Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation

The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p < 0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p < 0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p < 0.05) and 2.1-fold (p < 0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A–I transfer. In vitro, supplementation of HDL or apo A–I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-κB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality

ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Most current guidelines recommend two serological tests to diagnose chronic Chagas disease. When serological tests are persistently inconclusive, some guidelines recommend molecular tests. The aim of this investigation was to review chronic Chagas disease diagnosis literature and to summarize results of ELISA and PCR performance.</p> <p>Methods</p> <p>A systematic review was conducted searching remote databases (MEDLINE, LILACS, EMBASE, SCOPUS and ISIWeb) and full texts bibliography for relevant abstracts. In addition, manufacturers of commercial tests were contacted. Original investigations were eligible if they estimated sensitivity and specificity, or reliability -or if their calculation was possible - of ELISA or PCR tests, for chronic Chagas disease.</p> <p>Results</p> <p>Heterogeneity was high within each test (ELISA and PCR) and threshold effect was detected only in a particular subgroup. Reference standard blinding partially explained heterogeneity in ELISA studies, and pooled sensitivity and specificity were 97.7% [96.7%-98.5%] and 96.3% [94.6%-97.6%] respectively. Commercial ELISA with recombinant antigens studied in phase three investigations partially explained heterogeneity, and pooled sensitivity and specificity were 99.3% [97.9%-99.9%] and 97.5% [88.5%-99.5%] respectively. ELISA's reliability was seldom studied but was considered acceptable. PCR heterogeneity was not explained, but a threshold effect was detected in three groups created by using guanidine and boiling the sample before DNA extraction. PCR sensitivity is likely to be between 50% and 90%, while its specificity is close to 100%. PCR reliability was never studied.</p> <p>Conclusions</p> <p>Both conventional and recombinant based ELISA give useful information, however there are commercial tests without technical reports and therefore were not included in this review. Physicians need to have access to technical reports to understand if these serological tests are similar to those included in this review and therefore correctly order and interpret test results. Currently, PCR should not be used in clinical practice for chronic Chagas disease diagnosis and there is no PCR test commercially available for this purpose. Tests limitations and directions for future research are discussed.</p

Infusion of lipoproteins into volunteers enhances the growth of Candida albicans

Contains fulltext : 19815.pdf (publisher's version ) (Open Access

Hypocholesterolemia in clinically serious conditions--Review

Background: Cholesterol is an essential component of cell membranes, precursor of steroids, biliary acids and other components of serious importance in live organism. Cholesterol synthesis is a complicated and energy-demanding process. Real daily need of cholesterol and mechanisms of decline cholesterol levels in critical ill are unknown. During stressful situations a significant hypocholesterolaemia may be found. Hypocholesterolemia has been known for a number of years to be a significant prognostic indicator of increased morbidity and mortality connected with a whole spectrum of pathological conditions. The aim of article is the elucidation of the role and importance of hypocholesterolaemia during the intensive care. Methods and Results: We examined studies that are engaged in problems of hypocholesterolemia in critically ill. Very low levels of total as well as LDL cholesterol are most frequently found in serious polytrauma, after extensive surgery, in serious infections, in protracted hypovolemic shock. It is still not clear whether hypocholesterolemia refl ects only a serious metabolic disorder, which results from a life-threatening condition, or whether it has an active role in evolution and outcome. Conclusions: Hypocholesterolemia is commonly observed in critically ill patients. Nevertheless, it is not known whether it is a secondary manifestation of disease, or whether it actively contributes to deterioration of the disease. Although the contribution of hypocholesterolemia to mortality is modest compared with known risk factors such as increased severity of illness and the development of nosocomial infection, low serum lipid concentrations represent a potential therapeutic target in sepsis

Serum proteins modulate lipopolysaccharide and lipoteichoic acid-induced activation and contribute to the clinical outcome of sepsis

Bacterial cell wall components, such LPS and LTA, are potent initiators of an inflammatory response that can lead to septic shock. The advances in the past were centered around membrane-bound receptors and intracellular events, but our understanding of the initial interactions of these bacterial components with serum proteins as they enter the bloodstream remain unclear. In this study we identified several serum proteins, which are involved in the innate recognition of bacterial products. Using affinity chromatography and mass spectrometry we performed proteomic analysis of LPS- and LTA-binding serum proteins. We isolated proteins from normal serum that can interact with LPS and LTA. Fluorescent binding experiments and cytokine assays revealed that serum proteins, such as apolipoprotein, LDL, transferrin and holotransferrin could neutralize LPS/LTA binding as well as the subsequent inflammatory response, suggesting that serum proteins modulate LPS/LTA-induced responses. When compared with the proteomic profile of serum from septic patients it was shown that these proteins were in lower abundance. Investigation of serum proteins in 25 critically ill patients with a mortality rate of 40% showed statistically higher levels of these proteins in survivors. Patients surviving sepsis had statistically significant higher levels of apolipoprotein, albumin, LDL, transferrin and holotransferrin than individuals that succumbed, suggesting that these proteins have an inhibitory effect on LPS/LTA-induced inflammatory responses and in their absence there might be an augmented inflammatory response in sepsis