of tumor implantation at the sites of surgical injury and wound healing. One of the consequences of surgical trauma to malignant tissues is the dissemination of free tumor cells locally at the operative site. For example, patients with pancreatic cancer often exhibit peritoneal dissemination and hepatic metastasis after undergoing surgery. Adhesive molecules and receptors mediating the attachment of free-floating tumor cells and implantation at surgical sites and at sites of wound healing are frequently present on numerous other normal cell types. Surgical trauma also stimulates and potentiates the production and release of proteinases from tumor cells, inflammatory cells, and components of the extracellular matrix. Thus, a pharmaceutical approach aimed at interfering with the function of cell adhesion molecules to decrease tumor cell adhesion and inhibit the production and activation of proteinases is to deliver the therapeutic agents only to the tissues at risk for local tumor metastasis. Since the process of free tumor-cell attachment and invasion into the extracellular matrix or other cells during surgery is a dynamic process involving specific interactions temporally related to the operative trauma, the optimal time for pharmaceutical intervention is at the time of surgery. Discovery of the role of multiple adhesive proteins, adhesion receptors, and proteinases in the metastatic spread of cancer enables development of pharmaceutical compositions that block the attachment of tumor cells to extracellular matrix proteins and/or inhibit tumor cell invasion during surgical procedures.
Alleviating pain and suffering in postoperative patients is an area of special focus in clinical medicine, especially with the growing number of out-patient operations performed each year. The most widely used agents, cyclooxygenase inhibitors (e.g., ibuprofen) and opioids (e.g., morphine, fentanyl), have significant side effects including gastrointestinal irritation/bleeding and respiratory depression. The high incidence of nausea and vomiting related to opioids is especially problematic in the postoperative period. Therapeutic agents aimed at treating postoperative pain while avoiding detrimental side effects are not easily developed because the molecular targets for these agents are distributed widely throughout the body and mediate diverse physiological actions. Despite the significant clinical need to inhibit pain and inflammation, as well as vasospasm, smooth muscle spasm and restenosis, methods for the delivery of inhibitors of pain, inflammation, spasm and restenosis at effective dosages while minimizing adverse systemic side effects have not been developed. As an example, conventional (i.e., intravenous, oral, subcutaneous or intramuscular) methods of administration of opiates in therapeutic doses frequently is associated with significant adverse side effects, including severe respiratory depression, changes in mood, mental clouding, profound nausea and vomiting.
Prior studies have demonstrated the ability of endogenous agents, such as serotonin (5-hydroxytryptamine, sometimes referred to herein as xe2x80x9c5-HTxe2x80x9d), bradykinin and histamine, to produce pain and inflammation. Sicuteri, F., et. al., Serotonin-Bradykinin Potentiation in the Pain Receptors in Man, Life Sci. 4, pp. 309-316 (1965); Rosenthal, S. R., Histamine as the Chemical Mediator for Cutaneous Pain, J. Invest. Dermat. 69, pp. 98-105 (1977); Richardson, B. P., et. al., Identification of Serotonin M-Receptor Subtypes and their Specific Blockade by a New Class of Drugs, Nature 316, pp. 126-131 (1985); Whalley, E. T., et. al., The Effect of Kinin Agonists and Antagonists, Naunyn-Schmiedeb Arch. Pharmacol. 36, pp. 652-57 (1987); Lang, E., et. al., Chemo-Sensitivity of Fine Afferents from Rat Skin In Vitro, J. Neurophysiol. 63, pp. 887-901 (1990).
For example, 5-HT applied to a human blister base (denuded skin) has been demonstrated to cause pain that can be inhibited by 5-HT3 receptor antagonists. Richardson et al., (1985). Similarly, peripherally-applied bradykinin produces pain which can be blocked by bradykinin receptor antagonists. Sicuteri et al., 1965; Whalley et al., 1987; Dray, A., et. al., Bradykinin and Inflammatory Pain, Trends Neurosci. 16, pp. 99-104 (1993). Peripherally-applied histamine produces vasodilation, itching and pain which can be inhibited by histamine receptor antagonists. Rosenthal, 1977; Douglas, W. W., xe2x80x9cHistamine and 5-Hydroxytryptamine (Serotonin) and their Antagonistsxe2x80x9d, in Goodman, L. S., et. al., ed., The Pharmacological Basis of Therapeutics, MacMillan Publishing Company, New York, pp. 605-638 (1985); Rumore, M. M., et. al., Analgesic Effects of Antihistaminics, Life Sci 36, pp. 403-416 (1985). Combinations of these three agonists (5-HT, bradykinin and histamine) applied together have been demonstrated to display a synergistic pain-causing effect, producing a long-lasting and intense pain signal. Sicuteri et al., 1965; Richardson et al., 1985; Kessler, W., et. al., Excitation of Cutaneous Afferent Nerve Endings In Vitro by a Combination of Inflammatory Mediators and Conditioning Effect of Substance P, Exp. Brain Res. 91, pp. 467-476 (1992).
