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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The strong resemblance between the clinical manifestations of hemolytic transfusion reactions and sepsis, in which cytokine production has a central role, suggests that similar pathophysiologic mechanisms are involved. There is an expanding body of clinical and experimental evidence that cytokines, especially interleukin-1, tumor necrosis factor, interleukin-6, and interleukin-8, are principle mediators of immune responses to erythrocyte incompatibility. Recent studies have further suggested that the monocyte chemotactic and activating factor, monocyte chemoattractant protein-1, and the anti-inflammatory cytokine interleukin-1 receptor antagonist are produced in experimental models of hemolytic transfusion reactions. Differing levels and patterns of expression of these cytokines may be seen in models of intravascular hemolysis due to ABO incompatibility and extravascular hemolysis due to Rh incompatibility, which correlate with the recognized clinical differences between these two types of reactions. Furthermore, recent studies have demonstrated that several of these same cytokines are produced during the storage of platelet concentrates, which may account for some febrile reactions that are not prevented by the use of leukocyte reduction filters.
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PMID:Cytokines and erythrocyte incompatibility. 937 22

The purpose of this study was to evaluate the feasibility of developing multivariate equations that predicted blood pressure and measured levels of end-organ function indicators quantitatively up to 72 h in advance in critically ill patients with severe sepsis. Data collected prospectively from 59 patients entered into two sequential placebo-controlled clinical trials of recombinant interleukin-1 receptor antagonist in severe sepsis and septic shock was analyzed retrospectively. A series of multivariate equations were developed to predict systemic pressure, coagulation, and vital organ function indicators quantitatively at 24, 48, and 72 h after the onset of severe sepsis. These equations used physiologic and clinical laboratory measurements, plus circulating levels of eicosanoids and cytokines obtained when severe sepsis criteria first were met, and end-organ function indicators measured 24, 48, and 72 h later. Multivariate predictive equations were developed for temperature, white blood cell count, mean arterial pressure (MAP), Pao2/FiO2 ratio, the Murray acute lung injury score, alanine and aspartate aminotransferases, prothrombin time, partial thromboplastin time, platelet count, serum creatinine, and Glasgow Coma Scale. The percentage of data variation explained by the equations ranged from 11.4% (MAP at 48 h) to 85.1% (platelet count at 24 h). Linear regression analysis of predicted values, obtained by entering baseline data from individual patients into the multivariate equations, versus observed results at 24, 48, and 72 h yielded regression coefficients ranging from .371 (MAP at 48 h) to .924 (platelet count at 24 h). Among patients without end-organ dysfunction at baseline, sensitivities for predicting values consistent with the onset of organ failure were > or = 88% in 21/27 (78%) of the predictive equations. Resolution of organ failure indicators present at baseline was predicted successfully in individual patients, with 20/27 (74%) specificities > or = 76%. In critically ill patients with severe sepsis, multivariate analysis of interactions among clinical observations, standard laboratory tests, and inflammatory response mediators produced equations that predicted systemic blood pressure and inflammatory and end-organ function indicators quantitatively up to 72 h in advance. Whether or not this methodology might be developed further to predict subclinically the onset and resolution of acute organ failure and shock in critically ill patients, and if it can be validated in a prospective trial will require further studies.
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PMID:Multivariate regression modeling for the prediction of inflammation, systemic pressure, and end-organ function in severe sepsis. 937 72

The interleukin-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular isoform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellular forms have been cloned, and some of the functional cis-acting DNA regions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The tissue distribution of IL-1Ra in mice indicates that sIL-1Ra is found predominantly in peripheral blood cells, lungs, spleen, and liver, while icIL-1Ra is found in large amounts in skin. Studies in transgenic and knockout mice indicate that IL-1Ra is important in host defense against endotoxin-induced injury. IL-1Ra is produced by hepatic cells with the characteristics of an acute phase protein. Endogenous IL-1Ra is produced in numerous experimental animal models of disease as well as in human autoimmune and chronic inflammatory diseases. The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease. Treatment of human diseases with recombinant human IL-1Ra showed an absence of benefit in sepsis syndrome. However, patients with rheumatoid arthritis treated with IL-1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage.
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PMID:Interleukin-1 receptor antagonist: role in biology. 959 23

