To provide a laser scanning control apparatus for driving a light source adapted to emit a laser beam in accordance with image data defined in pixels to scan an image bearing member in a main scanning direction with the laser beam emitted from the light source through a rotating polygon mirror, the laser scanning control apparatus being characterized by including a correction portion for, every one or more correction points on a main scanning line of the image bearing member to be scanned with the laser beam, extending the pixel length for each pixel located in the correction point concerned to thereby correct the scanning magnification of the main scanning line, and for changing the rotational speed of the rotating polygon mirror to correct the magnification in a sub scanning direction to thereby correct the output magnification.

1. Field of the Invention
The present invention relates to a laser scanning control apparatus for forming a latent image on a latent image bearing member by scanning the latent image bearing member with a laser beam emitted from a laser light source.
2. Related Background Art
In general, in an image forming apparatus such as a laser beam printer or a digital copying machine, a semiconductor laser is driven with a laser beam driving circuit, a laser beam emitted from the semiconductor laser is modulated with an image signal, and a photosensitive drum is raster-scanned with the laser beam after the modulation using a rotating polygon mirror to thereby form a latent image.
At this time, in the apparatus having a plurality of semiconductor lasers, there is a problem in that the magnification of a latent image differs depending on the position on a photosensitive drum illuminated with the laser beams emitted from the respective semiconductor lasers. In addition, in the double-sided printable image forming apparatus, there is a problem in that heat of a fixing unit evaporates moisture contained in a sheet material so that a paper after fixing contracts in size, whereby even if ratios of the latent images on both the surfaces are identical to each other, the image sizes after printing are different from each other.
In contrast, there has been proposed a method in which, in order to obtain adjustment between them, an image clock signal with which image data is transferred is added at an arbitrary point to control the length between the image data to thereby correct the size of the image to be printed (refer to for example, Japanese Patent Application Laid-Open No. 2000-238342).
However, in the above-mentioned prior art, there is a possibility that since the image clock signal is corrected, the image data to be interpolated is fixed, and hence a space is generated in the position where the image clock signal is minutely lengthened to impair the printing quality.


The invention relates to a method and an apparatus for arranging data synchronization is a synchronization system which comprises at least a first synchronization device and a second synchronization device. The synchronization system defines binding data which associates a user data unit of the first synchronization device with at least one function of the first synchronization device. A first synchronization step is performed between the first synchronization device and the second synchronization device, the step comprising transferring the user data unit from the first synchronization device to the second synchronization device. After the first synchronization step has been performed, a second synchronization step is performed where binding data is transferred from the first synchronization device to the second synchronization device. Binding is formed in the second synchronization device between the user data unit and at least one function of the second synchronization device in accordance with the binding data.

The invention relates to data synchronization in a telecommunications system and particularly to synchronization of data which supplements user data.
Data of portable terminals, such as portable computers, PDA (Personal Digital Assistant) devices, mobile stations or pagers can be synchronized with databases of network applications, desktop applications or other databases of a communications system. Typically, it is data of calendar and e-mail applications that are synchronized. Synchronization has previously been based on the use of different manufacturer-specific protocols that are not compatible with each other. This restricts the use of different terminals and data types and is frequently difficult for the user. In mobile communication, in particular, it is important to acquire and update data irrespective of the terminal or application used. The SyncML (Synchronization Markup Language) has been developed based on the XML language (Extensible Markup Language) for more enhanced practical synchronization of application data. The SyncML synchronization protocol using messages in SyncML format allows data of any application to be synchronized between any networked terminals. Solutions have also been developed for synchronization of device specific data, such as mobile phone settings. An example of device management standards is the SyncML device management which is partly based on the SyncML data synchronization standard enabling data synchronization.
A situation where one user has various terminals, such as mobile phones, has become more common. These mobile stations may have very different properties: the memory capacity of one mobile station may be considerably large whereas the advantages of the other mobile station are its versatile functionality or small size. When the user changes from one mobile station to another, he would also like to transfer all the necessary personal in formation to the other mobile station. Methods have been devised for transferring user data, such as contact cards, calendar entries, SMS messages and images. SyncML synchronization or terminal-specific data transmission programs, for example, can be used for transferring user data. In addition to user data, an increasing amount of various supplementary data related to the function of the device is stored in existing terminals, such as speed dial numbers, call history, user profiles or general data related to a user data unit. It has not been possible to update data of this kind from one device to another by prior art methods because in portable devices, in particular, the data have been presented in very different manners due to their small memory capacity. Furthermore, there has not been a great need to transfer information of this kind from one device to another.


Molten metal is either poured or injected into the cavity of a permanent mold by way of a bush which comprises a metal sleeve, anchored to the mold itself, a first tubular element of ceramic material lodged internally of the sleeve, and a second tubular element, also ceramic, coaxial with the first. The stream of metal passes from a feeder into the inlet end of the bush, through the first and then the second ceramic element, and enters the cavity ultimately from an outlet end consisting of a metal annular element connected in a precise and effectively fluid-tight fit with the corresponding end of the second tubular element.

The present invention relates to a bush through which to direct a stream of molten metal into a mold, by pouring or injection.
In particular, the bush disclosed is advantageously suitable for use in directing a flow of castable alloy, for example aluminium alloy in the liquid state, into a permanent mold fashioned typically from steel.
Conventional bushes employed for the purpose in question appear essentially as a tubular element, fashioned generally in nickel-chromium cast iron or special steel. One end of such an element connects with the interior of a mold, and the remaining end with an item of equipment from which the stream of molten metal or metal alloy flows into the mold, either freely or pressurized to a greater or lesser degree, according to the casting technique adopted. A bush of this type is usually encircled at least in part by a heating element, typically comprising an electrical resistance, of which the function is to generate thermal energy in such a way that the molten metal can be kept heated and maintained in a fluid state when effectively occupying the bush, i.e. throughout the step in which it is poured or injected into the mold.
In the case of the conventional type of bush thus outlined, the need to supply abundant quantities of heat stems from the fact that the heat held in the molten metal passing through the bush is dissipated in an unwarranted and excessive manner, causing the metal itself to cool to a certain extent. Moreover, it is inevitable that heat will be transmitted to the bush substantially in continuous fashion, even where the resistance is activated intermittently, as the active generating periods ultimately become longer in duration and progressively more frequent. Thus, despite the provision of the heating element to the end of reducing the frequency with which the metal solidifies, causing a blockage of the bush, it happens in molding equipment using conventional bushes that the heat applied to the molten metal tends to be generated at temperatures higher than effectively necessary, resulting in wasted energy and high costs. In addition, the bushes themselves are somewhat costly, prone to wear in a relatively short space of time, and need replacing at notably frequent intervals, signifying repeated and costly stoppages in operation of the molding equipment. A further drawback, by no means unimportant, stems from the use of special metals and their limited workability post-solidification; in effect, the conventional type of bush must be secured to the relative molding equipment using complex clamping mechanisms which are laborious to fit and remove. Accordingly, the object of the present invention is to overcome the aforementioned drawbacks through the adoption of a pouring or injection bush capable of affording notable energy savings and ensuring significantly increased output from the molding equipment, of which the durability is distinctly greater than that of conventional bushes and the design such as to allow fitment to and removal from a mold in an extremely swift and simple manner.

Bush for directing a stream of molten metal into a mold


An electric power generation system combines a gas turbine generator with a solar power plant and utilizes the gas turbine exhaust for steam superheating and feed water heating only. The solar heater is only utilized for boiling or evaporation of feed water into steam, the feed water having previously been heated by a downstream portion of the turbine exhaust. In order to balance the disparity between the specific heats of water and steam to thus optimize the system, the steam is superheated by an upstream portion of the turbine exhaust to first drive a high pressure steam turbine and then reheated by the same exhaust over the same temperature range to drive a low pressure steam turbine.

Combined cycle electrical generating systems using solar and gas turbine units are probably known as illustrated in U.S. Pat. No. 5,444,972. In addition it is believed that Bechtel Corporation of San Francisco, Calif. have designs that have added to a standard General Electric gas turbine power plant (which by the way also used high pressure and low pressure steam turbines), a solar evaporator. However, in both of the above installations, there was no specific effort to optimize the overall system. Rather the solar energy portion of the system was merely added to the combined cycle, utilizing the original gas turbine steam generation equipment and cycle layout as originally designed for fuel firing.

Hybrid solar and fuel fired electrical generating system


A system for concentrating gas, using the concentrated gas to pump liquid, and recycling the gas and liquid is disclosed. The system comprises a body of liquid, a down pipe in fluid communication with the body of liquid, a gas injection apparatus for introducing gas into the liquid that passes through the down pipe, a separator for separating compressed gas from the liquid, and a gas-liquid recycle loop. The down pipe and the gas injection apparatus are structured and arranged to compress the gas. The gas-liquid recycle loop comprises a compressed gas storage vessel containing the separated gas, a reservoir containing liquid separated from the compressed gas, and a gas-liquid pump. The gas-liquid pump has a gas inlet in communication with the gas storage vessel, and a fluid inlet in communication with the reservoir. The gas-liquid pump is structured and arranged for pumping the liquid back to the body of liquid and delivering the gas to the gas injection apparatus. A turbine in fluid communication with the liquid that passes through the down pipe can be optionally included. A second loop system comprising a second body of liquid, a second down pipe in fluid communication with the second body of liquid, and a second gas-liquid pump is also disclosed. The second gas-liquid pump comprises a second gas inlet in communication with a compressed gas storage area, a second liquid inlet in communication with the second liquid that passes through the second down pipe, the second gas liquid pump structured and arranged for pumping the second liquid to the second body of liquid. A second turbine in fluid communication with the liquid that passes through the second down pipe can optionally be included.

