Immune Checkpoint VISTA Negatively Regulates Microglia Glycolysis and Activation via TRIM28-Mediated Ubiquitination of HK2 in Sepsis-Associated Encephalopathy.

V-domain immunoglobulin suppressor of T cell activation (VISTA) has emerged as a crucial player in the pathogenesis of neurological disorders. However, the specific mechanism by which VISTA regulates microglial activation remains unclear. Septic mice were intracerebroventricularly injected with an agonistic anti-VISTA antibody or isotype control. To investigate the differential gene expression profiles, RNA sequencing was conducted on brain tissues from these mice. In vitro, VISTA was silenced in BV2 microglial cells using shRNA. Co-immunoprecipitation assays were performed to identify protein-protein interactions involving hexokinase 2 (HK2), and ubiquitination assays were used to examine the ubiquitination status of HK2. Additionally, BV2 cells were transfected with either tripartite motif-containing 28 overexpression plasmids (TRIM28-PcDNA3.1( +)) or TRIM28-specific siRNA to assess the impact of TRIM28 on VISTA-mediated microglial activation. The cellular glycolytic activity was measured using extracellular acidification rate assays, and proinflammatory cytokine and chemokines were quantified. Treatment with VISTA antibodies significantly alleviated microglial activation and prevented cognitive impairment in septic mice. In contrast, VISTA silencing in BV2 microglia led to the overexpression of proinflammatory cytokines and enhanced glycolysis in an HK2-dependent manner. Mechanistically, HK2 expression was regulated by the E3 ubiquitin ligase TRIM28 through K63-linked ubiquitination, which targeted HK2 for proteasomal degradation. Furthermore, knockdown of TRIM28 reduced the elevated glycolysis and proinflammatory response observed in VISTA-silenced microglia. VISTA modulates microglial activation in sepsis-associated encephalopathy by regulating HK2 expression through TRIM28-mediated K63-linked ubiquitination. These findings highlight VISTA as a potential therapeutic target for modulating microglial activation in sepsis.

Unveiling the role of PD-L1 in vascular endothelial dysfunction: Insights into the mtros/NLRP3/caspase-1 mediated pyroptotic pathway.

BACKGROUND: Programmed death ligand-1(PD-L1) has been postulated to play a crucial role in the regulation of barrier functions of the vascular endothelium, yet how this novel molecule mediates dysfunction in endothelial cells (ECs) during acute lung injury (ALI) remains largely unknown. METHODS: PD-L1 siRNA and plasmids were synthesized and applied respectively to down- or up-regulate PD-L1 expression in human lung microvascular endothelial cells (HMVECs). RNA sequencing was used to explore the differentially expressed genes following PD-L1 overexpression. The expression levels of tight junction proteins (ZO-1 and occludin) and the signaling pathways of NLRP-3/caspase-1/pyroptosis were analyzed. A mouse model of indirect ALI was established through hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), enabling further investigation into the effects of intravenous delivery of PD-L1 siRNA. RESULTS: A total of 1502 differentially expressed genes were identified, comprising 532 down-regulated and 970 up-regulated genes in ECs exhibiting PD-L1overexpression. Enrichment of PD-L1-correlated genes were observed in the NOD-like receptor signaling pathway and the TNF signaling pathway. Western blot assays confirmed that PD-L1 overexpression elevated the expression of NLRP3, cleaved-caspase-1, ASC and GSDMD, and concurrently diminished the expression of ZO-1 and occludin. This overexpression also enhanced mitochondrial oxidative phosphorylation and mitochondrial reactive oxygen species (mtROS) production. Interestingly, mitigating mitochondrial dysfunction with mitoQ partially countered the adverse effects of PD-L1 on the functionality of ECs. Furthermore, intravenous administration of PD-L1 siRNA effectively inhibited the activation of the NLRP3 inflammasome and pyroptosis in pulmonary ECs, subsequently ameliorating lung injury in HEM/CLP mice. CONCLUSION: PD-L1-mediated activation of the inflammasome contributes significantly to the disruption of tight junction and induction of pyroptosis in ECs, where oxidative stress associated with mitochondrial dysfunction serves as a pivotal mechanism underpinning these effects.

Decoding the neurotoxic effects of propofol: insights into the RARα-Snhg1-Bdnf regulatory cascade.

The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the retinoic acid receptor-α, small nucleolar RNA host gene 1, and brain-derived neurotrophic factor (RARα-Snhg1-Bdnf) network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the Gene Expression Omnibus (GEO) database and utilizing JASPAR and RNA-Protein Interaction Prediction (RPISeq) database for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.NEW & NOTEWORTHY This study aimed to decode propofol's neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol's neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.

