[The preliminary efficacy of "quadri-combination" therapy on the treatment of bladder cancer].

To investigate the safety and efficacy of "quadri-combination" therapy including maximal transurethral resection of bladder tumor (mTURBT), combined with systemic chemotherapy and immunotherapy, concurrent radiotherapy, and immune maintenance therapy. The clinical data of 8 patients with bladder cancer who could not tolerate or refused radical cystectomy at the Department of Urology, Peking University Cancer Hospital from November 2019 to October 2021 were retrospectively analyzed. There were 5 males and 3 females with a mean age of 69 years. The Eastern Cooperative Oncology Group(ECOG) score was 0 in 6 cases and 1 in 2 cases. There were 5 cases of high-grade urothelial carcinoma (1 case of T3b; 2 cases were T2; 2 cases of T1 stage, with multiple tumors and repeated recurrence), 1 case of high-grade urothelial carcinoma with carcinoma in situ (T1/Tis stage), 1 case of high-grade urothelial carcinoma with squamous differentiation (T3b stage), and 1 case of high-grade urothelial carcinoma with glandular differentiation (T2). All patients underwent "quadri-combination" therapy.The patient's tolerance, success rate of bladder preservation and prognosis were evaluated.The median follow-up time was 22.5 (12-35) months. One patient with high-grade muscle-invasive bladder cancer (T2) received mTURBT, albumin-bound paclitaxel and durvalumab combined therapy for 3 cycles, concurrent radiotherapy, and immune maintenance therapy for 18 months, and the tumor recurrence was found. The pathology was high-grade urothelial carcinoma. Salvage radical cystectomy combined with pelvic lymph node dissection is recommended. The remaining 7 patients were regularly reexamined, and no recurrence or metastasis was found.The 2-year progression-free survival rate was 80%, and the success rate of bladder preservation was 87.5%(7/8). Treatment-related adverse reactions were resolved by symptomatic treatment, and patients' compliance and tolerance were acceptable.The "quadri-combination" bladder-preserving therapy is feasible and well tolerated, but further studies are needed.

Recurrent ZNF83-E293V Mutation Promotes Bladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8.

Urothelial carcinoma (UC) is the predominant form of bladder cancer. Significant molecular heterogeneity caused by diverse molecular alterations brings about large variations in the response to treatment in UC. An improved understanding of the genetic mechanisms underlying the development and progression of UC is essential. Through deep analysis of next-generation sequencing data of 99 UC patients, we found that 18% of cases had recurrent somatic mutations in zinc finger protein gene zinc finger protein 83 (ZNF83). ZNF83 mutations were correlated with poor prognosis of UC. We also found a hotspot mutation, p.E293V, in the evolutionarily well-conserved region of ZNF83. ZNF83-E293V increased tumor growth and reduced the apoptosis of UC cells compared to wild-type ZNF83 both in vitro and in mice xenografted tumors. ZNF83-E293V activated nuclear factor κB (NF-κB) more potently than did the wild-type protein owing to its decreased transcriptional repression for S100A8. The NF-κB inhibitors could pharmacologically block the tumor growth in mice engrafted with ZNF83-E293V-transfected UC cells. These findings provide a mechanistic insight and a potential therapeutic strategy for UC, which established a foundation for using the ZNF83-E293V mutation as a predictive biomarker of therapeutic response from NF-κB inhibitors.

Probing the Symmetry Energy with the Spectral Pion Ratio.

Many neutron star properties, such as the proton fraction, reflect the symmetry energy contributions to the equation of state that dominate when neutron and proton densities differ strongly. To constrain these contributions at suprasaturation densities, we measure the spectra of charged pions produced by colliding rare isotope tin (Sn) beams with isotopically enriched Sn targets. Using ratios of the charged pion spectra measured at high transverse momenta, we deduce the slope of the symmetry energy to be 42

Synergistic effects ofα-Fe2O3nanoparticles and Fe-doping on gas-sensing performance of NiO nanowires and interface mechanism.

