Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eleven patients with inoperable brain tumours were treated with high doses of corticosteroids (methylprednisolone 200-2000 mg/day) for up to 151 days (mean 55 days). Neurological improvement occurred in eight patients on high doses after deterioration on concentional doses (methylprednisolone 80-120 mg/day). In two patients steroids could be completely discontinued for several months. Serious adverse effects included sepsis in three patients and myopathy in tow. All three patients with sepsis also received chemotherapy. There were no deaths that could be attributed to steroids. The most likely effect of high dosage steroids is reduction of cerebral oedema. It is conceivable that in some instances high dose steroids may also result in tumour inhibition or oncolysis or both.
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PMID:Use of high dose corticosteroids in patients with inoperable brain tumours. 59 62

There is increasing experimental and clinical evidence that a number of cytokines play a major role in the response to injury and infection and in the development of organ damage in critically ill patients. Tumour necrosis factor (TNF) is now proposed to be a key mediator of organ injury during sepsis. It is elevated early in the course of septic shock and high levels correlate with unfavourable outcome. In animals it can produce the effects of endotoxin. The prophylactic administration of anti-TNF antisera protects mice and rabbits from lethal effects of lipopolysaccharide. Interleukin-1 (IL-1) is an endogenous pyrogen which induces leukocytosis and muscle catabolism. It causes hypotension and tachycardia by reducing smooth muscle contractility. IL-1 receptor blockers have been shown to diminish mortality in experimental endotoxic shock. Interleukin-6 (IL-6) is a pyrogen and lymphocyte activator. It is the major stimulus to acute phase protein production by the liver. A recently described neutrophil-activating peptide (Interleukin-8; IL-8) may be involved in the pathogenesis of ARDS. High blood levels of IL-8 have been found in patients with septic shock. Platelet-derived growth factor (PDGF) has been shown to stimulate TNF production, leukocyte chemotaxis and pulmonary vasoconstriction in response to endotoxin. Other cytokines and growth factors have not yet been studied in critical illness. The cytokine network can be either protective or damaging. Its activation during critical illness triggers complex and still poorly understood interactions. A better comprehension of its role in protection from infection and in the pathogenesis of multiple organ failure may allow therapeutic manipulations aimed at minimising adverse effects while retaining immunological protection.
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PMID:The cytokine network in the critically ill. 152 67

Tumor necrosis factors (TNF) alpha and beta are structurally related cytokines that mediate a wide range of immunological, inflammatory, and cytotoxic effects. During bacterial infection of the bloodstream (sepsis), TNF-alpha induction by bacterial endotoxin is thought to be a major factor contributing to the cardiovascular collapse and critical organ failure that can develop. Despite antibiotic therapy, these consequences of sepsis continue to have a high mortality rate in humans. Here we describe a potent TNF antagonist, a TNF receptor (TNFR) immunoadhesin, constructed by gene fusion of the extracellular portion of human type 1 TNFR with the constant domains of human IgG heavy chain (TNFR-IgG). When expressed in transfected human cells, TNFR-IgG is secreted as a disulfide-bonded homodimer. Purified TNFR-IgG binds to both TNF-alpha and TNF-beta and exhibits 6- to 8-fold higher affinity for TNF-alpha than cell surface or soluble TNF receptors. In vitro, TNFR-IgG blocks completely the cytolytic effect of TNF-alpha or TNF-beta on actinomycin D-treated cells and is markedly more efficient than soluble TNFR (24-fold) or monoclonal anti-TNF-alpha antibodies (4-fold) in inhibiting TNF-alpha. In vitro, TNFR-IgG prevents endotoxin-induced lethality in mice when given 0.5 hr prior to endotoxin and provides significant protection when given up to 1 hr after endotoxin challenge. These results confirm the importance of TNF-alpha in the pathogenesis of septic shock and suggest a clinical potential for TNFR-IgG as a preventive and therapeutic treatment in sepsis.
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PMID:Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. 166 Jan 40

