The present invention provides a method of treatment or prevention of sepsis and other diseases characteristic to the Systemic Inflammatory Response Syndrome (SIRS), including severe sepsis, septic shock, and sepsis related to cardiac dysfunction.

In 1989, an endotoxin-induced serum activity that induced interferon-γ (IFN-γ) obtained from mouse spleen cells was described (Micallef et al., 1996). This serum activity functioned not as a direct inducer of IFN-γ but rather as a co-stimulant together with IL-2 or mitogens. An attempt to purify the activity from post-endotoxin mouse serum revealed an apparently homogeneous 50-55 kDa protein. Since other cytokines can act as co-stimulants for IFN-γ production, the failure of neutralizing antibodies to IL-1, IL-4, IL-5, IL-6, or TNF to neutralize the serum activity suggested it was a distinct factor. In 1995, the same scientists demonstrated that the endotoxin-induced co-stimulant for IFN-γ production was present in extracts of livers from mice preconditioned with P. acnes (Novick et al., 1992). In this model, the hepatic macrophage population (Kupffer cells) expand and in these mice, a low dose of bacterial lipopolysaccharide (LPS), which in non-preconditioned mice is not lethal, becomes lethal. The factor, named IFN-γ-inducing factor (IGIF) and later designated interleukin-18 (IL-18), was purified to homogeneity from 1,200 grams of P. acnes-treated mouse livers. Degenerate oligonucleotides derived from amino acid sequences of purified IL-18 were used to clone a murine IL-18 cDNA (Novick et al., 1992). IL-18 is an 18-19 kDa protein of 157 amino acids, which has no obvious similarities to any peptide in the databases. Messenger RNAs for IL-18 and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IL-18 induces IFN-gamma more potently than does IL-12, apparently through a separate pathway (Novick et al., 1992). Similar to the endotoxin-induced serum activity, IL-18 does not induce IFN-γ by itself, but functions primarily as a co-stimulant with mitogens or IL-2. IL-18 enhances T cell proliferation, apparently through an IL-2-dependent pathway, and enhances Th1 cytokine production in vitro and exhibits synergism when combined with IL-12 in terms of enhanced IFN-γ production (Maliszewski et al., 1990).
Neutralizing antibodies to mouse IL-18 were shown to prevent the lethality of low-dose LPS in P. acnes pre-conditioned mice. Others had reported the importance of IFN-γ as a mediator of LPS lethality in pre-conditioned mice. For example, neutralizing anti-IFN-γ antibodies protected mice against Shwartzman-like shock (Fantuzzi et al., 1998), and galactosamine-treated mice deficient in the IFN-γ receptor were resistant to LPS-induced death (Byrn, 1990). Hence, it was not unexpected that neutralizing antibodies to murine IL-18 protected P. acnes-preconditioned mice against lethal LPS (Novick et al., 1992). Anti-murine IL-18 treatment also protected surviving mice against severe hepatic cytotoxicity.
After the murine form was cloned, the human cDNA sequence for IL-18 was reported in 1996 (Okamura et al., 1995). Recombinant human IL-18 exhibits natural IL-18 activity (Okamura et al., 1995). Human recombinant IL-18 is without direct IFN-γ-inducing activity on human T-cells, but acts as a co-stimulant for production of IFN-γ and other T-helper cell-1 (Th1) cytokines (Okamura et al., 1995). To date, IL-18 is thought of primarily as a co-stimulant for Th1 cytokine production (IFN-γ, IL-2 and granulocyte-macrophage colony stimulating factor) (Izaki, 1978) and also as a co-stimulant for FAS ligand-mediated cytotoxicity of murine natural killer cell clones (Novick et al., 1989).
By cloning IL-18 from affected tissues and studying IL-18 gene expression, a close association of this cytokine with an autoimmune disease was found. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes, which can be accelerated and synchronized by a single injection of cyclophosphamide. IL-18 mRNA was demonstrated by reverse transcriptase PCR in NOD mouse pancreas during early stages of insulitis. Levels of IL-18 mRNA increased rapidly after cyclophosphamide treatment and preceded a rise in IFN-γ mRNA, and subsequently diabetes. Interestingly, these kinetics mimic that of IL-12-p40 mRNA, resulting in a close correlation of individual mRNA levels. Cloning of the IL-18 cDNA from pancreas RNA followed by sequencing revealed identity with the IL-18 sequence cloned from Kupffer cells and in vivo pre-activated macrophages. Also NOD mouse macrophages responded to cyclophosphamide with IL-18 gene expression while macrophages from Balb/c mice treated in parallel did not. Therefore, IL-18 expression is abnormally regulated in autoimmune NOD mice and closely associated with diabetes development (Novick et al., 1992).
IL-18 plays a potential role in immunoregulation or in inflammation by augmenting the functional activity of Fas ligand on Th1 cells (Conti et al., 1997). IL-18 is also expressed in the adrenal cortex and therefore might be a secreted neuro-immunomodulator, playing an important role in orchestrating the immune system following a stressful experience (Chater, 1986).
In vivo, IL-18 is formed by cleavage of pro-IL-18, and its endogenous activity appears to account for IFN-γ production in P. acnes and LPS-mediated lethality. Because of its activity, blocking the biological activity of IL-18 in human disease is a therapeutic strategy in many diseases. This can be accomplished using soluble receptors or blocking antibodies to the cell-bound IL-18 receptor.
Cytokine binding proteins (soluble cytokine receptors) correspond to the extracellular ligand binding domains of their respective cell surface cytokine receptors. They are derived either by alternative splicing of a pre-mRNA, common to the cell surface receptor, or by proteolytic cleavage of the cell surface receptor. Such soluble receptors have been described in the past, including among others, the soluble receptors of IL-6 and IFN-γ (Nakamura et al., 1989), TNF (Dao et al., 1996; Engelmann et al., 1989), IL-1 and IL-4 (John, 1986), IFN-α/β (Mizushima and Nagata, 1990) and others. One cytokine-binding protein, named osteoprotegerin (OPG, also known as osteoclast inhibitory factor—OCIF), a member of the TNFR/Fas family, appears to be the first example of a soluble receptor that exists only as a secreted protein (Anderson, 1997; Bollon, 1980). The present invention deals with soluble IL-18 binding proteins.
Recently, it has been suggested that the interleukin IL-18 is involved in the progression of pathogenicity in chronic inflammatory diseases, including endotoxin shock, hepatitis, and autoimmune-diabetes (Kahiwamura and Okamura, 1998). A further indication of a possible role of IL-18 in the development of liver injury resulted from experiments published by Tsuij et al. (Tsuij et al., 1999), showing an elevated level of IL-18 in lipopolysaccharide-induced acute liver injury in a mouse model. However, the mechanism of the multi-functional factor IL-18 in the development of liver injury has not been elucidated so far.
Liver damage or injury may have diverse causes. It may be due to viral or bacterial infections, alcohol abuse, immunological disorders, or cancer, for example.
Viral hepatitis, due to Hepatitis B virus and Hepatitis C virus, for example, are poorly managed diseases that afflict large number of people worldwide. The number of known hepatitis viruses known is constantly increasing. Apart from Hepatitis B and C virus, at least four other viruses causing virus-associated hepatitis have been discovered so far, called Hepatitis A, D, E and G-Virus.
Alcoholic liver disease is another widespread disease associated with chronic consumption of alcohol. Immune hepatitis is a rare autoimmune disease that is poorly managed. Liver injury also includes damages of the bile ducts. Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by destruction of the intrahepatic bile ducts.
Several studies have demonstrated that damage to the liver in diseases such as alcoholic hepatitis, liver cirrhosis, viral hepatitis and primary biliary cirrhosis is associated with T-helper cell-1 (Th1) responses. In one study, a novel liver injury model was established in mice by targeting of ovalbumin-containing liposomes into the liver, followed by adoptive transfer of ovalbumin-specific Th1 cells. Combined treatment of mice with ovalbumin-containing liposomes and Th1 cell transfer caused an increase in serum transaminase activity that was paralleled with an elevation of serum IFN-γ levels. In sharp contrast, ovalbumin-specific Th2 cell transfer resulted in an increase of serum IL-4 levels but did not induce liver injury. The liver injury was blocked by anti-IFN-γ antibodies and anti-tumor necrosis factor (TNF)-α antibodies. These findings indicate that Th1 cells are the major effector cells in acute liver injury (Nishimura and Ohta, 1999) In another set of studies it was shown that mice over-expressing IFN-γ exhibit spontaneous hepatitis without any pathogen or any other stimulant (Okamoto et al., 1998).
Another study implicated Th1 responses in primary biliary cirrhosis (PBC). PBC is an autoimmune liver disease characterized by destruction of the intrahepatic bile ducts. It is generally believed that cellular immune mechanisms, particularly involving T cells, result in this bile duct damage. The relative strength of Th1 and Th2 responses has recently been proposed to be an important factor in the pathophysiology of various autoimmune diseases. In this study, the subset balance in PBC was evaluated by detection of cytokines specific to the two T-cell subsets, i.e., IFN-γ for Th1 cells and IL-4 for Th2 cells. IFN-γ and IL-4 messenger RNA (mRNA) positive cells were counted in liver sections from 18 patients with PBC and 35 disease controls including chronic active hepatitis C, extrahepatic biliary obstruction, and normal liver, using nonisotopic in situ hybridization and immunohistochemistry. Mononuclear cells expressing IFN-γ and IL-4 mRNA were aggregated in inflamed portal tracts in PBC livers, but were rarely present in extrahepatic biliary obstruction, alcoholic fibrosis, or normal liver sections. The IFN-γ and IL-4 mRNA positive cells in PBC livers were detected in significantly higher numbers than in control livers (P<0.01). Moreover, IFN-γ mRNA expression was more commonly detected than IL-4 expression in PBC livers, and the levels of IFN-γ mRNA expression were highly correlated with the degree of portal inflammatory activity. IFN-γ mRNA-positive cells were detected primarily around damaged bile ducts that were surrounded by lymphoid aggregates. The data indicate that Th1 cells are the more prominent T-cell subset in the lymphoid infiltrates in PBC (Harada et al., 1997).