In the body, 5-HT is located in platelets and in central neurons, histamine is found in mast cells, and bradykinin is produced from a larger precursor molecule during tissue trauma, pH changes and temperature changes. Because 5-HT can be released in large amounts from platelets at sites of tissue injury, producing plasma levels 20-fold greater than resting levels (Ashton, J. H., et. al., Serotonin as a Mediator of Cyclic Flow Variations in Stenosed Canine Coronary Arteries, Circulation 73, pp. 572-578 (1986)), it is possible that endogenous 5-HT plays a role in producing postoperative pain, hyperalgesia and inflammation. In fact, activated platelets have been shown to excite peripheral nociceptors in vitro. Ringkamp, M., et. al., Activated Human Platelets in Plasma Excite Nociceptors in Rat Skin, In Vitro, Neurosci. Lett. 170, pp. 103-106 (1994). Similarly, histamine and bradykinin also are released into tissues during trauma. Kimura, E., et. al., Changes in Bradykinin Level in Coronary Sinus Blood After the Experimental Occlusion of a Coronary Artery, Am Heart J. 85, pp. 635-647 (1973); Douglas, 1985; Dray et. al. (1993).
In addition, prostaglandins also are known to cause pain and inflammation. Cyclooxygenase inhibitors, e.g., ibuprofen, are commonly used in non-surgical and post-operative settings to block the production of prostaglandins, thereby reducing prostaglandin-mediated pain and inflammation. Flower, R. J., et. al., Analgesic-Antipyretics and Anti-Inflammatory Agents; Drugs Employed in the Treatment of Gout, in Goodman, L. S., et. al., ed., The Pharmacological Basis of Therapeutics, MacMillan Publishing Company, New York, pp. 674-715 (1985). Cyclooxygenase inhibitors are associated with some adverse systemic side effects when applied conventionally. For example, indomethacin or ketorolac have well recognized gastrointestinal and renal adverse side effects.
As discussed, 5-HT, histamine, bradykinin and prostaglandins cause pain and inflammation. The various receptors through which these agents mediate their effects on peripheral tissues have been known and/or debated for the past two decades. Most studies have been performed in rats or other animal models. However, there are differences in pharmacology and receptor sequences between human and animal species. There have been no studies conclusively demonstrating the importance of 5-HT, bradykinin or histamine in producing postoperative pain in humans.
Furthermore, antagonists of these mediators currently are not used for postoperative pain treatment. A class of drugs, termed 5-HT and norepinephrine uptake antagonists, which includes amitriptyline, has been used orally with moderate success for chronic pain conditions. However, the mechanisms of chronic versus acute pain states are thought to be considerably different. In fact, two studies in the acute pain setting using amitriptyline perioperatively have shown no pain-relieving effect of amitriptyline. Levine, J. D., et. al., Desipramine Enhances Opiate Postoperative Analgesia, Pain 27, pp. 45-49 (1986); Kerrick, J. M., et. al., Low-Dose Amitriptyline as an Adjunct to Opioids for Postoperative Orthopedic Pain: a Placebo-Controlled Trial Period, Pain 52, pp. 325-30 (1993). In both studies the drug was given orally. The second study noted that oral amitriptyline actually produced a lower overall sense of well-being in postoperative patients, which may be due to the drug""s affinity for multiple amine receptors in the brain.
Amitriptyline, in addition to blocking the uptake of 5-HT and norepinephrine, is a potent 5-HT receptor antagonist. Therefore, the lack of efficacy in reducing postoperative pain in the previously-mentioned studies would appear to conflict with the proposal of a role for endogenous 5-HT in acute pain. There are a number of reasons for the lack of acute pain relief found with amitriptyline in these two studies. (1) The first study (Levine et al., 1986) used amitriptyline preoperatively for one week up until the night prior to surgery whereas the second study (Kerrick et al., 1993) only used amitriptyline postoperatively. Therefore, no amitriptyline was present in the operative site tissues during the actual tissue injury phase, the time at which 5-HT is purported to be released. (2) Amitriptyline is known to be extensively metabolized by the liver. With oral administration, the concentration of amitriptyline in the operative site tissues may not have been sufficiently high for a long enough time period to inhibit the activity of postoperatively released 5-HT in the second study. (3) Since multiple inflammatory mediators exist, and studies have demonstrated synergism between the inflammatory mediators, blocking only one agent (5-HT) may not sufficiently inhibit the inflammatory response to tissue injury.
There have been a few studies demonstrating the ability of extremely high concentrations (1%-3% solutionsxe2x80x94i.e., 10-30 mg per milliliter) of histamine1 (H1) receptor antagonists to act as local anesthetics for surgical procedures. This anesthetic effect is not believed to be mediated via H1 receptors but, rather, due to a non-specific interaction with neuronal membrane sodium channels (similar to the action of lidocaine). Given the side effects (e.g., sedation) associated with these high xe2x80x9canestheticxe2x80x9d concentrations of histamine receptor antagonists, local administration of histamine receptor antagonists currently is not used in the perioperative setting.
