A steering column arrangement has an outer jacket tube as well as an inner jacket tube, which is displaceable within the former, as well as an adjusting device effective between the two jacket tubes for displacing one jacket tube in relation to the other jacket tube. The adjusting device comprises a drive unit and a servo component. The drive unit should be releasably fastened to a guiding device, and the drive unit should be mounted in a fashion permitting displacement along the guiding device.

This application claims the priority of German Patent Document 102 03 917.8, filed on Jan. 31, 2002, the disclosure of which is expressly incorporated by reference herein.
The invention relates to a steering column arrangement for a motor vehicle comprising an outer jacket tube, an inner jacket tube being displaceable within the outer jacket tube, and an adjusting device effective between the two jacket tubes for displacing one jacket tube in relation to the other jacket tube, the adjusting device comprising a drive unit and a servo component.
German Patent Document DE 195 24 196 C1 (corresponding to U.S. Pat. No. 5,690,362) discloses such a steering column arrangement. The known steering column arrangement has a steering spindle which supports a steering wheel and is mounted movably in terms of rotation in an inner jacket tube. The inner jacket tube is mounted inside an outer jacket tube in a telescopically displaceable fashion, the outer jacket tube being secured to the body support structure of the motor vehicle. An adjusting device is incorporated for displacing the inner jacket tube in relation to the outer jacket tube, said adjusting device being formed as a servo component taking the form of a spindle drive and being actuated by an electric motor. The spindle drive has a positioning spindle whose axis is parallel to the steering axis of the steering spindle and which runs along the outside of the outer and inner jacket tube, said spindle drive being positionally fixed on the inner jacket tube at one end face by means of a mounting. In the region of the outer jacket tube a threaded nut which is mounted between two energy-absorbing bearing blocks is seated on the positioning spindle which is formed as a threaded spindle. The electric positioning motor acts on the threaded nut via a corresponding toothed gearing. In the event of an impact load on the motor vehicle, additional impact energy can be absorbed in the region of the adjusting device by plastic deformation of the energy-absorbing bearing blocks through the introduction of forces through the adjusting spindle.
German Patent Document DE 198 12 179 C1 (corresponding to U.S. Pat. No. 6,264,239) discloses a further steering column arrangement, in which impact energy is absorbed by the adjusting device. This arrangement differs from the one described above in that the servo component running along the steering column axis is provided with a designated folding point, and in that a support bracket is provided at the height of the designated folding point, said support bracket being arranged in a positionally fixed manner on the inner jacket tube, extending at least partially over the designated folding point and being designed in a fashion permitting plastic deformation.
An aspect of the present invention is to create a steering column arrangement of the type described above, said steering column arrangement realizing a different principle of a safety steering column, in which impact energy is absorbed in the region of the adjusting device.
This aspect may be achieved in that the drive unit is releasably fastened to a guiding device and in that the drive unite is mounted so as to be displaceable along the guiding device.
According to this arrangement, the energy absorption does not take place in the region of the servo component of the adjusting device, but rather in the region of the drive unit of the latter. To this end the drive unit is releasably fastened to a guiding device, along which guiding device the drive unit is displaceably mounted under absorption of energy. This has the advantage that the absorption of energy occurs in conjunction with a defined motion of the drive unit along the guiding device. With this, the direction of motion is uniquely defined by the guiding device and is therefore predeterminable. Furthermore, as the energy absorption takes place during the motion of the drive unit in relation to the guiding device, i.e. during a defined motion, the extent and the profile of the energy absorption can be set particularly easily and accurately.
The guiding device can be assigned to a jacket tube, for example the outer jacket tube. The outer jacket tube is usually arranged fixed to the vehicle. This design has particular advantages for manufacturing, as it enables simple assembly of the guiding device on the jacket tube, as the latter is easily accessible. It is, of course, also conceivable for the guiding device to be assigned to a different vehicle component. The requirement is that this component does not move if a force is brought to bear on the steering column arrangement, said component being instead arranged in a positionally fixed fashion with regard to the vehicle.
According to one embodiment, the guiding device comprises at least one rail, the latter being aligned in the longitudinal direction of the steering column arrangement. The alignment in the longitudinal direction has the advantage that the drive unit also moves in a defined fashion in the longitudinal direction of the steering column arrangement. A guiding device which permits a motion of the drive unit in a different direction is also conceivable, but this would require greater build space.
For reasons of cost it is advantageous to have the guiding device and the jacket tube formed as a single part, as in this case the cost and effort of attaching the guiding device to the jacket tube are saved. Of course, an embodiment comprising a plurality of parts is also conceivable.
The drive unit can have receptacles assigned to the guiding configured. By way of the design of these receptacles, it is possible to define the resistance force opposing a displacement of the drive unit along the guiding device. In other words, by way of the receptacles it is possible to influence the extent of the energy absorption in a particularly simple manner.
The attachment of the drive unit to the guiding device can be configured in such a way that failure of the attachment occurs if a predetermined level of force being brought to bear on the steering column arrangement is exceeded. This embodiment represents a particularly simple way of activating the displacement of the drive unit and a simple way of activating the energy absorption. It is also conceivable for the attachment to be released depending on values measured by sensors, for example certain acceleration values.
Furthermore, it is also conceivable to assign an additional energy absorption element to the drive unit, which additional energy absorption element is then also activated if the drive unit is displaced in relation to the guiding device. In this way the extent of the energy absorption can be increased again. Depending on the type of energy absorption element chosen, the profile of the energy absorption can also be accurately set.
A metal element can be used, for example, as the energy absorption element, said metal element absorbing energy while being deformed. Such energy absorption elements are sufficiently well known and have the advantage that their deformation behavior and the energy required for and absorbed during the deformation process can be calculated with a high degree of accuracy. In this way, the extent of the energy absorption can be very accurately predetermined or set.
The energy absorption element can, for example, comprise a wire. A wire takes up little space, which is advantageous in terms of build space. It is furthermore conceivable to attach one end of the wire to the drive unit, so that a force is brought to bear on the wire at the moment when the drive unit starts to move. If the wire is routed around an obstacle, the wire is pulled around the latter at the moment when the force is brought to bear on the wire, and the wire deforms in the process. Energy is dissipated by this deformation. The profile and the extent of the energy absorption can be very easily set by the material and dimensions (cross section) of the wire.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

Steering column arrangement for a motor vehicle


Embodiments of the present invention provide an approach for provisioning a virtual resource instance (e.g., a server instance, etc.) in a networked computing environment (e.g., a cloud computing environment) based upon network characteristics (e.g., physical locations, email addresses/configurations, network connection types, internet protocol (IP) addresses, etc.) of a set (at least one) of intended end users of the virtual resource instance. Specifically, in a typical embodiment, the network characteristics associated with the set of intended end users will be gathered and analyzed (e.g., to determine end user location, etc.). The analysis of the network characteristics will then be used to calculate/determine relative (e.g., network) efficiency scores for each intended end user for a set of potential data centers for the virtual resource instance. The relative efficiency scores for each potential data center will be summed/totaled to yield a total (e.g., network) efficiency score for each potential data center. Thereafter, the particular data center with the highest/best total efficiency score may be selected, and the requested resource instance may be provisioned at that data center.

The networked computing environment (e.g., cloud computing environment) is an enhancement to the predecessor grid environment, whereby multiple grids and other computation resources may be further enhanced by one or more additional abstraction layers (e.g., a cloud layer), thus making disparate devices appear to an end-consumer as a single pool of seamless resources. These resources may include such things as physical or logical computing engines, servers and devices, device memory, and storage devices, among others.
When provisioning resource instances in networked computing environment (e.g., a cloud computing environment), an end user often has a choice where a running instance may be located (e.g., such as in a data center in the western United States, northeastern United States, etc.). However, challenges may exist in that an optimal location for a resource instance (e.g., based on its intended users) may not be known at the time the request is made by a requesting user. Moreover, it is often difficult to move an instance once it has been provisioned and is actively accessed by end users.

Determining resource instance placement in a networked computing environment

International Business Machines Corporation


A pressure vessel (10) is provided with: a cylinder part (1) that defines a pressure chamber (11); a screwing part (3) that is disposed inside at least one of the two ends of the cylinder part; a lid (2) that has a pressure-receiving surface (2A) facing the pressure chamber and that is disposed at a position closer to the pressure chamber than is the screwing part; and a reinforcing ring (4) that is fitted to the outer circumferential surface of the cylinder part. The reinforcing ring covers, along the axial direction of the cylinder part, a part on an outer circumferential surface (1F) corresponding to a portion or the entirety of the engaging portion (12) between the cylinder part and the screwing part.

Examples of a device for storing high-pressure gas include a pressure vessel for storing and transporting high-pressure hydrogen gas used at a hydrogen station or the like. Conventionally, the pressure vessel is manufactured using high-strength low-alloy steel such as Cr—Mo steel. However, in a case where hydrogen is stored in the pressure vessel, when the pressure vessel has a structure in which hydrogen comes into direct contact with a screwable portion constituting an opening portion of the pressure vessel, there is a concern that strength and ductility of a stress concentrated portion (for example, a screw-threaded portion between a male thread and a female thread) in the screwable portion may decrease due to so-called hydrogen environment embrittlement. Such embrittlement of the pressure vessel is not preferable because it may cause a reduction in an accumulation performance of the pressure vessel.
Therefore, in one of the conventional pressure vessels, a structure (a so-called screwable nut type lid structure) is adopted in which a lid-like structure is interposed between a screwable portion and an accumulator chamber, so that the screwable portion and hydrogen do not come into direct contact with each other. With this structure, the conventional pressure vessel suppresses hydrogen environment embrittlement at a screw-threaded portion (for example, roots of threads) between a male thread and a female thread of the screwable portion (see, for example, NPL 1).


