The present invention concerns a compound consisting of RNA, in particular RNA extracted from yeast, a pharmaceutical composition comprising such RNA and a method for the treatment of inflammatory and inflammatory-related disorders comprising administering to a patient in need of such torment a pharmaceutical composition comprising an amount effective to ameliorate the symptoms of inflammation or inflammatory-related disorder of ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent. The exogenous yeast RNA used in the present invention has a pronounced membrane-stabilizing action in a wide range of concentrations. At the same time, yeast RNA normalizes metabolism of arachidonic acid and levels of its key metabolites, thromboxane and leukotriene. Its anti-inflammatory action is accompanied by normalization of the activity of NO-synthetase and anti-oxidant activity.

The present invention concerns a compound and a pharmaceutical composition for the treatment of inflammation and diseases accompanied by inflammatory processes, in particular inflammatory processes which affect cellular membranes. The present invention also concerns therapeutic methods to ameliorate or prevent symptoms of inflammatory processes.
Inflammatory Processes
Inflammation is generally accompanied by changes in the metabolism of arachidonic acid, metabolism of nitric oxide, and creation of free radicals. Anti-inflammatory non-steroid drugs (NSAIDS), such as aspirin, can block certain links of an inflammatory process, but these drugs cannot stabilize damaged cellular membranes, which makes their influence on an inflammatory process limited and insufficient.
Inflammation is a localized reaction of live tissue due to an injury, which may be caused by various endogenous and exogenous factors. The exogenous factors include physical, chemical, and biological factors. The endogenous factors include inflammatory mediators, antigens, and antibodies. Endogenous factors often develop under the influence of an exogenous damage. An inflammatory reaction is inevitably followed by an altered structure and penetrability of the cellular membrane. At the tissue and organ level, inflammation is indicated by pain, swelling, reddening, increased temperature, and a lost function in some cases. Inflammation begins with a sublethal damage and terminates either with a complete recovery or long-term tissue ruination. There is no recovery from an injury without an inflammation.
An immediate response to a tissue damage is realized via mediators, which are released due to the exocytosis or lysis of cells. The main inflammatory mediators are compounds of the kinine and fibrinolytic systems, the complement system, metabolites of arachidonic acid, vasoactive amines, and other chemical compounds. The chemical mediators of inflammation include: histamine, serotonin, prostaglandins, CGRP, nitric oxide, among others.
An important role in inflammations is played by various reactive oxygen-containing species. These compounds are synthesized when oxygen transforms them into very dangerous forms, producing free radicals, which are atoms and molecules with unpaired electrons. Different free radicals have different activity levels.
The launch of an inflammation is influenced by various exogenous and endogenous agents. Endogenous factors, namely, mediators, antigens, and autogens define the nature and type of the inflammatory reaction, especially its course in the zone of injury. In the case where a tissue damage is limited to the creation of mediators, an acute form of inflammation develops. If immunologic reactions are also involved in the process, through the interaction of antigens, antibodies, and autoantigens, a long-term inflammatory process will develop. Various exogenous agents, for example, infection, injury, radiation, also provide the course of inflammatory process on a molecular level by damaging cellular membranes which initiate biochemical reactions.
Inflammatory processes rely on the metabolism of arachidonic acid, which converts to prostaglandines (PG), tromboxanes (TX), and leukotrienes (LT). Prostaglandines, tromboxanes, and leukotrienes are the main participants of all inflammatory processes. There are two known ways of arachidonic acid cascade. The first way leads to the creation of prostaglandines G2 and H2. This process is catalyzed by prostaglandin-cyclooxygenase. Cyclooxygenase catalyzes the production of PGA2, PGE2, PGD2, PGF2xcex1, while tromboxane-synthesis with PGH2 produces tromboxane A2 (TXA2).
The cascade of metamorphoses of arachidonic acid, which is a product of membrane and phospholypase A2, is best known. Through its cyclogenase and lypoxygenase cascades, arachidonic acid turns into prostaglandins and leukotrienes, respectively. The cyclooxygenase way leads to the formation of two bio-active products: prostacycline (PGI2) and thromboxane (TXA2). These products are involved in many inflammatory effects: bronchoconstriction, vazodilation, vasoconstriction, platelet aggregation, analgesia, pyrexia, et al.
Another way of arachidonic acid metabolism with 5-lipoxygenase leads to the synthesis of leukotrienes: LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4. These leukotrienes have a powerful anti-inflammatory and bronchoconstrictor action, and they play and important role in vascular penetrability. Besides, leukotrienes are known as potential chemotactic factors; they increase the migration of WBC and have a great influence on the slow-releasing substance of anafilaxis (SRS-A).
Prostaglandines can play an important role in the development of systemic inflammatory reactions. In rheumatic arthritis, large quantities of PG and LT in the synovial liquid support the development of an inflammatory process and demineralization of bone tissue surrounding joints. Leukotrienes are known to be the main patho-physiological mediators of inflammatory reactions. They influence, to a greater degree than prostaglandines, the penetrability of vessels and the adhesion of leukocytes to vessel walls as well as the development of edema.
Prostaglandines effectively regulate the aggregation of platelets. PGE1 is a powerful inhibitor of platelets aggregation, while PGE2, which is normally released from platelets, stimulates this process. However, the most important role in blood coagulability is played by PGI2, or prostacycline, which is synthesized in blood vessel walls by arachidonic acid. It is the most powerful inhibitor of platelets aggregation, which has vasodilator properties. Thromboxane, which is synthesized in platelets, has an opposite action.
When endothelium is damaged, the adhesion of platelets with subendothelium tissue and the aggregation of platelets is initiated. The main role in this process is played by thromboxane A2. Prostaglandin I2, on the contrary, inhibits the aggregation of platelets. Therefore, the proportion of PGI2 and TXA2 is crucial for the process of coagulation.
Further, a special role in the process of recovery from inflammation is played by nitrogen oxide (NO). This gas easily penetrates in different organs and tissues and, as a free radical, has a powerful reactivity. Nitrogen oxide is a potent vasodilator, neurotransmitter, and inflammatory mediator, which plays a significant role in asthmatic inflammation.
Nitrogen oxide is produced endogenously by L-arginine amino acid and NO-synthetase. There are three known forms of NO-synthetase, two of which are constituent, and one inducible. The inducible NO-synthetase, which is expressed in the epithelium cells, quickly increases its activity when anti-inflammatory cytokines (such as interleukin 1 beta (IL-1beta) and tumor necrosis factor (TNF-alfa) are released.
Nitrogen oxide has both positive and negative properties with respect to an inflammatory reaction. One important and potentially positive property is its ability to relax the smooth bronchial muscle, which results in bronchodilation. Its negative properties include the ability to help the inflammatory process by increasing chemotaxis neutrophils, monocytes, and oesinofils with the help of the guasine-monophosphate-dependent mechanism. It is believed that nitrogen oxide inhibits adhesion of leukocytes to vascular endothelium and bronchial epithelium.
NO plays an important biological role in defining basal vascular tonus, regulating contractions of myocardium, and modulating the interaction between thrombocytes and vascular walls (Zhou Q., Hellermann G. R., Solomonson L. P., Nitric oxide release from resting human platelets, Thromb.Res., 1;77(1):87-86; 1995). The role of thrombocyte activation in the pathogenesis of various thrombo-vascular conditions in humans and evidence about decreased NO-mediated effects in hypertension (Calver A., Collier J., Moncada S., Vallance P., Effect of local intra-arterial NG-monomethyl-L-arginin in patients with hypertension: the nitric oxide dilator mechanism appears abnormal, J.Hypertens., 10(9):1025-1031; 1990), diabetes (Calver A., Collier J., Valance P., Inhibition and stimulation of nitric oxide synthesis in the human foream arterial bed of patients with insulin-dependent diabet, J.Clin.Invest, 90(6):2548-2554; 1992), and artherosclerosis (Drexler H., Zeiher A. M., Meinzer K., Just H., Correction of endotelial dysfunction in coronary microcirculation of hypercholesterolaemic patient by L-arginine, Lancet., 21-28; 338(8782-8783); 1546-1550; 1991) suggests that drugs which increase the activity of NO-synthetase may effectively be used in treatment of patients. Human thrombocytes are capable of synthesizing nitric oxide. Large quantities of nitric oxide, for example, in the cells of endothelium, may be produced by intact thrombocytes, as well as by stimulated thrombocytes. Hence, nitric oxide of thrombocyte origin plays an important role in the support of vascular homeostasis and other NO-sensitive processes. (Zhou et al.,1995).
Beside some common features, inflammatory processes in each individual case have certain distinctions related to the peculiarities of functioning of the body organ and to the factors which caused the impairment: i.e., viruses, microorganisms, injuries, poisoning, etc.
For example, one of the common mechanisms of heart diseases, including acute infarct myocarditis, is a malfunction of the structure and function of the membrane of heart cells. As a result, the synthesis of leukotrienes, tromboxanes, etc., which have coronoconstrictor, arrythmogenic, hemoatractive and pro-aggregate action, increases (Bangham A. D., Hill M. W., Miller N., Preparation and use of liposom as model of biological membranes, Methods in Membrane Biology, Acad. Press, V.1, N. Y., P.1-68, 1974).
Another important factor in the pathogenesis of heart impairments is the coronoconstrictor and hemoattractive (with regard to neutrofiles) action of lipoxygenase derivatives LTC4, LTD4, LTB4 (Hoshida S, Kuzuya T., Nishida M., et al., Amer.J.Cardiol, 7; 63(10): 24E-2E; 1989; Lam B. K., Gagnon L., Austen K. F. et al., J.Biol.Chem., 15; 265(23): 13438-1341; 1990; Svendsen J. N., Hansen P. R., Ali S. et al., Cardiovasc.Res., 27(7): 1288-1294; 1993). Substances which can block this process can in turn reduce the size of necrosis at acute myocardial infarction and, therefore, significantly decrease the lethality in difficult cases of heart disease, such as gross myocardial infarction. At the same time, such substances can stabilize the membranes of heart cells. In addition, it is known that coronoconstrictor and hemoattractive effects during infarct are accompanied by an increased aggregation of platelets. Therefore, blocking this process also leads to a decrease of the size of impairment.
Further, disorders of the aggregate state of blood play an important role in the pathogenesis of various diseases. This is especially apparent in the pathogenesis of thrombo-vascular conditions in humans. It is known that a malfunction in the thrombo-vascular link of homeostasis is a key factor leading to disorders of the aggregate state of blood, by causing changes in the rheological properties of blood and triggering the formation of internal vascular aggregates. Thrombocyte-related injuries lead to failures in micro-circulation processes, which result in shortages of blood inflow to the tissue. At the initial stage of the formation of blood clots, platelets become activated and further undergo adhesion to the injured endothelium. Later on, they aggregate and an initial thrombocytic blood clot is formed.
Today, there is enough evidence of a close relation between inflammations, disorders in the aggregate state of blood, and cardio-vascular conditions (Anderson J. L. Cariqist J. L., et al., Evaluation of C-reactive protein an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction, J.Am. Coll. Card., 32: 35-41; 1998).
Role of Cell Membranes in Inflammatory Processes
The functions of cell membranes and their relation to inflammatory processes has been documented. It is known that the plasmatic cellular membrane occupies a special place among the other membrane structures and performs such important functions as barrier and transportation, provides a contact with the outside environment for the cell, participates in the regulation of cellular homeostasis, supports signal mechanisms of this regulation, and defines the cell""s individuality and wholeness. The structural organization, dynamics, and functions of erythrocytal membranes and various hemolysis patterns, such as osmotic, oxide, immune (induced by hemolytic viruses, toxins, complement), detergent hemolysis, photohemolysis, etc., are well studied (see, e.g., Bashford C. L., Alder G. M., Menestrina G.,et al., Membrane damage by hemolytic viruses, toxins, complement, and other cytotoxic agents. A common mechanism blocked by divalent cation. J. Biol. Chem., 15; 261(20): 9300-9308, 1986; Osorie e Castro V. R., Ashwood E. R., Wood S. G., Vernon L. P., Hemolysis of erythrocytes and fluorescence polarization changes elicited by peptide toxins, aliphatic alcohols, related glycols and benzylidene derivatives, Biochim. Biophys. Acta., 16; 1029(2): 252-258; 1990).
It was demonstrated that pH variation in the outside environment upsets the balance of forces influencing the membrane, which leads to structural changes and changes of the aggregation degree of membrane proteins. Two types of membrane structural changes are distinguished: those caused by pH variation in the range 7.0-6.0, and those for pH levels below 4.5 (Zavodnik I. B., Pileckaya T. P., Acid lysis of human erythrocytes, Biophizika., V.42, N.5, P.1106-1112, 1997). In the latter case, the membrane becomes destabilized and erythrocytal lysis follows. It is known that at pH 4.7, pores are formed in glycocalyx erythrocytal membranes (Arvinte T., Cudd A., Schulz B., Nicolau C., Biochim. Biophys. Acta., 19; 981(1): 61; 1989). In particular, decreased pH levels of the environment change the confirmation, package type, and mobility of phospholipids in model membranes. Thus, aggregation of membrane proteins, denatured due to a decreased pH, is the reason for membrane damages and acid lysis in erythrocytes.
The pattern of erythrocytal hemolysis by HCl was proposed based on the cooperative protonation of some center located in stroma or on the membrane of erythrocyte with a subsequent creation of pores, sufficient to release hemoglobin. By studying the mechanism and pattern of the acid hemolysis process, information about the structural organization of the membrane and membrane-stabilizing actions can be obtained.
The best known endogenous stabilizers of hemolysis in erythrocytes (osmotic hemolysis is the best-studied) are albumin of blood plasma, metallic ions K+, Na+, Mg2+ and, especially, Ca2+, which modulate the canals of plasmatic erythrocytal membranes, possibly including the proton canal (Anderson D. R., Davis J. L., Carraway K. L., Calcium-promoted changes of the human erythrocyte membrane. Involvement of spectrin, transglutaminase, and a membrane-bound protease. J. Biol. Chem., 10; 252(19): 6617-6623, 1977), cholesterol adsorbed on the surface of erythrocytes (Hui S. W., Stewart C. M., Carpenter M. P., Stewart T. P. Effects of cholesterol on lipid organization in human erythrocyte membrane, J. Cell. Biol., 85(2): 283-291; 1980), and polyamines, which bind with the fatty-acid residues of membrane phospholipids (Rennert O. M., Shukla J. B., Polyamines in health and disease Advances in Polyamine research, Raven Press, V.2, N.Y, P.195-21, 1978). The best known activators of endogenous hemolysis in erythrocytes are long-chain fatty acids (Rybszynska M., Csordas A, Chain length-dependent interaction of free fatty acids with the erythrocyte membrane, Life Sci., 44(9): 625-682; 1989), and especially free radicals of oxygen and nitrogen (Sato Y., Kamato S., Takahashi T. et al., Mechanism of free radical-induced hemolysis of human erythrocytes: hemolysis by water-soluble radical initiator. 18; 34(28): 8940-8949; 1955; Sen T.,Ghosh T. K., Chaudhuri A. K. Glucose oxidase-induced lysis of erythrocytes. J,Exp.Biol., 33;(1): 75-76; 1995; Wollny T., Yacoviello L. Propogation of bleeding time by acute hemolysis in rats: a role for nitric oxide. Am. J. Physiol. 272(6): 2875-2884; 1997).
In summary, there is evidence to suggest that the structure of the membrane is altered during inflammatory processes. However, the model of membrane damage in the inflammatory process has not been used for screening drugs and treating or preventing inflammation and inflammatory-related disorders.
Present Drugs Unsatisfactory
The present anti-inflammatory drugs are unsatisfactory because the difficult and various biochemical reactions involved in inflammations and the lack of reliable information about inflammatory pathogenesis complicate the experimental choice of pharmacological compounds capable to regulate inflammation. Thus, drugs are selected to have an effect on individual components of an inflammation. So far, there is no drug able to regulate most of the components of any inflammatory reaction.
Most of the known non-steroid anti-inflammatory drugs (NSAIDS) selectively influence certain phases of this pathological process. First, they influence the penetrability of blood vessels, which is often altered in acute inflammations, and various cell reactions, which are common for chronic inflammations. Also, many NSAIDS influence metabolism through the mechanism of free radicals.
The initial screening of anti-inflammation processes typically uses three groups of methods. First, the influence of drugs on easily-identifiable inflammatory symptoms is studied. These include swelling, hyperemia, necrosis, etc. A more advanced analysis includes experimental therapy methods, using model arthritis, carditis, etc., which are similar to human ailments. The third stage involves analysis of how the drug influences certain metabolic ways.
After the metabolism of arachidonic acid was studied in detail, many anti-inflammatory compounds, whose action was to regulate the formation of such metabolic products, were proposed. In most cases, such drugs act as inhibitors of the metabolic enzymes of arachidonic acid. One example is the anti-inflammatory pharmacological combination of cyclooxygenase 2 inhibitor and leukotriene A.sub.4 hydrolase inhibitor (Isakson, P. C., Anderson G. D., Gregory, S. A., Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A.sub.4 hydrolase inhibitor, U.S. Pat. No. 5,990,148, November 1999). A similar approach was proposed on the basis of analogues of pyrimidines, a component of nucleic acids (Connor D. T., Kostlan C. R., Unangst P.C., 2-heterocyclic-5-hydroxy-1,3-pyrimidines useful as antiinflammatory agents, U.S. Pat. No. 5,240,929, August 1993). Since these compounds are the inhibitors of key metabolic ferments of arachidonic acid, 5-lipoxygenase and cyclooxygenase, the authors suggested their use as anti-inflammatory drugs suitable for treatment of a wide range of diseases, from allergenic conditions and rheumatoid arthritis to artherosclerosis and myocardial infarction. Other researchers recommended prostacyclin analogues for treatment of thrombocyte aggregation and bronchoconstriction (Haslanger M. F., Prostacyclin analogs and their use in inhibition of arachidonic acid-induced platelet aggregation and bronchoconstriction, U.S. Pat. No. 4,192,891, March 1980).
However, since an inflammatory process initiates many different metabolic cascades, the use of inhibitors or metabolic analogues of arachidonic acid does not allow to balance all such reactions and, hence, cannot regulate the complex inflammatory process in a satisfactory manner.
Further, aspirin, which has been used in applied medicine for a long time, has also been proposed since it can block metabolic ferments of arachidonic acid. Inhibitors of prostaglandines, such as aspirin, quite effectively influence the inflammatory processes. For this reason, they are successfully used in clinics for the treatment of rheumatoid arthritis, osteoarthritis, and other similar inflammatory processes. Aspirin also has anti-coagulation properties, since it inhibits the synthesis of TXA2, and it influences at least partially the synthesis of PGI2. A daily dose of 3 g of aspirin is commonly used for prevention of stenocardia, as a post-infarct and post-insult treatment, or for patients with a high risk of cardio-vascular conditions.
However, studies on the synthesis of TXA2 and PGI2 in vivo have shown that peroral administration of aspirin decreases the secretion of PGI2 only for 2-3 hours, while the secretion of thromboxane is halted for 10 days (Vesterqvist O., Measurements of the in vivo synthesis of thromboxane and prostacyclin in humans, Scand. J. Clin. Lab. Invest. 48(5): 401-407; 1988). This author, as well as others (see, e.g., Lorenz R. L., Boehlin B., Uedelhoven M. W., Weber P. C., Superior antiplatelet action of alternate day pulsed dosing versus split dose administration of aspirin, Am. J. Cardiol. 15; 64(18): 1185-1188; 1989), not only show the difficulties in administering the right dose of aspirin, but also provide and experimental ground for the frequent side effects caused by aspirin during its long-term use.
Specifically, aspirin and other non-steroid anti-inflammatory drugs may be the cause of anaphylactoid reactions in sensitive individuals. The mechanism of these reactions is dose-dependent toxic-idiosyncratic, not immunologic. Also, aspirin is the most common cause of accidental poisoning. Children, treated by aspirin before poisoning, are also at great risk. Aspirin overdose, which occurs frequently, is difficult to correct. The effective aspirin dose for many diseases, including rheumatoid arthrtis, constitutes 3-6.5 mg per day, which leads to irritations of the gastro-intestinal tract. Patients with gastro-intestinal conditions do not tolerate aspirin. Aspirin also causes erosion, bleeding stomach ulcers, diarrhea, and duodenum ulcers. Further, aspirin is commonly used in treatment for its anti-thrombocytic action, but it is badly tolerated and causes side-effects when taken for a long period of time. In addition, by inhibiting non-selectively cyclooxygenesis, aspirin interferes with the synthesis of thromboxane, which is a powerful aggregant and vasoconstrictor, and may also lead to decreased levels of prostacycline, which is both anti-aggregant and vasodilator.
All these negative side-effects of aspirin and other NSAIDS motivate the search for new drugs which would have anti-inflammatory properties, but which are non-toxic in a wide range of concentration, have no side effects during a long-term use, and are capable of preventing and terminating inflammatory processes.
Pharmaceutical Use of Nucleic Acids
Nucleic acids are commonly used in pharmacology (Rothenberg M., Jonson G., Laughlin C. et al. Oligodeoxynucleotides as anti-sense inhibitors of gene expression: therapeutic implications, J. Natl. Cancer Inst., 18; 81(20): 1539-1544; 1989; Zon G., Oligonucleotides analogues as potential chemotherapeutic agents, Pharm. Res., 5; (9): 539-549; 1988). However, pharmaceutical uses for nucleic acids have not included inflammatory or inflammatory-related disorders. For example, Anderson et al., proposes the method of modulating the effects of cytomegalovirus infections with the help of an oligonucleotide, which binds with mRNA of cytomegalovirus, for treatment of cytomegalovirus infections in humans (Anderson K., Draper K., Baker B., Oligonucleotides for modulating the effects of cytomegalovirus infections, U.S. Pat. No. 5,442,049, Aug. 15, 1995). On the basis of a specific nucleic acid, which encodes the succession of 3xe2x80x2non-translated sector of protein kinase C, Boggs et al. propose a method for diagnosis and treatment of conditions, which are associated with protein kinase C alpha (Boggs R. T., Dean. N. M., Nucleic acid sequences encoding protein kinase C and antisense inhibition of expression thereof, U.S. Pat. No. 5,681,747, October 1997). Also, Yano et al. patented a DNA compound obtained from Mycobouterium bovis and Bacillus subtilis for treatment of stomach ulcers (Yano O., Kitano T., Method for the treatment of digestive ulcers, U.S. Pat. No. 4,657,896, April 1987).
