An oximeter for spectro-photometric in-vitro determination of hemoglobin derivatives in a sample, typically a hemolyzed blood sample, is provided comprising a single measurement light source emitting measurement radiation, a sample chamber, for instance a measurement cuvette containing the sample, a detector device, which records a spectrum of the measurement radiation after its interaction with the sample, and an evaluation unit following the detector device, which determines the hemoglobin derivatives and at least one further analyte from the spectrum recorded by the detector device. The measurement light source is a polychromatic LED, which for determination of hemoglobin derivatives emits measurement radiation in at least one spectral region B, in which the hemoglobin derivatives exhibit significant absorbance, and which for determination of the at least one further analyte emits measurement radiation in at least one other spectral region A, in which the at least one further analyte exhibits significant absorbance.

The present invention relates to oximeters for spectro-photometric in-vitro determination of hemoglobin derivatives and at least one further analyte in a sample.
Currently available oximeters mainly use incandescent lamps as measurement light sources. In "Technical Aspects of Bilirubin Determination in Whole Blood"; HALLEMANN et al.; Point of Care Volume 4, Number 1, March 2005, an oximeter module of a blood gas analyzer (OMNI Blood Gas Analyzer) is described, in which bilirubin is spectroscopically determined as an additional analyte beside hemoglobin derivatives. A halogen lamp with a broad spectral range is used as a measurement light source.
From JP 2004-108781 a spectroscope has become known, in which prior to irradiation into a sample, light emitted by a white light LED is split into its spectral components by means of two diffraction gratings and is then radiated into the sample through a projection slit, in order to determine an analyte in a sample, for instance. Variants based on a transmission geometry as well as variants based on a reflection geometry are described, where the intensity of transmitted or reflected light is measured in temporal sequence for each wavelength. A disadvantage of this known spectroscope is the time-consuming recording of a spectrum by means of the two diffraction gratings, which split the measuring light into its spectral components.
From U.S. Pat. Appln. Pub. No. 2005/0154277 A1 a miniaturized "in-vivo" spectroscope is known, which can be used inside the body for instance to detect hemorrhages in the gastrointestinal tract by means of spectral analysis of the hemoglobin derivatives present. LEDs may be used as light source.
Furthermore, use of a non-invasive oximeter is known from U.S. Pat. Appln. Pub. No. 2005/0267346 A1, where light is radiated into blood-filled tissue of a fingertip or earlobe, and the composition of the blood (oxygen saturation) is inferred from light-absorption in the blood using a transmitted-light or reflected-light method. A white light LED can be used as light source, but filters or diffraction gratings must be used prior to irradiation to select defined wavelengths for irradiation into the tissue.
From U.S. Pat. No. 6,262,798 B1 an oximetric method for measuring non-hemolyzed blood is known. In this measurement method a plurality of defined, monochromatic wavelengths are sequentially radiated into the sample, arrays of varicolored LEDs or conventional white light lamps being used from which defined wavelengths are filtered by means of a monochromator, which are then radiated into the sample.
In "Blood gases and oximetry: calibration-free new dry-chemistry and optical technology for near-patient testing"; Boalth et al.; Clinica Chimica Acta 307 (2001) 225-233, a spectrophotometric system for in-vitro oximetry is described, which works with a white light LED as light source. For the determination of hemoglobin derivatives the wavelength band of 470-670 nm is recorded by means of a 128-channel-linear-CCD-array and used for evaluation. This wavelength range exceeds the wavelength range conventionally used for determination of hemoglobin derivatives, thus offering the possibility of correcting the values of hemoglobin derivatives for bilirubin as an interfering substance, which overlays hemoglobin absorption in parts of the range. The enlarged wavelength range is only used for correcting the hemoglobin derivatives to be determined, but not for determining bilirubin as an additional analyte.
To produce polychromatic light by means of LEDs, it has become known to use luminescence conversion LEDs having one or more primary emission wavelengths, which are modified by luminescence conversion layers such that broad-band polychromatic light will be radiated as a result. Such light sources are for instance described in U.S. Pat. Appln. Pub. No. 2005/0127385 A1. The radiated polychromatic light is in this case composed of a short-wave spectral region of the primary emission wavelengths emitted by at LED-chip as primary emitter, and a spectral region of longer wavelengths radiated by dye layers excited by the primary emission of the LED as secondary emitters.
U.S. Pat. No. 6,809,347 B2 describes a white light LED which includes a LED emitting blue or UV-light and a superposed luminophore layer which absorbs part of the blue or UV-light emitted by the LED and subsequently emits light in the long-wave spectral region, thus producing white light by superposition, whose spectral characteristics can be defined by modification of the luminophore layer.
Finally, EP 1 473 771 A1 describes an alternative design of a white light LED, which consists of a plurality of at least partially transparent light-emitting LED layers of different emission wavelengths, which are stacked one above the other in such a way that the individual emission wavelength bands are superposed in radiation direction and white light is emitted as a result.

Oximeter for spectro-photometric in-vitro determination of hemoglobin derivatives


A system and method for dynamically configuring an information handling system includes a configurable backplane having one or more connectors, at least one switch, one or more terminations, and at least one sense engine. The switch includes an open state and a closed state while the terminations include an active state and an inactive state. The sense engine interfaces with the connectors, the switch, and the terminations and detects peripheral attachments to the connectors. Based on the detection information, the sense engine determines if the switch should be in the open or closed state and determines whether each termination should be in the active or inactive state. The sense engine alters the switch setting and the termination states.

As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for information handling systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
As information handling systems become more complex due to increasing operating demands, it is important for such systems to allow for user flexibility while maintaining high levels of operation and performance. One option manufacturers offer to satisfy consumer needs are information handling systems that include one or more configurable components. The configurable components allow consumers to use the system in one or more different modes of operation. The configurable components allow consumers to change the operation of their systems without having to buy a new system. Consumers desire the configurable components because it provides greater flexibility in performing tasks with the information handling system.
One example of a configurable component is a backplane or motherboard such as a Small Computer System Interface (SCSI) backplane. A reconfigurable backplane can be used by the consumer in a split mode or a non-split mode. In the non-split mode, the backplane has a single SCSI bus route. One controller, such as a Redundant Array of Independent Disks (RAID) controller, manages all of the hard disk drives interfaced with the backplane. However, some consumers may prefer a split backplane in order to optimize all the resources of the information handling system. Many management functions require a particular number of drives. For example, RAID 5 requires three hard disk drives. Therefore if a function uses only three of the eight hard disk drives interfaced with the backplane, it would be useful to utilize the other five drives. Therefore, a user may prefer to configure the backplane in a split mode including two SCSI bus routes and two RAID controllers managing the hard disk drives. Having two controllers allows for the drives associated with the backplane to be used for different functions. Therefore, a configurable backplane allows for flexible and efficient use of the information handling system.
Despite the flexibility of information handling systems having reconfigurable components such as a backplane, these systems typically suffer from problems due to the configurability. For instance, configurable backplanes experience problems with stubs and the placement of external connectors. Stubs are bus route dead ends and generally occur due to the placement of one or more passive terminations at the end of the bus route. The passive terminations do not allow for a single, uninterrupted bus route in different configurations of operation. Therefore, reconfigurable systems must be designed to have more than one bus route with the bus routes present in more than one modes of operation, but only intended for use in one mode of operation. Therefore, in one or more modes of operation the bus route serves no function and leads to an unnecessary bus route dead end or stub. The stubs typically have a detrimental effect on signal integrity by limiting the bus frequency and potentially resulting in corruption of data. When a signal encounters a stub, the signal travels along both the stub and the intended bus route. Because the signal travels along both routes, the signal strength decreases resulting in potential degenerate system performance. Furthermore, the stub generally causes reflections in the signal because the signal bounces back after hitting the dead end of the stub. This reflection may further add to the data corruption. And as information handling system operations increase in speed, these reflections magnify causing further data corruption.
Information handling systems including reconfigurable components such as configurable backplanes also experience problems with the placement of the components on the backplane. For instance, a configurable backplane having two modes of operation requires two connectors for two controllers to access the backplane when operating in a split mode. The two connectors are typically not located together on the backplane and are generally not located on an edge of the backplane for easy accessibility. It is difficult to move the passive terminations thereby requiring the second bus route to enter the backplane from a new route located on a side different than the first bus route. Having the connectors on two different sides of the backplane creates problems with manufacturability and serviceability.

System and method for dynamically configuring an information handling system


First codebook and second codebook respectively have two subcodebooks, and in respective codebooks, addition sections obtain respective excitation vectors by adding sub-excitation vectors fetched from respective two subcodebooks. Addition section obtains an excitation sample by adding those excitation vectors. According to the aforementioned constitution, it is possible to store sub-excitation vectors with different characteristics in respective sub-codebooks. Therefore, it is possible to correspond to input signals with various characteristics, and achieve excellent sound qualities at the time of decoding.