In one aspect, the present invention is directed towards preventing and treating tumor cell adhesion, and/or invasion and/or local metastasis in patients undergoing surgical procedures. The invention describes methods and pharmaceutical compositions based upon a combination of agents that will inhibit tumor cell attachment and/or invasion, and/or local metastasis during surgical procedures, and simultaneously inhibit pain, and/or inflammation, and/or smooth muscle spasm and/or restenosis associated with the operation. According to one aspect of the invention, a method is provided for reducing or preventing tumor cell adhesion, and/or invasion and/or local metastasis, which comprises administering directly to the operative site a composition which includes a combination of two or more metabolically active agents, at least one of which is an anti-tumor adhesion or anti-invasion or anti-local metastasis agent, in a pharmaceutically effective carrier for delivery in an irrigation fluid. Metabolically active agents include, but are not limited to, all compounds that act directly or indirectly to modulate or alter the biological, biochemical or biophysical state of a cell, including agents that alter the electrical potential of the plasma membrane, the binding of ligands to a receptor, the enzymatic activity or expression level of cellular receptors, enzyme inhibitors or activators, inhibitors of protein-protein interactions, RNA-protein interactions, or DNA-protein interactions. For example, functional receptor antagonists may include monoclonal antibodies that competitively inhibit receptor binding sites, soluble receptors that reduce the free ligand concentration available to activate a receptor, inhibitors of receptor signaling pathways, activators and inhibitors of intracellular or extracellular enzymes and agents that modulate the binding of transcription factors to DNA.
Specifically, the present invention provides a pharmacological method of treating tumor cell adhesion and/or invasion and/or local metastasis using a combination of agents delivered locally and periprocedurally to achieve maximal therapeutic benefit. The use of a combination of agents overcomes the limitations of existing therapeutic approaches which rely on the use of a single agent to block the multifactorial tumor cell adhesion and invasion processes which are modulated by numerous proinflammatory cytokines and receptors that are linked to the inflammatory response arising from surgical procedures. Proinflammatory cytokines have been reported to stimulate the expression of adhesion receptors and metalloproteinases present on both tumor cells and normal cells, thereby increasing their adhesive and invasive properties. A combination of an anti-adhesion agent and an anti-inflammatory agent, for example, may provide an additive or synergistic benefit to the pharmaceutical composition.
This invention utilizes the approach of combining agents that act simultaneously on molecular targets associated with tumor cell adhesion, and/or tumor cell invasion, and/or metastasis, and/or inflammation, and/or pain, and/or smooth muscle spasm, and/or restenosis and delivering these agents to the operative site throughout the surgical procedure. These combinations of agents will be able to achieve a preemptive inhibition of tumor cell adhesion and/or invasion during the entire period of the surgical procedure while also preemptively inhibiting pain, and/or inflammation, and/or smooth muscle spasm and/or restenosis. Inhibition of a single adhesion receptor-ligand interaction through systemic delivery is likely to lead to adverse reactions since these molecules also function to deliver signals to normal cells. For example, CD44 receptor binding plays a physiological role in the immune response of normal T-cells and other hematopoietic cells and, therefore, inhibition of CD44 binding could lead to undesirable effects on the immune system.
Specifically, the present invention provides pharmaceutical compositions of metabolically active agents that are based on a combination of at least two agents that act simultaneously on distinct molecular targets. At least one agent is an anti-tumor cell adhesion or anti-invasion or anti-local metastasis agent that directly reduces or prevents the attachment of tumor cells to either the extracellular matrix or to other cells (both normal and tumor). Suitable agents for inclusion in the pharmaceutical composition will be further characterized by a requirement for pharmacological selectivity and specificity which limits interactions of the agent to a single family (or class) of receptors or a single enzyme family (e.g., CD44, integrins, selecting, protein tyrosine kinases, MMPs and MAP Kinases). A particular suitable agent may interact specifically with one or more receptor subtypes (or isotypes) while exhibiting specificity for the receptor family. Each suitable agent will associate with its molecular target through a specific molecular mechanism which can be characterized by a defined stoichiometry (typically 1:1) for the ligand-receptor (or inhibitor-enzyme) complex and which can be characterized by its equilibrium binding or kinetic constant.
At least one second agent belongs to a class of receptor antagonists, enzyme inhibitors or cytokines that possess anti-pain, anti-inflammatory, anti-spasm, and/or anti-restenosis activity. The optimal drug combination includes at least one agent drawn from a class of anti-tumor cell adhesion and/or anti-invasion agents which include receptor antagonists that act to inhibit and reduce the activity or the expression of a cell adhesion receptor molecular target (e.g., integrin receptor antagonists, CD44 receptor antagonists and selectin receptor antagonists) or a proteinase inhibitor.