In particular, it is known that ribonucleic acid (RNA), products of its partial hydrolysis, and synthetic poly-ribonucleotides have a wide range of bioactivity (Kordyum V. A., Kirilova V. S., Likhachova L. I., Biological action of exogenous nucleic acids, Visnyk ASC USSR, V.41, N.6, P.67-78, 1977). They activate protein synthesis in cells (Sved S. C., The metabolism of exogenous ribonucleic acids injected into mice, Canad.J.Biochem.,V.43, N.7, P.949, 1965) and have anti-tumor activity (Niu M. C., Effect of ribonucleic acid on mouse acids cells, Sciens., N.131, P.1321, 1960). RNA can increase antibody generation and decrease the inductive phase of antibody genesis (Johnson A. G., Schmidtke I., Merrit K. et at., Enhancement of antibody formation by nucleic acids and their derivatives, in Nucleic acid in immunology, Berlin, P.379, 1968; Merrit K., Johnson A. G., Studies on the adjuvant of bacterial endotoxins on antibody formation, 6. Enhancement of antibody formation by nucleic acids, J.Immunol., V.94, N.3, P.416, 1965; Brown W., Nakono M., Influence of oligodeoxyribonucleotides on early events in antibody formation, Proc. Soc. Exper. Biol. Med., 5, V.119, N.3, P.701, 1967). It was shown that certain increased or decreased immunologic indicators normalize under the influence of RNA. In the first place, this applies to T-lymphocytes, cooperation of T- and B-lymphocytes, activation of macrophage function, etc.
Further, exogenous RNA is used for the DNA synthesis in dividing cells and for the RNA synthesis in metabolizing cells. It was also determined that 2 hours after the introduction, exogenous RNA was included in the RNA of lymphocytes and macrophages (Enesco N. E., Fate of 14C-RNA infected into mice, Exper. Cell Res., V.42, N.3, P.640, 1966). Evidence suggests that yeast tRNA can be included into cells in the form of intact molecules (Herrera F., Adamson R. H., Gallo R. C., Uptake of transfer ribonucleic acid by normal and leucemic cells, Proc.Nat.Acad.Sci.USA, 67(4): 1943-1950; 1970).
It was determined by analytical methods that RNA is present in practically all membranes of animal cells (membranes of endoplasmic reticulum, mitochondrial, nucleic, and plasmatic membranes). Its content, depending on the type of tissue and on the method of membrane isolation, varies between 0.5 and 4% of the dry weight of the membrane. Experimental results show that special membrane RNA exists in isolated membranes (Shapot V. S., Davidova S. Y., Liponucleoprotein as an integral part of animal cell membrans. Prog. Nucleic Acid Res. 11: 81-101; 1971; Rodionova N. P., Shapot V. S. Ribonucleic acid of the endoplasmatic reticulum of animal cells. Biochim et Biophis Acta, 24; 129(1); 206-209; 1966). The functions of membrane RNA are not fully understood.
The functions of membrane RNA in ribosome have been better studied. (Cundliffe E., Intracellular distribution of ribosoms and poliribosomes in Bacillus megaterriium. J.Mol.Biol., 28; 52(3): 467-481; 1970) Ribosomal RNA is contained in bacterial membranes, in the outer membranes of nuclei, inner and outer membranes of mitochondria, inner membrane of the Goldgi apparatus, which adjoins the plasmatic membrane, in the rugged endoplasmic reticulum, in different tissues in animals, humans, plants, microorganisms, and protozoa. It is possible that membrane glycolipids and glycoproteins, which contain N-acetylneuraminic acid, are involved in the formation of binding sites of ribosomal RNA in ribosomes, since membranes which are treated by neuronidase lose the ability to bind ribosomes. (Scott-Burden T., Hawtrey A. O., Preparation of ribosome free membranes from rat liver microsomes by means of lithium chloride. Biochem. J. 115(5): 1063-1069; 1969. Further, it is possible that binding sites of ribosomes and membranes are activated by the sexual hormones, and cancerogens damage this physiological mechanism. This conclusion is supported by decreased levels of membrane-bound RNA in the process of aging (Mainwaring W. J. The effect of age on protein synthesis in mouse liver. Biochem J. 113(5): 869-878; 1969) and after castration of animals (Tata J. R., The formation, distribution and function of ribosomes and microsomal membranes during induced amphibian metamorphosis. Biochem J. 105(2): 783-801, 1967). Extraction of spermine from a membrane leads to a separation of bound RNA from the membrane (Khawaja J. A. Interaction of ribosomes and ribosomal subparticles with endoplasmic reticulum membranes in vitro: effect of spermine and magnesium. Biochim. Biophis. Acta., 29; 254(1): 117-128); 1971). When membranes are treated with RNA of native small ribosomes of myeloma cells, they separate from the membranes, while large native subunits of ribosomes remain bound with the membranes (Mechler B.,Vassalli P., Membrane-bound ribosomes of myeloma cells.I.Preparation of free and membrane-bound ribosomal fractions. Assessment of the methods and properties of ribosomes. J.Cell.Biol. 67(1): 1-15; 1975 . Also, the nucleotide components of various membrane enzymes, for example, polyA-RNA enzyme of phosphofructokinase, constitute a possible pool of membrane RNA (Hofer H. W., Pette D. The complex nature of phosphofructokinasexe2x80x94a nucleic acid countaining enzyme, Life Sci. 4(16): 1591-1596; 1965).
However, nucleic acids, and in particular RNA, and compositions containing the same, have not been used to treat or prevent inflammatory or inflammatory-related disorders. In particular, most of the studies above rely on experiments in vitro. Further, none of these methods is directed to treating or preventing an inflammation or inflammatory-related disorder.
Need for New Drug
In view of the above, there is a need for new anti-inflammatory drugs which would regulate disorders of the aggregate state of blood and would have less negative effects than aspirin and other NSAIDS. In particular, since an inflammatory process in the initial stage is followed by alterations in the structure and functions of the membrane in the many cells involved in the inflammatory process, drugs are needed which, not only regulate all the components of an inflammatory metabolic cascade, but also stabilize membrane structures and functions in the involved cells. In particular, since the traditional therapy has little effectiveness in extensive infarcts, which are complicated by the cardiogen shock, there is a need for new drugs capable of stopping the destruction of cardiomyocytes.
The present invention offers a compound, a pharmaceutical composition and a method for the treatment or prevention of inflammation and diseases accompanied by inflammatory processes. The compound is an active ingredient consisting of RNA, in particular RNA extracted from yeast. Yeast RNA is a heterogenous compound of low-polymeric RNA, which comprises various quantities of nucleotides, nucleotide polymers, and usually 5 to 25 nucleotides. Oligonucleotides and transport RNA with a great number of minor bases prevail in yeast RNA.
Since one of the common features of all inflammatory processes at a molecular level is altered penetrability and structure of membrane, the present invention was made using a method of selecting drugs based on their ability to stabilize cellular membrane in inflammations. Thus, by analyzing destructive mechanisms induced by various factors in plasmatic membranes and learning about the structural elements of their interaction, which provide the optimal organization of a cell, it is possible to select drugs having membrane-stabilizing action for applied medicine. Specifically, it has now been established that, since membranes contain low-molecular RNA which probably plays a membrane-stabilizing role, introduction into the body of exogenous low-molecular RNA leads to stabilization of disturbed membranes, such as, for example, membranes of cells involved in inflammatory processes.
Stabilization of the cell membrane by the compound of the present invention leads to the normalization of arachidonic acid metabolism and nitric oxide metabolism, which have a powerful anti-inflammatory action and are the main participants of all inflammatory processes, for example, rheumatoid arthritis, osteoarthritis, allergies (such as asthma), and other inflammatory conditions, such as pain, swelling, fever, psoriasis, inflammatory bowel disease, gastrointestinal ulcers, cardiovascular conditions, including ischemic heart disease and atherosclerosis, partial brain damage caused by stroke, skin conditions (eczema, sunburn, acne), leukotriene-mediated inflammatory diseases of lungs, kidneys, gastrointestinal tract, skin, prostatitis, and paradontosis.
The yeast RNA is effective in decreasing the activity of iNOS in the course of an auto-immune process, both during its initiation and in the chronic stage. This property allows the usage of yeast RNA in pathological conditions which are accompanied by iNOS induction: diabetes, tumor, hepatitis, infections, neuro-degenerate diseases (Parkinson""s disease, Alzheimer""s disease, multiple sclerosis, encephalitis), and others.
In addition, the use of natural molecules of nucleic acids, such as the compound of the present invention, in large concentrations as pharmacological compounds causes no or little side effects, especially taking into account the fact that this compound constantly enters human and animal bodies with food.
Further, the present invention offers a method for the treatment of inflammation or inflammatory-related disorder comprising administering to a mammal in need of such treatment an amount effective to ameliorate the symptoms of inflammation or inflammatory-related disorder of ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent.
Still further, the present invention offers a method of stabilizing damaged cellular membranes which comprises administering to a mammal having damaged cellular membranes an amount effective to stabilize said damaged cellular membranes of ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent.
Still further, the present invention offers a method of normalization of NO-synthetase ability in a mammal which comprises administering to a mammal in need of such treatment an amount effective to normalize NO-synthetase ability in the mammal of ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent.
Still further, the present invention offers a method of inhibiting oxidation of components of cell membranes of a mammal, which comprises administering to a mammal in need of such treatment an amount effective to inhibit oxidation of components of cell membranes of the mammal of ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent.
Still further, the present invention offers a method of inhibiting thrombocyte aggregation, which comprises administering to a mammal in need of such treatment an amount effective to inhibit thrombocyte aggregation of ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent.
Also, the present invention offers a compound consisting of ribonucleic acid extracted from yeast, for example a Saccharomyces cerevisiae or a Candida utilis. Preferably, the ribonucleic acid has a nitrogen content of more than 14.5% by weight and a phosphorus content of more than 8.5% by weight, more preferably a nitrogen content of more than 14.7% by weight and a phosphorus content of more than 8.6% by weight, even more preferably a nitrogen content of more than 15.0% by weight and a phosphorus content of more than 9.0% by weight.
Further, the present invention offers a pharmaceutical composition for the treatment or the prevention of inflammation or inflammatory-related disorder, comprising ribonucleic acid and a pharmaceutically acceptable vehicle, carrier, or diluent.
A complex analysis of known nucleic acids was carried out using various in vitro and in vivo models. The models were chosen to correspond to certain types of inflammatory processes, both of common and immunologic origin. In the tests, the effects of ribonucleic acid (RNA), in particular yeast RNA, was compared to the effects of existing anti-inflammatory drugs over a wide range of anti-inflammatory activities.
Summary of Experimental Models and Results
1. Model of Thrombocyte Aggregation in Vitro
An initial screening of exogenous nucleic acids was conducted in vitro on the model of aggregation of human thrombocytes induced by arachidonic acid (Born L. V. R. The aggregation of blood platelets by difosfate and its reversal, Nature, V.94, P.327, 1962). Exogenous DNA and RNA from prokaryotes and eukaryotes were analyzed. We used aspirin as representative of a standard anti-inflammatory drug.
It was demonstrated that aspirin inhibited the aggregation of thrombocytes induced by arachidonic acid to a certain level. Desoxyribonucleic acid obtained from chicken erythrocytes (DNA-CE) produced by xe2x80x9cReanalxe2x80x9d (Hungary), inhibited thrombocytic aggragation within the range of aspirin. Further, DNA from cattle thymus (DNA-CT) produced by xe2x80x9cReanalxe2x80x9d (Hungary), and transport RNA of E. coli (tRNA) produced by xe2x80x9cServaxe2x80x9d (USA) inhibited aggregation of the induced thrombocytes almost twice. The highest inhibiting effect was demonstrated by total yeast RNA, which dramatically inhibited thrombocytic aggregation in a wide range of concentrations. Inhibition of thrombocytic aggregation by yeast RNA depended on the form (acid or its sodium salt), purity, and presence of protein. RNA-F with protein admixtures was less effective by a third. The sodium salt of yeast RNA-PN in high concentration was only half as effective, and did not act in low concentration.