High surface area nickel oxide nanowires (NiO NWs), Fe-doped NiO NWs andα-Fe2O3/Fe-doped NiO NWs were synthesized with nanocasting pathway, and then the morphology, microstructure and components of all samples were characterized with XRD, TEM, EDS, UV-vis spectra and nitrogen adsorption-desorption isotherms. Owing to the uniform mesoporous template, all samples with the same diameter exhibit the similar mesoporous-structures. The loadedα-Fe2O3nanoparticles should exist in mesoporous channels between Fe-doped NiO NWs to form heterogeneous contact at the interface of n-typeα-Fe2O3nanoparticles and p-type NiO NWs. The gas-sensing results indicate that Fe-dopant andα-Fe2O3-loading both improve the gas-sensing performance of NiO NWs sensors.α-Fe2O3/Fe-doped NiO NWs sensors presented the highest response to 100 ppm ethanol gas (55.264) compared with Fe-doped NiO NWs (24.617) and NiO NWs sensors (3.189). The donor Fe-dopant increases the ground state resistance and the absorbed oxygen content in air.α-Fe2O3nanoparticles in electron depletion region result in the increasing resistance in ethanol gas and decreasing resistance in air. In this way,α-Fe2O3/Fe-doped NiO NWs sensor presents the excellent gas-sensing performance due to the formation of heterogeneous contact at the interface.

IL-22 Preserves Gut Epithelial Integrity and Promotes Disease Remission during Chronic Salmonella Infection.

The cytokine IL-22 is rapidly induced at barrier surfaces where it regulates host-protective antimicrobial immunity and tissue repair but can also enhance disease severity in some chronic inflammatory settings. Using the chronic Salmonella gastroenteritis model, Ab-mediated neutralization of IL-22 impaired intestinal epithelial barrier integrity and, consequently, exaggerated expression of proinflammatory cytokines. As disease normally resolved, neutralization of IL-22 caused luminal narrowing of the cecum-a feature reminiscent of fibrotic strictures seen in Crohn disease patients. Corresponding to the exaggerated immunopathology caused by IL-22 suppression, Salmonella burdens in the gut were reduced. This enhanced inflammation and pathogen clearance was associated with alterations in gut microbiome composition, including the overgrowth of Bacteroides acidifaciens Our findings thus indicate that IL-22 plays a protective role by limiting infection-induced gut immunopathology but can also lead to persistent pathogen colonization.

[Safety and efficacy of laparoscopic microwave ablation combined with partial nephrectomy for renal tumors: initial experience].

Objective: To explore the safety and efficacy of laparoscopic microwave ablation combined with partial nephrectomy in the treatment of renal tumors. Methods: The 65 patients with renal tumors undergoing laparoscopic microwave ablation combined with partial nephrectomy from November 2017 to May 2021 were retrospectively analyzed. There were 46 males and 19 females. The average age was (56.6±14.1) years. The mean body mass index was (25.7±3.3) kg/m2. The tumors located in the left kidney in 30 cases and the right kidney in 35 cases. The ECOG score was 0 in 59 patients and 1 in 6 patients. The mean maximum diameter of the tumors was (2.3±1.0) cm(1.0-5.0 cm). According to R.E.N.A.L. scoring, 41 cases were of low difficulty (4-6 points), 23 cases of medium difficulty (7-9 points) and 1 case of high difficulty (10-12 points). The renal tumors were ablated by laparoscopic microwave ablation, then followed by partial nephrectomy. Postoperative complications were observed and the prognosis was assessed by CT or MRI. Results: The mean duration of operation was (76.6±19.4) min (40-120 min). The median intraoperative blood loss was 20 ml(5-50 ml). The median duration of postoperative hospitalization was 4 d(3-6 d). Complications of Clavien grade Ⅰ were found in 11 patients (fever, nausea and vomiting, lumbar pain), and no complications were grade Ⅱ or above. Postoperative pathology showed that no positive margin was found, and 46 cases of clear cell renal cell carcinoma (AJCC stage: T1a stage 42 cases, T1b stage 4 cases; WHO/ISUP classification: 21 cases of grade 1, 23 cases of grade 2, 2 cases of grade 3); 2 cases of type 1 papillary renal cell carcinoma (stage T1a, grade 1); 1 case of type 2 papillary renal cell carcinoma (T1b stage, grade 2); 2 cases of renal chromophobe carcinoma (all stage T1a); 1 case of low-grade malignant potential multilocular cystic renal tumor; 2 cases of adenocarcinoma (combined with the postoperative history of rectal cancer, metastasis was considered); 6 cases of renal angiomyolipoma; 2 cases of eosinophiloma; 1 case of papillary adenoma; 1 case of benign renal cyst and 1 case of renal hemangioma with calcification. The median follow-up was 24 months (1-42 months). Sixty-three patients survived and two died (one due to heart disease and one due to metastatic colorectal cancer). According to postoperative imaging, there were no signs of tumor recurrence or metastasis in other cases. Blood tests were performed regularly, and no significant abnormalities occurred. Conclusions: The safety and efficacy of laparoscopic microwave ablation combined with partial nephrectomy for the treatment of renal tumor is satisfactory, such as less intraoperative bleeding, fewer complications, less effect on renal function and postoperative pathology, providing a potential option for renal tumor treatment.

