The invention provides a block-encoded modulation scheme using multi-level partitioning techniques. This scheme is made transparent to phase ambiguities of .+-..pi./2 and of .pi., by means of differential encoding and appropriate mapping, it is applicable to 16-QAM modulation, and it has theoretical encoding gain that is optimal for the rate of the code. The decoder associated with this scheme uses the Wagner algorithm which is much less complicated to implement than the Viterbi algorithm or than the Reed-Solomon algorithm.

16-state quadrature amplitude modulation (16-QAM) is widely used in the field of radio communications because of its high spectral effectiveness (compared with the commonly used techniques of phase modulation and of frequency modulation), and because it is relatively simple to implement (implementing the modulator/demodulator, processing the signal, etc.).
Furthermore, in the context of radio transmission, the cost of leasing transmission channels is directly related to the transmitted spectrum width. That is why the channel encoding technique chosen for this type of link must have a high rate.
Finally, error-correcting encoding must not only have performance levels that are acceptable from the system point of view, but must also be as simple as possible to implement, in particular as regards the decoder.
In the context of the present invention, the data transmitted from a transmitter to a receiver is integrated into a framed structure having fixed redundancy. In which case, block coded modulation is preferable to trellis coded modulation (TCM).
It is known that, for such transmission, it is possible to use modulation and high-rate convolutional encoding that are separated from each other. In the case of a framed structure having a fixed rate (N redundancy bits being added to every K message information bits to be transmitted), 16-QAM modulation associated with a block code like the Reed-Solomon code with firm decision is a natural choice.
Unfortunately, the choice of convolutional encoding either separate from or associated with modulation (TCM encoding) implies a rate that is necessarily limited. In addition, such a choice is not compatible with the choice of a framed structure having a fixed rate. Furthermore, the corresponding decoder associated with a convolutional code (Viterbi algorithm) is relatively complex.
For modulation associating 16-QAM mapping with Reed-Solomon coding, it is necessary to use a complex decoder. Furthermore, that solution does not enable decoding to take place under flexible-decision conditions.
Moreover, when coherent demodulation is performed by a carrier-recovery system enabling the phase and the frequency of the signal to be synchronized on reception, there still remain phase ambiguities that must be removed after such synchronization. For example, all QPSK and n-QAM constellations (two-dimensional constellations) have three phase ambiguities (+.pi./2, -.pi./2, and .pi.) which must be removed. The encoding scheme is said to be "transparent to phase ambiguities" if it enables the sequence to be retrieved on reception as transmitted regardless of the phase ambiguity imparted on reception by carrier-recovery.

Encoding/decoding system using 16-QAM modulation encoded in multi-level blocks


The present invention relates to the use of the cyclic dinucleotide c-di-GMP and cyclic dinucleotide analogues thereof in a method for attenuating virulence of a microbial pathogen or for inhibiting or reducing colonization by a microbial pathogen. This method further inhibits microbial biofilm formation and is capable of treating bacterial infections. The microbial colonization or biofilm formation inhibited or reduced may be on the skin or on nasal or mucosal surface. The microbial colonization or biofilm formation inhibited can also be on the surfaces of medical devices, especially those in close contact with the patient, as well on the surfaces of industrial and construction material where microbial colonization and biofilm formation is of concern.

