Aqueous fabric softening composition having good high temperature stability comprising a cationic fabric softening compound and water soluble polysaccharide polymers comprising hydrophobic groups selected from aryl, alkyl, alkenyl, aralkyl each having at least 14 carbon atoms and cationic quaternary ammonium salt groups such that the cationic degree of substitution is from 0.01 to 0.2, the polymers having a molecular weight in the range from 100,000 to 700,000.

It is well known to provide liquid fabric softening compositions that soften treated fabric. Such compositions are typically added to fabric in the rinse cycle of the wash process. It has been observed that consumer preference is for liquid fabric conditioners that appear thick and creamy, cued by having a high viscosity and a high opacity. Conditioners that appear thin and/or translucent/watery may be perceived as being cheap and ineffective, whereas conditioners that appear thick and creamy are perceived as premium products. One route to achieve this is through the use of polymeric viscosity modifiers.
Fabric conditioners comprising polymeric viscosity modifiers and cationic softening agent are known in the art. For example, WO-A1-02/081611 discloses a fabric softener composition for the treatment of textile fibre materials in domestic applications comprises a fabric softener and a water-soluble polyurethane obtainable by reaction of (a) a diisocyanate, with (b) a polyether containing at least one hydroxyl group, (c) optionally a diol derived from an aliphatic residue having from 2 to 12 carbon atoms, and (d) an agent introducing a water-solubilising group.
US 2004/0214736, U.S. Pat. No. 6,827,795, EP0501714, US 2003/0104964 and U.S. Pat. No. 5,880,084 disclose fabric softening compositions comprising Polyquaternium 24 which is a polymeric quaternary ammonium salt of hydroxyethyl cellulose reacted with lauryl dimethyl ammonium epoxide.
EP-A2-0385749 discloses fabric conditioning compositions comprising a quaternary ammonium softening material and a polymeric thickener. The thickener has a hydrophilic backbone and two hydrophobic groups attached thereto.
EP 331237 discloses an aqueous fabric conditioning composition comprising a fabric softener and a non-ionic cellulose ether, characterised in that said non-ionic cellulose ether has a sufficient degree of non-ionic substitution selected from the class consisting of methyl, hydroxyethyl and hydroxypropyl to cause it to be water-soluble and wherein said non-ionic cellulose ether is hydrophobically modified by further substitution with one or more hydrocarbon radicals having abut 10 to 24 carbon atoms, in an amount between 0.2% by weight and the amount which renders the cellulose ether less than 1% by weight soluble on water at 20° C. Preferred non-ionic cellulose ethers are hydrophobically modified hydroxyethyl cellulose (HMHEC) commercially available from Hercules Incorporated under the trade designation "Natrosol Plus". Specific examples of HMHEC which have been disclosed in fabric conditioning compositions are Natrosol Plus 330 and Natrosol Plus 331.
HMHEC polymers achieve viscosity build up by forming links between dispersed particles of the fabric conditioner system i.e. they act as "associative thickener". This is in contrast to "continuous phase thickeners" which work simply by thickening the continuous phase without any association. The benefits of HMHEC's are that they are more weight effective and hence are a more cost effective solution to achieving high product viscosities and also reduces material consumption i.e. better for the environment generally.
Where these polymers have been used previously with dilute products these have generally proven to be most effective at moderate temperatures (<37° C.) with softener actives that contain predominantly dialkyl cationic species. At higher temperatures the viscosity tends to decrease significantly before the compositions gel due to hydrolysis. This is disadvantageous especially if the target viscosity is relatively high.
In order to maintain the product viscosity, the HMHEC must remain associated or "bound" to the dispersed phase. If the polymer loses this binding, the hydrophobic moieties of the polymer can associate intramolecularly such that the viscosity drops below specification and the product becomes thin and more liable to separation. Another key issue regarding TEAQ type actives is that these actives may contain a significant amount of more water soluble mono-ester components. These components become even more water soluble as the temperature of the system is raised and this is believed to lead to the formation of micellar type structures in the continuous phase. These micelles are believed to facilitate the release of the hydrophobic chains of the polymer from the bilayer of the dispersed organic phase. In addition, as the ester linked actives hydrolyse under these high temperature conditions, the more hydrophobic triester and diester species break down to form the mono-ester products, thus exacerbating the problem even further.
The invention has been made with the above points in mind.


A gateway module for connection of at least two sub-networks is described. A first sub-network of the at least two sub-networks supports a data transmission in accordance with a first communications protocol, especially CAN, FlexRay, LIN, MOST or Ethernet, and a second sub-network of the at least two sub-networks supports a data transmission in accordance with a second communications protocol, especially CAN, FlexRay, LIN, MOST or Ethernet. The gateway module has a configurable hardware circuit which is adapted to manipulate and forward data from the first sub-network and to the second sub-network taking into consideration the first communications protocol and the second communications protocol.

Various bus systems are known for transmitting messages between user stations or communications nodes of a communications system, for example between control units in a communications network of a vehicle. In so-called CAN bus systems, messages are transmitted using the CAN protocol described in the CAN specification in ISO 11898. Further examples of such bus systems are FlexRay, LIN, MOST and Ethernet. In many cases, the standardization is operated by a contractual alliance (consortium, association). An overview of currently used bus systems may be obtained, for example, from the following book by Werner Zimmermann and Ralf Schmidgall: "Bussysteme in der Fahrzeugtechnik—Protokolle, Standards and Softwarearchitektur" ("Bus systems in automotive technology—protocols, standards and software architecture"), Vieweg+Teubner, 4th edition, 2010.
A communications system is also known in which messages are transmitted with the aid of the Ethernet standard, which is defined by the IEEE 802 standards family.
AUTOSAR (AUTomotive Open System ARchitecture) refers to a development association of various companies in the automotive industry pursuing the objective of simplifying and harmonizing data communication and software exchange between control units of a vehicle. The relevant descriptions and the terminology used by Autosar may be found, for example, in the publicly available Autosar Specifications 3.2 and 4.0.
The growing volume of data in modern vehicles and the increasing networking of the vehicle both internally and outwardly make new communications technologies and architectures necessary in the vehicle in order to meet the requirements regarding safety, comfort and data rate and, at the same time, keep the complexity of the vehicle network manageable. The coupling of a plurality of communications networks of a communications system, also called sub-networks of the communications system, by a gateway is a customary approach to managing data volume. With that approach, communications nodes that communicate extensively with one another are usually placed in a common network and the gateways make specific, selected messages available in the various networks. A large proportion of the data is forwarded by a gateway usually transparently without being manipulated.
International Patent Application WO 2009/156820 A1 describes a method for establishing communication between communications nodes, in which a plurality of wireless communications networks are connected by suitable gateways to a connection network, called a backbone, and wired communication takes place between the gateways via the backbone. In that manner, the communications nodes of various communications networks are able to communicate with one another. In this case, the gateways have the task of forwarding messages or their useful data, and various possibilities for doing this are presented.
German Patent Application DE 10 2006 055 513 A1 discusses a multiprocessor gateway by which a plurality of communications networks may be connected to one another, in which a computer unit or gateway unit provided for that purpose ensures the communication between the connected communications controllers by using a system bus kept especially for the purpose.
It is problematic, however, that the discussed gateway technologies may have inadequate latency times owing to their use of known computer architectures. On the other hand, an architecture with sub-networks (meaning communications networks whose users communicate with one another via a continuous medium and using a common communications protocol) and a backbone (connection network) is only able to display its advantages properly if the communication of the sub-networks may be extended flexibly and transparently by way of the backbone while retaining quality of service (QoS) and without placing too great a load on processors.

Gateway module for a communications system, communications system, and method for transmitting data between users of a communications system


A thermal attachment assembly for heat generating electronic devices which includes a multi-element spring having low force, high deflection, spring fingers, and which is adjustable and attached by screws to a cover to apply pressure directly against electronic components arranged generally perpendicular to at least one edge of a printed wired board (PWB). The attachment assembly includes a heat sink housing in which the electronic components are pressed against an electrically insulating, thermally conductive film positioned against one wall of the heat sink housing. The PWB is snapped to a carrier and both are placed into the housing so that the electronic devices are positioned within spaces of the carrier. The carrier includes sloping surfaces, so that the spring fingers are deflected downward when the cover is attached to the housing, thereby insuring that the spring fingers are properly positioned onto the electronic devices, between the spaces of the carrier.

1. Field of the Invention
This invention relates to the attachment of printed circuit board mounted, heat generating electrical components to heat sinks. In particular, to the attachment to such electrical components which have heat transfer tabs to heat sink housings using spring type members.
2. Description of Related Art
One method by which tabbed printed circuit board mounted, heat generating electrical components have been attached to heat sinks has involved individually attaching each device to the heat sink with a screw through the hole in the tab of the electronic device, and utilizing an electrically insulating thermally conductive film between the heat sink and the device tab. A nut is tightened onto the screw to provide the compressive force required to provide adequate compression of the film to maximize heat transfer from the device to the heat sink through the film. There are many variations of this technique, such as using a threaded hole in the heat sink rather than a nut. Problems arise with this general manner of attachment because the tension created by the screw may be relieved by material creep in the insulating washer or grommet, or the screw may back out under certain operating conditions, such as where the device is subject to vibration or temperature cycling. Another disadvantage is that the large number of parts that must be manually assembled when there are a number of heat generating components in an assembly, and it is difficult to automate the production of such attachments for high volume manufacturing.
In addition to the various uses of attachment screws, numerous attachment techniques have been developed which use spring members. A number of these attachments use clips with multiple spring fingers, as can be seen by reference to U.S. Pat. Nos. 4,922,601; 4,891,735; 4,872,089; 4,845,590; and 4,707,726, for example. Difficulties are encountered with these techniques for various reasons. To achieve a compact assembly, the springs must achieve high forces at low deflections, and this means that the springs must be manufactured specifically for an individual device and changing the device may cause the spring to exert too much or too little force since stiff springs have force constants which create a very narrow range of deflections within which the proper pressure will be applied. Furthermore, there is often a need for special tools to insure that the device or the spring is not damaged during assembly. Historically, electrically insulating and thermally conductive pads require 300-500 psi for effective heat transfer; but this requires a material to be disposed between the spring and the device to distribute the spring force on the device, to prevent the spring from damaging the device. Some arrangements require that the heat sink be a separate part from the housing, and others require numerous unique parts that need to be manually assembled.
Thus, there is a need for a heat sink attachment which will enable the use of low force springs in order to increase the range of permissible spring deflections, thereby increasing the tolerances and the variety of heat sinks which may be attached, and to eliminate the need for intervening materials for distributing the spring force. Additionally, a need also exists for an arrangement which will not require numerous parts that require manual assembly.