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance the antimicrobial functions of mature neutrophils. G-CSF differs from GM-CSF in its specificity of action on developing and mature neutrophils, its effects on neutrophil kinetics, and its toxicity profile. The toxicity profile of recombinant (r) GM-CSF is consistent with priming of macrophages for increased formation and release of inflammatory cytokines, whereas rG-CSF induces production of antiinflammatory factors, such as interleukin-1 receptor antagonist and soluble tumor necrosis factor receptors, and is protective against endotoxin- and sepsis-induced organ injury. The low toxicity of rG-CSF, results of animal models of infection, and extensive experience with neutropenic subjects have promoted clinical studies in nonneutropenic subjects, which indicate that rG-CSF may be beneficial as adjunctive therapy for treatment of serious bacterial and opportunistic fungal infections in nonneutropenic patients, including those with alterations in neutrophil function.
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PMID:Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients. 1008 6

The relationship between fluctuating cytokine concentrations in plasma and the outcome of sepsis is complex. We postulated that early measurement of the activation of nuclear factor kappaB (NF-kappaB), a transcriptional regulatory protein involved in proinflammatory cytokine expression, may help to predict the outcome of sepsis. We determined NF-kappaB activation in peripheral blood mononuclear cells of 34 patients with severe sepsis (23 survivors and 11 nonsurvivors) and serial concentrations of inflammatory cytokines (interleukin-6, interleukin-1, and tumor necrosis factor) and various endogenous antagonists in plasma. NF-kappaB activity was significantly higher in nonsurvivors and correlated strongly with the severity of illness (APACHE II score), although neither was related to the cytokine levels. Apart from NF-kappaB activity, the interleukin-1 receptor antagonist was the only cytokine tested whose level in plasma was of value in predicting mortality by logistic regression analysis. These results underscore the prognostic value of early measurement of NF-kappaB activity in patients with severe sepsis.
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PMID:Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. 1072 86

The products of proinflammatory genes such as interleukin-1beta (IL-1beta) and cyclooxygenase-2 (COX-2) initiate many of the events associated with sepsis. Transcription of these genes is subsequently down-regulated, whereas expression of anti-inflammatory genes such as secretory interleukin-1 receptor antagonist (sIL-1 RA) is maintained. Differential expression is associated with endotoxin tolerance, a cellular phenomenon common to sepsis and characterized by reduced proinflammatory gene expression after repeated exposure to lipopolysaccharide. As a model for endotoxin tolerance, we examined the expression of COX-2 and sIL-1 RA in a human promonocyte cell line, THP-1. We observed a 5-fold decrease in COX-2 protein in endotoxin-tolerant cells relative to control cells. In contrast, sIL-1 RA protein increased 5-fold in control and tolerant cells and remained elevated. Decreased COX-2 production is due to repressed transcription and not enhanced mRNA degradation. In addition, COX-2 protein is turned over rapidly. Transcription of sIL-1 RA is also repressed during tolerance. However, sIL-1 RA mRNA is degraded more slowly than COX-2 mRNA, allowing continued synthesis of sIL-1 RA protein that is very stable. These results indicate that differential expression during endotoxin tolerance occurs by transcriptional repression of COX-2 and by protein and mRNA stabilization of sIL-1 RA.
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PMID:mRNA and protein stability regulate the differential expression of pro- and anti-inflammatory genes in endotoxin-tolerant THP-1 cells. 1076 54

Treatment of patients with sepsis with monoclonal antibodies against lipopolysaccharide, tumour necrosis factor or treatment with soluble TNF-receptors or interleukin-1 receptor antagonist have not had any effect on mortality. Treatment with intravenous polyclonal nonspecific immunoglobulin has been shown to have beneficial efficacy on mortality. However, the number of patients included in the latter treatment studies are limited, the patients studied are heterogeneous and do not allow to conclude that sepsis patients should be routinely treated with immunoglobulins.
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PMID:[Non-antibiotic treatment of sepsis]. 1086 Apr 25