Tumour necrosis factor-alpha (TNF-alpha)/cachectin is a multifunctional cytokine that has effects in inflammation, sepsis, lipid and protein metabolism, haematopoiesis, angiogenesis and host resistance to parasites and malignancy. TNF-alpha was first described in activated macrophages, but certain mouse or rat mast cell populations (reviewed in refs 4,5) and some in vitro-derived human cells with cytochemical features of mast cells-basophils may also contain products similar to TNF-alpha. Here we present evidence that resident mouse peritoneal mast cells constitutively contain large amounts of TNF-alpha bioactivity, whereas cultured, immature mast cells vary in their TNF-alpha content. IgE-dependent activation of cultured or peritoneal mast cells induces extracellular release of TNF-alpha and augments levels of TNF-alpha messenger RNA and bioactivity. These findings identify mouse mast cells as an important source of both preformed and immunologically inducible TNF-alpha, and suggest that release of TNF-alpha by mast cells may contribute to host defence, the pathophysiology of allergic diseases and other processes dependent on TNF-alpha.
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PMID:Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. 237 92

Sepsis and endotoxaemia are common in fulminant hepatic failure (FHF) and may contribute to multisystem disease in such patients. Tumour necrosis factor (TNF) is a probable mediator of endotoxic shock and infusion of this monokine into animals causes multi-organ failure that shares features with FHF. In patients with FHF, TNF production was increased and correlated closely with activity of interleukin-1, another cytokine that is released by monocytes/macrophages in response to infection and endotoxin and is produced in increased quantities in FHF. Interleukin-2 activity was impaired in FHF and correlated negatively with TNF production.
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PMID:Enhanced tumour necrosis factor and interleukin-1 in fulminant hepatic failure. 289

Tumour necrosis factor (TNF) is an early mediator of sepsis and multiple organ failure; increased concentrations in serum are also observed in acute pancreatitis. In the present study the predictive value of TNF and C-reactive protein (CRP) concentrations on admission were compared in order to differentiate complicated cases of acute pancreatitis from the mild course in 77 patients. Serum TNF concentration exceeded the detectable level only in seven of 77 patients (9 per cent), although complicated pancreatitis developed in 18 (23 per cent). The sensitivity and overall accuracy of TNF concentration in predicting severe disease were only 16 and 74 per cent respectively. The corresponding values for CRP (concentrations greater than 100 mg/l) were 84 and 74 per cent respectively. These data suggest that, in contrast with CRP, the early determination of peripheral blood TNF concentration is of no clinical value in assessing the severity of acute pancreatitis.
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PMID:Serum tumour necrosis factor compared with C-reactive protein in the early assessment of severity of acute pancreatitis. 774 9

Tumour necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1 beta) are the central mediators in the genesis of sepsis. The proinflammatory effects of these cytokines are counteracted in vivo by natural inhibitors. Soluble TNF receptors (sTNFR) are shed upon inflammatory stimuli such as IL-1 beta and TNF itself. Circulating TNF can be complexed by these receptors, thus preventing TNF from binding to effector cells. The binding of IL-1 beta to its receptor can be blocked by high concentrations of interleukin-1 receptor antagonist (IL-1Ra), which is produced and released upon nearly the same stimuli as IL-1 beta. This review presents some aspects of the kinetic behaviour of native sTNFR and of the production of native IL-1Ra during severe infections. It appears that in fulminant septicaemia, the plasma concentration of TNF is increased only transiently, during the very early stage of the infection. The concentration of sTNFR, in contrast, remains elevated much longer, probably due to a slower clearance. During the acute stage of severe infectious diseases, peripheral blood cells cannot be stimulated to produce IL-1 beta. The production of IL-1 Ra, in contrast, is not affected. Thus, the kinetic behaviour and regulation of TNF and IL-1 beta, is different from that of their antiinflammatory counterparts.
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PMID:Kinetics of tumour necrosis factor-alpha, soluble tumour necrosis factor receptors, interleukin 1-beta and its receptor antagonist during serious infections. 782 Dec 99