Electronic component heat sink attachment using a low force spring


The invention employs the principle of the prior art for cooling a heated body by means of so-called heat pipes, with seal devices for rotating shafts, in particular for a ship's propeller shaft. According to this principle, an externally closed chamber extending in the longitudinal direction and filled with a liquid working fluid extends on one end into the body to be cooled, and on the other end into a cold medium, whereby a constant circulation takes place, so that the work fluid is evaporated in the hot portion of the chamber, the vapor flows into the cold portion of the chamber, condenses there, and the condensate is returned to the hot portion by way of a capillary structure (FIG. 1 ).

Field of the Invention
This invention relates to a seal device for rotating shafts, in particular a stern tube seal for ship propeller shafts with or without a shaft bushing. The shafts are in contact with a relatively cold medium, preferably seawater, and a relatively hot medium, preferably lubricating oil. There are, on the shafts, two or more gaskets supported by a stationary support system and which gaskets are designed as lip seals and/or rotating mechanical seals. There is equipped a device to cool the gaskets, which has passages penetrating the shaft and/or the support system for the circulation of a liquid cooling medium in a closed circuit.

Seal device for rotating shafts, in particular stern tube seal for propeller shafts of a ship


A method and an apparatus for controlling exposure are disclosed. A light beam carrying gradation image information is projected to writing side of spatial light modulating means and another light beam is projected to reading side of the modulating means to obtain a light beam for exposure in accordance with the intensity of the light beam to the writing side. By varying the reflectance on the reading side in accordance with the gradation image information, the light beam for exposure is obtained and the amount of exposure is controlled. The reflectance on the reading side is controlled by continuously varying the intensity of the light to the writing side and/or by continuously varying the driving voltage of the modulating means.

As the means of controlling exposure in a photographic printer or a copying machine, there has been recently known a system using a liquid crystal element. When gradation is obtained by using the liquid crystal element, transmitted light is modulated by utilizing a gradation characteristic of the liquid crystal element itself. The gradation characteristic of the liquid crystal itself depends upon a threshold characteristic. The more gradually the threshold characteristic varies, much gradations to be obtained.
When a gradation image is exposed, it is preferable that it should be exposed with much gradations as possible. However, only 32 gradations or thereabouts are obtained in the present circumstances, and only 64 gradations or thereabouts are obtained in an experimental stage. On the other hand, in a photographic printer, multi-gradation exposure of 1024 gradations is required.
Further, since a liquid-crystal operation mode in which the liquid crystal itself has a middle tone characteristic is restricted, the degree of design freedom of a liquid crystal element is limited. As a result, it is difficult to provide a desirable modulating element at a low cost.

Method and apparatus for controlling exposure


An embodiment of the present invention allows a user to maintain the display of a video frame containing one or more interactive links while also maintaining access to the links. Thus allowing the user to select and examine any desired links at his own pace. For one embodiment, the display of a video frame is maintained by interrupting the refreshing of the frame buffer and the interactive link stream. Interrupting both the frame buffer refresh and the interactive link stream refresh results in the frame being “frozen” along with its associated links. For one embodiment, pressing a button on a control device effects the interruption of the frame buffer refresh and the interactive link refresh. The button may toggle to resume the video display. Alternatively, or additionally, the video display may resume if no action is taken in regard to the interactive links within an specified time.

Interactive TV allows interactive links to be embedded in live video. Such interactive links allow a user access to a variety of information. This information may include audio, visual, or text information and may be related to the video program in which it appears and/or may be commercial in nature. As interactive TV progresses, more and more programs will have interactive links embedded in live video, as differentiated from links embedded in static screens. And as technology further develops, not only will a single link be embedded in a video scene, but even numerous, multiple links may be embedded in a video scene. Furthermore, because the links may be embedded in live-action video, the links will be dynamic and some may only be displayed for a short time. Such live-action video with multiple embedded links may be designed for a system having a highly interactive pointer device that would allow a user to access the links quickly. However, a system having a set-top box that uses arrow keys to move a cursor may not be able to select a link during the limited time the link is displayed.
Even if a system has a highly interactive pointer device, such as a mouse, trackball, or similar device, it may be difficult for a user to follow a link in real time if the link represents, for example, a football player running across the screen, due to the speed of the moving image.

Freezing live video frames with interactive links


A method and apparatus for extending the effective circumferential extent of an original an aircraft simulator mirror cell having a base support structure mounted to a movable platform, the base support structure being in generally the shape of a portion of a sphere of a predetermined radius and having a predetermined circumferential extent defined by original edges of the support structure configured to support a vacuum-shaped reflective film. The improvement includes a pair of extension wing structures having substantially the same spherical radius as the base support structure and a substantial circumferential extent, each of the pair of wing structures being attached to one of the original edges of the base support structure and substantially sealed thereto, the extension wing structures, when attached, extending the effective circumferential extent of the base support structure by a substantial amount, each of the pair of extension wing structures having outer edges for supporting a vacuum-shaped reflective film.

For many years the flight simulator training industry has been using various visual display techniques to provide the pilots with an out of the window view of the world.
The "simulated display industry" started out as a few specialist vendors supplying rigid model systems that had a mechanical "eye" that "flew" over a model board. The movement of this "magic eye" was controlled by the movement of the control column/side sticks in the cockpit and was a purely mechanical linkage system that provided the pilots with some form of terrain and visual representation.
With the growing availability of commercial computer graphics in the early 1970s it was not long before visual system manufacturers moved away from rigid models to some form of computer generated imagery (CGI).
This new computer generated "virtual" environment required some form of electronic display medium to transfer the software driven 'virtual world' to something that the pilot could view in the 'real world'. In the early days this was a set of collimated monitor screens placed directly over each of the cockpit windows. This early simulation display system was the standard for the next decade.
In the early 1980's a company called Rediffusion Simulation Limited developed a unique display system that they christened WIDE (Wide-angled Infinity Display Equipment). This provided a cross cockpit out of the window view for the pilot and for the first time provided something approaching a real world scene. Since that time the word WIDE has been adopted by all visual system vendors as the generic term used to describe what is now the common standard in simulated display systems for aircraft simulators.
The first WIDE displays were all delivered with a 150 degree mirror, thus giving a continuous horizontal field of view of 150 degrees. This 150 WIDE as it is called by industry people is the most common and normal type of display delivered. A simplified schematic view of such a 150 degree display is depicted in FIG. 3.
Recently, the governing bodies of Europe have determined that the most effective training can only be accomplished by using a horizontal field of view of 180 degrees. For the past 4 years all training centers and airlines wishing to attain the highest certification level in Europe and Asia have had to use a 180 WIDE display. This common 180 standard became a pre-requisite for American training centers on Dec. 31, 2005.
This requirement has created a large upgrade market for the manufacturers of 180 mirrors to exploit. In the past few years a growing number of customers are having to remove their existing and perfectly useable 150 display mirrors and replace them with 180 display mirrors. The cost of replacing large state of the art optic display mirrors is very expensive and a complete system upgrade such as this usually costs more than $600,000 (US).
The existing 150 mirror cells that are removed are often sold for little more than the scrap value they bring to customers willing and able to train at lower certification levels.
After much analysis and investigation, the present inventors determined that the current approach of most vendors could be improved and provide an improvement in the geometric accuracy as viewed by the pilots. This analysis led the present inventors to investigate a new and better alternative to the current standard techniques for mirror installation used by other vendors.
The eventual result of this analysis was to develop a technique and subsequent set of tooling that very accurately replicated the standard curvature of the mirror cells in question. This curvature needed to be accurate in both horizontal and vertical directions in order to maintain accuracy and prevent undue distortions to the virtual image and also to prevent damage to the fragile Mylar™ material when being applied.

Method and apparatus for modifying aircraft simulator wide-angled infinity display equipment mirror to enlarge field of vision and for reskinning aircraft simulator spherical mirror cell to minimize mirror stress and distortion


Radiotherapy is one of the most effective treatments for cancer and its success depends critically on accurate targeting and delivery of the correct radiation dose. Accurate dosimetry is therefore essential to maintain and improve patient survival rates. However, size and long wait times currently limit water and graphite based calorimeters to standards laboratories leaving field-based dosimetry to ionization chamber measurements which depend upon a reference field-specified calibration factor. It would therefore be beneficial to provide radiotherapy equipment operators a direct approach of clinical reference dosimetry wherein the dosimeter provides increased independence on dose, dose rate, radiation energy, and energy type, etc. It would be further beneficial for such novel clinical dosimeters to be compact, function as secondary standards used routinely for measurements and allow radiotherapy doses to be measured directly and in an absolute manner. According to embodiments of the invention novel compact graphite probe calorimeters are provided.