Many liquid pumping systems have means for entrapping and compressing air in order to generate rotational mechanical energy. However, most traditional designs required a naturally occurring steep vertical fall that is fed by a stream of water, such as a waterfall, in order to be operational. This required that the water source must be located on ground having a high altitude and the compressed gas accumulator must be located on ground having a lower altitude. In conventional systems, water expelled from the system is returned to the moving water source at a return location that is different from the location that feeds the system, i.e., the water return point has a lower altitude than the point where water is taken from the stream to fill the conventional system. These geographic constraints drastically limited the areas that many hydraulic air compressor systems could be located. Furthermore, water passing through a traditional liquid pumping system could be used only once, thereby requiring a continuous renewable resource of liquid to drive the system. Accordingly, a need remains for a liquid pumping system that uses compressed gas to drive a mechanical device that does not require a continuous renewable water source. The present invention has been developed in view of the foregoing.


A method includes: providing a semiconductor die having a first main surface, a second main surface opposite the first main surface, and an edge between the first main surface and the second main surface; applying a temporary spacer to a first part of the first main surface of the semiconductor die, the first part being positioned inward from a peripheral part of the first main surface; after applying the temporary spacer, embedding the semiconductor die at least partly in an embedding material, the embedding material covering the edge and the peripheral part of the first main surface of the semiconductor die and contacting a sidewall of the temporary spacer; and after the embedding, removing the temporary spacer from the first main surface of the semiconductor die to expose the first part of the first main surface of the semiconductor die. A semiconductor device produced by the method is also provided.

Molding is a standard encapsulation method for semiconductor dies. In many cases, it is preferred to exclude some area of a device from the mold application. This is conventionally done by film assisted molding (FAM). Film assisted molding is a molding process that utilizes a foil that seals an area of the device being encapsulated against unwanted mold. The foil must accommodate height and size tolerances of the device being encapsulated, but also must be pressed against the device with high force to avoid mold flash. These competing requirements result in an expensive compromise and lead to improper edge formation at topographical features of the device being encapsulated. In other cases, it may be necessary to protect features from the high local pressure of the foil and/or topologies which are too small to be formed by a mold stamp covered with a thick foil may be required.
An underfill compound may be applied and/or the size of filler particles contained in the molding compound may be reduced. In both cases, however, reduced mechanical stability and/or isolation problems may result along with reduced long-term stability. Underfill and smaller filler particles also increase the material cost up to 100×. Further, these approaches include exposed imide/Cu plated border areas, possibly causing long-term stability issues due to an undefined interface. Foil assisted molding is not used with these approaches, and hence many products are not possible. In many cases, features are opened after molding which is laborious and can damage underlying structures.
Thus, there is a need for an improved embedding process for semiconductor devices.

Temporary post-assisted embedding of semiconductor dies


This invention relates to a hydrometallurgical process for the recovery and separation of valuable precious, base or rare elements such as platinum group metals (PGMs), gold or silver, and other valuable base and rare metals such as nickel, cobalt, copper, rare earth elements (REE), yttrium and scandium, as well as uranium, thorium, manganese, zinc, cadmium, molybdenum, titanium, tin, and other minor elements such as vanadium, germanium and gallium from a feed material comprising ores, concentrates and other materials. In particular, the process comprises quantitative removal of additional base, rare and gangue elements for increased efficiency of further treatment of the solids for valuable metals recovery and/or recycling and/or separation of valuable metals from pressure leach residue and may be integrated into one or more existing valuable element extraction processes.

This invention relates to a hydrometallurgical process for the recovery and separation of valuable precious, base or rare elements from a feed material comprising ores, concentrates and other materials. In particular, the process is a process integrated into one or more existing valuable element extraction processes.
Polymetallic orebodies or other feedstocks containing multiple valuable metals at lower grades are becoming increasingly attractive for resource companies to assess their potential for exploitation. However, to date there are far greater metallurgical challenges in the recovery and separation of such elements into commercially feasible concentrates or products. This is generally the case for ores containing valuable metals such as platinum group metals (PGMs), gold or silver, and other valuable base and rare metals such as nickel, cobalt, copper, rare earth elements (REE), yttrium and scandium, as well as uranium, thorium, manganese, zinc, cadmium, molybdenum, titanium, tin, and other minor elements such as vanadium, germanium and gallium.
Selection of the process route for recovery and separation of valuable elements from both sulphate and chloride pregnant leach solution (PLS) for any specific application is driven largely by project-specific criteria such as end-product requirements, as well as ore and concentrate assay suite and mineralogy. Production of market-driven end-products, such as separate PMs, oxides, salts or other products, as well as mixed high-grade concentrates with particular impurity profiles may be required, for example.
The PGMs, gold, silver and other value elements are in some cases recovered from the chloride PLS by adsorbing these elements onto ion-exchange (IX) resins or other sorbent media and subsequently recovering the elements by elution, for example using a thiourea solution. PMs can be precipitated from the eluate using a caustic or ammoniacal solution to form one or more high-grade PM concentrate products for direct sale or refining, as described in International Patent Publication No. WO 99/60178. Alternatively, the loaded resin or sorbent can be incinerated directly to produce a high-grade PM concentrate product for refining, or may be shipped directly to the refinery.
However, in other cases, production of end products with certain targeted specifications may be required, whereby such specifications are best achieved via alternative methods.
Thus, the direct IX route described above is not always optimal for all feed and product types, such as for cases where the PLS contains elements or species at levels that may interfere with the IX adsorption process. An alternative process for the recovery and separation of precious metals and other valuable elements from PLS that meets the criteria for other feed and product types is therefore needed.
Moreover, additional valuable elements are contained in the leach process streams described in steps (i) and (iv) above, and these valuable elements may equally warrant recovery and/or recycling and/or separation into added-value products.
Alternative processes for the quantitative removal of additional base, rare and gangue elements from pressure leach residue, allowing for increased efficiency of further treatment of the solids for valuable metals recovery and/or recycling and/or separation of valuable metals such as platinum group metals (PGMs), gold or silver, and other valuable base and rare metals such as nickel, cobalt, copper, rare earth elements (REE), yttrium and scandium, as well as uranium, thorium, manganese, zinc, cadmium, molybdenum, titanium, tin, and other minor elements to produce saleable high-grade value metals and/or metal cathodes, powders, salts or precipitate products thereof would therefore be very useful. In particular, a process for the efficient removal of iron and other gangue elements from the process that are responsible for high consumption of costly reagents would be highly beneficial. Furthermore, removal of these gangue elements should decrease the mass flow for downstream treatment, and effectively remove potential reagent consumers in the optional heat treatment step and non-optional chlorination leach step.
Furthermore, there is a considerable range of feedstock materials for potential extraction of precious, base or rare elements that are either untreatable using current conventional technologies, or that respond poorly, or may require the specific flowsheet development, design and construction of a custom-built plant that may be too costly to justify the capital spend given the size and other characteristics of the particular resource. In all cases, the ultimate precious, base or rare metals recovery may be less than desirable. It would be highly commercially beneficial to have a process that accepts a wide variety of refractory or non-refractory material types as feed, with no or minimal modifications to the circuit from one feed type to the next.

Hydrometallurgical treatment process for extraction of precious, base and rare elements


A method and apparatus is disclosed that allows people to carry on unobtrusive phone conversations in business or other settings where it is either not possible or impolite to talk. In the system of FIG. 1, the telephone user one will listen in the same manner as with a regular telephone. However, he will not speak into the telephone microphone. User one instead employs a unit including a keyboard to enter the text corresponding to what he wants to say. The text is converted into a synthesized speech using TTS apparatus and a voice output is sent to the microphone of the phone apparatus. The telephone apparatus transmits the synthesized voice signal over a standard telephone line to a unit including a conventional telephone speaker 26 and telephone microphone. User two, the party using the telephone at the other end, listens to a synthesized voice, but user one listens to the actual voice of user two with the telephone speaker, unless user two is also using a system similar to that of user one. Handwritten text may also be used in the system by employing a computer with a character recognition program as an input. In such a case handwriting is converted into synthesized sound and inputted into the telephone microphone. The telephone system can be used by the hearing impaired without involving a third party human transcriber.

1. Field of the Invention
The present invention relates to telephone communication systems, and more particularly to integrated messaging and voice free telephony.
2. Background Art
In telephone communication there are times at which people desire to talk normally into the telephone mouthpiece but are inhibited to do so because they. will disturb other people who are nearby.
With presently available technology, when a telephone call needs to be made, the speaker has to either disturb others or leave the room and handle the call in a more private setting.
The present invention provides a method and apparatus that allows people to carry on unobtrusive phone conversations in business or other settings where it is either not possible or impolite to talk. Some examples would be in business meetings, large conference rooms, game stadiums, airplanes and the like. The present invention is particularly significant with the use of cellular telephones which may be operated in any setting.
The present invention also allows a hearing impaired or deaf person to communicate using the telephone. The apparatus can be used either in isolation or as a service to this community. The apparatus allows both calls to be made as well as received. Currently, this community uses a relay service to communicate with others. This type of service is done with human intervention and is slow and rather expensive. Our apparatus allows the hearing impaired person more control over the call and reduces his long term cost of using relay services.
Some examples of presently available background technology include "text to speech" (TTS) systems that convert text to sound such as IBM's "Eloquent TTS", IBM's "Virtual Voices", and Bell Laboratories "Text to Speech Synthesis". This technology is presently used to read text passages aloud. For example, using this technology, a person can listen to his e-mail while he is driving. The text to speech conversion can be done in real time in software with presently available computer CPUs such as the 166 MHz Pentium processors.
Another technology referred to as "speech recognition" is also presently available. IBM's "ViaVoice" is an example of this technology. Speech recognition systems technology convert spoken words into text.