In addition, other suitable agents for inclusion in an optimal drug combination that are functional anti-tumor cell adhesion agents, which act to inhibit cellular signal transduction pathways, activated by cell adhesion receptors. The molecular targets that comprise these pathways include membrane associated and intracellularly localized enzymes that transduce and integrate the signals produced by activated cell surface adhesion receptors. As examples, these agents include inhibitors of the enzymes belonging to the following families: protein tyrosine kinases, protein kinase C, and mitogen-activated protein kinases (MAPK). Such enzyme inhibitors may interact with a particular member or members of the kinase family through specific mechanisms with are characterized by both a defined stoichiometry (typically 1:1) of the enzyme-inhibitor complex and which can be characterized by equilibrium inhibition constants.
Despite a number of experimental studies, an effective treatment for preventing tumor cell adhesion and/or invasion during surgical procedures has not been developed previously. It is the object of the present invention to provide a method for the preemptive treatment of tumor cell adhesion and/or invasion and/or local metastasis during surgical procedures employing irrigation fluids for the continuous delivery of therapeutic agents. Existing methods of delivery do not provide a means to initiate delivery of pharmaceutical agents directly to the operative site and maintain drug levels at or above therapeutically effective concentrations throughout the surgical procedure. Due to the use of large volumes of irrigation fluid during certain surgical procedures (e.g., laparoscopic surgery), inclusion of the agents in the irrigation fluid provides a method to prevent dilution of the agents and maintain therapeutic levels. Problems associated with systemic delivery of therapeutic peptides, proteins and small molecules as potential anti-tumor cell adhesion/invasion, and anti-metastasis agents, including toxicity, pharmaceutical stability and poor pharmacokinetic profiles, may be reduced or obviated by local delivery of these therapeutic agents in an irrigation fluid directly to the operative site.
A multiple drug combination can be delivered via irrigation locally and periprocedurally (i.e., intra-operative delivery alone or intra-operative delivery together with pre-operative and/or post-operative delivery). This invention also provides for an anti-tumor adhesion and/or anti-invasion and/or local metastasis agent to be delivered in combination with one or more analgesic and/or anti-inflammatory and/or anti-spasm and/or anti-restenosis agents.
A significant advantage of the invention is derived from the rapid onset of pharmacological action. Direct, local delivery of the anti-tumor adhesion agents initiated at the outset of the surgical procedure and continued during the surgical procedure (i.e., perioperatively) has the potential to inhibit one of the earliest steps of metastasis, the initial adhesion process. The immediate and constant delivery of therapeutically effective concentrations of anti-adhesion and/or invasion agents is expected to preemptively inhibit the initial attachment of tumor cells to both the extracellular matrix and other cells and subsequent invasion into these tissues. Studies have found that the highest rate of tumor implantation occurred when tumor cells were injected immediately after surgery, indicative of the critical timing for therapeutic inhibition of the adhesion process.
The method of delivery and pharmaceutical composition of the present invention provide distinct advantages which include: 1) a combination drug therapy directed to the multifactorial causes of tumor cell adhesion/invasion/local metastasis, inflammation, pain, smooth muscle spasm and restenosis during surgical procedures, 2) local delivery of the drug combination achieves an instantaneous therapeutic concentration of anti-tumor adhesion agents at the operative site, 3) continuous delivery of therapeutic agents in an irrigation solution provides a constant drug concentration in a therapeutically effective range at the operative site during a surgical procedure, 4) local delivery permits a reduction in total drug dose and dosing frequency compared to systemic delivery, and 5) direct, local delivery to the surgical site enables use of novel, pharmaceutically active agents, such as certain peptides and antibodies, which cannot be delivered systemically.