Radiotherapy is one of the two most effective treatments for cancer. The success of radiotherapy in curing cancer depends critically on accurate targeting and delivery of the correct radiation dose. If the dose delivered to a patient is too low then cancerous cells may survive leading to a recurrence of the cancer. If the dose delivered is too high then surrounding healthy tissue is more likely to be damaged. For example, optimal treatment of some head and neck tumours requires that the dose delivered should be within only a few percent of that prescribed. Uncertainty in patient positioning means that it is crucial for all other errors to be as small as is possible. Accurate dosimetry is therefore essential to maintain and improve patient survival rates.
Radiation dosimetry is the measurement and calculation of the absorbed dose in matter and tissue resulting from the exposure to indirect and direct ionizing radiation. It is a scientific subspecialty in the fields of health physics and medical physics that is focused on the calculation of internal (internal dosimetry) and external doses from ionizing radiation. In medical physics absorbed dose is reported in SI units of gray (Gy) where 1 Gy=1 J/kg, and in radiation protection dosimeters in units of Sieverts (Sv).
There are different ways of measuring absorbed dose from ionizing radiation. For workers who come in contact with radioactive substances or may be exposed to radiation routinely, personal dosimeters are typically employed and intended primarily for warning/notification rather than accurate determination of dose. In the United States, these dosimeters are usually thermoluminescent dosimeters (TLD) or optically stimulated luminescence (OSL) dosimeters, whilst personal dose monitors based on photographic emulsions that are sensitive to ionizing radiation are also available. In radiotherapy, such as with linear particle accelerators in external beam radiotherapy, routine accurate calibration is typically and most commonly obtained using ionization chambers. However other detectors ranging from semiconductor-based dosimeters to radiochromic films may also be used for certain applications.
Because the human body is approximately 70% water and has an overall density close to 1 g/cm3, for consistency, absorbed dose measurements are normally made in and/or reported as dose to water. National standards laboratories such as US National Institute of Standards and Technology (NIST) and UK National Physical Laboratory (NPL) provide calibration factors for ionization chambers and other measurement devices that are used to convert the instrument's readout, which may be for example ionization, optical density change, current, etc., to absorbed dose to water. The standards laboratories maintain a primary standard, which is normally based on either of three techniques: calorimetry, Fricke dosimetry, or free air ionization chambers. Out of the three, calorimetry, being the measurement of temperature rises due to radiation energy being absorbed in medium, is the most direct and absolute means of determining absorbed dose and is used most commonly.
A hospital or other users subsequently send their detectors (often ionization chambers) to the laboratory, where it is exposed to a known amount of radiation (as determined using the primary standard) and in turn a calibration factor is issued to convert the instrument's reading to absorbed dose. The user may then use this calibrated detector (secondary standard) to derive calibration factors for other instruments they use (tertiary standards) or field instruments. The uncertainty on the calibration factor of a detector increases inherently with the number of steps in the chain of calibrations relating the device to the primary standard.
Today many primary standards laboratories use water- or graphite-calorimeters to maintain an absolute photon dosimetry standard. In calorimetry, the basic assumption is that all (or a known fraction) of the absorbed radiation energy appears as heat, so that the measurement of absorbed dose reduces to a measurement of a temperature change. If the absorbed dose to water is to be established, ideally the calorimetric measurements should be made using water, see for example Ross et al in "Water Calorimetry for Radiation Dosimetry" (Phys. Med. Biol., Vol. 41, pp 1-29). However, due to many challenges with water calorimetry, including low signal to noise ratio and potential heat defect due to presence of impurities in water, in addition to the cumbersome nature of the device and difficulty of working with a water tank and related accessories, significant research has also been undertaken in the area of graphite calorimetry. Graphite has beneficial radiation absorption characteristics that are similar to those of water, and allows for thermally isolated segments to be machined and configured so as to permit the measurement of absorbed dose to graphite. At present due to advances in water calorimeters arising from the work of Domen, see for example "Absorbed Dose Water Calorimeter" (Med. Phys., Vol. 7, pp 157-159), both graphite and water calorimeters are exploited.
However, due to their general bulkiness and long wait times with establishing thermal equilibrium water and graphite based calorimeters have been to date, within the prior art, limited to standards laboratories. Accordingly, it would be beneficial to provide clinical medical physicists with an alternative approach to ionization chambers for the calibration and quality assurance of radiation therapy equipment including standard as well as small radiation fields. It would be further beneficial for such novel clinical dosimeters to be capable of operating as self-calibrating secondary standards, which may be used routinely for measurements rather than calibration activities only.
Radiotherapy is a field subject to continuing evolution as treatment protocols, radiopharmaceuticals, and radiotherapy equipment address both the rising rates of cancer, as more people live to an old age and as mass lifestyle changes occur in the developing world such that in 2007 approximately 13% of all human deaths worldwide (7.9 million) were cancer related, and currently there are over 200 different known types of cancers. Amongst such developments is the emergence of treatment units specifically designed for stereotactic radiosurgery, wherein small targets inside the body are treated using small static or rotating radiation fields that are at times highly modulated in both intensity and/or shape. Many radiotherapy units such as GammaKnife®, CyberKnife®, TomoTherapy®, and even most conventional linear accelerator (LINAC) manufacturers Varian®, Siemens®, Elekta® now provide the capabilities of delivering extremely complex treatment deliveries based on stereotactic radiotherapy (SRT) or intensity modulated radiation therapy (IMRT) to treat a given disease site with extreme accuracy and conformality. Accordingly, with these sophisticated techniques comes the requirement for new dosimetry protocols that address absorbed dose calibration in nonstandard radiation fields wherein practices are currently lacking international standards, see for example Alfonso et al in "A New Formalism for Reference Dosimetry of Small and Non-Standard Fields" (Med. Phys., Vol. 35, pp 5179-5186). Accordingly, calorimetry could offer a more direct and accurate way of measuring absorbed dose to water in small and composite radiation fields by doing away with the need to transfer calibration factors according to the radiation beam quality of interest.
However, calorimetry is not without its challenges when considering compact field-deployable calorimeters. Graphite has a specific heat capacity one-sixth that of water and therefore for a given radiation dose, its temperature rises 6 times more than an equivalent water based calorimeter give rise to a higher signal to noise ratio. A typical dose of radiation to a human during radiotherapy treatment is approximately, 1-2 Gy, which is 1-2 joules per kilogram. Accordingly, if we consider a calorimeter comprising a 1 cm3 piece of graphite, which weighs approximately 2 grams, this would therefore absorb around 2-4 mJ, which with a specific heat capacity of around 700 Jkg−1 K−1 equates to a temperature rise of just 1-2 mK. Accordingly, significant problems exist in insulating the graphite from the ambient clinical environment in order to measure such tiny temperature changes.
Accordingly, embodiments of the invention provide for compact graphite probe calorimeters (GPC) for absolute accurate clinical dosimetry to address the requirements of evolving radiotherapy systems and radiopharmaceutical therapies whilst providing medical radiation oncology technologists and medical physicists with compact, fast, low cost alternatives to ionization chambers for conventional radiotherapy calibration.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

The Royal Institution for the Advancement of Learning/McGill University


The specification describes a multi-chip module (MCM) that contains an integrated passive device (IPD) as the carrier substrate (IPD MCM). Parasitic electrical interactions are controlled at one or both interfaces of the IPD either by eliminating metal from the interfaces, or by selective use of metal in parts of the MCM that are remote from the sensitive device components. The sensitive device components are primarily analog circuit components, especially RF inductor elements. In the IPD layout, the sensitive components are segregated from other components. This allows implementation of the selective metal approach. It also allows parasitic interactions on top of the IPD substrate to be reduced by selective placement of IC semiconductor chips and IC chip ground planes. In preferred embodiments of the IPD MCM of the invention, the IPD substrate is polysilicon, to further minimize RF interactions. The various methods of assembling the module may be adapted to keep the overall thickness within 1.0 mm.

(Portions of the technical material contained in this section may not be prior art.)
State of the art radio frequency (RF) electrical circuits use large quantities of passive devices. Many of these circuits are used in hand held wireless products. Accordingly, miniaturization of passive devices and passive device circuits is an important goal in RF device technology.
Integration and miniaturization of passive devices on the scale of active silicon devices has not occurred for at least two reasons. One, typical passive devices to date employ different material technologies. But, more fundamentally, the size of many passive devices is a function of the frequency of the device, and thus is inherently relatively large. However, still, there is unrelenting pressure to produce more compact and area efficient IPDs.
Significant advances have been achieved. In many cases these involve surface mount technology (SMT). Small substrates containing large numbers of passive components are routinely produced using surface mount technology.
More recent advances in producing integrated passive device networks involve thin film technology where resistors capacitors and inductors are built as integrated thin film devices on a suitable substrate. See for example U.S. Pat. No. 6,388,290. This advance shows promise as the next generation of integration in passive device technology. However, just as the substrate material and character (pure single crystal silicon) have been key to the success in active device technology, it is becoming evident that the same is true as IPD integration develops. Because passive thin film devices are formed directly on the substrate, electrical interactions between the substrate and the passive devices are of major concern. U.S. patent application Ser. No. 10/835,338 addresses these issues, and describes and claims an IPD substrate that offers processing advantages coupled with the desired dielectric properties. This substrate can also be made thin, to reduce the profile of the IPD.
While a common concern from a miniaturization standpoint is the so-called "footprint" of a device or circuit, reducing thickness is a companion goal. A common approach to reducing the footprint of ICs is to stack two or more chips in an MCM. In MCM technology, the thickness of the packaged chips is often as important as the footprint.
The MCM approach to miniaturization in RF circuits is often avoided due to the problem of RF interactions between components, especially inductor elements. The usual approach for RF circuits and IPDs is to spread the devices laterally on the substrate. Typically an IPD substrate is larger than a typical semiconductor IC, so to implement an MCM containing an IPD substrate, the IPD substrate is the logical candidate for the carrier substrate of the MCM, i.e. the semiconductor chips would be mounted on top of the IPD substrate. However, stacking devices on an IPD substrate especially invites problematic interactions. An IPD substrate in this MCM configuration faces two issues of RF field interactions, one with the substrate on which the IPD substrate is mounted, and another with the IC chips on the top of the IPD substrate.