Global trends in research on endothelial cells and sepsis between 2002 and 2022: A systematic bibliometric analysis.

Sepsis is a systemic syndrome involving physiological, pathological, and biochemical abnormalities precipitated by infection and is a major global public health problem. Endothelial cells (ECs) dysfunction is a major contributor to sepsis-induced multiple organ failure. This bibliometric analysis aimed to identify and characterize the status, evolution of the field, and new research trends of ECs and sepsis over the past 20 years. For this analysis, the Web of Science Core Collection database was searched to identify relevant publications on ECs in sepsis published between January 1, 2002, and December 31, 2022. Microsoft Excel 2021, VOSviewer software, CiteSpace software, and the online analysis platform of literature metrology (http://bibliometric.com) were used to visualize the trends of publications' countries/regions, institutions, authors, journals, and keywords. In total, 4200 articles were identified and screened, primarily originating from 86 countries/regions and 3489 institutions. The USA was the leading contributor to this research field, providing 1501 articles (35.74 %). Harvard University's scientists were the most prolific, with 129 articles. Overall, 21,944 authors were identified, among whom Bae Jong Sup was the most prolific, contributing 129 publications. Additionally, Levi Marcel was the most frequently co-cited author, appearing 538 times. The journals that published the most articles were SHOCK, CRITICAL CARE MEDICINE, and PLOS ONE, accounting for 10.79 % of the total. The current emerging hotspots are concentrated on "endothelial glycocalyx," "NLRP3 inflammasome," "extracellular vesicle," "biomarkers," and "COVID-19," among others. In conclusion, this study provides a comprehensive overview of the scientific productivity and emerging research trends in the field of ECs in sepsis. The evidence supporting the significant role of ECs in both physiological and pathological responses to sepsis is continuously growing. More in-depth studies of the molecular mechanisms underlying sepsis-induced endothelial dysfunction and EC-targeted therapies are warranted in the future.

Global trends in perioperative stroke research from 2003 to 2022: a web of science-based bibliometric and visual analysis.

Background: Perioperative stroke is a potentially devastating complication in surgical patients, which has attracted global attention. This retrospective bibliometric and visual analysis evaluates the status and global trends in perioperative stroke research. Methods: Papers published between 2003 and 2022 were retrieved from the Web of Science core collection. Extracted data were summarized and analyzed using Microsoft Excel and further bibliometric and co-occurrence analyses were conducted using VOSviewer and CiteSpace software. Results: Publications on perioperative stroke have increased over the years. The USA topped the list of countries with the highest number of publications and citations, while Canada had the highest mean citation frequency. The Journal of Vascular Surgery and Annals of Thoracic Surgery had the highest number of publications and citation frequency for perioperative stroke. Regarding authors, Malas, Mahmoud B. contributed the most publications to the field, and Harvard University had the highest number of publications (409 papers). Based on an overlay visualization map, timeline view, and the strongest strength burst of keywords, "antiplatelet therapy," "antithrombotic therapy," "carotid revascularization," "bleeding complications," "postoperative cognitive dysfunction," "intraoperative hypotension," "thrombectomy," "cerebral revascularization," "valve surgery," "tranexamic acid," and "frozen elephant trunk" were trending topics in perioperative stroke research. Conclusion: Publications regarding perioperative stroke have experienced rapid growth in the past 20 years and are likely to continuously increase. Research on perioperative antiplatelet and antithrombotic, cardiovascular surgery, postoperative cognitive dysfunction, thrombectomy, tranexamic acid, and frozen elephant trunk has attracted increasing attention, and these topics are emerging hotspots of present research and possible candidates for future research.

ß-patchoulene alleviates cognitive dysfunction in a mouse model of sepsis associated encephalopathy by inhibition of microglia activation through Sirt1/Nrf2 signaling pathway.