The present invention further provides a solution constituting a mixture of multiple agents in low concentrations directed at inhibiting locally the mediators of pain, inflammation, spasm and restenosis in a physiologic electrolyte carrier fluid. The invention also provides a method for perioperative delivery of the irrigation solution containing these agents directly to a surgical site, where it works locally at the receptor and enzyme levels to preemptively limit pain, inflammation, spasm and restenosis at the site. Due to the local perioperative delivery method of the present invention, a desired therapeutic effect can be achieved with lower doses of agents than are necessary when employing other methods of delivery (i.e., intravenous, intramuscular, subcutaneous and oral). The anti-pain/anti-inflammation agents in the solution include agents selected from the following classes of receptor antagonists and agonists and enzyme activators and inhibitors, each class acting through a differing molecular mechanism of action for pain and inflammation inhibition: (1) serotonin receptor antagonists; (2) serotonin receptor agonists; (3) histamine receptor antagonists; (4) bradykinin receptor antagonists; (5) kallikrein inhibitors; (6) tachykinin receptor antagonists, including neurokinin, and neurokinin2 receptor subtype antagonists; (7) calcitonin gene-related peptide (CGRP) receptor antagonists; (8) interleukin receptor antagonists; (9) inhibitors of enzymes active in the synthetic pathway for arachidonic acid metabolites, including (a) phospholipase inhibitors, including PLA2 isoform inhibitors and PLCxcex3 isoform inhibitors, (b) cyclooxygenase inhibitors, and (c) lipooxygenase inhibitors; (10) prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; (11) leukotriene receptor antagonists including leukotriene B4 receptor subtype antagonists and leukotriene D4 receptor subtype antagonists; (12) opioid receptor agonists, including xcexc-opioid, xcex4-opioid, and xcexa-opioid receptor subtype agonists; (13) purinoceptor agonists and antagonists including P2X receptor antagonists and P2Y receptor agonists; and (14) adenosine triphosphate (ATP)-sensitive potassium channel openers. Each of the above agents functions either as an anti-inflammatory agent and/or as an anti-nociceptive, i.e., anti-pain or analgesic, agent. The selection of agents from these classes of compounds is tailored for the particular application.
Several preferred embodiments of the solution of the present invention also include anti-spasm agents for particular applications. For example, anti-spasm agents may be included alone or in combination with anti-pain/anti-inflammation agents in solutions used for vascular procedures to limit vasospasm, and anti-spasm agents may be included for urologic procedures to limit spasm in the urinary tract and bladder wall. For such applications, anti-spasm agents are utilized in the solution. For example, an anti-pain/anti-inflammation agent which also serves as an anti-spasm agent may be included. Suitable anti-inflammatory/anti-pain agents which also act as anti-spasm agents include serotonin receptor antagonists, tachykinin receptor antagonists, and ATP-sensitive potassium channel openers. Other agents which may be utilized in the solution specifically for their anti-spasm properties include calcium channel antagonists, endothelin receptor antagonists and the nitric oxide donors (enzyme activators).
Specific preferred embodiments of the solution of the present invention for use in cardiovascular and general vascular procedures include anti-restenosis agents, which most preferably are used in combination with anti-spasm agents. Suitable anti-restenosis agents include: (1) antiplatelet agents including: (a) thrombin inhibitors and receptor antagonists, (b) adenosine disphosphate (ADP) receptor antagonists (also known as purinoceptor1 receptor antagonists), (c) thromboxane inhibitors and receptor antagonists and (d) platelet membrane glycoprotein receptor antagonists; (2) inhibitors of cell adhesion molecules, including (a) selectin inhibitors and (b) integrin inhibitors; (3) anti-chemotactic agents; (4) interleukin receptor antagonists (which also serve as anti-pain/anti-inflammation agents); and (5) intracellular signaling inhibitors including: (a) protein kinase C (PKC) inhibitors and protein tyrosine kinase inhibitors, (b) modulators of intracellular protein tyrosine phosphatases, (c) inhibitors of src homology2 (SH2) domains, and (d) calcium channel antagonists. Such agents are useful in preventing restenosis of arteries treated by angioplasty, rotational atherectomy or other cardiovascular or general vascular therapeutic or diagnostic procedure.
The present invention also provides a method for manufacturing a medicament compounded as a dilute irrigation solution for use in continuously irrigating an operative site or wound during an operative procedure. The method entails dissolving in a physiologic electrolyte carrier fluid at least one inhibitor of tumor cell adhesion, invasion and/or metastasis and preferably a plurality of anti-pain/anti-inflammatory agents, and for some applications anti-spasm agents and/or anti-restenosis agents, each agent included at a concentration of preferably no more than 100,000 nanomolar, and more preferably no more than 10,000 nanomolar.
The method of the present invention provides for the delivery of a dilute combination of at least one inhibitor of tumor cell adhesion, invasion and/or metastasis and preferably multiple receptor antagonists and agonists and enzyme inhibitors and activators directly to a wound or operative site, during therapeutic or diagnostic procedures for the inhibition of pain, inflammation, spasm and restenosis. Since the active ingredients in the solution are being locally applied directly to the operative tissues in a continuous fashion, the drugs may be used efficaciously at extremely low doses relative to those doses required for therapeutic effect when the same drugs are delivered orally, intramuscularly, subcutaneously or intravenously. As used herein, the term xe2x80x9clocalxe2x80x9d encompasses application of a drug in and around a wound or other operative site, and excludes oral, subcutaneous, intravenous and intramuscular administration. The term xe2x80x9ccontinuousxe2x80x9d as used herein encompasses uninterrupted application, repeated application at frequent intervals (e.g., repeated intravascular boluses at frequent intervals intraprocedurally), and applications which are uninterrupted except for brief cessations such as to permit the introduction of other drugs or agents or procedural equipment, such that a substantially constant predetermined concentration is maintained locally at the wound or operative site.