A method for fabricating a vibratory structure gyroscope is provided herein. An annular cavity is formed in a first surface of a substrate, the annular cavity defining an anchor post located in a central portion of the annular cavity. A bubble layer is formed over the first surface of the substrate and over the annular cavity. The substrate and the bubble layer are heated to form a hemitoroidal bubble in the bubble layer over the annular cavity. A sacrificial layer is deposited over the hemitoroidal bubble of the bubble layer and an aperture is formed in the sacrificial layer, the aperture disposed over the anchor post in the annular cavity. A resonator layer is deposited over the sacrificial layer and the sacrificial layer between the bubble layer and the resonator layer is removed.

Vibrating structure gyroscopes detect rotation by sensing changes in the vibration of a vibrating structure such as a resonator. Typically, the resonator is induced to vibrate by some mechanism. Rotation of the vibrating resonator can cause changes in the vibration (e.g., angle, speed). These changes can be detected and used to determine the rotation of the resonator. Vibrating structure gyroscopes typically include piezoelectric, hemispherical, tuning fork, and wheel-type gyroscopes.
Hemispherical type vibrating structure gyroscopes can include a resonator having a hemispherical shell attached to a stem. The stem of the resonator is mounted to a structure, and the resonator can vibrate about the stem. These types of gyroscopes can be made using conventional high-precision machining techniques. It is typically desirable to build this type of gyroscope using micromachining techniques, allowing batch fabrication of many gyroscopes at one time.
In some examples, the uniformity of the hemispherical shell can affect the accuracy with which the vibrations in the hemispherical shell can be used to detect rotation. In addition, the positioning of the stem on the hemispherical shell (e.g., if the stem is off centered) can also affect the accuracy of the gyroscope. Thus, precision in the manufacture of the hemispherical type gyroscope is an important factor that can be difficult to achieve.


Disclosed herein are substantially pure glycosaminoglycan compositions derived from genetically modified cells.

Glycosaminoglycans such as heparan sulfate, chondroitin sulfate, keratan sulfate, and hyaluronic acid play important roles in cellular and tissue specific physiology, pathophysiology and development because of their specific binding to a wide variety of proteins. These proteins include enzymes, extracellular signaling molecules, chemokines, lipid- or membrane-binding proteins, adhesion proteins and pathogenic proteins giving glycosaminoglycans important biological roles in inflammatory processes, cell growth and differentiation, hematology, cell-cell and cell-matrix interactions, lipid transport and clearance/metabolism, and host defense and viral infection.

Cellular glycosaminoglycan compositions and methods of making and using


A flexible strip transmission line is disclosed. The flexible strip transmission lines consists of a plurality of flexible layers enabling the transmission line to be folded or repeatably bent. The central layer consists of a flexible dielectric material. On opposing side of the dielectric layer are first and second flexible ground planes formed of a metalized fabric. The flexible ground plane layers are bonded to the dielectric material using a bonding agent such as silicone adhesive. An abrasion resistant material is connected to the outer surface of the flexible ground plane layers to provide a protective exterior shell.

1. Technical Field of the Invention
The present invention relates to RF strip transmission lines, and more particularly, to a flexible RF strip transmission line constructed of flexible dielectric and ground plane materials to form a stripline structure.
2. Description of Related Art
The continued downsizing of mobile telephone hardware and the development of such features as the "flip" phone wherein a mobile telephone has a portion which folds over another portion of the phone in order to conserve space have generated a variety of problems. The decreased amount of space within a mobile telephone has required the need for the various transmission lines running through the mobile telephone to be folded prior to fixed installation in order to conserve space. Also within the "flip" type mobile telephones, transmission lines running from the main portion of the mobile telephone to the "flip" portion must have the ability to be repeatedly flexed between open and closed positions without destroying the integrity of the transmission lines passing between the two sections.
Current practice involves the use of either coaxial cable or planar stripline structures having a ground plane formed with copper foil or relatively rigid metalization systems. Both of these practices suffer from various shortcomings. Coaxial cables require the use of a separate cable for each signal being transmitted. This requires the installation and routing of each cable and takes a great deal of time. Furthermore, each cable must be individually connected to the mobile telephone circuitry. The use of coaxial cables and connectors requires a great deal of space which is at a premium within smaller mobile telephone models.
Traditional planar stripline systems may not be folded or used within a "flip" portion of a mobile telephone since the metalization employed in forming the upper and lower ground plane is too rigid to enable continuous flexing of the ground planes between the open and closed positions of the "flip" portion. Currently available planar stripline structures can employ patterned openings within the ground plane metalization to enable a degree of flexibility, but this solution limits the effectiveness of the shielding.
Thus, each of the previously used fabrication methods includes significant shortcomings in RF performance, space limitations and manufacturing costs. Ideally, the shielding effectiveness for a transmission line in a mobile telephone should be as close as possible to the shielding of a coaxial cable and be implemented with the fewest elements possible.


The present invention relates to new uses of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate, (amifostine) and other aminothiol compounds to treat and reverse toxicities caused by therapeutic agents, radiation treatment or diabetes. In particular, the invention provides a method for treating neurotoxicity and nephrotoxicity associated with the administration of chemotherapeutic agents.