Speech compression coding methods at low bit rates have been required in order to accept an increase of subscribers in digital mobile communications such as a portable telephone, and the researches and developments have been proceeded by many research institutions. In Japan, applied coding systems as a standard system in portable telephones are VSELP at a bit rate of 11.2 kbps developed by Motorola and PSI-CELP at a bit rate of 5.6 kbps developed by NTT Mobile Communications Network. INC., and portable telephones with these system are produced
In addition, internationally, the ITU-T selected CS-ACELP, which was co-developed by Nippon Telegraph and Telephone Corporation and France Telecom, as an international standard speech coding system G.729 at 8 kbps. The system is scheduled to be used in Japan as speech coding system for portable telephones.
The above-described systems are all achieved by modifying the CELP system (Code Excited Linear Prediction: M. R. Schroeder "High Quality Speech at Low Bit Rates" described in Proc. ICASSP '85 pp. 937-940). A feature of this system is to apply a method of dividing a speech into excitation information and vocal truct information, code the excitation information with indices of a plurality of excitation samples stored in a codebook, while coding the LPC (Linear Prediction Coefficients) with respect to the vocal truct information, and perform a comparison to an input speech considering of the vocal truct information in the excitation information coding (A-b-S: Analysis by Synthesis).
The basic algorithm of the CELP system will be described using FIG. 1. FIG. 1 is a block diagram illustrating a configuration of a speech coding apparatus in the CELP system. In the speech coding apparatus illustrated in FIG. 1, LPC analyzing section 2 executes autocorrelation analysis and LPC analysis on input speech data 1 to obtain the LPC. LPC analyzing section 2 further codes the obtained LPC to obtain the coded LPC. LPC analyzing section 2 furthermore decodes the obtained coded LPC to obtain the decoded LPC.
Excitation generating section 5 fetches excitation samples stored in adaptive codebook 3 and stochastic codebook 4 (respectively referred to as an adaptive code vector (or adaptive excitation) and stochastic code vector (or stochastic excitation)) and provides respective excitation samples to LPC synthesis section 6. LPC synthesis section 6 executes filtering on two excitations obtained at excitation generating section 5 with the decoded LPC obtained at LPC analyzing section 2.
Comparing section 7 analyzes the relation of two synthesized speeches obtained at LPC synthesis section 6 and the input speech, obtains an optimal value (optimal gain) for two synthesized speeches, adds each synthesized speech respectively subjected to power adjustment with the optimal gain to obtain a total synthesized speech, and executes a distance calculation between the total synthesized speech and the input speech. Comparing section 7 further executes, with respect to all excitation samples in adaptive codebook 3 and stochastic codebook 4, the distance calculations between the input speech and each of other many synthesized speeches obtained by functioning excitation generating section 5 and LPC synthesis section 6, and obtains an index of the excitation sample whose distance is the smallest among the obtained distances. Then, comparing section 7 provides the obtained optimal gain, indices of excitation samples of respective codebooks and two excitation samples corresponding to respective index to parameter coding section 8.
Parameter coding section 8 executes coding on the optimal gain to obtain the coded gain and provides the coded gain, the coded LPC and the indices of excitation samples to transmission path 9. Further, parameter coding section 8 generates an actual excitation signal (synthesized excitation) using the coded gain and two excitations corresponding to the respective index and stores the excitation signal in adaptive codebook 3 while deleting old excitation samples.
In addition, it is general for the synthesis at LPC synthesis section 6 to use together Linear Prediction Coefficients and a high-frequency enhancement filter or a perceptual weighting filter with long-term prediction coefficients (which are obtained by the long-term prediction analysis of input speech). It is further general to execute the excitation search on the adaptive codebook and stochastic codebook at an interval (called subframe) obtained by further dividing an analysis interval.
The stochastic codebook will be described next.
The adaptive codebook is a codebook for an effective compression using a long-term correlation existing at intervals of human vocal cord vibrations, and stores previous synthesized excitations. On the contrary, the stochastic code book is a fixed codebook to reflect statistical characteristics of excitation signals. As excitation samples stored in the stochastic codebook, there are, for example, random number sequence, pulse sequence, random number sequence/pulse sequence obtained by statistic training with speech data, or pulse sequence with relatively small number of pulses generated algebraically (algebraic codebook). The algebraic codebook has been especially paid attention recently and known by that a good sound quality is obtained at bit rates such as 8 kbps with small calculation amounts.
However, an application of algebraic codebook with a small number of pulses to coding at lower bit rates introduces a phenomenon that sound qualities greatly deteriorate mainly on unvoiced consonants and background noises. On the other hand, an application of excitation with a large number of pulses such as random number sequence to coding at lower bit rates introduces a phenomenon that sound qualities greatly deteriorate mainly on voiced speeches. In order to improve the deterioration, a method with multi-codebook, in which a voiced/unvoiced judgement is performed, is examined. However, the method has the complicated processing and sometimes generates an allophone caused by a judgement error on a speech signal.
As described above, there has been no algebraic codebook which matches any effective coding on voiced speeches, unvoiced speeches and background noises. Therefore, it has been required to obtain a speech coding apparatus and a speech decoding apparatus capable of effectively coding any of voiced speeches, unvoiced speeches and background noises.

Speech coding apparatus and speech decoding apparatus

Matsushita Electric Industrial Co., Ltd.


A multi-CPU computer which is capable of positively performing error handling, and restarting a system even when a fatal error has occurred in a CPU. When a hardware error has occurred in a first CPU, error information is notified to a second CPU by a first error notification circuit of the first CPU. Then, the error information notified from the first CPU is obtained by a second error notification circuit of the second CPU, and error handling based on the error information is requested of an operating system. The second CPU executes a process for storing fault information including the error information in a storage device and a process for restarting the system, according to the operating system.

1. Field of the Invention
This invention relates to a multi-CPU computer having a plurality of CPUs installed therein for operating on a common operating system, and a method of restarting a system for the multi-CPU computer, and more particularly to a multi-CPU computer for performing an emergency shut-down of the system when a hardware error has occurred, and a method of restarting the system for the multi-CPU computer.
2. Description of the Related Art
Recently, UNIX® servers, and IA servers (server machines having a microprocessor available from Intel Corporation installed therein) have been introduced to main systems. Many of the UNIX servers and the IA servers are configured as multi-processor servers for enhanced performance. It should be noted that as to servers used for the main systems, much importance is placed not only on the enhancement of performance but also on the enhancement of reliability. Particularly when a fatal hardware error has occurred, it is necessary to prevent the system from running out of control and data from being destroyed. To this end, when a fatal hardware error has occurred, the system is subjected to an emergency shut-down.
In the case of the main system, however, it is not permitted to stop the system for a long time period. Therefore, in the multi-processor server, even when the system is subjected to an emergency shut-down due to a hardware error, it is a critical requirement to restart the system quickly and automatically by isolating only a portion of the system where the error has occurred. Hardware errors which occur in the server include continuous occurrence of a multi-bit error in a CPU (Central Processing Unit) cache, for example.
In the prior art, when a fatal CPU error, such as the multi-bit error in the CPU cache, has occurred, the following error handling is conventionally carried out: First, a CPU in which the error has occurred sets error information in a register. Then, the CPU generates a trap to notify the operating system of occurrence of the error.
The operating system executes trapping at the CPU in which the error has occurred. In the trapping, the operating system refers to the register of the hardware to obtain the error information.
After that, the CPU in which the error has occurred carries out panic handling. The panic handling is to subject the system to an emergency shut-down and restart the same so as to prevent the system from running out of control and data from being destroyed. In the panic handling, the CPU displays and records the error information, performs synchronization of a file system to obtain a memory dump, and then restarts the system.
FIG. 8 is a diagram showing a conventional method of restarting the system when an error has occurred. A server 900 has a CPU 910 and a CPU, 920. The CPU number of the CPU 910 is "CPU #0", and the CPU number of the CPU 920 is "CPU #1". Processing executed by the CPU 910 and the CPU 920 includes processing executed in a hardware logic circuit 901 and processing executed according to an operating system 902.
The CPU 910 and the CPU 920 have error notification circuits 911 and 921 as processing functions executed by the hardware logic circuit 901. Further, the error notification circuits 911 and 921 notify the operating system of information indicative of a hardware error which has occurred in a CPU. It should be noted that notification of error information to the operating system is intended to mean processing for passing the error information to a process for performing error handling of the operating system. More specifically, each of the CPU 910 and the CPU 920 sets error information in a predetermined register when a hardware error has occurred, and generates a trap. The error information includes an error type, a CPU number, an address of data where the error has occurred. A process based on the operating system refers to the register storing the error information, whereby the error information is notified.
Processing functions executed according to the operating system 902 include trapping functions 912 and 922, and panic handling functions 913 and 923. The trapping functions 912 and 922 are each provided for obtaining a error type, a CPU number, and an address with reference to the register storing error information. The panic handling functions 913 and 923 are each provided for displaying and recording the error information, synchronizing the file system, obtaining a memory dump, and restarting the system.
The example illustrated in FIG. 8 shows a case in which an error has occurred in the CPU 910. In this case, the error notification circuit 911 of the CPU 910 notifies the operating system 902 of error information. Then, the trapping function 912 executed by the CPU 910 according to the operating system 902 performs trapping, whereby the operating system 902 obtains the information including the error type, the CPU number, and the address. Subsequently, the panic handling function 913 displays and records the error information, synchronizes a file system, obtains a memory dump, and then restarts the system.
As described above, when the error handling (trapping and panic handling) is executed by the operating system, it is also possible to notify a high-order computer of fault information obtained by the operating system of a low-order computer (see e.g. Japanese Unexamined Patent Publication No. 04-340631).
Further, a technique is also known in which a diagnosis processor having obtained fault information from a faulty processor notifies an high-order processor of occurrence of a fault, and the high-order processor initializes and restarts the faulty processor, to thereby restore the faulty processor to an operative state (see e.g. Japanese Unexamined Patent Publication No. 02-71336).
Further, there has been proposed a technique for obtaining fault information when a fault has occurred in the multi-CPU computer, in which a plurality of processors executes the obtaining of fault information in parallel with each other to thereby shorten a time period required for obtaining the fault information. In this technique, a processor in which is detected occurrence of the fault instructs other processors to obtain the fault information, and the instructed processors obtain the fault information (see e.g. Japanese Unexamined Patent Publication No. 11-338838).
However, in the procedure shown in FIG. 8, the trapping and the panic handling are carried out by the CPU in which the error has occurred, and the system is restarted. Therefore, when a multi-bit error has continuously occurred in the CPU cache, the CPU sometimes cannot operate normally. Even if the CPU incapable of operating normally is about to execute the trapping and the panic handling of the system, the accurate processing cannot always be performed. Therefore, there is a fear that when a hardware error has occurred, the system in operation is hung up or the restart thereof fails. This can cause a serious problem that the operation of the system is stopped for a long time period, for example.
When the system cannot carry out error handling accurately, the following problems, for example, are expected to occur.
When error information is not displayed, it is impossible to identify a CPU to be replaced for prevention of recurrence of the error. In this case, even when the system is manually restarted after occurrence of the problem, there is a possibility that the same problem is caused again by the same error.
When the synchronization of the file system cannot be executed, data existing on a file cache (memory) cannot be written on a disk. This can cause destruction of files and data.
When a memory dump fails to be obtained, it is impossible to analyze details of information based on the memory dump, e.g. as to when the error occurred, which process was being executed then, and what error occurred. For example, there is a case where the same CPU error occurs again during the panic handling in the error handling of a CPU error, which prevents accurate error information from being displayed. In this case, if the memory dump as well failed to be obtained, there is no means for identifying the primary factor.
When the restart of the system fails, there can be caused a serious problem that the operation of the system is stopped for a long time period. If the time period of stoppage of the system for key business operations becomes longer, it can also become an object of public concern.
It should be noted that in the technique disclosed in Japanese Unexamined Patent Publication No. 04-340631, the operating system of the low-order computer notifies the fault information. Therefore, there is no guarantee that the operating system operates normally on the faulty low-order computer. This can cause a state where the fault information cannot be notified to the high-order computer.
Further, in the technique disclosed in Japanese Unexamined Patent Publication No. 02-71336, the diagnosis processor obtains fault information from another faulty processor, and the high-order processor initializes and restarts the faulty processor. More specifically, it is assumed that the processors operate individually, and can be restarted independently. In many multi-CPU computers, however, a plurality of CPUs operate on a common operating system. In such multi-CPU computers, data shared by the CPUs exists, and to restart one of the CPUs, processing for ensuring consistency of data is required. Therefore, it is difficult to apply the technique disclosed in Japanese Unexamined Patent Publication No. 02-71336 to a multi-CPU computer in which a plurality of CPUs operate on a common operating system.
Furthermore, in the technique disclosed in Japanese Unexamined Patent Publication No. 11-338838, processors other than the processor in which a fault has occurred obtains fault information, and hence it is possible to obtain fault information by the normal processors. However, the system is restarted by the faulty processor. As a result, even when the process for restating the system is executed by the processor which does not operate normally, there is a possibility that the system cannot be started properly. If the system fails to be restarted, the time period of stoppage of the system becomes longer, which results in the degraded operating efficiency of the system.