Tumour necrosis factor alpha (TNF alpha) has been reported to play a key role in the pathogenesis of sepsis and chronic inflammatory diseases, including rheumatoid arthritis and atherosclerosis, suggesting that agents which inhibit TNF alpha production may have therapeutic utility for the treatment of such conditions. Production of TNF alpha by LPS (lipopolysaccharide)-stimulated murine, rat and human heparinized blood was investigated. LPS (1-100 micrograms/ml) caused a similar concentration- and time-dependent stimulation of TNF alpha production by rat and human blood, achieving levels of 750-5000 U/ml (L929 bioassay) at 6 h. In contrast, TNF alpha production by LPS-stimulated murine blood was poor and variable (0-150 U/ml). Dexamethasone and pentoxifylline caused a concentration-dependent inhibition of TNF alpha production by LPS-stimulated human and rat blood with IC50s of 0.26 +/- 0.05 and 73.0 +/- 26.4 microM for human and 5.7 +/- 1.8 nM and 20.6 +/- 8.0 microM for rat blood, respectively. Therefore, LPS-stimulated rat and human, but not murine, blood are suitable systems for the detection and evaluation of inhibitors of TNF alpha production.
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PMID:Production of TNF alpha by LPS-stimulated murine, rat and human blood and its pharmacological modulation. 831 28

Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 beta, IL-6 and IL-8 are thought to play a central role in the pathophysiology of sepsis but their role in acute pancreatitis is unknown. In the present study, monocytes were isolated from the peripheral blood of 26 patients with moderate or severe acute pancreatitis without biliary sepsis. Secretion of these cytokines in vitro was measured at intervals during the first week of illness. Sixteen patients developed systemic complications. Peak TNF-alpha secretion was significantly higher in patients who developed systemic complications (median (interquartile range (i.q.r.)) 18.5 (5.5-28.5) ng/ml) than in those with an uncomplicated course (3.7 (2.3-6.4) ng/ml, P < 0.01). Similarly, peak IL-6 and peak IL-8 secretion were significantly higher in the complicated group (IL-6: complicated median (i.q.r.) 48.9 (12.1-71.0) ng/ml, uncomplicated 16.3 (14.2-37.9) ng/ml, P < 0.05; IL-8: complicated 748 (643-901) ng/ml, uncomplicated 608 (496-749) ng/ml), P < 0.05). No significant difference in peak IL-1 beta secretion was observed between the two groups. Systemic complications of acute pancreatitis are associated with a significant increase in monocyte secretion of TNF-alpha, IL-6 and IL-8 suggesting that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease.
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PMID:Increased monocyte cytokine production in association with systemic complications in acute pancreatitis. 881 75

Tumour necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischaemia-reperfusion injury (I/R), sepsis, chronic heart failure and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leucocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether I/R induces an increase in cardiac TNF-alpha in a crystalloid-perfused model (in the absence of blood), and, whether adenosine decreases cardiac TNF-alpha and protects function after I/R. To study this, isolated rat hearts were crystalloid-perfused using the Langendorff method and subjected to I/R, with or without adenosine pretreatment. Post-ischaemic cardiac TNF-alpha (enzyme-linked immunosorbent assay and bioassay) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Adenosine decreased cardiac TNF-alpha and improved post-ischaemic functional recovery. This study demonstrates that: first, I/R induces an increase in cardiac tissue TNF-alpha in a crystalloid-perfused model: second, adenosine decreases cardiac TNF-alpha and improves post-ischaemic myocardial function; third, decreased cardiac TNF-alpha may represent a mechanism by which adenosine protects myocardium; and fourth, adenosine-induced suppression of cardiac TNF-alpha may provide an anti-inflammatory link to preconditioning and have implications for cardiac allograft preservation.
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PMID:Adenosine decreases post-ischaemic cardiac TNF-alpha production: anti-inflammatory implications for preconditioning and transplantation. 949 88


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