BACKGROUND: Sepsis associated encephalopathy (SAE) is a common but poorly understood complication during sepsis. Currently, there are no preventive or therapeutic agents available for this neurological disorder. The present study was designed to determine the potential protective effects of ß-patchoulene (ß-PAE) in a mouse model of SAE and explore the putative mechanisms underpinning the beneficial effects. MATERIALS AND METHODS: SAE was induced in C57BL/6 mice by cecal ligation and puncture(CLP). Mice were administrated with ß-PAE or saline by intra-cerebral ventricle(i.c.v) injection immediately after CLP surgery. The inhibitory avoidance tests and open field tests were performed at 24h, 48h and 7days after procedures. Cytokines expression, oxidative parameters, microglia polarization and apoptosis in the brain tissue were assessed. Sirt1, Nrf2, HO-1and cleaved-caspase3 expression in hippocampus was determined by western-blotting. Further, serum cytokines expression and spleen lymphocytes apoptosis were evaluated, and survival study was performed. RESULTS: Septic mice suffered severe cognitive decline following CLP as evidenced by decreased memory latency time and lower frequency of line crossing in the behavioral tests. A high dose of ß-PAE(1mg/kg) improved the cognitive impairment in SAE mice, which was accompanied by reduced cytokines expression and oxidative stress. Immunofluorescence assay showed that ß-PAE inhibited the expression of Iba-1 and iNOS in microglia. The mechanistic study indicated that ß-PAE could promote the nuclear expression of Sirt1/Nrf2 and enhance cytoplasmic HO-1 expression. Furthermore, i.c.v administration of ß-PAE decreased the expression of serum cytokines and apoptosis in the spleen, thus leading to an improved 7-day survival of septic mice. Finally, blockade of Nrf2 activation with ML385 largely mitigated the protective effects of ß-PAE on the cognitive function, neuroinflammation and survival in SAE mice. CONCLUSION: In this study, we found that ß-PAE significantly altered sepsis induced neuroinflammation and microglia activation, thus reversed the cognitive decline and improved the peripheral immune function. The neuroprotective effects were possibly mediated by the activation of Sirt1/Nrf2/HO-1 pathway. ß-PAE might serve as a promising therapeutic agent for SAE prevention and treatment.

ß-Patchoulene Preconditioning Protects Mice Against Hepatic Ischemia-Reperfusion Injury by Regulating Nrf2/HO-1 Signaling Pathway.

INTRODUCTION: Hepatic ischemia-reperfusion (I/R) injury is one of the main causes of liver dysfunction after the liver resection and transplantation. Hepatic I/R was characterized by the tissue hypoxia during ischemia phase and oxidative stress and immune response during hypoxia-reoxygenation. The objectives of the present study were to determine the protective effects of ß-patchoulene (ß-PAE), a novel bioactive agent, in a mice model of hepatic I/R injury and to explore its potential mechanisms. METHODS: A segmental liver warm I/R injury model was performed by occluding the portal vessels for 1 h followed by 6-h reperfusion. Twenty-four mice were randomly divided into three groups: Sham, I/R, and I/R + ß-PAE, with eight mice in each group. Mice were intravenously injected with ß-PAE (10 mg/kg) or saline 2 h before surgery, and parameters were measured 6 h after designated treatment. Serum aminotransferase, histologic changes, cytokines expression, and apoptosis were determined. The potential effects of ß-PAE on macrophage activation and apoptosis were further evaluated in a hypoxia and reperfusion (H/R) model in vitro. Oxidative stress markers (reactive oxygen species production and malondialdehyde) and cytokines expression were measured by commercial kits. Nrf2/HO-1 and NF-ƘB signaling pathways were determined by Western blotting. Finally, blockade of nuclear factor erythroid 2-related factor 2 (Nrf2) with ML385 was used to confirm the involvement of Nrf2/HO-1 pathway in H/R injury. RESULTS: Hepatic I/R induced apparent tissue injury as evidenced by the increased expression of serum aminotransferase, pro-inflammatory mediators production, hepatocellular apoptosis, and necrosis. ß-PAE pretreatment protected mice against I/R-induced injury, which was proved by decreased serum aminotransferase and cytokines production, reduced TUNEL-positive cells, and alleviated histopathological lesion. Immunofluorescence staining showed that ß-PAE suppressed the M1 polarization of Kupffer cell induced by I/R injury. Moreover, pretreatment with ß-PAE suppressed H/R-induced cytokines expression and apoptosis in cultured macrophage. The mechanistic study demonstrated that ß-PAE significantly promoted the nuclear Nrf2 translocation and upregulation of HO-1 while downregulating the NF-ƘB signaling pathway in both in vivo and in vitro experiments. Furthermore, blockade of Nrf2 abolished the protective effects of ß-PAE on the inhibition of H/R-mediated oxidative stress, inflammatory response, and apoptosis in vitro. CONCLUSIONS: ß-PAE preconditioning protects mice against hepatic I/R, which was at least in part through the reversing disequilibrium between Nrf2/HO-1 and NF-ƘB pathways. ß-PAE might serve as a promising therapeutic agent in the treatment of hepatic I/R injury.