Method and apparatus for a communication device for use by a hearing impaired/mute or deaf person or in silent environments

International Business Machines Corporation


A method for monitoring an exposure experienced by a patient during an examination with a magnetic resonance device having a transmitter device is provided. The method includes determining a coil power loss from measured amplitudes and phases of a first measuring device, and determining an overall transmitted power from voltage measurement values of the second measuring device. The method also includes determining a specific absorption rate (SAR) value describing a power entering a patient from the coil power loss and the overall transmitted power and comparing the SAR value with at least one limit value. A transmission operation of the transmitter device is terminated if the at least one limit value is exceeded.

The present embodiments relate to a method for monitoring an exposure experienced by a patient during an examination with a magnetic resonance device.
In magnetic resonance imaging, an excitation signal may be emitted via a high-frequency coil and excites nuclear spins aligned in a basic magnetic field. When this excitation decays, a magnetic resonance signal, from which a magnetic resonance image is generated, may be observed. High-frequency radiation generated using a corresponding transmitter device of the magnetic resonance device is used for the excitation.
The high-frequency radiation (e.g., a B1 field) is absorbed in the body of the patient under examination and is converted into heat. This absorption may be described by the specific absorption rate (SAR) in relation to the patient's mass. Various standardization bodies lay down rules for monitoring the SAR for correspondingly powerful magnetic resonance devices in order to counter harm to the patient caused by too high a power being input.
Magnetic resonance devices may use a single-channel high-frequency-power amplifier in a transmitter device (e.g., circularly polarized high-frequency coils with two power supply terminals), the amplitude relationships and phase relationships being constant at both power supply terminals (e.g., identical amplitudes and 90° phase difference in the case of circular polarization). Magnetic resonance devices, in which the high-frequency coil may be actuated via several transmission channels, have been proposed. A power amplifier is associated, for example, with each of the transmission channels, the amplitudes and phases for the various transmission channels or power supply terminals being freely selectable. Embodiments, in which the number of power amplifiers does not correspond to the number of transmission channels (e.g., one power amplifier supplies at least two transmission channels via a corresponding interconnection, or one combined power supply is provided with several of the at least two power amplifiers), may also be provided.
The high-frequency power absorbed in the patient is determined asPabs=Ptx−Ploss,where Pabs describes the power absorbed in the patient, Ptx describes the transmission power, and Ploss describes the coil power loss. The specific absorption rate (SAR) is thenSAR=Pabs/m where m corresponds to the mass of the irradiated region of the patient.
When single-channel transmitter devices are used, the coil power loss stands in a fixed relationship to the transmission power, so that the SAR may be formulated, as follows:SAR=k*Ptx.The factor k includes the efficiency and the mass.
For such single-channel transmitter devices, SAR monitoring and, consequently, monitoring of the patient's exposure during an examination may be enabled using broadband power measurement devices between the power amplifier and the power supply terminals (e.g., the high-frequency coil). Broadband may be that the measurement, in which the real-value amplitude of the voltage may be measured, is not limited to a particular frequency band (e.g., a frequency band around the magnetic resonance frequency), but all frequencies may be measured. Broadband measuring devices of this type enable the transmission amplitude (e.g., a voltage amplitude) to be determined, from which the overall transmitted power follows, Ptx. With knowledge of the factor k and with correspondingly fast scanning, online monitoring during the transmission procedures may be provided.
In multi-channel transmission (e.g., parallel transmission, pTX), the factor k is no longer constant, but depends on the respective amplitude relationships and phase relationships. Consequently, a single measurement of transmission amplitudes is no longer sufficient.
In order to implement monitoring of patient exposure, broadband measuring devices may still be used and fixed factors for the amplitude relationships and phase relationships that are most harmful with respect to the specific absorption rate may be provided. This is disadvantageous in that performance is severely restricted if the actual coil power loss is significantly larger than the minimum possible that is to be applied without knowledge of the specific amplitude relationships and phase relationships for complying with SAR limit values.
In one embodiment, narrowband measuring devices that also supply phase information about the voltage as measured values in addition to the transmission amplitude may be used. The excitation pulses that are to effect the high-frequency excitation of the nuclear spins may be calculated (e.g., in a complex simulation), and a setpoint/actual-value comparison for online monitoring may be performed. The disadvantage of this variant is that independent SAR monitoring online by the actuation signal (e.g., the previously calculated excitation pulses) is no longer possible. Instead, only fixed, previously calculated pulse shapes with a prior SAR check may be used. Pulses other than the previously calculated excitation pulses may not be used, even if the pulses would not themselves cause the SAR to be exceeded. A long, safety-related chain is provided for SAR monitoring (e.g., the SAR prior calculation for each excitation pulse, the transfer of large amounts of data for the pulse shapes to a monitoring device, the comparison of the emitted excitation pulses with the expected excitation pulses, and complex error analyses in the case of small deviations from the setpoint signal).
DE 10 2008 063 630 A1 relates to a method for controlling a high-frequency transmitter device of a magnetic resonance tomography system with a transmitting antenna system with a plurality of transmission channels during a magnetic resonance measurement of an examination subject. A reference scatter parameter matrix of the transmitting antenna system is determined in the non-loaded state, and a subject-specific scatter parameter matrix of the transmitting antenna system is determined in a state loaded with the examination subject. Transmission amplitude vectors are determined on a time-dependent basis, and represent the high-frequency voltage amplitudes on the individual transmission channels. On the basis of the subject-specific scatter parameter matrix, the reference scatter parameter matrix and the transmission amplitude vectors, absorbed high-frequency power values are determined in the examination subject at particular transmission times and based on a plurality of the determined high-frequency power values a number of control values are formed. The high-frequency transmitter device is deactivated whenever a control value exceeds a predefined limit control value.

Method for monitoring patient exposure in a magnetic resonance device


An interleave control device using a nonvolatile ferroelectric memory is disclosed. More specifically, a memory interleave structure using a nonvolatile ferroelectric register configured to individually control interleaves of banks is disclosed. In an embodiment of the present invention, interleaves of each bank can be individually controlled using a single nonvolatile ferroelectric memory chip, a multi-bank nonvolatile ferroelectric memory chip or a multi-bank interleave nonvolatile ferroelectric memory chip.