The cytokine pattern on viral antigen recognition is also believed to exert a profound influence on the resolution of viral infections and viral clearance. One study investigated whether a cytokine imbalance oriented toward Th2 type response plays a role in chronic hepatitis B. Cytokine profiles of peripheral blood mononuclear cells associated with chronic hepatitis B were analyzed by RT-PCR. Upon hepatitis B surface antigen (HbsAg) stimulation, expression of IFN-γ, IL-2, IL-4, and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively. Among these cytokines, the expression of the Th1 cytokine IFN-γ was associated with high levels of serum AST/ALT (Aspartate aminotransferase/Alanine aminotransferase), representing typical markers of liver damage. Th2 type cytokines were not shown to exert a protective effect on hepatocytes. In conclusion, production of a Th1 cytokine, IFN-γ, by HBsAg-reactive cells was associated with hepatocyte damage in chronic hepatitis B (Lee et al., 1999). High levels of the FAS ligand and its receptor (CD95) were reported in liver of hepatitis B patients (Luo et al., 1997). FAS ligand is considered to be one of the major cytotoxic agents leading to hepatocyte apoptosis.
Another study identified factors associated with the progression of liver injury in 30 hepatitis C virus/RNA (HCV/RNA)-positive untreated patients with chronic hepatitis. Necroinflammatory and architectural damage were evaluated using Ishak's score. Activated hepatic stellate cells (HSC) were visualized by immunohistochemistry for α-smooth muscle actin (αSMA) and quantitated by morphometry. Plasma HCV/RNA was evaluated using a competitive RT-PCR method. To study the type of immune response involved in the progression of liver injury, IFN-γ-positive cells (as expression of a Th1-like response) were evaluated by immunohistochemistry and quantitated by morphometry. It was found that HSC were mostly detected close to areas of lobular necroinflammation or lining fibrotic septa. The αSMA- and Sirius Red-positive parenchyma correlated significantly with necroinflammatory and architectural scores. IFNγ-positive cells were detected in periportal areas associated with the inflammatory infiltrates and significantly correlated with architectural damage. It was therefore concluded that HSC activation and progression of liver injury are associated with a Th1-like response (Baroni et al, 1999). Similarly to the case of Hepatitis B, FAS ligand and its receptor were found in liver and sera of hepatitis C patients (Hiramatsu et al, 1994; Okazaki et al, 1996; Lio et al., 1998)
Th1 cytokines and other Th1 markers were found to be associated with alcoholic hepatitis and liver cirrhosis. Inflammatory stimuli and lipid peroxidation activate nuclear factor κ B (NF-κB) and upregulate proinflammatory cytokines and chemokines. In one study, the relationship between pathological liver injury, endotoxemia, lipid peroxidation, and NF-κB activation and imbalance between pro- and anti-inflammatory cytokines was evaluated. Rats (5 per group) were fed ethanol and a diet containing saturated fat, palm oil, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. Pathological analysis was performed and measurements of endotoxin were taken, lipid peroxidation, NF-κB, and messenger RNA (mRNA) levels of proinflammatory cytokines (TNFα, IL-1beta, IFN-γ, and IL-12), C—C chemokines (regulated upon activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein [MCP]-1, macrophage inflammatory protein [MIP]-1-α), C—X—C chemokines (cytokine induced neutrophil chemoattractant [CINC], MIP-2, IP-10, and epithelial neutrophil activating protein [ENA]-78), and anti-inflammatory cytokines (IL-10, IL-4, and IL-13). Activation of NF-κB and increased expression of proinflammatory cytokines C—C and C—X—C chemokines was seen in the rats exhibiting necroinflammatory injury (fish oil-ethanol and corn oil-ethanol). These groups also had the highest levels of endotoxin and lipid peroxidation. Levels of IL-10 and IL-4 mRNA were lower in the group exhibiting inflammatory liver injury. Thus, activation of NF-κB occurs in the presence of proinflammatory stimuli and results in increased expression of Th1 proinflammatory cytokines and chemokines (Naji et al., 1999). FAS ligand and its receptor are also elevated in alcoholic liver diseases, suggesting once again that Th1 cytokines are involved in the autoimmune processes induced in alcoholic hepatitis (Galle et al., 1995; Taieb et al, 1998; Fiore et al., 1999).
TNF-α has also emerged as a common pathway in the pathogenesis of alcohol-related hepatic necro-inflammation. Increased levels of hepatic and serum TNF have been documented in animal models of alcoholic liver disease and in human alcoholic liver disease. This dysregulated TNF metabolism has been postulated to play a role in many of the metabolic complications and the liver injury of alcoholic liver disease (Grove et al., 1997; McClain and Cohen, 1989). For instance it was found in one study that patients with alcoholic hepatitis had higher TNF-α levels (mean, 26.3 ng/L; 95% Cl, 21.7 to 30.9) than normal subjects (6.4 ng/L; Cl, 5.4 to 7.4). Patients who subsequently died had a higher TNF-α level (34.7 ng/L; Cl, 27.8 to 41.6) than survivors (16.6 ng/L; Cl, 14.0 to 19.2). In patients with alcoholic hepatitis, TNF-α levels correlated positively with serum bilirubin (r=0.74; P=0.0009) and serum creatinine (r=0.81; P=0.0003). Patients with alcoholic hepatitis had higher TNF-α levels than patients with inactive alcoholic cirrhosis (11.1 ng/L; Cl, 8.9 to 13.3) and severely alcoholic persons without liver disease (6.4 ng/L; Cl, 5.0 to 7.8). Patients with abnormal renal function had lower TNF-α levels (14.1 ng/L; Cl, 5.4 to 22.8) than patients with alcoholic hepatitis. It was therefore concluded that elevations in TNF-α in alcoholic hepatitis are most marked in severe cases, suggesting that TNF-α plays a role in the pathogenesis (Bird et al., 1990)
TNF mediates many of the biologic actions of endotoxin. Recent studies have shown that TNF administration may cause liver injury and that TNF may mediate the lethality of the hepatotoxin galactosamine. One of the most potent TNF inducers is endotoxin. Because patients with alcoholic liver disease frequently have endotoxemia and because many of the clinical manifestations of alcoholic hepatitis are known biologic actions of TNF, its activity was evaluated in patients with alcoholic hepatitis. Basal and lipopolysaccharide-stimulated TNF release from peripheral blood monocytes, a major source of TNF production, was determined in 16 patients with alcoholic hepatitis and 16 healthy volunteers. Eight of 16 alcoholic hepatitis patients and only two of 16 healthy volunteers had detectable spontaneous TNF activity (p less than 0.05). After lipopolysaccharide stimulation, mean monocyte TNF release from alcoholic hepatitis patients was significantly increased to over twice that of healthy controls (25.3+/−3.7 vs. 10.9+/−2.4 units per ml, p less than 0.005). It was therefore concluded that monocytes from alcoholic hepatitis patients have significantly increased spontaneous and lipopolysaccharide-stimulated TNF release compared to monocytes from healthy volunteers (McClain and Cohen, 1989.
Lipopolysaccharide (LPS)-binding protein (LBP) and CD14 play key intermediary roles in the activation of cells by endotoxin. Gut-derived LPS has been postulated to participate in promoting pathological liver injury in alcoholic liver disease. It was demonstrated that rats fed intragastrically with ethanol in oil for 4 weeks had elevated levels of CD14 and LBP in their Kupffer cells and hepatocytes, respectively. Expression of CD14 mRNA was also elevated in nonmyeloid cells. Enhanced LBP and CD14 expression rapidly increases the LPS-induced expression of various pro-inflammatory cytokines and correlates with the presence of pathological liver injury in alcoholic liver injury (Su et al., 1998; Lukkari et al., 1999).
IL-6 is a 26 kd cytokine that plays a major role in the acute phase response, especially the hepatic aspects of the acute phase response. Patients with alcoholic hepatitis manifest many aspects of the acute phase response. Serial plasma IL-6 levels in 30 consecutive patients with moderate to severe alcoholic hepatitis was measured during 6 month. Mean admission plasma IL-6 activity was markedly increased (49.8+/−8.5 U/ml, normal less than 5 U/ml) in patients with alcoholic hepatitis, and levels decreased with clinical improvement to 15.6+/−6.1 U/ml at 6 months. Admission IL-6 activity correlated significantly (r=0.82) with the severity of liver disease as assessed by the discriminant function of Maddrey. IL-6 activity fell over time in a pattern similar to that of bilirubin and C-reactive protein. This and additional studies suggest that plasma IL-6 is probably a marker of inflammation and severity of disease in alcoholic hepatitis (Sheron et al., 1991; Hill et al., 1992).
IL-8, a cytokine produced by a number of cells, including monocytes, macrophages, Kupffer cells and hepatocytes, can activate neutrophils. Peripheral neutrophilia and liver neutrophil infiltration are frequently noted in patients with alcoholic liver disease. It was found that serum IL-8 levels were markedly elevated in patients with alcoholic hepatitis (437+/−51 pg/ml) when compared to all other groups (p<0.05). Levels of IL-8 in patients with alcoholic fatty liver, alcoholic cirrhosis and viral hepatitis were higher than those in controls and in patients with non-alcoholic fatty liver. In addition, IL-8 levels were higher in patients who died (p=0.007), and correlated with biochemical and histological parameters, and severity of liver injury: serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, prothrombin time, indocyanine green retention ratio, TNF-α and peripheral neutrophil count in patients with alcoholic hepatitis. After a 2-year follow up, patients with IL-8 above 479 pg/ml had a higher mortality rate in the alcoholic hepatitis group (p=0.033). These findings suggest that IL-8 as well as some other chemokines are activated in alcoholic liver disease, especially in alcoholic hepatitis, and is closely correlated with liver injury (Martinez et al., 1992; Hill et al., 1992).
