This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7-diaminophenothiazin-5-ium compounds (referred to herein as “diaminophenothiazinium compounds”) including Methythioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: nitrosylation (NOS); nitrosyl reduction (NR); thiosulfonic acid formation (TSAF); oxidative coupling (OC); Cr(VI) reduction (CR); isolation and purification of zwitterionic intermediate (IAPOZI); ring closure (RC); chloride salt formation (CSF); one of: sulphide treatment (ST); dimethyldithiocarbamate treatment (DT); carbonate treatment (CT); ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction (OE); and recrystallisation (RX). The present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment and diagnosis, etc., for example, for tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral diseases, bacterial diseases, or protozoal diseases.

Throughout this specification, including any claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and any appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
Methythioninium Chloride (MTC) (Also Known as Methylene Blue)
Methythioninium Chloride (MTC) (also known as Methylene blue (MB); methylthionine chloride; tetramethylthionine chloride; 3,7-bis(dimethylamino)phenothiazin-5-ium chloride; C.I. Basic Blue 9; tetramethylthionine chloride; 3,7-bis(dimethylamino)phenazathionium chloride; Swiss blue; C.I. 52015; C.I. Solvent Blue 8; aniline violet; and UROLENE BLUE® (methylene blue))is a low molecular weight (319.86), water soluble, tricyclic organic compound of the following formula:

Methythioninium Chloride (MTC) (also known as Methylene Blue), perhaps the most well known phenothiazine dye and redox indicator, has also been used as an optical probe of biophysical systems, as an intercalator in nanoporous materials, as a redox mediator, and in photoelectrochomic imaging.
See, for example, Colour Index (Vol. 4, 3rd edition, 1971) and Lillie et al., 1979, and references cited therein.
MTC was first described in a German Patent in 1877 (Badische Anilin-und Soda-Fabrik, 1877). In that patent, MTC was synthesized by nitrosylation of dimethylaniline, subsequent reduction to form N,N-dimethyl-1,4-diaminobenzene, and subsequent oxidative coupling in the presence of hydrogen sulphide (H2S) and iron(III) chloride (FeCl3).
Bernthsen described subsequent studies of MTC and methods for its synthesis (see Bernthsen, 1885a, 1885b, 1889).
Fierz-David and Blangley, 1949, also describes methods for the synthesis of MTC from dimethylaniline, as illustrated in the following scheme

In step (a), nitrosodimethylaniline is prepared from dimethylaniline by treatment with nitrite (NaNO2) in aqueous acid (HCl) solution. In step (b), the nitroso compound is reduced to form p-aminodimethylaniline in aqueous acid (HCl) solution using zinc dust solution. In steps (c), (d), and (e), the p-aminodimethylaniline is oxidized in aqueous acid solution with another molecule of dimethylaniline, and simultaneously a thiosulfonic acid group is introduced; the ring is then closed using manganese dioxide or copper sulfate. More specifically, a clear neutral solution of p-aminodimethylaniline is acidified (H2SO4), and a non-reducing zinc chloride solution is added (ZnCl2 with Na2Cr2O7). Aluminium thiosulfate (Al2(S2O3)3) and sodium thiosulfate (Na2S2O3) are added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated and aerated. Dimethylaniline is added. Sodium dichromate (Na2Cr2O7) is added. The mixture is heated, and becomes dark greenish-blue in colour due to the formation of the thiosulfonic acid of Bindschedler green. Manganese dioxide or copper sulfate is added, and the mixture heated, and the dye precipitates from the concentrated zinc chloride solution.
Very similar synthesis methods are described in the Colour Index (Vol. 4, 3rd edition, 1971), p. 4470.
Masuya et al., 1992, describe certain phenothiazine derivatives, and methods for their preparation and use in photodynamic therapy of cancer and in immunoassays utilizing chemiluminescence. The compounds are prepared by routes similar to those discussed above.
Leventis et al., 1997, describe methods for the synthesis of certain MTC analogs, which employ phenothiazine as a starting material and which add the desired 3,7-substituents by halogenation followed by amination. The authors assert that MTC is synthesized commercially by oxidation of N,N-dimethyl-p-phenylene diamine with Na2Cr2O7 in the presence of Na2S2O3, followed by further oxidation in the presence of N,N-dimethylamine.
Marshall and Lewis, 1975a, describes the purification of commercial MTC and Azure B by solvent extraction and crystallisation. They assert that aqueous MTC/Azure B mixtures at a buffered pH of 9.5 can be separated by extraction with carbon tetrachloride. The carbon tetrachloride removes the Azure B while leaving the MTC in the aqueous layer. They further assert that low temperature crystallisation of MTC at a concentration of 0.25 N with hydrochloric acid removes metal contaminants. However, the organic purity analysis reported therein is based on thin-layer chromatography, which is not suitable for quantification. Also, the microanalysis for sulphated ash does not indicate a metal free sample. (The preferred technique in 1975 was atomic absorption.)
Marshall and Lewis, 1975b, describes the analysis of metal contaminants in commercial thiazine dyes by atomic absorption spectrophotometry. They report 38 samples with metal concentrations that vary widely between 0.02% and 25.35% of individual samples; the metals examined were iron, potassium, sodium and zinc. They also report that other metals may be present which were not analysed. Aluminium, chromium, manganese, and copper, are all involved in synthetic procedures for MTC and are almost certain to be present. Importantly, they report large variations in the metal content of commercial samples of MTC.
Lohr et al., 1975, describes the purification of Azure B by column chromatography, specifically by separation to isolate the desired product followed by ion exchange back to the chloride. They assert that other cationic dyes such as MTC can be purified by this method. However, column chromatography is not a suitable method for the purification of MTC on a large scale.
Fierz-David et al., 1949, describes the synthesis of the zinc chloride double salt of MTC and the removal of zinc by chelation with sodium carbonate followed by filtration to generate zinc free methylene blue. However, the authors acknowledge that this technique cannot be used on a large scale, because the yields are poor.
Medical Uses of MTC
MTC is currently used to treat methemoglobinemia (a condition that occurs when the blood cannot deliver oxygen where it is needed in the body). MTC is also used as a medical dye (for example, to stain certain parts of the body before or during surgery); a diagnostic (for example, as an indicator dye to detect certain compounds present in urine); a mild urinary antiseptic; a stimulant to mucous surfaces; a treatment and preventative for kidney stones; and in the diagnosis and treatment of melanoma.
MTC has been used to treat malaria either singly (Guttmann & Ehrlich, 1891) or in combination with chloroquine (Schirmer et al. 2003; Rengelhausen et al. 2004). Malaria in humans is caused by one of four protozoan species of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, or P. malariae. All species are transmitted by the bite of an infected female Anopheles mosquito. Occasionally, transmission occurs by blood transfusion, organ transplantation, needle-sharing, or congenitally from mother to fetus. Malaria causes 300-500 million infections worldwide and approximately 1 million deaths annually. Drug resistance, however is a major concern and is greatest for P. falciparum, the species that accounts for almost all malaria-related deaths. Drugs or drug combinations that are currently recommended for prophylaxis of malaria include chloroquine/proguanil hydrochloride, mefloquine, doxycycline and primaquine.
MTC (under the name Virostat, from Bioenvision Inc., New York) has shown potent viricidal activity in vitro. Specifically Virostat is effective against viruses such as HIV and West Nile Virus in laboratory tests. West Nile virus (WNV) is a potentially serious illness affecting the central nervous system. The large majority of infected people will show no visible symptoms or mild flu-like symptoms such as fever and headache. About one in 150 will develop severe symptoms including tremors, convulsions, muscle weakness, vision loss, numbness, paralysis or coma. Generally, WNV is spread by the bite of an infected mosquito, but can also spread through blood transfusions, organ transplants, breastfeeding or during pregnancy from mother to child. Virostat is also currently in clinical trials for the treatment of chronic Hepatitis C. Hepatitis C is a viral infection of the liver. The virus, HCV, is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and liver cancer. HCV is spread primarily by direct contact with human blood. The major causes of HCV infection worldwide are use of unscreened blood transfusions, and re-use of needles and syringes that have not been adequately sterilized. The World Health Organization has declared hepatitis C a global health problem, with approximately 3% of the world's population infected with HCV and it varies considerably by region. The prevalence in the US is estimated at 1.3% or approximately 3.5 million people. Egypt has a population of approximately 62 million and contains the highest prevalence of hepatitis C in the world, estimated at over 20% of the nation's approximately 62 million people.
MTC, when combined with light, can prevent the replication of nucleic acid (DNA or RNA). Plasma, platelets and red blood cells do not contain nuclear DNA or RNA. When MTC is introduced into the blood components, it crosses bacterial cell walls or viral membrane then moves into the interior of the nucleic acid structure. When activated with light, the compounds then bind to the nucleic acid of the viral or bacterial pathogen, preventing replication of the DNA or RNA. Because MTC designed to inactivate pathogens, it has the potential to reduce the risk of transmission of pathogens that would remain undetected by testing.
Tauopathies, MTC and Other Diaminophenothiazinium Compounds
Conditions of dementia such as Alzheimer's disease (AD) are frequently characterised by a progressive accumulation of intracellular and/or extracellular deposits of proteinaceous structures such as β-amyloid plaques and neurofibrillary tangles (NFTs) in the brains of affected patients. The appearance of these lesions largely correlates with pathological neurofibrillary degeneration and brain atrophy, as well as with cognitive impairment (see, e.g., Mukaetova-Ladinska, E. B., et al., 2000, Am. J. Pathol., Vol. 157, No. 2, pp. 623-636).
In AD, both neuritic plaques and NFTs contain paired helical filaments (PHFs), of which a major constituent is the microtubule-associated protein tau (see, e.g., Wischik et al., 1988, PNAS USA, Vol. 85, pp. 4506-4510). Plaques also contain extracellular β-amyloid fibrils derived from the abnormal processing of amyloid precursor protein (APP) (see, e.g., Kang et al., 1987, Nature, Vol. 325, p. 733). An article by Wischik et al. (in 'Neurobiology of Alzheimer's Disease', 2nd Edition, 2000, Eds. Dawbarn, D. and Allen, S. J., The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford) discusses in detail the putative role of tau protein in the pathogenesis of neurodegenerative dementias. Loss of the normal form of tau, accumulation of pathological PHFs, and loss of synapses in the mid-frontal cortex all correlate with associated cognitive impairment. Furthermore, loss of synapses and loss of pyramidal cells both correlate with morphometric measures of tau-reactive neurofibrillary pathology, which parallels, at a molecular level, an almost total redistribution of the tau protein pool from a soluble to a polymerised form (i.e., PHFs) in Alzheimer's disease.
Tau proteins are characterised as being one among a larger number of protein families which co-purify with microtubules during repeated cycles of assembly and disassembly (Shelanski et al. (1973) Proc. Natl. Acad. Sci. USA, 70., 765-768), and are known as microtubule-associated-proteins (MAPs). Members of the tau family share the common features of having a characteristic N-terminal segment, sequences of approximately 50 amino acids inserted in the N-terminal segment, which are developmentally regulated in the brain, a characteristic tandem repeat region consisting of 3 or 4 tandem repeats of 31-32 amino acids, and a C-terminal tail. The tandem repeat sequence corresponds to the microtubule-binding domain (see, e.g., Goedert, M., et al., 1989, EMBO J., Vol. 8, pp. 393-399; Goedert, M., et al., 1989, Neuron, Vol. 3, pp. 519-526). Tau in PHFs is proteolytically processed to a core domain (see, e.g., Wischik, C. M., et al., 1988, PNAS USA, Vol. 85, pp. 4884-4888; Wischik et al., 1988, PNAS USA, Vol. 85, pp. 4506-4510; Novak, M., et al., 1993, EMBO J., Vol. 12, pp. 365-370) which is composed of a phase-shifted version of the repeat domain; only three repeats are involved in the stable tau-tau interaction (see, e.g., Jakes, R., et al., 1991, EMBO J., Vol. 10, pp. 2725-2729). Once formed, PHF-like tau aggregates act as seeds for the further capture and provide a template for proteolytic processing of full-length tau protein (see, e.g., Wischik et al., 1996, PNAS USA, Vol. 93, pp. 11213-11218).
The phase shift which is observed in the repeat domain of tau incorporated into PHFs suggests that the repeat domain undergoes an induced conformational change during incorporation into the filament. During the onset of AD, it is envisaged that this conformational change could be initiated by the binding of tau to a pathological substrate, such as damaged or mutated membrane proteins (see, e.g., Wischik, C. M., et al., 1997, in "Microtubule-associated proteins: modifications in disease", Eds. Avila, J., Brandt, R. and Kosik, K. S. (Harwood Academic Publishers, Amsterdam) pp. 185-241).
In the course of their formation and accumulation, PHFs first assemble to form amorphous aggregates within the cytoplasm, probably from early tau oligomers which become truncated prior to, or in the course of, PHF assembly (see, e.g., Mena, R., et al., 1995, Acta Neuropathol., Vol. 89, pp. 50-56; Mena, R., et al., 1996, Acta Neuropathol., Vol. 91, pp. 633-641). These filaments then go on to form classical intracellular NFTs. In this state, the PHFs consist of a core of truncated tau and a fuzzy outer coat containing full-length tau (see, e.g., Wischik et al., 1996, PNAS USA, Vol. 93, pp. 11213-11218). The assembly process is exponential, consuming the cellular pool of normal functional tau and inducing new tau synthesis to make up the deficit (see, e.g., Lai, R. Y. K., et al., 1995, Neurobiology of Ageing, Vol. 16, No. 3, pp. 433-445). Eventually, functional impairment of the neurone progresses to the point of cell death, leaving behind an extracellular NFT. Cell death is highly correlated with the number of extracellular NFTs (see, e.g., Wischik et al., in 'Neurobiology of Alzheimer's Disease', 2nd Edition, 2000, Eds. Dawbarn, D. and Allen, S. J., The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford). As tangles are extruded into the extracellular space, there is progressive loss of the fuzzy outer coat of the neurone with corresponding loss of N-terminal tau immunoreactivity, but preservation of tau immunoreactivity associated with the PHF core (see, e.g., Bondareff, W. et al., 1994, J. Neuropath. Exper. Neurol., Vol. 53, No. 2, pp. 158-164).
Diaminophenothiazines have previously been shown to inhibit tau protein aggregation and to disrupt the structure of PHFs, and reverse the proteolytic stability of the PHF core (see, e.g., WO 96/30766, F Hoffman-La Roche). Such compounds were disclosed for use in the treatment or prophylaxis of various diseases, including Alzheimer's disease. These included MTC amd DMMB (1,9-dimethyl-methyl-thioninium chloride; DMMTC) amongst others.
Additionally, WO 02/055720 (The University Court of the University of Aberdeen) discusses the use of reduced forms of diaminophenothiazines specifically for the treatment of a variety of protein aggregating diseases, although the disclosure is primarily concerned with tauopathies.
WO 2005/030676 (The University Court of the University of Aberdeen) discusses radiolabelled phenothiazines, and their use in diagnosis and therapy, for example, of tauopathies.
MTC and Purity
Oral and parenteral formulations of MTC are commercially available in the United States, usually under the name UROLENE BLUE® (methylene blue). However, these formulations contain substantial amounts of metal impurities. These impurities are highly undesirable, and many (e.g., including Al, Cr, Fe, Cu) exceed the safety limits set by European health agencies.
Consequently, there is a great need for higher purity (e.g., pharmaceutical grade purity, e.g., a purity safe for human consumption, e.g., with low or reduced metal content) diaminophenothiazinium compounds, including MTC.