2.1. Aminothiol Compounds
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyol.RTM., NSC 296961, and WR-2721 and which will hereinafter be referred to as "amifostine") and other aminothiol compounds are disclosed in U.S. Pat. No. 3,892,824 to Piper et al. These compounds were originally developed as antiradiation agents (radio-protectants), in particular to be used prior to exposure to x-ray or nuclear radiation, to protect against the harmful effects of such exposure which may be encountered during military conflicts.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant, i.e., as a protectant administered prior to therapy to reduce the undesirable adverse effects which arise during the use of chemotherapy and radiation therapy in the treatment of cancer. Nygaard et al., eds., 1983, Radioprotectors and Anticarcinogens, Academic Press, Inc., New York, pp. 73-85; Grdina et al., 1985, "Radioprotector WR-1065 Reduces Radiation-Induced Mutations of the HGPRT Locus in V79 Cells," Carcinogenesis (London) 6:929-931. In addition, these compounds have been reported to afford protection against the adverse effects of chemotherapeutic agents, for example, alkylating agents such as cisplatin and carboplatin, when administered before or concurrently with the chemotherapeutic agent. Jordan et al., 1982, "Modulation of cis-platinum renal toxicity by the Radioprotective agent WR-2721", Exp. Mol. Pathol. 36:297; Doz et al., 1991, "Experimental Basis for Increasing the Therapeutic Index of Carboplatin in Brain Tumor Therapy by Pretreatment With WR-Compounds", Cancer Chemother. Pharmacol. 28:308. Similarly, it has been reported that amifostine has been used experimentally prior to therapy to protect HIV-infected patients (AIDS) from the harmful side effects of 3'-azido-3'-deoxythymidine (AZT) therapy. International Published Application WO 90/14007, published Nov. 29, 1990. Amifostine and its derivatives have been shown to exert these reported protective effects without affecting the beneficial properties of the administered therapeutic agents. This is, in the case of chemotherapy, believed to be due to the selective uptake of the protective thiol and other metabolites into normal tissue. Yuhas, 1980, "Active versus Passive Absorption Kinetics as the basis for Selective Protection of Normal Tissues by WR-2721", Cancer Res. 40:1519-1524; Yuhas, 1979, "Differential Protection of Normal and Malignant Tissues Against the Cytotoxic Effects of Mechlorethamine" Cancer Treat. Rep. 63:971-976.
Amifostine and related aminothiol compounds have also been shown to stimulate bone marrow growth. See U.S. patent application Ser. No. 08/390,713; International Published Application WO 96/25045 published Aug. 22, 1996; List et al., "Amifostine Stimulated Formation of Multipotent Progenitor and Generated Macroscopic Colonies in Normal and Myelodysplastic Bone Marrow," Proc. Am. Soc. Clin. Oncol. 15:449 [1403] [Abstract]. Currently, amifostine is in Phase II clinical trials as a bone marrow stimulant in patients suffering from myelodysplastic syndrome. List et al., 1996, "Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial," Am. J. Hem. 1 (Abstract); List et al., 1996, "Amifostine Promotes in vitro and in vivo Hematopoiesis in Myelodysplastic Syndromes," Chem. Found Sympos. (Abstract); List et al., 1996, "Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial," Abstract, 8th Annual Meeting, American Society of Hematology, Orlando, Fla. Pre-exposure with aminothiol compounds is capable of causing the bone marrow function to more rapidly recover following chemotherapy. List et al., 1996, "Amifostine Protects Primitive Hematopoietic Progenitors Against Chemotherapy Cytotoxicity," Semin. Oncol. 23 (4) Supp. 8:58-63.
Presently, amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer. Physicians' Desk Reference, 51st ed. 1997, p. 485-486. The recommended starting dosage for adults in an FDA-approved indication is 910 mg/m.sup.2 administered once daily as a 15-minute intravenous (i.v.) infusion, starting 30 minutes prior to chemotherapy. However, clinical trials have used doses as low as 100 mg.
U.S. Pat. Nos. 5,567,686 and 5,488,042, both to Grdina, allege that the administration of an aminothiol compound before irradiation of a mammal affords protection against genotoxic mutagenesis. Although the U.S. Pat. No. 5,488,042 discloses administering an aminothiol up to about three hours after irradiation, both patents focus solely on prevention of mutations, rather than the treatment or reversal of radiation- or chemotherapy-induced damage. Further, the Grdina patents are silent as to the use of any aminothiol compound in humans to treat chemotherapy- or radiation-induced disorders and toxicities including neuro-, nephro-, hematological or mucosal disorders.
Nagy et al., 1986, "Protection Against cis-Diamminedichloroplatinum Cytotoxicity and Mutagenicity in V79 Cells by 2-[(Aminopropyl)amino]ethanthiol," Cancer Research 46:1132-1135, disclose that the free thiol metabolite of amifostine, also known as WR-1065, protects against cytotoxicity in V79-B310H Chinese hamster cells when administered before, during and immediately after treatment of the cells with cis-diamminedichloroplatinum (cis-DDP, "cisplatin"). Although some protection against cell death was observed under all conditions, Nagy et al. report that maximum protection was obtained when WR-1065 was present in the cell growth medium for 30 minutes prior to exposure of cells to cisplatin. In addition, Nagy et al. state that little if any difference in the magnitude of protection against cell killing was seen whether the WR-1065 was present either during or immediately following cisplatin exposure.
Treskes et al., 1992, "Effects of the Modulating Agent WR-2721 and its Main Metabolites on the Formation and Stability of Cisplatin-DNA Adducts in Vitro in Comparison to the Effects of Thiosulphate and Diethyldithiocarbonate," Biochemical Pharmacology 43(5):1013-1019 investigated the ability of amifostine and its main metabolites, WR-1065 and WR-33278, to prevent formation of adducts of cisplatin with the DNA of salmon sperm. They found that amifostine, WR-1065 and WR-33278 caused a decrease in the platination of salmon sperm in vitro when the compounds were present concomitantly with cisplatin. It was also observed that part of the already formed cisplatin-DNA adducts is disrupted during post-incubation with subject compounds, but this decrease in adduct levels was small compared to those obtained during co-incubations. Treskes et al. speculated that conformational changes in DNA induced by the WR-1065 metabolite of amifostine observed by other researchers might provide a rational for applying amifostine after cisplatin administration.
However, Treskes et al. later reported in 1993, "WR2721 as a Modulator of Cisplatin- and Carboplatin-induced Side Effects in Comparison with Other Chemoprotective Agents: A Molecular Approach," Cancer Chemother. Pharmacol. 33:93-106, that neither WR-1065 nor WR-2721 (amifostine) could protect cells from the cytostatic effect of cisplatin when the compounds were incubated with cells one hour after cisplatin exposure. Further, it was found that amifostine given 30 minutes after cisplatin did not protect mice at all from nephrotoxicity. Treskes et al. concluded that the selective protection of multiple non-tumor tissue by WR-1065 from cisplatin-induced toxicity is explained by a strong prevention, not reversal, of cisplatin-induced cellular damage. Treskes et al. further observed that these findings were in agreement with the hypothesis that the prevention of damage is the main mechanism of protection and that reversal of platinum-induced damage is not an important mechanism of protection.
Nephrotoxicity, produced by drugs such as cisplatin, has important consequences for the patient, with potential permanent loss of 50% or more of normal renal function (Kemp, et al. J. Clin. Oncology, 14:2101-2112, July, 1996). This can produce serious disability, requiring the need for dialysis in severe cases, and early mortality. It also has important consequences for the ability of the patient to be safely treated with other forms of life-sustaining chemotherapy and other medications such as antibiotics that are themselves renally toxic or require adequate renal function for elimination from the body.
Neurotoxicity may significantly decrease a patient's quality of life because of loss or distortion of sensation in the fingers, toes, hands and feet, as well as loss of fine muscle movements, resulting in the inability to perform routine functions such as buttoning of clothes. In more severe cases, patients suffer loss of sufficient motor function so that they require walkers or wheelchairs.
2.2. Cisplatin- and Paclitaxel-Induced Toxicities
Cisplatin continues to be an agent of choice for the treatment of advanced ovarian cancer, testicular cancer, bladder cancer and head, neck and lung cancers. McGuire et al., 1996, "Cyclophosphamide and cisplatin compared with Paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer," N. Engl. J. Med. 334:1-6. However, the cytotoxic effects of cisplatin on normal tissue, including the kidneys, can result in long-term debilitating effects which may limit the ability to deliver therapeutic doses against the cancer. Despite aggressive hydration and administration of mannitol, cisplatin-induced nephrotoxicity remains a significant cause of morbidity and mortality. Finley et al., 1985, "Cisplatin nephrotoxicity: A Summary of Preventative Interventions," Drug Intell. Clin. Pharm. 19:362-367; Kemp et al., 1996, "Amifostine Pretreatment of Protection Against Cyclophosamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer," J. Clin. Oncol. 14:2101-2112; Stewart et al., "Association of Cisplatin Nephrotoxicity with patient Characteristics and Cisplatin Administration Methods," Cancer Chemother. Pharmacol. 40:293-308.
Even when protective agents are administered prior to or during cisplatin treatment, toxicities may still be observed. The cumulative cisplatin nephro-toxicity that occurs can be treatment-limiting, precluding further administration of cisplatin and the ability to administer effective doses of renally-excreted second-line chemotherapy Kemp et al., 1996, J. Clin. Oncol. 14:2101-2112. In addition, drug therapy for other conditions can be affected, either because the agents are renally excreted, or because of their intrinsic potential to worsen renal function. Nephrotoxicity is also associated with other platinum coordination complexes such as carboplatin which are also used to treat cancers.
The nephrotoxicity associated with cisplatin is cumulative, i.e., incremental damage occurs with repeated courses of therapy. Daugaard et al., 1989, "Cisplatin nephrotoxicity," Cancer Chemother. Pharmacol. 21:1; du Bois, et al., 1994, "Cisplatin and carboplatin induced acute, cumulative and chronic nephrotoxicity," Proc. Annu. Meet. Am. Assoc. Cancer Res. 35: A1475. Loss of renal function occurring secondary to cisplatin is typically permanent. Macleod et al., 1988, "The effect of cisplatin on renal function in patients with testicular tumors," Clin. Radiol. 39: 190-192; Aass et al., 1990, "Renal function related to different treatment modalities for malignant germ cell tumors," Br. J. Cancer 62:842-846; Meijer, et al., 1983, "Influence of combination chemotherapy with cisdiammine chloroplatinum on renal function: Long term effects," Oncology 40:170-173. Risk factors for development of this toxic effect include age, a history of renal irradiation, dehydration, and alcoholism. Anand et al., 1993, "Newer insights into cisplatin nephrotoxicity," Ann. Pharmacother. 27:1519-1525.
Nephrotoxicity associated with administration of cisplatin and other platinum coordination complexes is generally observed during the second week after a dose and is manifested by elevations in BUN and/or serum creatinine and/or a decrease in creatinine clearance or serum magnesium. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Nephrotoxicity may be accentuated in patients with pre-existing risk factors such as diabetes or hypertension as well as individuals who are receiving other nephrotoxins such as aminoglycoside antibiotics or antifungals such as amphoterecin. Options available to reduce cumulative cisplatin renal toxicity are limited, and generally involve reducing its dosage or frequency of administration, both of which risk a potential reduction in antitumor effectiveness. Kemp et al., 1996, J. Clin. Oncol. 14:2101-2112. Pretreatment or simultaneous administration of amifostine is also an option, but these treatments are not always effective.
In addition to nephrotoxicity, many other toxicities are associated with the administration of platinum coordination compounds. For example, ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin (50 mg/m.sup.2) and is manifested by tinnitus and/or hearing loss in the high frequency range (4000-8000 Hz). Decreased ability to hear normal conversational tones may occur occasionally. Deafness after the initial dose of cisplatin has been reported rarely. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses. In addition, myelosuppression occurs in 25-30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 with most patients recovering by day 39. Leukopenia and thrombocytopenia are observed at higher doses (>50 mg/m.sup.2).
Neurotoxicity, usually characterized by peripheral neuropathies, is also associated with administration of platinum coordination complexes. The neuropathies, in the form of loss or distortion of sensation, or loss of fine motor function, usually occur after prolonged therapy (4-7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin-induced neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of the platinum coordination complex.
Generally, in the event of cisplatin-induced neuropathic symptoms, cisplatin is discontinued until the symptoms subside or disappear. The neuropathy, however, may progress even after treatment is stopped. Some preliminary evidence suggests that neuropathy may be irreversible in some patients. Lhermitte's sign, dorsal column myelopathy, autonomic neuropathy, loss of taste and seizures have also been reported. Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, or loss of sufficient motor function so that a patient requires a walker or wheel chair for movement, have been reported and are usually associated in patients receiving a relatively high cumulative dose of cisplatin and exhibiting advanced symptomatic stages of peripheral neuropathy. Amifostine has demonstrated the ability to reduce the incidence of neuropathies when administered prior to cisplatin. In a prospective evaluation of patients treated with cisplatin regimens.+-.amifostine at the Hospital of the University of Pennsylvania Cancer Center, patients pretreated with amifostine had a significantly lower incidence of cisplatin neuropathies and the onset of neuropathies occurred at a significantly higher cumulative dose of cisplatin [Mollman J E, Glover D J, Hogan W M, Furman R E: Cisplatin neuropathy: Risk factors, prognosis and protection by WR-2721. Cancer 61:2192-2195, 1988].The ability of amifostine pretreatment to significantly reduce the occurrence and severity of cisplatin neuropathy was confirmed in a randomized controlled trial of cisplatin and cyclophosphamide.+-.amifostine in women with advanced ovarian cancer [Kemp G, Rose P, Lurain J et al.: Amifostine pretreatment for protection against cyclophosphamide and cisplatin induced toxicities: Results of a randomized control trial in patients with advanced ovarian cancer. J. Clin. Oncol. 14:2101-2112, 1996].
Paclitaxel is indicated, after failure of first-line or subsequent chemotherapy, for the treatment of metastatic carcinoma of the ovary. Paclitaxel is also indicated for the treatment of breast cancer after failure of combination therapy for metastatic disease or relapse within six months of adjuvant therapy. Paclitaxel is known to have the following adverse effects: neutropenia, leukopenia, peripheral neuropathy, and arthralgia/myalgias and other neurological manifestations. The results of a clinical trial of amifostine and escalating doses of paclitaxel, indicated that pretreatment with amifostine allowed both higher single doses and cumulative doses of paclitaxel to be administered without the occurrence of dose limiting neuropathies and arthralgias/myalgias [DiPaolo R et al.: Amifostine and dose intense paclitaxel in patients with advanced malignancies. Cancer Therapeutics, Proc. Am. Soc. Clin. Oncology Vol. 16 (Abstract 826) 235a (1997)]. These may be accentuated when the drug is combined with other neurotoxic agents such as cisplatin. Many patients receiving paclitaxel also experience hypotension, asymptomatic bradycardia, and occasional episodes of silent ventricular tachycardia.
Hence, there is a need for a chemical agent for treating symptoms of neurotoxicity and nephrotoxicity which result from the administration of certain therapeutic agents, particularly, chemotherapeutics, radiation therapy, or disease states such as diabetes.

