Xenophagy in Helicobacter pylori‐ and Epstein–Barr virus‐induced gastric cancer

Helicobacter pylori and Epstein–Barr virus (EBV) account for roughly 80% and 10%, respectively, of gastric carcinomas worldwide. Autophagy is an evolutionarily conserved and intricately regulated cellular process that involves the sequestration of cytoplasmic proteins and organelles into double‐membrane autophagosomes that eventually fuse with lysosomes for degradation of the engulfed content. Emerging evidence indicates that xenophagy, a form of selective autophagy, plays a crucial role in the pathogenesis of H. pylori‐ and EBV‐induced gastric cancer. Xenophagy specifically recognizes intracellular H. pylori and EBV and physically targets these pathogens to the autophagosomal–lysosomal pathway for degradation. In this connection, H. pylori or EBV‐induced dysregulation of autophagy may be causally linked to gastric tumourigenesis and therefore can be exploited as therapeutic targets. This review will discuss how H. pylori and EBV infection activate autophagy and how these pathogens evade recognition and degradation by the autophagic pathway. Elucidating the molecular aspects of H. pylori‐ and EBV‐induced autophagy will help us better understand the pathogenesis of gastric cancer and promote the development of autophagy modulators as antimicrobial agents. Published by John Wiley & Sons, Ltd     

Phase Variation Mediates Reductions in Expression of Surface Proteins during Persistent Meningococcal Carriage

Asymptomatic and persistent colonization of the upper respiratory tract by Neisseria meningitidis occurs despite elicitation of adaptive immune responses against surface antigens. A putative mechanism for facilitating host persistence of this bacterial commensal and pathogen is alterations in expression of surface antigens by simple sequence repeat (SSR)-mediated phase variation. We investigated how often phase variation occurs during persistent carriage by analyzing the SSRs of eight loci in multiple isolates from 21 carriers representative of 1 to 6 months carriage. Alterations in repeat number were detected by a GeneScan analysis and occurred at 0.06 mutations/gene/month of carriage. The expression states were determined by Western blotting and two genes, fetA and nadA, exhibited trends toward low expression states. A critical finding from our unique examination of combinatorial expression states, “phasotypes,” was for significant reductions in expression of multiple phase-variable surface proteins during persistent carriage of some strains. The immune responses in these carriers were examined by measuring variant-specific PorA IgG antibodies, capsular group Y IgG antibodies and serum bactericidal activity in concomitant serum samples. Persistent carriage was associated with high levels of specific IgG antibodies and serum bactericidal activity while recent strain acquisition correlated with a significant induction of antibodies. We conclude that phase-variable genes are driven into lower expression states during long-term persistent meningococcal carriage, in part due to continuous exposure to antibody-mediated selection, suggesting localized hypermutation has evolved to facilitate host persistence.     

Clinical Demographics and Outcomes in Mechanically Ventilated Patients in Korean Intensive Care Units

Knowledge of clinical demographics and outcomes of mechanically ventilated patients is important but there are few prospectively collected data in Korea. The objective of the present study was to describe the current status of mechanically ventilated patients in Korea as of 2010. We analyzed the data of Korean patients (275 patients in 12 Korean intensive care units [ICU]) participating in a multinational prospective cohort study on mechanical ventilation. The most common indication for mechanical ventilation was pneumonia (23%). Pressure-limited ventilation modes were preferred over volume-cycled ventilation modes. Non-invasive positive pressure ventilation was used in only seven (2%) patients as the initial ventilatory support. Median duration of mechanical ventilation was 7 days and ICU mortality was 36%. The multiple logistic regression model revealed that the Simplified Acute Physiology Score II (SAPS II) score at ICU admission (odds ratio [OR], 1.034; 95% confidence interval [CI], 1.001-1.036; P=0.033), peak pressure (OR, 1.054; 95% CI, 1.016-1.095; P=0.006), and the number of failed organs (OR, 2.132; 95% CI, 1.634-2.781; P<0.001) were independently associated with ICU mortality. This study provides a snapshot of current practice of mechanical ventilation in Korea.

Graphical Abstract

相似文献   

Autosomal-dominant nystagmus,foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation

Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.     

Production of certified reference materials for the sports doping control of the REV‐ERB agonist SR9009

Two human metabolites of the REV‐ERB agonist SR9009, identified by researchers with an interest in sports doping control, have been synthesized and assessed for purity. The synthesis employed was a modification of published procedures for the parent SR9009, careful attention to the purification of intermediates and the final product ensuring materials of the highest purity were available for certification. For each candidate material impurities of related structure were identified and quantified as a relative mass fraction using high performance liquid chromatography–ultraviolet (HPLC–UV) detection and proton nuclear magnetic resonance (¹H NMR) spectroscopy. The quantification of water, occluded solvent, and inorganic residue was assessed using Karl Fischer, ¹H NMR, and thermogravimetric analysis, thereby completing the assessment of all impurities typically characterized by the mass balance approach. Summation and subtraction from 1000 mg/g afforded the mass fraction of the main component, the associated uncertainty ensuring certified reference material status can be applied to the resulting pure substance calibration standards. The availability of these standards to the sports doping control community will facilitate delivery of metrological traceability to the SI unit for mass (kg) to routine testing results and aid method development for the detection and quantification of SR9009 abuse.     