High-Affinity Anti-VISTA Antibody Protects against Sepsis by Inhibition of T Lymphocyte Apoptosis and Suppression of the Inflammatory Response.

BACKGROUND: B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis. METHODS: Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3+ T cell apoptosis and macrophage activation were determined in vitro. RESULTS: VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3+ T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro. CONCLUSION: The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis.

Blockade of endothelial, but not epithelial, cell expression of PD-L1 following severe shock attenuates the development of indirect acute lung injury in mice.

This study sets out to establish the comparative contribution of PD-L1 expression by pulmonary endothelial cells (ECs) and/or epithelial cells (EpiCs) to the development of indirect acute lung injury (iALI) by taking advantage of the observation that treatment with naked siRNA by intratracheal delivery in mice primarily affects lung EpiCs, but not lung ECs, while intravenous delivery of liposomal-encapsulated siRNA largely targets vascular ECs including the lung, but not pulmonary EpiCs. We showed that using a mouse model of iALI [induced by hemorrhagic shock followed by septic challenge (Hem-CLP)], PD-L1 expression on pulmonary ECs or EpiCs was significantly upregulated in the iALI mice at 24 h post-septic insult. After documenting the selective ability of intratracheal versus intravenous delivery of PD-L1 siRNA to inhibit PD-L1 expression on EpiCs versus ECs, respectively, we observed that the iALI-induced elevation of cytokine/chemokine levels (in the bronchoalveolar lavage fluid, lung lysates, or plasma), lung myeloperoxidase and caspase-3 activities could largely only be inhibited by intravenous, but not intratracheal, delivery of PD-L1 siRNA. Moreover, intravenous, but not intratracheal, delivery led to a preservation of normal tissue architecture, lessened pulmonary edema, and reduced neutrophils influx induced by iALI. In addition, in vitro mouse endothelial cell line studies showed that PD-L1 gene knockdown by siRNA or knockout by CRISPR/Cas9-mediated gene manipulation, reduced monolayer permeability, and maintained tight junction protein levels upon recombinant IFN-γ stimulation. Together, these data imply a critical role for pulmonary vascular ECs in mediating PD-1:PD-L1-driven pathological changes resulting from systemic stimuli such as Hem-CLP.

Blockade of IL-17A/IL-17R Pathway Protected Mice from Sepsis-Associated Encephalopathy by Inhibition of Microglia Activation.

Sepsis-associated encephalopathy (SAE) is a poorly understood condition that leads to long-term cognitive impairment and increased mortality in survivors. Recent research revealed that IL-17A/IL-17R might serve as a checkpoint in microglia-mediated neuroinflammation. The present study was designed to determine the specific role of IL-17A-mediated microglia activation in the development of SAE. A mouse model of SAE was induced by cecal ligation and puncture (CLP), and behavior performance was evaluated by the inhibitory avoidance test and the open field test. Cytokine expression and microglia activation in brain tissue were determined at 6 h, 12 h, 24 h, 48 h, and day 7 post surgery. Further, septic mice were intracerebral ventricle- (i.c.v.-) injected with recombinant IL-17A, anti-IL-17A ab, anti-IL-17R ab, or isotype controls to evaluate the potential effects of IL-17A/IL-17R blockade in the prevention of SAE. Septic peritonitis induced significant impairment of learning memory and exploratory activity, which was associated with a higher expression of IL-17A, IL-1ß, and TNF-α in the brain homogenate. Fluorescence intensity of Iba-1 and IL-17R in the hippocampus was significantly increased following CLP. Treatment with recombinant IL-17A enhanced the neuroinflammation and microglia activation in CLP mice. On the contrary, neutralizing anti-IL-17A or anti-IL-17R antibodies mitigated the CNS inflammation and microglia activation, thus alleviating the cognitive dysfunction. Furthermore, as compared to the sham control, microglia cultured from CLP mice produced significantly higher levels of cytokines and expressed with higher fluorescence intensity of Iba-1 in response to IL-17A or LPS. Pretreatment with anti-IL-17R ab suppressed the Iba-1 expression and cytokine production in microglia stimulated by IL-17A. In conclusion, blockade of the IL-17A/IL-17R pathway inhibited microglia activation and neuroinflammation, thereby partially reversing sepsis-induced cognitive impairment. The present study suggested that the IL-17A/IL-17R signaling pathway had an important, nonredundant role in the development of SAE.

The accuracy assessment of presepsin (sCD14-ST) for mortality prediction in adult patients with sepsis and a head-to-head comparison to PCT: a meta-analysis.