A controlled release fertilizer composition and methods to produce the controlled release fertilizer composition. The controlled release fertilizer composition includes a fertilizer core that is coated with a polymeric layer, such as polyurethane, that includes an organic carbonate additive.

Fertilizers have been used for many years to supplement plant nutrients in soil or other growing media. In recent years the art has focused on techniques to deliver controlled amounts of plant nutrients to the soil or other growing media. It is recognized, for example, that controlling the release of plant nutrients such as nitrogen from highly soluble fertilizer granules is desirable because releasing the nutrients over an extended period of time achieves advantages which include increased efficiency of fertilizer use by plants, reduced application costs since fewer applications of fertilizer are required and reduced nutrient loss caused by leaching and denitrification. Applying a coating on the surface of the fertilizer granules may reduce the dissolution rate of the granules and impart controlled-release characteristics. In essence, the water in the soil and rainwater are kept away from the very soluble fertilizer until a granule develops a flaw such as a crack or fissure in the coating or the coating develops porosity upon exposure to water.
In some applications, a sulfur coating is applied to fertilizer granules. Due to the inherent brittleness of the crystalline solid sulfur-coating and the thin, or even non-continuous, coating on many of the granules, it is typical to apply some type of secondary outer coating or sealant onto the sulfur-coated surface. This sealant conventionally is either a polymeric hydrocarbon, petroleum-based wax, or a combination of high viscosity polymeric paraffinic oil plus polyethylene, which is spray-applied as a hot melt liquid onto the hot, but solidified sulfur-coating surface.
Although these sulfur coated fertilizers have received substantial uses, there are problems from the standpoint of obtaining uniform coating thicknesses, obtaining predictable release characteristics, abrasion and impact resistance, and the complexity of the coating process steps. Because of these problems associated with sulfur coated fertilizers, polymer coated fertilizers have received substantial attention, particularly in view of the improved controlled release properties obtained with certain polymer coated fertilizers at lower coat weights. The polymer coated fertilizers may have multiple coating layers. Examples of polymeric fertilizer coatings include: an inner coating of a urethane reaction product derived from reacting isocyanate and polyol, with an outer coating of an organic wax; an oleo polyol(s) coating; a polyurea coating formed by applying an isocyanate-reactive component containing at least two amine groups and subsequently applying a polyisocyanate.
Various polymeric yet sulfur containing coatings are also known. Examples of such coatings include: sulfur containing isocyanate coatings prepared by applying a mixture of sulfur and an isocyanate to the fertilizer and then applying an isocyanate-reactive material; a coating formed by applying a sulfur coating and subsequently applying a polymer coating over the sulfur; a thermosetting resin coating such as urethane and a hydrophobic compound (e.g., wax); a multilayer coating comprising a polyurethane layer and a wax layer; and a multilayer coating comprising a polymer layer, a sulfur layer, and another polymer layer.
Other coatings are also known. For example, a fertilizer core can be coated with organic oil and particles to improve the release profiles of the fertilizer.

Fertilizer granules having polymeric coating with organic carbonate


The present invention relates to methods for detecting a target nucleotide sequence in a sample. More particularly, the present invention relates to methods for detecting a target nucleotide sequence in a sample which utilise a nuclease-aptamer complex. The present invention also provides nuclease-binding aptamers, nuclease-aptamer complexes and linker molecules that may be used in accordance with the methods of the present invention.

A range of molecular technologies for the detection of a nucleotide sequence of interest (also referred to herein as a 'target nucleotide sequence') have been developed. Such methods have application in, for example, public health, the detection of pathogens in food or water, epidemiological studies, genetically modified organism (GMO) detection, medicine, clinical diagnoses, disease susceptibility diagnoses, tissue typing, blood screening, forensic medicine, bioweapon detection, molecular toxicology, gene therapy, and DNA tagging, among many other applications.
Current methods for detecting a target DNA sequence generally involve one, or a combination of, molecular techniques. These techniques generally fall into three groups loosely defined as sequence-specific detection, sequence-specific enrichment and signal amplification.
Most detection techniques gain their sequence specificity through base paring of complementary probes or oligonucleotides to a sequence of interest within the target DNA sample.
The two most commonly used DNA detection methods, polymerase chain reaction (PCR) and Southern blotting, differ in how they proceed from this point. The PCR method enriches a target DNA through a series of amplification cycles and signal detection can be, for example, though the use of stains, fluorescence or radiolabelling. Southern blotting involves no DNA enrichment step, but uses high-energy 32P for signal amplification. These extensively used techniques, though highly developed, still retain significant drawbacks. For PCR, the equipment required is expensive, the process is time-consuming and the degree of expertise required is high. Southern blotting often uses hazardous radioactive labelling, takes up to a week to complete, and requires large amounts of substrate DNA.
An effective biosensor for detecting a specific DNA sequence in a sample that addresses one or more of the deficiencies of the currently available techniques, without substantially losing target-specificity or sensitivity, would be desirable. Furthermore, such a technique would also ideally require a low capital input (particularly in the case of equipment requirement), minimal expertise or technique-specific training, and provide quick and accurate results.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

Methods for detecting a target nucleotide sequence in a sample utilising a nuclease-aptamer complex

Australian Centre for Plant Functional Genomics Pty, Ltd


A gasket structure including a gasket that is disposed at a connecting portion between a first case and a second case, has a large-width portion at a certain portion of the first case where a key or a terminal is disposed, and is made of a flexible material; and a core member that is attached to at least the large-width portion of the gasket.

1. Field
This disclosure relates to a gasket structure used in a case having a waterproof structure and to a terminal device including a case having such a gasket structure.
2. Description of the Related Art
Waterproof terminal devices serving as compact terminal devices, such as mobile phone terminal devices, are being developed. The waterproof terminal devices use a gasket to maintain the airtightness inside a case. The gasket is formed of a flexible resin and is disposed at a connecting portion when the case is assembled. Because the gasket is disposed at the connecting portion of the case, the gasket fills a gap at the connecting portion, preventing water from entering the case.
PTL 1 discloses a waterproof structure achieved by filling a gap in a case with a gasket when the case of a mobile phone terminal device is assembled.

Gasket structure for a terminal apparatus


Phase shift amplifier formed by a differential pair of input transistors each collector of which transistors is connected to a respective phase shift resistor and to a phase shift capacitor, whereas the other ends of each phase shift resistor form nodes A and B respectively, while the other ends of the phase shift capacitors are connected in a cross-coupling. According to the invention, the nodes A and B are connected to the input of amplifiers of the transimpedance type at the output of which amplifiers a differential signal is available which is phase shifted relative to the differential input signal.

The invention relates to a phase shift amplifier comprising a first and a second transistor arranged to form a differential input pair supplied with steady current, these transistors each having a control electrode for receiving an input signal, and an output electrode, in which amplifier the output electrode of the first transistor is connected to a terminal of a first phase shift resistor and also to a terminal of a first phase shift capacitor, the output electrode of the second transistor is connected to a terminal of a second phase shift resistor and also to a terminal of a second phase shift capacitor, the second terminal of the first phase shift resistor is connected to the second terminal of the second phase shift capacitor at a first node, and the second terminal of the second phase shift resistor is connected to the second terminal of the first phase shift capacitor at a second node.
The invention likewise relates to a recombining circuit which effects for either one of the two differential input signals which are phase shifted relative to each other, an amplification and a summation of these signals after a complementary phase shift, one of the input signals presenting a first component of a given phase and the other input signal presenting a second component which has a quadrature phase relationship to the first component.
Phase shift amplifiers are used nowadays in numerous applications and, more particularly, in the field of radio frequency transmissions. A typical application consists of producing two signals which are quadrature signals in view of their transmission coding. A second particularly important example of the use of phase shift amplifiers with respect to reception comprises the realization of a mixer in which two phase shift amplifiers are used which allow, when the quadrature phase shift is ideally adhered to, the elimination of the image frequency in a superheterodyne receiver.
A phase shift amplifier of the type defined in the opening paragraph is known from document WO-A-9211704 where it is described more particularly with reference to FIG. 2 of that document. The known phase shift amplifier utilizes networks of the series arranged RC type connected in parallel between the output electrodes of the transistors of the input stage. This amplifier operates, in essence, with a voltage because circuits of phase shift resistors-phase shift capacitors produce at their junctions a signal in the form of an output voltage signal, so that a high input impedance should be used.
In effect, the impedance used affects the phase shift of the output signals when it is not large relative to the impedance of the elements of the RC network. This indicates a serious drawback from the point of view of current consumption. In effect, to maintain a high signal-to-noise ratio at the output of the phase shift amplifier, it is necessary to supply this amplifier with a relatively large current. But at the output of the phase shift amplifier, a power amplifier is necessary which is also to be supplied with a large current for the same reason.

Phase shift amplifier and its applications to a recombining circuit


A unit dose spoon having a bowl portion, a recessed handle portion communicating with the bowl portion. An upwardly extending pedestal is mounted in the recessed handle portion and is provided with an upwardly extending cutting blade on the top surface thereof A container is integrally hinged to the free end of the handle portion and contains a unit dose of fluid such as a medicine, which is sealed in the container by a rupturable plastic cover. When the container is folded forwardly toward the handle portion and pushed downwardly toward the pedestal, the blade thereon punctures the plastic cover to allow the fluid to flow from the container into the recessed handle portion and into the bowl portion. The unit dose spoon is formed of molded plastic and is disposable.