Since the model of aggregation of thrombocytes induced by arachidonic acid is recognized for the selection of anti-inflammatory drugs, the results of this comparative test showed that nucleic acids, and especially RNA, in particular, yeast RNA, have pronounced anti-inflammatory properties.
2. Model of Acid Resistance of Erythrocyte Membranes in Vitro
Based on the recognition that destabilization of cellular membranes is the main indication of an inflammatory process, we used the model of acid resistance of erythrocyte membranes in vitro for the screening of membrane-protecting, and thus, anti-inflammatory properties of the drugs. We chose rat erythrocytes to study the immune-stabilizing action of exogenous nucleic acids. We analyzed the reactions of erythrocytic membranes to the destructive influence of nitric oxide. We estimated the membrane-stabilizing action of exogenous nucleic acids and damaging actions of endogenous and exogenous nitrite anion by calculating the acid resistance of erythrocytes according to the kinetic method (Terskov I. A., Hittelzon I. I., Chemical (acid) erythrogram method, Biophizika, 2(2): 259-266; 1957). The main idea of the method is to determine historical changes in the number of cells, which eventually become hemolyzed under the influence of weak acids. The lysis of erythrocytes in acid environment undergoes three stages: penetration of hydrogen ions (protons, H+) through the plasmatic membrane of erythrocytes, protonation of hemoglobin and membrane proteins, and, as a result, osmotic destruction of erythrocytes.
Using this method, we estimated the influence of exogenous nucleic acids on the kinetics of the penetration of protons through the erythrocytic plasmatic membrane, which depends on the membrane""s nature. The speed of proton penetration in the cellular cytosol depends to a great extend on the oxidation status of the lipid component (Kellogg E. W., Fridovich I., Liposome oxidation and erythrocyte lysis by enzymically generated superoxide and hydrogen peroxide J. Biol. Chem. 10; 252(19): 6721-4728; 1977) and protein component, especially, the band 3 oxidation of plasmatic membranes and is defined by the activity [H+]-ATP-ase, and the activity of various exchangers (Sato Y., Kamo S., Takahashi T., Suzuki Y., Mechanism of free radical-induced hemolysis of human erythrocytes: hemolysis by water-soluble radical initiator, Biochemistry, 18; 34(28): 8940-8949; 1995; Lukacs G. L., Kapus A., Nanda A. et al, Proton conductance of the plasma membrane: properties, regulation, and functional role, Am. J. Physiol, 265(1 Pt 1): C3-C14; 1993).
Acid erythrograms were recorded by the kinetic method. In the in vitro tests, acid erythrograms were recorded in the presence of sodium nitrite (the damaging agent) and different concentrations of exogenous nucleic acids.
The in vitro tests, which used the oxide damage model of erythrocytes by nitrite anion, a stable metabolite of nitric oxide, demonstrated stabilizing and membrane-protector action of exogenous nucleic acids.
On the model of acid resistance of erythrocytic membranes, we tested the same set of preparations as in the model of thrombocytic aggregation.
Yeast RNA preparations demonstrated membrane-protecting properties in a wide range of concentrations. A more detailed analysis showed that the membrane-protector action of yeast RNA depends on their form (acid or sodium salt), purity, and the presence of protein. Well-purified ribonucleic acid RNA-P, whose erythmograms in the concentrations 10 and 100 xcexckg corresponded to the norm, showed the highest effectiveness. Sodium salt of yeast RNA-PN was less effective, especially in the concentration 10 xcexckg. Protein admixtures in RNA-F resulted in a complete loss of the membrane-stabilizing action. Other preparations, tRNA, DNA-CT, and DNA-EC destabilized erythrocyte membranes at the tested concentrations, which means that they cannot be used as anti-inflammatory drugs as advantageously despite their anti-inflammatory properties demonstrated on other models.
3. Model of Erythrocytal Auto-Immune Reaction in Rats
We used the model of acid injury of erythrocytal plasmatic membranes to study the membrane-stabilizing action of exogenous nucleic acids. Acid damages to the protein and lipid components of erythrocytal plasmatic membranes were tested in vivo in the process of development of an auto-immune reaction (adjuvant arthritis). The biosynthesis of nitric oxide, which is an active oxidizing agent, became activated and, especially, hemoglobin of erythrocytes (Eich R. F., Li T., Lemon D. D. Mechanism of NO-induced oxidation of myoglobin and hemoglobin. Biochemistry, 4; 35(22): 6976-6983; 1966; Huot A. E., Kruszyna H., Kruszyna R. et al., Formation of nitric oxide hemoglobin in erythrocytes co-cultured with alveolar macrophages taken from bleomycin-treated rats. Biochem.-Biophys. Res. Commun., 15; 182(1); 151-158; 1992; Kosaka H., Harada N., Watanabe M. et al. Synergistic stimulation of nitric oxide hemoglobin production in rats by recombinant interleukin 1 and tumor necrosis factor. Biochem. Byophis. Res. Commun. 30; 189(1): 392-398; 1992). Nitric oxide, as well as hydrogen peroxide, plays a crucial role in the damage to cells, including blood cells, in the process of development of autoimmune reactions. The anti-inflammatory cytokines (gamma-interferon, IL-1) induce expression of the inducible isoform of NO-synthetase (iNOS).
We studied changes in the activity of NOS in rat blood in the development of autoimmune reaction (adjuvant arthritis) in order to evaluate the preparation""s immune-modulating effect and to obtain information about possible levels of one of the most active oxidizing hemolytics, nitric oxide (in the form of its stable metabolite, nitrite anion). We calculated the activity of the enzyme NO-synthetase (NOS), which generates endogenous nitrite anion. These values characterize the protective effect of exogenous nucleic acids against the damaging influence of nitrite anion on erythrocytic membranes. Our focus on the changes in stability of erythrocytes in the process of autoimmune reactions is due to the large existing body of evidence supporting the immune-modulating properties of erythrocytes (Karalnik B. V., Erythrocytes, their receptors, and immunity, Uspekhi Sovremennoy Biologii., V.112, N.1, P52-61, 1992; Prokopenko L. H., Siplivaya L. E., Erythrocytes as modulators of immunologic reactions, Uspekhi Phiziologicheskikh Nauk., V.23, N.4, P.89-106, 1992), which has resulted in the use of the term xe2x80x9cerythrocytal immune systemxe2x80x9d.
Development of the autoimmune process was accompanied by a substantial decrease of acid resistance of erythrocytes during the early stage and, on the contrary, by a considerable excess over the norm during the final stage, in comparison with the resistance of normal erythrocytes.
Yeast RNA increased membrane stability, i.e., normalized the process of transportation of protons (which is attributed to the state of the protein and lipid components of etrythrocytal plasmatic membranes) during the initial stage and kept it stable, close to the norm, during the following stages of autoimmune reaction.
Further, it was demonstrated that, during the development of an autoimmune process, activities of NOS in rat blood changed. During the initial and final stages, an increased activation of NOS in rat blood was evidenced. Yeast RNA decreased NOS activity, so that at the final stage, the activity was practically normal.
Also, development of the autoimmune process was accompanied by a substantial decrease of acid resistance of erythrocytes during the early stage and, on the contrary, by a considerable excess over the norm during the final stage, in comparison with the resistance of normal erythrocytes. Yeast RNA increased membrane stability during the initial stage, by normalizing the process of proton transportation, which is dependent on the state of the protein and lipid components of etrythrocytal plasmatic membranes, and kept it stable, close to the norm, during the following stages of autoimmune reaction.
In view of the above, the protecting activities of yeast RNA as shown on the model of autoimmune process establish its ability to cure, not only allergic diseases, but other chronic inflammatory processes as well, such as arthritis, artherosclerosis, and other diseases that involve autoimmune reactions. ps 4. Model of Swelling Induced by Carrageenan in Rats
To screen nucleic acid""s anti-inflammatory action, we used a common model of inflammatory swelling of leg in mice provoked by a sub-plantar injection of carrageenan. Carrageenan-induced swelling is sensitive to the action of compounds which reduce capillary penetrability.
During the initial stage, a significant role in the mechanism of anti-inflammatory effect of carragenan is played by kinine, while at the later stage, proteolytic ferments and prostaglandins become more important. The carrageenan model has a slower development and is preserved for a sufficient time, which makes it possible to study the biochemical mechanism of the anti-inflammatory action of a drug. Therefore, we used this model to study the influence of yeast RNA on the synthesis of thromboxane and leukotriene. At the same time, we analyzed the influence of yeast RNA on NO-synthetase activity.
Analysis of the anti-inflammatory action of nucleic acids in the carrageenan model showed that they all have certain anti-inflammatory action. However, only yeast RNA in the concentration 10 mg of drug per mouse resulted in a 50% reduction of swelling. The concentrations of yeast RNA tested in mice represented 1 to 15 mg per mouse. Concentrations below 1 mg of yeast RNA preparation per mouse did not show any action. In concentrations above 15 mg, reduction of swelling was about 53-55%. Further, biochemical tests revealed a stabilizing influence of yeast RNA on the activity of NO-synthetase as well as on the quantities of thromboxane and leukotriene, which varied in the course of swelling process.
By contrast, aspirin, which was tested at the recommended therapeutic dose of 20 mg/kg, influenced swelling to a considerably smaller extend and did not show stabilizing properties at the level of biochemical metabolism.
5. Model of Acute Ischemia in Rats
Further analysis of yeast RNA was conducted on the model of acute ischemia-reperfusion of myocardium in rats. This model is based on a common fundamental mechanism in the development of a variety of different heart conditions, which includes alteration of structures and functions of the membranes in endotheliocytes, cardiocytes, and other heart cells. This alteration results in the degradation of membrane phospholipids and the creation of highly effective bio-active compounds, such as leukotrienes or thromboxanes, which have coronaroconstrictor, arythmogen, chemoactive, and pro-aggregant action (Bangham A. D., Hill M. W., Miller N., Preparation and use of liposom as model of biological membranes, Method in Membrane Biology, Acad.Press, V.1, N.Y, P.1-16, 1974).
As the tests demonstrated, yeast RNA, injected in rats intravenously in the concentration of 40 mg per rat, normalized heart function in acute infarcts. This was shown in a pronounced anti-arythmic action of the compound and a substantial decrease of the necrosis area in ischemized myocardium of heart. The drug almost completely normalized NO-synthetase activity in blood and in the border zone of ischemized heart. Yeast RNA injection normalized to a certain level the content of arachidonic acid in blood and heart of animals in acute infarctions. The injection of yeast RNA almost completely normalized the levels of eukosanoids in rat blood in ischemia cases. The activity of mieloperoxidase, the marker enzyme of neutrophils which helps to evaluate the preparation""s anti-oxidant action, decreased almost twice in animals with infarct treated by yeast RNA.
The analysis of yeast RNA activity in the ischemia-reperfusion model in rats determined that the drug has a substantial stabilizing action in different cascades of inflammatory processes in the ischemized heart, which is expressed in its long-term anti-infarct action and a decreased size of the infarct area in myocardium.
On the basis of the study of yeast RNA action in ischemia-reperfusion of animal heart, we can conclude that yeast RNA has an anti-infarct action, or anti-inflammatory action in infarcts, through stabilization of the structure and function of membranes in endotheliocytes, cardiocytes, and other heart cells.
Experimental Procedures and Test Results