1. Field of the Invention
The present invention relates to the use of cyclic dinucleotides to attenuate virulence of microbial pathogens and to inhibit biofilm formation, thereby controlling microbial colonization or infections caused by a wide variety of microbial species.
2. Description of the Related Art
Cholera is an important diarrheal disease of humans that results in significant morbidity and mortality (Pollitzer, 1959; and Kaper et al., 1995). Cholera affects more than 75 countries and every continent (Communicable Disease Surveillance and Response, World Health Organization, who.org). Cholera is acquired by drinking fecally contaminated food or water containing pathogenic Vibrio cholerae that can colonize the small intestine and release cholera toxin (CT) resulting in massive secretory diarrhea and death if untreated (Kaper et al., 1995). Because of its high death-to-case ratio, persistence in water supplies and its ability to occur in explosive epidemic form, cholera is a public health concern. Furthermore, because of the potential threat of weaponized V. cholerae to the food and water supply, it is a priority organism in biodefense research. The threat to the economy, environment and human health is also highlighted by the finding that V. cholerae has the potential to be transported internationally and invade new regions through the ballast water of ships (McCarthy et al., 1994). V. cholerae is known to persist in the environment, however, the factors promoting the environmental persistence of V. cholerae are not well understood.
V. cholerae can alter its phenotype and reversibly switch from EPSoff (smooth colony morphology) to EPSon (rugose colony morphology) in which the cells are embedded in extracellular polysaccharide or rugose exopolysaccharide (rEPS) and display a wrinkled "rugose" colony morphology (FIGS. 1A and 1B) and an associated biofilm (White, 1940 and Rice et al., 1993). The switch to EPSon and the rugose phenotype promotes biofilm formation (Rice et al., 1993; Morris et al., 1996; and Watnick et al., 1999). Importantly, EPS is essential for V. cholerae biofilm formation. The rugose variant is highly chlorine resistant and shows increased resistance to killing by acid, UV light and complement-mediated serum bactericidal activity (Rice et al., 1993; Morris et al., 1996; and Yildiz et al., 1999). Therefore, switching to EPSon and the rugose phenotype might be important in niche specialization and in promoting survival and fitness in particular environments. Rugose strains are virulent and cause fluid accumulation in rabbit ileal loops, produce diarrhea in human volunteers and are highly resistant to complement-mediated bactericidal activity (Rice et al., 1993; Morris et al., 1996; and Yildiz et al., 1999). The rugose or wrinkled colony phenotype consisting of aggregating cells has been reported in S. enterica Enteritidis (Petter, 1993), S. enterica Typhimunium (Anriany et al., 2001), V. parahaemolyticus (Güvener et al., 2003), P. aeruginosa (Parsek, 2003), and Enterobacter sakazakii (Farmer et al., 1980). Research by the laboratory of the present inventor and others has also shown that production of V. cholerae EPS is linked to the type II general extracellular protein secretion pathway which is also involved in secretion of important virulence factors (Ali et al., 2000; Davis et al., 2000).
The vps (Vibrio polysaccharide) gene cluster in V. cholerae carries the structural genes for the biosynthesis of rEPS (Yildiz et al., 1999). The vps gene cluster is thought to be comprised of two closely located but separate operons in which vpsA and vpsL represent the first genes of each operon (Yildiz et al., 1999 and 2001). Transcription of vpsA and vpsL is regulated by VpsR (a homolog of σ54 transcriptional activators) by a mechanism that is not well understood (Yildiz et al., 2001). VpsR has high homology to NtrC, AlgB and HydG bacterial enhancer-binding protein that activates transcription after phosphorylation of its receiver domain by an associated sensor kinase protein (Kern et al., 1999). Previous studies have found that HapR in some V. cholerae strains is linked to the rugose phenotype by some unknown mechanism (Jobling et al., 1997) and CytR can repress transcription of vps genes and the associated biofilm formation (Haugo et al., 2002). The present inventor has also found that switching to the rugose phenotype in V. cholerae is independent of ToxT, LuxS and RpoS (Ali et al., 2002). However, the molecular basis underlying switch from the smooth to the rugose phenotype of V. cholerae is still not well understood.
Early studies on the rugose phenotype of V. cholerae were impeded by the very low frequency of switching to EPSon and the rugose phenotype under the conditions tested (Morris et al., 1996; Yildiz et al., 1999; and Wai et al., 1998). The laboratory of the present inventor recently identified conditions that promote the rapid shift (up to ˜80%) to the rugose phenotype in a process called high frequency rugose production (HFRP) (Ali et al., 2002). It was found that there are differences in the expression and stability of the phenotype between epidemic strains and that the ability to switch at high frequency was more common in epidemic V. cholerae strains than in nonpathogenic strains (Ali et al., 2002). This suggests that the ability to switch to the rugose phenotype is important in V. cholerae and might provide an adaptive advantage under specific conditions.
Biofilms are the primary mode of existence of many bacterial species and are central to their survival, persistence and often virulence (Costerton et al., 1995; Davey et al., 2000; Donlan, 2002 and Watnick et al., 2000). Biofilms resist environmental stresses and adverse conditions better than free-living cells, have increased nutrient availability and can better avoid immune responses (Anwar et al., 1992). A common feature of biofilms is that microorganisms are embedded in an extracellular matrix comprised mostly of EPS (Costerton et al., 1981 and Wingender et al., 1999). EPS is important for the structural and functional integrity of biofilms and determines its physicochemical and biological properties and has a role in adhesion, protection and facilitates community interactions (Wimpenny, 2000). EPS provides protection from a variety of environmental stresses such as UV radiation, pH shifts, osmotic shock, and desiccation.
The role of biofilms in the environmental persistence and transmission of certain pathogens is also well recognized. Like V. cholerae (Ali et al., 2002; Morris et al., 1996 and Yildiz et al., 1999), Salmonella enterica Typhimurium has the ability to form a rugose EPS-producing phenotype which has increased biofilm forming ability and is proposed to have a role in increased persistence in the environment (Anriany et al., 2001). Salmonella enteritidis biofilms resistant to cleaning fluids have been shown to persist for at least 4 weeks in domestic toilets after episodes of salmonellosis (Barker et al., 2000). The finding that E. coli and Salmonella biofilms can be found on sprouts may make their eradication with antimicrobial compounds difficult and therefore increasing their persistence, resulting in ingestion and infection (Fett, 2000). The importance of biofilms is also highlighted in the process of horizontal gene transfer since some results suggest that DNA exchange may be increased in bacteria that are attached to a surface and in biofilms rather than between free-swimming planktonic cells (Ehlers, 2000). This has implications in the transfer of genes encoding functions such as antibiotic resistance or virulence and overall persistence.
Clinically, biofilm formation is known to be a key factor in the establishment and persistence of several difficult to treat infections. Cystic fibrosis is caused by certain P. aeruginosa strains which express copious amounts of EPS and form biofilms in the lung (Davies et al., 1995; Geesey et al., 1993 and Govan et al., 1996). The EPS of these P. aeruginosa strains makes them recalcitrant to antimicrobial treatment.
Interestingly, like the EPS of V. cholerae (Ali et al., 2002 and Morris et al., 1996), alginate EPS production by P. aeruginosa protects these strains against chlorine and may contribute to survival of these bacteria in chlorinated water systems (Grobe et al., 2001). Another example of a biofilm-mediated infection is chronic ear infection (otitis media) (Dingman et al., 1998). Peridontitis is also another example of a biofilm-mediated disease that results from chronic inflammation of the tissue supporting the gums and can lead to tooth loss. The main microbe causing this disease is Porphyromonas gingivalis (Lamont et al., 1998).
The EPS matrix of biofilms has the potential to physically prevent access of certain antimicrobial agents into the biofilm by acting as an ion exchanger, thereby restricting diffusion of compounds from the external milieu into the biofilm (Goodell et al., 1985; Nichols et al., 1988 and Nickel et al., 1985). Helicobacter pylori produces a biofilm that appears to be important in enhancing resistance to host defense factors and antibiotics and in promoting growth under low pH conditions in vivo (Stark et al., 1999). Biofilm bacteria can be up to 1,000-fold more resistant to antibiotic treatment than the same organism grown planktonically (Gilbert et al., 1997). Clinical biofilm infections are marked by symptoms that typically recur even after repeated treatments with antibiotics. Moreover, biofilm infections are rarely resolved by the host's immune system (Costerton et al., 1999). Bacterial biofilms on prosthetic valves are the leading cause of endocarditis in patients who have undergone heart valve replacement. Among patients who develop these infections, the mortality rate is as high as 70% (Hyde et al., 1998). Millions of catheters (e.g., central line, intravenous, and urinary catheters) are inserted into patients every year, and these implants serve as a potential surface for biofilms. Overall, it is thought that upwards of 60% of all nosocomial infections are due to biofilms. These biofilm-based infections can increase hospital stays by up to 2-3 days and cost upwards of $1 billion per year in added costs (Archibald et al., 1997).
Staphylococcus aureus is another biofilm-forming bacteria that has long been recognized as an important human and animal pathogen (Archer, 1998; Hermans et al., 2003; Kluytmans et al., 1997 and Sutra et al., 1994). S. aureus can be found on the skin and mucosal surfaces of humans, particularly the anterior nares. If followed over time, ˜20% of the human population are persistent carriers; ˜60%, intermittent carriers while ˜20% of the population will never be colonized (Peacock et al., 2001). S. aureus is a common cause of both community-acquired and hospital-acquired infections. In a recent population-based active surveillance study from Canada, the annual incidence of invasive S. aureus infection was 28.4 per 100,000 population (Laupland et al., 2003). Certain populations including patients with indwelling medical devices such as vascular catheters, patients on hemodialysis, patients who use intravenous drugs, patients with dermatologic disease and diabetes mellitus have higher rates of colonization than the general population (Kirmani et al., 1978; Tuazon et al., 1975 and 1974). The S. aureus carrier state is clinically important because a carrier is at risk for infection with the colonizing strain. Studies in patients on dialysis, patients with HIV infection and patients with bloodstream infection support the hypothesis that S. aureus isolates causing infection are endogenous in origin when strains are examined by molecular typing (Ena et al., 1994; Luzar et al., 1990; Nguyen et al., 1999; von Eiff et al., 2001 and Yu et al., 1986). Hence, ways to inhibit or reduce S. aureus carriage and colonization are needed.
According to the Center for Disease Control and Prevention's National Nosocomial Infection Surveillance system, S. aureus is particularly a common cause of nosocomial infections and is the most common cause of surgical site infection and the second most common cause of nosocomial bacteremia (National Nosocomial Infections Surveillance (NNIS) Report, 1998). The overall number of S. aureus infections in intensive care units increased from 1987 to 1997 with the majority of the increase due to S. aureus isolates resistant to methicillin (Lowry, 1998). S. aureus is often resistant to multiple antibiotics. Infections caused by methicillin- and multiple antibiotic resistant S. aureus (MRSA) are particularly difficult to treat and MRSA infections are often associated with higher mortality and increased healthcare costs than methicillin-sensitive strains (Cosgrove et al., 2003).
S. aureus is also a common cause of intramammary infections (IMI) in lactating females and often results in chronic mastitis with annual losses in the dairy industry associated with subclinical mastitis in dairy cows across the U.S. being estimated at approximately $1 billion (Ott, 1999). The drug of choice for infections due to methicillin-resistant S. aureus (MRSA) is vancomycin, although this antibiotic is given as a last line of treatment.
Like other bacterial species, biofilm formation is known to be a key factor in the establishment and persistence of staphylococcal infections. Bacterial cells in biofilms can be up to 1,000-fold more resistant to antibiotic treatment than the same cells grown planktonically. Consistent with this observation, biofilm formation on tissues or on medical devices is an important first step in the pathogenesis of S. aureus infection of humans and animals (Bradley et al., 1991; Cole et al., 2001; Cucarella et al., 2001, 2002 and 2004; Götz, 2002; Huang et al., 2003; Kluytmans et al., 1997; Mest et al., 1994; Muder et al., 1991; Peacock et al., 2001; Pujol et al., 1996; and Roghmann et al., 2001). Overall, it is thought that upwards of 60% of all nosocomial infections involve biofilms. These biofilm-based infections can increase hospital stays by up to 2-3 days and cost upwards of $1 billion per year in added costs. Although the risk of infection is high in people colonized with S. aureus, there is another compelling reason to prevent colonization and biofilm formation, which is to prevent the transmission of S. aureus to others (Muto et al., 2003). MRSA does not spontaneously emerge from existing methicillin-susceptible S. aureus. The majority of people with MRSA colonization acquire MRSA through exposure to the hands of healthcare workers transiently colonized with MRSA from prior contact with an MRSA infected or colonized patient (Muto et al., 2003). Infection control measures such as isolation and handwashing reduce but do not eliminate this transmission, although compliance with these policies is often low (Richet et al., 2003). Decolonization regimens, as an approach to controlling transmission to others, have generally been unsuccessful as the eradication of MRSA is generally only temporary. Therefore, the development of novel intervention strategies that prevent or inhibit colonization and biofilm formation are needed.
Cyclic nucleotides, such as cAMP and CGMP, are well recognized as important low-molecular weight signaling molecules in eukaryotes. In bacteria, while cAMP has a role in alleviating glucose catabolite repression (Jackson et al., 2002; Notley-McRobb et al., 1997), cGMP has not been shown to act as a signaling molecule. However, another guanosine nucleotide, the cyclic dinucleotide c-di-GMP (also known as 3′,5′-cyclic diguanylic acid, cyclic diguanylate, cyclic diguanosine monophosphate, cyclic bis(3′→5′)diguanylic acid, cyclic diguanylic acid, cGpGp, and c-GpGp)
where G in the above structure is guanine, has been reported to be an intracellular bacterial signaling molecule in a few species and whose structure is known and consists of two cGMP molecules bound head-to-tail (Jenal, 2004 and Ross et al., 1991). c-di-GMP was first identified in Acetobacter xylinum (renamed Gluconacetobacter xylinum) and shown to regulate cellulose production in this species (Amikam et al., 1989; Mayer et al., 1991; Ross et al., 1990 and 1991). The exact molecular mechanism remains unclear but regulation in G. xylinum appears to involve c-di-GMP binding to a membrane protein that activates gene expression. Cellulose production appears to be modulated by the opposing effects of two proteins with GGDEF domains, diguanylate cyclase (Dgc) and c-di-GMP phosphodiesterase (PdeA), each controlling the level of c-di-GMP in the cell. Thus, c-di-GMP is thought to be a signaling molecule.
Based on studies by the laboratory of the present inventor and others, it is now becoming increasingly reported that biofilm formation in many pathogens including Vibrio cholerae, Yersinia pestis, Salmonella enteritidis Typhimurium and Pseudomonas aeruginosa is associated with GGDEF proteins (Bomchil et al., 2003; D'Argenio et al., 2002; Jones et al., 1999 and Römling et al., 2000).
The increasing emergence of antimicrobial resistance in bacterial pathogens and the importance of colonization and biofilm in the infection process requires that alternate antimicrobial strategies be developed. Until the present invention, the application of cyclic dinucleotides such as c-di-GMP for use as an antimicrobial approach in the control of biofilms and potentially infection has not been described.
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement.

Method for attentuating virulence of microbial pathogens and for inhibiting microbial biofilm formation


A filling machine assembly (20) for filling a beverage container (24), such as a bottle or can, with a liquid beverage, such as beer or soft drinks. The filling machine (20) includes a support housing (40) having an inner fluid chamber (46) for supplying the liquid to be discharged into the container (24). A valve housing (48) is mounted to the bottom (16) of the support housing (40) for controlling the discharge of the liquid and a control device (52) is disposed adjacent to the top (14) of the support housing (40). A vent tube (54) is actuated upward and downward via the control device (52) and extends into the valve housing (48). The filling machine (20) is characterized by the control device (52) including at least one magnet (66) moveable between a first position and a second position for moving the vent tube (54) a predetermined stroke between a filling position and a non-use position. The subject invention also incorporates the novel feature of having a support tube (60) mounted within the support housing (40) and substantially surrounding the vent tube (54) with the support tube (60) having an upper portion (76) extending above the upper surface (42) outside of the fluid chamber (46).