Various spoons have been proposed having hollow handles containing various types of fluids adapted to be dispensed into the bowl portion of the spoon.
While these spoons have been satisfactory for their intended purpose, the unit dose spoon of the present invention is an inprovement thereon in that a container containing a unit dose of a fluid, such as a medicine, is integrally formed with the spoon and is adapted to be manipulated in such a way as to dispense the unit dose from the container into the bowl portion of the spoon. The spoon and container can be of plastic, simultaneously molded as a single entity, and is disposable after use.


An auto-focusing camera includes a stator (20), a rotor (30) rotatably disposed in the stator, and a lens unit (40) received in the rotor. The stator includes a stator core (23) and coils (25) winding on the stator core. The rotor is a permanent magnet (32) securely mounted around the lens unit. The lens unit forms three ears (414) at a bottom thereof, and a wave-shaped surface (220) is formed on a top of an inner, bottom flange (22) of the stator. The ears abut the wave-shaped surface. The ears of the lens unit move along the wave-shaped surface during rotation of the rotor and the lens mount, and thus the lens unit moves telescopically along an axial direction thereof.

1. Field of the Invention
The present invention relates generally to a lens drive mechanism of a camera, and more particularly to a lens drive mechanism of an auto-focusing camera.
2. Description of Related Art
Usually we need a camera to record the memorable moments. The designs of cameras have evolved toward lightweight and compactness, so have the currently popular digital cameras. Conventionally, an auto focus structure is used for controlling the telescopic movement of a lens of the camera.
The auto focus structure of the camera focuses on an object by comparing with the image on an image sensor. The image sensor is either a charge coupled device (CCD) sensor or a complementary metal oxide semiconductor (CMOS) sensor, and is controlled by a central processing unit (CPU) installed inside the digital camera. In the beginning, the lens moves back and forth around its original position (static position). As the lens moves, the CPU compares the image from the lens with the image in the image sensor. Finally, as the lens moves to the position where the image is the clearest, then the lens stops at the position. In this case, the lens has to be continuously driven back and forth by an annular cam. The annular cam is provided with a lens driving structure and driven to rotate by a stepping motor. At the moment when the CPU detects the clearest image as the lens moves back and forth, a stop signal is simultaneously sent to the lens. Therefore, the lens stops at the best focal position (static position). When the lens is to be moved back to the original position, the annular cam starts to rotate again. Once the lens moves back to its original position, the photo interrupter installed by the lens cylinder uses the shutter at the border of the lens cylinder to detect the original position of the lens. The shutter will interrupt the light of the penetration-type photo interrupter. The lens stops at the moment when the photo interrupter detects the original position.
Consequently, the lens in a digital camera auto focus system has to be driven continuously, so is the image detection. Every time an image is captured, the lens has to return to its original position. This method of searching for an optimal focal point makes use of mechanical and continuous lens motion to repeatedly check the image. Thus, the lens focusing procedure is very time-consuming, which, in most of cases, results in losing the best image-capturing time.

Fu Zhun Precision Industry (Shen Zhen) Co., Ltd.


A frame buffer having a size of one video frame of a video stream is provided. The video stream has a source frame rate. Image data units of the video stream are written consecutively to the frame buffer in accordance with a circular buffering scheme and in real-time response to the video stream. Image data units are read from the frame buffer in accordance with the circular buffering scheme with a frame rate that is twice the source frame rate so as to generate a target video stream having a frame rate which is twice the source frame rate. The frame buffer can be used in a real-time video system, for example in a vehicle.

A video frame is a still image that can be displayed on a video display, e.g., a liquid crystal display (LCD) or a cathode ray tube (CRT). A video stream is a stream of video frames. Consecutively displaying the video frames on a screen can give a viewer the impression of a moving image. The number of frames per second provided by the video stream and the number of frames per second displayed by the display are each known as a frame rate. The stream of video frames can be provided in the form of a stream of image data units, each frame comprising a certain number of consecutive image data units. Each image data unit may represent, for example, a single pixel or a group of pixels, e.g., a group of adjacent pixels.
In a real-time viewing system, a video camera can be operated to generate a video stream which can be fed to a video display to provide a live view of the scene captured by the video camera. Traditionally, a buffer connected between the video source and the video display can ensure a steady display of the video content.
Some types of video sources, e.g., cameras, and some types of video displays, e.g., LCDs, have a certain fixed frame rate which is tunable only within a very narrow range. For instance, certain cameras are designed to produce video streams with a frame rate of 30 frames per second (fps), and some video displays have a refresh rate of 60 Hertz (Hz), i.e. 60 fps.
It is an object of the invention to provide a buffering and a frame rate doubling device for driving a video display by a video stream having a frame rate which is half the frame rate of the video display. Furthermore, it is an object of the invention to provide a method of driving a video display by a video stream having a frame rate which is half the frame rate of the video display. It is desired to implement the device and to execute the method using low cost hardware.

Video buffering and frame rate doubling device and method


A method is provided for determining at least one operating parameter of a thermoelectric system in a vehicle, wherein the thermoelectric system comprises an energy conversion device having at least one photovoltaic element for converting thermal radiation, which is emitted by a heat source of the vehicle, into electrical energy. The method includes measuring an electrical power of the photovoltaic device, and determining an operating parameter of the thermoelectric system based on the measured electrical power of the photovoltaic device.

The increasing hybridization of vehicles makes it necessary to make available electrical energy in the vehicle to a greater degree than is necessary in a conventional motor vehicle for operating electrical systems. Since insufficient electrical energy can be made available with contemporary battery technology, it is necessary to provide the vehicle with devices for acquiring and recovering electrical energy. For this purpose, inter alia, methods for recovering energy such as, for example, the recuperation of braking energy or the thermoelectric conversion of energy from waste heat which is produced in the combustion process are known. The thermoelectric conversion of energy takes place, inter alia, by utilizing the photoelectric effect, wherein the thermal radiation which is emitted by a hot component is converted directly into an electric voltage by means of photovoltaic cells. The photovoltaic cells which are typically formed from semiconductor materials are arranged here as close as possible to the heat source in order to obtain the highest possible energy yield. In this environment, these sensitive components are subjected to conditions which can have an adverse effect on the functional capability and/or efficiency of the photovoltaic elements. It is therefore possible, for example, for heat and various chemical substances to contribute to an accelerated ageing process of the photovoltaic elements which are typically formed from semiconductor materials. Furthermore, soiling of the photovoltaic elements can lead to a loss of efficiency due to shadowing effects. In addition, the further components of the thermoelectric system such as, for example, the cabling or the plug-type connections of the photo cells may also lead to a reduction in the efficiency level of the system due to ageing or owing to damage.
In order to detect such disruption of the thermoelectric system in good time and avoid losses during the recovery of energy by means of suitable countermeasures, it is appropriate to monitor the operating state of the thermoelectric system.

Method and apparatus for determining at least one operating parameter of a thermoelectric system in a vehicle


An MR coil former apparatus includes a body, a coil array, and a coil cover. The body defines a patient-facing positive surface opposite a non-patient-facing negative surface. The positive surface of the body includes an anatomic contour, and the coil array is disposed adjacent and conformed to the anatomic contour. The coil cover is disposed overlying the coil array and conformed to the anatomic contour.