Compound, composition and method for the treatment of inflammatory and inflammatory-related disorders


A digital camera pedestal with cable in neck is provided which may comprise a base member, a neck, and a camera housing. The base member can comprise a surface mount, a cable exit annulus, and a neck mount. The surface mount and said neck mount can attach together forming an interior cavity. A cable enters the cavity through the neck mount, and exits through the cable exit annulus. An annular neck member is rotatably attached to the neck mount, such that it can rotate in a vertical plane, and a camera housing member is in turn rotatably attached to the neck member, where the housing member can rotate in a horizontal plane.

Small, surface mounted or clip mounted digital cameras, commonly referred to as "webcams" have proliferated as applications such as digital picture sharing, video file sharing, video conferencing, security monitoring and the like continue to expand. "Webcam" refers to digital cameras that are used for a host of purposes beyond uploading images or video to the internet, as the name implies.
One interesting new market for webcams is the video gaming market, where webcams will be used for a wide variety of functions, such as capturing a player's picture for upload to a gamer identification database, video conferencing, inserting custom pictures and videos into games, video feedback so games can react to player physical motion, and the like.
One problem facing any webcam design is making a webcam of sufficiently small size, so that it does not consume too much desktop or set-top real estate. While small size is desirable, so is camera stability. Users do not want webcams that are constantly falling over backward because a heavy cable extends from the back of the webcam. Size and stability are often inversely related, such that small size yields less stability. Another problem in webcam design is to allow the camera to aim at a desired angle and hold position. The angle at which a webcam is aimed should preferably be adjustable in both the vertical and horizontal planes.
A variety of solutions to the size and stability problem can be seen in today's market for webcams. Clipable webcams are available that can be clipped to a computer display. Webcams may also be made with a somewhat large flat-surfaced base member that supports an elevated digital camera. In this configuration, a cable extends out from directly behind the camera and tends to pull the camera backward. The base member must be sufficiently large to prevent the camera from falling over, which of course negatively impacts pedestal size requirements.
In light of the size and stability tradeoff, as well as a host of other potential advantages and improvements that can be obtained, the industry and the consuming public is in need of a better digital camera pedestal.

Digital camera pedestal with cable in neck


A system for signaling vehicle deceleration having an acceleration sensor, processor, lamp controller, power supply, mount, and lamp. The acceleration sensor gathers acceleration data of the vehicle, and the processor interprets the acceleration data gathered. If, based on that data, the processor determines that the vehicle is decelerating beyond a preset threshold, the processor powers the lamp via the lamp controller. The system adjusts for various orientations and positions of installment.

Each year, there are millions of rear-end collisions—a devastating type of car crash that is primarily caused by a following driver reacting too slowly to a vehicle's deceleration—otherwise known as braking. Normally, a vehicle's brake light is designed to alert following drivers to such braking. However, drivers often still do not react fast enough to avoid a crash. As a result, the market needs a technology that can improve upon existing brake lights: an enhanced, aftermarket brake light that improves safety by getting the attention of a following driver more quickly.
There is great potential for this type of brake light enhancement: studies show that by simply brightly pulsing—or flashing—a brake light at 5 hz upon rapid braking, following drivers can react far faster to a decelerating lead vehicle than they would if the lead vehicle had a normal, factory brake light. Since factory installed brake lights become outdated quickly, aftermarket brake light enhancements have the potential to help drivers add this type of cutting-edge safety to their vehicles. However, for any aftermarket technology to realize its commercial potential, it must be simple to install, easy to operate, and effective. If it is not simple to install, many drivers will be unable or unwilling to add the technology to their vehicle. If it is not easy to operate, drivers will have to interact with their car more, either through physical manipulation or mental consideration, both of which are a burden drivers would rather avoid. If it is not effective, there is no benefit to the cost.
Aftermarket brake light enhancements generally fall into two categories: wired and wireless systems. Wired systems tap into some portion of the existing brake light system of the vehicle. Often, this means connecting to the power lines of the brake light. Then, the system modifies the existing brake light on the vehicle by regulating the power it receives. This enables a brake light to flash or dim, rather than simply turn on or off with the brake pedal. On the other hand, wireless systems do not rely entirely on the existing brake system of the vehicle. Often, they use a separate power supply or accelerometer to provide power to lights and to sense the vehicle's braking, respectively. However, the automotive environment is particularly harsh; damage and wear can be caused by passengers, high heat, and intense vibration. Altering the vehicle's wiring or panelling can void factory warranties, and if the driver is affected by any changes to the vehicle, the driver's visibility can be impaired resulting in reduced safety. As a result, all aftermarket brake light enhancements are severely limited by some combination of three problems: a complicated installation, an inconvenient operation, and an ineffective signalling of deceleration.
Having an aftermarket product with a complicated installation is detrimental to the commercial value of the product because such complexity makes the driver less likely to perform a successful installation. The driver may not even attempt to have the product installed on their vehicle. Wired systems are particularly complex as they require using tools, removing vehicle panelling to access wires, stripping wires, and connecting wires. Such steps require extensive electro-mechanical knowledge that should only be undertaken by professionals. Additionally, since vehicles vary greatly, each vehicle may need its own set of installation instructions. Since the product is such that a professional must be hired at time and cost, this reduces the likelihood that a driver will want to go through the effort to install the product, thereby decreasing the product's commercial value and potential to add safety.
Once an aftermarket brake light system is installed, it is often inconvenient to operate. Wired systems are usually tucked away in the panelling of the vehicle, so any further adjustments or servicing will once again require the assistance of a professional at time and cost. Wireless systems are vulnerable to harsh driving environments such as road imperfections and vibration. Additionally, occupants of the vehicle may accidentally bump the wireless system, causing damage and inadvertent adjustments to settings. As a result, these aftermarket systems must be serviced and maintained regularly to so they can survive these intense conditions. Finally, since all aftermarket technologies must be affixed to the vehicle as an add-on, the driver's visibility through the rearview mirror is negatively affected. As a result, aftermarket brake light enhancements are inconvenient as they require inconvenient servicing and consideration during normal operation.
Lastly, these technologies are ineffective at signalling deceleration. Wired systems are limited to the location, size, and maximum brightness of the existing brake light of the vehicle. Wireless systems provide a light output to the following driver that is limited. This is a problem for drivers, as the purpose of an aftermarket brake light enhancement is to add safety through more effective signaling of the vehicle's deceleration.
All aftermarket brake light enhancements fall into at least one category of: complicated to install, inconvenient to operate, or ineffective at signalling. However, the invention of this disclosure solves all three of these problems.