Methods for treatment of neuro--and nephro--disorders and therapeutic toxicities using aminothiol compounds

The Arizona Board of Regents on behalf of the University of Arizona


The invention includes a base, a working wire, a grounding wire, a first division layer, a second division layer and a cover layer. The base has a reaction area. The working wire is formed with a first measure contact and a first bioreaction contact. The grounding wire is formed with a second measure contact and a second bioreaction contact. The first division layer and second division layer have a first inlet and a second inlet, respectively. The first inlet and the second inlet correspond to the reaction area in position to expose the first and second bioreaction contacts. The guiding trough is formed by the cover layer, the base and the first and second inlets.

1. Technical Field
The invention relates to diagnostic instruments, particularly to biological reagents.
2. Related Art
A biosensor is an analytical device, used for the detection of an analyte, that combines a biological component with a physicochemical detector. A common example of a commercial biosensor is the blood glucose biosensor, which uses the enzyme glucose oxidase to break blood glucose down. In doing so it first oxidizes glucose and uses two electrons to reduce the FAD (a component of the enzyme) to FADH2. This in turn is oxidized by the electrode (accepting two electrons from the electrode) in a number of steps. The resulting current is a measure of the concentration of glucose. In this case, the electrode is the transducer and the enzyme is the biologically active component.
For the sake of portability or home use, compact biosensors using disposable test strips appear in the market and are extensively used. Different types of test strips may have a similar or the same shape or appearance. Users must visually distinguish and confirm the compatibility between a biosensor and a test strip. It is possible that an incompatible test strip is misapplied in a biosensor. There must be a risk of misapplying an incompatible test strip. This is a really serious problem for users or patients.


The invention relates to (1,2,4)triazolo[4,3-a]quinoxaline derivatives which are inhibitors of phosphodiesterase 2 and/or 10, useful in treating central nervous system diseases.

Cognitive dysfunction plays a role in a lot of central nervous system disorders, including neurological disorders, such as Alzheimer's disease (AD), Parkinsonism and dementia, but also psychiatric disorders, such as schizophrenia, depression and bipolar disorder. As world population grows older the number of patients with dementia and AD is growing. Therefore, most people are familiar with the cognitive deficits related to these neurological diseases (Massoud and Gauthier, 2010).
However, also in psychiatric disorders cognitive impairment adversely affect the progress and the treatment outcome of the disease. A most prominent example is schizophrenia. Schizophrenia has a heterogeneous symptomatic picture (American Psychiatric Association, 1994) that may be divided into three distinct disease domains: positive symptoms (psychotic episodes of hallucinations, delusions and agitation), negative symptoms (social withdrawal, anhedonia, flattened affect and cognitive deficits (deficits in executive function, verbal learning and memory, verbal fluency) (Thompson and Meltzer, 1993).
Whereas positive symptoms are essentially alleviated by dopamine D2 antagonist and second class antipsychotics negative symptoms and cognitive deficits are still hardly affected by current treatment. Therefore, research of cognitive deficits in schizophrenia has been intensified over the past years. A worldwide network initiative, called MATRICS, has been founded to characterise the cognitive deficits more deeply and to find novel therapies (Young et al., 2009).
However, cognitive impairment is also seen in patients with depression, bipolar disorder (Sachs et al., 2007; Pavuluri et al., 2009) and in many patients with disorders usually first diagnosed in infancy, childhood and adolescence, such as attention deficit/hyperactivity disorder (ADHD) (Jucaite et al., 2005; Turner et al., 2003).
Depression is a severe mental disorder which extremely impairs daily life. Its prevalence is about 10% of the world population with an incidence of 2% according to WHO. Women are more affected than men and elder people more than younger people. The disorder mostly implies a lifelong treatment due to the progress of the disease and permanent total disability.
The most prominent symptoms of the disease are anhedonia, feeling of hopelessness, decreased self esteem, loss of appetite and sleep disturbance. Most patients are suicidal. Depression is often combined with anxiety disorders. Interestingly, it is less known that depression is also regularly associated with various cognitive impairments (Gualtieri et al., 2006; Mandelli et al., 2006). Here, deficits of attentional and executive function are mostly reported (Paelecke-Habermann et al., 2005). Cognitive deficits are even discussed to be involved in the development of the disease (Beck depression model, Beck, 2008). More recent studies indicate that the severity of the cognitive deficits may predict nonresponse to certain antidepressant treatment (Dunkin et al., 2000; Gorlyn et al., 2008).
Up to now, current antidepressant therapy seems not to be sufficient regarding cognitive deficits. Elder antidepressants are reported to impair memory in animal models of learning and memory probably due to their anticholinergic component (Kumar and Kulkarni, 1996). In contrast, SSRIs, especially fluoxetine, are described to impair hippocampal-independent but not hippocampal dependent learning in different rodent models (Valluzi and Chan, 2007). At least, in clinic current therapy it is not possible to fully reverse cognitive deficits. Thus, in depressive patients who had been successfully treated cognitive performance could be improved but not normalised (Gualtieri et al., 2006). Therefore, an antidepressant with higher efficacy on cognitive impairment may improve disease outcome.
Bipolar disorder is an illness with complex symptomatology. It includes severe symptoms of mood disorders but also manic episodes and cognitive deficits. The Diagnostic and Statistical Manual, 4th edition and International Classification of Mental Disorder recommend subgroups of bipolar disorder based on whether depressive or manic [psychotic] symptoms and episodes are dominating and on the frequency of the episodes (Gaiwani, 2009). Pharmacological agents commonly used in the management of bipolar disorder include lithium; anticonvulsants, such as valproate, carbamazepine and lamotrigine; and recent years have witnessed increasing use of atypical antipsychotics (Altamura et al., 2011). As a problem of current therapy the development of tolerance against anticonvulsant treatment and 30% of treatment refractory cases are described (Post and Weiss, 2010; Gaiwani, 2009).
Attention deficit hyperactivity disorder (ADHD) is a central nervous system disorder that is mainly defined by its clinical signs. ADHD shows a heterogeneous symptom pattern in humans. The most important indicators are attention deficits, impulsivity and a hyperactivity that is primarily seen in boys. The disease starts at an early age and symptoms are most intense during childhood. After puberty the signs of the disease are more masked and focus on cognitive dysfunction (Jucaite et al. 2005; Turner et al. 2003). Although modern research broadened the understanding of the pathomechanism the exact etiology of the disease remains unclear.
Interestingly, the symptoms seen in ADHD are not due to a hyperactivity but a hypoactivity of the so called executive loop of the striatum (Winstanley et al., 2006; Plizska, 2005). The executive loop is responsible for the regulation of cognitive processes such as planning, working memory and attention (Berke et al., 2003; Easton et al., 2007). A dysfunction of the prefrontal cortex or other pathways within the loop induces impulsivity and a loss of the ability to filter stimuli that come from the outside. The latter causes the symptoms of sustained attention and hyperactivity (Roberts and Wallis, 2000; Gonzales et al., 2000). The dopaminergic neurotransmitter system plays a central role in regulating the activity of the executive loop (Jucaite et al., 2005). This conclusion is also supported by the current treatment for AMID that aims for an activation of the dopaminergic neurotransmitter system (Jucaite et al., 2005).
Phosphodiesterases (PDE) are expressed in nearly all mammalian cells. To date eleven families of phosphodiesterases have been identified in mammals (Essayan, 2001). It is well established that PDEs are critically involved in cell signalling. Specifically, PDEs are known to inactivate the cyclic nucleotides cAMP and/or cGMP (Soderling and Beavo, 2000). The cyclic nucleotides CAMP and cGMP are synthesised by the adenylyl and guanylyl cyclases and are second messengers that control many key cellular functions. The synthesis of cAMP and cGMP is regulated by different G-protein-coupled receptor types including dopamine D1 and D2 receptors (Mutschier, 2001).
The phosphodiesterases of the different families vary in their substrate selectivity. Thus, some families only hydrolyse cAMP others only cGMP. Some phosphodiesterases, such as phosphodiesterase 2 and 10, inactivate both cAMP and cGMP (Menniti et al., 2006).
Furthermore, there is a difference in the distribution of the different phosphodiesterases within the organism and additionally, within any particular tissue or organ. For instance, the distribution pattern of the phosphodiesterases within the brain is quite specific (Menniti et al., 2006).
Finally, phosphodiesterase families have different regulatory properties and intracellular location; some are bound to cell membranes and some are dissociated in the cytoplasm, additionally, a division into various intracellular compartments has been reported (Conti and Jin, 1999).
These differences in the function and location of the different PDE enzyme families suggest that the individual phosphodiesterases are selectively involved in regulating many different physiological processes. Accordingly, selective phosphodiesterase inhibitors may with fine specificity regulate different physiological and pathophysiological processes.
PDE2 and PDE10 hydrolyse both, cGMP and cAMP (Menniti et al., 2006; Soderling et al., 1999; Kotera et al., 1999).
They are both abundantly expressed in the brain indicating their relevance in CNS function (Bolger et al., 1994; Menniti et al., 2001).
PDE2 mRNA is mainly distributed in olfactory bulb, olfactory tubercle, cortex, amygdala, striatum, and hippocampus (Lakics et al., 2005; van Staveren et al., 2003). PDE10 (PDE10A) is primarily expressed in the nucleus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti et al., 2001).
Although there are certainly fine differences in the function and expression patterns of PDE2 and 10 the expression of PDE2 in the hippocampus, the cortex and in the striatum and the expression of PDE10 in striatum, hippocampus and frontal cortex indicate an involvement in the mechanism of learning and memory/cognition. This is further supported by the fact that increased levels of both cGMP and cAMP are involved in the process of short and long term potentiation (LTP) forming (Blokland et al., 2006; Prickaerts et al., 2002). LTP is regarded as the electrophysiological basis of long term memory (Baddeley, 2003). Boess et al. (2004) showed that PDE2 inhibitors amplify the generation of LTP. Additionally, it is reported that the selective PDE2 inhibitor BAY60-7550 enhances learning and memory in rats and mice in different animal models (Boess et al., 2004; Rutten et al., 2006). Similar pro-cognitive effects are described for selective PDE10 inhibitors, such as papaverine and MP-10. Rodefer et al. (2005) have found that papaverine reverses attentional set-shifting deficits induced by subchronic administration of phencyclidine, an NMDA antagonist, in rats. Grauer et al. (2009) could show a positive effect of papaverine and MP-10 on cognitive deficits in the novel object recognition and in prepulse inhibition of acoustic startle response in rats. These data support the procognitive effect of PDE2 and/or 10 and a synergistic effect of PDE2 and 10 on cognition.
Furthermore, the expression of PDE2 in the nucleus accumbens (part of the striatum), the olfactory bulb, the olfactory tubercle and the amygdale and the expression of PDE10 in the nucleus accumbens, the olfactory tubercle and the thalamus supports additional involvement of PDE2 and 10 in the pathophysiology of anxiety and depression (Modell et al., 1990). This is supported by in vivo studies. The selective PDE2 inhibitors BAY60-7550 and ND-7001 are described to be effective in animal models of anxiety and stress-induced behavior (Masood et al., 2008, 2009).
In addition to the pro-cognitive and antidepressant potential of PDE10 inhibition there is evidence for an additional antipsychotic potential of PDE10 inhibitors. In the striatum PDE10 is predominately found postsynaptic in the medium spiny neurons (Xie et al., 2006). By this location PDE10 may have an important influence on the signal cascade induced by dopaminergic and glutamatergic input on the striatum, two neurotransmitter systems playing a predominate role in the pathomechanism of psychosis. Focusing on the dopaminergic input on the medium spiny neurons, PDE10A inhibitors by up-regulating cAMP and cGMP levels act as D1 agonists and D2 antagonists because the activation of Gs-protein coupled dopamine D1 receptor increases intracellular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases intracellular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., 2001). Accordingly, PDE10 inhibitors are reported to be active in several animal models of schizophrenia (Schmidt et al., 2008; Siuciak et al., 2006; Grauer et al., 2009).
Several families of PDE2 inhibitors are known, Imidazotriazinones are claimed in WO 2002/068423 for the treatment of e.g. memory deficiency, cognitive disorders, dementia and Alzheimer's disease. Oxindoles are described in WO 2005/041957 for the treatment of dementia. Further inhibitors of PDE2 are known from WO 2007/121319 for the treatment of anxiety and depression, from WO 2006/072615, WO 2006/072612, WO 2006/024640 and WO 2005/113517 for the treatment of arthritis, cancer, edema and septic shock, from WO 2005/063723 for the treatment of renal and liver failure, liver dysfunction, restless leg syndrome, rheumatic disorders, arthritis, rhinitis, asthma and obesity, from WO 2005/041957 for the treatment of cancer and thrombotic disorders, from WO 2006/102728 for the treatment of angina pectoris and hypertension from WO 2008/043461 for the treatment of cardiovascular disorders, erectile dysfunction, inflammation and renal failure and from WO 2005/061497 for the treatment of e.g. dementia, memory disorders, cancer and osteoporosis.
Finally, benzodiazepines are described in WO 2005/063723 for the general treatment of CNS diseases including anxiety, depression, ADHD, neurodegeneration, Alzheimer's disease and psychosis.
(1,2,4)Triazolo[4,3-a]quinoxalines without any substituent in position 4 were described in U.S. Pat. No. 5,153,196 to be excitatory amino acid receptor antagonists. These compounds were synthesized from 1,2-diaminobenzenes which were condensed with glyoxylic acid to form the corresponding quinoxalin-2-ones. Treatment with POCl3 yielded the 2-chloroquinoxalines which were treated with hydrazine to prepare the 2-hydrazino-substituted derivatives. The following condensation with triethylorthoacetate delivered 1-methyl-1,2,4-triazolo[4,3-a]quinoxaline derivatives.
Some other (1,2,4)triazolo[4,3-a]quinoxalines without any substituent in position 4 were described in WO 2007/087250 to be inhibitors of 5-lipoxygenase for the treatment of respiratory and cardiovascular diseases.
An alternative route for the synthesis of 4-methyl substituted derivatives was published by R. Aggarwal et. al, (Synthetic Communications 36 (2006), 1873-1878). 2-chloro-3-methylquinoxalines were treated with hydrazines to form the corresponding 2-hydrazino-3-methylquinoxalines. These hydrazines were condensed with aldehydes to prepare the corresponding hydrazones. Finally, an oxidative intramolecular cyclisation in the presence of iodobenzene diacetate (IBD) provided the desired 1,2,4triazolo[4,3-a]quinoxalines. Similar synthetic approaches were already described by K, Dalip et. al. (Green Chemistry 6 (2004), 156-157) and D. A. Vyas et. al. (Indian Journal of Heterocyclic Chemistry 14 (2005), 361-362) with modifications of the conditions in the final step. Some of these derivatives were described to have antimicrobial activities.
Based on the same synthetic pathway S. Wagle et al. (European Journal of Medicinal Chemistry (2009), 44, 1135-1143) described the use of 4-methyl-(1,2,4)triazolo[4,3-a]quinoxalines as intermediates for the synthesis of 4-styryl-(1,2,4)triazolo[4,3-a]quinoxalines which were tested on potential anti-convulsive activity.
Other (1,2,4)triazolo[4,3-a]quinoxalines are described in WO 2010/030785 to be inhibitors of histamine receptors for the treatment of inflammatory, autoimmune, allergic and ocular diseases.
4-Trifluoromethyl-substituted (1,2,4)triazolo[4,3-a]quinoxalines are published in US 20090163545 for altering the lifespan of eucariotic organisms, in Bioorganic & Medicinal Chemistry, 2010, 18 (22), 7773-7785 to be folate cycle inhibitors and in Chemistry & Biology, 2007, 14 (10), 1105-1118 to modulate the TNF-α induced expression of ICAM-1 in lung epithelial cells.