Technical Field
Embodiments of the invention relate generally to enhancing quality of images obtained from MR scanners, including PET-MR scanners. Particular embodiments relate to formers used for positioning MR coils adjacent patient anatomy.
Discussion of Art
Magnetic resonance imaging ("MR") uses RF antenna coils to detect rotating ("relaxation") magnetic fields that are produced by nuclei that have odd atomic numbers, i.e., total number of neutrons and protons is not divisible by two, in response to alternately imposing and removing a scanning exciting magnetic field. Typically, MR is accomplished by imposing on a target material a strong (e.g., 1.5, 3 or 7 Tesla) constant magnetic field ("alignment field") that spin-aligns nuclei of atoms within the target material. In order to obtain the relaxation magnetic field, an exciting field that fluctuates at radio frequencies (e.g., anywhere from about 64 MHz to about 900 MHz, typically at 1.5 T) is superimposed over the alignment field.
MR is frequently used for differentiating tissue types within a patient, and is also used for identifying fine detail structures. Typically, different pulse sequences are used for tissue differentiation. For example, a T1 pulse sequence can be used to obtain images with water appearing darker and fat brighter. On the other hand, a T2 pulse sequence can be used to obtain an image with fat darker, and water lighter.
One advantage of MR is that magnetic fields do not attenuate in body tissues, so that nucleus location can be determined (using Fourier analysis) based solely on frequency shifting between the imposed magnetic field and the response field. Another advantage is that by careful selection of pulse sequence, distinct tissues or materials can be highlighted.
For enhanced MR imaging, the detector coils typically are disposed as close as possible to the tissues being imaged. Typically, a "former" is provided both for positioning the detector coils and for positioning a patient within the MR field. Formers conventionally have been made of non-ferromagnetic materials that do not interfere with or mimic the MR response of patient tissues, and that exhibit high rigidity in a thin section (e.g., injection-molded polycarbonate or polyurethane). Such materials typically have been formed into a hollow shell, with the detector coils supported by the negative (non-patient-facing) surfaces of the former, inside the shell, and connected with ancillary circuitry housed within the shell. By locating the detector coils at the negative surface, it is possible to provide maximal room for assembly of detector coils and ancillary circuitry, enhance patient comfort, and avoid mechanical design complications associated with through-holes in the former surface. provide a flame barrier, Additionally, detector coils frequently couple and dissipate relatively large electrical power—often in excess of 15 W. By anchoring the detector coils at the "negative" (non-patient-facing) surface of the former, the former itself can then provides a flame barrier rated "V2" or higher (per UL standard 94) between the patient and the high-power detector coils. For example, a former may be fabricated to include greater than about 1.1 mm thickness of "Lexane 940"™ polycarbonate.
Although the conventional "shell" formers do provide maximal volume for ancillary circuitry, and facilitate connection of the detector coils to the circuitry, actually arranging and attaching the detector coils onto the negative surfaces has been identified as a manufacturing challenge. Partly because permanent adhesives are used for secure positioning, the negative surface coil arrays also are hard to repair. Nonetheless, many factors inform the conventional approach to building internal or negative-surface coil arrays.
MR can be combined with positron emission tomography (PET) within a single apparatus (a "PET-MR scanner"). Such scanners use one or more rings of scintillators or other detectors to generate electrical signals from gamma rays (photon pairs) that are produced from the recombination of electrons, within a target material, and positrons, emitted from decay of a radionuclide packaged in a tracer compound. Typically, recombination events occur within about 1 mm from the radionuclide decay event, and the recombination photons are emitted in opposite directions to arrive at different detectors. Paired photon arrivals that occur within a detection window (usually less than a few nanoseconds apart) are counted as indicating a recombination event, and, on this basis, computed tomography algorithms are applied to the scintillator position and detection data in order to locate the various recombination events, thereby producing three-dimensional images of the tracer disposition within the target material.
Typically, the target material is body tissue, the tracer compound is a liquid analogue to a biologic fluid, and the radionuclide is disposed primarily in body tissues that make use of the biologic fluid. For example, a common form of PET makes use of fludeoxyglucose (18F), which is analogous to glucose with the 18F radionuclide substituted for one of the hydroxyl groups ordinarily composing glucose. Fludeoxyglucose is preferentially absorbed by brain matter, by the kidneys, and by growing cells (e.g., metastasizing cancer cells). Thus, PET is frequently used for oncologic studies, for localizing particular organs, and for studying metabolic processes.
PET signal attenuation is very specific to patient anatomy and material properties. In particular, the dense and rigid polymers typically used in MR formers (e.g., polycarbonate, polyurethane) can significantly attenuate the gamma rays generated by positron recombination events. For example, a conventional head/neck coil former built from polycarbonate may attenuate PET sensitivity by as much as about 21 percent. Moreover, dense polymers tend to be absorptive of positrons, producing noisy recombinations that can obscure PET imaging of body tissues. However, given the conventional preference for negative surface coil and circuit assemblies, polycarbonate, polyurethane, and similar high-density, high-rigidity polymers have been seen as the typical materials for building coil formers.
One factor particularly promoting the retention of high-density polymers has been that lower-density materials would require increased shell wall thicknesses, thereby displacing coils from the patient and diminishing MR signal/noise ratio (SNR). Diminished SNR would require longer MR scan times, which detracts from a general goal of increasing scanner utilization. Thus, conventional designs and material choices for coil formers have presented a dilemma of optimizing either for PET or for MR imagery. One option has been to provide additional openings through the light structure of non-weight-bearing (anterior) formers. For example, anterior HNU formers in PET-MR environment may have additional holes to allow positrons to pass, but providing more openings is a technique that has only been used on non-supporting formers that are anterior to the patient. As PET relies upon near-simultaneous detection of two photons at opposite sides of a scintillator ring, having the additional holes only at the anterior side renders this option ineffective for actually enhancing the PET signal.

Expanded foam former apparatus and method for making the same


The present invention relates to the discovery that acetylsalicylic acid (ASA or aspirin), salicylic acid (SA) and related salicylate esters and their pharmaceutically acceptable salts, when coadministered in effective amounts with a drug or other bioactive agent which typically (in the absence of the salicylate compound) produces significant hepatotoxicity as a secondary indication, will substantially reduce or even eliminate such hepatotoxicity. Favorable therapeutic intervention results from the use of the present invention having the effect of reducing hepatotoxicity associated with the administration of certain drugs and other bioactive agents and in certain instances of allowing the administration of higher doses of a compound which, without the coadministration, would produce hepatotoxicity which limits or even negates the therapeutic value of the compound.

Acetaminophen (APAP) hepatotoxicity is the most common cause of death due to acute liver failure in the developed world, and is increasingly recognized as a significant public health problem (1, 2). The initial event in APAP induced hepatotoxicity is a toxic-metabolic injury leading to hepatocyte death by necrosis and apoptosis. This results in secondary activation of the innate immune response involving up-regulation of inflammatory cytokines with activation of NK, NKT cells and neutrophils, which significantly contributes to hepatotoxicity and mortality (3, 4). The molecular pathways for innate immune activation after hepatocyte death are of great interest as they are likely a common pathway in sterile inflammation.
IL-1β is a very potent pro-inflammatory cytokine, and IL-1β levels are known to be increased during APAP hepatotoxicity (5, 6). In addition signaling through the IL-1 receptor (IL-1R) was recently shown to be important in APAP induced hepatotoxicity (7). The mechanisms by which cellular death results in up-regulation of IL-1β and activation of the sterile inflammatory response are not known. In contrast to sterile inflammation there is extensive data on IL-1β up-regulation by a variety of pathogens. Activation of Toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) results in up-regulation of pro-IL-1β via a MyD88, NF-kB pathway. Analogous to other potent inflammatory steps, production of IL-1β requires a second signal resulting in caspase-1 mediated cleavage of pro-IL-1β to release the active molecule (8-10).
Our approach was to try to identify the two signals which were responsible for IL-1β production in APAP hepatotoxicity. TLR9 was of interest to us as a candidate molecule responsible for the first signal in sterile inflammation because in addition to being activated by bacterial DNA rich in un-methylated CpG motifs it can also be activated by DNA from mammalian cells (11) (12). When mammalian cells undergo apoptosis genomic DNA is modified by the caspase-activated DNAase (CAD)-mediated cleavage, and also aberrant methylation and oxidative damage (13-15). These apoptosis mediated changes increase the ability of mammalian DNA to activate TLR9 (16).
The activity of caspase-1 is regulated by a cytosolic protein complex called the inflammasome consisting of a NALP family member, the adaptor protein ASC and caspase-1 (17). A variety of molecules can result in activation of NALP pathways. These include molecules from dying mammalian cells causing activation of the inflammasome via NALP3, and molecules from gram negative organisms causing activation via IPAF (17). The NALP3 inflammasome was of interest to us as a candidate molecule responsible for providing the second signal required for IL-1β activity in APAP hepatotoxicity, and this was tested using mice deficient in caspase-1, ASC, or NALP3. We further aimed to identify clinically applicable strategies for down-regulating the caspase-1 inflammasome pathway, and test if they provide protection from APAP induced hepatotoxicity.

Compositions and methods for reducing hepatotoxicity associated with drug administration


The present invention relates to methods of using and pharmaceutical compositions containing compounds of Formula I: ##STR1## wherein R.sup.1 is hydrogen, --COR.sup.4 wherein R.sup.4 is C.sub.1 -C.sub.4 alkyl, or --COOR.sup.5 wherein R.sup.5 is C.sub.1 -C.sub.4 alkyl; R.sup.2 is C.sub.1 -C.sub.4 alkyl, phenyl, or --OR.sup.6 wherein R.sup.6 is C.sub.1 -C.sub.4 alkyl; and R.sup.3 is C.sub.6 -C.sub.8 alkyl, halogen, or NO.sub.2 ; with the proviso that when R.sup.1 is hydrogen, R.sup.2 is C.sub.1 -C.sub.4 alkyl; and a pharmaceutically acceptable carrier. Compounds of Formula I and pharmaceutical compositions containing them are inhibitors of 5-lipoxygenase and are useful in the treatment of conditions mediated by leukotrienes such as inflammation, allergy, hypersensitivity reactions, and proliferative skin diseases such as psoriasis.

