Introduction: Neutrophil CD64 (nCD64) expression appears to be a promising marker of bacterial infections. The aim of this meta-analysis was to assess the accuracy of nCD64 expression for the diagnosis of sepsis in critically ill adult patients. Methods: We systematically searched PubMed, Embase, ISI Web of Knowledge, and the Cochrane Library for literature published between database inception and 19 May 2014, as well as reference lists of identified primary studies. Studies were included if they included assessment of the accuracy of nCD64 expression for sepsis diagnosis in adult patients and provided sufficient information to construct a 2×2 contingency table. Results: A total of 8 studies comprising 1986 patients fulfilled the inclusion criteria for the final analysis. The pooled sensitivity and specificity were 0.76 (95 % confidence interval [CI], 0.73–0.78) and 0.85 (95 % CI, 0.82–0.87), respectively. The positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 8.15 (95 % CI, 3.82–17.36), 0.16 (95 % CI, 0.09–0.30), and 60.41 (95 % CI, 15.87–229.90), respectively. The area under the summary receiver operating characteristic curve of nCD64 expression with Q* value were 0.95 (Q* =0.89). Conclusions: On the basis of our meta-analysis, nCD64 expression is a helpful marker for early diagnosis of sepsis in critically ill patients. The results of the test should not be used alone to diagnose sepsis, but instead should be interpreted in combination with medical history, physical examination, and other test results.

Atherosclerosis is a chronic lipid-driven inflammatory disease largely influenced by hemodynamics. Neutrophil extracellular trap (NET)-mediated inflammation plays an important role in atherosclerosis. However, little is known about the relationship between low shear stress (LSS) and NET generation, as well as the underlying mechanism. We induced LSS by partial ligation of the left carotid artery in high-fat diet-fed male ApoE^-/- mice. To further validate the direct relationship between LSS and NET formation invitro, differentiated human promyelocytic leukemia HL-60 cells and bone marrow-derived neutrophils were suspended in fluid flow under normal or low shear stress using a parallel-plate flow chamber system. Four weeks after surgery, ligated carotid arteries had more lipid deposition, larger plaque area, and increased NET formation than unligated arteries. Inhibition of NETosis could significantly reduce plaque formation in ApoE^-/- mice. Invitro, LSS could promote NET generation directly through downregulation of Piezo1, a mechanosensitive ion channel. Downregulation of Piezol could activate neutrophils and promote NETosis in static conditions. Conversely, Yoda1-evoked activation of Piezo1 attenuated LSS-induced NETosis. Mechanistically, downregulation of Piezo1 resulted in decreased Ca²⁺ influx and increased histone deacetylase 2 (HDAC2), which increased reactive oxygen species levels and led to NETosis. LSS-induced NET generation also promoted apoptosis and adherence of endothelial cells. LSS directly promotes NETosis through the Piezo1-HDAC2 axis in atherosclerosis progression. This study uncovers the essential role of Piezo1-mediated mechanical signaling in NET generation and plaque formation, which provides a promising therapeutic strategy for atherosclerosis.

Introduction: The nucleotide-binding oligomerization domain-like receptor (NLR) family has been recognized as comprising intracellular pattern recognition receptors in which NLRP3 (NLR family, pyrin domain containing 3) plays an important role in the initiation of host immune inflammatory responses. The genetic variants have been recognized to be critical determinants of interindividual differences in both inflammatory responses and clinical outcomes in critical illness. However, little is known about the clinical relevance of NLRP3 gene polymorphisms in critical illness. Methods: A total of 718 patients with major blunt trauma were included in this study. Six tag SNPs (tSNPs) were selected from the entire NLRP3 gene through construction of haplotype bins, and they were genotyped using a pyrosequencing method. They were analyzed in relation to sepsis morbidity rate, multiple organ dysfunction (MOD) scores and IL-1β production. Moreover, the functionality of the rs2027432 polymorphism was assessed by the observation of its effect on transcriptional activities. Results: Among the six tSNPs genotyped in this study, two of them (rs2027432 and rs12048215) were significantly associated with sepsis morbidity rate and MOD scores. A significant association was also observed between these two polymorphisms and IL-1β production by peripheral leukocytes in response to ex vivo lipopolysaccharide stimulation. However, no combined effects were found between these two polymorphisms. In addition, the rs2027432 polymorphism could significantly enhance the promoter activities of the NLRP3 gene. Conclusions: rs2027432 and rs12048215 polymorphisms might be used as relevant risk estimates for the development of sepsis and MOD syndrome in patients with major trauma, in which rs2027432 might be a functional SNP.