Multi-CPU computer and method of restarting system


A steering angle sensor for motor vehicles for determining the steering angle of a steering element of a steering wheel assembly, which is rotatable during a steering movement is provided. The steering angle sensor comprises a rotatably mounted drive element which during a rotary movement of the steering element likewise performs a rotary movement, and a rotatably mounted driven element which is in engagement with the drive element and is driven by the same. The steering angle is determined by detecting the rotary movement and/or the angle of rotation of the driven element. The drive element and/or the driven element include elastic means via which the drive element and the driven element are braced against each other.

A steering angle sensor as mentioned above, which serves for determining the steering angle of a rotatably mounted steering element of a motor vehicle, e.g. of a steering wheel or an associated steering shaft, comprises a rotatably mounted drive element which during a rotary movement of the steering element likewise performs a rotary movement, and a rotatably mounted driven element which is in engagement with the drive element and is driven by the same. The steering angle is determined by detecting the rotary movement and/or the angle of rotation of the driven element.
The steering angle sensor for example can serve the determination of the steering angle of a steering wheel of a motor vehicle. For this purpose, the steering angle sensor normally is mounted in the steering column of the motor vehicle and detects e.g. the rotary movement of the steering shaft associated to the steering wheel.
From WO 96/27116 a method and an apparatus for angle measurement of a rotatable body is known, wherein a gear wheel is mounted on the axle of the rotatable body, which is coupled with two further gear wheels and drives the same for rotation. The angles of rotation of the two further gear wheels are measured by means of two periodic angle sensors. The angle sensors are connected with an electronic evaluation circuit which calculates the angle of rotation of the rotatable body.
The measurement accuracy of the steering angle sensor among other things depends on the precision of the toothing. In general, the engagement of the teeth is not without backlash, which is due to the manufacture of the gear wheels. This backlash additionally is increased by mounting tolerances. In addition, the wear of the gear wheels progressing with time plays a role. Furthermore, the inhomogeneity of the shape and the distribution of the teeth as well as non-circular gear wheels are to be noted, which possibly can lead to linearity errors. This backlash of the gear wheels ultimately leads to measurement errors of the steering angle sensor. In the case of a reversal of the direction of rotation of the gear wheel carrying the sensor this error manifests itself as hysteresis error.
As due to these factors the measurement result of the steering angle sensor is subject to error, wherein the error not necessarily is a systematic error, it is desirable to reduce the backlash of the gear wheels, in order to increase the measurement accuracy of the steering angle sensor.
For this purpose, EP 1 132 716 B1 proposes a position sensor as described above, in which the driven gear wheels in addition are pulled or urged radially to the center of the driving gear wheel by means of spring-elastic tension bars. The driven gear wheels are coupled with a movable, more exactly a rotating part of a rotary position sensor, which cooperates with a stationary part of the rotary position sensor, in order to determine the angle of rotation of the rotating part of the rotary position sensor and thus of the steering element. In this device it is disadvantageous that the driven gear wheels and the rotating parts of the rotary position sensors are radially shiftably mounted in a plane which extends orthogonally to the direction of extension of the axes of rotation. Accordingly, the axis of rotation of the movable parts is not stationary with respect to the stationary parts of the rotary position sensor, so that measurement errors are inevitable, even if the engagement of the teeth now is without backlash and mounting tolerances are compensated. At least the wear of the gear wheels progressing with time and the above-mentioned inhomogeneity of the teeth and gear wheels still lead to measurement inaccuracies. The fact that the clamping frame is an additional component which further reduces the anyway confined installation space also represents a disadvantage.

Steering angle sensor for motor vehicles


The embodiments of the present invention relate to improvements in the fluid-energy mills. Particularly, the fluid-energy mill of the present invention includes a deeper chamber for grinding of particulate material, wherein the discontinuities defining the stepped chamber are located at a distance of about 0.59 to 0.62 R, and preferably 0.61 R, from the axis of the chamber, wherein R is the radius of the grinding chamber measured from the axis to the inside wall of the chamber. In another improvement, providing interlocking joints in the liner discharge tube and extending the liner into the port for the feed tube, as well as providing a packing gland for the feed tube mitigate the problem of wear of the ceramic liner inside the fluid-energy mill.

Fluid-energy mills are used for reducing particle size of a variety of materials such as pigments, agricultural chemicals, carbon black, ceramics, minerals and metals, pharmaceuticals, cosmetics, precious metals, propellants, resins, toner and titanium dioxide. The particle size reduction typically occurs as a result of particle-to-particle collisions and particle collision with the walls.
Most fluid-energy mills are variations on a basic configuration of a disc-shaped grinding chamber enclosed by two, generally parallel, circular plates defining axial walls, and an annular rim defining a peripheral wall, with the axial length or height of the chamber being substantially less than the diameter. Around the circumference of the mill are located a number of uniformly spaced jets for injecting the grinding fluid which furnishes additional energy for comminution, along with one or more feed nozzles for feeding the particulate material to be comminuted. The jets are oriented such that the grinding fluid and particulate material are injected tangentially to the circumference of a circle smaller than the chamber circumference. Feed to the grinding chamber can be introduced either through a side inlet that is tangent to the grinding chamber, or at an angle from the top, usually at a 30° angle to the plane of the grinding chamber. Side feed micronizers generally produce the better grinding dispersion, while top feed micronizers can produce higher rates.
Within the grinding chamber, a vortex is formed by the introduction of the grinding fluid such as compressed gas, through the feed inlet or through fluid nozzles positioned in an annular configuration around the periphery of the grinding chamber. The grinding fluid (compressed gas, e.g., air, steam, nitrogen, etc.), fed tangentially into the periphery of the chamber, forms a high-speed vortex as it travels within the grinding chamber. The high-speed vortex sweeps up the particulate material, which results in high speed particle-to-particle collisions as well as collisions with the interior portion of the grinding chamber walls.
The grinding fluid velocity can be resolved into a tangential component of the velocity, Vt, which is a measure of the centrifugal force acting on the particle tending to keep it at the outer periphery of the chamber, and the radial component of velocity, Vr, which is a measure of the drag force generated by the action of the fluid against the particle tending to force the particle towards the central discharge conduit. By proper selection of conditions, such as rate and tangency of fluid injection, these opposing forces can be adjusted such that particles above a specific size are retained within the mill until sufficient attrition occurs, both by collision with other particles and the chamber walls, to reduce them to the desired sizes, up to the point when the drag forces become dominant over centrifugal forces and the particles are swept into the central discharge conduit that is coaxial to, and in direct communication with, the grinding chamber, and subsequently into a cyclone or bag filter for collection.
Clearly, heavier particles have longer residence time within the vortex. Lighter particles (i.e., those sufficiently reduced particles) move with the vortex of gas until the discharge conduit is reached. Typically, fluid-energy mills are capable of producing fine (less than 10 microns) and ultra fine (less than 5 microns) particles.
During grinding, undesirably large particle sizes frequently escape into the product. In other words, better classification of particulate material is required. Also during grinding, the inside liner of the grinding chamber is subjected to abrasion. Generally, the liner is a large casting of silicon carbide and because of its size has many joints. The joints are a potential source of problem. Particulate material and grinding fluid such as steam circulate around the liner at a velocity, for example, of about Mach 1. The momentum of even small particles at such velocities is very high. The liner is susceptible to abrasion and penetration by such particles, particularly where a joint occurs in the ceramic liner of the grinding chamber.
The fluid-energy mill of the present invention overcomes these problems, in that, it helps retain larger particles for a longer time in the chamber and discharging them only after required attrition is achieved, and it provides for interlocking joints that prevent penetration of particulate material into the ceramic liner. Consequently, the inside liner of the fluid-energy mill of the present invention lasts two to three times longer than a standard liner. Secondly, it produces a much narrower particle size distribution and a smaller number of large particles, thus improving quality. Finally, it can run at about 20% higher rate with a lower motive gas requirement in the grinding chamber.