(a) Field of the Invention
This invention relates to pharmaceutical compositions containing a class of 2-(4-substituted)phenylmethylene derivatives useful as inhibitors of 5-lipoxygenase, an enzyme which plays an important role in leukotriene biosynthesis. This invention also relates to the use of 5-phenyl-1,3-dioxoalkenyl compounds as inhibitors of 5-lipoxygenase. By inhibiting 5-lipoxygenase and thus leukotriene biosynthesis, the compounds of this invention are useful in preventing or alleviating conditions associated with leukotrienes, such as allergic reactions, inflammatory conditions, immediate hypersensitivity reactions, asthma, and certain proliferative skin disorders such as psoriasis.
Arachidonic acid is converted enzymatically to various biologically active products, such as prostaglandins, thromboxanes, various hydroxyeicosatetraenoic and hydroperoxyeicosatetraenoic acids, and leukotrienes. The leukotrienes, products of the 5-lipoxygenase pathway, are implicated in allergic reactions, particularly asthma, see M. Griffin et al. , N. Engl. J. Med. , 308 , 436-439 (1983); inflammatory conditions; and skin diseases such as psoriasis. One leukotriene, LTD.sub.4, is the major active constituent of slow reacting substance of anaphylaxis (SRS-A), a potent bronchoconstrictor that is released during allergic reactions. See R. A. Lewis and K. F. Austen, Nature , 293 , 103-108 (1981). When administered to humans and guinea pigs, LTD.sub.4 causes bronchoconstriction by two mechanisms: 1) directly by stimulating smooth muscle; and 2) indirectly through release of thromboxane A.sub.2, which causes contraction of respiratory smooth muscle. Because antihistamines are ineffective in the management of asthma, SRS-A is believed to be a mediator of the bronchoconstriction occurring during an allergic attack. LTD.sub.4 may also be involved in other inflammatory conditions such as rheumatoid arthritis. Another leukotriene, LTC.sub.4, is also a very potent bronchoconstrictor. A third leukotriene, LTB.sub.4, is associated with leukocyte chemotaxis, a phenomenon in which leukocytes migrate from the blood to an inflammatory site in response to chemical or biological stimuli, and may be involved in both acute and chronic inflammation. LTB.sub.4 also appears to be associated with rheumatoid spondylitis and gout. Thus, the 5-lipoxygenase inhibitors of this invention, by inhibiting the production of leukotrienes, may prevent or alleviate the allergic, inflammatory, or hypersensitivity conditions associated with leukotrienes.
Non-steroidal antiinflammatory agents, such as aspirin, indomethacin, ibuprofen, and the like, inhibit prostaglandin biosynthesis by blocking the cyclooxygenase pathway of arachidonic acid metabolism. As a consequence, leukotriene levels may increase as arachidonic acid is metabolized along the 5-lipoxygenase pathway, producing allergic reactions. Administration of 5-lipoxygenase inhibitors of this invention may be effective in reducing undesirable side effects associated with non-steroidal antiinflammatory agents when administered separately or in combination.
See (1) P. Sirois, "Pharmacology of Leukotrienes" in Advances in Lipid Research , 21 , 79-101 (1985); (2) M. K. Bach, "Inhibitors of Leukotriene Synthesis and Action" in The Leukotrienes: Chemistry and Biology , L. W. Chakrin and D. M. Bailey, eds., pp. 163-194 (Orlando: Academic Press, 1984); (3) M. K. Bach, Bioch. pharmacol. , 33 , 515-521 (1984); (4) C. W. Lee et al. , "Human Biology and Immunoreactivity of Leukotrienes" in Advances in Inflammation Research , 6 , 219-225 (1984); (5) P. Sharon and W. F. Stenson, Gastroenterology , 84 , 454-460 (1984); (6) E. L. Becker, Trends Pharmacol. Sci. , 4 , 223-225 (1983); (7) Editorial, "Leukotrienes and Other Lipoxygenase Products in the Pathenogenesis and Therapy of Psoriasis and Dermatoses" in Arch. Dermatol. , 119 , 541-547 (1983); (8) B. Samuelsson, Science , 220 , 568-575 (1983); (9) R. A. Lewis et al. , Int. J. Immunopharmac. , 4 , 85-90 (1982); (10) M. W. Musch et al. , Science , 217 , 1255-1256 (1982).
Unlike earlier therapeutic agents that treat symptoms rather than causes, the compounds of this invention and the pharmaceutical compositions thereof block the formation of causative mediators of allergic and inflammatory conditions and are therefore useful in the treatment of allergic reactions, inflammation, and other conditions associated with leukotrienes.
(b) Background Information
European Patent Applications EP 0195097 and EP 0142145 disclose compounds of the formula ##STR2## or a salt thereof,
in which Y is a group ##STR3##
where m is an integer of from 1 to 5
n is an integer of from 4 to 12
each of R.sup.1 and R.sup.2, which may be the same or different, represents hydrogen or C.sub.1-6 alkyl
X represents a double or triple bond, and each of
A and B represents hydrogen when X is a double bond, or both A and B are absent when X is a triple bond.
These compound are arachidonic acid analogues which are said to be useful in treating allergic diseases. These compounds differ structurally from the compounds of the present invention since they always have unsaturation in the hydrocarbon chain attached to the phenyl.
Some 2-(4-substituted)phenylmethylene compounds have been used as intermediates in the synthesis of other compounds.
J. MED. CHEM., 15(12):1297-1306 (1972) generically discloses intermediates of the formula ##STR4## wherein R =H, alkyl, cycloalkyl which are used to make indan-1-carboxylic acids of the formula ##STR5##
The indan-1-carboxylic acids are said to have antiinflammatory activity. Intermediates in which R is isopropyl, isobutyl, cyclopentyl, cyclohexyl, and cycloheptyl are specifically disclosed in Table II on page 1296. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 3,925,395 generically discloses intermediates of the formula ##STR6## wherein R.sup.2 is phenyl, unsubstituted or substituted by 1 to 3 of the same or different substituents selected from the group consisting of alkyl, especially lower alkyl, alkoxy, especially lower alkoxy, halogen, nitro. cyano, trifluoromethyl, carbalkoxy, especially carb/lower alkoxy and SO.sub.3 -alkyl, especially lower alkyl. These intermediates are used to make 4-aryl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid esters which are said to be useful as coronary agents and as anti-hypertensive agents. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 3,962,269 generically discloses intermediates of the formula EQU ArCH.dbd.C(CO.sub.2 C.sub.2 H.sub.5).sub.2
wherein Ar is phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, methylphenyl, trifluoromethylphenyl, or 3-pyridyl. Intermediates of the formula ##STR7## wherein R is 2-methyl, 3-methyl, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2,4-dichloro, 4-fluoro, or 4-.phi.CH.sub.2 O are disclosed (See Table 2 at columns 13 and 14). No biological activity is given for these intermediates. They are used to make 2-substituted-1,3-propanediols which are also intermediates.
U.S. Pat. No. 3,799,936 and its divisional, U.S. Pat. No. 3,932,646 generically disclose intermediates of the formula ##STR8## wherein R is phenyl, unsubstituted or substituted by up to three substituents selected from the group consisting of lower alkyl, lower alkoxy, halogeno, trifluoromethyl, or carbo-(lower alkoxy). These intermediates are used to make unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylates which are cardiovascular agents. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 4,769,375 discloses benzylidene intermediates of the formula ##STR9## in which R.sup.1 is phenyl which may be substituted with C.sub.1 -C.sub.4 -alkyl, F, Cl and NO.sub.2 ; R.sub.2 can be H or --COR.sup.5, wherein R.sup.5 is C.sub.1 -C.sub.4 alkyl or --OR.sup.6, wherein R.sup.6 is C.sub.1 -C.sub.6 alkyl; R.sup.3 can be phenyl or C.sub.1 -C.sub.4 alkyl. These benzilidene derivatives are used to prepare circulation-active 1,4-dihydropyridine derivatives. No biological activity is disclosed for the derivatives. No compounds in which R.sup.1 is C.sub.1 -C.sub.4 -alkylphenyl are exemplified. No p-chlorophenyl or p-nitrophenyl compounds are exemplified.
U.S. Pat. No. 3,946,026 generically discloses dicarbonyl intermediates of the formula ##STR10## wherein R can be phenyl which can be substituted with lower alkyl, halogen or nitro; R.sup.1 can be H, lower alkyl, phenyl, or pyridyl; and R.sup.2 can be lower alkyl. These intermediates are used to make 2-amino-1,4-dihydropyridine derivatives which are said to be useful as antihypertensive agents and coronary vessel dilators. No biological activity is disclosed for the dicarbonyl intermediates.
U.S. Pat. No. 4,755,512 discloses intermediates of the formula ##STR11## wherein R.sup.4 can be cycloalkyl, aryl including phenyl, or hetaryl, which can be substituted with lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, etc., R.sup.5 can be lower alkyl, R.sup.6 can be lower alkyl, alkanol, alkoxyalkyl, or alkylaminoalkyl. Specifically disclosed are compounds of the formula wherein R.sup.4 =p-nitrophenyl, R.sup.5 =ethyl; R.sup.4 =o-chlorophenyl, R.sup.5 =ethyl; R.sup.4 =m-methylphenyl, R.sup.5 =ethyl; and R.sup.4 =phenyl, R.sup.5 =ethyl (See Table 2 at Columns 15-16). These intermediates are used to make dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinyl moieties which are said to be useful as calcium and alphaadrenergic blockers and to have antihypertensive, antiischemic, and platelet function inhibiting actions. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 4,414,213 discloses intermediates of the formula ##STR12## wherein R.sup.3 can be phenyl substituted with acetamino, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, cyano, halogen, hydroxyl, nitro, etc., and R.sup.4 can be lower alkyl or alkoxyalkyl. Specifically disclosed are compounds in which R.sup.4 is ethyl and R.sup.3 is phenyl, p-nitrophenyl, m-chlorophenyl, and o-chlorophenyl (See Table 2 at Columns 8-9). These intermediates are used to make dihydropyridyl cyclicinidate esters which are said to demonstrate blockage of calcium ion flux and vasodilation activities. No biological activity is disclosed for the intermediates.
Weis, A. L, et al., ISR. J. CHEM., 27(1):105-10 (1986) discloses intermediates of the formula ##STR13## wherein Ar is phenyl and R.sup.2 is methyl or ethyl; Ar is o-nitrophenyl and R.sup.2 is methyl or ethyl; and Ar is m-nitrophenyl or p-nitrophenyl and R.sup.2 is ethyl. The intermediates are used to make 4-aryl-1,4-dihydropyrimidine-5-carboxylate calcium antagonists. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 3,905,987 discloses intermediates of the formula EQU ArCH.dbd.C(CO.sub.2 C.sub.2 H.sub.5).sub.2
wherein Ar can be phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, methylphenyl, trifluoromethylphenyl, or 3-pyridyl (See Table 2 at Columns 14-15). These intermediates are used to make m-dioxane-5-methylamine analgesics. No biological activity is disclosed for the intermediates.
CA 109:128499f discloses benzilideneacetone intermediates of the formula RC.sub.6 H.sub.4 CH:CHCOMe (R=4-NO.sub.2, 4-Cl) used in a condensation reaction with arylamines. No biological activity is disclosed for the benzilideneacetone intermediates.
J. A. Cabello, et al., J. ORG. CHEM., 51(10):1786-90 (1986) discloses regioselective 1,4-hydrogenation of benzilidene ketone intermediates of the formula XC.sub.6 H.sub.4 CH.dbd.CHCOR. Specifically disclosed are compounds in which X,R=Me; X=Me, R=Ph (See Table II on page 1788). No biological activity is given for the benzilidene ketones.
J. A. Ciller, et al., ORG. PREP. PROCED. INT., 18(4):227-36 (1986) discloses intermediates of the formula ##STR14## wherein Ar=p-CH.sub.3 C.sub.6 H.sub.4, p-ClC.sub.6 H.sub.4 ; R.sub.1 =CH.sub.3 or C.sub.6 H.sub.5, R.sub.2 =CH.sub.3 or C.sub.6 H.sub.5 (See Table 1 at page 230).