1. Field of the Invention
The present invention relates to an interleave control device using a nonvolatile ferroelectric memory, and more specifically, to an interleave control device configured to control interleaves of each bank individually in a signal FeRAM chip, a multi-bank FeRAM chip or a multi-bank interleave FeRAM chip, thereby reducing a row access latency.
2. Description of the Prior Art
Generally, a ferroelectric randaom access memory (hereinafter, referred to as 'FeRAM') has attracted considerable attention as next generation memory device because it has a data processing speed as fast as a Dynamic Random Access Memory DRAM and conserves data even after the power is turned off.
The FeRAM having structures similar to the DRAM includes the capacitors made of a ferroelectric substance, so that it utilizes the characteristic of a high residual polarization of the ferroelectric substance in which data is not low even after eliminating an electric field applied thereto.
FIG. 1 is a characteristic curve illustrating a hysteresis loop of a general ferroelectric substance.
A polarization induced by an electric field does not vanish but remains at a certain portion ('d' or 'a' state) even after the electric field is cleared due to existence of a residual (or spontaneous) polarization. The FeRAM cell is used as a memory device by corresponding the 'd' and 'a' states to binary values of '1' and '0', respectively.
FIG. 2 is a structural diagram illustrating a unit cell of the conventional FeRAM device.
The unit cell of the conventional FeRAM is provided with a bitline BL arranged in one direction and a wordline WL arranged in another direction vertical to the bitline BL. A plateline PL is arranged parallel to the wordline WL and spaced at a predetermined interval.
The unit cell is also provided with a transistor T1 having a gate connected to an adjacent wordline WL and a source connected to an adjacent bitline BL. A drain of the transistor T1 is connected to one terminal of a ferroelectric capacitor FC0. The other terminal of the ferroelectric capacitor FC0 is connected to the plateline PL.
The data input/output operation of the conventional FeRAM is now described referring to FIGS. 3a and 3b.
FIG. 3a is a timing diagram illustrating a write mode of the conventional FeRAM.
At an active period, a chip enable signal CSB applied externally transits from a high to low level. If a write enable signal WEB simultaneously transits from a high to low level, the array is enabled to start a write mode. Thereafter, when an address is decoded in the write mode, a pulse applied to a corresponding wordline transits from a low to high level, thereby selecting the cell.
In the interval where the wordline WL is held at a high level, a high signal of a predetermined interval and a low signal of a predetermined signal are sequentially applied to a corresponding plateline PL. In order to write binary logic values '1' or '0' in the selected cell, 'high' or 'low' signals synchronized in the write enable signal are applied to a corresponding bitline BL. Here, a sense amplifier enable signal SEN is maintained at a high level.
In other words, when a high signal is applied to a bitline BL and a low signal is applied to a plateline PL, a logic value "1" is written as input data DIN in the ferroelectric capacitor FC0. When a low signal is applied to a bitline BL and a high signal is applied to a plateline PL, a logic value "0" is written as input data DIN in the ferroelectric capacitor FC0.
FIG. 3b is a timing diagram illustrating a read mode of the FeRAM.
At an active period, a chip enable signal CSB externally transits from a high to low level. All bitlines BL are equalized to a low level by an equalization signal before selection of a required wordline WL.
After each bitline BL is inactivated and an address is decoded, the required wordline WL depending on the decoded address is transited from a low to high level by the decoded address, thereby selecting a corresponding unit cell. A high signal is applied to a plateline PL of the selected cell to destroy data Qs corresponding to the logic value "1" stored in the FeRAM.
If the logic value "0" is stored in the FeRAM, its corresponding data Qns will not be destroyed. In this way, the destroyed and non-destroyed data output different values, respectively, according to the above-described hysteresis loop characteristics.
In other words, as shown in the hysteresis loop of FIG. 1, the state moves from the 'd' to 'f' when the data is destroyed while the state moves from 'a' to 'f' when the data is not destroyed. As a result, the sense amplifier is enabled by the sense amplifier enable signal SEN after the lapse of a predetermined time. When the data is destroyed, the sense amplifier outputs a logic value "1" as output data DOUT. However, when the data is not destroyed, the sense amplifier outputs a logic value "0" as output data DOUT.
After the sense amplifier amplifies the data, the data should be recovered into the original data. Accordingly, the plateline PL is inactivated from a high to low level at the state whereby a 'high' signal is applied to the required wordline WL.
FIG. 4 is a blcok diagram illustrating a conventional unit memory bank including a nonvolatile ferroelectric memory.
The conventional unit memory bank comprises a row selection unit 1, a column selection unit 2, a cell array block 3, a sense amplifier page buffer unit 4 and a data I/O buffer 5.
The row selection unit 1 selects a corresponding row address of inputted row addresses to output the selected row address. The cell array block 3 activates a row by a corresponding row address applied from the row selection unit 1. Data corresponding to the selected row address is outputted into the sense amplifier page buffer unit 4, and then amplified and stored therein.
The column selection unit 2 selects a corresponding column address among inputted column addresses to output the selected address into the sense amplifier page buffer unit 4. The sense amplifier page buffer unit 4 outputs data having a byte or a word width out of data stored when a corresponding column address is activated into the data I/O buffer 5. The data I/O buffer 5 buffers data from the sense amplifier page buffer unit 4.
Since a column address is a page address in the conventional unit memory bank, an extra sensing process is not required to access data. The data stored in the sense amplifier page buffer unit 4 is outputted without being sensed.
A row address further senses and amplifies data stored in a cell when data is accessed, and maintains data in a sense amplifier. Since a restore time (precharge time) is added to a row access time when data is accessed between row addresses, a longer access time is required. As a result, a row address requires a relatively longer data access time than a column address.
In the conventional unit memory bank, however, since the access time is ineffectively controlled regardless of kinds of addresses when data is accessed, the reliability of memory chips is degraded.
As a result, a device configured to perform an interleave operation using the above-described nonvolatile ferroelectric memory has been much required to reduce an unnecessary data access time and preserve stored program data even when power is off.

Interleave control device using nonvolatile ferroelectric memory


System and methods for measuring parameters of a battery system using a battery sensing circuit are presented. In certain embodiments, the systems and methods allow a vehicle battery sensing circuit and/or other associated system to measure a compensation parameter. The compensation parameter may be utilized by the battery sensing circuit and/or other associated system in measuring other parameters relating to the battery system including cell voltages.

Passenger vehicles often include electric batteries for operating a vehicle's electrical and drivetrain systems. For example, vehicles commonly include a 12V lead-acid automotive battery configured to supply electric energy to vehicle starter systems (e.g., a starter motor), lighting systems, and/or ignition systems. In electric, fuel cell ("FC"), and/or hybrid vehicles, a high voltage ("HV") battery system may be used to power electric drivetrain components of the vehicle (e.g., electric drive motors and the like).
A battery system may be associated with a battery sensing circuit. The battery sensing circuit may be configured to perform one or more measurements relating to the battery system and/or report a state of the battery system. In certain circumstances, sensing paths between the battery sensing circuit and the battery system may have variable resistances. These variable resistances may decrease the accuracy of measurements performed by the battery sensing circuit which, in turn, may adversely affect battery system performance.

Battery sensing circuit path resistance compensation systems and methods


Methods for treating psychiatric disorders include intracranial administration of a therapeutically effective amount of a neurotoxin, such as a botulinum toxin type A, to a human patient.