Objective: The soluble cluster of differentiation 14 subtype (sCD14-ST) or presepsin has recently been identified as a promising biomarker in sepsis. The present meta-analysis is performed to assess the prognostic value of presepsin in septic patients. Further, we compare the prognostic performance between presepsin and procalcitonin (PCT) in predicting all-cause mortality in these patients. Methods: A systemic and comprehensive search was conducted in PubMed, Embase and Cochrane databases by using Exploded Medical Subject Headings and appropriate corresponding keywords. Studies were eligible if they assessed the prognostic value of presepsin in sepsis and provided sufficient information to construct a 2×2 contingency table. A bivariate meta-analysis model was used to calculate the pooled sensitivity, specificity, positive/negative likelihood ratios and diagnostic odds ratio. The Chi-square and I 2 index were used to assess the heterogeneity and inconsistency. The Deek's funnel plot asymmetry test was used to assess the likelihood of publication bias. Results: Nine publications, comprising 1,561 patients, were included in this study. The overall area under the receiver operating characteristic curve (AUROC) of presepsin was 0.77 (95% CI, 0.73-0.81) with a pooled prognostic sensitivity (SEN) and specificity (SPE) of 0.83 (95% CI, 0.72-0.90) and 0.69 (95% CI, 0.63-0.74), respectively. Additionally, the PLR, NLR and DOR of presepsin were 2.6 (95% CI, 2.1-3.3), 0.25 (95% CI, 0.15-0.44) and 10 (95% CI, 5-22), respectively. The AUROC of PCT was 0.81 (95% CI, 0.78-0.84) with a pooled SEN of 0.76 (95% CI, 0.55-0.89) and SPE of 0.74 (95% CI, 0.33-0.94). There is no statistically significant difference in the performance of pooled SEN and SPE between presepsin and PCT, with a p value of 0.39 and 0.71, respectively. Conclusions: Based on the results of this meta-analysis, both presepsin and PCT are promising biomarkers for the prognosis of mortality in sepsis.

Probiotics for preventing ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is common in intensive care units (ICUs). Some evidence indicates that probiotics may reduce the incidence of VAP. Several additional published studies have demonstrated that probiotics are safe and efficacious in preventing VAP in ICUs. We aimed to systematically summarise the results of all available data to generate the best evidence for the prevention of VAP. OBJECTIVES: To evaluate the effectiveness and safety of probiotics for preventing VAP. SEARCH METHODS: We searched CENTRAL (2014, Issue 8), MEDLINE (1948 to September week 1, 2014) and EMBASE (2010 to September 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing probiotics with placebo or another control (excluding RCTs that use probiotics in both study groups) to prevent VAP. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and the quality of trials, and extracted data. MAIN RESULTS: We included eight RCTs, with 1083 participants. All studies compared a form of probiotic (Lactobacillus casei rhamnosus; Lactobacillus plantarum; Synbiotic 2000FORTE; Ergyphilus; combination Bifidobacterium longum + Lactobacillus bulgaricus + Streptococcus thermophilus) versus a control group (placebo; glutamine; fermentable fibre; peptide; chlorhexidine). The analysis of all RCTs showed that the use of probiotics decreased the incidence of VAP (odds ratio (OR) 0.70, 95% confidence interval (CI) 0.52 to 0.95, low quality evidence). However, the aggregated results were uncertain for ICU mortality (OR 0.84, 95% CI 0.58 to 1.22 very low quality evidence), in-hospital mortality (OR 0.78, 95% CI 0.54 to 1.14, very low quality evidence), incidence of diarrhoea (OR 0.72, 95% CI 0.47 to 1.09, very low quality evidence), length of ICU stay (mean difference (MD) -1.60, 95% CI -6.53 to 3.33, very low quality evidence), duration of mechanical ventilation (MD -6.15, 95% CI -18.77 to 6.47, very low quality evidence) and antibiotic use (OR 1.23, 95% CI 0.51 to 2.96, low quality evidence). Antibiotics for VAP were used for a shorter duration (in days) when participants received probiotics in one small study (MD -3.00, 95% CI -6.04 to 0.04). However, the CI of the estimated effect was too wide to exclude no difference with probiotics. There were no reported events of nosocomial probiotic infections in any included study.The overall methodological quality of the included studies, based on our 'Risk of bias' assessments, was moderate with half of the included studies rated as a 'low' risk of bias; however, we rated four included studies as a 'high' risk of bias across one or more of the domains. The study limitations, differences in probiotics administered and participants, and small sample sizes across the included studies mean that the power to detect a trend of overall effect may be limited and chance findings cannot be excluded.To explore the influence of some potential confounding factors in the studies, we conducted an intention-to-treat (ITT) analysis, which did not change the inference of per-protocol analysis. However, our sensitivity analysis did not indicate a significant difference between groups for instances of VAP. AUTHORS' CONCLUSIONS: Evidence suggests that use of probiotics is associated with a reduction in the incidence of VAP. However, the quality of the evidence is low and the exclusion of the one study that did not provide a robust definition of VAP increased the uncertainty in this finding. The available evidence is not clear regarding a decrease in ICU or hospital mortality with probiotic use. Three trials reported on the incidence of diarrhoea and the pooled results indicate no clear evidence of a difference. The results of this meta-analysis do not provide sufficient evidence to draw conclusions on the efficacy and safety of probiotics for the prevention of VAP in ICU patients.