Wire-free system and method for signaling deceleration in vehicles


In a rotary table of a seat for automobiles, a bolt-coupled holder and an end of a push plate are rotated by being engaged with an end of a fixing plate fixed to the bottom of the automobile to reduce a noise caused by the rotation and sustain a shock occurring in a car accident. A projecting disc portion has a thruhole in the center of the fixing plate, fixing grooves with inner sides opened are formed along the border of the thruhole, the push plate coupled with the holder via coupling holes is formed with a fixing groove in front of the coupling holes in a central circular portion, locker fixing holes are formed in front of the fixing groove of the push plate, the holder coupled via the coupling holes along the outer side of a thruhole in the center has an abutment adjacent to the outer border, a fixing groove with outer side opened is formed into one side of the border to fix the border of the thruhole of the fixing plate between the push plate and outer border of the holder, a fixing plate with opposing projecting brackets is fixed via locker fixing holes of the push plate, a handle is installed to the projecting brackets by welding a fixing rod to a concave semi-circle and having a circular hole in the center for being inserted into the projecting brackets, and a locking device having a circular rod inserted into the circular hole of the projecting brackets fits a locking bracket and a spring into the circular rod.

1. Field of the Invention
The present invention relates to a rotary table mounted to a seat for automobiles, wherein a holder and an end portion of a push plate bolt-coupled to an end portion of a fixing plate fixed to the bottom of the automobile are rotatably installed to rotate the seat by rotating the holder and push plate engaged with the end portion of the fixing plate, thereby minimizing a noise occurring at the rotary table when the seat is rotated and maximally preventing the jolting of the seat when a passenger sits in the seat.
2. Description of the Prior Art
A generally-employed conventional rotary table of automobile as shown in FIG. 1 is formed by a fixing plate 102 fixed to a fixing member 101 fixed onto the bottom of the automobile, a holder 104 fixed to fixing plate 102 by means of a bolt 103 and a rotating plate 105 fitted to be rotated between fixing plate 102 and holder 104.
In view of a locking device of the conventional rotary table, a locking jaw 107 of a locker consisting of a locking lever 106 and locking jaw 107 is inserted into/released from a plurality of fixing grooves formed in the same position of rotating plate 105 by the operation of locking lever 106, thereby performing the locking operation.
However, the above-stated conventional rotary table is formed such that rotating plate 105 is fitted to be fixed between fixing plate 102 and holder 104 when the seat is rotated as required. Thus, it is disadvantageous of impeding smooth rotation or inducing a noise.
That is, when the space formed for fitting rotating plate 105 between fixing plate 102 and holder 104 is large, rotating plate 105 fit fixed to be rotated by being fitted between fixing plate 102 and holder 104 is shaken due to the gap between fixing plate 102 and holder 104. In addition to the shaking, rotating plate 105 is in contact with fixing plate 102 and holder 104 while being rotated inciting a frictional sound. Also, if the space between fixing plate 102 and holder 104 is narrowed, rotating plate 105 is not smoothly rotated.


The disclosure relates to methods, apparatuses, electronic devices, and storage media for acquiring programs in a live streaming room. The method includes acquiring a program acquisition condition and triggering to save live streaming room data of a user account as a target program in response to detecting that a live streaming behavior of the user account meets the program acquisition condition, to provide the target program to an associated user account of the user account.

Nowadays, webcast, such as live shopping, live performances, live teaching, industry exhibitions, or the like is gradually integrated into in work and life of users. Users with associated user accounts can easily participate in rich, real-time live streaming interactions, to satisfy their demand for live interaction.
However, due to high real-time and high participation of interaction in the live streaming room, it is often difficult for users to predict moments when highlights in the live streaming content will appear during the interaction in the live streaming room In that regard, the users may not have the opportunity to save live streaming room data corresponding to the highlights in time, which greatly affects the interactive experience of users and their associated users in the live streaming room.

Method, apparatus, electronic device and storage medium for acquiring programs in live streaming room

BEIJING DAJIA INTERNET INFORMATION TECHNOLOGY CO., LTD.


A system and method of recommending and rating content and/or for generating a determined affinity between content consumers and reviewers. The method includes determining a rating for one or more user-surveyed content items and determining a rating for one or more reviewer-surveyed content items for each of a plurality of content reviewers. Comparisons are then performed between user ratings and reviewer ratings for commonly surveyed content items. As a result, affinities between user(s) and content reviewers are established and the user is provided with reviews and ratings produced by high-affinity content reviewers.

The Internet and other communication networks have grown in sophistication in terms of their offering of solutions to connect users with relevant content. Despite this, the Internet and other networks still constitute a vast wilderness of information in which it can be extremely difficult for users to identify information that is assured of being useful and/or interesting. Various approaches exist for addressing this problem, including collaborative filtering and various social recommendation tools.
For example, many e-commerce websites employ functionality that will recommend alternate or supplemental products to a user based on the user's browsing among particular items featured on the site. These recommendations in many cases are based on purchaser data accumulated by the website, for example, data which shows that users buying a first product are also likely to want to buy a second, related product. One issue with such an approach is that there is no mechanism for establishing that a given user will have preferences that are similar to other users of the website. Therefore, the recommendations can be very speculative, and these systems are therefore limited in the ability to provide relevant recommendations to users.

Content recommendation system and method


In accordance with the present invention, there are provided high molecular weight polyethylene molecular orientation molded articles formed from high molecular weight polyethylenes having a weight average molecular weight of 300,000-600,000, said molecular orientation molded articles having a fineness of not more than 15 deniers, a tensile strength of more than at least 1.7 GPa and satisfying the tensile strength S (GPa)-weight average molecular weight M. (g/mol)-fineness D (denier) relationship represented by the formula [I] ##EQU1## and processes for preparing the same. Further in accordance with the present invention, there are also provided high molecular weight polyethylene molecular orientation molded articles formed from high molecular weight polyethylene having a weight average molecular weight of exceeding 600,000 and satisfying the relationship represented by the formula [II]. ##EQU2##