Induction of adhesion molecules such as ICAM-1 is associated with the activation and attraction of a special population of inflammatory cells characteristic for alcoholic hepatitis. Frozen liver samples from patients who died with signs of acute alcoholic hepatitis show elevated ICAM-1 expression in the membranes of hepatocytes, as well as the occurrence of CD11b positive polymorphonuclear leukocytes (neutrophils) suggesting a possible major role of the beta 2-integrin Mac-1 as a ligand for ICAM-1. It was concluded that in alcoholic hepatitis cytokines may be responsible for the induction of the adhesion molecule ICAM-1 on hepatocytic membranes and activate a defined population of inflammatory cells, thus contributing to the characteristic histological picture of acute alcoholic hepatitis with its concentration of neutrophils especially in areas with ballooned Mallory body-containing hepatocytes (Afford et al., 1998).
A significant increase in both NK cells (CD3−/CD56+) and the cytotoxic T cells coexpressing the CD3 and the CD56 molecules together with an increased NK cytotoxic activity were observed in patients having alcoholic hepatitis. Interestingly these abnormalities persisted during the withdrawal period (Ohlinger et al., 1993).
Arthritis is a disease involving joint inflammation. The joints show swelling, stiffness, tenderness, redness or warmth. The symptoms may be accompanied by weight loss, fever or weakness. When these symptoms last for more than two weeks, inflammatory arthritis e.g. rheumatoid arthritis may be the cause. Joint inflammation may also be caused by infection, which can lead to septic arthritis. A very common type of arthritis is degenerative joint disease (osteoarthritis). Joint inflammation is not a prominent feature of osteoarthritis.
The medicaments commonly prescribed for arthritis and related conditions are non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs include aspirin and aspirin-like drugs. They reduce inflammation, which is the cause for joint pain, stiffness and swelling of the joints. However, NSAIDs are unspecific drugs having a number of side effects, involving bleeding of the stomach (Homepage of the Department of Orthopaedics of the University of Washington on Arthritis, Frederick Matsen (Chairman)). In addition to NSAIDs, Celebrex™, a cyclooxygenase (COX-2) inhibitor, is used to relieve the signs and symptoms of osteoarthritis and rheumatoid arthritis in adults. It is also indicated for the treatment of patients with familial adenomatous polyposis.
Further, TNF antagonists are used for the treatment of arthritis. TNF antagonists are described, for example, in WO 9103553.
Recent studies indicate that the interleukin IL-18 plays a proinflammatory role in joint metabolism. Olee et al. (1999) showed that IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. The IL-18 mRNA was induced by IL-1 in chondrocytes. Chondrocytes produced the IL-18 precursor and in response to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18 effects on chondrocytes further showed that it inhibits TGF-β-induced proliferation and enhances nitric oxide production. IL-18 stimulated the expression of several genes in normal human articular chondrocytes including inducible nitric oxide synthase, inducible cyclooxygenase, IL-6, and stromelysin. Gene expression was associated with the synthesis of the corresponding proteins. Treatment of normal human articular cartilage with IL-18 increased the release of glycosaminoglycans. These finding identified IL-18 as a cytokine that regulates chondrocyte responses and contributes to cartilage degradation.
The localisation of Interleukin-1β-converting enzyme (ICE)/caspase-1 in human osteoarthritic tissues and its role in the maturation of interleukin-1 beta and interleukin-18 have been shown by Saha et al. (1999). Saha et al. studied the expression and production of caspase-1 in human normal and osteoarthritic (OA) cartilage and synovium, quantitated the level of ICE in OA chondrocytes, and examined the relationship between the topographic distribution of ICE, interleukin-1β (IL-1β), and IL-18, as well as apoptosis of chondrocytes. The experiments performed in this study indicated that ICE was expressed and synthesised in both human synovial membrane and cartilage, with a significantly greater number of cells staining positive in OA tissue than in normal tissue. ICE production was preferentially located in the superficial and upper intermediate layers of articular cartilage. The production of mature IL-1beta in OA cartilage explants and chondrocytes was completely blocked by treatment with a specific ICE inhibitor, which also markedly diminished the number of IL-18-positive cells. The relationship between active IL-1beta and ICE suggests that ICE may promote OA progression by activating this proinflammatory cytokine, and that IL-18 may play a role in cartilage pathology.
Gracie et al. (1999) suggested a proinflammatory role for IL-18 in rheumatoid arthritis. Gracie et al. detected the IL-18 mRNA and protein within rheumatoid arthritis synovial tissues in significantly higher levels than in osteoarthritis controls. It was also shown that a combination of IL-12 or IL-15 with IL-18 induced the IFN-γ production by synovial tissues in vitro. Furthermore, IL-18 administration of collagen/incomplete Freund's adjuvant-immunized mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 may be proinflammatory in vivo.
However, so far, apart from chemical compounds, only the blockade of TNFα and IL-1β by using soluble receptors or monoclonal antibodies have been shown to decrease murine collagen-induced arthritis (CIA, which is a mouse model for rheumatoid arthritis) (Williams et al., 1994), and were therefore suggested as a therapeutic for rheumatoid arthritis.
The term "systemic inflammatory response syndrome (SIRS)" describes the familiar clinical syndrome of sepsis, independent of its cause. SIRS can result from trauma, pancreatitis, drug reactions, autoimmune disease, and other disorders; when it arises in response to infection, sepsis is said to be present (Nathens and Marshall 1996).
Septic shock is the most common cause of death in medical and surgical intensive-care units (Aestiz and Rackow 1998). The terms sepsis, severe sepsis and septic shock are used to identify the continuum of the clinical response to infection. Patients with sepsis present evidences of infection and clinical manifestations of inflammation. Patients with severe sepsis develop hypoperfusion with organ dysfunction. Septic shock is manifested by hypoperfusion and persistent hypotension. Mortality ranges from 16% in patients with sepsis to 40-60% in patients with septic shock. Bacterial infection is the most common cause of septic shock. The most frequent sites of infection are the lungs, abdomen, and urinary tract. General anti-inflammatory therapies such as the use of corticosteroids, failed to show improvement in survival from sepsis and septic shock. Three monoclonal antibodies specific to endotoxin have been tested in clinical trials and have failed to improve survival rates. Therapy with antagonists to tumor necrosis factor, interleukin 1, bradykinin, ibuprofen, and platelet activating-factor, did not show improvement on survival from septic shock (Aestiz and Rackow 1998).
Sepsis is caused inter alia by Gram-positive bacteria e.g., Staphylococcus epidermidis. Lipoteichoic acids and peptidoglycans, which are the main cell wall components of the Staphylococcus species, are thought to be the inducers of cytokine release in this condition (Grupta et al. 1996 and Cleveland et al. 1996). However, other Gram-positive components are considered as stimulators of cytokine synthesis as well (Henderson et al. 1996). Production of IL-1, TNF-α and IFN-γ are thought to be the major contributors in the pathogenesis of septic shock (Dinarello 1996 and Okusawa et al. 1988). In addition, the chemokine IL-8 was shown to be induced by neutrophils in response to S. epidermidis (Hachicha et al. 1998). Important factors in the regulation of IL-1, TNF-α and IFN-γ induction by S epidermidis are IL-18, IL-12, IL-1β and TNF-α. IL-1 and TNF-α can be considered as a co-stimuli for IFN-γ production by T lymphocytes in a manner similar to IL-18. These two cytokines have a co-stimulatory activity on IFN-γ production in the context of IL-12 or bacterial stimulation (Skeen et al. 1995 and Tripp at al. 1993).
Recently it was reported by Nakamura et al. (2000) that concomitant administration of IL-18 and IL-12 to mice results in high toxicity similar to that found in endotoxin-induced septic shock.
The levels of IL-18 have been shown to be elevated in sera from patients with sepsis (Endo et al. 2000) but this increase correlated with creatinine levels suggesting that the elevated levels of IL-18 may result from renal failure. In another study (Grobmyer et al. 2000), the levels of IL-18 in 9 subjects with sepsis during the first 96 hours following hospital admission were high and did not correlate with creatinine levels.
Dayer (1999) summarized the different and partially contradicting functions of IL-18. IL-18 is a pleiotropic interleukin having both inflammatory enhancing and attenuating functions. On the one hand, it enhances production of the proinflammatory cytokines like TNFα, therefore promoting inflammation. On the other hand, it induces the production of NO, an inhibitor of caspase-1, thus blocking the maturation of IL-1β and IL-18, and possibly attenuating inflammation. This ambiguous role of IL-18 seriously questioned the efficacy of IL-18 inhibitors in inflammatory diseases. Furthermore, because of the interaction of a huge variety of different cytokines and chemokines in the regulation of inflammation, it could not have been expected to obtain a beneficial effect by blocking only one of the players in such a complicated scenario.
Netea et al. (2000) reported that administration of anti-IL-18 polyclonal antibody protected mice against the deleterious effects of both LPS derived from E. coli or S. typhimurium species tested, supporting the concept that IL-18 has an important pathogenic role in lethal endotoxemia. However, the uncertainty regarding the efficiency of a potential treatment formulation based on administration of IL-18 inhibitors, is manifested in that IL-18 knock out mice are not less susceptible to sepsis as compared to wild type animals (Sakao et al. 1999) and in that recent reports suggest that the proinflammatory activity of IL-18 is essential to host defences against severe infections (Nakanishi et al. 2001 and Foss et al. 2001).
Thus, there exists a need to provide means to treat and/or prevent sepsis despite the above-mentioned considerations regarding the use of IL-18 inhibitors.