2-(4-substituted)phenylmethylene derivatives and methods of use


Apparatus of injection molding three-layer moldings, especially bottle blanks with an inner and an outer layer of polyethylene terephthalate and a middle layer of recycled polyethylene terephthalate, employing a mold with several cavities. The material (component A) for the inner and outer layers is supplied through one molten-component conveying channel and the material (component B) for the middle layer through another molten-component conveying channel. The channels are separately heated and their temperatures independently regulated. The melt for component A flows the same distance as the melt for component B. The melts flow into the injection-molding dies such as to ensure a uniform front.

The present invention concerns a method of injection-molding three-layer moldings, especially bottle blanks with an inner and an outer layer of polyethylene terephthalate and a middle layer of recycled polyethylene terephthalate. The method employs a mold with several cavities.
The invention is not, however, restricted to either bottle blanks or polyethylene terephthalate. It can also be employed to make moldings for any purpose and out of any plastic or combination thereof. It can for example be employed to injection mold multiple-layer blanks of polyethylene terephthalate and polyethylene naphthalate. Although both polyethylene terephthalate and polyethylene naphthalate are polyesters, the terephthalate has much better heat-resistance, mechanical, and barrier properties. It is relatively new but has already been approved by the various governmental agencies as a packaging material for the foodstuffs industry. Due to its outstanding properties, even small percentages, 10 to 25% by molding weight, definitely increase the quality of the final bottles. Bottles of polyethylene terephthalate or phthalate are particularly useful for example for bottling hot juices and for storage in hot climates.
The middle layer, made of a material called component B hereinafter, constitutes the core of the bottle wall, and the inner and outer layer, of "component A", constitute a continuous skin.
A device for carrying out such a method is known from European Patent 0 647 514 A1. The melts are supplied to the dies through a series of channels consisting of a number of bores extending through a hot-runner block. Components A and B are accordingly always at the same temperature.
The pins that close the die in this known device are pneumatically driven in accordance with the two-piston principle by two independently acting pistons accommodated in a single housing and subjected to different pressures. It is impossible to ensure synchronized opening and closing of the molten-component conveying channels that open into the various cavities and hence to obtain a uniform flow front because the compressed air responds compressibly, subsequent to a delay, that is, in accordance with the specific opening-and-closing impedances. It will not respond uniformly. The requisite synchronization of all the cavities cannot be attained, and the blanks will have different percentages of components A and B in their layers.
Another drawback of the known device is the impossibility of controlling the flow of melt or even to keep it flowing into the cavities when shifting back and forth between the components. The result is flow lines on the surface of the blank. This is because the flow of the components is also controlled by the injection pistons.

Apparatus for injection-molding three-layer moldings


In an apparatus at a spinning preparation machine, especially at a carding machine, cleaner, draw frame, combing machine or the like, having at least one electric motor-driven roller, which is rotatably mounted about its longitudinal axis, the roller is caused to rotate by means of forces of an electromagnetic field that act on at least one roller end-face. In order to achieve a substantially increased drive output and braking output and a high torque in a simple manner, an electromotive drive means is present having a rotor and a stator which are integrated into the roller and into an immobile machine element associated with the roller.

The invention relates to an apparatus at a spinning preparation machine, especially at a carding machine, cleaner, draw frame, combing machine or the like, having at least one electric motor-driven roller.
In a known apparatus (DE 28 22 712 A), a cylinder drive is provided for a textile machine, especially for a carding machine. The drive has a ferromagnetic, conductive annular plate which is arranged "at least one end face of the cylinder". The annular plate lies opposite to an asynchronous linear motor. That motor is evidently rotatably (inclinably) mounted in relation to the perpendicular axis of the cylinder. A change in the speed of the cylinder is said to be effected in dependence on the inclination or the "angle of inclination ø". "Regulation of the speed of the cylinder" is also said to be possible by that means. A disadvantage is that, in order to effect a control, a means is required for the automatic adjustment or deplacement of the motors, since a change in speed is possible only by altering the angle of inclination of the linear motors. Also necessary, in addition, are means for ascertaining the actual speed, as well as a corresponding controlling and regulating device. Especially disadvantageous is the fact that one or even two "linear motors" are not capable of applying the necessary very high output and the implicitly required torgue. A problem especially is that electric coils are present only in the region of the linear motors.
It is an aim of the invention to provide an apparatus of the type described at the outset that avoids or mitigates the mentioned disadvantages, that especially enables a substantially increased output and a torque and that allows an adjustment or alteration of the speed.

Apparatus at a spinning preparation machine having at least one electric motor-driven roller


A processor, scan controller, and method for protecting sensitive information from electronic hacking is disclosed. To maintain the security of the sensitive data present in a processor, the scan controller denies access to the scan chain until data is cleared from scan-observable portions of the processor, then clears the scan chain again prior to exiting test mode and resuming normal operation. Clearing or otherwise modifying data stored in the scan-observable portions of a processor when transitioning to and/or from a test mode will prevent unauthorized personnel from simply shifting secure data out of the scan chain, and from pre-loading data into the scan chain prior to normal operation in an attempt to set sensitive state information.

In its most basic form, a scan-chain is a series of elements linked together so that an output of one element is linked to an input of the next element in the series, which in turn has an output linked to an input of a subsequent element, and so on. Sometimes, circuit designers use scan-chains to provide test access to internal elements of a processor that would be otherwise inaccessible. By using a scan chain, a test engineer can shift data into a processor sequentially, using a single input port. The processor operates on the data, and the results of the operations are then read out sequentially using a single output port. In this way a maximum amount of internal circuitry can be tested with a minimum of additional complexity.
This ease of testing, however, gives rise to data access issues that must be taken into consideration, especially in light of the encryption and security requirements of the software, telecommunications, entertainment, and other industries. For example, the telecommunications industry has a need to have secure codes stored in some of the semiconductor chips used to process information in mobile phones, pagers, and the like. These secure codes may be used as part of proprietary data processing methods, for hardware identification and authentication, to specify a secure state, or for any number of other purposes. However, if the circuitry responsible for handling these codes is accessible via a scan chain, competitors might be able to exploit the scan chain to gain access to the secure codes stored in the chip or to enter a secure state.
In order to address the problem of exploiting the scan chain to gain access to secure information stored in the chip or to fool the chip into thinking it is in a secure state, manufacturers have generally removed circuitry used to process secure information from the scan chain. By removing this circuitry from the scan chain, it becomes more difficult for unauthorized users to gain access to the secure codes. However, this solution leaves a significant portion of the chip unable to be completely tested.
As should be apparent from the above discussion, currently available testing methodologies are less than ideal, in that they force a designer to choose either test access with decreased data security, or data security without test access for significant portions of a data processor. What is needed is some way to permit test access to portions of a processor that process secure information, but maintaining the secrecy of any secure information in the processor.

Method and apparatus for secure scan testing


Disclosed is footwear including a ventilation and shock-absorbing device having an air pump and a check valve for passing air supplied by the air pump. The footwear includes an air chamber provided at a front of the check valve for storing the air supplied through an inlet passage connected to the check valve, and an air tube having one or more discharge holes for discharging the air stored in the air chamber into the footwear.

In general, footwear is means for protecting feet of a pedestrian, and is made of a leather, synthetic resin or the like having no ventilating function. Since it is difficult to circulate air within the footwear, the footwear gives out an offensive odor due to perspiration or moisture, which causes athlete's foot, eczema or the like.
There has been proposed footwear having a ventilation device to solve the above problem. The footwear is composed of an air pump installed under a sole for pumping air, a check valve for passing the air supplied by the air pump in one direction, and an air discharge tube connected to the check valve and discharging the air passed through the check valve to an interior of the footwear.
According to the ventilated footwear composed as described above, the air pump is repeatedly compressed to pump the air, so that the external air is continuously supplied to the interior of the footwear. The air circulation may effectively remove the perspiration or offensive odor in the footwear, but has the following drawbacks.
Conventional ventilated footwear has only ventilating function for circulating the air in the footwear, but does not provide shock absorbing means for alleviating shock applied to the feet when walking. The pedestrian has a feeling of fatigue induced by the shock continuously applied to the feet when walking.
More perspiration comes likely out between the toes than the sole. Conventional ventilated footwear supplies the air in the footwear, but cannot supply intensively to a particular portion. Accordingly, there is a drawback in that an effective ventilating function is not obtained.

Footwear with ventilating and shock-absorbing device


A system and method for the treatment and reduction of sludge via ozonation in a wastewater treatment process is disclosed. The sludge treatment system comprises: a sludge ozonation reactor coupled to an activated sludge treatment basin and adapted to receive a liquid stream of sludge containing biosolids from the activated sludge treatment basin. The sludge treatment system also includes an ozone-enriched gas injection system operatively coupled to the reactor and adapted to inject ozone-enriched gas into the liquid stream at or upstream of the sludge ozonation reactor. The sludge ozonation reactor is configured to allow effective gas-liquid contacting between the ozone-enriched gas and the liquid stream so as to oxidize the biosolids in the liquid stream and initiate bacterial cell lysis thereby reducing the biosolids. Upon reduction of the biosolids, the liquid stream is returned via a return line to the activated sludge basin or other discharge point.