1) Technical Field
The subject invention relates to a beverage filling machine having an adjustable vent tube.
2) Description of the Prior Art
Filling mechanisms used for filling containers, such as cans, jars, or bottles, with a beverage, such as beer or soft drinks, are well known in the art. The conventional filling mechanisms feed the containers into a star wheel conveyor which individually positions each container on a rotating turntable below a valve assembly of an individual filling machine. The container moves into sealing engagement with the valve assembly by either moving the container upwardly or by lowering the valve assembly. The filling machines are known in the art as counter pressure filling machines as is discussed below. There may be as many as 120 individual filling machines disposed circumferentially around the turntable. The filling machines typically include a support housing having an inner fluid chamber or ring bowl disposed above the valve assembly. The ring bowl is usually annular and contains the liquid or beverage for filling the containers and has a space above the liquid for a pressurized inert gas such as carbon dioxide or nitrogen. This space above the liquid is known as the headspace. A common storage tank or reservoir feeds each individual ring bowl with the liquid and gas.
In the typical filling operation, the container, which is sealed against the valve assembly, is initially purged with the inert gas from the ring bowl for a predetermined time in order to flush air and other impurities from the container. A vent tube is introduced into the container to accomplish this an other operations. The liquid is filled into the container from the ring bowl while the gas from the container vents through the vent tube into the headspace. The liquid will at least partially rise into the vent tube during the filling of the container. The gas pressure in the container and the ring bowl are equalized when filling begins. This is what is known as counter pressure, which allows the liquid to flow into the container solely under the influence of gravity. After the container is filled to a desired level, the vent tube rises out of the container. Finally, gas is released from the headspace of the container to the atmosphere by an process commonly known as "snifting".
The beverage filling industry continuously strives for machinery and methods which facilitate rapid, economical, efficient, and sterile filling of containers. As discussed above, methods and apparatuses for filling containers with carbonated liquids have evolved into counter pressure filling machines. The prior art devices utilize complicated mechanical or pneumatic mechanisms for adjusting the height of the vent tube during the filling operation.
Examples of such devices are shown in U.S. Pat. No. 3,595,280 to Fissel and U.S. Pat. No. 3,633,635 to Kaiser. These known devices can be expensive and difficult to maintain.
Further, such mechanical or pneumatic devices could significantly jeopardize the sterile environment of the filling machines. In particular, the known prior art devices utilize a number of seals which separate the inner working components of the filling machine, which include the vent tube, with the atmosphere. The pressures exerted against the seals can be significant. Hence, after repeated use, the seals are subject to failure which reduces the operating life of the filling valves and effects the integrity of the entire filling machine.
Accordingly, there is a need for a vent tube adjustment mechanism which is of a relatively simple design and does not jeopardize the sterile environment of the filling machines. The adjustment mechanism preferably eliminates the seals which are subject to the counteracting pressures of the filling machines, thereby reducing the likelihood of a failure.

Filling machine assembly having a magnetic adjustment mechanism


An adapter for a memory device for connecting a detachable memory device to an AT attachment (ATA) interface of a host computer and a connecting method using the adapter are presented. With a conventional adapter which is not supplied with a number of heads and a number of sectors per track of the memory device in advance, the actual numbers of the memory area of the memory device may be different from those supplied the adapter for a memory device. This prevents the memory device from being normally accessed in a cylinder head sector (CHS) mode by the adapter. The adapter for a memory device according to the present invention identifies a file format of data stored in the memory area in the memory device, and retrieves and saves data about the number of heads and the number of sectors per track. Even if the adapter is not previously supplied with the number of heads and the number of sectors per track of the memory device, it accordingly allows the memory device to be accessed in the CHS mode.

1. Field of the Invention
The present invention relates to an adapter for a memory device used in a host computer and particularly to a PC card adapter arranged for detachably connecting a memory device smaller in size than the PC card to the PC card ATA interface of a host computer.
2. Description of the Related Art
A variety of portable apparatuses have rapidly prevailed throughout the market. Those portable apparatuses are commonly accompanied with a detachable external memory device for exchanging data with other apparatuses. A representative external memory device is a PC card. The PC cards are generally installed in personal computers, digital cameras, personal digital assistants (PDA), and hand-held terminals. Digital cameras commonly accompany small memory devices such as smart media cards, which can not conform to the ATA interface, for storage of image data. A PC card adapter is used for connecting the PC card to the ATA interface and allowing a personal computer to read and write image data on the memory device. Such a PC card adapter is illustrated below as a typical adapter for a memory device.
The PC card ATA interface is commonly used as the interface to a PC card. The ATA interface has two modes used for accessing the memory area: a logical block access (LBA) mode for allocating sector numbers to the memory area from the top to be accessed; and a cylinder head sector (CHS) mode for reading and writing data by pointing to the location determined by a cylinder, a head, and a sector. It is also essential for the reading and writing of data in the CHS mode to specify the number of heads (the maximum of the applicable head number plus one) and the number of sectors per track (the maximum of the sector number to be specified).
A conventional PC card adapter is pre-arranged to accommodate such a size of memory capacity that the number of heads specified by the PC card adapter is equal to the number of heads needed for reading and writing data on the memory area of a memory device in the CHS mode. Simultaneously, the numbers of sectors per track specified by the PC card adapter is equal to the number of sectors per track needed for reading and writing data in the CHS mode. This allows a host computer to selectively use either the number of heads and the number of sectors per track specified by the PC card adapter or those in the memory area of the memory device. In each case, the number of heads and the number of sectors per track are equal to the others, hence allowing the host computer to read and write data in the memory device in the CHS mode.
For pre-arranging to match the number of heads and the number of sectors per track, the number of heads and the number of sectors per track depending on the memory capacity are stored in the form of a table in a ROM.
However, if not pre-arranged to match the number of heads and the number of sectors per track with the memory device, the number of heads and the number of sectors per track specified by the conventional PC card adapter may be different from those stored in the memory area of the memory device. If different, a known adapter for a memory device such as the conventional PC card adapter is prevented from normally accessing the memory device in the CHS mode.
When loaded with a newly introduced memory device which is unique in the number of heads and the number of sectors per track, the conventional adapter for a memory device is not compatible and it is difficult to access the memory device in the CHS mode.
The number of combinations of the number of heads and-the number of sectors per track stored in the form of a table in the ROM is dependent on the memory capacity. When being compatible to various types of memories, an adapter needs a large table, thus requiring a large capacity ROM.
This invention provides an adapter for a memory device which can access the memory device in the CHS mode when being incompatible in the number of heads and the number of sectors with the memory device and a connecting method using the same.
The adapter for a memory device according to the present invention arranged for connecting the memory device having a memory area the ATA interface of a host computer comprises:
(a) a first connector for connecting to the memory device;
(b) a second connector for connecting to the ATA interface of the host computer;
(c) a memory device accessing means for reading and writing data on the memory area of the memory device;
(d) an ATA interface controller for exchanging data with the host computer through the ATA interface of the host computer; and
(e) a file format identifying means for identifying the file format of data stored in the memory area of the memory device, the file format identifying means comprising (e-1) a means for identifying the type of the file format from a file format data stored in the memory device and (e-2) a means for retrieving and saving the number of heads and the number of sectors per track.
The number of heads and the number of sectors per track specified by the adapter for a memory device can accordingly be equal to those in the memory area of the memory device. The problem with a conventional adapter being that the action of accessing is hardly executed in the CHS mode can be solved with the adapter of the present invention. The adapter of the present invention can access, in the CHS mode, the memory device with a newly-provided number of heads and a newly-provided number of sectors per track.
Another adapter for a memory device according to the present invention comprises:
(a) a first connector for connecting the adaptor to the memory device;
(b) a second connector for connecting the adaptor to the ATA interface of the host computer;
(c) a memory device accessing means for reading and writing data on the memory area of the memory device;
(d) an ATA interface controller for exchanging data with the host computer through the ATA interface of the host computer; and
(e) a file format detecting means for examining whether or not the data stored in the memory area of the memory device includes a file format data, the file format detecting means comprising (e-1) a means for calculating and holding the number of heads and the number of sectors per track when it is possible to retrieve both the number of heads and the number of sectors per track from the data stored in the memory area of the memory device. Consequently, even if the memory area of the memory device fails to accommodate the number of heads and the number of sectors per track in the adapter, it can successfully be accessed in the CHS mode. Also, it is unnecessary to hold the data about the number of heads and the number of sectors per track in the form of a table in the ROM depending on the memory capacity and the size of the ROM can thus be minimized.
The present invention is equally applicable to a PC card adapter which conforms to the PC card ATA interface standard.

Adapter for memory device and connecting method using the same

Matsushita Electric Industrial Co., Ltd.


In accordance with embodiments, there are provided mechanisms and methods for rendering data of an on-demand database service safe. These mechanisms and methods for rendering on-demand database service data safe can enable embodiments to alleviate any security risk that would otherwise be posed by such data. The ability of embodiments to provide such additional safety may lead to improved security in the context of an on-demand database service.