Interleukin-18 binding proteins, their preparation and use for the treatment of sepsis

Yeda Research and Development Company Ltd.


Parboiled rice having the beneficial properties of parboiled rice, such as intact grain structure and texture, and having improved color vis-a-vis a typical parboiled rice, and further in the case of a brown rice starting material being substantially without the characteristic parboiled flavor and color, and methods of making same.

Parboiled rice is usually defined as rice which has been steeped, heat treated and dried. During the heat treatment step of parboiling, the starch in the endosperm of the rice is substantially gelatinized. The parboiling process and the resulting gelatinization of the starch have several beneficial effects.
First, rice is routinely parboiled to achieve a better milling yield (less broken rice). Less broken rice has significant economic and quality consequences; whole rice commands a higher price because whole grains are valued by consumers of rice as high quality. Upon cooking, a rice with less brokens is generally accepted world-wide as having a more pleasing appearance.
Parboiling also causes a very important second quality change, which becomes evident upon cooking. Cooked parboiled rice grains are significantly more intact and retain their natural shape as compared to non-parboiled rice. In selected rice eating cultures of the world, this is viewed as a quality improvement over non-parboiled rice.
Also, during the parboiling process, the rice grain is strengthened to impart increased resistance to the rigors of abrasive milling. (Unparboiled rice easily shatters.) The strengthening of the grain is manifest in the cooked finished product. The rice is so strengthened by parboiling that it typically takes somewhat longer to cook during preparation by consumers than does unparboiled rice. Furthermore, parboiled rice often has a firmer texture and is less sticky than unparboiled rice. Even with the cooktime increase, these changes make parboiled rice more attractive than unparboiled rice in selected cultures around the world.
Parboiling of rice apparently originated, principally, in India. In the early history of parboiling, the rough (paddy) rice was simply soaked in warm water overnight and then dried in the sun. The perceived benefit was that the rice hulls were split open and were thus easily removed from the rice kernel. In modern times, it has been realized that parboiling also provides a more nutritional rice as thiamine and other essential nutrients, which are normally present in the rice bran, migrate to the rice endosperm during the water steeping or soaking step. Since almost all rice is milled to remove the bran, this migration preserves at least some of the nutritional value initially contained in the bran. Parboiling is also beneficial since the starch in the rice endosperm is changed from a partially crystalline-partially amorphous state to a substantially amorphous state. With the starch in the amorphous state, the kernel is tougher, resulting in a higher yield of whole rice kernels after milling. As mentioned earlier, unparboiled (crystalline) rice easily shatters. Gelatinization via parboiling, simply put, is the water-assisted melting of starch granules upon heat treatment. The presence of too much or too little water when heat is applied to the starch can have beneficial or deleterious results. Another significant benefit of parboiling is that the lipase in the bran layer of brown rice becomes inactivated due to the heat treatment. This improves the shelf life of parboiled brown rice by reducing the tendency for oxidative rancidity.
As a rule of thumb, prior parboiling practices can be divided into three broad categories: the "atmospheric steaming" method, the "dry-heat" method and the "pressure-steaming" method. The atmospheric steaming method comprises soaking, draining, and steaming at atmospheric pressure, followed by drying and milling stages. The dry-heat method replaces the steaming step of the conventional method with a heating stage in which the rice is cooked in dry-hot air, hot non-aqueous liquids or hot sand prior to drying. Sometimes, the hot dry heat media are replaced by electromagnetic energy heating, such as microwave heating. In all cases with the dry heat method, the use of water or steam is avoided. The consequences of avoiding the use of water will become apparent later in the text. Finally, the pressure-steaming method comprises a low-moisture initial soak followed by pressurized steaming prior to drying and milling.
Today, commercial parboiling processes generally include the steps of: (I) soaking rough (or paddy) rice in 50.degree.-70.degree. C. water for 3-4 hours to yield a rough rice having a 30 weight percent water content; (2) draining the free water from the soaked rice; (3) applying steam heat under pressure for 10 to 20 minutes to effect gelatinization; and (4) drying the steamed rice with hot air to reduce its water content to about 14 weight percent water. The dried, parboiled rough rice is then ready for shelling (to remove the hull) and milling to remove the bran.
Parboiling has been an active topic in the patent literature. There have been numerous efforts to improve upon the basic technology. For example, U.S. Pat. No. 5,017,395 teaches an extra predrying step at an elevated temperature. U.S. Pat. No. 4,810,511 prescribes use of microwave energy for partial gelatinization. According to U.S. Pat. No. 4,361,593, the rice starch is not completely gelatinized during steaming, and a tempering step is performed under non-gelatinizing conditions to reduce subsequent rupturing. In U.S. Pat. No. 4,338,344, there is disclosed an inclined enclosed chamber where rice is cooked in hot water in a first zone at a lower end, and then is steamed in a second zone at an upper end.
Unfortunately, despite these treatments, two undesirable conditions persist: conventional processes cause parboiled rice to be yellow and to develop a characteristic "parboiled" flavor in appreciable part due to Maillard-browning effects (and also in part as a result of the effects of agents contained in the rice hull when using paddy rice). To many cultures and consumers, these conditions are objectionable. In fact, many consumers believe that the yellow color and parboiled flavor signify that the rice is old and stale. This is important because, as widely accepted in culinary arts, the first impression of a food is generally visual. That is, the willingness of a person to eat a particular food depends largely on preconceptions as to appealing color and other visual cues. Color is an influential quality attribute pre-supposed by people to be an indicator of deteriorative changes undergone by food. Aroma and flavor can also be influential upon smelling and tasting. Thus, an off-color, increases the likelihood that a food will be rejected, and this phenomenon jeopardizes the acceptability of parboiled rice amongst the majority of rice eating cultures around the world. This is so to an even greater extent if the rice has a foreign flavor. It is desired that rice color be near-white and that rice flavor be near bland and subtle.
Only a relatively small group of consumers of conventional parboiled rice accept its appearance and flavor. Indeed, the overwhelming majority of rice consumers, worldwide, eat non-parboiled rice. To our knowledge, none of the prior parboiling practices has resulted in a rice which combines the beneficial features of parboiled rice such as intact grain structure with an improved color vis-a-vis that exhibited by typical parboiled rice. This is especially true of such a rice having those advantages and being substantially free from typical parboiled flavor and color. Provision of a parboiled rice product having a full complement of advantageous features without one or more of the common shortcomings would be a substantial advance over the technology discussed heretofore.

Parboiled rice product and method of making same


Network elements are identified as being connected to optical nodes by instructing two network elements in a spectrum group of the CMTS to transmit at frequencies f1 and f2, respectively. Frequencies f1 and f2 are selected such that they produce intermodulation distortions (intermods) in the laser transmitter at f3 when combined. If intermods are produced which exceed a predetermined threshold, then the two network elements are determined to be on the same node. If the total power of the signal by the laser transmitter exceeds an impact threshold, then the test is stopped and new network elements are selected for testing.

Coaxial cable television systems have been in widespread use for many years and extensive networks have been developed. The extensive and complex networks are often difficult for a cable operator to manage and monitor. A typical cable network generally contains a headend which is usually connected to several nodes which provide access to an IP or ISPN network. The headend also interfaces with a cable modem termination system (CMTS) which typically contains several receivers, each receiver typically connects to several nodes each of which connect to several network elements, such as modems, MTA (media terminal adaptors) and set top boxes of many subscribers, e.g., a single receiver may be connected to hundreds of network elements.
The standard architecture for an HFC cable plant is a tree and branch structure where terminal network elements (MTA, cable modem, set top box, etc.) reside on various optical nodes. Nodes may be combined and serviced by common components at the headend. Typically, the method for tracking which terminal devices are attached to which optical node is a manual process by which as the customer services are enabled, the operator manually resolves (via out of date and often inaccurate maps which were also manually entered and prone to the shortcomings of human data entry) the specific node that the user is attached to and enters this into the customer management database.
Information of the connections to a node is valuable to resolving physical layer communications issues, performing periodic HFC plant maintenance, and planning future service expansions. However, when the data is inaccurate, it can often lead to misdiagnosis of issues, excessive costs associated with maintenance, and prolonged new deployments which jeopardize customer expectations. In addition, as communication traffic increases or new services are deployed the need to understand the loading of individual nodes becomes important, particularly if the number of users on each node must be reallocated, e.g. to split the user loads on a node.

Efficient use of trusted third parties for additional content-sharing security


An image forming apparatus includes an image carrier that has an image carrier surface moving in a direction; a supporting member that faces the image carrier; a plurality of light emitting elements which are provided on a surface of the supporting member facing the image carrier and emit light to form a latent image on the image carrier; a roller which is arranged on the surface of the supporting member facing the image carrier such that a rotational shaft thereof extends in a direction traversing an image carrier surface; and an urging unit which urge the supporting member against the image carrier so that the roller comes into contact with the image carrier.

The present invention relates to an image forming apparatus (image printing apparatus) in which a latent image is formed on an image carrier by light emitted from light emitting elements.
In general, an image forming apparatus includes an image carrier and a head facing the surface of the image carrier. A photoreceptor drum is generally used as the image carrier. A plurality of light emitting elements formed of a light emitting material, such as an organic EL (electroluminescent) material, is formed on a surface of the head facing the photoreceptor drum. A latent image is formed on the surface of the photoreceptor drum by light emitted from each light emitting element.
In the image forming apparatus according to the related art, when light emitted from each light emitting element reaches the surface of the photoreceptor drum to form a latent image (hereinafter, referred to as a 'spot image') in each region on the surface, a large variation in the area or shape of the latent image may occur. When a large variation occurs in the area or shape of the spot image, it is difficult to form a high-resolution latent image composed of fine pixels. The large variation in the area or shape of the spot image may occur due to a difference in distances between the surface of the photoreceptor drum and the light emitting elements. In order to solve this problem, JP-A-7-178956 discloses a structure in which a guide member coming into contact with the surface of a photoreceptor drum is fixed to a head, and JP-A-5-27563 discloses a structure in which end surfaces of light emitting elements come into contact with the surface of a photoreceptor drum.
However, in these structures, there is a fear that the head may be elastically deformed by friction force acting on the head (including the guide member and the light emitting elements) from the photoreceptor drum, which is generated by the rotation of the photoreceptor drum, and then restored to the original shape thereof when the stress of the head exceeds a threshold value, that is, the head may be vibrated. When the photoreceptor drum is driven at high speed, the vibration of the head becomes more remarkable. When the head is vibrated, a gap between the photoreceptor drum and each light emitting element is changed, which results in a large variation in the area or shape of the spot image with the passage of time. In addition, in these structures, there is a fear that the surfaces of the head and the photoreceptor drum may be rapidly worn away by friction therebetween, resulting in a large variation in gap between each light emitting element and the photoreceptor drum. That is, there is a fear that the area or shape of the spot image may be greatly varied with the passage of time.