Blockade of ICAM-1 improves the outcome of polymicrobial sepsis via modulating neutrophil migration and reversing immunosuppression.

Intercellular adhesion molecule-1 (ICAM-1) is a key adhesion molecule mediating neutrophil migration and infiltration during sepsis. But its role in the outcome of sepsis remains contradictory. The current study was performed to investigate the role of anti-ICAM-1 antibody in the outcome of polymicrobial sepsis and sepsis-induced immune disturbance. Effect of anti-ICAM-1 antibody on outcome of sepsis induced by cecal ligation and puncture (CLP) was evaluated by the survival analysis, bacterial clearance, and lung injury. Its influence on neutrophil migration and infiltration, as well as lymphocyte status, in thymus and spleen was also investigated. The results demonstrated that ICAM-1 mRNA was upregulated in lung, thymus, and spleen of CLP mice. Anti-ICAM-1 antibody improved survival and bacterial clearance in CLP mice and attenuated lung injury. Migration of neutrophils to peritoneal cavity was enhanced while their infiltration into lung, thymus, and spleen was hampered by ICAM-1 blockade. Anti-ICAM-1 antibody also prevented sepsis-induced apoptosis in thymus and spleen. Positive costimulatory molecules including CD28, CD80, and CD86 were upregulated, while negative costimulatory molecules including PD-1 and PD-L1 were downregulated following anti-ICAM-1 antibody administration. In conclusion, ICAM-1 blockade may improve outcome of sepsis. The rationale may include the modulated neutrophil migration and the reversed immunosuppression.

Effect of protective ventilation on postoperative pulmonary complications in patients undergoing general anaesthesia: a meta-analysis of randomised controlled trials.

OBJECTIVE: To determine whether anaesthetised patients undergoing surgery could benefit from intraoperative protective ventilation strategies. METHODS: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to February 2014. Eligible studies evaluated protective ventilation versus conventional ventilation in anaesthetised patients without lung injury at the onset of mechanical ventilation. The primary outcome was the incidence of postoperative pulmonary complications. Included studies must report at least one of the following end points: the incidence of atelectasis or acute lung injury or pulmonary infections. RESULTS: Four studies (594 patients) were included. Meta-analysis using a random effects model showed a significant decrease in the incidence of atelectasis (OR=0.36; 95% CI 0.22 to 0.60; p<0.0001; I(2)=0%) and pulmonary infections (OR=0.30; 95% CI 0.14 to 0.68; p=0.004; I(2)=20%) in patients receiving protective ventilation. Ventilation with protective strategies did not reduce the incidence of acute lung injury (OR=0.40; 95% CI 0.07 to 2.15; p=0.28; I(2)=12%), all-cause mortality (OR=0.77; 95% CI 0.33 to 1.79; p=0.54; I(2)=0%), length of hospital stay (weighted mean difference (WMD)=-0.52 day, 95% CI -4.53 to 3.48 day; p=0.80; I(2)=63%) or length of intensive care unit stay (WMD=-0.55 day, 95% CI -2.19 to 1.09 day; p=0.51; I(2)=39%). CONCLUSIONS: Intraoperative use of protective ventilation strategies has the potential to reduce the incidence of postoperative pulmonary complications in patients undergoing general anaesthesia. Prospective, well-designed clinical trials are warranted to confirm the beneficial effects of protective ventilation strategies in surgical patients.

Ginsenoside Rg1 protects mouse liver against ischemia-reperfusion injury through anti-inflammatory and anti-apoptosis properties.