The present invention relates to methods for treating neuropsychiatric disorders. In particular, the present invention relates to methods for treating neuropsychiatric disorders by intracranial administration of a neurotoxin.
Neuropsychiatric Disorders
A neuropsychiatric disorder is a neurological disturbance that is typically labeled according to which of the four mental faculties are affected. For example, one group includes disorders of thinking and cognition, such as schizophrenia and delirium; a second group includes disorders of mood, such as affective disorders and anxiety; a third group includes disorders of social behavior, such as character defects and personality disorders; and a fourth group includes disorders of learning, memory, and intelligence, such as mental retardation and dementia.
Accordingly, neuropsychiatric disorders encompass schizophrenia, delirium, Alzheimer's disease, depression, mania, attention deficit disorders, drug addiction, dementia, agitation, apathy, anxiety, psychoses, post-traumatic stress disorders, irritability, and disinhibition.
Schizophrenia
Schizophrenia is a disorder that affects about one percent of the world population. Three general symptoms of schizophrenia are often referred to as positive symptoms, negative symptoms, and disorganized symptoms. Positive symptoms may include delusions (abnormal beliefs), hallucinations (abnormal perceptions), and disorganized thinking. Hallucinations may be auditory, visual, olfactory, or tactile.
Disorganized thinking may manifest itself in schizophrenic patients by disjointed speech and the inability to maintain logical thought processes. Negative symptoms may represent the absence of normal behavior. Negative symptoms include emotional flatness or lack of expression and may be characterized by social withdrawal, reduced energy, reduced motivation, and reduced activity. Catatonia may also be associated with negative symptoms of schizophrenia. The symptoms of schizophrenia should continuously persist for a duration of about six months in order for the patient to be diagnosed as schizophrenic. Based on the types of symptoms a patient reveals, schizophrenia may be categorized into subtypes including catatonic schizophrenia, paranoid schizophrenia, and disorganized schizophrenia.
The brains of schizophrenic patients are often characterized by enlarged lateral ventricles, which may be associated with a reduction of the hippocampus and an enhancement in the size of the basal ganglia. Schizophrenic patients may also have enlarged third ventricles and widening of sulci. These anatomical characterizations point to a reduction in cortical tissue.
Although the cause of schizophrenia is not precisely known, there are several hypotheses regarding the causes. One hypothesis is that schizophrenia is associated with increased dopamine activity within the cortical and limbic areas of the brain. This hypothesis is supported by the therapeutic effects achieved by antipsychotic drugs that block certain dopamine receptors. In addition, amphetamine use may be associated with schizophrenia-like psychotic symptoms; amphetamines act on dopamine receptors.
Examples of antipsychotic drugs that may be used to treat schizophrenic patients include phenothizines, such as chlorpromazine and trifluopromazine; thioxanthenes, such as chlorprothixene; fluphenazine; butyropenones, such as haloperidol; loxapine; mesoridazine; molindone; quetiapine; thiothixene; trifluoperazine; perphenazine; thioridazine; risperidone; dibenzodiazepines, such as clozapine; and olanzapine. Although these agents may relieve the symptoms of schizophrenia, their administration may also result in undesirable side effects including Parkinson's disease-like symptoms (tremor, muscle rigidity, loss of facial expression); dystonia; restlessness; tardive dyskinesia; weight gain; skin problems; dry mouth; constipation; blurred vision; drowsiness; slurred speech; agranulocytosis.
Antipsychotic drugs are believed to primarily act on dopamine receptors with a particular affinity for the D2, D3, and D4 receptors. It is believed that the D3 and D4 receptors may have a higher affinity for certain antipsychotics, such as clozapine, as compared to the others. Brains of schizophrenic patients appear to have increased numbers of D2 receptors in the caudate nucleus, the nucleus accumbens (ventral striatum), and the olfactory tubercule.
Dopamine neurons may be organized into four major subsystems: the tuberoinfundibular system; the nigrostriatal system; the mesolimbic system; and the mesocortical system. The tuberoinfundibular dopaminergic system originates in cell bodies of the arcuate nucleus of the hypothalamus and projects to the pituitary stalk. This system may be involved in secondary neuroendocrine abnormalities in schizophrenia. The nigrostriatal dopaminergic system originates in the substantia nigra and projects primarily to the putamen and the caudate nucleus. The mesolimbic dopaminergic system originates in the ventral tegmental area and projects to the mesial component of the limbic system, which includes the nucleus accumbens, the nuclei of the stria terminalis, parts of the amygdala and hippocampus, the lateral septal nuclei, and the mesial frontal, anterior cingulate, and entorhinal cortex. The nucleus accumbens is a convergence site from the amygdala, hippocampus, entorhinal area, anterior cingulate area, and parts of the temporal lobe. Thus, the mesolimbic dopaminergic projection may modulate and transform information conveyed from the nucleus accumbens to the septum, hypothalamus, anterior cingulate area, and frontal lobes, and overactive modulation of the nucleus accumbens output to these areas may contribute to positive symptoms associated with schizophrenia. The mesocortical dopaminergic system originates in the ventral tegmental area and projects to the neocortex and heavily to the prefrontal cortex. This component may be important in the negative symptoms of schizophrenia.
The ventral tegmental area, which is the source of origination of the dopaminergic input to the nucleus accumbens, receives a cholinergic input from the pedunculopontine nuclei of the brainstem. The pedunculopontine nucleus provides an excitatory cholinergic input to the ventral tegmental area (Clarke et al., Innervation of substantia nigra neurons by cholinergic afferents from the pedunculopontine nucleus in the rat. Neuroanatomical and electrophysiological evidence, Neuroscience, 23:1011–1019,1987). It has been reported that schizophrenic patients have an increased number of cholinergic neurons in the pedunculopontine nuclei (Garcia-Rill et al., Mesopontine neurons in schizophrenia, Neuroscience, 66(2):321–335, 1995). However, these results were not confirmed in one study (German et al., Mesopontine cholinergic and non-cholinergic neurons in schizophrenia, Neuroscience, 94(1):33–38, 1999).
Mania
Mania is a sustained form of euphoria that affects millions of people in the United States who suffer from depression. Manic episodes may be characterized by an elevated, expansive, or irritable mood lasting several days, and is often accompanied by other symptoms, such as, overactivity, overtalkativeness, social intrusiveness, increased energy, pressure of ideas, grandiosity, distractibility, decreased need for sleep, and recklessness. Manic patients may also experience delusions and hallucinations.
Depressive disorders may involve serotonergic and noradrenergic neuronal systems based on current therapeutic regimes that target serotonin and noradrenalin receptors. Serotonergic pathways originate from the raphe nuclei of the brain stem, and noradrenergic pathways originate from the locus ceruleus. Decreasing the electrical activity of neurons in the locus ceruleus may be associated with the effects mediated by depression medications.
Mania likely results from an imbalance in the chemical messengers within the brain. It has been proposed that mania may be attributed to a decline in acetylcholine. A decline in acetylcholine may result in a relatively greater level of norepinephrine. Administering phosphotidyl choline has been reported to alleviate the symptoms of mania.
Anxiety
Anxiety disorders may affect between approximately ten to thirty percent of the population, and may be characterized by frequent occurrence of symptoms of fear including arousal, restlessness, heightened responsiveness, sweating, racing heart, increased blood pressure, dry mouth, a desire to run or escape, and avoidance behavior. Generalized anxiety persists for several months, and is associated with motor tension (trembling, twitching, muscle aches, restlessness); autonomic hyperactivity (shortness of breath, palpitations, increased heart rate, sweating, cold hands), and vigilance and scanning (feeling on edge, exaggerated startle response, difficult in concentrating).
Benzodiazepines, which enhance the inhibitory effects of the gamma aminobutyric acid (GABA) type A receptor, are frequently used to treat anxiety. Buspirone is another effective anxiety treatment.
Alzheimer's Disease
Alzheimer's disease is a degenerative brain disorder characterized by cognitive and noncognitive neuropsychiatric symptoms, which accounts for approximately 60% of all cases of dementia for patients over 65 years old. Psychiatric symptoms are common in Alzheimer's disease, with psychosis (hallucinations and delusions) present in approximately fifty percent of affected patients. Similar to schizophrenia, positive psychotic symptoms are common in Alzheimer's disease. Delusions typically occur more frequently than hallucinations. Alzheimer's patients may also exhibit negative symptoms, such as disengagement, apathy, diminished emotional responsiveness, loss of volition, and decreased initiative.
Alzheimer's disease patients may also exhibit enlargement of both lateral and third ventricles as well as atrophy of temporal structures.
It is possible that the psychotic symptoms of Alzheimer's disease may involve a shift in the concentration of dopamine or acetylcholine, which may augment a dopaminergic/cholinergic balance, thereby resulting in psychotic behavior. For example, it has been proposed that an increased dopamine release may be responsible for the positive symptoms of schizophrenia. This may result in a positive disruption of the dopaminergic/cholinergic balance. In Alzheimer's disease, the reduction in cholinergic neurons effectively reduces acetylcholine release resulting in a negative disruption of the dopaminergic/cholinergic balance. Indeed, antipsychotic agents that are used to relieve psychosis of schizophrenia are also useful in alleviating psychosis in Alzheimer's patients.
Several of the symptoms associated with the neuropsychiatric disorders appear to be, at least in part, attributed to hyperexcitability of neurons within the brain. This interpretation is supported by the pharmacology associated with current therapeutic treatments. For example, many of the antipsychotic treatments are directed to interfering with binding of dopamine to dopamine receptors, as discussed above. Similarly, mania and anxiety are often treated with benzodiazepines, which enhance the inhibitory effects of GABA-mediated inhibition. U.S. Pat. No. 6,306,403 discloses intracranial administration of a botulinum toxin to treat various movement disorders. Additionally, it is known that stereotactic procedures can be used to administer a pharmaceutical to a discrete brain area to successfully alleviate a parkinsonian tremor. See e.g. Pahapill P.A., et al., Tremor arrest with thalamic microinjections of muscimol in patients with essential tremor, Ann Neur 46(2); 249–252 (1999).
However, current therapeutic treatments result in several adverse side-effects. These side-effects may be attributed to the fact that the pharmaceutical agents are typically administered systemically, and therefore, the agents have a relatively non-specific action with respect to the various biological systems of the patient. For example, administration of benzodiazepines may result in sedation and muscle relaxation. In addition, tolerance may develop to these drugs, as well as withdrawal seizures may develop. Current therapeutic strategies also require consistent and repeated administration of the agents to achieve the desired effects.
Botulinum Toxin
The genus Clostridium has more than one hundred and twenty seven species, grouped according to their morphology and functions. The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of a commercially available botulinum toxin type A (purified neurotoxin complex)1 is a LD50 in mice (i.e. 1 unit). One unit of BOTOX® contains about 50 picograms (about 56 attomoles) of botulinum toxin type A complex. Interestingly, on a molar basis, botulinum toxin type A is about 1.8 billion times more lethal than diphtheria, about 600 million times more lethal than sodium cyanide, about 30 million times more lethal than cobra toxin and about 12 million times more lethal than cholera. Singh, Critical Aspects of Bacterial Protein Toxins, pages 63–84 (chapter 4) of Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New York (1976) (where the stated LD50 of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 20 grams each. 1 Available from Allergan, Inc., of Irvine, Calif. under the tradename BOTOX® in 100 unit vials)
Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B. Additionally, botulinum toxin type B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD50 for botulinum toxin type A. Moyer E et al., Botulinum Toxin Type B: Experimental and Clinical Experience, being chapter 6, pages 71–85 of "Therapy With Botulinum Toxin", edited by Jankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinumtoxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Regardless of serotype, the molecular mechanism of toxin intoxication appears to be similar and to involve at least three steps or stages. In the first step of the process, the toxin binds to the presynaptic membrane of the target neuron through a specific interaction between the heavy chain, H chain, and a cell surface receptor; the receptor is thought to be different for each type of botulinum toxin and for tetanus toxin. The carboxyl end segment of the H chain, HC, appears to be important for targeting of the toxin to the cell surface.
In the second step, the toxin crosses the plasma membrane of the poisoned cell. The toxin is first engulfed by the cell through receptor-mediated endocytosis, and an endosome containing the toxin is formed. The toxin then escapes the endosome into the cytoplasm of the cell. This step is thought to be mediated by the amino end segment of the H chain, HN, which triggers a conformational change of the toxin in response to a pH of about 5.5 or lower. Endosomes are known to possess a proton pump which decreases intra-endosomal pH. The conformational shift exposes hydrophobic residues in the toxin, which permits the toxin to embed itself in the endosomal membrane. The toxin (or at a minimum the light chain) then translocates through the endosomal membrane into the cytoplasm.
The last step of the mechanism of botulinum toxin activity appears to involve reduction of the disulfide bond joining the heavy chain, H chain, and the light chain, L chain. The entire toxic activity of botulinum and tetanus toxins is contained in the L chain of the holotoxin; the L chain is a zinc (Zn++) endopeptidase which selectively cleaves proteins essential for recognition and docking of neurotransmitter-containing vesicles with the cytoplasmic surface of the plasma membrane, and fusion of the vesicles with the plasma membrane. Tetanus neurotoxin, botulinum toxin types B, D, F, and G cause degradation of synaptobrevin (also called vesicle-associated membrane protein (VAMP)), a synaptosomal membrane protein. Most of the VAMP present at the cytoplasmic surface of the synaptic vesicle is removed as a result of any one of these cleavage events. Botulinum toxin serotype A and E cleave SNAP-25. Botulinum toxin serotype C1 was originally thought to cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Each of the botulinum toxins specifically cleaves a different bond, except botulinum toxin type B (and tetanus toxin) which cleave the same bond.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. A botulinum toxin type A complex has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus and hemifacial spasm. Non-type A botulinum toxin serotypes apparently have a lower potency and/or a shorter duration of activity as compared to botulinum toxin type A. Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months.
Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. Botulinum toxin types B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally, botulinum toxin type C1 has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes. Apparently, a substrate for a botulinum toxin can be found in a variety of different cell types. See e.g. Biochem, J 1;339 (pt 1):159–65:1999, and Mov Disord, 10(3):376:1995 (pancreatic islet B cells contains at least SNAP-25 and synaptobrevin).
The molecular weight of the botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum toxin types B and C1 is apparently produced as only a 700 kD or 500 kD complex. Botulinum toxin type D is produced as both 300 kD and 500 kD complexes. Finally, botulinum toxin types E and F are produced as only approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A and C Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, J Neurochem 51(2);522–527:1988) CGRP, substance P and glutamate (Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks Glutamate Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J. Biochem 165;675–681:1897. Thus, when adequate concentrations are used, stimulus-evoked release of most neurotransmitters is blocked by botulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterization of Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373–1412 at 1393; Bigalke H., et al., Botulinum A Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons in Culture, Brain Research 360;318–324:1985; Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the release of [3H]Noradrenaline and [3H]GABA From Rat Brain Homogenate, Experientia 44;224–226:1988, Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Release and Uptake of Various Transmitters, as Studied with Particulate Preparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 316;244–251:1981, and; Jankovic J. et al., Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 5.
Botulinum toxin type A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known procedures. All the botulinum toxin serotypes are initially synthesized as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum toxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. In contrast, botulinum toxin serotypes C1, D and E are synthesized by nonproteolytic strains and are therefore typically unactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for example, the botulinum toxin type B serotype only cleave a portion of the toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture. Therefore, a certain percentage of any preparation of, for example, the botulinum toxin type B toxin is likely to be inactive, possibly accounting for the known significantly lower potency of botulinum toxin type B as compared to botulinum toxin type A. The presence of inactive botulinumtoxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy. Additionally, it is known that botulinum toxin type B has, upon intramuscular injection, a shorter duration of activity and is also less potent than botulinum toxin type A at the same dose level.
High quality crystalline botulinum toxin type A can be produced from the Hall A strain of Clostridium botulinum with characteristics of >3×107 U/mg, an A260/A278 of less than 0.60 and a distinct pattern of banding on gel electrophoresis. The known Shantz process can be used to obtain crystalline botulinum toxin type A, as set forth in Shantz, E. J., et al, Properties and use of Botulinum toxin and Other Microbial Neurotoxins in Medicine, Microbiol Rev. 56;80–99:1992. Generally, the botulinum toxin type A complex can be isolated and purified from an anaerobic fermentation by cultivating Clostridium botulinum type A in a suitable medium. The known process can also be used, upon separation out of the non-toxin proteins, to obtain pure botulinum toxins, such as for example: purified botulinum toxin type A with an approximately 150 kD molecular weight with a specific potency of 1–2×108 LD50 U/mg or greater; purified botulinum toxin type B with an approximately 156 kD molecular weight with a specific potency of 1–2×108 LD50 U/mg or greater, and; purified botulinum toxin type F with an approximately 155 kD molecular weight with a specific potency of 1–2×107 LD50 U/mg or greater.
Botulinum toxins and/or botulinum toxin complexes can be obtained from List Biological Laboratories, Inc., Campbell, Calif.; the Centre for Applied Microbiology and Research, Porton Down, U.K.; Wako (Osaka, Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals of St Louis, Mo.
Pure botulinum toxin is so labile that it is generally not used to prepare a pharmaceutical composition. Furthermore, the botulinum toxin complexes, such as the toxin type A complex are also extremely susceptible to denaturation due to surface denaturation, heat, and alkaline conditions. Inactivated toxin forms toxoid proteins which may be immunogenic. The resulting antibodies can render a patient refractory to toxin injection.
As with enzymes generally, the biological activities of the botulinum toxins (which are intracellular peptidases) is dependant, at least in part, upon their three dimensional conformation. Thus, botulinum toxin type A is detoxified by heat, various chemicals surface stretching and surface drying. Additionally, it is known that dilution of the toxin complex obtained by the known culturing, fermentation and purification to the much, much lower toxin concentrations used for pharmaceutical composition formulation results in rapid detoxification of the toxin unless a suitable stabilizing agent is present. Dilution of the toxin from milligram quantities to a solution containing nanograms per milliliter presents significant difficulties because of the rapid loss of specific toxicity upon such great dilution. Since the toxin may be used months or years after the toxin containing pharmaceutical composition is formulated, the toxin can stabilized with a stabilizing agent such as albumin and gelatin.
A commercially available botulinum toxin containing pharmaceutical composition is sold under the trademark BOTOX® (available from Allergan, Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxin type A complex, albumin and sodium chloride packaged in sterile, vacuum-dried form. The botulinum toxin type A is made from a culture of the Hall strain of Clostridium botulinum grown in a medium containing N-Z amine and yeast extract. The botulinum toxin type A complex is purified from the culture solution by a series of acid precipitations to a crystalline complex consisting of the active high molecular weight toxin protein and an associated hemagglutinin protein. The crystalline complex is re-dissolved in a solution containing saline and albumin and sterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-dried product is stored in a freezer at or below −5° C. BOTOX® can be reconstituted with sterile, non-preserved saline prior to intramuscular injection. Each vial of BOTOX® contains about 100 units (U) of Clostridium botulinum toxin type A purified neurotoxin complex, 0.5 milligrams of human serum albumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative.
To reconstitute vacuum-dried BOTOX®, sterile normal saline without a preservative; (0.9% Sodium Chloride Injection) is used by drawing up the proper amount of diluent in the appropriate size syringe. Since BOTOX® may be denatured by bubbling or similar violent agitation, the diluent is gently injected into the vial. For sterility reasons BOTOX® is preferably administered within four hours after the vial is removed from the freezer and reconstituted. During these four hours, reconstituted BOTOX® can be stored in a refrigerator at about 2° C. to about 8° C. Reconstituted, refrigerated BOTOX® has been reported to retain its potency for at least about two weeks. Neurology, 48:249–53:1997.
It has been reported that botulinum toxin type A has been used in clinical settings as follows:
(1) about 75–125 units of BOTOX® per intramuscular injection (multiple muscles) to treat cervical dystonia;
(2) 5–10 units of BOTOX® per intramuscular injection to treat glabellar lines (brow furrows) (5 units injected intramuscularly into the procerus muscle and 10 units injected intramuscularly into each corrugator supercilii muscle);
(3) about 30–80 units of BOTOX® to treat constipation by intrasphincter injection of the puborectalis muscle;
(4) about 1–5 units per muscle of intramuscularly injected BOTOX® to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.
(5) to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1–5 units of BOTOX®, the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. amount of diopter correction desired).
(6) to treat upper limb spasticity following stroke by intramuscular injections of BOTOX® into five different upper limb flexor muscles, as follows:
(a) flexor digitorum profundus: 7.5 U to 30 U
(b) flexor digitorum sublimus: 7.5 U to 30 U
(c) flexor carpi ulnaris: 10 U to 40 U
(d) flexor carpi radialis: 15 U to 60 U
(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX® by intramuscular injection at each treatment session.
(7) to treat migraine, pericranial injected (injected symmetrically into glabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX® has showed significant benefit as a prophylactic treatment of migraine compared to vehicle as measured by decreased measures of migraine frequency, maximal severity, associated vomiting and acute medication use over the three month period following the 25 U injection.
Additionally, intramuscular botulinum toxin has been used in the treatment of tremor in patients with Parkinson's disease, although it has been reported that results have not been impressive. Marjama-Jyons, J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging 16(4);273–278:2000.
It is known that botulinum toxin type A can have an efficacy for up to 12 months (European J. Neurology 6 (Supp 4): S11114 S1150:1999), and in some circumstances for as long as 27 months. The Laryngoscope 109:1344–1346:1999. However, the usual duration of an intramuscular injection of Botox® is typically about 3 to 4 months.
The success of botulinum toxin type A to treat a variety of clinical conditions has led to interest in other botulinum toxin serotypes. Two commercially available botulinum type A preparations for use in humans are BOTOX® available from Allergan, Inc., of Irvine, Calif., and Dysport® available from Beaufour Ipsen, Porton Down, England. A Botulinum toxin type B preparation (MyoBloc®) is available from Elan Pharmaceuticals of San Francisco, Calif.
In addition to having pharmacologic actions at the peripheral location, botulinum toxins may also have inhibitory effects in the central nervous system. Work by Weigand et al, Nauny-Schmiedeberg's Arch. Pharmacol. 1976; 292,161–165, and Habermann, Nauny-Schmiedeberg's Arch. Pharmacol. 1974; 281, 47–56 showed that botulinum toxin is able to ascend to the spinal area by retrograde transport. As such, a botulinum toxin injected at a peripheral location, for example intramuscularly, may be retrograde transported to the spinal cord.
U.S. Pat. No. 5,989,545 discloses that a modified clostridial neurotoxin or fragment thereof, preferably a botulinum toxin, chemically conjugated or recombinantly fused to a particular targeting moiety can be used to treat pain by administration of the agent to the spinal cord.
Acetylcholine
Typically only a single type of small molecule neurotransmitter is released by each type of neuron in the mammalian nervous system. The neurotransmitter acetylcholine is secreted by neurons in many areas of the brain, but specifically by the large pyramidal cells of the motor cortex, by several different neurons in the basal ganglia, by the motor neurons that innervate the skeletal muscles, by the preganglionic neurons of the autonomic nervous system (both sympathetic and parasympathetic), by the postganglionic neurons of the parasympathetic nervous system, and by some of the postganglionic neurons of the sympathetic nervous system. Essentially, only the postganglionic sympathetic nerve fibers to the sweat glands, the piloerector muscles and a few blood vessels are cholinergic as most of the postganglionic neurons of the sympathetic nervous system secret the neurotransmitter norepinephine. In most instances acetylcholine has an excitatory effect. However, acetylcholine is known to have inhibitory effects at some of the peripheral parasympathetic nerve endings, such as inhibition of heart rate by the vagal nerve.
The efferent signals of the autonomic nervous system are transmitted to the body through either the sympathetic nervous system or the parasympathetic nervous system. The preganglionic neurons of the sympathetic nervous system extend from preganglionic sympathetic neuron cell bodies located in the intermediolateral horn of the spinal cord. The preganglionic sympathetic nerve fibers, extending from the cell body, synapse with postganglionic neurons located in either a paravertebral sympathetic ganglion or in a prevertebral ganglion. Since, the preganglionic neurons of both the sympathetic and parasympathetic nervous system are cholinergic, application of acetylcholine to the ganglia will excite both sympathetic and parasympathetic postganglionic neurons.
Acetylcholine activates two types of receptors, muscarinic and nicotinic receptors. The muscarinic receptors are found in all effector cells stimulated by the postganglionic, neurons of the parasympathetic nervous system as well as in those stimulated by the postganglionic cholinergic neurons of the sympathetic nervous system. The nicotinic receptors are found in the adrenal medulla, as well as within the autonomic ganglia, that is on the cell surface of the postganglionic neuron at the synapse between the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic systems. Nicotinic receptors are also found in many nonautonomic nerve endings, for example in the membranes of skeletal muscle fibers at the neuromuscular junction.
Acetylcholine is released from cholinergic neurons when small, clear, intracellular vesicles fuse with the presynaptic neuronal cell membrane. A wide variety of non-neuronal secretory cells, such as, adrenal medulla (as well as the PC12 cell line) and pancreatic islet cells release catecholamines and parathyroid hormone, respectively, from large dense-core vesicles. The PC12 cell line is a clone of rat pheochromocytoma cells extensively used as a tissue culture model for studies of sympathoadrenal development. Botulinum toxin inhibits the release of both types of compounds from both types of cells in vitro, permeabilized (as by electroporation) or by direct injection of the toxin into the denervated cell. Botulinum toxin is also known to block release of the neurotransmitter glutamate from cortical synaptosomes cell cultures.
A neuromuscular junction is formed in skeletal muscle by the proximity of axons to muscle cells. A signal transmitted through the nervous system results in an action potential at the terminal axon, with activation of ion channels and resulting release of the neurotransmitter acetylcholine from intraneuronal synaptic vesicles, for example at the motor endplate of the neuromuscular junction. The acetylcholine crosses the extracellular space to bind with acetylcholine receptor proteins on the surface of the muscle end plate. Once sufficient binding has occurred, an action potential of the muscle cell causes specific membrane ion channel changes, resulting in muscle cell contraction. The acetylcholine is then released from the muscle cells and metabolized by cholinesterases in the extracellular space. The metabolites are recycled back into the terminal axon for reprocessing into further acetylcholine.
What is needed therefore is a method for effectively treating a neuropsychiatric disorder by administration of a pharmaceutical which has the characteristics of long duration of activity, low rates of diffusion out of a chosen intracranial target tissue where administered, and nominal systemic effects at therapeutic dose levels.

Botulinum toxin therapy for neuropsychiatric disorders


Embodiments of the present invention are directed to an illuminating optical device for forming a field of illumination. The optical device includes a first one-dimensional homogenizer positioned to homogenize a first dimension/axis of the field of illumination and a second one-dimensional homogenizer positioned to homogenize a second dimension/axis of the field of illumination.

To perform laser or photon material processing it is often desirable to create a field of uniform irradiation so that the process will produce consistent results within an area of a homogenous optical field. An unrequited goal of current technology is to create a beam homogenizer device capable of transforming a non-uniform light input into a field of homogenized illumination of, for example, rectangular shape with a high aspect ratio. In this context, a high aspect ratio rectangular field is a field having one dimension in the X direction/axis greater than three (3) times the dimension in the (perpendicular) Y direction/axis (or visa versa). High aspect ratio illuminated fields are also known as "long line" fields of illumination.
Long line fields of uniform illumination are useful in many applications such as, for example, photolithography, laser micromachining, laser annealing and other laser or optical surface treatment. Often, a uniformly illuminated mask is imaged using homogenized light onto a target using a projection lens. The mask may be scanned through a uniform field in Coordinated Opposing Motion (COM) to create large patterns in the target plane.
To produce a homogenized field of illumination, beam homogenizers are used. Beam homogenizers are devices that modify an incoming illumination beam such that the uniformity of the output illumination field is largely independent of the illumination uniformity of the raw laser beam (i.e., the beam is homogenized). When non-uniform laser illumination is input into a homogenizer, the beam is angularly or spatially (or both) mixed in a manner that allows a uniform field of illumination to be produced at the output.
There are several prior art methods of fabricating a beam homogenizer. For instance, a multi-lenslet array, known as fly's eye homogenizer, can be used to form a uniform homogenized illumination field. Another method utilizes a multi-segmented reflective or refractive surface to overlap portions of the incident beam to produce a uniform field. Yet another widely used homogenizer technique utilizes the kaleidoscope principle. Holographic devices may also be utilized to create uniformity and control beam divergence.
The prior art devices encounter difficulties creating simple and cost-effective high aspect ratio homogenized fields of illumination. For example, using a simple fly's eye device, to create a 5:1 aspect ratio field homogenized in the x and y directions, the dimensional aspect ratio of the individual fly's eye elements (i.e., ratio of element height to width) must be 25:1 in order to insure field uniformity to approximately ±5%. For 5% uniformity with a 100:1 aspect ratio homogenized field, the optical elements will have an aspect ratio of 500:1. Optical parts with such high aspect ratios are extremely difficult to manufacture. Although such mechanical aspect ratios can be moderated by introducing an anamorphic imaging device between the fly's eye and the mask, such an addition increases complexity to the system.
The nature of the non-uniformity of the raw beam dictates the number of homogenization elements that must be utilized in a given direction. For instance, for a fly's eye array with a 10×10 element array (or 100 elements), each element contributes 1% of the total power to the homogenized field. If the raw input beam possesses a 20% linear non-uniformity, then the aperture of each lenslet will be illuminated uniformly to better than 2% and the homogenized beam will be uniform to better than 2%. For a typical excimer laser application requiring +/−5% homogenization, empirical rules dictate the utilization of at least 6 elements per direction. Thus, for a 1:1 aspect ratio field, at least 36 fly's eye elements are required.
Moreover, the higher the aspect ratio, the more fly's eye homogenizer elements in the lens array are required for good homogenization. For example, to produce an illumination field having an aspect ratio of 5:1, and if the empirical rule for such a system designates 6 elements per direction, then a lens array of 180 elements are required to produce the homogenous optical field.
FIGS. 1A–1D illustrate this problem. For example, FIG. 1A illustrates a fly's-eye array required to create a uniform, 6×6 square field (i.e., aspect ratio of 1:1). If the empirical rule requiring 6 segments per direction is obeyed, the array will contain 36 elements. In FIG. 1B, a 2:1 aspect ratio field has been created. This geometric constraint requires that the number of elements in the vertical direction double and since the horizontal direction requires at least 6 elements for uniformity, 12 are needed for the vertical (i.e 6×12=72 total lenses). In FIG. 1C the problem gets worse—to create a 10:1 aspect ratio field, 60 segments are required in the vertical direction resulting in the total number of elements equaling 6×60=360. FIG. 1D illustrates the problem as it approaches a line field limit. In this case, 3600 elements are required (6×600). It becomes obvious to one of skill in the art that this design becomes prohibitively expensive and impractical to fabricate for this high aspect ratio beam.
Other problems exist for kaleidoscope homogenizers. To produce uniformity in two directions/axes (d1 and d2), a high aspect ratio forces the length of the kaleidoscope homogenizer to become exceedingly long, since the length of the kaleidoscope is proportional to the longest dimension (d1) of the homogenized field. FIGS. 2A through 2C illustrate this problem. For example (FIG. 2A), in a square field kaleidoscope homogenizer, the length of the kaleidoscope controls how many times the light is segmented. For example, for a square kaleidoscope with a given input dimension of, say, 1 cm, and an input cone angle of, say 5 degrees, the light beam may reflect three (3) times and the cone angle will be segmented 7 times per direction. This will typically produce good homogenization. For such a case, the kaleidoscope length will be 34.3 cm. However, for a 2:1 aspect ratio kaleidoscope (FIG. 2B) with the same short dimension of 1 cm, the 3 reflection condition requires the kaleidoscope to become twice as long (68.6 cm) since the long dimension is 2 cm and more path is required to achieve the segmenting. Now, for a 10:1 aspect ratio system (FIG. 2C) with a 1 cm short axis dimension, the length of the kaleidoscope becomes 343 cm. A 100:1 case is worse yet, resulting in a length of 3430 cm (or about 100 feet!). It becomes obvious to one of ordinary skill in the art, that for a high aspect ratio homogenizer, such a kaleidoscope design becomes impractical to implement and extremely cost prohibitive.
Furthermore, to achieve a high aspect ratio field with good laser coupling efficiency, one might expand the laser beam in one direction and compress it in the other. Since the divergence of the beam changes inversely proportionally to the expansion ratio, the divergence will increase beyond the acceptance numerical aperture (NA) of the lens if a great deal of compression is performed. Such homogenization system results in poor light utilization efficiency.
Because of the above noted problems, current long line illumination fields are implemented with only single axis homogenization. In some cases, the long axis would be homogenized while the short axis is left as spatially non-uniform as the original beam spatial intensity distribution in the relevant direction. In other cases, the full length cannot be accommodated, because the long axis of the field is not sufficiently uniform. In these applications, the laser beam is truncated so that only the more uniform section of the beam is used. This truncation lowers efficiency of the beam delivery system.