Image forming apparatus for forming a latent image on an image carrier


Exemplary embodiments of the invention include methods, systems, and storage mediums for optimizing a device. The method includes detecting a suboptimal condition associated with the device and analyzing the suboptimal condition in light of selected operator preferences and device-related data. In response to the analysis, the method includes modifying a configuration of the device, the current state of said device, a current state of a networked device associated with said device, or a configuration of a networked device associated with said device. Alternatively, in response to the analyzing, the method includes notifying the operator of the suboptimal condition. The selected operator preferences include at least one of personality settings, expert level settings, communications means settings, intrusion level settings, and reactive/predictive settings.

The present invention relates generally to task-based assistance tools, and more particularly, to methods, systems, and storage mediums for optimizing a device. As the number of features and interfaces increase on devices, the level of sophistication of the device operators tends to decrease as each new advancement in technology typically translates to an abundance of new, and often complex, functions and utilities that need to be mastered. Consumers of these devices possess varying degrees of technical savvy ranging from novice to expert. Often, by the time a user comfortably learns each feature and function, the device becomes obsolete as new advancements are incorporated into newer versions. In the meantime, however, novice users often face difficulties in effectively using a device that, in turn, might not perform satisfactorily or may altogether fail. Existing help features that are provided to an operator tend to be boilerplate information and are not tailored to the needs and sophistication levels of these operators. Many of today's help tools provide too much or too little information about operating the device, may falsely assume that an operator has already acquired baseline knowledge about the device, or may inundate the operator with useless information that does not address the operator's interests or concerns.
What is needed, therefore, is a flexible assistance tool that provides an operator with the type and level of assistance desired by the operator, thereby eliminating confusion and maximizing the learning process.

Methods, systems, and storage mediums for optimizing a device


An apparatus for controlling a beamforming microphone considering the location of a driver seat may include: a driver seat sensor configured to sense the location of the driver seat and output the sensed location as a driver seat signal; a directivity control unit configured to calculate a beamforming angle based on the driver seat signal; and a signal processing unit configured to process voice signals outputted from first and second microphones, respectively, and extract and output a voice signal generated from a direction which coincides with the beamforming angle.

The present disclosure relates to an apparatus and method for controlling a beamforming microphone considering the location of a driver seat, and more particularly, to an apparatus and method for controlling a beamforming microphone considering the location of a driver seat, which controls a beamforming microphone used in a hands free system for a vehicle such that the directivity of the beamforming microphone traces the location of the driver seat.
A hands free system for a vehicle collects the voice of a driver through a microphone installed in the vehicle and transmits the collected voice to a phone line such that the driver can talk on the phone even while driving the vehicle.
Inside the vehicle, however, unnecessary sounds, such as engine sound or audio sound, as well as the voice of the driver may be transmitted to the hands free system. Thus, a beamforming microphone capable of minimizing the influence of surrounding noise or interfering sound using multiple microphones may be used as the microphone which is employed in the hands free system and installed inside the vehicle. Such a beamforming microphone may be applied to a hands free system or voice recognition system for a vehicle. In the interior space of a vehicle, two microphones are typically used to collect voice.
The related art is disclosed in Korean Patent Laid-open Publication No. 1996-0024488 published on Apr. 6, 1999 and entitled "Hands free device of vehicle phone".

Apparatus and method for controlling beamforming microphone considering location of driver seat


A single cardiac ventricular assistance device intended to integrate the ctions of a ventricular assistance device (V.A.D.) proper and of an aortic balloon pump (IABP) includes a single energy source which causes the simultaneous rhythmic contraction of two chambers which are intended to be filled with blood. One of the contractible chambers has two one-way valves for the inlet and outlet of the blood respectively, while the other has a single inlet-outlet connector without valves for connection to the outlet of the first chamber downstream of its outlet-valve portion.

The present invention relates to devices for use in the treatment of acute or chronic mono- or bi-ventricular myocardial insufficiency.
In general terms, two different kinds of device are known for the treatment of this condition.
The first kind of device is that currently known as an aortic pulsator (an I.A.B.P., that is, an intra-aortic balloon pump).
Its operation is based on the reduction of the so-called post-loading (the overall resistance of the vascular system) in synchronism with the systolic expulsion from the left ventricle in order indirectly to increase the output of the heart.
This device usually takes the form of a hollow catheter with a spindle-shaped balloon about 25-30 cm long at its end which, in its inflated condition, can occupy a volume of about 40 cm.sup.3.
The catheter in question is positioned in the thoracic aorta by being passed along the femoral artery. The catheter is connected to a driver unit with a compressor and a system for synchronising it with the patient's electrocardiogram or arterial pressure. The driver unit inflates and deflates the balloon in the thoracic aorta in synchronism with the stages of the heart's activity. In general, at the beginning of the ventricular systole (the emptying of the left ventricle and the corresponding expulsion of a quantity of blood), the intra-aortic balloon is deflated so as to reduce the telediastolic pressure (the "minimum" pressure) which is equivalent to the reduction of the peripheral resistance of the vascular system, that is, the so-called post-loading.
It is thus possible to create conditions favourable to the admission of a greater quantity of blood to the arterial system. The difference between the volume of the systolic output with and without the balloon pump represents the gain in terms of the efficiency of the system (15-20% on average). During the diastole, that is, when the aortic valve is closed, the intra-aortic balloon is inflated and consequently pushes back a quantity of blood approximately equal to its own volume (about 40 cm.sup.3) in both a cranial direction (that is, towards the upper part of the body ) and a caudal direction (that is, towards the lower part of the body). This raises the arterial pressure which has the positive result of an increase in the coronary flow-rate.
The other kind of device is essentially that currently known as a ventricular assistance device (V.A.D.). It is based on the bypassing of the right and/or left ventricles by the withdrawal of blood from the atria or directly from the ventricles and its readmission to the pulmonary artery and/or to the aorta.
Devices of this type can be divided further into alternating V.A.D.s (for example, electropneumatic, electromagnetic, electromechanical systems, etc.) which effect intake stages followed by compression stages so as to create a pulsed blood-flow, and continuous V.A.D.s which create a continuous flow by means of a system with a centrifugal pump.
The main advantage of these devices is their ability to keep a patient alive even when the heart has stopped or is fibrillating. For this reason, V.A.D. systems are used most successfully for mechanically supporting circulation whilst a heart transplant is awaited (a transplant bridge).
They have been found to be much less effective, however, when used in parallel with the heart in an attempt to compensate for temporarily weakened heart function.
A plausible explanation for this ineffectiveness is that all V.A.D.s reduce the preloading of the heart muscle but increase the aforementioned post-loading (an increase in the average arterial pressure). With an inadequate ventricle (that is, a ventricle without functional reserve) the increase in the post-loading reduces the volume of blood expelled during the ventricular systole until, in certain extreme cases of weakened contractile activity of the heart, the aortic valve fails to open (the volume of blood expelled is zero). The resulting increased post-systolic volume creates a series of physical-metabolic conditions in the ventricles which create conditions unfavourable to the functional recovery of the heart.

Cardiac ventricular assistance device particularly for compensating for weakened heart muscle function and for maintaining the vital body functions

Ministero dell'Universita e della Ricerca Scientifica e Tecnologica


A connector is described herein that includes a plurality of layers patterned in two dimensions and joined in a stack with a bore there through. At least a subset of the plurality of layers are contact layers that include deflectable members (e.g., springs) that deflect in plane or out of plane upon insertion of a lead into the bore through the connector. The deflectable members form redundant electrical connections with the lead when the lead is inserted into the bore. For example, the connector can be incorporated into an implantable medical device (e.g., IPG). Moreover, methods of manufacturing a connector are set forth herein.

1. Field
This application relates generally to a connector for a medical device and, more specifically, to a connector with a plurality of layers patterned in two dimensions joined in a stack with at least one of the layers being a contact layer with deflectable members.
2. Background
Medical devices have been implanted in patients to perform a variety of tasks. For example, programmable pulse generating systems are used to treat chronic pain by providing electrical stimulation pulses from an epidural electrode array placed near a patient's spine. Such Spinal Cord Stimulation (SCS) is useful for reducing pain in certain populations of patients. SCS systems typically include one or more electrodes connected to one or more connectors of an External Pulse Generator (EPG) or an Implanted Pulse Generator (IPG) via leads. In the case of an EPG, the lead must be connected to the EPG via an exit from the body. The pulse generator, whether internal or external, generates pulses that are typically delivered to the dorsal column fibers within the spinal cord through the electrodes which are implanted along or near the dura of the spinal cord. In a typical situation, the attached leads exit the spinal cord and are tunneled around the torso of the patient to a subcutaneous pocket where the IPG is implanted, or the wires exit the patient for connection to the EPG.
Generally, smaller sized IPGs that incorporate increased numbers of contacts are being manufactured and employed in SCS systems. For instance, leads with a larger number of inline contacts having decreased pitches are being utilized with electrical connectors integrated into the IPGs. However, decreasing the size of IPGs and increasing the number of contacts incorporated into IPGs yields a packaging problem for the electrical connectors included in the IPGs. Moreover, reliability of forming a contact between the inline contacts of a lead and the corresponding respective contacts of the electrical connectors included in the IPGs is typically diminished with conventional electrical connectors as the size of the electrical connectors is decreased and the number of contacts of the electrical connectors is increased. Further, since a lead is oftentimes fairly limp, as the number of contacts of the electrical connector is increased, it can become more difficult to insert the lead without buckling of the lead.
A conventional electrical connector for IPGs incorporates a set screw that can be tightened on top of a ring to physically retain a lead inserted into such connector. Another conventional electrical connector incorporated in IPGs has a coiled spring inside a contact block. Ends of the spring are welded together yielding a torus shape through which a lead is inserted. The spring coils cant to conform to the lead and the contact block, thus making electrical contact. Each coil that contacts both the lead and the contact block forms a separate, redundant electrical contact. However, such common electrical connectors can be difficult to manufacture with smaller sizes, particularly as sizes of IPGs and lead pitches generally decrease. For instance, utilization of canted coiled springs in electrical connectors typically is unable to be extended to leads with millimeter or below pitches. Moreover, additional parts or functionality is commonly difficult at best to add to an electrical connector assembly having canted coiled springs. Further, contact forces associated with insertion of a lead into a conventional electrical connector assembly having canted coiled springs are not easily tuned; accordingly, difficulty of use can result since a lead commonly can buckle when attempting to insert the lead into a conventional electrical connector with a number of canted coiled springs since such springs can present a large cumulative resistance to insertion of the lead.