(1,2,4)triazolo[4,3-A]quinoxaline derivatives as inhibitors of phosphodiesterases


A method for processing a signal characteristic of cardiac activity in the atrium (A) and/or ventricle (V) of a heart (H) and for evaluating this signal with a view to obtaining a control signal for a cardiac pacemaker and/or defibrillator (3) can be carried out by: receiving a time dependent signal from at least one intracardial signal sensor (1, 2) in the atrium and/or ventricle; feeding the signal picked up by each signal sensor (1, 2) to a read and evaluation circuit (6) with a threshold characteristic; comparing the signals with a detection threshold; evaluating the result of the comparison to obtain an indication as to the presence of normal sinus-type cardiac activity or fibrillations; and producing the control signal, which characterizes the comparison result. The signal from the at least one sensor (1, 2) is fed to a first input stage (8, 11) which has a first adjustable detection threshold (TS(A), TS(V) that is constant in time and to a second input stage (9, 10) which has a second adjustable detection threshold TL(A), TL(V) that can be adjusted independently of the first detection threshold but is constant in time once set. The signal from the at least one intracardial signal sensor is processed in these first and second input stages.

The invention relates to a method for receiving signals characteristic of cardiac activities in the atrium and/or ventricle of a heart and for evaluating the signals to obtain a control signal for a heart pacemaker and/or defibrillator. The invention also relates to a device for performing the method.
Implantable heart pacemakers and defibrillators have an input stage connected to an intracardial electrode for receiving and amplifying intracardially picked-up cardiac activity potentials and an evaluation unit for evaluating them and deriving control signals for operating the pacemaker or defibrillator. If signals from the heart chamber (ventricle) as well as the atrial area (atrium) are required for the control, then one electrode is provided for each, and the input stages (if necessary also components of the evaluation unit) generally form separate channels, for which the processing characteristics (sensitivity or detection threshold, filtering and amplification parameters) can be adjusted separately.
With automatic defibrillators and double-function pacemakers, which function as defibrillators if necessary, the initial stages must also detect and preprocess as signals the cardiac action potentials or signals that appear with normal cardiac action (sinus rhythm), such as occur with the various arrhythmic conditions of the heart.
The signal amplitudes for the intracardially picked-up signals, which characterize the different heart rhythm conditions, differ considerably from each other, as can be seen in FIG. 2. Graph I here illustrates a typical sinus rhythm with normal heart function, Graph II the electrogram for a ventricular tachycardia and Graph III that of a heart chamber fibrillation (ventricular fibrillation). A suitable detection threshold TI, TII, TIII is respectively marked here with a dashed line (Graph I), a dash-dot line (Graph II) or a double dash-dot line (Graph III).
An embodiment of the initial stage of a pacemaker with an automatic gain control (AGC) is known--for example from EP 0 349 130 A1. It is designed to improve the signal/noise ratio when operating jointly with a band-pass filtering.
Furthermore, it is known from U.S. Pat. No. 4,184,493 A1 to provide an automatic gain control with an automatic, implantable defibrillator. Together with a high-pass filtering, this causes a far-reaching suppression of S and T components of the electrogram and thus prevents a possible faulty interpretation of a "normal" electrogram as ventricular fibrillations, based on the detection of these signal components.
In an implantable cardioverter/pacemaker according to DE 37 39 014 A1, the AGC can be used further in connection with the detection of signal components with low amplitude and thus a ventricular fibrillation.
Such a function of the AGC is illustrated in FIG. 3, where the drawn-out graph represents an electrogram where a sinus rhythm can be seen in the left segment (range A), a ventricular tachycardia in the center segment (range B) and ventricular fibrillations in the right segment (range C). The upper, dashed line represents the effective detection threshold as it is adjusted by the AGC, and the events demonstrated for the illustrated, time-dependent course of the detection threshold are shown in the lower section of the Figure.
Certain appearances of ventricular fibrillation are characterized in the intracardial electrogram by the occurrence of a relatively low-frequency signal pattern with comparably high amplitude, superimposed on the fibrillation signals with considerably higher frequency and weaker fibrillation signals; compare in this case perhaps U.S. Pat. No. 4,523,595, especially FIGS. E12 and E13. Such an electrogram is shown (diagrammatically) in FIG. 4, for which the layout is analogous to FIG. 3. As is illustrated with this Figure, with the relatively slow rise of the amplification and the correspondingly slow decline of the detection threshold after each signal of the superimposed signal pattern that respectively increases the threshold, the AGC prevents a detection of the signals that characterize the fibrillation. As a result of this, the defibrillator cannot become operational, even though it may be needed.
With an automatic defibrillator, the automatic gain control (AGC) therefore can possibly result in grave operational defects--not to mention the fact that its realization for strongly differentiated signal images in the form of cardiac electrograms is not simple and is rather costly.