Methods of treatment of a tauopathy condition comprising the use of thioninium compounds


A method and apparatus for detecting lock instructions and lock release instruction, as well as predicting critical sections is herein described. A lock instruction is detected with detection logic, which potentially resides in decode logic. A lock instruction entry associated with the lock instruction is stored/created. Address locations and values to be written to those address location of subsequent potential lock release instruction are compared to the address loaded from by the lock instruction and the value load by the lock instruction. If the addresses and values match, it is determined that the lock release instruction matches the lock instruction. A prediction entry stores a reference to the lock instruction, such as a last instruction pointer (LIP), and an associated value to represent the lock instruction is to be elided upon subsequent detection, if it is determined that the lock release instruction matches the lock instruction.

Advances in semi-conductor processing and logic design have permitted an increase in the amount of logic that may be present on integrated circuit devices. As a result, computer system configurations have evolved from a single or multiple integrated circuits in a system to multiple cores and multiple logical processors present on individual integrated circuits. A processor or integrated circuit typically comprises a single processor die, where the processor die may include any number of cores or logical processors.
The ever increasing number of cores and logical processors on integrated circuits enables more threads to be executed. However, the increase in the number of threads that may be executed simultaneously has created problems with synchronizing data shared among the threads. One common solution to accessing shared data in multiple core or multiple logical processor systems comprises the use of locks to guarantee mutual exclusion across multiple accesses to shared data. However, the ever increasing ability to execute multiple software threads potentially results in false contention and a serialization of execution.
For example, consider a hash table holding shared data. With a lock system, a programmer may lock the entire hash table, allowing one thread to access the entire hash table. However, throughput and performance of other threads is potentially adversely affected, as they are unable to access any entries in the hash table, until the lock is released. Alternatively, each entry in the hash table may be locked. However, this increases programming complexity, as programmers have to account for more locks within a hash table.

Critical section detection and prediction mechanism for hardware lock elision


A device for dissipating a heat from addressing integrated circuits (addressing ICs) of a plasma display panel that uses a back plate which has a greater surface area, to dissipate the heat from the addressing integrated circuits directly. For embodiment of the device thereof, it provides a heat-conducting sheet attached on the addressing ICs to conduct the heat from the addressing ICs to the back plate rapidly, therefore increase the efficiency of the dissipation without add the volume of the plasma display panel.