BACKGROUND: Ginsenoside Rg1, the major effective component of ginseng, possesses a variety of pharmacologic activities. The objective of this study was to investigate the effects of Rg1 on liver ischemia-reperfusion (IR) injury and explore its potential mechanisms. MATERIALS AND METHODS: Liver warm IR injury was achieved by occluding the portal vein and hepatic artery for 1 h followed by 6-h reperfusion. Eighteen mice were equally randomized into three groups: sham group, IR group, and IR plus Rg1 group (n = 6 mice per group). Mice received an intravenous dose of 20 mg/kg Rg1 or an equivalent volume of saline before ischemic insult. Liver samples and serum were collected for analyses. Serum aminotransferase, histopathology, and apoptosis were determined. Cytokines were measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The phosphorylation of nuclear factor kappa B (NF-κB) p65 was assessed by Western blotting. In addition, the effect of Rg1 in a simulated IR model in vitro was also investigated. Rg1 (100 ug/mL and 500 ug/mL) was administered 1 h before hypoxia insult, and then apoptosis was measured after 12-h reperfusion. RESULTS: Liver IR injury led to a dramatic increase in aminopherase activity, apoptosis and necrosis of hepatocytes, and production of proinflammatory cytokines. Pretreatment with Rg1 protected mice from IR-induced liver injury. Treatment with a high-dose Rg1 (500 ug/mL) significantly suppressed apoptosis compared with a lower dose or control (both P < 0.001). Phosphorylation of NF-κB p65 was increased significantly in IR group, and administration with Rg1 suppressed the level of phosphorylation. CONCLUSIONS: Pretreatment of mice with Rg1 reduced hepatocellular apoptosis and inhibited inflammatory response, which was in part through the NF-κB signaling pathway. Rg1 may provide a novel therapeutic strategy for the treatment of IR-induced liver injury.

Soluble tumor necrosis factor related apoptosis inducing ligand level as a predictor of severity of sepsis and the risk of mortality in septic patients.

BACKGROUND: Tumor necrosis factor related apoptosis inducing ligand (TRAIL) as a member of the TNF gene superfamily induces apoptosis primarily in tumor cells. TRAIL also plays an important role in the modulation of inflammatory responses, especially in the process of immune paralysis. The aim of the present study was to examine soluble TRAIL (sTRAIL) levels in septic patients in an attempt to explore the association between sTRAIL level and the risk of mortality. METHODS: Plasma sTRAIL levels were detected by ELISA in 50 septic patients and 20 healthy volunteers. HLA-DR expression in monocytes was detected by flow cytometry. Selective biochemical parameters were recorded, and patients were monitored in a 28-day period for mortality. RESULTS: The mean plasma sTRAIL level in septic patients was significantly lower than that in healthy controls (16.9±8.3 vs. 68.3±8.6 pg/ml, P<0.01), and was significantly higher in 28-day survivors than those in non-survivors (19.4±9.8 vs. 13.9±4.7 pg/ml, P<0.05). Univariate analysis indicated that plasma sTRAIL level was positively correlated with monocyte and lymphocyte counts and HLA-DR expression level (r = 0.5, P<0.01; r = 0.3, P<0.05; r = 0.43, P<0.01, respectively). STRAIL level was negatively correlated with APACHE II score, BUN and age (r = -0.48, P<0.01; r = -0.29, P<0.05; r = -0.45, P<0.01, respectively). Multiple linear regression analysis indicated that the predictor of plasma soluble TRAIL level was HLA-DR expression (P<0.01). CONCLUSION: Low plasma sTRAIL levels were associated with immune paralysis and a high risk of mortality in patients with septic shock. sTRAIL may prove to be a potential biomarker of immune function and predict the survival of septic patients.

PD-L1 blockade attenuated sepsis-induced liver injury in a mouse cecal ligation and puncture model.

Liver plays a major role in hypermetabolism and produces acute phase proteins during systemic inflammatory response syndrome and it is of vital importance in host defense and bacteria clearance. Our previous studies indicated that programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) are crucial modulators of host immune responses during sepsis. Our current study was designed to investigate the role of PD-L1 in sepsis-induced liver injury by a mouse cecal ligation and puncture (CLP) model. Our results indicated that there was a significant increase of PD-L1 expression in liver after CLP challenge compared to sham-operated controls, in terms of levels of mRNA transcription and immunohistochemistry. Anti-PD-L1 antibody significantly alleviated the morphology of liver injury in CLP mice. Anti-PD-L1 antibody administration decreased ALT and AST release in CLP mice, decreased the levels of tumor necrosis factor (TNF)-α , interleukin (IL)-6, and IL-10 mRNA in liver after sepsis challenge. Thus, anti-PD-L1 antibody might have a therapeutic potential in attenuating liver injury in sepsis.