The advantages of low dose applications of agents are three-fold. The most important is the absence of systemic side effects which often limit the usefulness of these agents. Additionally, the agents selected for particular applications in the solutions of the present invention are highly specific with regard to the mediators on which they work. This specificity is maintained by the low dosages utilized. Finally, the cost of these active agents per operative procedure is low.
The advantages of local administration of the agents via luminal irrigation or other fluid application are the following: (1) local administration guarantees a known concentration at the target site, regardless of interpatient variability in metabolism, blood flow, etc.; (2) because of the direct mode of delivery, a therapeutic concentration is obtained instantaneously and, thus, improved dosage control is provided; and (3) local administration of the active agents directly to a wound or operative site also substantially reduces degradation of the agents through extracellular processes, e.g., first- and second-pass metabolism, that would otherwise occur if the agents were given orally, intravenously, subcutaneously or intramuscularly. This is particularly true for those active agents that are peptides, which are metabolized rapidly. Thus, local administration permits the use of compounds or agents which otherwise could not be employed therapeutically. For example, some agents in the following classes are peptidic: bradykinin receptor antagonists; tachykinin receptor antagonists; opioid receptor agonists; CGRP receptor antagonists; and interleukin receptor antagonists. Local, continuous delivery to the wound or operative site minimizes drug degradation or metabolism while also providing for the continuous replacement of that portion of the agent that may be degraded, to ensure that a local therapeutic concentration, sufficient to maintain receptor occupancy, is maintained throughout the duration of the operative procedure.
Local administration of the solution perioperatively throughout a surgical procedure in accordance with the present invention produces a preemptive analgesic, anti-inflammatory, anti-spasmodic or anti-restenotic effect. As used herein, the term xe2x80x9cperioperativexe2x80x9d encompasses application intraprocedurally, pre- and intraprocedurally, intra- and postprocedurally, and pre-, intra- and postprocedurally. To maximize the preemptive anti-inflammatory, analgesic (for certain applications), antispasmodic (for certain applications) and antirestenotic (for certain applications) effects, the solutions of the present invention are most preferably applied pre-, intra- and postoperatively. By occupying the target receptors or inactivating or activating targeted enzymes prior to the initiation of significant operative trauma locally, the agents of the present solution modulate specific pathways to preemptively inhibit the targeted pathologic process. If inflammatory mediators and processes are preemptively inhibited in accordance with the present invention before they can exert tissue damage, the benefit is more substantial than if given after the damage has been initiated.
Inhibiting more than one tumor cell adhesion, invasion and/or metastasis, inflammatory, spasm or restenosis mediator by application of the multiple agent solution of the present invention is useful to dramatically reduce the degree of cell adhesion, invasion and/or metastasis, inflammation, pain, and spasm, and theoretically should reduce restenosis. The irrigation solutions of the present invention include combinations of drugs, each solution acting on multiple receptors or enzymes. The drug agents are thus simultaneously effective against a combination of pathologic processes, including tumor cell adhesion, invasion and/or metastasis, pain and inflammation, vasospasm, smooth muscle spasm and restenosis. The action of these agents is considered to be synergistic, in that the multiple receptor antagonists and inhibitory agonists of the present invention provide a disproportionately increased efficacy in combination relative to the efficacy of the individual agents. The synergistic action of several of the agents of the present invention are discussed, by way of example, below in the detailed descriptions of those agents.
In addition to arthroscopy, the solution of the present invention may also be applied locally to any human body cavity or passage, operative wound, traumatic wound (e.g., burns) or in any operative/interventional procedure in which irrigation can be performed. These procedures include, but are not limited to, urological procedures, cardiovascular and general vascular diagnostic and therapeutic procedures, endoscopic procedures and oral, dental and periodontal procedures. As used hereafter, the term xe2x80x9cwoundxe2x80x9d, unless otherwise specified, is intended to include surgical wounds, operative/interventional sites, traumatic wounds and burns.
Used perioperatively, the solution should result in a clinically significant decrease in operative site pain and inflammation relative to currently-used irrigation fluids, thereby decreasing the patient""s postoperative analgesic (i.e., opiate) requirement and, where appropriate, allowing earlier patient mobilization of the operative site. No extra effort on the part of the surgeon and operating room personnel is required to use the present solution relative to conventional irrigation fluids.

Irrigation solution and methods for inhibition of tumor cell adhesion, pain and inflammation


A percutaneous ostomy implant for implantation into the abdominal wall of a patient. The implant has a cylindrical part for mounting an external detachable device thereto, an ingrowth mesh and a circular flange for anchoring the implant. The cylindrical part and circular flange are attached to opposite ends of the ingrowth mesh. The ingrowth mesh is arranged such that when the implant is implanted in the abdominal wall of a patient, the epidermis meets the ingrowth mesh and is able to attach therethrough directly to serosal tissue of a bowel segment inside the implant.