Traditional methods of wastewater treatment involve bringing wastewater streams into contact with bacteria either in an aerobic or anaerobic type process in what is known as activated sludge treatment. These bacteria consume parts of the substrate material or waste contained in the wastewater, which are typically organic compounds containing carbon, nitrogen, phosphorus, sulfur, and the like. Typically, a portion of the waste is consumed to further the metabolism of the bacterial cells or maintain the physiological functioning of the bacterial cells. In addition, a portion of the waste is also consumed as part of the process of synthesis of new bacterial cells. The activated sludge treatment process yields a certain amount of sludge and associated solids which must be continuously removed from the treatment basin to maintain the steady state sludge balance which is critical to the effective functioning of the activated sludge treatment system.
In order to maintain waste removal capacity of the treatment plant at steady state it is important to control the generation of new bacterial cells within the activated sludge treatment process. Too much synthesis of new bacterial cells in excess of what is required for the treatment of the waste at or near steady state results in excess biosolids formation attributable to the accumulation of such newly synthesized but unneeded bacterial cells. This excess biosolids must be continuously removed during the activated sludge treatment process.
Existing methods for dealing with the removal of sludge includes transporting the sludge to landfills, utilization of sludge for land application or agricultural purposes, and incineration of the sludge. Most sludge disposal operations require some prior treatment of the sludge; a process known in the art as solids handling. Solids handling processes are often costly and time consuming operations and typically involve one or more of the following steps: (a) the concentration of the sludge in a thickener, usually requiring the use of polymers; (b) digestion of the sludge in order to stabilize the bacteria and to further reduce the volume and pathogen content of the sludge; (c) dewatering of the sludge to reach approx 15-25% solids content; which involves the passage of the sludge through centrifuges or other solid-liquid separation type devices; (d) storage of the sludge; and (e) transportation to sites for landfill, land application by farmers, or other end use.
It is estimated that the costs associated with solids handling and disposal processes can be between 20-60% of total operating costs associated with the overall wastewater treatment process. Due to the cost and time associated with solids handling and disposal, it is beneficial to minimize the amount of excess sludge produced in the wastewater treatment process.
In conventional activated sludge treatment systems and methods, oxygen is required both for the chemical oxidation of the substrate material (i.e. waste) as well as for the synthesis of new cells and metabolic processes of the bacterial cells. Use of ozone in addition to oxygen for the treatment of sludge has also been reported. More particularly, ozone treatment of sludge has been reported in combination with mechanical agitators and/or a pump providing the motive mixing. The sludge-ozone contact typically occurs in a continuously stirred tank reaction (CSTR) mode, and lysis (breaching of the integrity of the cell wall) results as a consequence of the strong oxidizing action of ozone on the cell walls. Lysis leads to the release of the substrate rich cellular content of the bacterial cells. In this way, the solid cells which would otherwise have been discharged as excess sludge are lysed, and by so doing, they are transformed to substrate which can then be consumed by bacteria in the treatment basin.
The cellular content is a liquid matrix which is comprised of proteins, lipids, polysaccharides and other sugars, DNA, RNA and organic ions. Because of the low selectivity that occurs when sludge ozone contacting is carried out in a continuously stirred reactor mode, excessive amounts of ozone are consumed using prior methods for sludge ozonation. In addition, some prior reported uses of ozone required specialized pre-treatment or modification of the sludge. Such pre-treatments and modifications may include adjusting the pH of the sludge, increasing the temperature of the sludge, increasing the pressure of the ozone treatment vessel, or passing the sludge through anaerobic pre-digestion steps. Thus, the prior use of ozone in the treatment of sludge involved additional complexity, materials, equipment and the increased costs associated therewith.
Three major methods for reactor systems are known, these being the Continuously Stirred Tank Reactor system (CSTR), the higher selective Plug Flow Reactor (PFR) and the Batch Reactor System (BRS). The major difference between the different reactor modes lies fundamentally in: (i) the average amount of time that a molecule stays within the reaction space, also known as the residence time distribution; (ii) the interaction between reacting 'parcels' e.g., there is significant back-mixing in the CSTR, while the PFR is characterized by very limited, if any, back-mixing; and (iii) the yield obtained. Batch Reactor Systems are typically applied for small scale wastewater treatment operations.

This patent is subject to a terminal disclaimer.

System and method for eliminating sludge via ozonation


In a cogeneration system having a generator unit that generates DC power, an internal combustion engine for driving the generator unit, a battery that stores DC power for starting the engine, and an inverter that inverts the DC power generated by the generator unit to AC power, there are provided a solar unit that generates DC power by converting radiant energy of sunlight into electrical energy and a DC/DC converter that boosts the DC power stored in the battery, such that one of the battery and the solar unit is connected to the inverter through the DC/DC converter, thereby enabling them to share the DC/DC converter and thus to make the structure simple.

1. Field of the Invention
This invention relates to a cogeneration system, particularly to a cogeneration system combined with a solar electric generation system in an efficient manner.
2. Description of the Related Art
In recent years, cogeneration systems have been developed that are equipped with an internal combustion engine-driven generator for supplying power to the load and also for supplying hot water or air or the like, heated by using exhaust heat from the engine to a thermal load. Further, a cogeneration system combined with a solar electric generation system is disclosed in Japanese Laid-Open Patent Application No. Hei 11 (1999)-55860.
The cogeneration system taught in the reference includes a sunlight cogeneration system utilizing solar electric generation to generate DC power, an engine cogeneration system utilizing engine electric generation to generate DC power, and an inverter that inverts generated DC power to AC power to be supplied to electrical loads. Since the output of the sunlight cogeneration system fluctuates depending on hours of sunlight, the sunlight cogeneration output is monitored and if it drops, the engine cogeneration system is operated to increase its output.
In this system, since the sunlight cogeneration system and the engine cogeneration system are independent from each other, it is disadvantageously complicated, although they share the inverter.


A non-intrusive electrical cable tester determines the nature and location of a discontinuity in a cable through application of an oscillating signal to one end of the cable. The frequency of the oscillating signal is varied in increments until a minimum, close to zero voltage is measured at a signal injection point which is indicative of a minimum impedance at that point. The frequency of the test signal at which the minimum impedance occurs is then employed to determine the distance to the discontinuity by employing a formula which relates this distance to the signal frequency and the velocity factor of the cable. A numerically controlled oscillator is provided to generate the oscillating signal, and a microcontroller automatically controls operation of the cable tester to make the desired measurements and display the results. The device is contained in a portable housing which may be hand held to facilitate convenient use of the device in difficult to access locations.

The present invention relates in general to a method and apparatus for determining the location of a short circuit or an open circuit in an electrical cable, based on impedance measurements made at one end of the cable.
The Space Shuttle uses dedicated signal conditioners (DSCs) for the purpose of conditioning transducer outputs and other signals to make them compatible with orbiter telemetry, displays and data processing systems. The DSCs are located throughout the orbiter, often in difficult to access locations in the vehicle fuselage. When troubleshooting a potential instrumentation problem, personnel frequently have to demate cables to verify that the cables are not the source of the problem. However, once a cable is demated, all DSCs and other systems which have a wire passing through the cable's connector have to be retested after the cable is reconnected. Due to their inaccessibility, the DSCs sometimes have to be removed in order to check them. This results in many man hours of revalidation testing on systems that were unrelated to the original problem. The cost to the Shuttle program for these retesting procedures is exorbitant. A system which allows cable continuity to be checked non-intrusively without demating the cables would therefore save many hours of testing and substantially reduce testing costs.
One known technique for non-intrusively checking cable continuity is time domain reflectometry (TDR). In TDR, a high frequency pulse is injected into one end of the cable. A discontinuity in the cable will cause a reflection of the pulse that can be detected back at the end where the pulse was injected. The location of this discontinuity can be determined by measuring the time interval between when the pulse is injected into the cable, and when the reflected pulse is detected. Also, the polarity of the reflected pulse is indicative of whether the discontinuity is a short circuit or an open circuit.
Unfortunately, TDR is not feasible for detecting cable faults in the Space Shuttle. This is because the faults are typically only a few meters or less from the injection point, and TDR is ineffective at these distances due to the extremely short total travel time (e.g., a few nanoseconds) of the high frequency pulse.
In view of the foregoing, a need therefore exists for a non-intrusive cable testing technique which provides the accuracy necessary for use in the Space Shuttle environment.

Non-intrusive impedance-based cable tester

The United States of America as represented by the Administrator of the National Aeronautics and Space Administration


A sensor for use in magnetostrictive testing of a structure. The sensor has a thin ferromagnetic strip with a series of parallel crimps across its width. A first wire coil is wrapped around the width of the strip and along its entire length, such that portions of wire that cross the bottom surface of the strip are located inside the crimps, and portions of wire that are wrapped across the top surface of the strip are between the crimps. The sensor further has a second coil wrapped around the length of the strip, or for pipeline applications, around the pipeline.

Many processing plants, such as refineries, chemical plants, and electric power generation plants, use networks of pipelines. Failure of these pipelines can cause major disruption of plant operation and an unscheduled outage. To ensure safe operation of such plants, there is a need for on-line non destructive testing methods to inspect and monitor pipelines.
One effective method for inspecting and monitoring a long length of pipelines is guided wave testing (GWT) using magnetostrictive sensor (MsS) technology. A common implementation of this method uses primarily torsional waves (T-waves) that are generated in a thin ferromagnetic strip placed around and coupled to the pipe under test. If the generated waves are coupled to the pipe, the waves propagate along the pipe and are partially reflected by geometric irregularities present in the pipeline, such as welds or corrosion defects.
The reflected signals are then detected in a pulse-echo mode. From the arrival time of the reflected signal and the signal amplitude, the axial location of the irregularity and its severity are determined. In above-ground pipelines, this method can detect 2 to 3% defects over 500 feet from an MsS sensor location. The % refers to the defect's cross-sectional area relative to the total cross section of the pipe wall.
Magnetostrictive testing, although especially useful for testing pipelines, is not limited that type of testing. Magnetostrictive testing has been adapted for testing of structures of other shapes, and in general, can be used to test for defects in any shape, even to plate structures.