1. Field of the Invention
The present invention relates generally to a plasma display panel, in particularly to a device of increasing the efficiency of heat dissipation of the addressing ICs of the plasma display panel and the method thereof.
2. Description of the Related Art
A conventional plasma display panel (PDP) mainly has a substrate, a back plate mounted behind the substrate, a plurality of tape carrier packages (TCP) disposed at a margin of the substrate, across the back plate to connect with a printed circuit board (PCB), each of TCP is disposed with an addressing integrated circuit (addressing IC), a frame cover a margin of the panel and a back plate mounted at a back of the substrate.
While the plasma display panel works, the temperature thereof will increase and if the panel has a greater resolution, it generates greater heat. The heat is generated mainly by the addressing ICs. The addressing IC is sensitive to temperature that if the addressing IC is working in a high temperature, it will be unstable. The conventional panel is disposed with a radiator to dissipate the heat of the addressing ICs.
U.S. Pat. No. 6,198,222 discloses a heat dissipating device, which provides two fans in an inlet and an outlet of the frame to enforce the heat dissipation. This device increases the size of the panel and the cost of fabrication, so that it is not an optimal solution.
Another heat dissipating device is taught by U.S. Pat. No. 6,288, 489 and U.S. Pat. No. 6,617,767 and it uses the back plate to be the heat sink. The back plate is made of aluminum and a heat-conductive rubber sheet is disposed at between the back plate and the substrate. The heat-conductive rubber sheet has a well property of heat conduction to conduct the heat generated from the addressing ICs to the back plate. The back plate has a larger area to dissipate heat. Although the device does not use fan to force dissipating heat, it also has a good efficiency of heat dissipating.
The main drawback of the second device is that the dissipating heat of the back plate is mainly from the substrate rather than from the addressing ICs. In other words, the heat generated by the addressing ICs is conducted to the substrate, and then conducted to the back plate, it is an indirect dissipating heat function.
To overcome aforesaid drawback, a new heat dissipating device is provided. As shown in FIG. 1, the device has a substrate 20 and an aluminum frame 21 is mounted at a margin of the substrate, a plurality of addressing ICs 22 are disposed at between a TCP 23 and the frame 21, an inner heat-conducting sheet 24 is provided at between the TCP 23 and a back plate 26 to bond the TCP 23 on the back plate 26 and an outer heat-conducting sheet 25 is provided at between the addressing ICs 22 and the frame 21. As a result, the heat of the addressing ICs 22 is directly dissipated by the frame 21 via the outer heat-conducting sheet 25.
Aforesaid invention has a well heat dissipation efficiency and it takes less space. But the present plasma display panel is required for a smaller and lighter panel, the heat dissipating device still has to be improved. Such as how to increase the efficiency of heat dissipation without having to change the layout and the sizes or sharps of the substrate, the TCP and the addressing IC.

Device for decreasing the temperature from address IC of plasma display panel and the method thereof


A gun for producing adhesive foam has a nozzle tube, a delivery lever, a nozzle needle coaxial in the nozzle tube, and pressed by a force storage member into its dosing position. A coupling device is positioned between the delivery lever and the nozzle needle, by which a given position of the delivery lever corresponds to a given position of the nozzle needle. A cavity borders on the nozzle tube. A wall section is arranged between the coupling device and the cavity and bounds the cavity. A guide and a seal are arranged in the wall section. The guide is integrated into the seal.

1. Field of the Invention
This invention relates to a gun for producing adhesive foam, and more particularly, to a gun with a nozzle tube, a delivery lever, and a nozzle needle arranged coaxially in the nozzle tube.
2. Discussion of Relevant Art
Such a device is known, for example, from German Patent DE 44 12 282.
When the adhesive foam can is screwed on, the fluid under pressure is present in a cavity and in the nozzle tube of the gun. Passing through the cavity and nozzle tube is a nozzle needle which in its closing position seals off the outlet opening of the nozzle tube. When the delivery lever is pulled, the nozzle needle is pulled out of its closing position, and the fluid under pressure can emerge from the outlet opening. The cavity is bounded by a wall section which has a bore in which is arranged the guide means for guiding the nozzle needle.
In the known guns, the guiding is effected by a bore in the wall section. So that the fluid under pressure does not get out into the housing space of the gun and in the course of time render inoperative the coupling device between the delivery lever and the nozzle needle, and also further elements located in the housing of the gun, two lip seals for sealing the needle are provided in the known guns on the side of the guide remote from the cavity.
In these known guns a sufficient sealing is indeed attained. However, the production and materials costs are disadvantageous here, as are the difficulties which arise when the seal becomes damaged.


The invention concerns a timepiece including a dial (12) fitted with an aperture (16) behind which is mounted a moon phase disc (18) driven in rotation by a moon phase train (24). According to the invention said disc (18) is mounted so as to move in rotation about a fixed sun pinion (36). Moreover, two planetary wheels (44a, 44b), secured in rotation to representations of the moon (19a, 19b), are mounted so as to move in rotation on the disc (18), at least indirectly meshed with the sun pinion (36), so as to form a planetary train with the sun pinion (36).

They generally include a moon phase mechanism, formed of a gear train driven by an hour wheel and of a disc to which two representations of the moon are affixed. The disc is visible behind an aperture in the general shape of a semi circle, the diameter side of which includes two convex portions arranged such that the moon appears to be ascending, full, then descending progressively during its path through the aperture. This conventional representation of the phases of the moon does not permit any fun or surprising effects, although such effects are greatly sought after in horology. Moreover, this representation is not true to reality, since the incline of the moon relative to the 12 o'clock-6 o'clock axis of the watch, varies depending upon the position of the moon in the aperture. When a face is drawn on the moon, as is commonly the case, at first the face is perpendicular to the 12 o'clock-6 o'clock axis, then parallel, then perpendicular again. The effect obtained is neither realistic nor attractive.
The present invention overcomes these drawbacks by proposing a timepiece fitted with a moon phase indication wherein the representations of the moon are mobile in rotation on the moon phase disc.


The present disclosure describes systems and methods for monitoring, diagnosing and optimizing operation of an electric submersible pump (ESP). At least some illustrative embodiments include a method that includes collecting measured data representative of a state of an ESP within a well or of well conditions and storing the measured data, matching a nodal analysis model of the well to the well by matching one or more modeled values to corresponding measured data, and identifying one or more likely conditions of the ESP based at least in part on data generated by a matched model. The method further includes updating the matched model to reflect a selected correction of one of the likely conditions identified, generating ESP performance curves using the updated model, and presenting to a user an action recommended to achieve an ESP performance consistent with an ESP operating point selected from one of the ESP performance curves.

Oil field operators dedicate significant resources to improve the recovery of hydrocarbons from reservoirs while reducing recovery costs. To achieve these goals, reservoir engineers both monitor the current state of the reservoir and attempt to predict future behavior given a set of current and/or postulated conditions. Reservoir monitoring, sometimes referred to as reservoir surveillance, involves the regular collection and monitoring of measured production data from within and around the wells of a reservoir. Such data may be collected using sensors embedded behind the well casing and/or from measurement devices introduced into the well within or in line with the production tubing. The data may include, but is not limited to, water saturation, water and oil cuts, fluid pressure and fluid flow rates, and is generally collected at a fixed, regular interval (e.g., once per minute) and monitored in real-time by field personnel. As the data is collected, it is generally archived into a database.
In addition to monitoring conditions within the well, the equipment used to extract product from the well is also monitored. Such monitoring ensures that the equipment is functioning as close to its optimal operating point as possible or practical, and that failures are detected and resolved promptly. One type of equipment used downhole to extract product from oil and gas wells is an electric submersible pump (ESP). ESPs are generally mounted in line with the production tubing where they are submerged within the product present within the well when the tubing is lowered into the well's production casing. ESPs both pump the product to the surface and lower the flowing bottom hole pressure (FBHP). The decrease in FBHP increases the pressure differential between the formation and the well and accelerates the movement of product from the formation into the well through perforations in the casing.
Power to drive an ESP is provided from the surface via cables that also provide conductors for signals to be received from the ESP at the surface. Data transmitted to the surface may include, but is not limited to, motor temperature, motor drive current frequency, pump intake pressure and pump discharge pressure. Although the data provided enables monitoring of the performance of an ESP, determining the underlying cause of a failure or a variation in the performance of an ESP is a more complicated task. A given ESP failure or performance variation can have numerous causes and operators strive to identify the cause of such conditions quickly to reduce any resulting downtime or reduced production. While experienced reservoir personnel may rely on their personal experience to diagnose and resolve such conditions, a more automated approach based on a broader information base offers the possibility of diagnosing conditions and providing more optimal solutions in a shorter period of time.
It should be understood that the drawings and corresponding detailed description do not limit the disclosure, but on the contrary, they provide the foundation for understanding all modifications, equivalents, and alternatives falling within the scope of the appended claims.

Monitoring, diagnosing and optimizing electric submersible pump operations


An electrophotographic liquid developer includes a carrier liquid and toner particles. The toner particles include a colorant and a resin component and are dispersed in the carrier liquid. The resin component includes a polyester resin as a main component. When 0.3 g of the liquid developer is dropped on a filter paper (which is defined in JIS P 3801) from a point of 10 mm height, the carrier liquid diffuses in the filter paper at a speed not lower than 1 mm/minute.