The present invention relates to a percutaneous ostomy implant and a surgical method, which may use that implant, for creating a continent reservoir in communication with a percutaneous port.
Ileostomy and colostomy are common operations which may be necessitated, for example, by malignancy or chronic bowel inflammation. The surgery is called an ileostomy if the colon and rectum are removed and a colostomy if the rectum alone is removed. In these operations, a stoma is formed in the abdominal wall to which the ileum or colon respectively is connected. The stoma in most cases has to be connected to a bag.
However, instead of a conventional ileostomy, it is possible to make a reservoir known as a "Kock pouch" from the distal part of the ileum. It is formed in such a way that nipple valve is created which serves to close the reservoir, whilst allowing it to be drained intermittently by means of a catheter.
This is an example of a so-called continent ileostomy (CI); it was formerly an attractive alternative to conventional ileostomy, but is now rarely used. The complexity of the procedure and the high potential for complications—most of them related to dysfunction of the continence nipple valve—has deterred many surgeons from adopting the operation today. FIG. 1 illustrates (a) a conventional ileostomy and (b) a Kock's pouch ileostomy.
The advantages and drawbacks of the Kock pouch are discussed in Wasmuth, H. H., M. Svinsas, et al. (2007). "Surgical load and long-term outcome for patients with Kock continent ileostomy." Colorectal Dis 9(8): 713-7; Olof Jonsson, Gunnar Olofsson, Elisabet Lindholm, Harriet Törnqvist, "Long-Time Experience with the Kock Ileal Reservoir for Continent Urinary Diversion", Reconstructive Urology, Eur Urol 2001; 40:632-640; and Olof Jonsson, Bo Rangert, Frank Aldenborg, Magnus Campanello, Gunnar Wikholm and Staffan Akerlund, "Stabilization of the Nipple Base with Titanium Rings when Reoperating Patients with Continent Urostomies for Nipple Dysfunction", Scand J Urol Nephro 30: 51-56, 1996.
The ileopouch anal anastomosis (IPAA) is today the gold standard worldwide for these patients, but as with a CI, this operation is also risky and failures are common, mostly leading to pouch excision with loss of bowel. Conversion of a failed IPAA to a CI would be a preferable option but again, surgeons are again reluctant to perform this complex and unreliable technique.
In their earlier patent application EP 1632201-A1, the present applicants disclosed a percutaneous ostomy implant comprising a solid-walled cylindrical body and an anchoring section in the form of a circular flange. The device was designed to be implanted through the abdominal wall and secured by the anchoring section which was located below the muscle layer. This section comprised inner and outer concentric rings interconnected by S-shaped members in order to provide an axially resilient structure which could absorb shear stresses and consequently reduce the risk of tissue damage. Spaces around the S-shaped members and provision of numerous apertures in the rings allowed for tissue ingrowth and vascularisation. It was proposed to connect the device to the side of the vessel (colon etc.) wall and by providing a removable lid a continent ostomy could be provided.
A development of this implant was disclosed in WO 2007/099500 in which the single solid-walled cylindrical body of EP 1632201-A1 was replaced by an outer skin-penetrating ring-like part spaced from the anchoring section by circumferentially-spaced legs. This implant was designed to receive a vessel drawn up through it; the spaces between the legs allowed the generation of a tissue bond between the inner part of the abdominal wall and the serosal tissue of the bowel in order to provide a more secure, stable, leak-proof and well-vascularised skin-implant junction. In some embodiments, a circumferential ingrowth mesh was additionally provided. This extended along most of the length of the cylindrical body with an annular gap being provided between it and the outer ring-like part to allow tissue to grow through the mesh within the outer ring-like part.
In a further development, in WO 2009/024568, the present applicants proposed a cylindrical body formed of two axially-spaced tubular parts. The outer tubular part penetrated the skin and was provided with means for connection to a bag or lid. The inner tubular part was attached to an anchoring flange of the type previously described. The two parts were connected together by a "distance means" comprising either radially-spaced legs or a rigid cylindrical ingrowth mesh which allowed for the generation of a tissue bond between the abdominal wall and the bowel. By means of this arrangement, a break was provided in the possible infection path along the implant from the skin. Furthermore, the outer tubular part penetrated the skin surface thereby isolating the skin surface—where sources of infection may be present—from the bowel tissue.


The present invention relates to a dielectric resonator (20) comprising a dielectric resonator body (30, 40, 50, 60, 70, 80), where the resonator body includes at least two resonant elements (25, 26), wherein by altering the shape of the dielectric resonator body the resonance frequency (fr) in the dielectric resonator can be adjusted. The alteration of the shape of the resonant body is performed by rotation of one element in relation to another element in such a way that said elements are in mechanical contact, through connecting means, in at least one location at any time.

The present invention relates to a device for tuning of a resonator, more specifically to a resonator comprising a resonator body where the shape of the body can be changed and thus change the resonance frequency.