阻塞性睡眠呼吸暂停患者肺动脉僵硬度的评价及其与低氧的关系

目的:旨在研究阻塞性睡眠呼吸暂停患者(OSA)夜间间歇性缺氧程度对肺动脉僵硬度(PAS)和右心室功能的影响。方法:对可疑OSA的患者进行多导睡眠图(PSG)和经胸超声心动图检查(n=376)。按夜间最低脉搏血氧饱和度(SpO2)分为三组(对照组:Sp O2≥90%,轻中度低氧组:80%≤SpO2<90%,重度低氧组:SpO2<80%)。比较三组患者的PAS和右心室功能,并进一步分析其相关影响因素。结果:最终本研究对278例患者进行分析。重度低氧组PAS显著升高(P=0.003),与平均肺动脉压(mPAP)有良好的相关性(r=0.780,P<0.001),而mPAP在不同组间差异无统计学意义(P>0.05)。各组间右心室功能相关参数,差异无统计学意义(P>0.05)。单因素和多因素Logistic分析表明,只有夜间最低SpO2(OR=1.807,P=0.001)是PAS升高的相关因素。结论:在重度低氧血症的OSA患者中PAS增加,仅夜间最低SpO2是其相关因素。     

Non-alcoholic fatty liver disease in a young multiracial Asian population: a worrying ethnic predilection in Malay and Indian males

Purpose

Previous studies on multiracial Malaysian populations found inordinately high prevalence of NAFLD among Malays and Indians. Whether the prevalence of NAFLD is different among young adults of different ethnic origins is not known. We aimed to determine racial differences in NAFLD in a young multiracial Malaysian population and associated factors.

Methods

This was a cross-sectional study on medical students from the University of Malaya. Diagnosis of NAFLD was by transabdominal ultrasonography and following exclusion of significant alcohol intake and other causes of chronic liver disease.

Results

Data of 469 subjects were analyzed (mean age 23.2 ± 2.4 years, 40.3 % male). The racial distribution was: Chinese 53.9 %, Malay 30.5 % and Indian 15.6 %. The overall prevalence of NAFLD was 7.9 %. Subjects with NAFLD were older, had greater BMI and WC, higher SBP and DBP, higher FBS, serum TG and LDL levels, and lower serum HDL level. The prevalence of NAFLD was higher among males compared to females (17.9 % vs. 3.3 %, p < 0.001). The highest prevalence of NAFLD was seen among Indian and Malay males at 33.3 and 25.5 %, respectively, compared to Chinese males at 6.8 % (p < 0.001). No significant difference was seen among females of different races. Independent factors associated with NAFLD were male gender, obesity and hypertriglyceridemia.

Conclusions

The difference in prevalence of NAFLD among the different ethnic groups can be observed as early as young adulthood. An inordinately high prevalence of NAFLD was observed among Malay and Indian males consistent with the higher prevalence of obesity in these groups.     

大于80岁老年患者前列腺癌根治术随访结果和临床分析

目的 探讨大于80岁且健康状况良好的前列腺癌老年患者接受前列腺根治术的可行性。方法 回顾性分析了同济大学附属第十人民医院2012年12月—2016年3月的40例80岁及以上前列腺癌患者接受前列腺根治性切除术的相关资料。结果 40例前列腺癌患者年龄为80~86岁,平均（82.30±2.01）岁;血清前列腺特异性抗原为1.2～101.0 ng/mL,平均为（23.59±12.42） ng/mL。查尔森合并症指数（Charlson comorbidity index, CCI)评分,0分35例,1分的5例。cT1N0M0 19例,cT2N0M0 7例,cT3N0M0 14例。Gleason评分＜7分9例,Gleason评分为7分24例,Gleason评分＞7分7例。手术时间95~156min,平均（122.13±14.57） min。术后随访时间2~36个月,平均（11.03±3.61）个月。尿控恢复时间1~18个月,平均（4.26±1.65）个月。术后有5例接受雄激素剥夺治疗（androgen deprivation therapy, ADT）,7例接受ADT同时进行局部外放射疗。术后病理报告1例切缘阳性,尿道狭窄2例。结论 大于80岁且健康状况良好的前列腺癌患者接受前列腺根治术是安全可行的,同时需要在手术获益和手术风险之间进行综合考虑。