Early life Adversity,functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6

ObjectiveExposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity.MethodsThree-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity.ResultsHigher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: β_indirect −0.0234, 95% CI: −0.0573 to −0.0074; CTQ physical neglect: β_indirect = −0.0316, 95% CI: −0.0741 to −0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (β_indirect = −0.0618, 95% CI: −0.1523 to −0.285).ConclusionThis work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6′s association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.     

1例产后哺乳期腹泻患者分离单增李斯特菌的生物学特征分析

目的 分析1例单增李斯特菌所致产后哺乳期腹泻患者的临床特征、病原学、菌株的毒力基因携带及分子特征。方法 搜集病例的临床相关信息;采用选择性增菌和显色培养基分离单增李斯特菌,用VITEK- 2 COMPACT30 全自动细菌分析仪鉴定分离菌株,采用单增李斯特菌诊断血清对分离株进行血清分型,使用脉冲场凝胶电泳技术及多位点序列分型技术进行分子分型,应用PCR检测毒力基因,并用E-test方法检测分离菌株对5种抗生素的药物敏感性。结果 产后哺乳期患者食用甜瓜和冰箱冷藏的酸奶后引起不能自限的腹泻,检测结果证实病原为4b血清型、ST145序列型单增李斯特菌。分离菌株携带毒力基因plcB、act、hly、iap、prfA、inlA,对青霉素、氨苄西林、美罗培南、红霉素和复方磺胺均敏感。结论 单增李斯特菌引起的腹泻患者容易漏诊,加强孕妇等高危人群腹泻患者粪便标本中单增李斯特菌的检测,对于单增李斯特菌病病人的及时治疗,预防不良预后具有重要的公共卫生意义,尤其对这一特殊型别单增李斯特菌在我国引起的病例感染应引起重视,其可能的感染来源和致病风险值得进一步的研究。     

A case of listerial meningitis treated with a regimen containing panipenem-betamipron

Although panipenem-betamipron, which is commercially available only in Japan, is recommended for treatment of pediatric bacterial meningitis by some experts, only a limited number of clinical studies have been reported. In the present report, we describe a 2-year-old boy with meningitis caused by Listeria monocytogenes who was treated with a regimen containing panipenem-betamipron and recovered without any apparent neurological sequelae. On the basis of our experience and previous reports, panipenem-betamipron appears to be effective for the treatment of listerial meningitis.     

Drastic Therapy for Listerial Brain Abscess Involving Combined Hyperbaric Oxygen Therapy and Antimicrobial Agents

Background

Listeria monocytogenes (L. monocytogenes) is a rare causative pathogen of brain abscess that is often found in immunocompromised patients. Although patients with supratentorial listerial abscesses showed a longer survival with surgical drainage, the standard therapy for patients with subtentorial lesions has not been established.

Case Report

We report herein a patient with supra- and subtentorial brain abscesses caused by L. monocytogenes infection. These abscesses did not respond to antibiotics, and his symptoms gradually worsened. Drainage was not indicated for subtentorial lesions, and the patient was additionally treated with hyperbaric oxygen therapy, which dramatically reduced the volume of abscesses and improved the symptoms.

Conclusions

This is the first report of drastic therapy for a patient with listerial brain abscesses involving combined antibiotics and hyperbaric oxygen therapy. The findings suggest that hyperbaric oxygen therapy is a good option for treating patients with deep-seated listerial abscesses and for who surgical drainage is not indicated.     

IFN‐γ protects from apoptotic neutrophil‐mediated tissue injury during acute Listeria monocytogenes infection

Listeria monocytogenes (LM) is a foodborne Gram‐positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN‐γ‐producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN‐γ. IFN‐γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng^?/? mice. Moreover, IFN‐γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM‐induced neutrophil apoptosis and spleen damage. In addition to this, IFN‐γ could effectively drive macrophage‐mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF‐β secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN‐γ at the early stage of LM infection, which is characterized by both LM elimination and tissue‐protective effects.     

Treatment strategies for central nervous system infections: an update

Introduction: Central nervous system infection continues to be an important cause of mortality and morbidity worldwide. Our incomplete knowledge on the pathogenesis of how meningitis-causing pathogens cause CNS infection and emergence of antimicrobial resistance has contributed to the mortality and morbidity. An early empiric antibiotic treatment is critical for the management of patients with bacterial meningitis, but early recognition of bacterial meningitis continues to be a challenge.

Areas covered: This review gives an overview on current therapeutic strategies for CNS infection with a focus on recent literature since 2010 on bacterial meningitis. Bacterial meningitis is a medical emergency, requiring early recognition and treatment. The selection of appropriate empiric antimicrobial regimen, after incorporating the epidemiology of bacterial meningitis, impact of vaccination, emergence of antimicrobial-resistant bacteria, role of adjunctive therapy and the current knowledge on the pathogenesis of meningitis and associated neuronal injury are covered.

Expert opinion: Prompt treatment of bacterial meningitis with an appropriate antibiotic is essential. Optimal antimicrobial treatment of bacterial meningitis requires bactericidal agents able to penetrate the blood–brain barrier, with efficacy in cerebrospinal fluid. Emergence of CNS-infecting pathogens with resistance to conventional antibiotics has been increasingly recognized, but development of new antibiotics has been limited. More complete understanding of the microbial and host factors that are involved in the pathogenesis of bacterial meningitis and associated neurologic sequelae is likely to help in developing new strategies for the prevention and therapy of bacterial meningitis.     