1. Field of the Invention
The present invention relates to a liquid developer (sometimes referred to as an electrophotographic liquid developer) for use in electrophotography, electrostatic recording, electrostatic printing and the like and to image forming methods using the electrophotographic liquid developer. In addition, the present invention also relates to an image forming apparatus and method using the liquid developer.
2. Discussion of the Background
Electrophotographic developers are classified into dry developers and liquid developers. Liquid developers have an advantage over dry developers in that clearer images can be prepared because of the inclusion of a toner having a finer particle diameter than that of the toner included in dry developers.
Liquid developers are typically prepared by dispersing a resin, a colorant and a charge controlling agent in a carrier liquid made of a non-aqueous solvent having a high electric resistance. The particle diameter of the toner dispersed in such liquid developers is typically from 0.1 to 2.0 μm.
In the above-mentioned conventional, electrophotographic developers, a non-aqueous solvent having a high boiling point is typically used as the carrier liquid to prevent the carrier liquid from evaporating, resulting in stabilization of the developers. Such a non-aqueous solvent having a high boiling point has good stability, but has a drawback in that fixation of the image is not satisfactory, such that images fade away when rubbed for example by a finger because the carrier liquid tends to remain in a toner layer and on a receiving material after the images are fixed.
Therefore, the development of an electrophotographic liquid developer having high image density and capable of having high resolution image is desired.

This patent is subject to a terminal disclaimer.

Electrophotographic liquid developer, image forming method and apparatus using the electrophotographic liquid developer


Systems and methods for aligning substrates that include microstructures. The microstructures may be electronic or micromechanical components. The system includes a first substrate having a first alignment structure and a second substrate having a second alignment structure. The substrates are positioned so that the first alignment structure contacts the second alignment structure without the substrates directly contacting each other, and one of the substrates is adjusted in relation to the other substrate until the first and second alignment structures lock into place. After alignment, the microstructures on the first substrate and the second substrate may establish a connection with or be positioned in near proximity to each other.

1. Field of Invention
The invention relates to systems and methods for aligning wafers or substrates. More specifically, the invention relates to systems and methods that align wafers or substrates that include microstructures or microcomponents.
2. Description of Related Art
During the arrangement of microstructures, a process may require that at least two substrates or wafers be aligned to each other so that the microstructures on the substrates are accurately aligned. The microstructures may be active or passive microstructures including electronic or micromechanical components. The substrates may include microcomponents, or microoptical or micro-electro-mechanical system (MEMS) devices. The MEMS devices may include accelerometers, gyroscopes, pressure sensors, and micromirrors. The substrates may be patterned with electronic devices such as transistors, inductors and sensors, or patterned with simple microstructures such as conducting lines or other geometries. The microoptical devices may include lasers, light-emitting-diodes, mirrors or lenses. Microchannels, fiber-clips and CLAW(ClawConnect™)-type contact springs may also be included on the substrates. Large substrates sometimes have to be aligned during an assembly, for example, of an image sensor array or display.
With conventional methods, most of the alignment of the substrates or wafers is performed optically with an x-y alignment stage. For example, the alignment may be performed by optical alignment with x-y stages and alignment marks. With this process, a calibration mask pattern and calibration wafer test pattern may include checkerboard-like arrays of mutually orthogonal (x-oriented and y-oriented) periodic gratings which are frequency matched to each other in the wafer plane, e.g., the image plane of the mask. The wafer test pattern may be carried by a die at the center of the wafer and by opposing radially displaced dies which align with the x-axis and the y-axis of the exposure tool, thereby enabling measurement of overlay air at various locations on the wafer.
MEMS fabrication technology is conventionally employed to align or join structures or substrates. Anisotropic etching of silicon is used to form optical benches. Moreover, Lithographie, Galvanoformung, Abformtechnik (LIGA) structures, (e.g., formed by X-ray lithography, electroplating, molding) are used to make connectors and to align optical components. These systems also align the components using x-y stages and alignment marks.
If an alignment process is required for substrates used with micro-optics or MEMS packaging, special tools or sophisticated optical systems are required for the alignment process. These areas may include assembly of displays or image sensors where the large area substrates must be aligned, e.g., the alignment of X-ray conversion screens or color phosphor screens to the pixels.
As shown in FIG. 1, and in order to fabricate, for example, an X-ray imager, a wafer 104 with the imager electronics, e.g., pixels 110, has to be aligned to a micro-patterned X-ray conversion screen 100. The alignment has to be precise so that each pixel 100 on the image sensor array matches a cell on the X-ray conversion screen 100. As shown in FIG. 2, CLAW springs 210 may be positioned on an upper substrate 202 and electrical contact pads 208 may be positioned on a lower substrate 204. After alignment of the two substrates 202 and 204, the upper substrate 202 may be lowered (and the lower substrate 204 may be adjusted in the x-y direction) so that an electrical connection is established between the CLAW springs 210 and the contact pads 208. The alignment accuracy may depend on the size of the CLAW spring 210 and the size of the contact pad 208. Using the conventional systems and methods, it is difficult to achieve an accurate alignment of the upper substrate 202 with the CLAW springs 210 and the lower substrate 204 with the contact pads 208 so that the electrical components establish a good connection.
Because a special optical alignment table may be required, an accurate alignment can be difficult to achieve. Furthermore, the equipment used for alignment using the conventional devices discussed above may be rather expensive and the alignment procedure time-consuming. In many instances, after the alignment of the substrates, the substrates have to be held in place with an adhesive. Thus, it becomes impossible to test and rework the devices after the adhesive cures. Some applications may require frequent exchange of parts which makes the optical alignment steps impractical.

Systems and methods for aligning wafers or substrates


The torque detecting apparatus comprises an input shaft to which a torque is inputted, an output shaft for outputting the inputted torque, a connecting shaft for connecting the input shaft and the output shaft to transmit the torque, a coil for detecting a torque applied from the input shaft to the connecting shaft based on a torsional angle which arises at the connecting shaft, and a holding cylinder for holding the coil coaxially, wherein the holding cylinder has inside thereof a recess extending in the circumferential direction, and the coil is fitted in the recess. Projections for supporting the holding cylinder at a predetermined position are provided on the outer surface of an axial portion which does not have the recess. Accurate torque detection can be effected even when pressure applied to the projections provided at the holding cylinder constituting the torque detecting apparatus is changed.

The present invention relates to a torque detecting apparatus, and in particular to a noncontact torque detecting apparatus for detecting a torque applied to a connecting shaft by detecting a torque inputted into an input shaft as a change in the inductance of a coil due to torsion which arises at the connecting shaft.
A torque detecting apparatus comprises: an input shaft to which a torque is inputted; an output shaft for outputting the inputted torque; a connecting shaft of a torsion bar for connecting the input shaft and the output shaft; and a coil, which surrounds the connecting shaft, the input shaft and the output shaft, for detecting a torque applied from the input shaft to the connecting shaft based on a torsional angle which arises at the connecting shaft. The input shaft and the output shaft respectively comprise a detection ring made of magnetic material on the outer circumference thereof, wherein when a torque is inputted into the input shaft, the connecting shaft is tortured, so that the relative positions of two detection rings in the circumferential direction are changed and the inductance of the coil surrounding the connecting shaft, the input shaft and the output shaft is changed. By detecting this change in the inductance as a change in the impedance of a coil connected to an AC circuit, a torque which is inputted into or outputted from the input shaft and the output shaft and applied to the connecting shaft is detected. The coil is held coaxially in a holding cylinder formed of green compact and engaged in a recess extending over the entire circumference of the inner surface of the holding cylinder.
By the way, the holding cylinder comprises on the outer surface thereof a projection for locating the holding cylinder at a predetermined position, the projection being formed over an area between the annular faces of the holding cylinder in a conventional torque detecting apparatus. The projection is a strip formed integrally with coating member made of synthetic resin for coating the holding cylinder (Japanese Patent Application Laid-Open No. 2002-13990).
A torque detecting apparatus constructed in such a manner is used in a vehicle electric power steering apparatus, for example. That is, the apparatus is used for detecting a torque which is inputted into the input shaft connected to a steering wheel for operating the vehicle by rotation of the steering wheel. Attachment of the torque detecting apparatus is effected by bringing the projection of the torque detecting apparatus into contact with the inner circumferential surface of a hollow housing constituting the electric power steering apparatus and fitting the torque detecting apparatus fixedly.
It should be noted that green compact has an electric resistance higher than that of iron, stainless steel or the like. Accordingly, by forming the holding cylinder with green compact, eddy current to be caused in the holding cylinder by current passing through the coil can be decreased and the detection accuracy of torque can be enhanced in comparison with a case where the holding cylinder is formed of iron, stainless steel or the like.
However, when an electric power steering apparatus is used, the temperature of the torque detecting apparatus and the housing is changed in a large way from ordinary temperature. When the temperature is changed, the housing and the torque detecting apparatus expand or contract in different ratios due to a difference in the coefficients of linear expansion of members constituting the housing and the torque detecting apparatus, so that a large pressure, i.e. a pressure larger than a pressure which is to be applied to the projection at ordinary temperature, is applied to the projection provided at the holding cylinder. In particular, when the temperature is low, a housing made of aluminum contracts more than the torque detecting apparatus and a large pressure is applied to the projection. When pressure in the radial direction of the holding cylinder is applied to the projection, the holding cylinder is deformed and the inductance of the coil is changed, so that the detected value of torque is changed. Thus, a conventional torque detecting apparatus has a problem that the torque detection becomes inaccurate when pressure applied to the projection for supporting the torque detecting apparatus at a predetermined position is changed.
When a torque detecting apparatus is used in an electric power steering apparatus, if a change in the temperature of the vehicle makes the torque detection inaccurate, the operations of the electric power steering apparatus for assisting steering based on the detected value of torque also becomes inaccurate, giving rise to deterioration of feeling in steering the vehicle.
There is another problem that the green compact forming the holding cylinder has a low strength and, in particular, a portion of the holding cylinder having the recess has a small thickness, so that this portion of the holding cylinder might be damaged while pressing the torque detecting apparatus into the housing and the torque detecting apparatus cannot be pressed into the housing with a large force.
When the torque detecting apparatus cannot be pressed into the housing with a large force, it is impossible to bring the projection into contact with the inner circumferential surface of the housing with a large force, so that the torque detecting apparatus cannot be attached in a stable manner.


The present invention relates to a container for the separate packaging and mixing of at least one base product and at least one secondary product in a single body. The container is provided with an internal stopper, a device for opening the internal stopper, and a membrane, and can be easily and economically manufactured.

Field of the Invention
The present invention relates to a container for the separate packaging, then mixing, of at least two products. It is often necessary to obtain a mixture of several products at the time of their use, the separate products readily enduring prolonged storage, whereas their mixture rapidly changes. Such a packaging may be used, for example, for the marketing of pharmaceutical, cosmetic or photographic products. The container of the present invention relates to the storage and mixing of products with a poor flow rate, in particular the storage and mixing of several products of which at least one is viscous, as for example, the storage and mixing of a powder with a cream or a paste, or of two creams. By way of example, we may cite dyeing products.

Monopiece body for the separate packaging and mixing of at least two products


The present invention provides improved aptamer libraries useful for discovery of aptamers that have high binding affinity for a single or a plurality of targets. The libraries contain higher copies of each member candidate such that they are more likely to be available to the application of acyclic identification methods that obviate the most time-consuming and costly step in traditional SELEX method, the multiple cycles of evolutionary selection.

Aptamers are nucleic acids or peptide molecules that bind targets with an affinity and specificity that rival antibody-antigen interactions. DNA/RNA aptamers promise to provide a cost-effective alternative to antibodies because there is no need for selection in animals or cell lines, they have shelf-lives of years, and they can be easily modified to reduce cross-reactivity with undesired targets. This ability to bind, and in some instances, alter their targets' functions have earned aptamers potential applications in biosensor development, affinity chromatography and recently therapeutics and diagnostics.
Traditionally, artificial aptamer sequences are discovered by SELEX (Systematic Evolution of Ligands by EXponential Enrichment) and other closely related methods of in vitro evolution. Starting libraries have relatively long oligomers of DNA/RNA sequences (80-120 nt) with central randomized regions (30-120 nt). These are sparsely represented libraries with a probability of ˜10−4 that any particular sequence occurs in a typical starting pool for a randomized 30 mer, and of ˜10−29 with randomized 70 mers. This means that nearly all SELEX experiments begin with single copies of those sequences that are present by random chance. Evolution occurs via the selective pressure of binding to a target followed by amplification of the survivors; selection and amplification are repeated in typically 5-20 rounds. Winning aptamers are found by cloning and sequencing, after which a minimal core binding sequence is sought by truncating segments of the parent aptamer that are not needed for the interaction with the target.
Despite the wide adoption of the SELEX procedure for their discovery, DNA/RNA aptamers for only a few hundred targets have been discovered to date using this method compared with the discovery of thousands of antibodies during the same period. This limited success may stem primarily from a significant number of drawbacks with the SELEX method itself. Particularly relevant here, the SELEX methodology of repeated rounds of selection and amplification are cumbersome, time-consuming and very expensive. There is a need for faster and less expensive methods of aptamer discovery and improvement.

Library compositions and methods for acyclic identification of aptamers


A navigation system includes two or more navigation instruments connected with a network, and two or more sensors connected with the network and for detecting information to be used by the navigation instruments. The navigation instrument includes a switch control module for switching between a state in which the navigation instrument functions as a mother unit and as a child unit, a delivery module for transmitting through the network, when one of the navigation instruments functions as the mother unit, representative sensor selection related information to another navigation instrument that functions, the representative sensor selection related information being information about which sensor is to be used among the two or more sensors, and a representative sensor selecting module for selecting the sensor to be used based on the representative sensor selection related information received from the navigation instrument that functions as the mother unit.

Typically, various kinds of sensors and navigation instruments including a radar, a fishfinder, and a GPS receiver are carried in a ship. In many cases, these devices are interconnected through network(s) including a Local Area Network to establish a network system. JP2009-58246A discloses this kind of network system for the ship instruments.
The ship instrument network system disclosed in JP2009-58246A includes, as its main components, a server device having a server function, two or more sensors for detecting the same physical property, and two or more display units for displaying the data detected by these sensors.
The server device selects one from two or more sensors, and shares the detection value of this selected sensor among the two or more display units. Particularly, the ship instrument network system has two or more communication networks, and the detection value of the sensor can be shared among the two or more communication networks.
In the network system of JP2009-58246A, the sharing of data is performed by instructions only from the server device having the server function. Therefore, when a failure occurs in this server device, this single failure can easily make the sharing of the sensor detection value impossible. Thus, there is a need for an improvement in this regard.
In addition, since, in the network system of JP2009-58246A, the communication network to which the server device is directly connected and the communication network to which the sensors are directly connected are separate networks, the network system may also have the following disadvantage.
The disadvantage is that the detection value of the sensor needs to pass through a network instrument which connects the different communication networks, which creates a time lag in the transmission. Moreover, when a failure occurs in the network instrument, the system cannot use the sensor and the like connected with this network instrument.

Navigation data sharing system and navigation instrument


A thermoelectric conversion material includes a sintered body composed mainly of cobalt and antimony, wherein cobalt and antimony as main components form a compound of cubic CoSb.sub.3, a phase composed mainly of an Sb phase is contained as a secondary phase, and a volumetric rate of the phase closed mainly of the Sb phase is less than 10 vol % with respect to 100 vol % of the thermoelectric conversion material.

(1) Field of the Invention
The present invention relates to thermoelectric conversion materials to be used for exhibiting so-called thermoelectric effects (direct energy conversion without relying upon moving parts) such as thermoelectric generation due to the Seebeck effect or thermoelectric cooling due to the Peltier effect. The invention also relates to a process for producing such thermoelectric conversion materials.
(2) Related Art of the Invention
The thermoelectric conversion such as thermoelectric generation and thermoelectric cooling by using a thermoelectric conversion material enables the production of a simplified energy direct conversion device which has no moving parts causing vibration, noise, abrasion, etc., is simple in structure with high reliability, possesses long service life, and is simple to maintain. For example, the thermoelectric conversion is suitable for directly obtaining DC electric power by combustion of a variety of fossil fuels, etc. and for controlling the temperature without use of a cooling medium.
In evaluating the performances of the thermoelectric conversion materials, an electric power factor Q and a performance index Z (also commonly known as "Figure-of-merit") expressed by the following equations are used. EQU Q=.sigma..alpha..sup.2, Z=.sigma..alpha..sup.2 /K
in which .alpha. is a Seebeck coefficient, .sigma. is an electrical conductivity, and .kappa. is a heat conductivity. As to the thermoelectric conversion material, it is desired that the performance index Z is large, that is, the Seebeck coefficient is high, the electric conductivity .sigma. is high, and thermal conductivity .kappa. is low.
When the thermoelectric conversion material is used for thermoelectric cooling or thermoelectric generation, particularly when the thermoelectric conversion material is used as a thermoelectric cooler for a high-temperature generating member or a thermoelectric generator for the utilization of waste heat, it is desired that the thermoelectric conversion material has a high Figure-of-merit Z of not less than 3.times.10.sup.-3 [1/K] as the thermoelectric performance, and operates stably in a use condition for a long time period. Further, it is also desired that the thermoelectric conversion material has sufficient heat resistance and chemical stability in a temperature range of not less than 300.degree. C. Furthermore, if a cooler utilizing thermoelectric cooling or a thermoelectric generator is mass produced for vehicles, etc., it is desired that a material to be effectively produced at a low cost and a process for producing the same are available.
Heretofore, tellurium based compounds such as Bi.sub.2 Te.sub.3,
Bi.sub.2 Sb.sub.8 Te.sub.15, and BiTe.sub.2 Se have been known as thermoelectric conversion materials having high performance indexes Z=3.times.10.sup.-3 [1/K]. Further, thermoelectric conversion materials using Sb compounds such as TSb.sub.3 (T: Co, Ir, Ru), for example, thermoelectric conversion materials in which an impurity for determining a type of electrical conduction is added into a material having a main component of CoSb.sub.3 in its chemical composition are described in the following documents.
1) L. D. Dadkin and N. Kh. AbrikoSov, Soviet Physics Solid State Physics (1959) pp. 126-133 PA0 2) B. N. Zobrinaand, L. D. Dudkin, Soviet Physics Solid State Physics (1960) pp. 1668-1674 PA0 3) K. Matsubara, T. Iyanaga, T. Tsubouchi, K. Kishimoto and T. Koyanagi, American Institute of Physics (1995) pp 226-229.
However, although the thermoelectric conversion materials made of the Te based compounds represented by Bi--Te series have large performance indexes Z of about 3.times.10.sup.-3 [1/K] at near room temperature, their characteristics are deteriorated at not less than 300.degree. C., so that the use temperature is unfavorably limited to a large extent. Further, since a volatile component such as Te or Se is contained in the compositions of the materials, these thermoelectric conversion materials unfavorably have low melting points and lack chemical stability. Furthermore, since a producing process is complex, the characteristics are likely to vary due to changes in the composition, and the intended materials cannot be unfavorably effectively mass produced. In addition, a poisonous element (Te) is contained in the starting materials, and since an expensive starting material having a high purity is needed, an inexpensive product cannot be offered.
As to thermoelectric conversion materials composed mainly of Sb compounds such as TSb.sub.3 (T: Co, Ir, Ru), for example, CoSb.sub.3 in their chemical compositions, it is known that raw materials are relatively inexpensive and contain no poisonous elements, and chemically stable even in a temperature range of not less than 300.degree. C. Although the use temperature of the thermoelectric conversion material having the chemical composition of CoSb.sub.3 is wider than that of the Bi--Te based material, the former is inferior to the latter in that the electric conductivity is lower and the Figure-of-merit (Z<1.times.10.sup.-3 [1/K]) is far smaller.
It is considered that the formerly known thermoelectric conversion material having the chemical composition of CoSb.sub.3 has only a cubic CoSb.sub.3 crystalline phase as its constituting chemical phase, and that other crystalline phases (CoSb, CoSb.sub.2, Sb) function to deteriorate the thermoelectric characteristics.
However, it is known that when such a thermoelectric conversion material is obtained by melting CoSb.sub.3, phases other than CoSb.sub.3 (e.g., CoSb, CoSb.sub.2, Sb) (e.g., CoSb, CoSb.sub.2, Sb) are precipitated during solidification. In order to attain a single CoSb phase, heat treatment needs to be effected at around 600.degree. C. for about 200 hours. This unfavorably prolongs the producing period.
Further, according to a process for producing a thermoelectric material by grinding CoSb obtained through melting and sintering the milled powder, since a foreign phase precipitated during the melting, that is, CoSb and CoSb.sub.2 having densities higher than that of CoSb.sub.3 are converted in phase to CoSb.sub.3 during firing, the volume of the material increases to hinder the sintering. For example, a sufficiently densified thermoelectric conversion material has not been obtained even by hot press under the condition that the pressure was 5.times.10.sup.3 kg/cm.sup.2 and the temperature was 600.degree. C. (K. Matsubara, T. Iyanaga, T. Tsbouchi, K. Kishimoto and T. Koyanagi, American Institute of Physics (1995) pp. 226-229). As a result, a material fired under atmospheric pressure is brittle, and has conspicuously low electrical conductivity and extremely poor thermoelectric property.
As mentioned above, although the thermoelectric conversion material having the chemical composition of CoSb.sub.3 has the wider usable temperature range as compared with the Bi--Te based one, the former has the problems in terms of both the material characteristics and the production process. Therefore, there has been demanded a thermoelectric conversion material which is chemically stable and unlikely to be degraded, has excellent thermoelectric property and high strength in a wide temperature range of from room temperature to not less than 300.degree. C. Further, a simplified process for producing such a thermoelectric conversion material has been demanded.

Thermoelectric conversion material and a process for producing the same


A cabinet for storing items has at least one carousel rotatable about an axis of the cabinet, and each carousel has a plurality of compartments formed about the axis. The cabinet is structured to store items into the compartments or discharge items out of the compartments.

Storing of items e.g. in cabinets, apparatuses, dispensers (or the like) may be for various purposes, where in some cases the method and structure of storage may depend on the type of items to be stored.
US2010324728 for example describes an automatic dispenser for dispensing drugs and medications to patients. The dispenser includes a remote dispenser that transmits and receives information from a communications network and dispenses prescription drugs to the patient.
US2011014018 in another example describes a storage apparatus for packages. The apparatus has a rack of storage bins and a pick head drive unit to drive a pick head to an access location for a selected bin. Withdrawal of packages acts by dragging a desired package from the selected bin.
US2012004770 in yet another example describes a vending machine, in communication with a remote station, that delivers a labeled container to a user from storage holding containers of different sizes and shapes and containing different products such as medicaments.
Certain storing cabinets and/or storing methods may be referred to as automated storage and retrieval system (ASRS or AS/RS) that typically consist of a variety of computer-controlled systems for automatically placing and retrieving loads from defined storage locations.
Such automated storage and retrieval systems (AS/RS) are typically used in applications where there is a very high volume of loads being moved into and out of storage AS/RS systems may be designed for automated storage and retrieval of parts and items in manufacturing, distribution, retail, wholesale and institutions (or the like).
An example of other systems that may be referred to as fulfilling storage of goods may be of a type generally similar to so-called vending machines that are configured to dispense items to customers automatically, in response to action made to a customer.
The term "last mile delivery" is nowadays associated to supply chain management and relates to the last leg of transportation and/or delivery of goods to their final-destination. Such "last mile delivery" entails challenges relating, inter alia, to processing deliveries e.g. in urban areas, to retail stores, merchants (and the like).
Growth in e-commerce for example entails challenges in efficiency of "last leg of delivery" or "last block delivery" to a consumer's home or business, e.g. due to consumers often being away from home when deliveries are normally made. Some solutions to these challenges include lockers that are placed in urban centers where customers can obtain their goods.


An image forming apparatus is able to form steady test-pattern toner images for calibration of reflection density detection characteristics with ample toner. The operation consists of forming a test-pattern toner image for calibration of the reflection density detection characteristics, which is formed of a plurality of toner images of different colors aside from a reference test-pattern toner image for controlling image forming conditions, detecting the detection characteristics of a reflection density sensor from the result of detection of the quantity of toner attached to the test-pattern toner image for calibration of the reflection density detection characteristics, and calibrating the output characteristics of the reflection density sensor.

This invention relates to an image forming apparatus, such as a printer, facsimile, copier, and the like, that forms images by use of an electrophotographic method to develop electrostatic latent images with colored particles (toner), and to a method for detecting the detection characteristics of an optical reflection density sensor which is used in the image forming apparatus.
In the electrophotographic image forming field of copiers and laser printers, to stabilize the supply of toner to developers (replacement of developers) and the formation of images, the image forming apparatus forms a reference test pattern for controlling the image forming conditions on a photosensitive element or an intermediate transfer element under a preset operating condition, detects the quantity of toner on the test pattern, controls the supply of toner to the developer or the image forming condition (such as the charging potential, the exposure intensity, and the developing bias on the photosensitive element) and thus controls the quality of the recorded image.
In the steps of detecting the quantity of toner on the test pattern and controlling the image forming conditions, it is important that the detection characteristics of the optical reflection density sensor are stable with time. However, the detection characteristics of the optical reflection density sensor in actual use tend to deteriorate because of time-lapse deterioration of the light emitting diode (LED) that is used as is a light source for illuminating the test pattern and the light receiving photo diode (PD) that is used as a detection element and because of time-lapse contamination of the optical system. To suppress this influence, the detection characteristics of the optical reflection density sensor must be detected before the quantity of attached toner is detected.
One of the known methods for detecting the detection characteristics of the optical reflection density sensor is disclosed in Japanese Application Patent Laid-open Publication Hei 07-225501. Using a calibration reflector as a reference, this method detects the intensity of light reflected by the reflector and effects control to keep the result of detection at a preset value.
Another known detecting method is disclosed in Japanese Application Patent Laid-open Publication Hei 01-197777. Using a reflection density sensor having a characteristic in which the detection output is reduced as more toner attaches, this method forms a high-density test pattern toner image containing 1.5 to 3 times the usual quantity of toner attachment on the toner retainer by increasing the developing bias, detects the quantity of toner attached to the test pattern toner image and corrects the detection output.
Among the conventional methods for detecting the detection characteristics of an optical reflection density sensor, the detection method using a reference calibration reflector requires a driving mechanism for retracting the calibration reflector when the characteristic detection is not being implemented. This increases the required amount of mounting space and the number of parts. Therefore, it is hard to apply this method to a small inexpensive image forming apparatus.
Further, the method which uses a high-density test pattern toner image cannot detect such a high-density test pattern toner image when the high-density test pattern toner image cannot be formed by increasing the developing bias. This decreases the control precision. As one of the reasons why a high-density test pattern image cannot be formed, we can assume that this is due to deterioration of the developing ability of the developers that form the test pattern toner image.

Image forming apparatus and method of detecting the detection characteristics of a reflection density sensor


A store fixture for displaying apparel or other hangable merchandise employs a horizontal support bar that is supported at an elevated position, and at least one swing-arm hang bar is pivotally supported situated underneath the horizontal support bar. The swing-arm hang bar has one or more projecting rods or tubes serving as arms on which the hangable merchandise can be suspended. The swing arm has a sleeve journaled on a pivot that is affixed to the support arm. There is a detent arrangement provided between the pivot and the sleeve, so that the swing-arm hang bar releasably locks into a first position that is at one angle to the horizontal support bar, parallel to the support bar, and a second position that is at another angle, a right angle, to it. Store personnel can change the orientation of the hang bars by simply lifting them up slightly to release the detents and ten rotating them to the desired position. Re-arranging the hang bars does not require any tools, nor removal or installation of any parts.