Introduction: An excessive inflammatory response is thought to account for the pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS) after severe trauma. The interleukin-10 (IL-10) is a potent anti-inflammatory cytokine. The objectives of this prospective study were to investigate the distribution of IL-10 promoter polymorphisms in a cohort of 308 Chinese Han patients with major trauma, and to identify associations of IL-10 promoter polymorphisms with IL-10 production and incidence of sepsis and MODS. Methods: A total of 308 patients with major trauma were included in this study. The genotypes of polymorphisms -1082, -819 and -592 were determined by polymerase chain reaction-restriction fragment length polymorphism. The IL-10 levels in the supernatants were determined with enzyme-linked immunoabsorbent assay. Results: The -1082A and -592A alleles were significantly associated with lower lipopolysaccharide-induced IL-10 production in an allele-dose dependent fashion. There was no significant difference for the -819 polymorphism. Except for the -1082 polymorphism, the -819 and -592 polymorphisms were not significantly associated with sepsis morbidity rate and MOD scores. Conclusions: Our results further confirm the functionality of the IL-10 promoter single nucleotide polymorphisms in relation to IL-10 production. They also suggest that individual difference in IL-10 production in trauma patients might be at least in part related to genetic variations in the IL-10 promoter region.

Background: Previous epidemiological studies have presented conflicting evidence regarding associations between interleukin-1 (IL-1) polymorphisms and sepsis susceptibility. We have performed a meta-analysis to evaluate possible associations between IL-1 polymorphisms and sepsis risk. Methods: Eligible literature was retrieved from PubMed, Embase and Web of Knowledge databases until Jun 15, 2013. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random-effects model in the overall and subgroup analysis based on ethnicity, sepsis severity and quality score. Results: Eighteen studies addressing five IL-1 polymorphisms were included in this meta-analysis. For IL-1A-889 (rs1800587) polymorphism, significant association was observed in overall comparison for allelic effect (OR = 1.47, 95% CI = 1.01-2.13, P = 0.04). There were no significant associations between either IL-1B-511 (rs16944) or IL-1B-31 (rs1143627) and sepsis susceptibility in overall or subgroup analyses. For IL-1B + 3594 (rs143634) polymorphism, genotype TT decreased sepsis risk in overall analysis (OR = 0.59, 95% CI = 0.36-0.97, P = 0.04), as well as in Caucasian (OR = 0.57, 95% CI = 0.34-0.95, P = 0.03) and sepsis (OR = 0.55, 95% CI = 0.31-0.97, P = 0.04) subgroup analysis. For IL-1RN VNTR polymorphism, significant association was observed in overall comparison for allelic effect (OR = 1.40, 95% CI = 1.01-1.95, P = 0.04). Furthermore, the effect sizes of IL-1RN VNTR on sepsis risk increased with disease severity (septic shock OR > severe sepsis OR > sepsis OR). Conclusions: Our meta-analysis indicated that IL-1A-889, IL-1B + 3954 and IL-1RN VNTR might be associated with sepsis susceptibility. However, further studies with larger sample sizes and from homogenous populations would be necessary to validate these findings.

Introduction: Recently, researchers in a number of studies have explored the association between the Toll-like receptor 2 (TLR2) Arg753Gln polymorphism and sepsis risk. However, the results were conflicting. In this meta-analysis, we aimed to confirm the effect of the TLR2 Arg753Gln polymorphism on sepsis risk. Methods: Relevant records up to 1 June 2015 were retrieved from the PubMed, Embase, and Web of Knowledge databases. The odds ratios with their corresponding 95 % confidence intervals were used to assess the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The selection of a fixed or random effects model was made according to a heterogeneity test in total and subgroup analyses. Sensitivity analysis and publication bias test were performed to ensure the reliability of our results. Results: A total of 12 studies with aggregate totals of 898 cases and 1517 controls met our inclusion criteria for meta-analysis. There were significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk in overall analyses under two genetic models (the allele comparison and the dominant model). In addition, subgroup analyses based on age group, ethnicity, sepsis type, and source of control also showed a significant effect of the TLR2 Arg753Gln polymorphism on sepsis risk. Conclusions: Our present meta-analysis supports a direct effect of the TLR2 Arg753Gln polymorphism on sepsis risk, especially in Europeans. The TLR2 Arg753Gln polymorphism might be used as a relevant risk estimate for the development of sepsis. Studies with larger sample sizes and homogeneous groups of patients with sepsis are required for further analysis.