The subject matter discussed in the background section should not be assumed to be prior art merely as a result of its mention in the background section. Similarly, a problem mentioned in the background section or associated with the subject matter of the background section should not be assumed to have been previously recognized in the prior art. The subject matter in the background section merely represents different approaches, which in and of themselves may also be inventions.
In conventional database systems, users access their data resources in one logical database. A user of such a conventional system typically retrieves data from and stores data on the system using the user's own systems. A user system might remotely access one of a plurality of server systems that might in turn access the database system. Data retrieval from the system might include the issuance of a query from the user system to the database system. The database system might process the request for information received in the query and send to the user system information relevant to the request.
There is often a desire to utilize rich text (e.g. with enhanced formatting, features, etc.) when assembling various documents for being served by the aforementioned database systems. Unfortunately, the use of such rich text and the like may pose a security risk during use. For example, various scripts may be included with a malicious intent. Such scripts may, for instance, allow access to otherwise secure data, be used to compromise a system, and/or initiate any other unwanted activity, etc.

This patent is subject to a terminal disclaimer.

System, method and computer program product for rendering data of an on-demand database service safe


An overlapping device which is configured to detect the center positions of a substrate and a support which are held in a center position detecting portion, carry the substrate and the support from the center position detecting portion to an overlapping portion, and overlap the substrate and the support such that the detected center positions of the substrate and the support are overlapped in the overlapping portion.

Products such as a mobile telephone, digital AV equipment, and an IC card have been improved to have more sophisticated functions. This gives rise to an increase in the demand that semiconductor silicon chips (hereinafter, referred to as chips) provided in the products are downsized and thinned so that chips can be provided with higher density in a package. In order to provide the chips with higher density in the package, it is necessary to thin the chips to a thickness in a range of 25 μm to 150 μm.
By a grinding process, semiconductor wafers (hereinafter, referred to as wafers) which serve as bases for the respective chips are thinned. However, this weakens the strength, and cracks or warpages are likely to be formed in the wafer. In addition, the wafers weakened in strength through the thinning have difficulty being carried automatically and need to be carried manually. As can be understood from this, handling of the wafers is troublesome.
For this reason, a wafer support system is developed which holds strengths of the wafers and prevents the wafers from being cracked or warped by bonding a plate called a support plate, which is made from glass or hard plastic, to the wafers to be thinned. Because the strength of the wafers can be secured by the wafer support system, it is possible to automatically carry the semiconductor wafers after the thinning process.
The wafers and the support plates are bonded to each other by use of an adhesive tape, a thermoplastic resin, an adhesive, or the like. The wafers to which the support plate is attached are thinned. After that, the support plate is peeled off from a substrate before the wafers are diced.
Here, PTL 1 and PTL 2 disclose technology in which when bonding a support plate to a wafer, first, the wafer and the support plate are overlapped in a state in which the alignment of the wafer and the support plate is performed using an overlapping device, and the overlapped wafer and support plate are carried to an attaching apparatus and bonded.

Overlapping device, and overlapping method


An endoscopic system includes an insertion-section, a wire, an adjustment-unit, a memory, a shape-acquiring-unit and a controller. The insertion-section includes a tubular-section and a bending-section. The wire is inserted in the insertion-section and pulled and loosened to bend the bending-section. The adjustment-unit adjusts tensile force applied to the wire. The memory stores correspondent information including a relationship between increase/decrease information indicative of increase/decrease in the tensile force due to a shape of the tubular-section and shape information indicative of the shape of the tubular-section. The shape-acquiring-unit acquires the shape of the tubular-section. The controller obtains the increase/decrease information corresponding to the shape information acquired by the shape-acquiring-unit with reference to the correspondent information, generates an adjustment signal configured to drive the adjustment-unit based on the increase/decrease information, and outputs the adjustment signal to the adjustment-unit.

1. Field of the Invention
The present invention relates to an endoscopic system comprising a bending flexible tube section and a bending section.
2. Description of the Related Art
In general, an endoscope includes an elongated insertion section that is inserted into a subject and an operating section that is connected to a proximal end side of the insertion section. Further, the insertion section has an elongated flexible tube section having flexibility and a bending section that is provided on a distal end side of the flexible tube section and operated to bend. The bending section has a bending tube having a configuration that node rings are aligned in the longitudinal direction of the insertion section and coupled through joints capable of swinging. To operate the bending section to bend, a pair of wires having one end coupled with each bending tube is arranged in the insertion section. The other end of the pair of wires is fixed to a pulley coupled with a bending operation knob of the operating section. When the bending operation knob is rotated, the pulley is rotated on an axis, and one of the pair of wires is taken up, and the other is veered out. When the wires are taken up and veered out (pulled and loosened), the bending section is operated to bend. Further, when the two pulleys each having such a bending mechanism are provided, the bending section can be operated to bend in both a right-left direction and an up-down direction. Based on a combination of these bending directions, the bending section can bend in arbitrary directions. For example, Jpn. Pat. Appln. KOKAI Publication No. 8-224241 discloses a medical manipulator comprising such a bending mechanism.


Methods, systems and apparatuses are disclosed for treating aluminum desmutting solutions by reacting, mixing and filtering an aluminum desmutting solution flow from an aluminum desmutting solution tank and controlling the amount of copper ions in an aluminum desmutting solution tank by directing a portion of the desmutting solution from a desmutting solution tank to a treatment line, reacting a portion of the desmutting solution in the treatment line and recirculating a filtered aluminum desmutting solution to the aluminum desmutting solution tank during active desmutting operation of the aluminum desmutting solution tank.

Aluminum and aluminum alloys are desirable manufacturing materials across many industries. When processing aluminum and aluminum alloys, care is taken to remove naturally occurring layers of oxidation (e.g. aluminum oxides) that develop on exposed aluminum and aluminum alloy surfaces. Such removal of aluminum oxide layers can desirably lower surface resistivity to, for example, facilitate welding, facilitate or enhance adherence of later-applied protective coatings, enhance anodizing or conversion coating, and/or facilitate other aluminum and/or aluminum alloy processing, etc.
Solutions used to dissolve or otherwise ameliorate the undesirable effects of oxidation on aluminum and aluminum alloy surfaces are referred to as deoxidizing solutions or cleaning solutions. Such deoxidizing solutions are typically strongly acidic, and not only remove the oxide layer, but also attack the base metal surface under the oxide layer to a certain extent. Since many aluminum alloys comprise copper, some of the copper will be dissolved along with the oxide layer. If the copper ion concentration is allowed to rise to, or above, certain levels, some of the copper may redeposit onto the aluminum workpiece being deoxidized. Such layers of redeposited copper are referred to as "smut".
Such smut layers must be removed via desmutting processes to obtain aluminum and aluminum alloy workpieces in desired processing condition, as copper smut interferes with further aluminum processing stages including, without limitation, uniform aluminum protective coatings, aluminum coatings applied to aluminum workpieces for purposes of improving adhesion of subsequent coatings and treatments, etc.
Various agents and processes are known for smut removal, also known as "desmutting" operations. However, when the smut is removed, the copper ions and compounds are retained in the deoxidizing solution used to desmut the aluminum, requiring the eventual replacement of large amounts of desmutting solution from desmutting tanks and cleaning of the tanks. For example, such desmutting tanks may contain from about 30,000 gallons to about 50,000 gallons, or more. Replacement of such amounts of desmutting solution with regularity is time-consuming and expensive, not only in terms of the cost of replenishing the solution, but also in terms of waste, storage, removal and other costs associated with changing out the desmutting solution. Further costs are realized with respect to environmental concerns, as well as the adverse production impact caused by processing lines being shut down or otherwise interrupted from days or weeks while old aluminum desmutting solution is removed and replenished with new aluminum desmutting solution.

Methods, systems and apparatuses for copper removal from aluminum desmutting solutions


An improved system and method for an eye patch can comprise a patch and a pad. The patch can be substantially flat and flexible. Furthermore, the patch can comprise a bottom surface, a top surface, and a concave edge. The bottom surface can comprise an adhesive capable of temporarily attaching to a skin. The concave edge can be on one side of the patch. Additionally, the concave edge can substantially match the anatomical curve of a human's eye socket. The pad can be a raised portion on the patch that can be capable of pushing upper natural eyelashes upward when a client closes her eyes. The pad can be attachable along the concave edge.

This disclosure relates to a system and method for an eye patch used in eyelash extension procedure.
Eyelash extension procedure involves bonding individual fake lashes to a person's natural lashes, one lash at a time. The procedure can usually involve applying an under eye patch to a client's eye, which can cover the lower lashes while hydrating and relaxing the under eye. Furthermore, such procedure separates the bottom natural lashes from the top natural lashes of the client's eyes. Though such procedure helps in preventing lower lash from interfering with upper lashes during eyelash extension procedure, it does little to aid the eyelash technician on applying individual fake lashes to natural lashes of the client.
Thus, having a raised portion at an edge of the eye patch can be advantageous and can aid in pushing the clients eyelashes upwards. By pushing eyelashes upwards, upper natural lashes can spread outwards, which can help the eyelash technician from accessing each natural lashes of the client. As such it would be useful to have an improved system and method for an eye patch.

System and method for an eye patch used in eyelash extension procedure


A stacked display has the different color layers (20r), (20g), (20b) ordered with respect to the wavelength-dependency of the lens focus so that there is better focus of the colors on the display layers that modulate those colors. The optical system (30), (32) can be designed to have a wavelength-dependent focus that matches the position of each of the light modulating layers.