In the generic designation of polyethylene, there are involved commonly used polyethylene (general-purpose polyethylene) of a molecular weight of 50,000-200,000 or thereabouts, low-molecular weight polyethylene (so-called wax), high-molecular weight polyethylene and ultra-high-molecular weight polyethylene.
Of such polyethylene as referred to above, the ultra-high-molecular weight polyethylene generally has a molecular weight of more than 1,000,000 and possesses characteristics entirely different from those of general-purpose polyethylene. That is, because of extremely excellent characteristics such as impact resistance, abrasion resistance, chemical resistance and tensile strength, this ultra-high-molecular weight polyethylene has come to be newly used as engineering plastics, taking advantage of such characteristics as mentioned above.
The ultra-high-molecular weight polyethylene possesses such excellent characteristics on the one hand, but, on the other hand, has an extremely high intrinsic viscosity because of its high molecular weight. Accordingly, this ultra-high-molecular weight polyethylene is extremely low in flowability. In preparing molded articles form the ultra-high-molecular weight polyethylene, therefore, there is scarcely employed the extrusion molding or injection molding method used so far in the preparation of molded articles from general-purpose polyethylenes.
Where desired molded articles are prepared using such ultra-high-molecular weight polyethylene as illustrated above, there is adopted a method which comprises preparing in advance a mixture by adding a small amount of the ultra-high-molecular weight polyethylene to a diluent, and forming the resulting mixture into an article of a desired shape, followed by removing the diluent therefrom.
For example, Japanese Patent L-O-P No. 81612/1983 discloses a process for preparing filaments having a tensile strength of more than 1.5 GPa by using a solution containing not more than 20% by weight of an ethylene polymer or copolymer having a weight average molecular weight of more than 400,000, wherein the weight average molecular weight/number average molecular weight ratio (Mw/Mn) is less than 5, and at least 80% by weight of a solvent.
In the polyethylene solution used in this process, however, the upper limit of the polyethylene concentration as defined is 20% by weight, because the polyethylene used is high in molecular weight. Concretely, even such polyethylene as having a weight average molecular weight of 500,000 is used for preparing a solution of polyethylene, the polyethylene concentration of the resulting solution used is defined as low as 8% by weight. And, the filaments obtained by the use of such polyethylene solution as mentioned above come to have a tensile strength of about 1.9 GPa (Mw/Mn=2.9). Where filaments having a tensile strength of more than 2 GPa, the polyethylene used therefore must have a very high molecular weight such as about 1,100,000, and the polyethylene concentration of a solution containing such polyethylene as mentioned above is merely about 2% by weight.
Japanese Patent L-O-P Publn. No. 167010/1986 discloses a process for preparing polyethylene molded articles having a tenacity of at least 13 g/denier and a modulus of 350 g/denier by the use of a solution preparing by mixing polyethylene having a weight average molecular weight of 200,000-4,000,000 with a diluent. Basically, this process is technically identical with the process disclosed in the above-mentioned Japanese Patent L-O-P Publn. No. 81612/1983, and the polyethylene concentration of the polyethylene solution actually used is merely about 10% by weight.
In this manner, when molded articles are prepared from ultra-high-molecular weight polyethylenes, there must be used large amounts of the diluent, and it is difficult to improve markedly the working efficiency in the process for preparing the molded articles.
As stated above, when polyethylene fiber having an excellent tensile strength such as more than 1.5 GPa is intended to be prepared, the ultra-high-molecular weight polyethylene so far used therefore had a molecular weight of more than about 600,000, preferably more than 1,000,000. The reason therefor is that, because deterioration in tensile characteristics, especially tensile strength, has been considered to be attributable to structural defect in the terminal of molecule of the resulting fiber, the higher is the molecular weight of polyethylene, the higher is the strength of the resulting fiber. For example, Japanese Patent L-O-P Publn. No. 66316/1988 discloses a process for obtaining filaments excellent in tensile characteristics, which comprises preparing gel filaments from a dilute solution of ultra-high-molecular weight polyethylene having a molecular weight of more than 600,000, and stretching the resulting gel filaments. In this publication, actually used is the ultra-high-molecular weight polyethylene having a molecular weight reaching even about 1,500,000.
Japanese Patent L-O-P Publn. No. 187614/1984 also discloses a process for preparing polyethylene fiber, and according to the example of the process, the polyethylene fiber having a fiber diameter of 4.2 deniers and a strength of 3.16 GPa is obtained.
Furthermore, Japanese Patent L-O-P Publn. No. 240432/1985 discloses a process for preparing stretched articles excellent in tensile characteristics, which comprises melt kneading a mixture of ultra-high-molecular weight polyethylene having an intrinsic viscosity of more than 5 dl/g and an aliphatic hydrocarbon derivative, and then extruding the resulting kneadate through a die, followed by stretching. Concretely, it is reported according to this publication that the polyethylene fiber having a maximum tensile strength of 3.04 GPa is obtained from the ultra-high molecular weight having an intrinsic viscosity of 8.2 dl/g.
However, the higher is the molecular weight of polyethylene, the poorer is the moldability of the polyethylene. For example, where filaments excellent in tensile characteristics are intended to be prepared, when the molecular weight of the polyethylene increases higher and higher, and the solubility in solvent of the polyethylene decreases or the viscosity of the polyethylene solution as a given concentration becomes exceedingly high, with the result that the resulting filaments tend to break in the spinning or stretching step. Accordingly, when polyethylene having a very high molecular weight is used, it was necessary to lower the concentration of the polyethylene solution or slow down the spinning speed or stretching speed in order to avoid occurrence of such troubles as mentioned above. In this manner, fiber having excellent tensile characteristics can be obtained when the starting polyethylene used is higher in molecular weight, but on the other hand, because of poor moldability of the polyethylene having a higher molecular weight, a decrease in industrial productivity of the resulting fiber was unavoidable.
The ultra-high-molecular weight polyethylene having a very high molecular weight are liable to heat degradation at the time of molding thereof. On that account, a decrease in molecular weight to a certain degree is unavoidable at the time of preparing this starting polyethylene or at the time of spinning the same. Furthermore, it is considered that carbonyl group or the like formed at the time of heat degradation of the starting polyethylene will have an adverse effect on weathering properties of the resulting polyethylene fiber.
In this connection, polyethylene fiber high in tenacity is used mainly for making woven fabrics. Such woven fabrics are used concretely as reinforced textile fabrics, bulletproof fabrics and cut-protective clothes. For application of such polyethylene fiber in composite material reinforcing fiber, the advent of high tenacity polyethylene fiber smaller in fineness is desired from the standpoint of weave density and adhesion properties of the fiber at the time of weaving thereof, and for application of such polyethylene fiber in bulletproof fabrics and cut-protective clothes, the advent of polyethylene fiber excellent in tenacity and small in fineness is desired from the standpoint of bulletproofing properties and resistance to cutting and the advent of the polyethylene fiber excellent in touch and small in fineness is desired from the standpoint of a bodily sensation.
Molecular orientation articles molded from high molecular weight polyethylene are sometimes used as composite material reinforcing fiber in which excellent adhesion between the fiber and matrix is required. However, polyethylene is generally not so excellent in adhesion properties, and hence there are adopted various measures to improve the polyethylene in adhesion properties, and known as one of such measures is corona discharge treatment.
When molecular orientation articles molded from high molecular weight polyethylenes are subjected to corona discharge treatment, the thus treated articles sometimes deteriorated greatly in tensile strength, though they improved in adhesion properties.
The present inventors conducted extensive researches with the view of overcoming such drawbacks associated with high molecular weight polyethylenes as mentioned above, and eventually have accomplished the present invention on the basis of their finding that even from high molecular weight polyethylene having a weight average molecular weight of not more than 600,000 and excellent in moldability, there is obtained fine polyethylene fiber, i.e., a molecular orientation article formed from polyethylene, which hardly deteriorates in tensile strength and is excellent in tenacity even when said article is subjected to corona discharge treatment, by making finer said fine polyethylene fiber when it is formed from the high molecular weight polyethylene.

Molecular orientation articles molded from high-molecular weight polyethylene and processes for preparing same


An absorbent article such as a sanitary napkin, panty liner, tampon, diaper, pant diaper, adult incontinence guard, containing a bacterial composition (8) in a lipid phase (9), the bacterial composition containing at least one lactic acid producing bacterial strain. The lipid phase (9) containing said bacterial composition (8) is applied on or in a carrier member (10) which at least before use of the article is impermeable to the lipid phase. The carrier member is located on a wearer facing side of the absorbent structure (4) so as to prevent significant transfer of the lipid phase into the absorbent structure.

The urogenital area harbors a complex microbial ecosystem comprising more than 50 different bacterial species (Hill et al., Scand. J. Urol. Nephrol. 1984; 86 (suppl.) 23-29). The dominating species for fertile women in this area are lactic acid producing bacteria belonging to the genus Lactobacillus. These lactic acid producing members are important for retaining a healthy microbial flora in these areas, and act as probiotic bacteria with an antagonistic effect against pathogenic microbial species. Lactic acid producing bacteria inhibit growth and colonization by other microorganisms by occupying suitable niches for colonization, by forming biofilms and competing for available nutrients, thereby excluding colonization by harmful microorganisms. Also, the production of hydrogen peroxide, specific inhibiting substances, such as bacteriocines, and organic acids (including lactic acid and acetic acid) that lower the pH, inhibit colonization by other microorganisms.
The microbial ecosystem of a healthy individual can be disturbed by the use of antibiotics, during hormonal changes, such as during pregnancy or use of contraceptives with estrogen, during menstruation, after menopause, in people suffering from diabetes etc. Also, microorganisms may spread from the anus to the urogenital area, thereby causing infections. This results in a disturbance of the normal microbial flora and leaves the individual susceptible to microbial infections that cause vaginitis, urinary tract infections and ordinary skin infections. Microorganisms commonly associated with these kinds of infections belong to the genera Escherichia, Enterococcus, Psedomonas, Proteus, Klebsiella, Streptococcus, Staphylococcus, Gardnerella and Candida. Women are at particular risk due to their shorter distance between the anus and the urogenital tract; specially at risk are young women, who not yet have a well developed microflora in the urogenital area and older women, who no longer have a protective flora.
One way to reduce the problems with the kinds of infections described above is to have a good personal hygiene. However, excessive use of cleaning agents not only decrease the amount of harmful microbes, but can harm the beneficial microbial flora, again render it susceptible for pathogenic species to colonize and cause infections. Alternatively, administration of lactic acid producing bacteria to the urogenital area and the skin in order to outcompete pathogenic species and facilitate reestablishment and maintenance of a beneficial microbial flora in these areas, have been found to be a successful means to treat and prevent microbial infections.
It has been suggested that lactic acid producing bacteria can be delivered via absorbent products, such as diapers, sanitary napkin, incontinence guards, panty liners and tampons, as described in, for example, WO 92/13577, WO 97/02846, WO 99/17813, WO 99/45099 and WO 00/35502.
A major problem with providing products intended to be used for transfer of lactic acid producing bacteria, is that the bacteria have to retain viability during transport and storage of the products. A major problem with products comprising lactic acid producing bacteria is that the bacteria rapidly lose viability under semi-moist conditions, and it is therefore important that the products are not exposed to moisture.
With "semi-moist" conditions is meant that the water activity (aw) is between about 0.2 and about 0.9. Water activity aw measures the vapour pressure generated by the moisture present in a hygroscopic product.aw=p/ps,where:    p: partial pressure of water vapour at the surface of the product    ps: saturation pressure, or the partial pressure of water vapour above pure water at the product temperature
Water activity reflects the active part of moisture content or the part which, under normal circumstances, can be exchanged between the product and its environment.
Water activity is usually defined under static conditions of equilibrium. Under such conditions, the partial pressure of water vapour (p) at the surface of the product is equal to the partial pressure of water vapour in the immediate environment of the product. Any exchange of moisture between the product and its environment is driven by a difference between these two partial pressures.
One way to partly overcome this problem has been to supply products with freeze-dried lactic acid producing bacteria. However, if the bacteria in the products are not protected from moisture after manufacturing of the products, the air humidity will subsequently kill the bacteria and the shelf-life of such products will then be shortened. Another disadvantage with the direct application of dried lactic acid producing bacteria to a hygiene product, such as an absorbent product, is that transfer of the bacteria to the urogenital area will be low.
In order to overcome the problem with air humidity decreasing the shelf-life of products containing lactic acid producing bacteria it has been suggested to prepare dispersions of lactic acid producing bacteria and a hydrophobic substance, such as a fat or an oil. Research experiments have shown that storage in sterile vaseline oil results in a high level of viable lactobacilli cells after 8 months of storage (Arkadéva et al., N A. Nauchnye Doklady Vysshei Shkoly. Biologicheskie Nauki, 1983, 2:101-104). However, Stoianova et al. (Mikrobiologiia, 2000, 69:98-104), found that immersion in mineral oil was not effective to preserve viability of lactic acid producing bacteria. U.S. Pat. No. 4,518,696 describes liquid suspensions of Lactobacilli in sunflower oil for oral administration to animals. However, none of the above references are concerned with the problems associated with retaining a high viability of lactic acid producing bacteria on hygiene products to be used to administer lactic acid producing bacteria to the urogenital area of a subject.
There are additional examples of the combination lactic acid producing bacteria and an oil, although these do not describe the effect of the oil on the survival of the lactic acid producing bacteria. WO 01/13956 describes the use of pharmaceutical compositions comprising Emu oil, antimicrobial agents and/or Bacillus coagulans to be used for antimicrobial treatments. However, Bacillus coagulans is not naturally occurring in the normal human urogenital flora and is mainly used as odor inhibitor and is not adapted to improve the microbial flora in humans. Bacillus coagulans is forming spores and is therefore not sensitive for normal moisture. WO 02/28446 describes the use of an essentially hydrophobic carrier and freeze-dried lactic acid producing bacteria to prepare a distribution to be applied to an absorbent product. The hydrophobic carrier was mainly chosen to overcome problems with applying the bacteria to the absorbent product during manufacturing, but the carrier also protects the bacteria from air humidity.
In conclusion, there is still a need to develop products for delivery of lactic acid producing bacteria to the urogenital area that are convenient to use, result in efficient transfer of the bacteria to the area where they are applied and that can be stored for long time periods without loss of viability of the bacterial cells.