Deep-chamber, stepped, fluid-energy mill


According to an embodiment, an information processing apparatus includes a secure OS, a non-secure OS, and a monitor. The monitor is configured to switch between the OSs. The secure OS includes a memory protection setting controller, a processing determination controller, and a secure device access controller. The memory protection setting controller is configured to set a protection address in a memory for each certain processing. The processing determination controller is configured to receive an access type, a physical address of an access destination, and data to be written, acquire a list of processing, and determine a type of processing to be performed. The secure device access controller is configured to receive the access type, the physical address of an access destination, and data to be written, and access a peripheral identified by the physical address.

Virtualization techniques in which a plurality of operating systems (OSs) are concurrently run on a single computer have been widely used from servers to embedded devices. The use of the virtualization techniques makes it possible to monitor access to peripherals.
ARM TrustZone (registered trademark) has a memory protection function. In an ARM processor, buffers and registers of the peripherals are mapped in a memory space. The access to the peripherals thus can be monitored. The ARM TrustZone, however, has no clear functional structure to securely filter the access to the peripherals. The virtualization of peripherals needs a structure to perform conversion of contents of the access to the peripherals by filtering the access such as encryption.

This patent is subject to a terminal disclaimer.

Information processing apparatus and computer program product


A leadless cardiac pacemaker is adapted for implantation into triangle of Koch or His bundle with a plurality of individual electrodes spread in the vicinity of implantation site. Individual electrodes are first evaluated for their suitability for sensing and pacing of atrial and ventricular chambers of the heart. Individual electrodes are then selected for delivery of cardiac pacing to multiple heart chambers from a single intra-cardiac location. Remaining non-selected individual electrodes may be abandoned. Also described is an adapter with multiple electrodes configured to dock with a conventional leadless or standard pacemaker to operate in the same way.

Without limiting the scope of the invention, its background is described in connection with implantable medical devices, in particular, implantable leadless cardiac pacemakers or defibrillators. More specifically, the invention describes the single pacemaker with a plurality of electrodes located inside the heart, such cardiac pacemaker is configured for pacing one or more heart chambers from a single intra-cardiac location.
As used herein, the term "leadless" generally refers to an absence of electrically-conductive leads or wires that traverse vessels or other anatomy outside of the intra-cardiac space, while "intra-cardiac" means generally, located entirely within the heart and associated vessels, such as the superior vena cava (SVC), inferior vena cava (IVC), coronary sinus (CS), pulmonary arteries (PA) and the like. The term "His bundle" generally refers to a heart electrical signals conduction system traversing His bundle as well as further distal parts thereof including but not limited to left bundle branch and right bundle branch.
An implantable device, such as an implantable cardiac rhythm management device (e.g., a pacemaker, a defibrillator, or a cardioverter—all of which are contemplated by this disclosure and referred to generally as a "pacemaker"), may be used to monitor cardiac function and provide cardiac stimulation therapy for a patient who suffers from cardiac arrhythmia. For example, to maintain regular cardiac rhythm, the implantable device may track the type and timing of native cardiac signals. In this way, the implantable device may determine whether cardiac events (e.g., contractions) are occurring and whether they are occurring at the proper times.
The implantable heart rhythm management device may track cardiac signals and provide suitable cardiac pacing stimulation by using one or more leads implanted in or near the heart of the patient. For example, the implantable device may process signals received via implanted leads and then attempt to characterize the received signals as a particular cardiac event. Such cardiac events may include, for example, P waves, R waves, T waves, or arrhythmia events. By analyzing the type and timing of these cardiac events, the implantable device may determine whether therapy should be provided and, if so, the type of therapy to be provided (e.g., stimulation pulses).
For example, conventional heart pacemakers typically employ one or more intravascular leads that connect to a so-called "can" or a pacemaker housing containing a battery and associated electronic circuitry configured for pacing and sensing. Single-chamber pacemakers in the right atrium (RA) or right ventricle (RV) would typically be programmed in AAI or VVI modes, respectively, to inhibit pacing whenever intrinsic activity in that chamber is detected.
A dual-chamber pacemaker with RA and RV leads or a dual-chamber lead may have the ability to sense both atrial and ventricular electrical activity. For any patient with intermittent AV node conduction, it may be preferable to inhibit ventricular pacing and allow an intrinsic R wave to occur for a time after any P wave is detected on the RA lead. If ventricular pacing is needed, it is desirable to synchronize ventricular activity to atrial activity using an AV delay. The VDD programming mode has become common in dual-chamber pacemakers for patients with various degrees of AV block. Other common dual chamber modes include ODD and DDDR.
Current conventional implantable cardiac pacemakers include a housing and one or more electrically-conductive leads that connect to the housing through an electromechanical connection. The housing is implanted outside of the heart, such as in the pectoral region of the patient and contains controller electronics (e.g., a power source, microprocessor, capacitors, etc.) that provide pacemaker functionality. The leads traverse blood vessels between the housing and heart chambers in order to position one or more electrodes carried by the leads within the heart, thereby allowing the device electronics to electrically stimulate or pace cardiac tissue and measure or sense myocardial electrical activity.
To sense atrial cardiac signals and to provide a right atrial chamber stimulation therapy, the housing is conventionally coupled to an implantable right atrial lead including an atrial tip electrode that typically is implanted in the patient's right atrial appendage. The right atrial lead may also include an atrial ring electrode to allow bipolar stimulation or sensing in combination with the atrial tip electrode.
Before implantation of the pacemaker housing into a subcutaneous pocket of the patient, however, an external pacing and measuring device known as a pacing system analyzer (PSA) is used to ensure adequate lead placement, maintain basic cardiac functions, and evaluate pacing parameters for an initial programming of the device. In other words, a PSA is a system analyzer that is used to test how the leads would perform with an implantable device, such as an implantable pacemaker.
To sense right ventricular cardiac signals and provide ventricular stimulation therapy, the pacemaker housing is coupled to an implantable right ventricular lead including a right ventricular (RV) tip electrode and a right ventricular ring electrode. The lead for an implantable cardioverter defibrillator may also contain one or more electrodes for delivery of high-voltage therapy, such as a right ventricular coil electrode, a superior vena cava (SVC) coil electrode, or both. Typically, the right ventricular lead is transvenously inserted into the heart so as to place the right ventricular tip electrode in the right ventricular apex such that the RV coil electrode is positioned in the right ventricle and the SVC coil electrode is positioned in the right atrium and/or superior vena cava. Accordingly, the right ventricular lead can receive cardiac signals and deliver stimulation in the form of pacing and shock therapy to the right ventricle.
A cardiac rhythm management system may also deliver resynchronization therapy, in which electrical stimulation is delivered to coordinate the electromechanical activity of the chambers of the heart. Such system may use the leads placed in the right atrium and right ventricle along with an additional lead coupled to the pacemaker housing that extends through the coronary sinus to a distal tip electrode on the outer surface of the left ventricle. There may be one or more ring electrodes in electrical contact with the left ventricle, the left atrium or both. The tip electrode may reach a location in the venous vasculature of the left ventricle, including any portion of the coronary sinus, great cardiac vein, left marginal vein, left posterior ventricular vein, middle cardiac vein, and/or small cardiac vein, or any other cardiac vein accessible by the coronary sinus.
Accordingly, the coronary sinus lead may be designed for some or all of the following functions: receive atrial and/or ventricular cardiac signals; deliver left ventricular pacing therapy using a left ventricular tip electrode for unipolar configurations or in combination with at least one left ventricular ring electrode for bipolar configurations; deliver left atrial pacing therapy using at least one left atrial ring electrode; deliver high-voltage therapy using at least one coil electrode.
Although a portion of the leads is located within the heart, a substantial portion of the leads, as well as the pacemaker housing itself are outside of the patient's heart. Consequently, bacteria and the like may be introduced into the patient's heart through the leads, as well as the pacemaker housing, thereby increasing the risk of infection within the heart. Additionally, because the pacemaker housing is placed outside of the heart, the patient may be susceptible to Twiddler's syndrome, which is a condition caused by the shape and weight of the pacemaker housing itself. Twiddler's syndrome is typically characterized by subconscious, inadvertent, or deliberate rotation of the pacemaker housing within the subcutaneous pocket formed in the patient, hi one example, a lead may retract and begin to wrap around the pacemaker housing. Also, leads may dislodge from the endocardium or veins and cause the device to malfunction. Further, in another typical symptom of Twiddler's syndrome, the device may stimulate the diaphragm, vagus, or phrenic nerve, pectoral muscles, or brachial plexus. Overall, Twiddler's syndrome may result in sudden cardiac arrest due to conduction disturbances related to the device.
In addition to the foregoing complications, implanted leads may experience certain further complications such as incidences of venous stenosis or thrombosis, device-related endocarditis, lead perforation or disruption of the tricuspid valve and concomitant tricuspid insufficiency; and lacerations of the right atrium, right ventricle, coronary sinus, superior vena cava, and innominate vein or pulmonary embolization of electrode fragments during lead extraction.
To combat the foregoing limitations and complications, small sized devices configured for intra-cardiac implantation have been proposed. These devices, termed leadless pacemakers, are typically characterized by the following features; they are devoid of leads that pass out of the heart to another component, such as a pacemaker housing outside of the heart; they include electrodes that are affixed directly to the pacemaker housing of the device; the entire device is attached to the heart; and the device is capable of pacing and sensing in the chamber of the heart where it is implanted.
Leadless pacemaker devices that have been proposed thus far offer limited functional capability. These devices can sense electrical activity in one chamber and deliver pacing pulses in that same chamber, and thus offer single chamber functionality. For example, a leadless pacemaker device which is located in the right atrium would be limited to offering AAI mode functionality. An AAI mode leadless pacemaker can only sense electrical activity in the right atrium, pace in the right atrium and inhibit pacing function when an intrinsic event is detected in the right atrium within a preset time limit.
Similarly, a leadless pacemaker device that is located in the right ventricle would be limited to offering VVI mode functionality—see FIG. 1. Shown here is a conventional leadless pacemaker 10 implanted in the apex of the right ventricle using a helix screw 11, which also serves as an electrode. One or more other electrodes 12 may be used for sensing electrical activity in the right ventricle; wherein electrode 11 is used for pacing in the right ventricle or inhibiting pacing function when an intrinsic event is detected in the right ventricle within a preset time limit. To gain widespread acceptance by clinicians, it would be highly desirable for leadless pacemaker devices to have dual chamber pacing/sensing capability (VDD or ODD mode) along with other features, such as rate adaptive pacing.
It has been proposed to implant sets of multiple leadless pacemaker devices within a single patient, such as when one or more leadless pacemaker devices are located in the right atrium and one or more leadless pacemaker devices are also located in the right ventricle. The atrial leadless pacemaker devices and the ventricular leadless pacemaker devices may wirelessly communicate with one another to convey pacing and sensing information therebetween so as to coordinate pacing and sensing operations between various leadless pacemaker devices.
However, these sets of multiple leadless pacemaker devices experience various limitations. For example, if there is a wireless communication link between these devices, all devices must expend power to maintain the link. The wireless communication link should be maintained continuously in order to constantly convey pacing and sensing information between, for example, atrial pacemaker device(s) and ventricular pacemaker device(s). This exchange of pacing and sensing information is necessary to maintain continuous synchronous atrioventricular coordination.
Further, it is difficult to maintain a reliable wireless communications link between leadless pacemaker devices. The leadless pacemaker devices utilize low-power transceivers that are located in a constantly changing electrical environment within the associated heart chamber. The transmission characteristics of the environment surrounding a leadless pacemaker device change due in part to the continuous cyclical motion of the heart and change in blood volume. Hence, the potential exists that the communication link is broken or intermittent.
A further limitation of the existing cardiac leadless pacemakers is theft limited life span, which is typically less than about 5 years. This limitation is a result of having to use a very small battery so as to minimize the overall size of the device and facilitate its minimally invasive implantation techniques. The need exists to configure a leadless pacemaker in such as way as to extend its useful life, for example by providing a longer lasting battery, allowing for a battery recharge or battery replacement when it is depleted.
To overcome the issues of sensing and pacing in multiple chambers of the heart, my previously filed '653 patent application proposes to implant a plurality of electrodes in the triangle of Koch, His bundle and surrounding areas. This location is unique in the cardiac conduction system of the heart in that it may allow pacing multiple heart chambers from a single location in accordance with my '653 application. Since the exact location of specific conduction pathways is not always easy to find based on geometrical and anatomical variations between patients, a plurality of electrodes may be used to cover the entire area of the interest with locations where electrical activity may be probed. Subsequent selection process may be used to identify the best electrodes suitable for sensing and pacing one or more cardiac chambers depending on the particular anomaly of rhythm for a specific patient. While proposed approach is generally useful, it mostly described the use of conventional pacemaker technology connected to the heart by a single conduit containing a plurality of leads. Given the limitations of the pacemaker technology described above, it may be more desirable to adapt leadless pacemaker technology for use with this approach, namely cardiac pacing via triangle of Koch and His bundle.
The need therefore exists for a single long-lasting leadless pacemaker device capable of sensing and pacing one or more chambers of the heart from a single location, such as triangle of Koch and His bundle and closely surrounding areas of the heart.