The present disclosure teaches analogs of human chemokines and methods of using them in the prevention, treatment, and ameliorization of diseases that can benefit from therapeutic angiogenesis. The teachings are generally directed to compositions comprising SDF-1 mimetics, as well as methods that include the use of SDF-1 mimetics to induce neo-vessel formation. The disclosure also teaches articles of manufacture that can be useful in practicing the methods taught herein.

1. Field of the Invention
This invention relates generally to analogs of human chemokines and methods of using them in the prevention, treatment, and ameliorization of diseases that can benefit from therapeutic angiogenesis.
2. Description of the State-of-the-Art
Therapeutic angiogenesis is a relatively new procedure that is recognized as a viable treatment strategy for increasing the supply of blood to a tissue in the treatment of a disease. Angiogenesis is generally described as the growth of new blood vessels, and there are many medical situations in which an increase in blood supply is indicated. In a broad sense, this growth of new blood vessels can be derived from an old blood vessel or from bone marrow-derived cells, such as endothelial progenitor cells and hematopoietic stem cells.
Examples of such situations include, for example, tissue injuries, such as burns and wound healing, where an increased blood supply can increase the rate of healing and reduce the risk of infection; cardiovascular diseases, where an increased blood supply can assist in the repair of cardiac tissue; peripheral vascular diseases, where an increased blood supply can assist in providing sufficient oxygen and nutrients to extremities; a stroke, where an increased blood supply can reduce the risk of transient ischemic attacks and vascular deficiencies that can create damage to brain tissue; diabetes, which often includes peripheral vascular disease, for example; and cancer, where drug treatments can be improved by inducing angiogenesis in a tumor to facilitate transport of a drug into the cancerous tissue. Accordingly, the methods taught herein have many uses, of which a predominant use includes the treatment of ischemic conditions associated with various diseases.
Ischemia is a condition involving a restricted blood flow to a tissue and is the most common consequence of vessel dysfunction. Ischemic conditions result in a disruption of oxygen and nutrient delivery to tissue, as well as the accumulation of waste metabolites in tissue. Cells cannot survive an extended case of severe ischemia but may be able to adapt to a moderate condition where diffusion to and from a bordering non-ischemic region is capable of sustaining vital cellular functions. Under these moderate conditions, the secondary functions of affected tissues may be impaired, and a new metabolic equilibrium may be established depending on the level of cross-diffusion and hypoxia present in the tissue.
In fact, in tissues that normally have a high metabolic turnover, such as skeletal and cardiac muscle, even a mild case of ischemia can create serious conditions that include hypoxia, acidosis, and a depressed tissue function that may eventually threaten the viability and function of the tissue. Ischemic cardiac muscle, for example, is particularly vulnerable to a "reperfusion injury" from ischemia, because the reperfusion that usually must occur in an ischemic cardiac muscle to restore its function introduces free radicals to the ischemic tissue during the reoxygenation process. In fact, the reperfusion injury can sometimes cause as much damage as the ischemic condition itself.
The options available to one of skill in the art of preventing and treating ischemia are currently limited. The administration of lipid/cholesterol-lowering agents, diet, and anti-platelet adherence therapy (e.g. treatment with aspirin) may help slow the progression of vessel disease in some instances; but surgery may still be the only option in advanced stages of the disease. Such surgeries can include coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. Unfortunately, even surgery may not be an option at times. In some cases, the only treatment option may be limited to activating endogenous angiogenic or arteriogenic pathways to stimulate revascularization of the ischemic tissue.
Diseases that include the complications of ischemia remain a large problem faced by our society. Cardiovascular disease is responsible for over 17 million deaths worldwide each year, and coronary heart disease is the biggest contributor. Coronary artery disease is a contributor that, alone, is responsible for over 550,000 deaths each year in the United States. Peripheral vascular diseases create ischemic conditions that result in limb amputations for over 150,000 patients each year, and these patients have a subsequent mortality rate of about 40% within two years of amputation.
Our society can benefit significantly from the introduction of therapeutic methods that can reduce or eliminate the need for surgical procedures. The present invention is based on the discovery that select analogs of the chemokines known as stromal cell-derived factor-1 (SDF-1) and interleukin-8 (IL-8) are effective at inducing endothelial cell differentiation, neo-vessel formation and, furthermore, angiogenesis in tissue. Accordingly, those skilled in the art will appreciate the novel and effective methods that are taught herein. The teachings represent a valuable contribution to the field of therapeutic angiogenesis, a relatively new field that has been developed to prevent, treat, and ameliorate symptoms of, diseases affecting the circulatory system.

Cyclic peptides for modulating growth of neo-vessels and their use in therapeutic angiogenesis


SRAM comprises a word line driving circuit selecting a predetermined number of word lines in accordance with an input address at the time of a normal operation, and simultaneously selecting all word lines or word lines, which are more than the number of word lines to be selected at the time of the normal operation, at the time of a voltage stress applying test, and a bit line load circuit applying a predetermined bias voltage to said pair of bit lines at the time of the normal operation, and controlling the bias voltage not to be applied to at least one of said pair of bit lines or applying the bias voltage, which is lower than the bias voltage at the time of the normal operation, at the time of the voltage stress test.

1. Field of the Invention
The present invention relates to a static random access memory (SRAM) and more particularly to a MOS type SRAM having a voltage stress test circuit for performing a screening test of an initial defective mode due to a voltage acceleration.
2. Description of the Related Art
In general, when the semiconductor devices are manufactured and shipped, a screening test for exposing potential defectiveness of the device and removing the defective device in order to prevent the good devices from being deteriorated and ensure high reliability of the devices. As a screening method, there is often used a burn-in method, which can realize an electrical field acceleration and a temperature acceleration at the same time. In the burn-in method, the device is operated in a state that a voltage is set to be higher than the voltage, which is actually used, and temperature is set to be higher than the temperature, which is actually used. As a result, stress, which is higher than stress for a period of time of an initial trouble in a condition of the actual use, can be applied on the device in a short period of time. Thereby, a certain device having a possibility in which the initial operation trouble will occur is selected before shipping and screened. As a result, the device having a possibility in which the initial operation trouble will occur can be effectively removed and reliability of the device can be improved.
The initial trouble of the semiconductor memory occurs mainly in memory cells. This is because the memory cells occupy substantially all the number of elements on the memory. Moreover, since working in the memory cells is the finest and the memory cells are sensitive to the defective.
Particularly, in order to screen deterioration of a gate oxidation film of a MOS FET having a relatively high frequency of generating troubles in the memory cell, it is required that high voltage stress be applied between both ends of the gate oxidation film. Moreover, in order to screen defective leak current of an impurity diffusion region in the memory cell, it is required that high voltage stress is applied between a reverse-biased pn junction between the diffusion region and a semiconductor substrate.
The following explains the case in which the above-mentioned burn-in process is applied to a SRAM using SRAM cells shown in FIG. 1.
In FIG. 1, NMOS transistors Q1, Q2 and resistors R1, R2 constitute a flip-flop circuit. Q3 and Q4 are NMOS transistors for a transfer gate, and each end of the respective transistors Q3 and Q4 is connected to a pair of bit lines BL, /BL, and each gate thereof is connected to a word line WL.
Voltage stress is applied to the transfer gates Q3 and Q4 of the memory cell during only the time when the word line WL is selected. Moreover, inner nodes N1 and N2 for retaining storage data of the memory cell are connected to a power voltage VCC via high resistors R1 and R2. Due to this, voltage stress is applied to the diffusion region, which constitutes the inner nodes N1 and N2, and the gate oxide film of each of the driving transistors Q1 and Q2 for the period of time of 1/2 the whole test (that is, for the period of time when data "1" or "0" is supplied).
However, in recent years, the SRAM cells are designed such that the values of high resistors R1 and R2 are set to about lTO in order to reduce stand-by power consumption to several .mu.A. Due to this, even if a little leak current starts to flow at the time when voltage stress is applied to the inner nodes N1 and N2 via high resistors R1 and R2, the voltages of the inner nodes N1 and N2 decrease and sufficient stress may not be applied to these nodes.
From the above-mentioned points, it can be considered that the voltage stress actually is applied to the inner nodes N1 and N2 during only the time when the word line WL is selected.
Regarding the burn-in of SRAM, there is conventionally used a method in which the word lines are scanned in order of address and assessed sequentially. Due to this, voltage stress is applied to the SRAM cell with the frequency, which is much smaller than that of the transistors of the peripheral circuits. This will be explained by use of 1M bit SRAM in which 64 cells are connected to one word line as follows.
For example, while the burn-in process is performed for 100 hours, actual time for applying stress to one cell is only about 6 seconds (as shown in the following calculation below) if stress is applied during only the time when the word line WL is selected. EQU 100.times.60.times.60.times.(2.sup.5 /2.sup.20).times.(1/2)=6
The above time is stress applying time to the transfer gates Q3 and Q4. Stress applying time to the driving transistors Q1 and Q2 is haft of time is stress applying time to the transfer gates Q3 and Q4. Actually, the word line is selected during only the partial time of one memory cycle.
As mentioned above, stress applying time per one memory cell is 1/10.sup.10 of the testing time. If voltage stress, which is necessary for screening the initial trouble, is to be applied, burn-in time is considerably prolonged non-efficiently, and manufacturing cost of the memory is increased.
In order to solve the above-mentioned problems and extremely improve the efficiency of screening the defective device, one of inventors, who are inventors of the present invention, proposed a semiconductor memory in published Unexamined Japanese Patent Application (Kokai) No. 3-35491 T.FURUYAMA, which corresponds to U.S. application Ser. No. 07/544,614. In this semiconductor memory, voltage stress is simultaneously applied to all word lines or the word lines, which is more than the number of word lines selected at the time of a normal operation of the memory.
In the SRAM, cell arrays are divided into a plurality of blocks and cell current flows to a pair of bit lines of only the block to which the selected cell belongs at the time of the normal operation. However, if all word lines are selected in a state that an operation power is supplied to the memory at the time of screening the defectiveness, a cell current flows to all pairs of bit lines. Due to this, the total bit line current at the time of screening the defectiveness becomes several tens times at the normal operation, so that there is a possibility that the operation fault of SRAM will occur.
Moreover, voltage stress is preferably applied to not only the transfer gates but also the driving transistors in applying voltage stress to the memory cell of SRAM.