单核细胞增生性李斯特菌溶血素基因的原核表达

目的为获得大量的单核细胞增生性李斯特氏菌（Listeria monocytogenes，Lmo）溶血素（Hemolysin，hty）蛋白，以便研制Lmo诊断试剂及其在疫苗研制方面的作用。方法本文应用Primer Premier5．00设计引物，引入13amHI和x幻工酶切位点。以前期合成构建的pMDl8-T-hly质粒为模板，通过PCR方法扩增出Lmo0586株溶血素基因。相应酶切后，克隆到原核表达载体pGEX-6p-1中，构建pGEX-6p-hly重组质粒，转化入大肠杆菌BL21（DE3）进行表达。带有重组质粒pGEX-6p-hly的大肠杆菌BL21（DE3）经IPTG诱导后，进行SDS-PAGE及免疫印记分析。结果PCR体外扩增hly基因产物大小约为1624bp，成功构建了重组表达质粒pGEX-6p—hly；SDS-PAGE显示蛋白表达带的分子量约为72ku，重组蛋白主要以包涵体形式表达。表达量占菌体总蛋白的20．8％；Western免疫印记表明具有良好的反应原性。结论在国内首次构建重组质粒pGEX-6p-hly，并以融合蛋白的形式进行了高效表达，同时该蛋白具有特异的抗原反应性，为研制Lmo诊断试剂及其在疫苗研制中的作用奠定了基础。     

Microglial activation and expression of immune‐related genes in a rat ex vivo nervous system model after infection with Listeria monocytogenes

A wide variety of microorganisms has previously been identified as causes of brain infection. Among them, Listeria monocytogenes has a particular tropism for the central nervous system. To gain knowledge about the immune response elicited by L. monocytogenes in the brain, we used a rat ex vivo organotypic nervous system culture as a model for Listeria infection. Scanning electron microscopy (SEM) revealed that activated microglial cells showing a typical amoeboid morphology are quickly recruited to the surface of the explants after the infection. After bacterial engulfment, these cells appear to act as Trojan horses, releasing the engulfed bacteria inside the brain tissue. We describe cycles of microglial phagocytosis, necrotic cell death and the subsequent removal of cell debris for the first time. Furthermore, we used this ex vivo model to assess the expression profiles of immune relevant genes up to 24 h postinfection by means of q‐PCR‐arrays, finding that a number of inflammation‐promoting genes are upregulated. Shortly after infection by L. monocytogenes, upregulated genes were those that encoded molecules involved in Th1 responses, being the Ccl2 chemokine and members of the interleukin1‐β family the most abundant immunomodulatory signals expressed. After 5 h of infection, L. monocytogenes caused a substantial increase in the expression of TLR1 and TLR2 genes, as well as in several downstream genes of the TLR signaling pathways. © 2013 Wiley Periodicals, Inc.     

北京市昌平区2010-2015年市售食品中单核细胞增生李斯特菌污染状况分析

目的 了解北京市昌平区市售食品中单核细胞增生李斯特菌污染状况,为政府部门有效监管提供技术支持。 方法 2010-2015年,在辖区内农贸市场、超市/便利店和餐饮单位抽取12类368件食品样品进行单核细胞增生李斯特菌检测。 结果 368件食品样品中检出单核细胞增生李斯特菌16株,总检出率为4.35%。其中,不同类别食品中生禽肉检出率最高(25.71%),其次是生畜肉(11.11%)和鲜冻水产品(6.67%);各季度样品中三季度样品检出率最高(7.41%),其次是二季度(4.11%),一、四季度样品未检出;农贸市场、超市/便利店和餐饮单位等不同销售场所样品检出率分别为4.85%、4.11%和4.20%。 结论 2010-2015年北京市昌平区市售生禽肉、生畜肉和鲜冻水产品存在单核细胞增生李斯特菌污染,且以三季度污染较为突出。     

Bacterial hepatocyte growth factor receptor agonist stimulates hepatocyte proliferation and accelerates liver regeneration in a partial hepatectomy rat model

Hepatocyte growth factor (HGF) is central to liver regeneration. The Internalin B (InlB) protein is a virulence factor produced by the pathogenic bacterium Listeria monocytogenes. InlB is known to mimic HGF activity by interacting with the HGF receptor (HGFR) and activating HGFR‐controlled signaling pathways. We expressed and purified the HGFR‐binding InlB domain, InlB321/15, cloned from the fully virulent clinical L. monocytogenes strain. HGFR and Erk1/2 phosphorylation was determined using Western blotting. The capacity of InlB321/15 to bind HGFR was measured using microscale thermophoresis. Liver regeneration was studied in a model of 70% partial hepatectomy (70%PHx) in male Wistar rats. The nuclear grade parameters were quantified using manual (percentage of binuclear hepatocytes), automated (nuclear diameters), or combined (Ki67 proliferation index) scoring methods. Purified InlB321/15 stimulated HGFR and Erk1/2 phosphorylation and accelerated the proliferation of HepG2 cells. InlB321/15 bound HGFR with Kd = 7.4 ± 1.3 nM. InlB321/15 injected intravenously on the second, fourth, and sixth days after surgery recovered the liver mass and improved the nuclear grade parameters. Seven days post 70% PHx, the liver weight indexes were 2.9 and 2.0%, the hepatocyte proliferation indexes were 19.8 and 0.6%, and the percentages of binucleated hepatocytes were 6.7 and 4.0%, in the InlB321/15‐treated and control animals, respectively. Obtained data demonstrated that InlB321/15 improved hepatocyte proliferation and stimulated liver regeneration in animals with 70% hepatectomy.