Leadless multi-electrode cardiac pacemakers and methods of implantation thereof


An electric pen is used as a data input/output device with the same feel as though writing on paper with an ordinary pen. The electric pen can be used in conjunction with an external data processor, such as a compact portable electric note book. Hand written characters inputted by the electric pen is data processed in the external data processor and characters can be printed in a designated print area on paper or the like in print form.

1. Field of the Invention
The present invention relates to an electric pen used as a portable personal information device.
2. Description of the Related Art
There have been known a variety of pointing devices for inputting desired positional and direction data to a computer. One typical example of a pointing device is a mouse unit. In one type of mouse unit, positional and direction data are inputted to the computer by moving the mouse unit itself over the top of a surface such as a desk top. Moving the mouse unit in this way rotates a ball mounted internally to the mouse unit. The direction and amount that the ball rotates is transmitted to a roller in abutting contact with the ball. In this way, the distance and direction in which the mouse unit moves is detected and inputted to the computer. There is also known an optical mouse unit which emits light to illuminate a mouse pad provided with a special lattice at its upper surface. The distance and direction of movement of the mouse unit can be determined by the pattern of reflected light and inputted to the computer.
Recently, input devices that are more user compatible than mouse units have been developed. One example is pen input systems which include a tablet and a special pen. The tablet can be a liquid crystal display or a special optical tablet and is provided with a transparent conductive film. The special pen is provided with a conductive tip. The position and speed of the pen tip can be detected by bringing the pen tip into contact with the transparent conductive film.
Various output devices have been used with these input devices. Normally, output devices of ink jet type, electrophotographic type, silver halide photographic type, or thermal transfer type are used for outputting a hard copy. However, all of these devices are desk top units and therefore are not portable.
Japanese Utility Model Application (KOKAI) No. HEI-4-94693 describes an electric pen including a compact ink jet type printing mechanism. Because the printing mechanism is formed in the shape of a pen, a user can electrically print in a desired color with the same feel as though writing with a pencil or ordinary pen. The electric pen is provided with an analog type color-adjustment switch which a user operates to select a desired color. The electric pen is also provided with an ejection switch which the user presses to cause the electric pen to eject droplets of colored ink. The droplets will impinge on a print medium at a position indicated by the user pointing the electric pen. However, the electric pen is an independent electric writing tool and is only usable to print when the user indicates what to print.
There has been a demand for a device which allows a user to input and output to and from an external data processor, such as a portable information device, with the same feel as through writing with a pen. However, such a device with sufficient functions has yet to be realized.

Electric pen that functions as hand-held printer with multiple colors and adjustable print area


Disclosed are methods for treating cancer by administering an inhibitor of the interaction of glutamate with the KA receptor complex.