Transverse Single-Spin Asymmetry for Very Forward Neutral Pion Production in Polarized p+p Collisions at sqrt[s]=510 GeV.

Transverse single-spin asymmetries of very forward neutral pions generated in polarized p+p collisions allow us to understand the production mechanism in terms of perturbative and nonperturbative strong interactions. During 2017, the RHICf Collaboration installed an electromagnetic calorimeter in the zero-degree region of the STAR detector at the Relativistic Heavy Ion Collider (RHIC) and measured neutral pions produced at pseudorapidity larger than 6 in polarized p+p collisions at sqrt[s]=510 GeV. The large nonzero asymmetries increasing both in longitudinal momentum fraction x_{F} and transverse momentum p_{T} have been observed at low transverse momentum p_{T}<1 GeV/c for the first time, at this collision energy. The asymmetries show an approximate x_{F} scaling in the p_{T} region where nonperturbative processes are expected to dominate. A non-negligible contribution from soft processes may be necessary to explain the nonzero neutral pion asymmetries.

TLR9 limits enteric antimicrobial responses and promotes microbiota-based colonisation resistance during Citrobacter rodentium infection.

Mammalian cells express an array of toll-like receptors to detect and respond to microbial pathogens, including enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC). These clinically important attaching and effacing (A/E) pathogens infect the apical surface of intestinal epithelial cells, causing inflammation as well as severe diarrheal disease. Because EPEC and EHEC are human-specific, the related murine pathogen Citrobacter rodentium has been widely used to define how hosts defend against A/E pathogens. This study explored the role of TLR9, a receptor that recognises unmethylated CpG dinucleotides present in bacterial DNA, in promoting host defence against C. rodentium. Infected Tlr9-/- mice suffered exaggerated intestinal damage and carried significantly higher (10-100 fold) pathogen burdens in their intestinal tissues as compared with wild type (WT) mice. C. rodentium infection also induced increased antimicrobial responses, as well as hyperactivation of NF-κB signalling in the intestines of Tlr9-/- mice. These changes were associated with accelerated depletion of the intestinal microbiota in Tlr9-/- mice as compared with WT mice. Notably, antibiotic-based depletion of the gut microbiota in WT mice prior to infection increased their susceptibility to the levels seen in Tlr9-/- mice. Our results therefore indicate that TLR9 signalling suppresses intestinal antimicrobial responses, thereby promoting microbiota-mediated colonisation resistance against C. rodentium infection.

Research Progress on the Relationship between Genetic Polymorphism and Violent Behavior of Patients with Schizophrenia.

ABSTRACT: Schizophrenia is a common disease characterized by thinking obstructions and accompanied by cognitive, emotional and behavioral disorders. Under the control of psychiatric symptoms, patients with schizophrenia may self-injure or impulsively wound others, resulting in public risk and increase in the burden of family and society. In recent years, many studies have shown that the violent behavior of patients with schizophrenia is related to genetic factors. This article reviews the research progress on the relationship between genetic polymorphism and violent behavior of patients with schizophrenia, analyzes the possible mechanism of the correlation between the two, puts forward the limitations of current research and the directions of future research, and provides scientific basis for risk assessment and prevention of violent behavior of patients with schizophrenia.

Substituting brown rice for white rice on diabetes risk factors in India: a randomised controlled trial.