Most common colour displays have a pixel structure with multiple colour components next to each other. Examples of such pixel structures are RGB stripes and the so-called "PenTile" arrangement. These arrangements require sub-pixellation, so that the native resolution of the display (i.e. the sub-pixels) is higher than the resolution of the image (i.e. the pixels).
An alternative is to employ emissive layers that are also transparent. A pixel is formed by multiple layers with each layer capable of emitting light in a selected colour. Organic light emitting diode (OLED) technology is one example that allows such a display to be formed. By stacking the transparent sub-pixel layers, the resolution of each sub-pixel layer only needs to be as high as the eventual pixel resolution of the display.
Reflective display techniques are also known, such as electrowetting displays and electrophoretic displays. These are in principle able to provide nearly full-gamut colour if combined in layers with a subtractive colour system such as cyan-magenta-yellow (CMY).
Limited colour displays are also known, which have only two colour components. An example is a subtractive colour system with black and red. Another example is an additive colour system with just blue and green.
The index of refraction (IOR) of optical materials such as glass and plastic is not a constant but rather depends on the wavelength due to dispersion. One way to describe the dispersion of a material is by the Abbe number. Dispersion in lenses creates chromatic aberration. The difference in focal length of red and blue is referred to as axial chromatic aberration. Chromatic aberration in the focal plane is lateral chromatic aberration. In photo camera lenses, techniques such as the use of an achromatic doublet are employed to avoid both types of chromatic aberration.
FIG. 1 shows an alternative type of lens based on diffraction. These lenses rely on the interference of light in a repetitive structure.
Diffractive components alter the phase and/or amplitude of light.
A Fresnel zone plate is shown in FIG. 1(a) and a fractal zone plate is shown in FIG. 1(b). These are flat structures, but they can focus light. A photon sieve, such as a fractal photon sieve as shown in FIG. 1(c) is a similar structure that has favourable properties.
The primary focal length of a zone plate (f) is given by Rm2/mλ with Rm being the radius of the mth ring. Thus, the focal length has a direct but inverse relation with the wavelength. For diffractive lenses, blue (e.g. 475 nm) has a longer focus than red (e.g. 650 nm) because of this relation. The width of the outmost zone (ΔRm) may be approximated by fλ/2Rm.
This zone width is an approximation that works for large m, so in this case Rm would typically be the outmost zone. The width of the zones decreases with radius, so the outmost zone determines the required manufacturing precision.
FIG. 2 shows the light intensity as a function of axial distance from a lenticular lens structure for red, green and blue light passing through the lens structure. FIG. 2(a) is for a Fresnel zone plate and FIG. 2(b) is for a Fresnel photon sieve. The intensity peaks correspond to the locations at which the light is focussed, and it can be seen that the different colours are focussed at different distances from the lens.
In a lenticular based autostereoscopic display, a lens overlies a group of sub-pixels in the row direction. In this way, the output of each sub-pixel in the group is imaged by the lens to a different viewing direction. At the intended viewing distance, adjacent pixels are imaged to locations spaced apart by the inter-ocular distance of around 60 mm, so that different eyes see a different sub-pixel set. In this way, autostereoscopic viewing is enabled, with different images provided simultaneously to the two eyes.
If a lenticular display is created from a thick stacked display, then the focus of the lens is optimal (i.e. with the focal plane at the display pixel plane) only for a small range of wavelengths—i.e. the wavelength corresponding to the stack colour which is at the focal plane. This may for instance be all saturated greenish colours. Other colours and white create 3D crosstalk.


The cycle time for mounting electronic components supplied from a tray can be shortened. An electronic component feeder (16) for mounting electronic components has a plurality of height levels (L1, L2, and L3) and can move tables (19, 20, 21) horizontally at the respective levels (L1, L2, and L3). A plurality of conveyers (22, 23, 24) are provided for the respective tables to move them to a pickup stage (A) from a standby stage (B). Transfer head (13) includes nozzles (14a, 14b, 14c) for attracting electronic components by suction, and an upward-downward moving mechanism which moves the nozzles in accordance with the height level of each tray on the pickup stage (A). Since the trays are arranged at the different height levels at the pickup stage position, the conveyers can be moved independently and the transfer heads can individually move the nozzles between the position at which each nozzle picks up electronic components and another position at which the nozzle does not interfere with the pickup operation. Movement of a necessary tray from and to the pick up stage position can be performed quickly without being hindered by an other tray and, as a result, the cycle time for mounting electronic components can be shortened.

At present, a common type of electronic component mounting equipment picks up a selection of electronic components supplied via an electronic component feeder by vacuum suction of a transfer head nozzle and transfers and mounts them onto a substrate. There are various types of feeders which supply electronic components to the nozzle of the transfer head, and one type employs a tray.
An electronic component feeder of the prior art which employs this tray is explained next.
FIG. 13 shows a side view of an electronic component feeder of the prior art. In FIG. 13, a magazine 1 houses a tray 2 which stores more than one electronic component aligned lengthwise and crosswise in vertical multiple stages. A certain in/out level 3 is specified in the conventional electronic component feeder, and the magazine 1 is raised or lowered by elevation means 4 to move the tray 2 to this in/out level 3 for moving the tray 2 to a subsequent pickup stage 6 next. In/out means 5 is for ejecting the tray 2 at the in/out level 3 from the magazine 1 to the pickup stage 6, or to return the tray 2 on the pickup stage 6 to the magazine 1.
When the tray 2 required to be on the pickup stage 6 (refer to the tray 2 represented by a dotted line) is ejected, a nozzle 8 of a transfer head 7 lowers toward the tray 2, and an electronic component P on the tray 2 is picked up by suction at the tip of the nozzle 8. The electronic component P, shown by a dotted line, is then transferred and mounted onto a substrate 9, for example, a printed circuit board.
With the above electronic component feeder of the prior art, however, a long time is required to replace the tray 2 positioned on the pickup stage 6, resulting in a longer feeding cycle time, which in turn lowers productivity. The reasons are as follows. For replacing the tray 2 shown by the dotted line in FIG. 13 with the tray 2x in the magazine 1, the following series of operations cannot be avoided:
(1) the in/out means 5 returns the tray 2 from the pickup up stage 6 to the magazine 1; PA1 (2) the elevation means 4 raises the magazine 1 to set the tray 2x to the in/out level 3; and PA1 (3) the in/out means 5 ejects the tray 2x set to the in/out level 3 to the pickup stage 6.

Equipment and method for mounting electronic components

Matsushita Electric Industrial Co., Ltd.


An improved detection reaction for benzene in gas analysis with a gas detector tube formed of a carrier material impregnated with gold(III) oxide in a display layer.

The gas analysis of benzene gas mixtures by means of gas detector tubes has hitherto been carried out colorimetrically on the basis of p-quinoid compounds with paraformaldehyde/sulfuric acid or with iodine pentoxide. The determination with I2O5 yields full, sharp display, which can be read by the user with certainty. The sensitivity of 2 ppm of benzene and the selectivity against, e.g., gasoline hydrocarbons are, however, insufficient.
A process for detecting benzene in gases, which comprises the reacting of the gas to be tested with a mixture of paraformaldehyde and anhydrous sulfuric acid, which said mixture is preferably applied to silica gel, is known from DE 865 384 B. The sensitivity of the detection reaction can be increased by adding dimethyl sulfate. The detection on the basis of paraformaldehyde/sulfuric acid is selective and sensitive enough in its application with a detection limit of about 0.5 ppm of benzene. However, the display accuracy is insufficient because of a diffuse change in color, so that the user can read the concentration displayed in an only poorly defined manner. In addition, the measurement times with 20 minutes and 20 strokes are not user-friendly and not accepted in the container fumigation market. Said tubes cannot be used for release measurements, e.g., in the container fumigation market because of poor sensitivity, reading accuracy, measurement time and selectivity. A qualitative measurement, which provides information on whether a container can be safely accessed or not, is required for this application.

Gas detector tube for determining benzene


A recoil control mechanism for a weapon which fires a projectile which is characterized by the generation of a forward counterforce to the rearward recoil simultaneously with absorption of rearward recoil force upon initiation of propoulsion of the projectile. The forward counterforce is generated by propelling a first mass forwardly upon firing the projectile and substantially simultaneously propelling a second mass rewardly for absorbing some of the recoil force. In one mechanism (10), the first mass may be the weapon""s barrel (12) and the second mass its breach block (14). Expaning gases (36) from detonation of propellant in cartridge (24) enter a reaction volume (28) between the barrel (12) and breech block (14). These gases drive barrel (12) forwardly against force transmission spring (16) to impose a forward counterforce on the weapon""s frame (18). Substantially simultaneously recoil from detonation of cartridge (22) together with the gasses (36) in reaction volume (28) drive breech block (14) rearwardly against force absorbing spring (20).