Methods and apparatuses for homogenizing light


A sensor device includes: a holder having an insertion hole; a probe having a proximal end to be inserted in the insertion hole and having a portion to be inserted in the insertion hole, a diameter of the portion of the probe to be inserted in the insertion hole being smaller than a hole diameter of the insertion hole; piezoelectric elements housed in the holder, configured to be brought into contact with the proximal end of the probe directly or indirectly, a vibration of the probe acting on the piezoelectric elements; an O-ring (prevention member) disposed in the insertion hole and holding the probe to prevent the probe from contacting the holder, the probe being configured such that a tip of the probe is pushed against a measurement object to detect a vibration of the measurement object.

As described in Japanese Patent No. 5933144, for example, a known sensor device detects vibrations by pressing a part of the sensor device against a measurement object. In this sensor device, a proximal end of a probe is inserted in a holder, and in this holder, a piezoelectric element is kept in contact with the proximal end of the probe. In this sensor device, when a tip of the probe is pressed against a measurement object so that vibrations of the measurement object are transferred to the probe. The vibrations transferred to the probe act on the piezoelectric element as pressure variations to thereby cause voltage fluctuations. A signal concerning the voltage fluctuations is sent to a signal processing circuit, and vibrations of the measurement object are detected.


Provided are therapeutic methods employing preparations of recombinant soluble Complement Receptor type 1 (sCR1) defined with respect to the distribution of sCR1 glycoforms. The methods are suitable for treatment of disease involving inflammation, inappropriate complement activation, and in thrombotic or shock state conditions. Preferred methods employ sCR1 glycoforms that are sialylated, have a pI of .ltoreq.5.1, or have a sialic acid:mannose molar ratio of .gtoreq.0.25.

The Complement System
Constituting about 10% of the globulins in normal serum, the complement system is composed of many different proteins that are important in the immune system's response to foreign antigens. The complement system becomes activated when its primary components are fragmented and the fragments, alone or with other proteins, activate additional complement proteins resulting in a proteolytic cascade. Activation of the complement system leads to increased vascular permeability, chemotaxis of phagocytic cells, activation of inflammatory cells, opsonization of foreign particles, direct killing of cells and tissue damage. Activation of the complement system may be triggered by antigen-antibody complexes (the classical pathway) or for example, by lipopolysaccharides present in cell walls of pathogenic bacteria (the alternative pathway).
The Membrane Bound Complement Receptor Type 1
Complement receptor type 1 (CR1) is present on the membranes of erythrocytes, monocytes/macrophages, granulocytes, B cells, some T cells, splenic follicular dendritic cells, and glomerular podocytes. CR1 binds to the complement components C3b and C4b and has also been referred to as the C3b/C4b receptor. The structural organization and primary sequence of CR1 is known (Klickstein et al., 1987, J. Exp. Med. 165:1095-1112, Klickstein et al., 1988, J. Exp. Med. 168:1699-1717; Hourcade et al., 1988, J. Exp. Med. 168:1255-1270). It is composed of 30 short consensus repeats (SCRs) that contain 60-70 amino acids. In each SCR, 29 of the average 65 amino acids are conserved. Each SCR has been proposed to form a three dimensional triple loop structure through disulfide linkages with the third and first and the fourth and second half-cystines in disulfide bonds. CR1 is further arranged as 4 long homologous repeats (LHRs) of 7 SCRs each. Following a leader sequence, which is post-translationally removed, the CR1 molecule consists of the most N-terminal LHR-A comprising a C4b binding domain, the next two repeats, LHR-B and LHR-C comprising C3b binding domains, and the most C terminal LHR-D followed by 2 additional SCRs, a 25 residue putative transmembrane region and a 43 residue cytoplasmic tail.
CR1 is a member of a protein superfamily characterized by this SCR homology. Some superfamily members that have C3/C4 binding function include CR2, C4 binding protein, factor H, factor B, and C2, while proteins lacking this function include interleukin-2 receptor, .beta.2-glycoprotein I, Cir, haptoglobin .alpha. chain, and factor XIIIb.
CR1 is known to be a glycoprotein and its deduced amino acid sequence has 25 potential sites for N-linked glycosylation (amino acid consensus sequence NXS or NXT) in the extracellular region. Only 6-8 of the available sites were reported to be linked to oligosaccharides (Sim, 1985, Biochem. J. 232:883). A non-glycosylated form of CR1 has been produced in the presence of tunicamycin and showed reduced binding to iC3 (Lublin et al., 1986, J. Biol. Chem. 261:5736). The N-terminus of the glycoprotein appears to be blocked.
Thus far, four different CR1 allelic forms or allotypes have been identified, and differ in size by 30-50 kDa increments. The gene frequencies of these allotypes differ in the human population (Holer et al. 1987, Proc. Natl. Acad. Sci. USA 84:2459-2463). The F (or A) allotype is composed of 4 LHRs and has a molecular weight of about 250 kDa; the larger S (or B) allotype, with a molecular weight of about 290 kDa, contains a fifth LHR that is a chimera of the 5' half of LHR-B and the 3' half of LHR-A and is predicted to have a third C3b binding site (Wong et al., 1989, J. Exp. Med. 169:847). The smallest F' (or C) allotype, most likely arising from the deletion of LHR-B and one C3b binding site, has increased prevalence in patients with systemic lupus erythematosus (SLE) (Van Dyne et al., 1987, Clin. Exp. Immunol. 68:570; Dykman et al., 1983, Proc. Natl. Acad. Sci. USA 80:1698).
Soluble Complement Receptor Type 1
A naturally occurring soluble form of CR1 has been detected in the plasma of normal individuals and certain individuals with SLE (Yoon et al., 1985, J. Immunol. 134:3332-3338). Its characteristics are similar to those of erythrocyte (cell-surface) CR1, both structurally and functionally. Hourcade et al., 1988, J. Exp. Med. 168:1255-1270) also observed an alternative polyadenylation site in the human CR1 transcriptional unit that was predicted to produce a secreted form of CR1. The mRNA encoded by this truncated sequence comprises the first 8.5 SCRs of CR1, and encodes a protein of about 80 kDa which includes the C4b binding domain. When a cDNA corresponding to this truncated sequence was transfected into COS cells and expressed, it demonstrated the expected C4b binding activity but did not bind to C3b (Krych et al., 1989, FASEB J. 3:A368). Krych et al. also observed a mRNA similar to the predicted one in several human cell lines and postulated that such a truncated soluble form of CR1 with C4b binding activity may be synthesized in humans.
Several soluble fragments of CR1 have also been generated via recombinant DNA procedures by eliminating the transmembrane region from the DNAs being expressed (Fearon et al., Intl. Patent Publ. WO 89/09220, Oct. 5, 1989; Fearon et al., Intl. Patent Publ. WO 91/05047, Apr. 18, 1991). The soluble CR1 fragments were functionally active, bound C3b and/or C4b and demonstrated factor I cofactor activity depending upon the regions they contained. Such constructs inhibited in vitro the consequences of complement activation such as neutrophil oxidative burst, complement mediated hemolysis, and C3a and C5a production. A soluble construct, sCR1/pBSCR1c, also demonstrated in vivo activity in a reversed passive Arthus reaction (Fearon et al., 1989, 1991, supra; Yeh et al., 1991, J. Immunol. 146:250), suppressed post-ischemic myocardial inflammation and necrosis (Fearon et al., supra; Weisman et al., Science, 1990, 249:146-151) and extended survival rates following transplantation (Pruitt & Bollinger, 1991, J. Surg. Res 50:350; Pruitt et al., 1991 Transplantation 52; 868). Furthermore, co-formulation of the soluble product of vector sCR1/pBSCR1c with p-anisoylated human plasminogen-streptokinase-activator complex (APSAC) resulted in similar anti-hemolytic activity as the sCR1/pBSCR1c product alone, indicating that the combination of the complement inhibitor sCR1 with a thrombolytic agent was feasible (Fearon et al., supra).
Each of International Patent Publication Number WO 89/09220, published Oct. 5, 1989,and WO 91/05047, published Apr. 18, 1991, are incorporated by reference herein in their entirety.

Therapeutic methods employing sialylated glycoforms of soluble complement receptor 1 (SCR 1)