India has the second largest number of people with type 2 diabetes (T2D) globally. Epidemiological evidence indicates that consumption of white rice is positively associated with T2D risk, while intake of brown rice is inversely associated. Thus, we explored the effect of substituting brown rice for white rice on T2D risk factors among adults in urban South India. A total of 166 overweight (BMI ≥ 23 kg/m2) adults aged 25-65 years were enrolled in a randomised cross-over trial in Chennai, India. Interventions were a parboiled brown rice or white rice regimen providing two ad libitum meals/d, 6 d/week for 3 months with a 2-week washout period. Primary outcomes were blood glucose, insulin, glycosylated Hb (HbA1c), insulin resistance (homeostasis model assessment of insulin resistance) and lipids. High-sensitivity C-reactive protein (hs-CRP) was a secondary outcome. We did not observe significant between-group differences for primary outcomes among all participants. However, a significant reduction in HbA1c was observed in the brown rice group among participants with the metabolic syndrome (-0·18 (se 0·08) %) relative to those without the metabolic syndrome (0·05 (se 0·05) %) (P-for-heterogeneity = 0·02). Improvements in HbA1c, total and LDL-cholesterol were observed in the brown rice group among participants with a BMI ≥ 25 kg/m2 compared with those with a BMI < 25 kg/m2 (P-for-heterogeneity < 0·05). We observed a smaller increase in hs-CRP in the brown (0·03 (sd 2·12) mg/l) compared with white rice group (0·63 (sd 2·35) mg/l) (P = 0·04). In conclusion, substituting brown rice for white rice showed a potential benefit on HbA1c among participants with the metabolic syndrome and an elevated BMI. A small benefit on inflammation was also observed.

Assessing somatization in urologic chronic pelvic pain syndrome.

BACKGROUND: This study examined the prevalence of somatization disorder in Urological Chronic Pelvic Pain Syndrome (UCPPS) and the utility of two self-report symptom screening tools for assessment of somatization in patients with UCPPS. METHODS: The study sample included 65 patients with UCPPS who enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Study at Washington University. Patients completed the PolySymptomatic PolySyndromic Questionnaire (PSPS-Q) (n = 64) and the Patient Health Questionnaire-15 Somatic Symptom Severity Scale (PHQ-15) (n = 50). Review of patient medical records found that only 47% (n = 30) contained sufficient documentation to assess Perley-Guze criteria for somatization disorder. RESULTS: Few (only 6.5%) of the UCPPS sample met Perley-Guze criteria for definite somatization disorder. Perley-Guze somatization disorder was predicted by definite PSPS-Q somatization with at least 75% sensitivity and specificity. Perley-Guze somatization disorder was predicted by severe (> 15) PHQ-15 threshold that had > 90% sensitivity and specificity but was met by only 16% of patients. The moderate (> 10) PHQ-15 threshold had higher sensitivity (100%) but lower specificity (52%) and was met by 52% of the sample. CONCLUSIONS: The PHQ-15 is brief, but it measures symptoms constituting only one dimension of somatization. The PSPS-Q uniquely captures two conceptual dimensions inherent in the definition of somatization disorder, both number of symptoms and symptom distribution across multiple organ systems, with relevance for UCPPS as a syndrome that is not just a collection of urological symptoms but a broader syndrome with symptoms extending beyond the urological system.

[Transurethral bipolar plasmakinetic prostatectomy for benign prostatic hyperplasia in high-risk and senior patients in China: a systematic review and meta-analysis].

Objective: To evaluate the effectiveness and safety of transurethral bipolar plasmakinetic prostatectomy in the treatment of benign prostatic hyperplasia in high-risk and senior patients in China. Methods: The PubMed, Cochrane Library, CBM, CNKI and WanFang databases were searched with computer for collecting relevant interventional case series from establishment dates to September 14, 2018. After quality evaluation and data extraction independently conducted by two authors, the Meta-analysis was performed using the Comprehensive Meta-analysis V2 software. Results: Eighteen studies involving 1 899 patients are included. Maximum flow rate increased to 12.28 ml/s (95%CI: 8.42-16.14), 12.88 ml/s (95%CI: 9.85-15.92) ,14.32 ml/s (95%CI: 10.47-18.18), 14.93 ml/s (95%CI: 10.19-19.67) and 20.00 ml/s (95%CI: 19.08-20.92) in 1, 3, 6, 12 and 24 months after surgery, respectively. International prostate symptom score decreased to -18.60 (95%CI: -23.20--14.00), -17.62 (95%CI: -20.21--15.03), -19.14 (95%CI: -20.70--17.59), -19.06 (95%CI: -21.53--16.60) and -22.90 (95%CI: -24.26--21.54), respectively. Quality of life decreased to -2.38 (95%CI: -4.26--0.50), -3.39 (95%CI: -4.57--2.21),-3.75 (95%CI: -4.14--3.36), -3.36(95%CI: -4.56--2.16), and -4.58(95%CI: -4.75--4.41). Post void residual decreased to -231.16 ml (95%CI: -288.30--174.01), -76.10 ml (95%CI: -116.71--35.50), -159.90 ml(95%CI: -207.21--112.59) and -87.70 ml (95%CI: -91.91--83.48). The event rate of postoperative adverse reactions all were not high. Conclusion: Transurethral bipolar plasmakinetic prostatectomy has better clinical efficacy and no obvious side effects in the treatment of benign prostatic hyperplasia in high-risk and senior patients in China.

Histogram analysis of stretched-exponential and monoexponential diffusion-weighted imaging models for distinguishing low and intermediate/high gleason scores in prostate carcinoma.

BACKGROUND: Noninvasive measures to evaluate the aggressiveness of prostate carcinoma (PCa) may benefit patients. PURPOSE: To assess the value of stretched-exponential and monoexponential diffusion-weighted imaging (DWI) for predicting the aggressiveness of PCa. STUDY TYPE: Retrospective study. SUBJECTS: Seventy-five patients with PCa. FIELD STRENGTH: 3T DWI examinations were performed using b-values of 0, 500, 1000, and 2000 s/mm2 . ASSESSMENT: The research were based on entire-tumor histogram analysis and the reference standard was radical prostectomy. STATISTICAL TESTS: The correlation analysis was programmed with Spearman's rank-order analysis between the histogram variables and Gleason grade group (GG). Receiver operating characteristic (ROC) regression was used to analyze the ability of these histogram variables to differentiate low-grade (LG) from intermediate/high-grade (HG) PCa. RESULTS: The percentiles and mean of apparent diffusion coefficient (ADC) and distributed diffusion coefficient (DDC) were correlated with GG (ρ: 0.414-0.593), while there was no significant relation among α value, skewnesses, and kurtosises with GG (ρ:0.034-0.323). HG tumors (ADC:484 ± 136, 592 ± 139, 670 ± 144, 788 ± 146, 895 ± 141 mm2 /s; DDC: 410 ± 142, 532 ± 172, 666 ± 193, 786 ± 196, 914 ± 181 mm2 /s) had lower values in the 10th , 25th , 50th , 75th percentiles and means than LG tumors (ADC: 644 ± 779, 737 ± 84, 836 ± 83, 919 ± 82, 997 ± 107 mm2 /s; DDC: 552 ± 82, 680 ± 94, 829 ± 112, 931 ± 106, 1045 ± 100 mm2 /s). However, there was no difference between LG and HG tumors in α value (0.671 ± 0.041 vs. 0.633 ± 0.114), kurtosises (ADC 0.09 vs. 0.086; DDC -0.033 vs. -0.317), or skewnesses (ADC -0.036 vs. 0.073; DDC -0.063 vs. 0.136). The above statistics were P < 0.01. ADC10 with AUC = 0.840 and DDC10 with AUC = 0.799 were similar in discriminating between LG and HG PCa at P < 0.05. DATA CONCLUSION: Histogram variables of DDC and ADC may predict the aggressiveness of PCa, while α value does not. The abilities of ADC10 and DDC10 to discriminate LG from HG tumors were similar, and both better than their respective means. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:491-498.

Tricellular Tight Junction Protein Tricellulin Is Targeted by the Enteropathogenic Escherichia coli Effector EspG1, Leading to Epithelial Barrier Disruption.

Enteropathogenic Escherichia coli (EPEC)-induced diarrhea is often associated with disruption of intestinal epithelial tight junctions. Although studies have shown alterations in the expression and localization of bicellular tight junction proteins during EPEC infections, little is known about whether tricellular tight junction proteins (tTJs) are affected. Using Caco-2 cell monolayers, we investigated if EPEC is capable of targeting the tTJ protein tricellulin. Our results demonstrated that at 4 h postinfection, EPEC induced a significant reduction in tricellulin levels, accompanied by a significant loss of transepithelial resistance (TEER) and a corresponding increase in paracellular permeability. Conversely, cells overexpressing tricellulin were highly resistant to EPEC-induced barrier disruption. Confocal microscopy revealed the distribution of tricellulin into the plasma membrane of infected epithelial cells and confirmed the localization of EPEC aggregates in close proximity to tTJs. Moreover, infections with EPEC strains lacking genes encoding specific type III secreted effector proteins demonstrated a crucial role for the effector EspG1 in modulating tricellulin expression. Complementation studies suggest that the EspG-induced depletion of tricellulin is microtubule dependent. Overall, our results show that EPEC-induced epithelial barrier dysfunction is mediated in part by EspG1-induced microtubule-dependent depletion of tricellulin.

[Expression and clinical significance of long non-coding RNA CCAT1 in gastric cancer].

Objective: To investigate the expression and clinical significance of long non-coding RNA colon cancer associated transcript-1 (CCAT1) in gastric cancer (GC), and to further explore the effect of CCAT1 on cell proliferation of GC. Methods: The mRNA expressions of CCAT1 in GC tissues and matched adjacent normal tissues from 62 patients who received resection for gastric carcinoma between January 2013 and May 2015 in Nanjing Medical University Affiliated Wuxi Second Hospital and expressions in GC cell lines were assessed by quantitative real-time PCR (qRT-PCR). The clinical significance of CCAT1 expression was then analyzed. The expressions of CCAT1 in MGC-803 and SGC-7901 cells were inhibited by small interfering RNA (siRNA) transfection. The effect of CCAT1 on cell proliferation was studied by cell counting kit (CCK)-8 assay. Results: The expressions of CCAT1 mRNA in GC tissues were significantly higher than in the normal tissues (3.39±2.37 vs 1.28±0.74, P<0.05). Compared with immortalized human gastric epithelial cell line (GES-1), the expressions of CCAT1 mRNA were significantly higher in GC cell lines MGC-803 and SGC-7901 (3.07±0.69, 2.23±0.32 vs 1.01±0.12, both P<0.05). Besides, the expression of CCAT1 varied significantly among patients with different TNM stage, depth of invasion, and lymph node metastasis (χ(2) =5.199, 5.395, 9.239, all P<0.05). The results of CCK-8 assay showed that down-regulation of CCAT1 in MGC-803 and SGC-7901 cells significantly inhibited the cell proliferation (both P<0.05). Conclusions: CCAT1 is up-regulated in GC and may be significantly correlated with the progression of GC. Decreased expression of CCAT1 can suppress the proliferation of GC cells. CCAT1 might be used as a novel target for GC early diagnosis and treatment.

Small Molecules for Active Targeting in Cancer.

For the purpose of this review, active targeting in cancer research encompasses strategies wherein a ligand for a cell surface receptor expressed on tumor cells is used to deliver a cytotoxic or imaging cargo. This area of research is more than two decades old, but in those 20 and more years, how many receptors have been studied extensively? What kinds of the ligands are used for active targeting? Are they mostly naturally occurring molecules such as folic acid, or synthetic substances developed in campaigns for medicinal chemistry efforts? This review outlines the most important receptor or ligand combinations that have been used in active targeting to answer these questions, and therefore to address the most important one of all: is research in active targeting affording diminishing returns, or is this an area for which the potential far exceeds progress made so far?

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.

[Therapeutic effects and related mechanisms of erythropoietin sustained-release gelatin hydrogel microspheres on a murine model of hindlimb ischemia].