Static random access memory including stress test circuitry


A composition and a method of treatment utilizing a combination of statins (or HMG-CoA reductase inhibitors), a class of drug used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, with mixtures of an omega-3 fatty acid formulation containing about 90% or more omega 3 fatty acids by weight including a combination of Eicosapentaenoic acid (EPA), Docosapentaenoic acid (DPA) and Docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 5.7 to 6.3, wherein the sum of the EPA, DHA and DPA represent about 82% by weight of the total formulation and about 92% of the total omega 3 fatty acid content of the composition, the compositions and method designed to stabilize vulnerable plaque while mediating omega-3 deficiencies in individuals in need thereof.

Cardiovascular disease (CVD) represents the primary cause of mortality for men and women in developed countries globally. These premature deaths come at great cost to both the individuals and their families, as well as representing a huge burden to the health care system of the country. The risk factors for coronary heart disease are well-recognized and include: higher than average serum cholesterol, elevated levels of LDL; a low level of HDL in proportion to the LDL level; higher than average serum triglycerides; higher levels of lipid oxidation products creating plaques and streaks which cause blockages of coronary arteries, and in the case of vulnerable plaques, represent a causative factor in promulgating ACS. An additional risk factor for coronary heart disease and stroke is high blood pressure. Reduction in these risk factors is effective to reduces the prevalence of coronary heart disease and its many costs.
In accordance with the findings of the U.S. 2005 Dietary Guidelines Advisory Committee, 70% of Americans are omega-3 fatty acid deficient. Further studies indicate that over 84% of CVD patients are deficient in omega-3 fatty acids, specifically Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA) and Docosapentaenoic acid (DPA).
Cardiovascular disease (CVD) represents the primary cause of mortality for men and women in developed countries globally. These premature deaths come at great cost to both the individuals and their families, as well as representing a huge burden to the health care system of the country. The risk factors for cardiovascular disease are well-recognized and include: higher than average serum cholesterol, elevated levels of LDL; a low level of HDL in proportion to the LDL level; higher than average serum triglycerides; and higher levels of lipid oxidation products and inflammatory processes creating plaques and streaks which cause blockages of coronary arteries. An additional risk factor for cardiovascular disease and stroke is high blood pressure. Reduction in these risk factors is effective to reduce the prevalence of CVD and its many costs.
Although in some cases, genetic predisposition contributes to CVD incidence, poor diet and sedentary lifestyle are major factors that contribute to increased risk for the development, and progression of CVD. Because of this, clinical management of CVD often includes an attempt to modify a patient's lifestyle to increase exercise, and incorporate a balanced diet, rich in omega-3 fatty acids. Due to non-compliance, and often an inability of a patient to adhere to lifestyle modifications, optimal patient care is not achieved through these efforts alone, and other therapeutic interventions or strategies must be considered.
Treatment options may include lipid-regulating medications, such as statins, or fibrates that act to lower low density lipoprotein (LDL) cholesterol and concomitantly APO-B and/or triglycerides (TG), metabolic components that are thought to contribute to atherosclerotic plaque buildup, and increase the risk for heart attack or stroke. However, many of these treatment options come with unwanted side effects that could add additional health risks, or cause physical discomfort.
With regard to obstruction of vessels with plaque, it is observed that plaque deposits can be large or small. In the case of large plaques, they may act to obstruct the vessel, causing a gradual incremental reduction in the size of the arterial lumen. This ongoing process may be treatable with medication, or the use of stents or the like to reopen arterial flow. In the case of small, but vulnerable plaques, these unstable deposits have the ability to suddenly burst, resulting in a cascade effect, which may lead to formation of a thrombus which obliterates blood flow in a coronary or cerebral artery, creating a myocardial infarction or stroke.
Statins are cholesterol-lowering drugs, which work by blocking an enzyme the liver needs for cholesterol production. There are at least a half-dozen statins available on the market, from a number of different manufacturers. These statins vary somewhat in their potency and ability to lower LDL cholesterol.
In the field of CVD prevention, there is no single prior art composition which reduces the variety of risk factors associated with this pervasive disease and which has wide spread applicability to the population in developed countries.
In one aspect, the present invention provides a novel composition, which may be incorporated into an orally administered dietary regimen for the reduction of risk factors associated with CVD. The composition of the invention represents a unique combination of one or more statins with an omega 3 fatty acid formulation which have been shown to reduce risk factors associated with CVD, and in one aspect contribute to the stabilization of vulnerable plaque.
Omega-3 fatty acids are natural polyunsaturated fats found in sea foods like fish and which are presently also available as dietary supplements. They contain more than one double bond in the aliphatic chain. They are named according to the number (>1), position and configuration of double bounds. The three major types of omega-3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). These omega-3 polyunsaturated fatty acids have been shown to protect against several types of cardiovascular diseases such as myocardial infarction, arrhythmia, atherosclerosis, and hypertension (Abeywardena and Head, 2001; Kris-Etherton et al., 2003). It is widely accepted that (EPA) (C20:5n-3) and (DHA) (C22:6n-3) are the major biological active polyunsaturated fatty acids contributing to the prevention of a variety of cardiovascular disorders by improving endothelium-dependent vasodilatation and preventing activation of platelets. Fish oil, EPA and DHA have been shown to induce relaxation and inhibit contraction by mechanisms that are endothelium-dependent (Shimokawa et al., 1987; Yanagisawa and Lefer, 1987). High contents of omega-3 polyunsaturated fatty acids, especially EPA, inhibited platelet aggregation and increased bleeding time, presumably due to a reduced generation of thromboxane A2. Previous studies have also shown that dietary supplementation with cod-liver oil purified omega-3 fatty acids potentiated endothelium-dependent relaxations in isolated porcine coronary arteries (Shimokawa et al., 1988).
If a combination therapy including a novel omega-3 formulation in combination with one or more statins, could be provided for enhancing the patient's lipid profile and mitigating the various risk factors for cardiovascular disease, particularly reduction of overall serum cholesterol levels, reductions in high blood pressure, increase in the HDL:LDL ratio, reduction of triglycerides and homocysteine levels, reduction in apolipoprotein-B levels, and prevention of lipid oxidation, formation of plaques, and stabilization of vulnerable plaques, a long felt need would be realized.

This patent is subject to a terminal disclaimer.

Process and composition for stabilization of vulnerable plaque utilizing a combination of a statin and omega 3 fatty acids


The present disclosure provides a driving chip, a display substrate, a display device and a method for manufacturing a display device. The driving chip according to the present disclosure includes a substrate; and a plurality of connecting bumps and a plurality of supporting bumps disposed on the substrate. The plurality of connecting bumps include at least one set of connecting bumps arranged along a first direction, and the plurality of supporting bumps include the supporting bump that is located between the adjacent connecting bumps arranged along the first direction.

Flexible substrates are increasingly applied to display devices due to their thinness and good impact resistance. For such display device, a flexible substrate is generally fixed on a glass substrate during manufacturing and then the following manufacture processes for the flexible display panel are conducted, which is compatible with existing LCD devices. After the flexible display panel is completed, the flexible substrate is separated from the glass substrate, a membrane material (back film) is attached to the back surface of the flexible substrate to flatten the flexible substrate, and then the processes such as Chip-On-Film (COF) bonding and the like are conducted to realize the bonding of the driving chip (also referred to as IC, in which there is an integrated circuit). However, because COF is expensive and the lines for COF cannot be made too thin, it is impossible to apply COF to manufacturing of the products with high resolution.
Directly bonding a driving chip (COP: Chip on plastic) on a flexible display panel is the future development direction. However, the driving chip has a high hardness, and when the driving chip is compression-bonded to the flexible display panel, it is easy for the connecting bumps on the driving chip to go down to sink due to the effect of high bonding pressure and the flexible display panel may be deformed. This may cause the metal wirings on the flexible display panel connected to the connecting pads to be broken down, thus resulting in defects in the products, such as an open circuit or a short circuit.

Driving chip, display substrate, display device and method for manufacturing display device


An actively ventilated vehicle seat includes a lower air-impermeable seat cushion or backrest part, an air-permeable intermediate layer made of a spacer fabric and an upholstered cover. The vehicle seat is divided into upholstered areas which are delimited from each other by seams anchored at the air-impermeable seat cushion. Air bridges are provided which extend transversely to the seams for connecting the intermediate layer between the individual upholstered areas. An unobstructed seat ventilating system and a permanently secure attachment of the seams are achieved in a simple manner in terms of production and without affecting the seating comfort in that the air bridges are integrated all around into the air-impermeable seat cushion and the seams are anchored above the air bridges in the air-impermeable material of the upholstered part covering the air bridges.