The present invention relates to a weapon and in particular to a recoil control mechanism for a weapon. The invention will be described generally in relation to a firearm, however it is to be understood that the invention is applicable to other forms of weapons for firing a projectile. Thus the weapon may, for example, be a large calibre weapon which is supported on a mounting such as a stand or platform instead of a hand held portable weapon such as a firearm.
In this specification the term xe2x80x9cprojectilexe2x80x9d is to be understood as encompassing one piece generally solid projectiles such as bullets, pellets, darts, flechettes, artillery warheads, projectiles as in for example WO 97/04281, mortar shells (eg. 120 mm) or rocket boosted artillary shells, plus multiple piece charges which are fired as one, such as the shot in a shotgun cartridge or a plurality of bullets fired as one.
A problem with all weapons which fire a projectile, particularly those that rely upon detonation of an explosive propellant, is recoil. That is, firing the weapon (for example by detonation of a charge of explosive propellant within the weapon) produces a forward propelling thrust on the projectile and an equal and opposite rearward force, or recoil. Recoil limits the accuracy and portability of weapons. First it produces a force which has the effect of rotating the weapon about the centre of gravity of the weapon and its support (which for a firearm would be the shooter), resulting in vertical climb and lateral drift of the muzzle end of the barrel for succeeding firings. Recoil forces also cause torque, which has the effect of xe2x80x98twistingxe2x80x99 the weapon. The muzzle is thrown off the target in an irregular half circular motion around the longitudinal axis of the barrel. Similar to the effect of muzzle climb, the time of reacquisition of the target is therefore increased for subsequent rounds and accuracy is therefore significantly affected.
During automatic firing recoil can significantly affect the accuracy of the succeeding rounds. Second, the force of recoil must be absorbed by the weapon, or the shooter if the weapon is a firearm, or transmitted to a support mounting and thus to ground for heavier weapons such as artillery pieces. Thus it may cause discomfort and fatigue or even injury to a shooter, or require heavier supporting structures, or complex xe2x80x9csoftxe2x80x9d mounting carriages for mobile artillery weapons. Large masses are sometimes used in firearms to absorb the recoil velocity, however this compromises portability.
Clearly, if the recoil of a weapon could be substantially reduced if not eliminated within the weapon itself, it would reduce the above problems.
There are many known recoil reducing mechanisms, including arrangements which are initiated by the rapidly expanding gases produced by the detonation and burning of an explosive propellant. Generally, however, the known arrangements effectively only reduce the recoil without cancelling or at least substantially eliminating it.
An object of the present invention is to provide an improved recoil control mechanism.
The invention is characterised by the generation of a forward counterforce to the rearward recoil simultaneously with absorption of rearward recoil force momentarily after propulsion of the projectile is initiated.
Accordingly, in a first aspect the invention provides a recoil control mechanism for a weapon for firing a projectile in a forward direction which includes a first mass and a second mass which are driven in substantially opposite directions upon firing, wherein the first mass is driven in the forward direction to counter a rearward recoil of the weapon and the second mass is driven in the rearward direction for absorbing some of the recoil force.
The first mass and the second mass are solid inertial weights.
Preferably the mechanism includes a frame, the first mass and the second mass being associated with the frame for the frame to guide their respective forwards and rearwards movement, and including a force absorbing means which is operative between the second mass and the frame and a force transferring means which is operative between the first mass and the frame.
In a second aspect the invention provides a method of countering recoil of a weapon caused by the firing of a projectile, the method including providing a first mass to be driven forwardly in the same direction as the projectile to counter a rearwards recoil force and providing a second mass to be driven rearwardly against a force absorbing means for substantially simultaneously absorbing some of the rearwards recoil force.
The generation of a forward counterforce simultaneously with absorption of the residual recoil force over the time period of the recoil, allows the achievement of a resultant force-time characteristic which may be reasonably predetermined. For example, for a projectile which is fired by detonation of an explosive propellant, the recoil force of a weapon is reasonably calculable from, knowledge of the amount and type of propellant and the masses etc. that are involved, or it may be empirically determined experimentally, and from this appropriate parameters for the counterforce and recoil absorption sub mechanisms can be calculated (and possibly experimentally adjusted) to give a predetermined resultant force-time characteristic. Thus the invention gives an improved recoil control mechanism. It is envisaged that in some embodiments of the invention, the recoil of the weapon may be at least substantially eliminated if not fully cancelled (that is, the resultant force is substantially zero over the recoil time period). It is also considered that a resultant forward force could be generated.
Preferably the first mass is a barrel and the second mass is a breech block of the weapon and a means is provided associated with the barrel and a frame of the weapon for transferring a forwards force to the frame from the forward motion of the barrel. This means may include a compression spring or pneumatic or hydraulic piston and cylinder arrangement or electromagnetic means which is operative to return the barrel to its firing position.
The barrel and the breech block are also preferably biased towards each other relative to the frame of the weapon. This bias may be provided by a tension spring which is connected between the barrel and the breech block. Thus, as force from the forward momentum of the barrel is being transferred to the frame, the rearwards recoil force imparted to the breech block is being absorbed by the tension spring. Thus the tension spring provides a force absorbing means against which the breech block is driven. The tension spring may also be operative to restrain the breech block in its firing position momentarily upon detonation of the propellant to provide an adequate reaction surface for initiating the forward movement of the projectile and then to return it to its firing position after its rearward movement.
Alternatively the bias of the breech block and the barrel towards each other may be provided by means acting independently between the barrel and the frame and the breech block and the frame. Such means acting between the barrel and the frame may constitute the above described means for transferring a forwards force to the frame from the forward motion of the barrel. The independent means may each comprise a helical spring.
Although the preferred embodiment combines simultaneous xe2x80x9cblow forwardxe2x80x9d of the barrel and xe2x80x9cblow backxe2x80x9d of the breech block to control recoil, as described above, it is to be understood that the invention may be realised in alternative embodiments. For example, it is envisaged that the first mass and the second mass may be additional components and that a gas for driving them apart may be tapped from the barrel or firing chamber. The recoil control mechanism may also be provided as an attachment per se for a weapon. Various of the foregoing or following features for biasing the breech block and barrel and providing gas reaction surfaces may be adapted to the masses of such alternative embodiments.
In the preferred arrangement wherein the first mass is a barrel and the second mass is a breech block of the weapon, a chamber for receiving a cartridge containing the projectile (such as a bullet) and explosive propellant is preferably provided at a loading end of the barrel. The chamber is associated with the barrel and the breech block to provide an interposed gas contact region therebetween for receiving expanding gases from the chamber upon firing of the projectile from the cartridge. Thus, upon firing of the cartridge, expanding gases from the propellant force the projectile from the cartridge and propel it through the barrel, and momentarily after initiation of the projectile""s movement, the expanding gases following the projectile which emerge from the cartridge into the chamber expand into the interposed gas contact region to blow the barrel forward and simultaneously blow the breech block backwards to thereby reduce if not eliminate the recoil of the weapon. The chamber may be provided by the barrel, by the breech block, or the barrel and the breech block in combination, or by a separate chamber member. Preferably the component or components providing the chamber are in a structural relationship such that the interposed gas contact region is defined in part by at least two facing reaction surfaces, with each reaction surface being directly or indirectly associated with one of the barrel or the breech block. Preferably the reaction surfaces are substantially normally orientated relative to the forward and rearward directions to maximise the forces applied thereto in the forward and rearward directions by the gas pressure. The aforesaid structural relationship may be realised by a telescopic arrangement of one component relative to another, as will be described in more detail below.
It is to be understood that the weapon will include a firing mechanism for initiating detonation of the explosive propellant and in the preferred embodiment this may include a firing pin associated with the breech block which is operable via a trigger mechanism carried by the frame, as is known. The weapon may also provide for semi automatic or fully automatic operation utilising the energy stored during the blow back of the breech block, as is also known, in which case a magazine will need to be provided. A suitable firing mechanism and a mechanism for providing semi or fully automatic operation including a magazine for the cartridges will not be described in further detail herein as there are many such known mechanisms from which a person skilled in the art may choose to provide suitable such mechanisms for the weapon.
A weapon incorporating the invention, in its preferred form involving blow forward of the barrel, may include additional features associated with the barrel for increasing the forwards momentum thereof. Such additional features include, for example, the provision of a conical bore for the barrel and/or muzzle breaks for redirecting the gas from the barrel, as are known. The weapon in its preferred form may be a firearm such as a rifle, shotgun, pistol or revolver.
For a better understanding of the invention, the principle thereof for various embodiments, as well as a specific embodiment, which are given by way of non limiting example only, will now be described with reference to the accompanying drawings (which are not to scale).


A vehicle behavior control device (S) determines, by using a vehicle velocity (V), a transmission function (K(s)) which is determined based on a specification of the vehicle, receives as an input a wheel turning speed (ω) obtained by differentiating a wheel turning angle (δ) of left and right front wheels (FW1, FW2) with respect to time, and outputs a target yaw moment (My). The device (S) also calculates, by using the determined target yaw moment (My), a left-wheel-side forward/backward force (FxCL) imparted to a left wheel side (left front wheel FW1 and left rear wheel RW1) of a vehicle (10) and a right-wheel-side forward/backward force (FxCR) imparted to a right wheel side (right front wheel FW2 and right rear wheel RW2) of the vehicle (10). Then, the device (S) performs control to drive brake units (14-17) and in-wheel motors (IWMfl, IWMfr, IWMrl, IWMrr) depending on a turning direction of the vehicle (10), with the left-wheel-side forward/backward force (FxCL) serving as a braking force (or driving force) and the right-wheel-side forward/backward force (FxCR) serving as a driving force (or braking force). It is thus possible to ensure directional stability and responsiveness when the vehicle turns, taking into account a frequency response characteristic of a motion state amount generated on the vehicle (10).

Conventionally, proposals for improving directional stability and responsiveness during a turn of a vehicle have been made. For example, Japanese Patent Application Laid-Open (kokai) No. S63-279976 describes a vehicle steering device for determining a hydraulic pressure control value, which increases as a front wheel steering angle increases, and decreases as the vehicle speed increases, and applying a brake hydraulic pressure corresponding to the determined hydraulic pressure control value to a brake device on a steering direction side of front wheels of a pair of left and right brake devices applying braking forces to rear wheels. Then, in this conventional vehicle steering device, the brake device on the steering direction side of the front wheels imparts a braking force to a rear wheel on the steering direction side, the brake force can generate a moment toward the steering direction of the front wheel on a body, and satisfactory head turn property and responsiveness of the vehicle are obtained.