Glutamate is a major neurotransmitter but possesses also a wide metabolic function in the body. It is released from approximately 40% of synaptic terminals and mediates many physiological functions by activation of different receptor types (Watkins and Evans (1981) Excitatory amino acid transmitters, Annu. Rev. Pharmacol., 21: 165-189; Gasic and Hollmann (1992) Molecular neurobiology of glutamate receptors, Annu. Rev. Physiol., 54: 507-536). Two main categories of glutamate receptors have been identified, ionotropic and metabotropic (Bettler and Mulle, (1995) Neurotransmitter Receptors II, AMPA and Kainate Receptors, Neuropharmacology, 34: 123-139; Pin and Duvoisin (1995) Neurotransmitter receptors I, The Metabotropic Glutamate Receptors: Structure and Functions, Neuropharmacology, 34: 1-26; Mori and Mishina (1995) Neurotransmitter Receptors VIII, Structure and Function of the NMDA Receptor Channel, Neuropharmacology, 34: 1219-1237). Ionotropic glutamate receptors can be subdivided into N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), and kainate receptors. Metabotropic glutamate receptors can be subdivided into three classes, mGluRI, mGluRII and mGluRIII (Pin and Duvoisin (1995) Neurotransmitter receptors I, The Metabotropic Glutamate Receptors: Structure and Functions, Neuropharmacology, 34: 1-26). Five receptor subunits form the functional NMDA receptor which is modulated by glycine and polyamines and blocked by Mg2+. Activation of NMDA receptors leads to influx of Na+- and K+-ions into the cell as well as Ca2+-ions, either through the receptor channel itself or through voltage dependent Ca2+-channels (Bettler and Mulle, (1995) Neurotransmitter Receptors II, AMPA and Kainate Receptors, Neuropharmacology, 34: 123-139; Mori and Mishina (1995) Neurotransmitter Receptors VIII, Structure and Function of the NMDA Receptor Channel, Neuropharmacology, 34: 1219-1237). Four different subunits, named GluR1-GluR4, form the AMPA receptor channel. AMPA receptors are highly permeable to Na+- and K+-ions. AMPA receptor assemblies lacking the GluR2 subunit are also permeable to Ca2+-ions (Hollmann M, Heinemann S (1994): Cloned glutamate receptors, Annu. Rev. Neurosci., 17: 31-108).
Kainate receptors are built from five subunits, GluR5-7 as well as KA1 and KA2. Kainate receptor associated ion channels are permeable to Na+- and K+-ions as well as Ca2+. Ca2+-permeability of kainate receptor associated ion channels is dependent on the presence of the GluR6 subunit within the receptor complex (Hollmann M, Heinemann S (1994): Cloned glutamate receptors, Annu. Rev. Neurosci., 17: 31-108). There is considerable experimental and clinical evidence indicating that glutamate is involved in the pathogenesis of neuronal degeneration in the context of hypoxia/ischemia and trauma of the central nervous system, seizures and hypoglycemia. In addition, glutamate is thought to be involved in the pathogenesis of chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis, Huntington's, Alzheimer's and Parkinson's disease. Functional glutamate receptors have been also identified in lung, muscle, pancreas and bone (Mason D J, Suva L J, Genever P G, Patton A J, Steuckle S, Hillam R A, Skerry T M (1997) Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone 20: 199-205; Patton A J, Genever P G, Birch M A, Suva L J, Skerry T M (1998) Expression of an N-methyl-D-aspartate-type receptor by human and rat osteoblasts and osteoclasts suggests a novel glutamate signaling pathway in bone, Bone 22; 645-649). However, no link has been established so far between glutamate receptor stimulation and tumor growth.
Many forms of cancer have been described affecting every form of tissue known in man. Of the described forms of human cancer, none is curable in 100% of the affected patients. Treatment modes include surgical removal, chemotherapy with cytostatic agents alone or in combination with hormone receptor modulators and/or steroids and/or interferons, and radiation (Hill R (1992): Cellular basis for radiotherapy, in The Basic Science of Oncology, McGraw-Hill, pp. 259-275).
I. The term inhibitor of the interaction of glutamate with the AMPA receptor complex applies to:
1. all agents that bind to the AMPA receptor and prevent or reduce the binding of glutamate to the AMPA binding site in a competitive- or non-competitive manner. These are antagonists of the binding of glutamate to the AMPA receptor;
2. all agents that do not bind to the AMPA receptor binding site but bind or interact with AMPA receptor modulatory sites and thus prevent glutamate from triggering the signal that would occur when glutamate binds to the AMPA binding site;
3. all agents that interact directly with the AMPA-ion channel, i.e. AMPA receptor channel blockers. These agents reduce permeability of the ion channels associated with the AMPA receptor to ions (preferably Na+, K+ and/or Ca2+);
4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus prevent glutamate from binding to the AMPA binding sites and from triggering the signal that would occur as a result of binding of glutamate to AMPA binding site;5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to its binding sites;6. all agents that increase the metabolism of glutamate and therefore prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;7. all agents that increase the uptake of glutamate and thus decrease the binding of glutamate to AMPA binding site;8. all agents that interfere with glutamate transporter systems and decrease the concentration of glutamate in synaptic cleft and thus prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;9. all agents that interact with glutamate and prevent its binding to the AMPA receptor. Such compounds include i.e. glutamate partial agonists or molecules binding to glutamate;10. antibodies to AMPA receptor subunits, or to the AMPA receptor, or to glutamate decreasing the binding of glutamate to AMPA binding site.II. The term inhibitor of the interaction of glutamate with the KA receptor complex applies to:1. all agents that bind to the KA receptor and prevent or reduce the binding of glutamate to the KA binding site in a competitive- or non-competitive manner. These are antagonists of the binding of glutamate to the KA receptor;2. all agents that do not bind to the KA receptor binding site but bind or interact with KA receptor modulatory sites and thus prevent glutamate from triggering the signal that would occur when glutamate binds to the KA binding site;3. all agents that interact directly with the KA-Ion channel, i.e. KA receptor channel blockers. These agents reduce permeability of the ion channels associated with the KA receptor to ions (preferably Na+, K+ and/or Ca2+).4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus prevent glutamate from binding to the KA binding sites and from triggering the signal that would occur as a result of binding of glutamate to KA binding site;5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to its binding sites;6. all agents that increase the metabolism of glutamate and therefore prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;7. all agents that increase the uptake of glutamate and thus decrease the binding of glutamate to KA binding site;8. all agents that interfere with glutamate transporter systems and decrease the concentration of glutamate in synaptic cleft and thus prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;9. all agents that interact with glutamate and prevent its binding to the KA receptor. Such compounds include e.g. glutamate partial agonists or molecules binding to glutamate;10. antibodies to KA receptor subunits, or to the KA receptor, or to glutamate decreasing the binding of glutamate to KA binding site.III. The term inhibitor of the interaction of glutamate with the NMDA/glycine/polyamine receptor complex applies to:1. all agents that bind to the NMDA receptor or NMDA ion channel associated glycine or polyamine binding site and prevent or reduce the binding of glutamate to the NMDA binding site in a competitive- or non-competitive manner. These are antagonists of the interaction of glutamate with the NMDA receptor;2. all agents that do not bind to the NMDA receptor binding site but bind or interact with NMDA receptor modulatory sites and thus prevent glutamate from triggering the signal that would occur when glutamate binds to the NMDA binding site;3. all agents that interact directly with the NMDA-ion channel, i.e. NMDA receptor channel blockers. These agents reduce permeability of the ion channels associated with the NMDA receptor to ions (preferably Na+, K+ and Ca2+).4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus prevent glutamate from binding to the NMDA binding sites and from triggering the signal that would occur as a result of binding of glutamate to NMDA binding site;5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to NMDA and NMDA channel associated binding sites;6. all agents that increase the metabolism of glutamate and therefore prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to NMDA and NMDA channel sites;7. all agents that increase the uptake of glutamate and thus decrease the binding of glutamate to NMDA binding site;8. all agents that interfere with glutamate transporter systems and decrease the concentration of glutamate in synaptic cleft and thus prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to NMDA binding sites;9. all agents that interact with glutamate and prevent its binding to the NMDA receptor. Such compounds include e.g. glutamate partial agonists or molecules binding to glutamate;10. antibodies to NMDA receptor subunits, or to the NMDA receptor, or to glutamate decreasing the binding of glutamate to NMDA binding site.
Various glutamate antagonists and receptor channel blockers that are within the scope of the present invention will now be described in greater detail:
A. AMPA Receptor Antagonists
AMPA receptor antagonists refer to compounds that bind to AMPA receptors in a competitive manner or interact with AMPA receptor associated sites and block AMPA mediated signal in a non-competitive manner.
Such antagonists include L-glutamate derivatives, amino alkanoic acid derivatives, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate derivatives, acetyl-aminophenyl-dihydro-methyl-dioxolo-benzodiazepine, acid amide derivatives, amino-phenyl-acetic acid, 2,3-benzodiazepin-4-one, alkoxy-phenyl-benzodiazepine, amino- or desamino-2,3-benzodiazepine, benzothiadiazine, β-carboline-3-carboxylic acid, fused cycloalkylquinoxalinediones, decahydroisoquinoline, 4-hydroxypyrrolone, 4-hydroxy-pyrrolo-pyridazinone, imidazo-pyrazinone, imidazolo-quinoxalinone, indeno-pyrazine-carboxylic acid, indeno-pyrazinone, indoloneoxime, indolo-pyrazinone, isatine, isatinoxime, oxadiazole, phenyl-azolophthalazine, phenylpyridazino-indole-1,4-dione, quinoline, quinolinone, quinoxaline, quinoxalinedione, quinazolinone, quinolone, nitroquinolone, and sulphamate derivatives.
B. AMPA Receptor Channel Blockers
AMPA receptor channel blockers refer to compounds that reduce the permeability of channels associated with the AMPA receptor to cations (preferably to Na+, K+ and/or Ca2+ ions). AMPA receptor channel blockers can therefore be used to prevent a signal being transmitted due to ionic flux that would otherwise occur when glutamate binds to the AMPA receptor.
AMPA receptor channel blockers include e.g. fluorowillardiine, Joro spider toxin, NSTX spider toxin, argiotoxin.
C. KA Receptor Antagonists
KA receptor antagonists refer to compounds that bind to KA receptors in a competitive manner or interact with KA receptor associated sites and block KA mediated signal in a non-competitive manner.
Such antagonists include L-glutamate derivatives, kainic acid derivatives, acid amide derivatives, aminoalkanoic acid derivatives, aminophenyl(alkyl)acetic acid derivatives, fused cycloalkylquinoxalinediones, quinoxalinedione, imidazolo-quinoxalinone, isatine, phenyl-azolophthalazine, pyridothiazines, 4-phosphonoalkyl-quinolinone, quinolinone, quinazoline, quinazolinedione, quinoxalinedione and sulphamate derivatives.
D. KA Receptor Channel Blockers
KA receptor channel blockers refer to compounds that reduce the permeability of channels associated with the KA receptor to cations (preferably to Na+, K+ and/or Ca2+ ions). KA receptor channel blockers can therefore be used to prevent a signal being transmitted due to ionic flux that would otherwise occur when glutamate binds to the KA receptor.
KA receptor channel blockers include i.e. Joro spider toxin, NSTX spider toxin and argiotoxin 636.
E. NMDA/Glycine/Polyamine Receptor Antagonists
NMDA/glycine receptor antagonists refer to compounds that bind to NMDA receptors in a competitive manner or interact with NMDA receptor associated sites and block NMDA mediated signal in a non-competitive manner.