Method of processing signals characteristic of cardiac activity and an associated device

Biotronik Mess- und Therapiegeraete GmbH


A pulverulent adhesive composition which comprises (a) at least one polymer selected from the group consisting of vinyl ester polymers, (meth)acrylate polymers and styrene(meth)acrylate polymers, (b) at least one tackifying resin (tackifier) and, optionally, (c) one or more protective colloids, and, optionally, (d) one or more anticaking agents. The present composition is suitable for use in formulations used for the adhesive bonding of porous and/or semiporous substrates.

1. Field of the Invention
The present invention relates to pulverulent adhesive compositions, to processes for their preparation and to their use in formulations for the adhesive bonding of porous and semiporous substrates.
2. Description of Related Art
In order to avoid solvent wastes and solvent emissions, aqueous dispersions are increasingly being employed, in accordance with TRGS 610/GISCODE, as binders for producing pollutant-free adhesives. Suitable aqueous dispersions usually include, in addition to a synthetic, free-radically polymerized polymer, also tackifying resins, known as tackifiers. Such aqueous dispersions are described, for example, in U.S. Pat. No. 4,654,388, DE-A 23 01 497, EP-A 0 221 461, EP-A 0 315 070, EP-A 0 490 191 and EP-A 0 620 243.
These resins are generally rosins or esters thereof, and also hydrocarbon resins, which can if desired be esterified or otherwise modified. Aqueous resin dispersions with resin contents of between 50 and 70% by weight are generally also employed as tackifiers. The tackifier resin is added, generally in the form of an organic solution or else as a resin melt, to an aqueous dispersion of the polymer, or is added to the dispersion in combination with a wetting agent, plasticizer or high-boiling component. When aqueous resin dispersions are used, all that is generally required is a simple combination with a polymer dispersion appropriate as a binder. Since aqueous products form a good nutrient substrate for microorganisms, they are generally treated with a preservative. Examples of preservatives employed include chloroacetamide, N-methylolchloroacetamide, 2-bromo-2-nitropropane-1,3-diol or isothiazolinones. EP-A 0 134 451 discloses dispersion powders which can be employed for preparing adhesives but which do not themselves possess sufficient tack.


A semiconductor memory device enabling change of the output organization has a plurality of memory cell array portions each having a plurality of memory cells for storing data, a plurality of data buses for transferring data, a plurality of sense amplifiers for sensing data of a selected memory cell of the memory cell array portions, and a plurality of output gates connected to the sense amplifiers. At least two of the sense amplifiers are connected to each of the memory cell array portions through the data buses, respectively. The selection of the sense amplifiers is controlled to be activated or deactivated by control signals, to thereby change the output organization. Therefore, a delay in data transmission can be eliminated, and a high speed operation can be realized.

1. Field of the Invention
The present invention relates to a semiconductor memory device, more particularly, to a semiconductor memory device enabling selection and change of the output organization.
2. Description of the Related Art
In recent years, various types of semiconductor memory devices have been developed and marketed in accordance with various requirements of users. Note, in the prior art, it requires a large amount of cost and a long period to develop new semiconductor memory devices, even when the differences between the new semiconductor memory devices differ only the output organizations (word-bit organizations) in the same memory matrix.
In the related art, there has been provided a semiconductor memory device enabling a reconfigurable organization, e.g., 4 mega word.times.1 bit (4M.times.1) and 1 mega word.times.4 bit (1M.times.4) organizations in a 4M-bit memory device. In this semiconductor memory device, the selection from the 4M.times.1 organization and the 1M.times.4 organization is carried out in accordance with the requirements organization in the manufacturing (maker side) or working stage (user side). Namely, this semiconductor memory device can be used both for .times.1 and .times.4 organizations without having to design and produce exclusive masks, wiring patterns, and the like. Therefore, the development period and required cost can be largely decreased.
In recent years, a capacity of a semiconductor memory device has been largely increased in accordance with improvements of semiconductor production technique, and the like. Therefore, a required time for testing the semiconductor memory device should be lengthened.
The semiconductor memory device enabling to select between the .times.1 and .times.4 organizations can realize to decrease the testing time by carrying out the memory test at .times.4 organization. In this case, for instance, the semiconductor memory device is provided as a one-bit output organization memory device, and the four-bit output organization is electrically reconfigured for carrying out the memory test.
In the prior art, a semiconductor memory device enabling to set a one-bit output organization (.times.1 organization) and a four-bit output organization (.times.4 organization) of output data has been provided. However, in the prior art semiconductor memory device, switch units formed by MOS transistors are employed to change the output organization. Therefore, due to the ON resistance (turn-ON resistance) of the MOS transistors that form the switch units as well as wiring capacitance, the prior art semiconductor memory device has a large delay in data transmission, and thus a high speed operation (high speed reading) cannot be realized.

Semiconductor memory device enabling change of output organization with high speed operation


The present invention is a method and apparatus for centering a belt-shaped material. A conveying direction leading end portion and a conveying direction trailing end portion of triangular portions of the belt-shaped material are displaced in advance in directions opposite directions in which the conveying direction leading end portion and the conveying direction trailing end portion of the belt-shaped material are displaced when applied onto a forming drum. Centering of a constant-width portion of the belt-shaped material is carried out as follows. A width of the constant-width portion of the belt-shaped material is measured while the belt-shaped material is conveyed. In accordance with the measured width, a distance between a pair of guide portions which are disposed so as to be movable in a widthwise direction of the belt-shaped material is adjusted. The belt-shaped material is passed through a space between the adjusted guide portions.

1. Field of the Invention
The present invention relates to a method and apparatus for centering a belt-shaped material such as belt material for tires.
2. Description of the Related Art
In a process of manufacturing tires, a centering apparatus is used to center a belt material before the belt material is wound around a forming drum.
In such a centering apparatus, when a belt material, which has a constant width and is wound around a supply reel in a belt feed section, is fed out, the belt material is further conveyed by a cutting conveyer disposed at the downstream side of the supply reel, i.e., the side in the direction of feeding out the belt material. The conveying direction leading end of the belt material on the cutting conveyor is first cut obliquely by a cutter, and then the belt material is again cut obliquely by the cutter after being conveyed a predetermined distance. Thus, a piece of the belt material having a predetermined length is obtained.
The belt material cut to the predetermined length is fed out of the cutting conveyer, and is conveyed to an applying conveyer disposed at the conveying direction downstream side of the cutting conveyer. A forming drum which is rotatably supported is disposed at the downstream side of the applying conveyor. The belt material conveyed by the applying conveyer is wound onto the outer circumferential surface of the forming drum, which is rotating.
On the forming drum, the leading end and trailing end of the belt material must be joined together such that the cut surfaces of both ends coincide. Further, the widthwise center line of the constant-width portion of the belt member must coincide with the circumferential direction of the forming drum (i.e., the belt material must not meander).
In order to satisfy the above requirements, belt materials have conventionally been centered in accordance with, for example, (1) a method in which the belt material is centered through use of guides having a predetermined guide width without measurement of the overall width of the belt material, or (2) a method in which a cutting conveyer is moved in the widthwise direction of the belt material by a motor-driven mechanism in order to control the position at which the belt material is conveyed from the cutting conveyer to the applying conveyer such that the leading end, the trailing end, and the constant-width portion of the belt material are conveyed to respective predetermined positions (Japanese Patent Application Laid-Open No. 7-195570).
However, method (1), in which the overall width of the belt material is not measured, has the following drawbacks:
(a) When the width of the belt material is larger than the distance between the guides, widthwise end portions of the belt material ride onto the guides, resulting in improper centering of the belt material; PA1 (b) When the width of the belt material is smaller than the distance between the guides, the belt material abuts none of the guides, resulting in improper centering of the belt material, and play is present between the guides and the belt member such that the belt material shifts to the right or left side in the widthwise direction; and PA1 (c) If the leading end and the trailing end of the belt material come out of position relative to each other at the joint portion such that a stepped portion is formed, such a problem cannot be handled. PA1 (d) Since the entire cutting conveyer is moved, the belt material is skewed when it is conveyed from the belt feed section to the cutting conveyer; and PA1 (e) Since the entire cutting conveyer, including the cutter apparatus, must be moved at high speed, a large amount of energy is required.
Method (2) has the following drawbacks:
Moreover, due to cords disposed in the belt material such that they are inclined with respect to the longitudinal direction of the belt material, when the obliquely cut leading and trailing ends of the belt material ride onto the forming drum, the leading end and the trailing end may shift in the widthwise direction. No measures have been employed to cope with such a problem.

Method for centering belt-shaped material