Wileyfallon9092

Improved management of severe sepsis has been one of the major health care accomplishments of the last two decades. Due to enhanced recognition and improved management of severe sepsis, in-hospital mortality has been reduced by up to 40%. With that good news, a new syndrome has unfortunately replaced in-hospital multi-organ failure and death. This syndrome of chronic critical illness (CCI) includes sepsis patients who survive the early "cytokine or genomic storm," but fail to fully recover, and progress into a persistent state of manageable organ injury requiring prolonged intensive care. These patients are commonly discharged to long-term care facilities where sepsis recidivism is high. As many as 33% of sepsis survivors develop CCI. CCI is the result, at least in part, of a maladaptive host response to chronic pattern-recognition receptor (PRR)-mediated processes. This maladaptive response results in dysregulated myelopoiesis, chronic inflammation, T-cell atrophy, T-cell exhaustion, and the expansion of suppressor cell functions. We have defined this panoply of host responses as a persistent inflammatory, immune suppressive and protein catabolic syndrome (PICS). Why is this important? We propose that PICS in survivors of critical illness is its own common, unique immunological endotype driven by the constant release of organ injury-associated, endogenous alarmins, and microbial products from secondary infections. While this syndrome can develop as a result of a diverse set of pathologies, it represents a shared outcome with a unique underlying pathobiological mechanism. Despite being a common outcome, there are no therapeutic interventions other than supportive therapies for this common disorder. Only through an improved understanding of the immunological endotype of PICS can rational therapeutic interventions be designed.Introduction Endoplasmic reticulum stress (ERS) is involved in inflammatory organ failure. Our objective was to describe ERS, its unfolded protein response (UPR) expression/kinetics during cardiac surgery with cardiopulmonary bypass (CPB) and its association with postoperative organ failure (OF). Methods Prospective study conducted on patients undergoing cardiac surgery with CPB. Blood samples were taken before (Pre-CPB), 2 h (H2-CPB) and 24 h (H24-CPB) after CPB. Plasma levels of 78 kDa Glucose- Regulated Protein (GRP78, final effector of UPR) were evaluated by ELISA. The expression of genes coding for key elements of UPR (ATF6, ATF4, sXBP1, CHOP) was evaluated by quantitative PCR performed on total blood. OF was defined as invasive mechanical ventilation and/or acute kidney injury and/or hemodynamic failure requiring catecholamines. RMC-4550 cell line Results We included 46 patients, GRP78 was decreased at H2-CPB [1,328 (878-1,730) ng/ml vs. 2,348 (1,655-3,730) ng/ml Pre-CPB; p less then 0.001] but returned to basal levels at H24-CPB [2,068 (1,436-3,005) ng/ml]. The genes involved in UPR had increased expression at H2 and H24. GRP78 plasma levels in patients with OF at H24-CPB (n = 10) remained below Pre-CPB levels [-27.6 (-51.5; -24.2)%] compared to patients without OF (n = 36) in whom GRP78 levels returned to basal levels [0.6 (-28.1; 26.6)%; p less then 0.01]. H24-CPB ATF6 and CHOP expressions were lower in patients with OF than in patients without OF [2.3 (1.3-3.1) vs. 3.0 (2.7-3.7), p less then 0.05 and 1.3 (0.9-2.0) vs. 2.2 (1.7-2.9), p less then 0.05, respectively]. Conclusions Low relative levels of GRP78 and weak UPR gene expression appeared associated with postoperative OF. Further studies are needed to understand ERS implication during acute organ failure in humans.Sepsis represents one of the most pressing problems in pediatrics, characterized by pathogenic bacteria invading the blood, growing and multiplying in the blood circulation, and ultimately causing severe infections. Most children with sepsis have a rapid disease onset and frequently exhibit sudden high fever or first chills. Here we performed comprehensive metabolomic profiling of plasma samples collected from pediatric sepsis patients to identify specific metabolic alterations associated with these patients (n = 84, designated as case subjects) as compared to healthy cohorts (n = 59, designated as control subjects). Diagnostic models were constructed using MetaboAnalyst, R packages, and multiple statistical methods, such as orthogonal partial least squares-discriminant analysis, principal component analysis, volcano plotting, and one-way ANOVA. Our study revealed a panel of metabolites responsible for the discrimination between case and control subjects with a high predictive value of prognosis. Moreover, significantly altered metabolites in sepsis survivors versus deceased patients (non-survivors) were identified as those involved in amino acids, fatty acids, and carbohydrates metabolism. Nine metabolites including organic acids and fatty acids were also identified with significantly higher abundance in sepsis patients with related microbes, implicating greater potentials to distinguish bacterial species using metabolomic analysis than blood culture. Pathway enrichment analysis further revealed that fatty acid metabolism might play an important role in the pathogenesis of sepsis.

Gq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.

To determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.

Transgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signaling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI

) mice and absent in homozygous (GqI

) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition.