Design, synthesis, biological evaluation of novel piperidine-based derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial member of DNA repair enzymes responsible for repairing DNA single-strand breaks. Developing PARP inhibitors based on synthetic lethality strategies is an effective approach for treating breast cancer and other diseases. In this study, a series of novel piperidine-based benzamide derivatives were designed and synthesized using structure-based drug design principles. The anticancer activities of these compounds were evaluated against five human cancer cell lines (MDA-MB-436, CAPAN-1, SW-620, HepG2, SKOV3, and PC3) and the preliminary structure-activity relationships were delineated. Among the compounds, 6a and 15d demonstrated potent antiproliferative effects against MDA-MB-436 cells with IC50 values of 8.56 ± 1.07 µM and 6.99 ± 2.62 µM, respectively. Furthermore, both compounds exhibited excellent inhibitory activity against PARP-1, with IC50 values of 8.33 nM and 12.02 nM, respectively. Mechanistic investigations revealed that 6a and 15d effectively inhibited colony formation and cell migration of HCT116 cells. Moreover, they induced apoptosis by upregulating the expression of Bax and cleaved Caspase-3, while downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. Based on its impressive pharmacodynamic data in vitro, we conducted a study to evaluate the efficacy of 15d in a xenograft tumor model in mice when used in combination with cytotoxic agents. Collectively, these findings suggest that 15d could be promising drug candidates worthy of further investigation.

Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity.

The cell wall is a dynamic structure that is important for the pathogenicity of Candida albicans. Mannan, which is located in the outermost layer of the cell wall, has been shown to contribute to the pathogenesis of C. albicans, however, the molecular mechanism by which this occurs remains unclear. Here we identified a novel α-1,6-mannosyltransferase encoded by MNN10 in C. albicans. We found that Mnn10 is required for cell wall α-1,6-mannose backbone biosynthesis and polysaccharides organization. Deletion of MNN10 resulted in significant attenuation of the pathogenesis of C. albicans in a murine systemic candidiasis model. Inhibition of α-1,6-mannose backbone extension did not, however, impact the invasive ability of C. albicans in vitro. Notably, mnn10 mutant restored the invasive capacity in athymic nude mice, which further supports the notion of an enhanced host antifungal defense related to this backbone change. Mnn10 mutant induced enhanced Th1 and Th17 cell mediated antifungal immunity, and resulted in enhanced recruitment of neutrophils and monocytes for pathogen clearance in vivo. We also demonstrated that MNN10 could unmask the surface ß-(1,3)-glucan, a crucial pathogen-associated molecular pattern (PAMP) of C. albicans recognized by host Dectin-1. Our results demonstrate that mnn10 mutant could stimulate an enhanced Dectin-1 dependent immune response of macrophages in vitro, including the activation of nuclear factor-κB, mitogen-activated protein kinase pathways, and secretion of specific cytokines such as TNF-α, IL-6, IL-1ß and IL-12p40. In summary, our study indicated that α-1,6-mannose backbone is critical for the pathogenesis of C. albicans via shielding ß-glucan from recognition by host Dectin-1 mediated immune recognition. Moreover, our work suggests that inhibition of α-1,6-mannose extension by Mnn10 may represent a novel modality to reduce the pathogenicity of C. albicans.

Aging-related Atg5 defect impairs neutrophil extracellular traps formation.

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.

Enhancement in Tonically Active Glutamatergic Inputs to the Rostral Ventrolateral Medulla Contributes to Neuropathic Pain-Induced High Blood Pressure.

Neuropathic pain increases the risk of cardiovascular diseases including hypertension with the characteristic of sympathetic overactivity. The enhanced tonically active glutamatergic input to the rostral ventrolateral medulla (RVLM) contributes to sympathetic overactivity and blood pressure (BP) in cardiovascular diseases. We hypothesize that neuropathic pain enhances tonically active glutamatergic inputs to the RVLM, which contributes to high level of BP and sympathetic outflow. Animal model with the trigeminal neuropathic pain was induced by the infraorbital nerve-chronic constriction injury (ION-CCI). A significant increase in BP and renal sympathetic nerve activity (RSNA) was found in rats with ION-CCI (BP, n = 5, RSNA, n = 7, p < 0.05). The concentration of glutamate in the RVLM was significantly increased in the ION-CCI group (n = 4, p < 0.05). Blockade of glutamate receptors by injection of kynurenic acid into the RVLM significantly decreased BP and RSNA in the ION-CCI group (n = 5, p < 0.05). In two major sources (the paraventricular nucleus and periaqueductal gray) for glutamatergic inputs to the RVLM, the ION-CCI group (n = 5, p < 0.05) showed an increase in glutamate content and expression of glutaminase 2, vesicular glutamate transporter 2 proteins, and c-fos. Our results suggest that enhancement in tonically active glutamatergic inputs to the RVLM contributes to neuropathic pain-induced high blood pressure.

Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation.

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome after hemorrhagic shock (HS) resulting from major surgery and trauma. The increased susceptibility in HS patients to the development of ALI suggests not yet fully elucidated mechanisms that enhance proinflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AMϕ) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMNs) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMNs regulating AMϕ anti-inflammatory mechanisms involving autophagy. Using a mouse "two-hit" model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide, we demonstrate that HS initiates high mobility group box 1/TLR4 signaling, which upregulates NOD2 expression in AMϕ and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, upregulated NOD2 signaling induces autophagy in AMϕ, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AMϕ, possibly through NAD(P)H oxidase-mediated signaling to enhance I-κB kinase γ phosphorylation, NF-κB activation, and nucleotide-binding oligomerization domain protein 3 inflammasome activation, and therefore augment post-HS lung inflammation. These findings explore a previously unidentified complexity in the mechanisms of ALI, which involves cell-cell interaction and receptor cross talk.

Perioperative angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers for preventing mortality and morbidity in adults.

BACKGROUND: Perioperative hypertension requires careful management. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) have shown efficacy in treating hypertension associated with surgery. However, there is lack of consensus about whether they can prevent mortality and morbidity. OBJECTIVES: To systematically assess the benefits and harms of administration of ACEIs or ARBs perioperatively for the prevention of mortality and morbidity in adults (aged 18 years and above) undergoing any type of surgery under general anaesthesia. SEARCH METHODS: We searched the current issue of the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 12), Ovid MEDLINE (1966 to 8 December 2014), EMBASE (1980 to 8 December 2014), and references of the retrieved randomized trials, meta-analyses, and systematic reviews. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing perioperative administration of ACEIs or ARBs with placebo in adults (aged 18 years and above) undergoing any type of surgery under general anaesthesia. We excluded studies in which participants underwent procedures that required local anaesthesia only, or participants who had already been on ACEIs or ARBs. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, assessed the risk of bias, and extracted data. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included seven RCTs with a total of 571 participants in the review. Two of the seven trials involved 36 participants undergoing non-cardiac vascular surgery (infrarenal aortic surgery), and five involved 535 participants undergoing cardiac surgery, including valvular surgery, coronary artery bypass surgery, and cardiopulmonary bypass surgery. The intervention was started from 11 days to 25 minutes before surgery in six trials and during surgery in one trial. We considered all seven RCTs to carry a high risk of bias. The effects of ACEIs or ARBs on perioperative mortality and acute myocardial infarction were uncertain because the quality of the evidence was very low. The risk of death was 2.7% in the ACEIs or ARBs group and 1.6% in the placebo group (risk ratio (RR) 1.61; 95% confidence interval (CI) 0.44 to 5.85). The risk of acute myocardial infarction was 1.7% in the ACEIs or ARBs group and 3.0% in the placebo group (RR 0.55; 95% CI 0.14 to 2.26). ACEIs or ARBs may improve congestive heart failure (cardiac index) perioperatively (mean difference (MD) -0.60; 95% CI -0.70 to -0.50, very low-quality evidence). In terms of rate of complications, there was no difference in perioperative cerebrovascular complications (RR 0.48; 95% CI 0.18 to 1.28, very low-quality evidence) and hypotension (RR 1.95; 95% CI 0.86 to 4.41, very low-quality evidence). Cardiac surgery-related renal failure was not reported. ACEIs or ARBs were associated with shortened length of hospital stay (MD -0.54; 95% CI -0.93 to -0.16, P value = 0.005, very low-quality evidence). These findings should be interpreted cautiously due to likely confounding by the clinical backgrounds of the participants. ACEIs or ARBs may shorten the length of hospital stay, (MD -0.54; 95% CI -0.93 to -0.16, very low-quality evidence) Two studies reported adverse events, and there was no evidence of a difference between the ACEIs or ARBs and control groups. AUTHORS' CONCLUSIONS: Overall, this review did not find evidence to support that perioperative ACEIs or ARBs can prevent mortality, morbidity, and complications (hypotension, perioperative cerebrovascular complications, and cardiac surgery-related renal failure). We found no evidence showing that the use of these drugs may reduce the rate of acute myocardial infarction. However, ACEIs or ARBs may increase cardiac output perioperatively. Due to the low and very low methodology quality, high risk of bias, and lack of power of the included studies, the true effect may be substantially different from the observed estimates. Perioperative (mainly elective cardiac surgery, according to included studies) initiation of ACEIs or ARBs therapy should be individualized.

Single dose intra-articular morphine for pain control after knee arthroscopy.

BACKGROUND: Knee arthroscopy is a common procedure and is associated with postoperative pain. Intra-articular (IA) injection of morphine for pain control has been widely studied, but its analgesic effect after knee arthroscopy is uncertain. OBJECTIVES: To evaluate the relative effects on pain relief and adverse events of IA morphine given for pain control after knee arthroscopy compared with placebo, other analgesics (local anaesthetics, non-steroidal anti-inflammatory drugs (NSAIDs), other opioids) and other routes of morphine administration. SEARCH METHODS: We searched CENTRAL (The Cochrane Library Issue 4, 2015), MEDLINE via Ovid (January 1966 to May 2015), EMBASE via Ovid (January 1988 to May 2015), and the reference lists of included articles. We also searched the metaRegister of controlled trials, clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials. SELECTION CRITERIA: We identified all the randomised, double-blind controlled trials that compared single dose IA morphine with other interventions for the treatment of postoperative pain after knee arthroscopy. We excluded studies with fewer than 10 participants in each group, using spinal or epidural anaesthesia, or assessing the analgesic effect of IA morphine on chronic pain. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the quality of each trial and extracted information on pain intensity, supplementary analgesics consumption and adverse events. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables. MAIN RESULTS: We included 28 small, low quality studies (29 reports) involving 2564 participants. Of 20 studies (21 reports) comparing morphine with placebo, nine studies with adequate data were included in the meta-analysis. Overall, the risk of bias was unclear. Overall, the quality of the evidence assessed using GRADE was low to very low, downgraded primarily due to risk of bias, small study size, and imprecision.No statistical difference was found between 1 mg IA morphine and placebo in pain intensity (visual analogue scale (VAS)) at early phase (zero to two hours) (mean difference (MD) -0.50, 95% CI -1.15 to 0.14; participants = 297; studies = 7; low quality evidence), medium phase (two to six hours) (MD -0.47, 95% CI -1.09 to 0.14; participants = 297; studies = 7; low quality evidence) and late phase (six to 30 hours) (MD -0.88, 95% CI -1.81 to 0.04; participants = 297; studies = 7; low quality evidence). No significant difference was found between 1 mg and 2 mg morphine for pain intensity at early phase (MD -0.56, 95% CI -1.93 to 0.81; participants = 105; studies = 2; low quality evidence), while 4 mg/5 mg morphine provided better analgesia than 1 mg morphine at late phase (MD 0.67, 95% CI 0.08 to 1.25; participants = 97; studies = 3; low quality evidence). IA morphine was not better than local anaesthetic agents at early phase (MD 1.43, 95% CI 0.49 to 2.37; participants = 248; studies = 5; low quality evidence), NSAIDs at early phase (MD 0.95, 95% CI -0.95 to 2.85; participants = 80; studies = 2; very low quality evidence), sufentanil, fentanyl or pethidine for pain intensity. IA morphine was similar to intramuscular (IM) morphine for pain intensity at early phase (MD 0.21, 95% CI -0.48 to 0.90; participants = 72; studies = 2; very low quality evidence).Meta-analysis indicated that there was no difference between IA morphine and placebo or bupivacaine in time to first analgesic request. Eleven out of 20 studies comparing morphine with placebo reported adverse events and no statistical difference was obtained regarding the incidence of adverse events (risk ratio (RR) 1.09, 95% CI 0.51 to 2.36; participants = 314; studies = 8; low quality evidence). Seven of 28 studies reported participants' withdrawal. There were not enough data for withdrawals to be able to perform meta-analysis. AUTHORS' CONCLUSIONS: We have not found high quality evidence that 1 mg IA morphine is better than placebo at reducing pain intensity at early, medium or late phases. No statistical difference was reported between IA morphine and placebo regarding the incidence of adverse events. The relative effects of 1 mg morphine when compared with IA bupivacaine, NSAIDs, sufentanil, fentanyl and pethidine are uncertain. The quality of the evidence is limited by high risk of bias and small size of the included studies, which might bias the results. More high quality studies are needed to get more conclusive results.

Efficacy of dexmedetomidine on postoperative shivering: a meta-analysis of clinical trials.

PURPOSE: Shivering is a frequent complication in the postoperative period. The aim of the current meta-analysis was to assess the efficacy of dexmedetomidine on postoperative shivering. METHODS: Two researchers independently searched PubMed, EMBASE and the Cochrane Central Register of Controlled Trials for controlled clinical trials. The meta-analysis was performed by Review Manager. RESULTS: Thirty-nine trials with 2,478 patients were included in this meta-analysis. Dexmedetomidine reduced postoperative shivering compared with placebo (risk ratio [RR] = 0.26; 95% confidence interval [CI]: 0.20 to 0.34), with a minimum effective dose of 0.5 µg·kg(-1) (RR = 0.36; 95% CI: 0.21 to 0.60). The anti-shivering effect can be achieved both intravenously and epidurally when administered within two hours prior to the end of surgery. The efficacy of dexmedetomidine was similar to widely used anti-shivering agents, such as fentanyl, meperidine, tramadol, clonidine and so on; however, dexmedetomidine may increase the incidence of sedation, hypotension, bradycardia and dry mouth. CONCLUSIONS: The present meta-analysis indicates that dexmedetomidine shows superiority over placebo, but not over other anti-shivering agents. Therefore, considering its high price and potential adverse events, dexmedetomidine may not be appropriate solely for the purpose of the prevention of postoperative shivering.

Chitosan aerosol inhalation alleviates lipopolysaccharide- induced pulmonary fibrosis in rats.

PURPOSE: Pulmonary fibrosis (PF) is an insidiously progressive scarring disorder of the alveoli and is associated with high mortality. Currently, therapies available are associated with restricted efficacy and side effects. This study aimed to investigate the effect of chitosan aerosol inhalation on lipopolysaccharide (LPS)-induced pulmonary remodeling and fibrosis in rats. METHODS: A rat model of PF was established by intratracheal injection of LPS (5 mg/kg). Chitosan was nebulized to rats from day 4 to 28 after LPS injection. We analyzed the effect of chitosan on LPS-induced pulmonary remodeling and fibrosis by hematoxylin-eosin staining (HE), Masson staining, and the determination of the hydroxyproline content. The expression intensities of matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed by western blots. RESULTS: Histological assessments showed that chitosan aerosol inhalation attenuated the fibrotic changes in LPS-induced PF in rats. Compared with the LPS group, the fibrosis parameters were significantly improved in the LPS + chitosan group (LCh group), although not as good as those of the control group. The expressions of MMP-3 and TIMP-1 in the LCh group were markedly less than that of the LPS group on the 28th day. CONCLUSIONS: Our findings show that chitosan aerosol inhalation inhibits the expression of MMP-3 and TIMP-1, and ameliorates LPS-induced pulmonary remodeling and fibrosis in rats.

GPX4, ferroptosis, and diseases.

GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Ferroptosis, a form of iron-dependent non-apoptotic cell death, has gained considerable attention in recent years due to its involvement in multiple pathological processes. GPX4 is closely associated with ferroptosis and functions as the primary inhibitor of this process. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases, including sepsis, nervous system diseases, ischemia reperfusion injury, cardiovascular diseases, and cancer. This review comprehensively explores the regulatory roles and impacts of GPX4 and ferroptosis in the development and progression of these diseases, with the aim of providing insights for identifying potential therapeutic strategies in the future.

The gasdermin family: emerging therapeutic targets in diseases.

The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

Supraglottic airway devices: a powerful strategy in airway management.

The escalating airway management demands of cancer patients have prompted us to continually curate airway devices, with supraglottic airway devices (SADs) playing a significant role in this regard. SADs serve as instrumental tools for maintaining an open upper airway. Since the inception of the earliest SADs in the early 1980s, an array of advanced and enhanced second-generation devices have been employed in clinical settings. These upgraded SADs integrate specific features designed to enhance positive-pressure ventilation and mitigate the risk of aspiration. Nowadays, they are extensively used in general anesthesia procedures and play a critical role in difficult airway management, pre-hospital care, and emergency medicine. In certain situations, SADs may be deemed a superior alternative to endotracheal tube (ETT) and can be employed in a broader spectrum of surgical and non-surgical cases. This review provides an overview of the current evidence, a summary of classifications, relevant application scenarios, and areas for improvement in the development or clinical application of future SADs.

Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials.

INTRODUCTION: The ideal measures to prevent postoperative delirium remain unestablished. We conducted this systematic review and meta-analysis to clarify the significance of potential interventions. METHODS: The PRISMA statement guidelines were followed. Two researchers searched MEDLINE, EMBASE, CINAHL and the Cochrane Library for articles published in English before August 2012. Additional sources included reference lists from reviews and related articles from 'Google Scholar'. Randomized clinical trials (RCTs) on interventions seeking to prevent postoperative delirium in adult patients were included. Data extraction and methodological quality assessment were performed using predefined data fields and scoring system. Meta-analysis was accomplished for studies that used similar strategies. The primary outcome measure was the incidence of postoperative delirium. We further tested whether interventions effective in preventing postoperative delirium shortened the length of hospital stay. RESULTS: We identified 38 RCTs with interventions ranging from perioperative managements to pharmacological, psychological or multicomponent interventions. Meta-analysis showed dexmedetomidine sedation was associated with less delirium compared to sedation produced by other drugs (two RCTs with 415 patients, pooled risk ratio (RR)=0.39; 95% confidence interval (CI)=0.16 to 0.95). Both typical (three RCTs with 965 patients, RR=0.71; 95% CI=0.54 to 0.93) and atypical antipsychotics (three RCTs with 627 patients, RR=0.36; 95% CI=0.26 to 0.50) decreased delirium occurrence when compared to placebos. Multicomponent interventions (two RCTs with 325 patients, RR=0.71; 95% CI=0.58 to 0.86) were effective in preventing delirium. No difference in the incidences of delirium was found between: neuraxial and general anesthesia (four RCTs with 511 patients, RR=0.99; 95% CI=0.65 to 1.50); epidural and intravenous analgesia (three RCTs with 167 patients, RR=0.93; 95% CI=0.61 to 1.43) or acetylcholinesterase inhibitors and placebo (four RCTs with 242 patients, RR=0.95; 95% CI=0.63 to 1.44). Effective prevention of postoperative delirium did not shorten the length of hospital stay (10 RCTs with 1,636 patients, pooled SMD (standard mean difference)=-0.06; 95% CI=-0.16 to 0.04). CONCLUSIONS: The included studies showed great inconsistencies in definition, incidence, severity and duration of postoperative delirium. Meta-analysis supported dexmedetomidine sedation, multicomponent interventions and antipsychotics were useful in preventing postoperative delirium.

Butorphanol prevents morphine-induced pruritus without increasing pain and other side effects: a systematic review of randomized controlled trials.

PURPOSE: Pruritus is a frequent adverse event after administration of morphine. Butorphanol has been used to prevent morphine-induced pruritus, but its efficacy is still controversial. The aim of this systematic review was to evaluate the efficacy of using butorphanol to prevent morphine-induced pruritus. SOURCE: We searched PubMed, Cochrane Library, EMBASE, and China's BioMedical Disc for full reports of randomized controlled trials that compared the use of butorphanol with either placebo or no treatment for preventing morphine-induced pruritus. The number of patients experiencing pruritus or other side effects was analyzed using relative risk (RR) with 95% confidence intervals (CI). PRINCIPAL FINDINGS: Sixteen trials (795 patients) were analyzed. Continuous intravenous and epidural butorphanol reduced pruritus with RR 0.22 (95% CI 0.10 to 0.45) and RR 0.24 (95% CI 0.16 to 0.36), respectively. Use of epidural butorphanol decreased the number of patients requesting rescue treatment for pruritus (RR 0.57; 95% CI 0.41 to 0.81). Butorphanol decreased postoperative pain intensity at four, eight, and 12 hr with standardized mean differences of -0.29 (95% CI -0.52 to -0.05), -0.30 (95% CI -0.56 to -0.04), and -0.23 (95% CI -0.46 to -0.01), respectively. Epidural but not intravenous butorphanol reduced postoperative nausea and vomiting (PONV) (RR 0.35; 95% CI 0.19 to 0.66). Butorphanol did not increase respiratory depression (RR 0.71; 95% CI 0.31 to 1.63), somnolence (RR 0.71; 95% CI 0.22 to 2.37), or dizziness (RR 2.45; 95% CI 0.35 to 17.14). CONCLUSION: Butorphanol administered with morphine may be an effective strategy for preventing morphine-induced pruritus as it decreases pain intensity and PONV without increasing other side effects. Thus, it can be recommended for preventing morphine-induced pruritus during the perioperative period.

UFL1 promotes antiviral immune response by maintaining STING stability independent of UFMylation.

The precise regulation of STING homeostasis is essential for its antiviral function. Post-translational modification, especially ubiquitination, is important for the regulation of STING homeostasis. Previous studies have focused on how STING is degraded, but little is known about its maintenance. Here, we show that UFM1 specific ligase UFL1 promotes innate immune response by maintaining STING expression independent of UFMylation. Mechanistically, UFL1 inhibits TRIM29 to interact with STING, thereby reducing its ubiquitination at K338/K347/K370 and subsequent proteasomal degradation. DNA virus infection reduces the UFL1 expression, which may promote STING degradation and facilitate viral expansion. Our study identifies UFL1 as a crucial regulator for the maintenance of STING stability and antiviral function, and provides novel insights into the mechanistic explanation for the immunological escape of DNA virus.

Autologous transplantation of peripheral blood-derived circulating endothelial progenitor cells attenuates endotoxin-induced acute lung injury in rabbits by direct endothelial repair and indirect immunomodulation.

BACKGROUND: Studies have demonstrated the role of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function and in endothelial repairing. This study was aimed to observe the protective effects of autologous transplantation of circulating EPCs against endotoxin-induced acute lung injury in rabbits and to investigate the underlying mechanisms. METHODS: One-hundred-and-fifty rabbits were enrolled. After acute lung injury was induced by endotoxin, autologous circulating EPCs, endothelial cell, or normal saline were transfused intravenously, respectively. Pao(2)/FiO(2) ratios, concentrations of plasma nitric oxide, malonyldialdehyde, and activity of superoxide dismutase were examined. The lung wet-to-dry weight ratios were counted; polymorphonuclear cell ratios and areas of hyaline membrane formation and hemorrhage were measured. The levels of interleukin-1ß, E-selectin, intercellular adhesion molecule-1, interleukin-10, vascular endothelial growth factor protein, and inducible nitric oxide synthase protein were analyzed. RESULTS: Pao(2)/FiO(2) ratios were significantly increased with EPC transfusion. Infiltration of polymorphonuclear cells, lung wet-to-dry weight ratios, and area of hyaline membrane and hemorrhage in lung tissue were significantly decreased after EPC transplantation. Plasma level of nitric oxide and malondialdehyde were significantly inhibited, and the activity of superoxide dismutase was enhanced in the EPC-treated animals. EPC transplantation significantly increased level of interleukin-10 and vascular endothelial growth factor protein and reduced levels of interleukin-1ß, E-selectin, intercellular adhesion molecule-1, and inducible nitric oxide synthase in injury lung tissues. CONCLUSIONS: Autologous transplantation of circulating EPCs can partly restore the pulmonary endothelial function and effectively attenuate endotoxin-induced acute lung injury by direct endothelial repair and indirect immunomodulation of antioxidation and antiinflammation.

Antihypertensive effects and safety of eprosartan: a meta-analysis of randomized controlled trials.

PURPOSE: The benefits of reducing blood pressure (BP) have been well established, but uncertainty remains about the comparative effects of different BP-lowering regimens. We aimed to estimate the efficacy and the tolerability of eprosartan compared with other agents as monotherapy. METHODS: PubMed, EMBASE, and Cochrane Library were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager and Stata/SE. RESULTS: Twenty-two articles were ultimately included out of 78 studies, involving 6,460 patients. Eprosartan had a greater systolic blood pressure (SBP) reduction than placebo [weighted mean difference (WMD): 6.55, 95% confidence interval (CI) 4.86-8.25] and losartan (WMD: 2.24, 95% CI 0.08-4.40) and a greater diastolic blood pressure (DBP) reduction than placebo (WMD 3.95, 95% CI 2.77-5.13). Therapeutic response rate of BP favored eprosartan [risk ratio (RR) 1.13, 95% CI 1.03-1.24] compared with enalapril. There were no statistical differences in SBP or DBP reductions comparing eprosartan with enalapril or telmisartan. Original RCTs included comparing eprosartan with valsartan and nitrendipine reported no differences in BP-lowering efficacy. CONCLUSIONS: Eprosartan monotherapy is equivalent to many first-line antihypertensive agents and is effective for the treatment of essential hypertension, especially for isolated systolic hypertension. The favorable efficacy and tolerability make eprosartan worthwhile to be taken into consideration by physicians.

Postreperfusion syndrome during orthotopic liver transplantation: a single-center experience.

BACKGROUND: Marked hemodynamic alteration, commonly referred to as postreperfusion syndrome (PRS), often occurs after revascularization of the donor organ during orthotopic liver transplantation (OLT) and is associated with poor outcomes. This study aimed to investigate the incidence, predictive factors and clinical outcomes of PRS in Chinese patients following OLT at a liver transplantation center in China. METHODS: Over a 5-year period, 330 consecutive patients who had undergone OLT for hepatocellular carcinoma or cirrhosis were included in this retrospective study. PRS was defined as a >30% decrease in the mean arterial pressure compared with that before revascularization for more than 1 minute during the first 5 minutes of graft reperfusion. The patients were divided into 2 groups according to the development of PRS: group 1 (patients with PRS, n=56) and group 2 (patients without PRS, n=274). The demographic characteristics, operative and postoperative courses, and outcomes of the patients were analyzed using SPSS version 18.0. RESULTS: Multivariate regression analysis showed that left ventricular diastolic dysfunction determined by echocardiography and prolonged cold ischemia time were the independent risk factors for PRS. More patients in group 1 showed postoperative renal dysfunction than those in group 2 (19.23% vs 8.4%). Moreover, patients in group 1 also had higher intraoperative (7.14% vs 0%) and postoperative mortalities (26.92% vs 12.04%). CONCLUSION: Left ventricular diastolic dysfunction and prolonged cold ischemia time contribute to a high incidence of PRS, which is associated with adverse outcomes in Chinese patients following OLT.

Application of "twelve-step" approach based on SEEKflex for difficult awake tracheal intubation in patients with cervical spinal tumor.

Difficult airway always occurs in patients with cervical spinal tumor. Awake tracheal intubation (ATI) is usually a primary safe approach for clinical doctors in these intractable difficult airways. It is of great significance to establish specific strategies to reduce related acute airway accidents. A novel "twelve-step" approach of awake tracheal intubation based on an improved introducer (Safe Easy Endotracheal Kit-flexible, "SEEKflex") was developed and practiced in model successfully. Patients with cervical spinal tumor in a single tertiary hospital were chosen to secure airway with this approach. Primary outcomes were safety and feasibility, defined as completion of ATI without serious adverse events, Secondary outcome was the first intubation attempt rate, total intubation time, satisfaction of patients in the whole process and relevant complications. We performed awake tracheal intubation with this approach to solve the difficult airway in five patients with cervical spinal tumor. The courses went successfully in all patients without any relevant complications. This novel "twelve-step" approach based on SEEKflex for ATI can be considered as one of optional safe choices for difficult airway in patients with cervical spinal tumor.

Development of endotracheal intubation devices for patients with tumors.

The incidence and mortality of malignant tumors are rapidly increasing in the world. Patients with malignant tumors often need surgery for treatment. Endotracheal intubation is a necessary technique for surgical patients undergoing general anesthesia. It is also an important procedure for critically ill patients in the emergency room or ICU. Most patients with head and neck tumors and some specific patients have difficult airways, so the operator may need to use a variety of intubation devices. The commonly used devices for endotracheal intubation include endotracheal tube, direct laryngoscope, video laryngoscope, introducer, optical stylet, fiberoptic bronchoscope. With the advancement in science and technology, the endotracheal intubation devices have been improved, and new devices have been developed. These devices are safer and more feasible in clinical practice. In this review, we summarized the features and applications of some of the currently used devices. Each device has its own uniqueness and meets different needs. The devices and their respective properties are strongly suggested to be mastered by the anesthesiologists as well as related staffs, so as to select the appropriate device for intubation.