Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Hemorrhagic shock (HS) is a common cause of death in severely injured patients and is associated with impairment of organ perfusion, systemic inflammatory response and multiple organ failure. The aim of the present study was to evaluate the effects of artesunate, the drug of choice for the treatment of falciparum malaria, on organ injury and dysfunction associated with HS in the rat. ⋯ A single-centre placebo-controlled randomized phase II clinical trial will be conducted at Barts Health NHS Trust (TOP-ART) in late 2015 to evaluate the effects of GMP-artesunate in patients with severe hemorrhage following trauma.
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Due to the limited sample volume (total blood volume is 1.5-2.5 mL), metabolic parameter sets in mice are usually assessed by killing a defined number of animals at selected time points with subsequent analysis of pooled plasma. However, reducing the number of animals used is a cornerstone of the ARRIVE guidelines, and, moreover, may reduce costs and workload. Therefore, we developed a stable-isotope-based gas chromatography/mass spectrometry (GC/MS) method to allow for serial quantification of metabolic pathways in mice. ⋯ This method enables simultaneous, repetitive in vivo monitoring of kidney function (glomerular filtration), determinants of energy metabolism (glycolysis, lipolysis), and nitrogen balance as a function of hepatic urea production and protein degradation (leucine production).
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The crucial role of the endothelium in sepsis is well recognized. The aim of this study was to establish a flow model to study endothelial activation induced by lipopolysaccharide (LPS) or by plasma from septic patients. We report on the application of this model to assess the effect of adsorbent-based cytokine modulation on endothelial activation. ⋯ The flow model allows to study endothelial activation and the interaction of activated endothelial cells with blood cells. Cytokine modulation with PS-DVB polymers reduced endothelial activation and decreased monocyte adhesion.(Figure is included in full-text article.).
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The role of sphingosine-1-phosphate (S1P) and its receptors (S1PR1-5) in septic cardiomyopathy is not known. The S1P mimetic FTY720-P acts as an agonist on all S1P receptors except S1PR2 and as a functional antagonist on S1PR1. ⋯ We show here for the first time that the impaired left ventricular systolic contractility caused by LPS/PepG is attenuated by a pharmacological or genetic approach to alter S1P-serum levels. Mechanistically, our results indicate that activation of S1PR2 by increased serum S1P and the subsequent activation of PI3K signalling contribute to the observed cardioprotective effect of FTY720 in experimental sepsis.
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Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. ⋯ Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidence that ER stress participates in the pathogenesis of sepsis. In this review, we summarize current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma-hemorrhage and ischemia/reperfusion injury. We also discuss the potential implications of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.