This invention is directed to store fixtures or racks of the type used for displaying merchandise, and is more particularly concerned with store fixtures that can be used for displaying hanging articles, e.g., shirts, jackets, or other articles of apparel. The invention is more particularly concerned with a display rack in which can be easily reconfigured in the store without tools between an in-line orientation and a transverse orientation.
Retailing of apparel and other similar items to customers requires that the articles be displayed in a way that will be attractive to the purchaser, and which will allow store personnel to display the clothing articles in an optimal way. Typical display racks have a hang bar that is supported on a standard or between standards above the floor, or else have a hang bar that is cantilevered from a wall or other support, with the clothing articles being hung from the hang bar.
It is desirable that the store fixtures be a simple a design as possible, so that the store personnel can set them up and reconfigure them without having to use tools and without having to remove or add any parts. A number of foldable or reconfigurable display racks have been presented, and some of these appear in U.S. Pat. No. 4,655,354 to Cohen; U.S. Pat. No. 4,981,227 to Ingram; and U.S. Pat. No. 4,316,547 to Varon. The Varon display rack is of interest in that it employs a main transverse hang rail and additional transverse hang rails that are cantilevered at right angles onto the main rail. Varon has U-shaped brackets for the transverse hang rails, so that the transverse hang rails can only be positioned at a right angle to the main rail.
What is not currently available is a store display rack that can be easily set up and reconfigured from an in-line display orientation for clothing to a transverse orientation, and in which the rack can be easily reconfigured, in only a few seconds, without need for tools or additional parts.


A search query is used to search on a corpus of documents. A statistical collocation analysis is performed on the search results. A list of collocations is determined and can be presented to a user. The search can be refined by modifying the search query, so that the search results include documents with desirable collocations or exclude documents with undesirable collocations.

When performing search queries of large corpora (e.g., the Internet), many irrelevant documents are often included in the search results because they contain all of the query terms. For example, a user searching for reviews of a particular model of camera may search for the name of the camera. In addition to the desired reviews, many online stores selling the camera may be returned, and these results may dominate the top of the result set. A conventional technique that users can apply to refine the search results is to add one or more terms to the query, such as the term "review." Many online stores, however, allow shoppers to submit product reviews, so some of those documents may contain text, such as "Be the first to review this product," making the refinement ineffective.


A method for estimating the severity of generator unit outage and multi-terminal branch outage contingencies with respect to voltage collapse in large-scale electric power systems which includes the steps of estimating a post-contingency saddle-node bifurcation induced voltage collapse point of an electric power system following a set of generator unit outages and/or a set of branch outages and calculating a distance to collapse of said power system. The post-contingency voltage collapse point is determined by application of a nonlinear contingency screening method.

1. Field of the Invention
This invention relates to an analytical and computational method for estimating the severity of generator unit outage and multi-terminal branch outage contingencies with respect to voltage collapse in large-scale electric power systems. The severity of a contingency is defined by the xe2x80x9cdistance to collapsexe2x80x9d along a given transfer direction. More particularly, this method estimates how much stress, expressed in megawatts (MWs) and/or megavars (MVARs), a power system can handle before a widespread blackout occurs.
2. Description of Prior Art
Voltage collapse is a physical phenomenon found in electric power systems where voltage magnitudes decline rapidly, resulting in widespread disturbances. Voltage collapse has caused widespread blackouts in major metropolitan areas all over the world, for example Tokyo in 1987 and the entire Western System Coordinating Council (WSCC) region including San Francisco and Los Angeles in 1996. Thus, there is a need for a method to determine or estimate a point at which voltage collapse will occur.
U.S. Pat. No. 5,796,628 teaches a method for preventing voltage collapse in a power-generating system in which a performance index is calculated, which is directly correlated to load demands. The performance index is then used to identify weak areas in the power-generating system. A direct relationship between performance index and load demand enables assessment of the status of the power-generating grid system, in order to avoid a potential voltage collapse. Voltage profiles are generated to identify weak areas of the power-generating system, so that certain loads can be shed.
U.S. Pat. No. 5,745,368 teaches a method for analyzing voltage stability of low and high voltage applications in which two or more contingencies of a bulk power supply system are selected, screened and ranked based on a predetermined ranking algorithm. A voltage collapse index is generated and a stable branch of the bulk power supply system is approximated. A voltage versus power curve is created using a plurality of stable equilibrium points. An approximate voltage collapse point is then calculated.
U.S. Pat. No. 5,719,787 teaches on-line dynamic contingency screening of electric power systems. A sequence of contingency classifiers are used in a method for finding the controlling unstable equilibrium point of the power system, known as the boundary of stability region based controlling unstable equilibrium point method (the BCU method). Contingencies identified as definitely stable require no further analysis. Other contingencies classified as being unstable or undecided are applied to a time-domain simulation program to determine if the contingencies are unstable and require further action.
U.S. Pat. No. 4,974,140 teaches a voltage stability discriminating system for a power system in which a multiple load flow solution relating to a voltage stability discrimination is calculated for a power system. A pair of multiple load flow solutions are calculated and are closely located to each other with respect to the voltage stability discrimination for the power system.
U.S. Pat. No. 5,642,000 teaches a method for determining a performance index for power-generating systems, which are directly correlated to load demands. A performance index is used to assess the amount of load increase that a power-generating system can tolerate, prior to voltage collapse conditions. The performance index can also be used to assess whether the system can sustain a contingency without collapse.
U.S. Pat. No. 5,610,834 teaches a method for improving voltage stability security in a power transmission system that has a plurality of buses and a plurality of sources of reactive reserves coupled to the buses. A first voltage enhancement and a second voltage enhancement may include switchable shunt capacitors, synchronous voltage condensers, static var compensators or a combination of such devices. A third enhancement can include a series of capacitors, parallel lines, or a combination of series capacitors and parallel lines.
U.S. Pat. No. 5,594,659 teaches a method for performing voltage stability security assessment for a region of an electric power transmission system in which a multiple contingency analysis is performed for each of a plurality of reactive reserve basins, using single contingencies with a corresponding quantity that exceeds a predetermined threshold.
U.S. Pat. No. 5,566,085 teaches a stability transfer limit calculation for a power network having two or more independent alternating current generators that supply a common load over separate alternating current transmission lines.
Contingency screening is becoming more important in the new deregulated environment. As the electric power industry moves toward an open and competitive electric power market, the commercial success of the new market depends on accurate, up-to-date information. Open Access, one of the basic tenets of the deregulated power industry, allows all parties equal access to the transmission grid. As the number of energy transactions increases, so does the complexity of determining the capability of the transmission network.
To serve all parties equally, the Federal Energy Regulatory Commission (FERC) has mandated that all transmission owners must publicly declare the xe2x80x9cAvailable Transfer Capabilityxe2x80x9d (ATC) of their transmission facilities. ATC has been characterized by the North American Electric Reliability Council (NERC) as a measure of the transfer capability remaining in the physical transmission network for further commercial activity over and above already committed uses. ATC is defined as the Total Transfer Capability (TTC), less the Transmission Reliability Margin (TRM), less the sum of existing transmission commitments (which includes retail customer service) and the Capacity Benefit Margin (CBM).
Currently, the electric power industry has chosen to use a linear approximation technique for determining ATCs. In some cases, xe2x80x9cMW proxiesxe2x80x9d are used to represent voltage and stability problems, but the proxies are only valid for a single operating point yet the power system evolves constantly due to event and loading disturbances. In special situations, a full nonlinear AC power flow simulation is used to back up the linear analysis. Since the nonlinear AC power flow techniques are computationally expensive, the faster linear techniques are used in many situations where nonlinear analysis should be used.
Contingency screening based on linear analysis is not sufficient for determining ATCs, but it is quick. The acceptance of a nonlinear tool would be swift if the tool could screen contingencies faster than it takes to run a full nonlinear AC power flow.
Accordingly, it is one object of this invention to provide a system having the ability to handle the nonlinearity in transfer capability while requiring less than the computation time of a single nonlinear AC power flow solution.
It is another object of this invention to provide a nonlinear system which is capable of screening contingencies faster than it takes to run a full nonlinear AC power flow.
These and other objects of this invention are addressed by a method for estimating the amount of stress, expressed in megawatts and/or megavars, a power system can handle before occurrence of a widespread blackout comprising the steps of estimating a voltage collapse point of said power system following a set of generator unit outages and/or a set of branch outages and calculating a distance to collapse of said power system. Voltage collapse in accordance with the method of this invention is determined by nonlinear contingency screening.
Nonlinear contingency screening is an analytical and computational method for estimating the severity of generator unit outage and multi-terminal branch outage contingencies with respect to voltage collapse in large-scale electric power systems. To determine the severity of generator unit outage and multi-terminal branch outage contingencies with respect to voltage collapse, the nonlinear contingency screening method estimates the (post-contingency) voltage collapse (saddle-node bifurcation) point of a large-scale power system following a generator unit outage or a branch outage. Once the post-contingency state has been estimated, then the xe2x80x9cdistance to collapsexe2x80x9d can be determined. The critical step in determining contingency severity with respect to voltage collapse is the estimation of the post-contingency voltage collapse point of the power system. Nonlinear contingency screening in accordance with the method of this invention estimates the post-contingency voltage collapse point (saddle-node bifurcation point) quickly and accurately.

Nonlinear contingency screening for voltage collapse


The present invention relates to methods for the treatment and diagnosis of immune related diseases, including those mediated by cytokines released primarily either Th1 or Th2 cells in response to antigenic stimulation. The present invention further relates to methods for biasing the differentiation of T-cells in either the Th1 subtype or the Th2 subtype, based on the relative expression levels of the gene TCCR, and its agonists or antagonists. The present invention further relates to a method of diagnosing Th1- and Th2-mediated diseases.

Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.
Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.
T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e. lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.
A central event in both humoral and cell mediated immune responses is the activation and clonal expansion of helper T cells. Helper T cell activation is initiated by the interaction of the T cell receptor (TCR)—CD3 complex with an antigen-MHC on the surface of an antigen presenting cell. This interaction mediates a cascade of biochemical events that induce the resting helper T cell to enter a cell cycle (the G0 to G1 transition) and results in the expression of a high affinity receptor for IL-2 and sometimes IL-4. The activated T cell progresses through the cycle proliferating and differentiating into memory cells or effector cells.
The immune system of mammals consists of a number of unique cells that act in concert to defend the host from invading bacteria, viruses, toxins and other non-host substances. The cell type mainly responsible for the specificity of the immune system is called the lymphocyte, of which there are two types, B and T cells. T cells take their designation from being developed in the thymus, while B cells develop in the bone marrow. The T-cell population has several subsets, such as suppressor T cells, cytotoxic T cells and T helper cells. The T-helper cell subsets define 2 pathways of immunity: Th1 and Th2. The Th1 cells, a functional subset of CD4+ cells, are characterized by their ability to boost cell mediated immunity. The Th1 cell produces cytokines Il-2 and interferon-γ, and are identified by the absence of Il-10, Il-4, Il-5 and Il-6.
The Th2 cell is also a CD4+ cell, but is distinct from the Th1 cell. The Th2 cells are responsible for antibody production and produce the cytokines Il-4, Il-5, Il-10 and Il-13. (see FIG. 1). These cytokines play an important role in making the Th1 and Th2 responses mutually inhibitory. The interferon-γ that is produced by the Th1 cells inhibits the proliferation of Th2 cells (FIG. 2) while IL-10 produced by the Th2 cells represses the production of interferon-γ (FIG. 2).
Members of the four helical bundle cytokine family (Bazan, J. F., 1990, Proc Natl Acad Sci USA, 87:6934-8) have been found to play a critical role in the expansion and terminal differentiation of T helper cells from a common precursor into distinct populations of Th1 and Th2 effector cells. O'Garra, A., 1998, Immunity, 8:275-83. IL-4 influence predominantly the development of Th2 cells while IL-12 is a major factor involved in the differentiation of Th1 cells. Hsieh, C. S., et al., 1993, Science, 260:547-9; Seder, R. A., et al., 1993, Proc Natl Acad Sci USA, 90:10188-92; Le Gros, G., et al., 1990, J Exp Med, 172:921-9; Swain, S. L., et al., 1991, Immunol Rev, 123:115-44. Accordingly, mice deficient in IL-4 (Kuhn, R., et al, 1991, Science, 254:707-10), IL-4 receptor chain (Noben-Trauth, N., et al., 1997, Proc Natl Acad Sci USA, 94:10838-43), or the IL-4 specific transcription factor STAT6 (Shimoda, K., et al., 1996, Nature, 380:630-3) are defective in Th2 responses, while mice deficient in IL-12 (Magram, J., et al., 1996, Immunity, 4:471-81), IL-12 receptor (IL-12R) 1 chain (Wu, C., et al., 1997, J Immunol, 159:1658-65), or the IL-12 specific transcription factor STAT4 (Kaplan, M. H., et al., 1996, Nature, 382:174-7) have impaired Th1 responses.
Th-1 and Th-2 cell subtypes are believed to be derived from the common precursor, termed a Th-0 cell. In contrast to the mutually exclusive cytokine production of the Th-1 and Th-2 subtypes, Th-0 cells produce most or all of these cytokines. The release profiles of the different cytokines for the Th-1 and Th-2 subtypes plays an active role in the selection of effector mechanisms and cytotoxic cells. The Il-2 and γ-interferon secreted by Th-1 cells tends to activate macrophages and cytotoxic cells, while the Il-4, Il-5, Il-6 and Il-10 secreted by Th-2 cells tends to increase the production of eosinophils and mast cells as well as enhance the production of antibodies including IgE and decrease the function of cytotoxic cells. Once established, the Th-1 or Th-2 response pattern is maintained by the production of cytokines that inhibit the production of the other subset. The γ-interferon produced by Th-1 cells inhibits production of Th-2 cytokines such as Il-4 and Il-10, while the Il-10 produced by Th-2 cells inhibits the production of Th-1 cytokines such as Il-2 and γ-interferon.
The upset of the delicate balance between the cytokines produced by the Th1 and Th2 cell subsets leads to a host of disorders. For example, the overproduction of Th1 cytokines can lead to autoimmune inflammatory diseases, multiple sclerosis and inflammatory bowel disease (e.g., Crohn's disease, regional enteritis, distal ileitis, granulomatous enteritis, regional ileitis, terminal ileitis). Similarly, overproduction of Th2 cytokines leads to allergic disorders, including anaphylactic hypersensitivity, asthma, allergic rhinitis, atopic dermatitis, vernal conjunctivitis, eczema, urticaria and food allergies. Umetsu et al., Soc. Exp. Biol. Med. 215: 11-20 (1997).
WO 97/44455 filed 19 May 1997 and Sprecher et al., Biochem. Biophys. Res. Commun. 246: 82-90 (1998) describe cytokine receptor molecules possessing a certain degree of sequence identity with the murine and human TCCR molecules herein. The murine and human prior art cytokine receptors are purported to be expressed in lymphoid tissue, including the thymus, spleen, lymph nodes and peripheral blood leukocytes—and are further indicated to be present on both B- and T-cells and have a function relating to the proliferation, differentiation and/or activation of immune cells, perhaps in the development and regulation of the immune response. However, WO97/44455 and Sprecher et al., supra identify neither the precise role of TCCR and its homologs in the mediation of T-cell differentiation and cytokine release profiles into Th1 subtype and Th2 subtype, nor the host of disorders that are implicated by the release of the cytokine T-cell subtypes.

Modulation of T cell differentiation for the treatment of T helper cell mediated diseases


A pharmaceutical formulation for subcutaneous, intramuscular or intradermal administration comprising recombinant coagulation factor VIII and use thereof for manufacture of a medicament for treating haemophilia is provided. The formulation comprises a highly purified recombinant coagulation factor VIII in a concentration of at least 1000 IU/ml, which gives surprisingly high levels of active factor VIII in the blood stream after subcutaneous, intramuscular or intradermal administration. The formulation is intended for treatment of haemophilia by subcutaneous, intramuscular or intradermal administration. The recombinant factor VIII is preferably a deletion derivative thereof, which can be used for the manufacture of a medicament for subcutaneous administration.

Haemophilia is an inherited disease which has been known for centuries but it is only within the last three decades that it has been possible to differentiate between the various forms; haemophilia A, haemophilia B and haemophilia C. Haemophilia A is the most frequent form. It affects only males with an incidence of one or two individuals per 10 000 live-born males. The disease is caused by strongly decreased level or absence of biologically active coagulation factor VIII (antihaemophilic factor), which is a protein normally present in plasma. The clinical manifestation of haemophilia A is a strong bleeding tendency and before treatment with factor VIII concentrates was introduced, the mean age of those patients was less than 20 years. Concentrates of factor VIII obtained from plasma have been available for about three decades. This has improved the situation for treatment of haemophilia patients considerably and given them possibility to live a normal life.
Therapeutic factor VIII concentrates have until now been prepared by fractionation of plasma. However, there are now methods available for production of factor VIII in cell culture using recombinant DNA techniques as reported in e.g. J Gitschier et al. Nature 312, p.330-37, 1984 and EP-A-160 457.
Factor VIII concentrates derived from human plasma contain several fragmented fully active factor VIII forms (Andersson et al, Proc. Natl. Acad. Sci. USA, Vol 83, p. 2979-83, May 1986). The smallest active form has a molecular mass of 170 kDa and consists of two chains of 90 kDa and 80 kDa held together by a metal ion bridge. Reference is here made to EP-A-197 901. Kabi Pharmacia has developed a recombinant factor VIII product which corresponds to the 170 kDa plasma factor VIII form in therapeutic factor VIII concentrates. The truncated recombinant factor VIII molecule is termed r-VIII SQ and is produced by Chinese Hamster Ovary (CHO) cells in a cell culture process in serum-free medium.
The structure and biochemistry of recombinant factor VIII products in general have been described by Kaufman in Tibtech, Vol 9, 1991 and Hematology, 63, p. 155-65, 1991. The structure and biochemistry of r-VIII SQ have been described in WO-A-91/09122.
Large proteins are normally given intravenously so the medicament directly available in the blood stream. It would however be advantageous if a medicament could be given subcutaneously, intramuscularly or intradermally as these administration forms are much easier to handle for the patient. Especially if the medicament must be taken regularly during the whole life and treatment is to start early, already when the patient is a child. However, a medicament with a very large and labile molecule, such as coagulations factor VIII of 170 to 300 kDa, have normally a very low bioaviability if given subcutaneously, intramuscularly or intradermally, since the uptake is not enough and degradation is severe. To our knowledge, the only coagulation factor protein which has been administered by subcutaneous injection is factor IX (90 kDa).
All presently available factor VIII preparations on the market are made as a formulation for intravenous administration and are stabilised with human serum albumin.

Method for treatment of hemophilia by extravascular administration of factor VIII deletion derivatives