OBJECTIVE: To investigate the therapeutic effects of erythropoietin sustained-release gelatin hydrogel microspheres (EPO-GHM) on a murine model of hindlimb ischemia and related mechanisms. METHODS: Fifty two ten weeks old male C57BL/6J mice were assigned to 5 groups: sham-operated group (the right femoral artery suture was passed through the right femoral artery but not tied, n=8); saline group (right femoral artery ligation and intramuscular injection of saline at a dose of 4 ml/kg into the right hind limb, n=12); EPO group(right femoral artery ligation and intramuscular injection of EPO at a dose of 5 000 IU/kg into the right hind limb, n=12), empty GHM group (right femoral artery ligation and intramuscular injection of empty GHM at a dose of 4 ml/kg into the right hind limb, n=8); EPO-GHM group(right femoral artery ligation and intramuscular injection of EPO-GHM at a dose of 5 000 IU/kg into the right hind limb, n=12). The blood flow ratio of ischemic limb (right)/nonischemic limb (left) was measured using a laser Doppler perfusion imager. After 8 weeks, immunohistochemical analysis were used to evaluate the vessel density (vessel density of CD31 positive), arteriole density(vessel density of α-smooth muscle actin(α-SMA) positive) and muscle area(HHF35 positive area). The proliferating index of vessels was evaluated by double immunofluorescent labeling to evaluate effect of EPO-GHM on angiogenesis of ischemia limb. Western blot was used to evaluate the protein expression of EPO receptor, protein kinase B(AKT), p-AKT, endothelial nitric oxide synthase(eNOS), p-eNOS and matrix metalloproteinase 2(MMP-2). RESULTS: (1) Eight weeks later, the blood flow ratio of ischemic limb/nonischemic limb was significantly higher in the EPO-GHM group compared with other groups(0.810±0.080, 0.563±0.051, 0.570±0.056 and 0.561±0.052 respectively, all P<0.05). (2) CD31 antibody positive and α-SAM antibody positive densities were higher in the EPO-GHM group compared with other groups(P<0.01 or 0.05). (3)HHF35 positive area in saline group, EPO group, empty GHM group and EPO-GHM group were smaller than that of sham-operated group(all P<0.05). HHF35 positive area in saline group, EPO group, empty GHM group and EPO-GHM group were similar(all P>0.05). (4)The proliferating index of vessels was higher in the EPO-GHM group compared with other groups(P<0.01 or 0.05). (5) Compared with other groups, the protein levels of EPO receptor, AKT, p-AKT, p-eNOS and MMP-2 were significantly higher in EPO-GHM group(P<0.01 or 0.05) and level of eNOS was similar among five groups(P>0.05). CONCLUSION: RESULTS from present study suggest EPO-GHM could improve blood perfusion of ischemia limb in mice through increasing capillary and arteriolar densities and these beneficial effects are possibly mediated by EPOR up-regulation and AKT/p-eNOS/MMP-2 signaling pathway activation.

SepD/SepL-dependent secretion signals of the type III secretion system translocator proteins in enteropathogenic Escherichia coli.

UNLABELLED: The type III protein secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE) is essential for the pathogenesis of attaching/effacing bacterial pathogens, including enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and Citrobacter rodentium. These pathogens use the T3SS to sequentially secrete three categories of proteins: the T3SS needle and inner rod protein components; the EspA, EspB, and EspD translocators; and many LEE- and non-LEE-encoded effectors. SepD and SepL are essential for translocator secretion, and mutations in either lead to hypersecretion of effectors. However, how SepD and SepL control translocator secretion and secretion hierarchy between translocators and effectors is poorly understood. In this report, we show that the secreted T3SS components, the translocators, and both LEE- and non-LEE-encoded effectors all carry N-terminal type III secretion and translocation signals. These signals all behave like those of the effectors and are sufficient for mediating type III secretion and translocation by wild-type EPEC and hypersecretion by the sepD and sepL mutants. Our results extended previous observations and suggest that the secretion hierarchy of the different substrates is determined by a signal other than the N-terminal secretion signal. We identified a domain located immediately downstream of the N-terminal secretion signal in the translocator EspB that is required for SepD/SepL-dependent secretion. We further demonstrated that this EspB domain confers SepD/SepL- and CesAB-dependent secretion on the secretion signal of effector EspZ. Our results thus suggest that SepD and SepL control and regulate secretion hierarchy between translocators and effectors by recognizing translocator-specific export signals. IMPORTANCE: Many bacterial pathogens use a syringe-like protein secretion apparatus, termed the type III protein secretion system (T3SS), to secrete and inject numerous proteins directly into the host cells to cause disease. The secreted proteins perform different functions at various stages during infection and are classified into three substrate categories (T3SS components, translocators, and effectors). They all contain secretion signals at their N termini, but how their secretion hierarchy is determined is poorly understood. Here, we show that the N-terminal secretion signals from different substrate categories all behave the same and do not confer substrate specificity. We further characterize the secretion signals of the translocators and identify a translocator-specific signal, demonstrating that substrate-specific secretion signals are required in regulating T3SS substrate hierarchy.