Upgradable functions which are to be a target of trial are previously stored as software (program) or hardware in a storage section of a system. When a user desires to try out the functions, the user gives an instruction to do so to the system via a display panel or the like. The system, upon receipt of the instruction (including the start, termination, extension of a period, etc., of a trial), provides the target functions as required, thus providing the trial of a functionally upgraded, new system to users more easily and flexibly than ever before.

When the foregoing device is a copying machine for example, it is a service company or a distributor that takes charge of functional upgrading of a device after the shipment. The functional upgrading includes, for example, provision of additional devices such as an automatic document feeder, a discharge copy paper processing device and the like, depending on reasons such that a change is made in a user's use environment, the user demands additional functions, and the like.
At the time of such functional upgrading, there may be a case where the original program requires addition of, rewriting as, or replacement with a new program, in addition to the provision of the additional devices to the device. Under such circumstances, conventionally, it was the job of a maintenance person (a serviceperson) to fulfil the foregoing requirements by, for example, installing a new system program so that it overwrites a previous system program which is under the management of a memory or hard disk, replacing the memory or hard disk managing the system program with a new memory or hard disk managing the new system program, and the like.
The foregoing conventional technique has a problem. When installation is carried out for the purpose of functional upgrading, complicated steps should be taken. Therefore, the installation should be carried out by a person who has professional techniques and expert knowledge on the structure of the devices.
On the other hand, when components such as a substrate, a memory and the like are replaced with the new ones for the purpose of functional upgrading, there too arises a problem that the expert knowledge and techniques are required in replacing steps. Another problem is that a manufacturer should stock a variety of substrates and memories, the initially installed basic programs of which respectively include one or a plurality of additional program(s) in combination. This increases the cost of components and requires operation check for each combination of programs. In addition, a user faces a problem of unnecessary components remaining unused after the functional upgrading. Further, there arises a problem that an unauthorized imitation substrate or memory is used, which hinders the manufacturer from obtaining a proper profit and may cause a mechanical failure.
As discussed, the conventionally taken step of shifting a system to a new, functionally upgraded one requires a certain cost and time. Therefore, it has been difficult to provide a user with a trial use of the new, functionally upgraded system.

Trial management system, program, and computer readable recording medium recording the program


A power amplifier includes an input circuit, three power supply lines with voltages successively decreasing in an order of first, second and third power supply lines, a push-side driving circuit and a pull-side driving circuit which receive control signals from the input circuit, three driving signal lines which are led out of the driving circuits, three output transistors which have current paths connected at one ends to the first, second and third power supply lines, and have gates connected to the three driving signal lines, respectively, an output terminal which is commonly connected to the other ends of the current paths of the output transistors, an impedance circuit which adjusts a gate impedance of the output transistor connected to the third power supply line, and a feedback circuit connected between the output terminal and the input circuit.

1. Field of the Invention
The present invention relates generally to a power amplifier for an audio signal, and more particularly to a semiconductor integrated circuit including a high-efficiency power amplifier that amplifies audio signals of a plurality of channels with high efficiency, for example, a power amplifier circuit suitably applicable to a monolithic power amplifier IC mounted in a car stereo apparatus.
2. Description of the Related Art
In recent years, there has been a trend that car audio apparatuses have more power, multi-channel configurations and multimedia capabilities. With this trend, there has been an increasing demand for a power amplifier with high efficiency and low heat production. Conventionally, various attempts have been made to realize an audio power amplifier system with lower heat production (i.e. lower power consumption) while keeping the level of output power.
For instance, Jpn. Pat. Appln. KOKAI Publication No. 2002-353746 discloses, as an example of an analog-type high-efficiency amplifier system, an amplifier system of a scheme called "keyed B class (KB-class)", wherein a plurality of power amplifiers are vertically stacked between a plurality of power supply rails. In this scheme, for example, two bridge tied load (BTL) amplifiers, each including an output bridge circuit in which output transistors are bridge-connected, are vertically stacked and used. When a power supply voltage is Vcc, a push-pull operation is executed with a Vcc/2 power supply at a time when a small signal is input. On the other hand, when a large signal is input, the push-pull operation is switched to a conventional class AB operation using a Vcc power supply. Thereby, a power amplifier circuit with high efficiency and low heat production is realized (see FIG. 2 to FIG. 4 of the above-mentioned KOKAI 2002-353746).
As will be described later in detail, a conventional KB-class amplifier comprises an output transistor Q1 that is connected to a first power supply rail (power supply line), an output transistor Q2 that is connected to a second power supply rail, and an output transistor Q3 that is connected to a third power supply rail. The output transistors Q1 and Q2 are switched, whereby a push-pull operation and a class AB operation are switched. The KB-class amplifier further comprises potential detection/driving control transistors for controlling the operation states of the transistors Q1 and Q2, an input circuit for delivering an input signal, a driving circuit for amplifying the signal from the input circuit and driving the output transistor Q3 at the rear stage, and a feedback circuit for feeding the signal at an output terminal back to the input circuit.
This type of KB-class amplifier, however, has a problem in that switching of power supply from a plurality of different power supply rails has to be executed in a low output power state, and a sufficiently high efficiency cannot be exhibited. To avoid this, there arises another problem that the chip area of the transistor Q2 has to be increased to sufficiently enhance the load driving performance of the transistor Q2.
Under the circumstances, there has been a demand for a power amplifier system that can amplify audio signals of plural channels with high efficiency, while the amount of heat produced is small. To be more specific, there has been a demand for a circuit scheme for a power amplifier system using a plurality of power supply rails and a plurality of output transistors, wherein smooth switching can be effected between the output transistors and the high-efficiency function can be exhibited to the maximum, without unnecessarily increasing the chip area of the power transistors.


The present invention provides methods and apparatuses for the continuous processing and solids handling in near-critical and supercritical fluids. The present invention also allows for treatment of the starting material with the near-critical or supercritical fluid. The remaining raffinate is then continuously transferred and may be collected in a barrier fluid.

The processing of solids using supercritical fluids is typically carried out by either batch or semi-continuous methods. In a production environment, these methods require an increased number of vessels, as well as large volumes. Additionally, batch processes are more time consuming and carry a higher risk of product contamination. There is also an increase in equipment fatigue due to pressurization and depressurization steps and supercritical fluid losses during the process. Because of these factors, supercritical fluid processing has been directed toward specialty products instead of commodity products. These disadvantages, however, may be overcome by the development of a continuous process for near-critical or supercritical fluids.
Supercritical fluids have gained wide acceptance in the past decade for their use in a number of processes. They are unique in the sense that density can be manipulated by simply changing pressure or temperature. Thus, all density-dependent properties are also varied. This makes supercritical fluids ideal candidates for extraction solvents. At a given set of conditions, a substance can be dissolved and extracted in the supercritical fluid. Once extracted, the extracted product can be separated from the supercritical fluid simply by modifying the thermodynamic properties of the fluid (changing temperature and/or pressure) or by a separating means such as an absorption column or an adsorption vessel. No further separation steps are necessary. Carbon dioxide is a popular supercritical fluid because it is nontoxic, inexpensive, and widely available. Another popular fluid that can be used is propane. Propane is also relatively inexpensive and can be used at low pressures.
A wide variety of solids can be processed using supercritical fluids such as various vegetable seeds, food ingredients, herbs, botanicals, solids contaminated with toxic organic material or pharmaceutical materials. By performing the extraction with a supercritical fluid, as opposed to an organic solvent, such as hexane, residual solvent levels are negligible and meet regulatory standards for both the food and pharmaceutical industries. Therefore, by developing a continuous process for solids that utilizes supercritical fluid technology, many advantages can be realized.
Some continuous processes for solids have been developed in the past, including U.S. Pat. No. 4,675,133 and U.S. Pat. No. 5,041,245. While these patents disclose continuous processes for the extraction of vegetable oil, a screw press was used in both instances to transfer the material into the vessel. While screw feeders are widely known in the art, they do possess certain limitations. In particular, a screw press typically imparts force upon the material and compacts it while moving it from one place to another. Extracting from a highly-compacted material can reduce yield and quality because the reduced surface area does not allow for intimate contact between the starting material and the extracting fluid. Additionally, a screw press has pressure limitations and requires a significant amount of energy input.

Continuous processing and solids handling in near-critical and supercritical fluids