The invention relates to an actively ventilated vehicle seat having a lower air-impermeable seat cushion or backrest part, an intermediate layer arranged on the latter, and through which air flows, and an upholstered cover. The vehicle seat is divided by seams into mutually delimited upholstered zones through which air flows on the side of the intermediate layer.
In the case of an actively ventilated vehicle seat of the type known from German patent document DE 100 24 879 C1, the seams or quiltings are constructed as stitch seams in the air-permeable upholstery cover consisting of a flexible-foam layer and the fabric cover. In this case, the drawing-in depth of the seams is limited to the thickness of the upholstery cover. Moreover, no load-resistant anchoring of the seams on the lower upholstered part is present.
Furthermore, an actively ventilated motor vehicles seat is known from European patent document EP 1 364 827 B1, where the upholstery cover is fastened by way of the intermediate layer, through which the air flows, to the lower upholstered part such that, distributed in the longitudinal direction of the seams, studs are screwed to the lower upholstered part and reach through the intermediate layer. The studs are detachably hooked together with quilting rods pulled into the upholstery cover. Although, as a result, major constrictions of the air-guiding intermediate layer are avoided in the area of the seams, the sitting comfort is considerably impaired by the studs projecting upward beyond the intermediate layer.
Finally, in the case of the vehicle seat of the above-mentioned type known from German patent document DE 101 56 658 C1, in the case of which the intermediate layer, through which the air flows, is divided along the seams into individual sections, which are separated from one another with respect to ventilation, insertion strips in the form of spacing textures are arranged in a sunk manner in the lower seat part and extend in conformance with respect to the length of the seams below the seam-side edge sections of the intermediate layer and act as air bridges between the latter. The seams are produced by pull wires, which extend through the insertion strips and are anchored in the lower seat part. However, the production and arrangement of the air-bridge-forming insertion strips requires increased manufacturing expenditures and, since the insertion strips are compressed in a manner narrowing their cross-section by the active pulling forces of the quilting wires, the air exchange between the individual sections of the intermediate layer may be impaired.
It is an object of the invention to achieve an unhindered seat ventilation and a durably secure fixing of the seams in a manner that is simple with respect to the manufacturing and does not impair the sitting comfort in the case of such an actively ventilated vehicle seat.
According to the invention, an actively ventilated vehicle seat, having a lower air-impermeable seat cushion or backrest part, an intermediate layer through which air flows, and an upholstered cover which, via seams anchored on the lower seat cushion, is divided into mutually delimited upholstery zones. Air bridges extend between the individual upholstery zones transversely to the seams for connecting the intermediate layer. The air bridges are enclosed all around by the air-impermeable seat cushion, and the seams are anchored above the air bridges in the air-impermeable material of the upholstered part covering the air bridges.
According to the invention, the air bridges of the air-guiding intermediate layer are fully enclosed by the air-impermeable material of the upholstered part, and the seams are anchored above the air bridges to wall sections of the upholstered part covering the air bridges. As a result, a durably pull- and slide-resistant fastening of the upholstery cover along the seams is ensured without any stressing of the air bridges in a cross-section-constricting manner by the tension forces resulting from the quilting. This leads to an unhindered air flow through the intermediate layer on the path via the air bridges, while the sitting comfort is simultaneously high in connection with a seat construction that is simple with respect to its manufacturing and remains stable for a long time.
In a further development of the invention preferred with respect to the manufacturing, the air bridges and the intermediate layer are prefabricated as a one-piece blank, specifically normally consisting of a spacing textured material.
For the purpose of a particularly secure fastening of the seams to the air-impermeable seat part, it is recommended to anchor these seams on a seam element which extends continuously along the seams in the air-impermeable part above the air bridges.
The air-impermeable upholstered part preferably consists of a foam material. In order to prevent the foam material from penetrating into the air bridges during the foaming process, which air bridges are surrounded by its flow, and, as a result impairing or even blocking the air guidance in the air bridges, the contact surfaces of the air bridges on the foamed-material side advantageously have a design that is impervious to foam.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of one or more preferred embodiments when considered in conjunction with the accompanying drawings.

Bayerische Motoren Werke Aktiengesellschaft


The subject matter provides dynamically variable idle time thread scheduling in a device with a high system tick rate. A device based on the subject matter includes an operating system, a set of application program modules, and one or more hardware elements. A thread scheduling mechanism in the operating system schedules threads at a periodic rate. Upon determining that there are no threads to execute, at least a subset of components are deactivated for a dynamic variable amount of time before they are is re-activated. The at least one subset of components are selected from the hardware elements, one or more program modules comprising the operating system, and the like. The dynamic variable amount of time is independent of the periodic rate and based on a sleep state of a set of threads in a sleep queue.

Real-time performance is essential for time-critical responses required in high-performance applications such as telecommunications switching equipment, medical monitoring equipment, space navigation and guidance, and the like. Such applications must deliver responses within specified time parameters in real-time.
Real-time performance is typically provided by operating systems that use thread scheduling mechanisms. Such mechanisms schedule threads for execution on a thread priority basis. For example, Microsoft's WINDOWS CE® operating system provides two-hundred-fifty-six (256) priority levels in a basic round-robin scheduler. Threads of higher priority always run before threads of lower priority. Threads of equal priority run in a first-in-first-out round-robin fashion. For example, thread A runs, then thread B runs, followed by thread C, and back to thread A.
Thread scheduling mechanisms typically use a hardware timer to produce a system tick to determine a maximum amount of time or "quantum" of time that a thread can run in the system without being preempted. When a timer reaches the quantum of time, a thread is preempted to determine if there are other threads of equal or higher priority to execute, or run. The system tick is the rate at which a hardware timer interrupt is generated and serviced by the operating system. When the timer fires, the operating system (OS) schedules a new thread for execution if one is ready to be scheduled. Thus, a thread's quantum is a multiple of the time between system ticks.
For example, FIG. 1 is a graph 100 that shows the relationship between thread execution and thread preemption. The vertical axis 101 represents a number of threads 102-1 through 102-N that are in queue for execution. The horizontal axis 103 represents the passage of time to illustrate servicing by the operating system of the system tick 104, which in turn results in a thread being scheduled and/or preempted if there are any threads ready to be scheduled. A system tick occurs once every time interval 106. The time interval can be any duration of time that is supported by a hardware timer, such as 10 milliseconds.
In this example, all threads 102 are of the same priority. In response to a first system tick 104-1, the scheduler executes thread 102-1 for time duration 106-1. The amount of time that a thread 102 will execute before being preempted to determine if there are any other threads to execute is known as a "thread quantum". Thus, each time interval 106 represents the thread quantum. The system tick is generated every thread quantum.
In response to system tick 104-2, the scheduler preempts the execution of thread 102-1 to run thread 102-2 for time duration 106-2. In response to system tick 104-3, the scheduler preempts the execution of thread 102-2 to run thread 102- . . . for time duration 106- . . . . In this manner, threads are scheduled and executed by a real-time operating system.
If there are no threads ready to be scheduled, meaning that all threads are blocked in the system, there is no work for an operating system to perform. All threads may be blocked in a system because threads often have to wait for one or more events to occur before continuing to execute. Such events include waiting for another thread to release a resource such as a file, waiting for a key-press event, or waiting for an amount of time to pass. Thus, a thread will often yield processor control to the thread scheduler by placing itself into a yield, inactive, or sleep state for a specified time period, such as a certain number of milliseconds before continuing execution.
A thread that specifies that it wants to yield or sleep for a millisecond ("sleep (1)") returns or "wakes up" on a system timer tick. If the system timer tick is set to 25 milliseconds, a sleep (1) would result in the thread yielding for at least 1 millisecond, but perhaps yielding up to 25 milliseconds because the timer is set to fire at 25 millisecond intervals. Thus, this thread will not be provided with the scheduling accuracy that it specified—in this example, a millisecond—resulting in poor real-time performance. However, if the system timer interrupt were fired every millisecond, a thread issuing a sleep (1) command would result in the thread sleeping for only a millisecond, which would be the precise amount of time that the thread requested to sleep. Of course, this is dependent on the priority of the thread, and the priority of other threads. This smaller system timer tick value of a millisecond provides the thread's specified scheduling accuracy, which results in higher real-time performance as compared with a scenario where the system tick is set to a larger value.
When there are no threads to schedule, the operating system typically saves power by deactivating or turning off the system's central processing unit (CPU) to place the operating system into an Idle state. The issuance of a system timer tick forces the operating system out of the Idle state by turning the CPU back on so that the operating system can determine if there are any new threads that are ready to be scheduled.
If no threads are ready to be scheduled, the operating system again places itself into an Idle state. Significantly, the frequency at which the system timer tick fires determines how often the system transitions from the Idle state to activate the operating system to determine if there are any threads to schedule. In other words, the amount of time between consecutive system ticks is also the amount of time that the operating system is deactivated when the system is in an Idle state. This amount of time is traditionally static and does not change. Thus, traditional systems typically use static idle time scheduling mechanisms.
Setting the system timer to a millisecond to obtain substantial real-time performance means that if there are no threads to schedule, the system will leave an Idle state every millisecond to activate the operating system to determine if there are any threads to schedule. Upon making this transition, the operating system may determine that there are no new threads to schedule, whereupon the operating system will again be deactivated for a millisecond by placing the system into the Idle state. The process of resuming the operating system when there are no new threads to reschedule is a power consuming process. On a battery-powered device, such transitions use valuable battery life and result in the depletion of limited power reserves.
Consumers are aware about the battery life of a product as the battery life can make or break a product's acceptance in the marketplace. Thus, OEMs and embedded developers, especially those involved in power management of battery powered devices, are concerned with the power efficiency aspects that are a consequence of a system timer interrupt firing every millisecond—especially when the system is idle.
To conserve battery power, OEMs typically preset the system timer, or thread quantum, to a constant of ten (10) milliseconds or greater to preserve the limited battery reserves on battery powered devices. However, as discussed above, increasing the value of the system timer in this manner results in poor real-time performance of time-critical applications because threads may not be provided with the scheduling accuracy required of such applications.
In light of the above, a system is needed that provides real-time thread scheduling performance essential to time-critical responses in high-performance applications without increasing power consumption.

Dynamically variable idle time thread scheduling