The size of endotracheal tube and sore throat after surgery: a systematic review and meta-analysis.

BACKGROUND: Recent studies showed that sore throat following endotracheal intubation was a common problem following surgery. The objective of this systematic review and meta-analysis of published randomized controlled trials (RCTs) or cohort studies was to estimate whether the size of endotracheal tube (ETT) affects the incidence of postoperative sore throat (POST) after general anesthesia. METHODS: The following databases were searched electronically: PubMed (updated to Dec 2012), EMBASE (updated to 15 Dec 2012), Google scholar, World Health Organization International Clinical Trials Registry Platform (Jul 2011), Chinese BioMedical Literature Database (1978 to Jul 2011), and China National Knowledge Infrastructure (1994 to Jul 2011). Studies comparing the size of endotracheal tube for elective surgery were included. RESULTS: Three trials with a total of 509 female patients were included in the current analysis. The size of ETT used were 6.0 mm and 7.0 mm. Pooled studies from these trials showed that the smaller size of ETT (6.0 mm) significantly decreased the incidence of POST in post-anesthesia care unit (PACU) (RR = 0.56, 95% CI 0.42-0.75, P<0.01) and at 24 h after surgery (RR = 0.69, 95% CI 0.48-0.99, P<0.05). A smaller size of ETT (6.0 mm) was associated with a lower incidence of PH in PACU (RR = 0.69, 95% CI 0.55-0.87, P<0.01), but did not affect the incidence of PH at 24 h after surgery (RR = 0.73, 95% CI 0.46-1.15, P>0.05). CONCLUSION: Our meta-analysis suggests that patients under general anesthesia with a smaller size of ETT (6.0 mm) were associated with a lower incidence of POST in female patients. More studies with adequate numbers of patients were warranted to evaluate other size of ETT on the incidence of PH and POST after general surgery among different populations.

Ginsenoside Rg1 improves survival in a murine model of polymicrobial sepsis by suppressing the inflammatory response and apoptosis of lymphocytes.

BACKGROUND: Unbalanced inflammatory response and lymphocyte apoptosis are the main reasons for high mortality in patients with sepsis. Ginsenoside Rg1 (Rg1), the most important component isolated from Panax ginseng, has long been used to treat inflammatory and immune-related diseases. We designed this study to investigate the therapeutic effect of this agent on cecal ligation and puncture (CLP)-induced sepsis in mice. MATERIALS AND METHODS: We randomly divided C57BL/6 mice into four experimental groups: sham, sham plus Rg1, CLP, and CLP plus Rg1. We intravenously injected Rg1 (20 mg/kg) 1 h after CLP and evaluated survival, bacterial clearance, cytokine production, histology, neutrophil emigration, and lymphocyte apoptosis. RESULTS: Our study showed that treatment with Rg1 significantly improved survival in septic mice (P < 0.01). Rg1 administration suppressed the inflammatory response and enhanced bacterial clearance. Histologic examination of lung and liver showed only minor abnormalities in mice that received Rg1. In addition, Rg1 increased neutrophil counts in peritoneal cavity and inhibited lymphocyte apoptosis in thymus and spleen. CONCLUSIONS: Ginsenoside Rg1 has a protective role against CLP-induced polymicrobial sepsis by attenuating the proinflammatory response, enhancing innate immunity and preserving adaptive immunity. Rg1 could be a promising new agent for treatment of sepsis.

The top cited clinical research articles on sepsis: a bibliometric analysis.

INTRODUCTION: The objective of this study was to identify and characterize the most highly cited clinical research articles published on sepsis. METHODS: A comprehensive list of citation classics in sepsis was generated by searching the database of Web of Science-Expanded (1970 to present) using keywords 'sepsis' or 'septic shock'. The top 50 cited clinical research papers were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information, including country of origin, article type, journals, authors, and funding sources. RESULTS: A total of 2,151 articles were cited more than 100 times; the 50 top-cited clinical articles were published between 1974 and 2008. The number of citations ranged from 372 to 2,932, with a mean of 678 citations per article. These citation classics came from nine countries, of which 26 articles came from the United States. Rush University and the University of Pittsburgh lead the list of classics with six papers each. The 50 top-cited articles were published in 17 journals, with the New England Journal of Medicine and Journal of the American Medical Association topping the list. The top 50 articles consisted of 21 clinical trials and 29 observational studies. CONCLUSIONS: Our bibliometric analysis provides a historical perspective on the progress of clinical research on sepsis. Articles originating from the United States and published in high-impact journals are most likely to be cited in the field of sepsis research.