A variable gain amplifying circuit comprises two stages, a first stage and a second stage with a common voltage-to-current converter. Each stage comprises two BJTs, two voltage controlled current sources, a variable resistor with a variable resistance, and the common voltage-to-current converter. The two BJTs construct a differential amplifier for amplifying a pair of differential signals. The variable resistor with the variable resistance is connected between the emitters of the two BJTs wherein the variable resistance of the variable resistor is represented as RE. The variable resistance RE is controlled by a control voltage Vctrl. The two voltage controlled current sources are respectively connected between the corresponding emitter of BJTs and ground. The currents respectively through the voltage controlled current sources are equal to each other and represented as IE. The current IE is controlled by the common voltage-to-current converter according the control voltage Vctrl. The variable resistance RE and the current IE of the voltage controlled current sources can be varied simultaneously by the control voltage Vctrl so as to rapidly adjust the gain of the variable gain amplifying circuit.

Automatic gain control (AGC) systems are generally used in many kinds of electronic products, such as communication products, memory storage products, wireless transceivers, etc. The automatic gain control system comprises a variable gain amplifier (VGA) to amplify the received signals whose amplitudes may vary within a wide range so that amplified signals output from the variable gain amplifier can have a substantially constant amplitude.
FIG. 1 is a circuit diagram illustrating a conventional variable gain amplifying circuit 10. The variable gain amplifying circuit 10 is provided for amplifying the differential input signals Vin+ and Vin−. The variable gain amplifying circuit 10 comprises a plurality of stages, such as a first stage 101 and a second stage 102. The first stage 101 comprises two bipolar junction transistors (BJT) 110, 120, three resistors 130, 132, 134, and two voltage controlled current sources 140, 142. The base of BJT 110 is used for receiving the input signal Vin+ and the base of BJT 120 is used for receiving the input signal Vin−. The collector of BJT 110 is used for outputting the output signal Vout1− and the collector of BJT 120 is used for outputting the output signal Vout1+. The output signals Vout1+ and Vout1− are amplified by the first stage 101. The resistor 130 is connected between the emitters of the BJTs 110 and 120. The resistance of resistor 130 is represented as RE. The resistor 132 is connected between VDD and the collector of BJT 110 and the resistor 134 is connected between a voltage source VDD and the collector of BJT 120. Both of the resistances of resistors 132 and 134 are represented as RL. The voltage controlled current source 140 is connected between the emitter of BJT 110 and ground, and the voltage controlled current source 142 is connected between the emitter of BJT 120 and ground. The currents respectively flowing through the voltage controlled current sources 140 and 142 are equal to each other and represented as IE. The current IE of each current source is controlled by a control voltage Vctrl.
As shown in FIG. 1, the gain Av of each stage of the variable gain amplifying circuit 10 can be derived as equation (1):
                    Av        =                                                            g                m                                                          R                L                                                    1              +                                                g                  m                                                                  R                  E                                                              =                                    R              L                                                                        V                  T                                                  I                  C                                            +                              R                E                                                                        (        1        )            where gm is a transconductance of BJT 110 or 120, VT is a thermal voltage of BJT 110 or 120, and IC is a collector current of BJT 110 or 120.
According to equation (1), the gain Av of each stage will be decreased if the collector current IC decreases due to the decrease of the control voltage Vctrl. The emitter current IE is approximate to the collector current IC according to the basic characteristic of the BJT. The emitter current IE is very low when the gain of each stage is very low. It causes that the voltage Vheadroom (i.e. the voltage drop between two ends of resistor 132, Vheadroom=IE×RL) is very small. The input signals will be "clipped" by the stage of variable gain amplifying circuit 10 when the input signals are large swing AC signals. In other words, the peak of waveform of large swing AC signals will be cut because the voltage Vheadroom of variable gain amplifying circuit 10 is very small. Accordingly, the variable gain amplifying circuit 10 needs more stages to avoid such a phenomenon.
FIG. 2 is a circuit diagram illustrating another conventional variable gain amplifying circuit 20. The variable gain amplifying circuit 20 is similar to aforementioned variable gain amplifying circuit 10, but instead of using the resistor 130 and two voltage controlled current sources 140, 142 in each stage, a field-effect transistor (FET) 200 is connected to provide the resistance RE between the emitters of two BJTs 210, 220, and two current sources 240, 242 to provide a steady emitter current IE to the corresponding BJT respectively. A control voltage Vctrl is inputted into the gate of the FET 200 for controlling the resistance RE.
As shown in FIG. 2, the gain Av of each stage of the variable gain amplifying circuit 20 can be derived as equation (2):
                    Av        =                                                            g                m                                                          R                L                                                    1              +                                                g                  m                                                                  R                  E                                                              =                                    R              L                                                      1                                  g                  m                                            +                              R                E                                                                        (        2        )            where gm is a transconductance of BJT 210 or 220.
According to equation (2), the gain Av of each stage will be decreased if the resistance RE increases due to the decrease of the control voltage Vctrl. The FET 200 will reach a cut-off or saturation regions when the control voltage Vctrl is low during a low gain Av. It causes that the gain range of each stage is very limited. Accordingly, the variable gain amplifying circuit 20 needs more stages to obtain wider gain range.
Therefore, there is a need for a variable gain amplifying circuit having larger gain range in each stage thereof so that the variable gain amplifying circuit needs fewer stages thereof.


A piezoelectric speaker which generates sound by vibrating a plane diaphragm using a plurality of piezoelectric drivers is disclosed. The diaphragm is formed of resin foam plates and the piezoelectric drivers are contained therein while being interposed and supported at the centers thereof. The piezoelectric drivers are divided into at least two groups which have different primary resonance frequencies.

(1) Field of the Invention
This invention relates speaker and, more particularly to a piezoelectric speaker which generates sound by vibrating a diaphragm using piezoelectric drivers.
(2) Description of the Prior Art
A conventional piezoelectric speaker has a construction in which a vibrating film is stretched on a frame while being applied tension and a plurality of piezoelectric drivers are directly stuck on the film.
According to this conventional technique, although a plane speaker having a large surface area can be obtained, there has been room for improvement because its frequency characteristic is not so excellent.


The present invention provides a cocrystal of (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one and an organic acid capable of forming a cocrystal with the compound.

Patent document 1 describes a compound represented by the formula 1:
wherein each group is as defined in patent document 1 (hereinafter sometimes to be abbreviated as "compound 1") as a pyridinyl triazolone derivative or a fused pyridinyl triazolone derivative, which is an inhibitor of Bruton's tyrosine kinase (hereinafter sometimes to be abbreviated as "BTK"). Also, in Example 5 of patent document 1, (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one represented by the following formula:
(hereinafter sometimes to be abbreviated as "compound (A)") is produced as one embodiment of compound 1.
In addition, paragraph [0083] of patent document 1 describes that compound 1 may be present as a cocrystal. Cocrystal generally means a crystal in which multicomponents constituting the cocrystal are bonded by a bond or interaction other than an ionic bond (e.g., a hydrogen bond, Van der Waals' force, a π-π bond, etc.), and is distinguished from a salt in which multicomponents are bonded by an ionic bond.

Cocrystal, production method thereof, and medicament containing cocrystal


A water-conducting household appliance having a heating element to heat washing liquid; a reservoir to store the washing liquid; and a reservoir cleaning program during which the reservoir is at least temporarily and at least partially filled with the washing liquid heated by the heating element.

The invention relates to a water-conducting household appliance, in particular a dishwasher or washing machine.
A reduction in water and energy consumption is of great importance for water-conducting household appliances. Therefore, energy reduction can be achieved, for example, by reducing the process temperatures. The use of a so-called mixture store can result in water reduction. To this end, for example in the case of a dishwasher, rinsing water from one wash cycle is deposited in the mixture store until the next wash cycle and is used for prewashing the items to be washed in the dishwasher.
A dishwasher with a control device which controls a wash cycle with a number of subprogram steps is known from WO 2005/063109 A1. After performing one of the subprogram steps, for instance the rinsing step, the washing liquid no longer required is stored temporarily in the mixture store, or generally in a reservoir, and reused in a subsequent subprogram step, e.g. prewashing.
In the course of the wash cycles, the mixture store becomes greasy. The additional reduction of process temperatures during the wash cycles furthermore results in greasy films of dirt collecting in the filter and sump area of a water-conducting household appliance.

Water-conducting household appliance having a mixture store to store washing liquid


The present invention provide a method for the prevention and treatment of a neurodegenerative disease including Alzheimer's Disease, Huntington's Disease, and Parkinson's Disease, using a grape seed extract or one or more compounds derived therefrom. In particular, the present invention provides a method to treat a patient diagnosed with, or at the risk of developing, a neurodegenerative disease by administering a pharmaceutical composition comprising a grape seed extract or one or more compounds derived therefrom to the patient in a therapeutic amount to reduce the accumulation, aggregation or deposition of amyloid beta or its oligomers, and/or to reduce the misfolding, accumulation and/or aggregation of tau proteins or other proteins.