Among high-frequency and microwave resonator structures, so-called dielectric resonators have recently become increasingly interesting as they offer e.g. the following advantages over conventional resonator structures: smaller circuit sizes, higher integration level, higher efficiency and lower cost of manufacture. Any element having a simple geometric shape made of a material having low dielectric losses and a high relative dielectric constant can be used as a high Q dielectric resonator. For reasons of manufacturing technique, the dielectric resonator is usually cylindrical, such as a cylindrical disc.
The resonance frequency of the dielectric resonator is primarily determined by the dimensions of the resonator body. Another factor affecting the resonance frequency is the environment of the resonator. The electric or magnetic field of the resonator and, thus, the resonance frequency can be intentionally affected by introducing a metal surface or any other conductive surface in the vicinity of the resonator. To adjust the resonance frequency of the dielectric resonator, a common practice is to adjust the distance between the conductive metal surface and the planar surface of the resonator. The adjusting mechanism may be e.g. an adjustment screw attached to the housing surrounding the resonator.
Alternatively, it is also possible to bring another dielectric body to the vicinity of the resonator body instead of a conductive adjustment body. One prior art design of this kind, based on dielectric plate adjustment is shown in FIG. 1.
In this kind of adjusting method, however, it is typical that the resonance frequency varies nonlinearly as a function of the adjusting distance. Due to the non-linearity and the steep slope of adjustment, accurate adjustment of the resonance frequency is difficult and demands great precision, particularly at the extreme ends of the control range.
Frequency adjustment is based on a highly accurate mechanical movement, the slope of adjustment also being steep. In principle, the length and thus the accuracy of the adjusting movement may be increased by reducing the size of the metallic or dielectric adjustment plane.
Due to the non-linearity of the above mentioned adjusting techniques, however, the achieved advantage is small, since the portion of the adjusting curve which is too steep or too flat either at the beginning or at the end of the adjusting movement can not be used. As a result, adjusting the resonance frequency of a dielectric resonator with these solutions sets very high demands on the frequency adjustment mechanism, which in turn, increases the material and production costs. In addition, as the mechanical movements of the frequency adjustment device must be made very small, adjustment will be slower.
In U.S. Pat. No. 5,703,548, by Sxc3xa4rkkxc3xa4, the above problems was solved by introducing a dielectric resonator comprising a plurality of dielectric adjustment planes. This results in improved linearity of frequency adjustment and a longer adjusting distance, which both improve the accuracy of adjustment.
In U.S. Pat. No. 4,459,570, by Delaballe et al., a similar problem has been solved by introducing a resonator having a dielectric constant of an adjustment plate with half the value of the dielectric constant of the resonator disc.
In U.S. Pat. No. 5,315,274, by Sxc3xa4rkkxc3xa4, where tuning of a resonance frequency is achieved by a dielectric resonator comprising two cylindrical discs positioned on top of each other, which are radially displaceable with respect to each other and thereby varying the shape of the resonator.
The basic idea of the invention is to utilise the linear part of the adjustment curve although the curve is steep, thus difficult to adjust and to keep stable.
The object of the invention is a dielectric resonator in which the resonance frequency can be adjusted more accurately than previously within the steep slope.
In accordance with the invention this object is achieved by an inventive dielectric resonator, comprising a dielectric resonator body, where the resonator body includes at least two resonant elements, wherein by altering the shape of the dielectric resonator body the resonance frequency of said dielectric resonator can be adjusted. The alteration of the shape of the resonant body is performed in such a way that said elements are in mechanical contact, through connecting means, in at least one location at any time. This contact may be established via an interconnecting element. The dielectric resonator body also comprise means for moving at least a first resonant element in relation to at least a second resonant element of the resonant body and thus altering the shape of said body. The movement is be performed by rotation of the first element around an axis.
The dielectric resonator body may further comprise connecting means for connecting said first and second element, and the rotation, of said first element, can cause a displacement of said first element, in relation to said second element, in a direction of the rotation axis.
The resonator may comprise additional means for adjustment of the displacement by means for mechanical guidance. These means for adjustment may be incorporated in the connecting means by which the resonating elements are in contact with each other in at least one location.
The resonating elements may also be circularly cylindrical, where the connecting means are implemented in a circular or part-circular path, having a centre at said rotation axis.
A first advantage with the present invention is that a maximal stability in respect of relative displacement and vibrations between the elements is achieved.
A second advantage is that a temperature compensating resonator structure easily can be implemented.
A third advantage is that a compact resonator structure is obtainable.
A fourth advantage is that a high sensitivity can be obtained in respect of resonance frequency versus displacement.
A fifth advantage is that this type of dielectric resonator body can operate in a high power environment.
In the following, the invention will be disclosed in greater detail by way of example with reference to the attached drawings.

Device for tuning of a dielectric resonator