Such antagonists include L-glutamate derivatives, tetrahydroquinolines, imidazoloquinoxalinones, isatines, fused cycloalkylquinoxalinediones, quinoxalines, spermine, 4-hydroxy-3-nitro-1,2-dihydroquinolon-2-one derivatives, indole derivatives, benzo-thiadiazine dioxide derivatives, indeno(1,2-b)pyrazin-3-ones or corresponding 2,3-diones, quinoline derivatives, ethyl(phenyl-carbamoyl)-ethenyl)dichloroindole carboxylates, thienopyrazine 2,3-dione derivatives, 2-(2,3-dicarboxycyclopropyl) glycine, 2-amino-3-substituted phenyl propionic acid derivatives, 1-carboxyalkylquinoxaline-2.3(1H,4H)dione derivatives, thienyl-glycine derivatives, benzo-fused azacyclic compounds, tricyclic quinoxaline-diene derivatives, 3-hydroxy anthranilic acid and salts, decahydroisoquinolines, tri- or terta-substituted guanidine derivatives, D- or L-tryptophan derivatives, tetrazolyl(alkyl)-cyclohexyl-aminoacid derivatives, octahydrophenanthrene derivatives, benzomorphan, piperazinyl or piperidinyl-alkyl substituted isoxazole derivatives, decahydroisoquinoline-3-carboxylic ester or its amide preparation, compounds based on Conantokin-G peptide, 3-heterocyclyl-alkyl-benzopyran-2-one derivatives, phosphono-alkyl imidazo-pyrimidine carboxylic acid derivatives, amantadine, memantine, rimantidine, histogranin and analogues, nitrobenzoic acid derivatives, e.g 4-((2-methoxycarbonyl-4-nitrophenyl)methyl)piperazine carboxylic acid, diamine derivatives with selective sigma receptor affinity, remacemide (2-amino-N-(1,2-diphenyl-1-methylethyl)acetamide), phosphono-alkylidene- or phosphono-alkoxy-imino-piperidine acid, benzothiadiazine carboxylic acid derivatives, dihydro-benzothiadiazine dioxide carboxylic acid derivatives, 4-hydroxy 2(H) pyrrolone derivatives, quinoxaline derivatives, tetrahydro-imidazo(1,2-a)pyrimidines or their salts, 4-hydroxy-pyrrolo(1,2-b)pyridazin-2(1H)-one derivatives, nitroquinolone derivatives, 3-aryl-substituted 2(1H)quinolone, 2(1H)-quinolone, phosphonic acid quinoline-2-carboxylic acid derivatives, benzimidazole(s) carrying 2 acidic groups, N,N′-disubstituted guanidine derivatives, tricyclic quinoxalinediones, 2-(2,3-dicarboxycyclopropyl) glycine, isatine derivatives, 3-amino-indolyl-derivatives, 2-phenyl-1,3-propanediol dicarbamate (felbamate), benzomorphan derivatives, dihydrothienopyridine derivatives, (aminophenyl)-heteroaryl ethylamine, pyridazinedione derivatives, a 2H-1-benzopyran-2-one compound, a 4-sulphonylamino-quinoline derivative, R(plus)-3-amino-1-hydroxy-pyrrolidine-2-one, 2-carboxy indole, substituted. imino-methano dibenzo(A,D)cycloheptene derivatives, indole-hydrazone, piperazine derivatives, 4,6-disubstituted tryptophan and kynurenine derivatives, fluorenamine, diketo-pyridopyrazine derivatives or its salts, 2-amino-3,4-dioxo-1-cyclobutene derivatives, 2-acyl-amido derivatives of 3,4-dihydro-3-oxo-quinoxaline, benzimidazole phosphono-aminoacid derivatives, quinoxaline phosphono-aminoacid derivatives, piperazine, piperidine or pyrrolidone derivatives, its salts and isomeric forms including stereoisomers, 4-hydroxy-2(1H)-quinolinone derivatives, its salts and prodrugs, fused pyrazine derivatives, 2-phenyl or 2-thienyl-(2)-piperidine derivatives, 3-amido or 3-sulphamido-indolyl derivatives, 3-aryl-4-hydroxy-2-(1H)-quinolone derivatives, 2-heterocyclyl-2-hydoxy-ethylamine derivatives, 1-aryl-2-aminomethyl pyrrolidine, its optical isomers and acid-addn. salts, 4,6-dihalo indole-2-carboxylic acid derivatives, cyclic amino-hydroxamate derivatives, tetracyclic amine derivatives, 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivatives, 2,4-dioxo-1,2,3,4-tetrahydroquinoline derivatives, 3-phosphonopiperidine and p-pyrrolidine derivatives, benzothieno(2,3-B)-pyrazine-2,3-(1H,4H)-dione, spiro dibenzosuberane derivatives, benzomorphan derivatives, preparation of 3,4-disubstituted 2-isoxazoline(s) and isoxazoles(s), 3-indolyl thio-acetate derivatives, arginine-derived nitric oxide biosynthesis inhibitors, dicyclic amine derivatives, spiroisoindole derivatives, imidazo(1,2-A)-pyridinylalkyl, 1,2,3,4-tetrahydro-9H-pyridoindole or benzothiophene derivatives, indole-2,3-dione-3-oxime derivatives, 1-aryl-2-(aminomethyl)cyclopropanecarboxamide derivatives, 4-phosphono-2-amino-alkenoic acid derivatives, naphthopyran derivatives, beta-ketone, beta oxime or beta hydrazine phosphonate, topa quinone aminoacid, kynurenic acid, quinoline- or thienopyridine-carboxylic acid derivatives, 10,5-(imino-methano)-10,11-dihydro-5H-dibenzo(A,D)cycloheptene or its derivatives, bicyclic amino-hydroxamate derivatives, indole-2-carboxylic acid derivatives, substituted adamantane derivatives, benzobicycloalkane derivatives, 2,4-disubstituted-1,2,3,4-tetrahydro-quinoline derivatives, dihydro-alkyl-substituted-(immunomethano)-5H-dibenzo-cycloheptene, aryl-cyclohexylamine, N-substituted. benzobicycloalkane amine, isoquinoline phosphonates, N,N′-disubstituted.-guanidine, phosphonopropenyl piperidine carboxylic acid, (2R,3S,4S)-alpha-carboxy-cyclopropyl-glycine, pyrrolidine derivatives, dihydroxy-fused heterocyclyl quinoxaline derivatives, hydrogenated derivatives of MK 801 and analogues, 5-substituted 10,11-dihydro 5H-dibenzo(a,d)cycloheptene5,10-imine, 11-exo-hydroxy MK 801 preparations, tetra hydro-isoquinoline or 2-benzazepine derivatives, N-3-phenyl-propionyl-substituted. spermine or related polyamine derivatives, 4-amino-fluorene or its heterocyclic analogues, cyclooctane-imine derivatives, R-3-amino-1-hydroxy pyrrolidin-2-one or methionine hydroxamate, 10,11-dihydro-5H-dibenzo-cyclohepten-5,10-imine, polyhydro-10,11-dihydro-5H-benzo(a,d)cyclohepten-5,10 imine derivatives, 4-oxo-1,4-dihydroquinoline with 2-acidic groups, heterocyclyl-alkene-phosphonic acid, phosphono group-containing pyridine 2-carboxylic acid, alpha-amino-alpha-(3-alkylphenyl)alkyl ethanoic acid, its esters or amides, 10,11-dihydro-5H-dibenzo-A,D-cyclohepten-5,10-imine, phosphorus containing unsatturated amino acids or their salts, 5 substituted-1-,11-dihydro-5H-dibenzo-cyclohepten-5,10-imine or analogues, heterocyclic phosphonic acid derivatives or their salts, substituted 4-(amino-carbonyl-amino)quinoline derivatives, tricyclic quinoxaline derivatives, butyryl-tyrosine spermine or one of its analogues, tri- or tetra-substituted guanidine, quinoxalinylalkyl-aminoalkane phosphonic acid derivatives, 2-(aminophenyl)-3-(2-carboxy-indol-3-yl)-propenoic acid derivatives, 6-piperidinylpropionyl-2(3H)-benzoxazolone derivatives, 6-(3-[4-(4-fluorobenzyl)piperidin-1-yl]propionyl)-3H-benzoxazol-2-one or its salts, imidazo(1,2-a)pyridine, tetrahydroquinoline derivatives or their salts, 2-methyl-5,8-substituted 2,3,4,5-tetra- or 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, 3-aminoindolyl, 6-pyrrolyl-quinoxaline-2.3-dione derivatives, imidazolyl-(mercaptoalkyl)-quinoxaline-dione, 3-amidoindolyl derivatives, heterocyclyl-imidazolo-quinoxalinone, naphthyl-substituted alpha-amino acid derivatives, 5-hetero-aryl-2,3-quinoxaline-dione derivatives, quinoxaline derivatives, 5H,10H-imidazo indeno 4-pyrazinone derivatives, hydroxy-(aryl-substituted phenyl)-quinolone, imidazo indolo pyrazinone derivatives, ((phenyl-amino)-(m)ethyl)-pyridine derivatives, tetrahydro-isoquinoline derivatives, 4-substituted piperidine analogues, 2-substituted piperidine derivatives, tri- or tetra-substituted guanidine derivatives, 3-hydroxy-4-imidazolidinone, 3-aminoquinoxalin-2-one derivatives, 1-amino-1-cyclobutanecarboxylic acid, thiamorphinan derivatives, pyrido[4,3-b]indole derivatives, 4-phenyl carbamoyl methylene tetrahydro quinoline-2-carboxylic acid or derivatives thereof, (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl)-chroman-4,7-diol, indeno-pyrazin-4-one, 2,3-dioxo-1,2,4,5-tetrahydro-quinoxalinyl derivatives, 4,5-bridged quinoxalinedione or quinolone, (1S,2S)-1-(4-hydroxyphenyl)2-(4-hydroxy 4-phenyl piperidin-1-yl) 1-propanol methane sulphonate trihydrate, 4-sulphanimide-quinoline derivatives, methanobenzocyclodecen-13-amine, quinoxalinyl-(alkane, alkene, or alkyne)-phosphonic acid derivatives and esters, diarylalkylamine related to spider and wasp venom toxins, piperazine R-alpha-carboxylic acid derivatives, imidazo-indeno-pyrazin-4-one derivatives, pyridazino-quinoline derivatives, 1-substituted or 1,3-di-substituted 1,3-diaryl-guanidine, aza-cycloalkyl-fused quinoxaline-dione, 3-substituted 2-carboxy-indole derivatives or intermediates, (2R)-N-trityl-4-oxo-5-(dimethyl phosphono)-nor-valinate ester, kynurenic acid derivatives, indole carboxylic acid derivatives, 6-(tetrazolyl or isoxazolyl)-decahydroisoquinoline-3-carboxylic acid derivatives, phenyl- or pyridinyl-thieno-pyridinone derivatives, fused cycloalkyl-quinoxaline-dione derivatives, pyridazino-quinoline derivatives, 1-alpha-amino-3-biphenyl-propanoic acid derivatives, 3-(Indol-3-yl)propenoic acid derivatives, spiro-heterocycle-imidazo-indeno-pyrazine-4-one derivatives, 2-heterocyclyl-3-indolylpropenoic acid derivatives, piperidinoalkyl heterocyclic ketone, pyrrolyl-tetrahydro-benzoquinoxaline-dione derivatives, 7-imidazolyl or dialkylamino, tetrahydroquinoxaline dione, dibenzocycloheptene, quinoxaline derivatives, aryl-thio-quinoxaline derivatives, heterocyclic substituted imidazolo-quinoxaline derivatives, 1,4-dihydro-quinoxaline-2,3-dione derivatives, oxa- or thia-aliphatically bridged quinoxaline derivatives, aza-aliphatically bridged quinoxaline-2,3-dione, 3-amido- or 3-sulphamido-indole, 3,5-disubstituted phenyl-naphthalene derivatives, imidazo (1,2-a)indeno (1,2-e) pyrazine-2-carboxylic acid derivatives, 3-phenyl-fused ring pyridine-dione derivatives, 2-phenyl-pyridazino-indole-dione derivatives, 4,6-disubstituted kynurenine, phosphono derivatives of imidazo(1,2-a)pyrimidine-2-carboxamide, tetrahydro-quinoxaline-dione derivatives with N-(alkyl)carbonyl-amino- or ureido group, tryptophan derivatives, hetero-aliphatic or hetero-araliphatic substituted quinolone derivatives, imidazo-pyridine dicarboxylic acid derivatives, compositions containing pyrazolo-quinoline derivatives, ethanodihydrobenzoquinolizinium salt, oxopyridinylquinoxaline derivatives, indeno-triazolo-pyrazin-4-one derivatives, imidazo-indeno-pyrazinone derivatives, imidazo-indeno-pyrazin-4-one derivatives, imidazo(1,2-a)pyrazine-4-one derivatives, 5H-indeno-pyrazine-2,3-dione derivatives, phenyl-aminoalkyl-cyclopropane N,N-diethyl carboxamide, dexanabinol derivatives, substituted chroman derivatives, sulphonamide quinazoline-2-4-dione, 6- and 8-aza-, and 6,8-diaza-1,4-dihydro-quinoxaline-2,3-dione derivatives, substituted quinoline derivatives, tetrazolylalkyl cyclohexyl aminoalkanoic acid, tricyclic indole 2-carboxylic acid derivatives, 6-substituted-7H-imidazo-8-pyrazinone derivatives, tricyclic pyridazinopyridine derivatives, N-substituted heterocyclylidenemethyl-indole carboxylic acid derivatives, 3-aza-8-substituted-bicyclo(3.3.0)octane-2-carboxylic acid derivatives, ethano-heterocyclo-isoquinolinium, phenyl alkanolamine derivatives, dihydrobenzothiadiazinedioxide carboxylic acid derivatives, methyl-butenylmethyl(hydroxy-propyl)carbazoledione, imidazo pyrazinone derivatives, imidazo-(1,2-a)pyrazine-4-one, benzazepine-dione derivatives, disulfiram, 3-(indol-3-yl)-propenoic acid derivatives, 1,2,3,4-tetrahydro-quinoline-2,3,4-trione-3 or 4-oxime, 2-amino-2-phenyl(alkyl)-acetic acid derivatives, 6-halo-tryptophan or a 4-halo-kynurenine, 6-tetrazolyl or isoxazolyl-decahydro-isoquinoline-3-carboxylic acid derivatives, or imidazolylbenzene or salts thereof.
F. NMDA Receptor Channel Blockers
NMDA receptor channel blockers refer to compounds that reduce the permeability of channels associated with the NMDA receptor to cations (preferably to Na+, K+ and Ca2+ ions). NMDA receptor channel blockers can therefore be used to prevent a signal being transmitted due to ionic flux that would otherwise occur when glutamate binds to the NMDA receptor.
NMDA receptor channel blockers include i.e. magnesium, dizocilpine, phencyclidine, ketamine, memantine, tiletamine, budipine, flupirtine, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), (+)-(3S,4S)-7-hydroxy-delta6-tetrahydrocannabinol-1,1-dimethylheptyl (HU211).
G. Glutamate Release Inhibitors
Such agents decrease the release of glutamate from nerve endings and prevent glutamate from binding to either AMPA, kainate, or NMDA binding sites and from triggering the signal that would occur as a result of binding of glutamate to these binding sites.
Glutamate release inhibitors include e.g. riluzole, lamotrigine, diphenylhydantoin, tetrodotoxin, agatoxin-glutamate-release-inhibitor (AG-GI), [5-(2,3,5-trichlorophenyl)]-2,4-diamino-pyrimidine (BW1003C87), (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) and 4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (BW619C89).
H. Glycine Release Inhibitors
Such agents decrease the release of glycine from nerve endings and prevent glycine from binding to glycine B binding sites and from triggering the signal that would occur as a result of binding of glutamate to NMDA binding site.
I. Glutamate Synthesis Inhibitors and Drugs Interfering With Glutamate Metabolism
Such compounds block synthesis of glutamate or increase metabolism of glutamate preventing activation of either AMPA, kainate or NMDA binding sites.
Compounds interacting with glutamate synthesis or metabolism and preventing activation of either AMPA, kainate or NMDA receptors include e.g. gabapentin, L-canaline, phenylsuccinate, spermidine, putrescine, gentamicin, orthovanadate, vanadyl sulphate, vanadyl acetylacetonate, methionine sulphoximine, chloroquine, amodiaquine, quinacrine, chinidine, chinine, α-monofluoromethylputrescine and (R,R)-delta-methyl-α-acetylenic-putrescine.
J. Compounds Accelerating Glutamate Uptake
Such agents decrease synaptic concentration of glutamate by activating uptake mechanisms for glutamate preventing activation of either AMPA, kainate or NMDA receptors.
Compounds accelerating glutamate uptake mechanisms include e.g. γ-glutamyl-transpeptidase.
K. Agents That Interact With Glutamate and Prevent its Binding to its Receptors
Such agents include i.e. glutamate partial agonists which activate glutamate receptors by themselves but are less active than glutamate at these receptors and therefore decrease activation of these receptors by glutamate at physiological and excessively high concentrations or molecules binding to glutamate which change conformational state of glutamate and therefore decrease its binding capability to its receptors.
Glutamate partial agonists are e.g. D-serine, D-cycloserine, γ-L-glutamylglutamate, N-phthalamoyl-L-glutaminic acid, (R,S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid, α-N-acetylaspartylglutamate, 1-aminocyclopropanecarboxylic acid, aminocyclobutane cyrboxylic acid, (+,R)-3-amino-1-hydroxy-2-pyrrolidine (HA966) and D,L-threo-3-hydroxyasparate.
Furthermore such agents include soluble forms of NMDA, kainate or AMPA receptors or parts thereof. These soluble forms can be used to circulate and to bind to glutamate and therefore decrease its binding capability to the receptors. Membrane bound forms of the glutamate receptors may also be incorporated into liposomes, circulate and bind to glutamate so as to prevent it binding to its receptors.
L. Agents That Interact With Glutamate Transporter Systems
Such agents accelerate glutamate transporter function and decrease glutamate concentration at its receptors preventing activation of either AMPA, kainate or NMDA receptors.
Such agents include e.g. 12-O-tetradecanoylphorbol-13-acetate, phorbol-12-myristate 13-acetate.
M. Antibodies Interacting With AMPA Receptors or With Glutamate
The AMPA, kainate or NMDA receptors or a part or parts of them, or glutamate can be used for raising antibodies that bind thereto. Preferred antibodies bind specifically to either AMPA, kainate or NMDA receptor or a part thereof, or to glutamate. The antibodies may be monoclonal or polyclonal. Polyclonal antibodies can be raised by stimulating their production in a suitable animal host (e.g. a mouse, rat, guinea pig, rabbit, sheep, goat or monkey) when either AMPA, kainate or NMDA receptor, or a part thereof, or glutamate is injected into the animal. If necessary an adjuvant may be administered together with the AMPA, kainate or NMDA receptor, or a part thereof, or with glutamate. In addition to whole antibodies, antagonists of the present invention include derivatives thereof.