Neurodegenerative diseases are associated with conditions in which neuronal cells deteriorate, lose function, and often die. As they are generally progressive, the consequences of neurodegenerative diseases are often devastating. Patients with neurodegenerative disease may suffer severe deterioration in cognitive or motor skills. As a result, their quality of life and life expectancy may be considerably reduced. In humans, these diseases include, but are not limited to, Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, Fronto-Temporal Dementia, and Cortico Basal Degeneration, among others.
Parkinson's Disease is a progressive disorder that affects brain neuronal cells controlling muscle movement. These neuronal cells make dopamine, which is an important chemical for transmitting signals between cells to facilitate movement of the body. Therefore, the loss of these neurons leads to movement disorders, such as tremor and speech impairment that are typically exhibited by Parkinson's patients. According to the National Institute of Neurological Disorders and Stroke, at least 1 million people suffer from Parkinson's Disease, and about 50,000 new cases are reported each year in the United States.
A highly conserved pre-synaptic protein, α-synuclein, has been implicated in the pathology of Parkinson's Disease. It is thought that conformational changes in α-synuclein lead to the proteinaceous accumulation and fibrillogenesis characteristic of this disease. See U.S. Pat. No. 7,045,290 (to Lindquist et al.). Current treatment options include levodopa and dopamine agonists. These drugs, however, only give temporary relief to the symptoms and have serious side effects if used in large amounts. Deprenyl, a monoamine oxidase B inhibitor, was the first drug suggested to provide causal treatment of Parkinson's Disease by alleviating symptoms and attenuating the progression of the disease, but the therapeutic efficacy of deprenyl is controversial. See U.S. Pat. No. 6,417,177 (to Nelson).
Huntington's Disease (HD) is a genetic neurological disorder, with symptoms of abnormal body movement and impaired mental abilities. Huntington's Disease is caused by a trinucleotide repeat expansion in the Huntingtin gene (htt), which in turn produces a mutant form of the htt protein having an pathological expansion of a polyglutamine (PolyQ) tract. The mutant htt protein misfolds and forms aggregates in the brain and other affected tissues, resulting in neuronal cell death (Wolfgang et al., Proc Nat Acad Sci 2005; 102: 11563-11568). Most of the drugs used to treat the symptoms of Huntington's Disease have side effects such as fatigue, restlessness, or hyperexcitability.
Alzheimer Disease (AD) is a progressive brain disease known generally as senile dementia. More than 4.5 million Americans have been diagnosed with AD, and this number is expected to triple in the next 40-50 years (Lyketsos et al., Am J Geriatr Psychiatry 2006; 14(7): 561-72).
It is believed that the pathophysiological root of Aβ lies, in part, in the misprocessing or mutation of the amyloid precursor protein. The misprocessed protein may produce an increased amount of amyloid beta peptides (Aβ) or variant forms thereof. The accumulation of Aβ leads to the deposition of insoluble Aβ plaques, and eventually to synaptic failure, neuronal injury, formation of tangles of hyperphosphorylated tau protein, and apoptotic neuronal death. The injury or death of neurons leads to the loss of multiple neurotransmitters, which in turn leads to the emergence of the cognitive and functional symptoms of the disease.
Currently available medications offer relatively small symptomatic benefit for some patients and do not slow disease progression. Therefore, various symptomatic strategies for treating or preventing AD are ongoing. For example, AD has been found to be associated with brain inflammation, and thus, nonsteroidal anti-inflammatory drugs such as ibuprofen and indomethacin have been used to lower risk of developing AD. However, the drugs have long-term risks of gastrointestinal bleeding and renal disease, and are associated with rare cardiovascular toxicity. An association of oxygen free radicals with AD has also raised the possibility of antioxidant therapy. The American Psychiatric Association and the American Academy of Neurology Treatment Guidelines for AD both recommend high-doses of vitamin E as a treatment option. This recommendation is tempered, however, by recent findings that vitamin E therapy did not delay progression of mild cognitive impairment associated with AD, and that vitamin E in very high doses increased mortality in older people. See Lyketsos et al., 2006, supra.
Another treatment option for AD is to reduce the naturally occurring degradation of acetylcholine by an enzyme known as acetylcholine esterase (AChE) Inhibition of AChE leads to increased acetylcholine levels. The U.S. Food and Drug Administration has approved four cholinesterase inhibitors drugs for the treatment for Aβ: tacrine, donepezil, rivastigmine, and galanthamine. Short-term (up to 6 months) clinical trials of the cholinesterase inhibitors showed that these drugs improved or slowed cognitive losses associated with AD, but clinical trial results on their long-term benefits are not conclusive. In very mild or more severe AD, the benefits of cholinesterase inhibitors are less substantiated. See Lyketsos et al., 2006, supra.
Treatments of AD that target removing Aβ from the brain are under development. For example, U.S. Pat. No. 7,262,223 (to Kong et al.) describes the use of amidine compounds in the treatment of amyloid-related diseases; U.S. Pat. No. 7,279,501 (to Kim) describes the use of natural product compounds isolated from plants (e.g., turmeric, gingko biloba, and ginger) and their synthetic chemical analogues for the treatment of an Aβ-induced disease. Recent evidence suggests that moderate consumption of red wine may reduce the incidence of AD and may attenuate AD-type cognitive deterioration and amyloid neuropathology (Dartigues et al., Therapie 1993; 48: 185-187; Dorozynski, BMJ 1997; 314: 997; Luchsinger et al., J Am Geriatr Soc 2004; 52: 540-546). Accumulation of soluble extracellular high molecular weight (HMW) oligomeric Aβ species in the brain is considered a major risk factor for the onset and progression of cognitive deterioration (Klyubin et al., Nat Med 2005; 11: 556-561; Selkoe, J Alzheimer's Dis 2001; 3: 75-80). It has also been suggested that grape-derived polyphenolic compounds may inhibit oligomerization of Aβ in vitro (Porat et al., Chem Biol Drug Des 2006; 67: 27-37). However, studies to date were limited to in vitro testing.
Many types of neurodegenerative diseases are linked with abnormal protein folding, accumulation, aggregation, and/or deposition of proteins. For example, there are two types of abnormal protein deposits in the brains of Alzheimer's patients. There are amyloid plaques composed of amyloid beta peptides that are deposited extracellularly in the brain parenchyma and around the cerebral vessel walls, and there are neurofibrillary tangles that are composed of aggregates of hyperphosphorylated tau protein located in the cytoplasm of degenerating neurons. In patients with Parkinson's Disease, Lewy bodies are observed in the cytoplasm of neurons of the substantia nigra. The major constituents of Lewy bodies are fragments of a protein named α-synuclein. In patients with Huntington's disease, intranuclear deposits of a polyglutamine-rich version of the mutant Huntingtin protein are a typical feature of the brain. Patients with hereditary Amyotrophic Lateral Sclerosis have aggregates primarily composed of superoxide dismutase in cell bodies and axons of motor neurons. Additionally, diverse forms of transmissible spongiform encephalopathy are characterized by accumulations of protease-resistant aggregates of the prion protein.
Evidence from biochemical, genetic, and neuropathological studies suggests an active involvement of protein misfolding and/or aggregation in the pathology of neurodegenerative diseases. For example, the presence of abnormal aggregates usually occurs in the brain regions mostly damaged by the disease. Mutations in the gene encoding the misfolded protein produce inherited forms of the disease, which usually have an earlier onset and more severe phenotype than the sporadic forms. Transgenic animals expressing the human mutant gene for the misfolded protein develop some of the typical neuropathological and clinical characteristics of the human disease. Also, misfolded protein aggregates produced in vitro are neurotoxic and induce cell death.
Tauopathies are a family of neurodegenerative diseases that implicate malfunction of tau proteins (a family of closely related intracellular microtubule-associated proteins). These neurodegenerative diseases include, for example, Alzheimer's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Argyrophilic Grain Disease, Pick's Disease, as well as others. Common features among tauopathies are abnormal hyperphosphorylation of tau and accumulations of tau into detergent-resistant intracellular inclusions known as neurofibrillary tangles (NFTs) among neurons or glial cells in the brain. Abnormally hyperphosphorylated tau proteins are readily dissociated from microtubules and aggregated into oligomeric tau paired helical filaments that are ultimately deposited as intracellular NFTs. (Mi, K. et al., Curr Alzheimer Res 2006; 3: 449-463). The formation of oligomers serves as nucleation sites that sequester additional hyperphosphorylated tau as well as normal non-phosphorylated tau into fibrillary aggregates. (Sorrentino et al., Neurol Sci 2007; 28: 63-71). Thus, a theory of tau-mediated neurodegeneration is based on a "toxic gain of function" model, in which abnormally phosphorylated tau proteins promote removal of both hyperphosphorylated and normal tau proteins from microtubules. This leads to microtubule instability and alterations of microtubule-mediated processes such as axonal transport, which in turn leads to impaired function and reduced viability of neuronal and glial cells in the brain (Sorrentino et al., 2007, supra).
U.S. Patent Application Publication No. 2007/0122504 (to Moon et al.) discloses a process of manufacturing a grape seed extract and methods of using such grape seed extract to treat neurodegenerative diseases, including AD. The extract is prepared by (1) extracting the grape seed in an alkaline solution having a pH of 8 to 11, at preferably 20-50° C. to obtain alkaline soluble substance; (2) neutralizing with acidic solution to adjust to the pH ranging from 2 to 4, and centrifuging the resulting solution and obtaining precipitated layer; (3) adding lower alcohol and obtaining the supernatant layer, then concentrating the supernatant layer; and (4) adding non-polar solvent and removing non-polar solvent soluble layer to obtain purified fraction and subjecting to repeated purification and lyophilzation to obtain dried grape seed extract. (See Moon, paragraphs [0030]-[0035]).
Due to the prevalence of neurodegenerative disease and the lack of proven effective pharmaceutical compositions or methods to treat symptoms associated with the neurodegenerative diseases, there is still a need for improved pharmaceutical compositions and methods for treatment and prevention thereof.

Methods for preventing and treating neurodegenerative diseases