This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin-1 receptor antagonist (IL-1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC). A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia. We found a significant association between IL-1RN* polymorphism and survival. Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6.47-fold increased risk of death (95% CI 1.01--41.47, P = 0.04). Besides, compared with patients homozygous or heterozygous for the allele *1, IL-1RN*2 homozygotes produced significantly lower levels of IL-1Ra from their PBMC. Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL-1RN*2 homozygous genotype.
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PMID:Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. 1187 38

The ongoing evaluation of the cytokine-cascade and the steadily growing knowledge about cytokine mediated processes seem to open striking therapeutical options in the fields of sepsis, autoimmune and chronic inflammatory joint or bowel diseases via modulation or inhibition of the cytokine-cascade. There is no doubt about the efficacy of the various anticytokine-treatments in the therapy of chronic inflammatory rheumatic diseases. A large number of preclinical and clinical studies forms the scientific basis for these almost widely established therapies. These so-called "biologicals" are fully accepted as disease modifying antirheumatic drugs, equal to or even more potent than the classical substances. On the one hand, these agents are acting as tumor necrosis factor-alpha-blockers, like a chimeric (human/mouse) monoclonal anti-tumor-necrosis-factor-alpha-antibody (Infliximab), a recombinant soluble tumor necrosis factor-receptor p75 fusion protein (Etanercept), and a fully humanized anti-tumor-necrosis-factor-alpha-antibody (Adalimumab); on the other hand a recombinant human interleukin-1 receptor antagonist (Anakinra) is used in clinical practice. Generally these drugs are very well tolerated; the most common adverse events are higher infection rates (including tuberculosis) and injection-site reactions for the subcutaneously administered agents. Of course one should be aware of the possibly elevated risk for malignancies although there is no evidence for that so far, but the observation time since launching of these drugs is considerably short. To conclude, involved physicians should use these new "tools" very carefully and critically, because long-term tolerance and safety is a matter of ongoing investigation and last but not least because of the growing importance of cost effectiveness when using such expensive medications. Above all initiation and monitoring of those therapies should be restricted to rheumatologists
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PMID:[Biologicals in treatment of rheumatoid arthritis and other inflammatory arthropathies]. 1292 5

Inflammatory cytokines may mediate the host response to infection via central nervous system (CNS), endocrine, and/or paracrine pathways. The purpose of the present study was to determine whether intracerebroventricular (ICV) infusion of interleukin-1 receptor antagonist (IL-1ra) influences the effects of sepsis on protein metabolism in peripheral organs (skeletal muscle, kidney, and liver). A constant ICV infusion of IL-1ra (100 microg/h) or saline was begun immediately before the induction of sepsis or sterile inflammation and continued for 5 days. ICV infusion of IL-1ra did not alter protein metabolism in animals with a sterile abscess. Sepsis reduced muscle weight, protein content, and rates of protein synthesis in gastrocnemius. ICV infusion of IL-1ra attenuated the sepsis-induced loss of muscle mass and protein and the inhibition of protein synthesis in gastrocnemius by augmenting the translational efficiency. Similar results were observed in kidney, with respect to kidney weight, total protein, rates of protein synthesis, and translational efficiency. However, central infusion of IL-1ra did result in a small (12%) increase in the renal RNA content in either sterile or septic abscess rats. In liver, ICV infusion of IL-1ra prevented the sepsis-induced inhibition of protein synthesis and reduction in translational efficiency. These results suggest that central administration IL-1ra can modulate protein metabolism in peripheral organs during sepsis by preventing the sepsis-induced defects in the translational efficiency.
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PMID:Effect of central administration of interleukin-1 receptor antagonist on protein synthesis in skeletal muscle, kidney, and liver during sepsis. 1450 30


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