Magnetostrictive sensor having crimped magnetostrictive strip for high temperature operation


A motor control device includes a DC motor, a power source configured to supply power to each of the DC motor and a load unit, and a controller configured to control power supply to the DC motor and the load unit. When reducing the power to be supplied to the DC motor, the controller increases the power to be supplied to the load unit during a predetermined period of time including a timing at which the power to be supplied to the DC motor is reduced.

1. Technical Field
The present disclosure relates to a motor control device for driving a unit to be driven by a DC (direct current) motor and an imaging apparatus using such a motor control device.
2. Related Art
A motor control device is known which drives a unit to be driven connected to a DC motor by controlling the DC motor and detects the position of the unit to be driven by counting the number of pulses generated by an encoder connected to the DC motor (refer to JP 2003-262904 A, for example).
For example, a digital camera provided with such a motor control device can adjust a field angle of a subject by moving a zoom lens along the optical axis direction by the DC motor. Moreover, the digital camera detects the position of the zoom lens by counting the number of pulses outputted from the encoder connected to the DC motor, and thus obtains information such as a zoom magnification.

Motor control device and imaging apparatus with improved power source stability

PANASONIC INTELLECTUAL PROPERTY MANAGEMENT CO., LTD.


A semiconductor structure is provided. In one embodiment, a bond pad is formed above one or more underlying layers of a substrate. A plurality of dummy plugs are spaced around the bond pad, the plurality of dummy plugs substantially vertically traversing the one or more underlying layers, wherein the plurality of dummy plugs anchor at least two of the underlying layers together to achieve improved mechanical strength.

The present invention relates generally to the fabrication of semiconductor devices, and more particularly, to a de-lamination resistant bond pad structure.
In a typical integrated circuit chip, active circuit elements such as transistors, resistors, etc., are positioned in the central portion, i.e., the active region, of the chip whilst the bond pads are normally arranged around the periphery of the active region such that active circuit elements are not likely to be damaged during a subsequent bonding process. When a wire bonding process is performed on a bond pad of a chip, the process normally entails the bonding of a gold or aluminum wire to the bond pad by fusing the two together with ultrasonic energy, for example. The wire is then pulled away from the bond pad after the bond is formed. During the bonding of the wire to the pad and the pulling away of the wire from the pad, high mechanical stress is placed on the bond pad. When the bond pads are not properly formed, defects such as de-lamination of the bond pad from underlying layers of the chip have been encountered. This occurs due to the fact that during the attachment of the wire to the bond pad, a high level of mechanical stress is placed on the bond pad. It occurs when a relatively large, heavy bond is placed on top of layers, which may not have strong adhesion to the underlying layers. For instance, one factor that may affect adhesion between the layers is the use of low dielectric constant (low-k) materials that cause adhesion problems between these low-k dielectric materials and the underlying oxide layers. The adhesion of low-k dielectric material, or inter-metal-dielectric (IMD) material to oxide is poorer than that of oxide to oxide. The use of low-k dielectric materials, such as HSQ (hydrogen silsesquioxane) and MSQ (methylsilsesquioxane) have been desirable in high performance semiconductor structures since due to their low-k characteristics, thinner layers of the materials may be utilized as insulating layers. Another drawback of these low-k dielectric materials is their low thermal conductivity when compared to that of regular oxide. During a chip bonding process, the local temperature around a bond pad is significantly higher due to the poor thermal conductivity of the low-k dielectric material. The thermal stress caused by the poor thermal conductivity of IMD, in addition to the mechanical stresses caused by the bonding operation, may cause de-lamination of the low-k IMD layers from their underlying oxide layers.
One conventional method for overcoming such increased de-lamination characteristics provides for the forming of a polysilicon pattern under a bond pad to prevent the bond pad from peeling during subsequent manufacturing processes. The use of a polysilicon interface between the metal bond pad and the interlayer dielectric prevents bond pad peeling or lifting by having chemically compatible interlayer surfaces, thereby providing attendant increased adhesive properties. However, a significant disadvantage is that the polysilicon layer is typically deposited directly over a layer of insulating material rather than over a layer of a metallic material, thereby providing adhesion and anchoring characteristics that are not optimal. Various other approaches to solving the de-lamination and poor thermal conductivity issues require additional fabrication process steps during the fabrication of the bond pads.
For these reasons and other reasons that will become apparent upon reading the following detailed description, there is a need for an improved bond pad structure that avoids the de-lamination and thermal conductivity problems associated with conventional bond pad structures.

Bond pad structure having dummy plugs and/or patterns formed therearound

Taiwan Semiconductor Manufacturing Co., Ltd.


An optoelectronic device that radiates mixed light including a first semiconductor light source which radiates light in a first wavelength range at a first intensity, a second semiconductor light source which radiates light in a second wavelength range at a second intensity, a third semiconductor light source which radiates light in a third wavelength range at a third intensity, a resistance element having a temperature-dependent electrical resistance, and a semiconductor light source control element that controls the intensity of the third semiconductor light source.

To generate mixed light, that is to say non-monochromatic light and in this case, for example, white light, it is customarily possible, when light-emitting diodes (LEDs) are used, to employ LEDs that emit in different colors and/or a plurality of luminescent materials. To generate white light, for example, spectral components in the yellow-green and the red wavelength ranges which are radiated by different LEDs can be superimposed.
What is challenging, in addition to meeting optical requirements, such as, for example, the mixing of light emitted by different LED chips, is also the stabilization of the color location, for example, of the white point in the case of white light, with respect to temperature. This relates, for example, to different temperature dependencies of the chip technologies involved. A stabilizing element is shown in the non-prior-published DE 10 2008 057 347.7.
Also of interest, in addition to the stabilization of the color location, is the possibility of controlling the color temperature (CCT) of such a light source, for example, to vary between warm-white light and cold-white light. Typical implementations of color-temperature-controllable light sources have an optical and/or thermal sensor, a microcontroller and a plurality of LED drivers to control the LEDs. For the compensation of thermal effects, typical LED characteristics are stored in the microcontroller.
The problem posed is that of defining a color-temperature-controllable and color-location-stabilized light source of simple construction.


The present invention identifies P-selectin as a modulator of hemostasis. Accordingly, the present invention relates to methods for the identification and use of modulators of P-selectin activity as modulators of hemostasis. The invention also relates to methods and compositions for the diagnosis and treatment of hemostatic disorders, including, but not limited to, hemorrhagic disorders and thrombotic disorders. The present invention describes methods for the diagnostic evaluation and prognosis of various hemostatic conditions, and for the identification of subjects exhibiting a predisposition to such conditions. In addition, the present invention provides methods for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of a hemostatic or vascular disorders, and for monitoring the efficacy of compounds in clinical trials.

The ability of cells to adhere to one another plays a critical role in development, normal physiology, and disease processes. This ability is mediated by adhesion molecules, generally glycoproteins, expressed on the cell surface. Several important classes of adhesion molecules include the integrins, the selectins, and members of the immunoglobulin (Ig) superfamily. Selectins play a central role in mediating leukocyte adhesion to activated endothelium and platelets.
Blood clotting, along with inflammation and tissue repair, are host defense mechanisms which function in parallel to preserve the integrity of the vascular system after tissue injury. In response to tissue injury, platelets, endothelial cells and leukocytes are essential for the formation of a platelet plug, deposition of leukocytes in injured tissue, initiation of inflammation, and wound healing.
P-selectin, also known as CD62, granule membrane protein-140 (GMP-140), and platelet activation-dependent granule external membrane protein (PADGEM), is an integral membrane glycoprotein that is expressed on vascular endothelial cells and platelets, and is involved in the recognition of various circulating cells. The P-selectin molecule has an N-terminal lectin domain, a region with homology to epidermal growth factor, a region with homology to complement regulatory proteins, a transmembrane domain, and a short cytoplasmic tail. The P-selectin ligand includes the Lex carbohydrate structure, sialic acid, and the PSGL-1 protein (U.S. Pat. No. 5,843,707).
P-selectin is constitutively stored in secretory granules (e.g., α-granules and Weibel-Palade bodies) and is translocated to the surface of platelets and endothelial cells in response to a variety of stimuli, including cell activation, where it mediates platelet-leukocyte and endothelium-leukocyte interactions. The cell surface expression of P-selectin is tightly regulated, and P-selectin is rapidly shed from the cell surface upon platelet activation, appearing as a soluble fragment in the plasma (Berger, G. et al. Blood (1998)92:4446-4452). Soluble P-selectin may also result from an alternatively spliced isoform of P-selectin lacking the transmembrane domain (Ishiwata, N. et al. J Biol Chem (1994)269:23708). The plasma of healthy humans and mice contains little soluble P-selectin, as detected by ELISA, and an increase in plasma P-selectin concentration may indicate in vivo activation of and/or damage to platelets and endothelial cells.
In addition to its role in leukocyte rolling and extravasation in inflammation, P-selectin mediates platelet-leukocyte adhesion within thrombi, and increases tissue factor expression on monocytes, thereby promoting fibrin deposition by leukocytes and thrombogenesis (Palabrica, T. et al. Nature (1992)359:848-851; Celi, A. et al. Proc Natl Acad Sci USA (1994)91:8767-8771).

Methods of treating hemophilia or von willebrand disease with p-selectin