Use of glutamate antagonists for the treatment of cancer


An apparatus is disclosed which is a microprocessor based instrument designed to conveniently and rapidly measure various analytes in environmental and biological samples. The instrument operates as a stand-alone unit powered by a battery or a DC power module and may be equipped with a communication port allowing uploading test results to a computer. Several unique electronic, microchip and software configurations were developed for the device to make it a portable, low-cost, safe, automated and simple-to-operate instrument particularly adapted for precise and accurate measurement of metal ions such as heavy metals such as lead in human blood.

This application claims the benefit of U.S. Provisional Application No. 60/002,636 filed Aug. 22, 1995.
A portion of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by any one of the patent disclosure, as it appears in the Patent and Trademark Office patent files or records, but otherwise reserves all rights whatsoever.
A copy of the computer program listing is provided as an appendix in the patent file which will not be printed, but will be available subsequent to the grant of patent or when the application is otherwise made publicly available.


A liquid crystal display device of electrically controlled birefringence mode includes the combination of a liquid crystal cell having a liquid crystal layer sandwiched between a pair of substrates, and a hybrid retardation layer in which liquid crystal molecules are hybrid-aligned, and the hybrid retardation layer is formed by deposition at the liquid crystal layer side on one substrate of the pair of substrates.

1. Field of the Invention
The present invention relates to a liquid crystal display device of Electrically Controlled Birefringence (ECB) mode having a retardation layer in which liquid crystal molecules are hybrid-aligned, electronic equipment using the device, and a method of manufacturing the liquid crystal display device.
2. Background Art
In related art, as a general drive mode in a liquid crystal display device for personal computers, the twist nematic mode that provides high transmittance and display in simple combination with polarizing plates has been applied. Recently, there has been a sharply increasing demand for display devices for use in mobile electronic equipment such as Personal Digital Assistants (PDAs) or cellular phones, and semi-transmissive liquid crystal display devices that enable lower power consumption and higher visibility outdoors compared to transmissive liquid crystal display devices have been developed.
In the semi-transmissive liquid crystal display devices, generally, the ECB mode in combination with retardation layers is applied. In order to obtain display characteristics of reflection and transmission, the semi-transmissive liquid crystal display device has a configuration in which a liquid crystal cell is sandwiched with one or two retardation layers at one side.
Further, in the liquid crystal display device of ECB mode, a retardation layer having a hybrid structure is used as the retardation layer. Since the combination of the hybrid-structured retardation layer with the ECB mode provides a wide viewing angle, the combination has been applied not only to the semi-transmissive liquid crystal display devices but also to the transmissive liquid crystal display devices these days.
As a liquid crystal display device using the hybrid-structured retardation layer, a configuration in which a liquid crystal cell is sandwiched with hybrid-structured retardation layers having negative refractive anisotropy is proposed (see JP-A-10-197862 (FIG. 1, paragraph 0006) (patent document 1), JP-A-2004-118222 (FIG. 1, paragraph 0045) (patent document 2), and JP-A-2004-309598 (paragraphs 0020, 0052) (patent document 3)).

Liquid crystal display device, electronic equipment, and method of manufacturing liquid crystal display device