Novel dose-dependent alterations in excitatory GABA during embryonic development associated with lead (Pb) neurotoxicity

Lead (Pb) is a heavy metal that is toxic to numerous physiological processes. Its use in industrial applications is widespread and results in an increased risk of human environmental exposure. The central nervous system (CNS) is most sensitive to Pb exposure during early development due to rapid cell proliferation and migration, axonal growth, and synaptogenesis. One of the key components of CNS development is the Gamma-aminobutyric acid (GABA)-ergic system. GABA is the primary inhibitory neurotransmitter in the adult brain. However, during development GABA acts as an excitatory neurotrophic factor which contributes to these cellular processes. Multiple studies report effects of Pb on GABA in the mature brain; however, little is known regarding the adverse effects of Pb exposure on the GABAergic system during embryonic development. To characterize the effects of Pb on the GABAergic system during development, zebrafish embryos were exposed to 10, 50, or 100 ppb Pb or a control treatment. Tissue up-take, gross morphological alterations, gene expression, and neurotransmitter levels were analyzed. Analysis revealed that alterations in gene expression throughout the GABAergic system and GABA levels were dose and developmental time point specific. These data provide a framework for further analysis of the effects of Pb on the GABAergic system during the excitatory phase and as GABA transitions to an inhibitory neurotransmitter during development.     

Metabolism of KO143, an ABCG2 inhibitor

The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice. K1 is an analog of KO143 without the ester group. We found that the metabolic stability of K1 was significantly improved in HLM when compared to KO143. These data suggest that the ester group in KO143 is the major cause of the poor metabolic stability of KO143. The data from this study can be used to guide the development of KO143 analogs with better metabolic properties.     

Obstetric emergencies

For more than 60 years the Confidential Enquiries into Maternal Deaths triennial reports have helped build a picture of maternity care within the UK, highlighting not only our successes but failures in caring for women within the puerperal period. Despite most obstetric emergencies being well described and having clear management strategies and guidance, there continues to be substandard management with poor outcomes recorded and this has been highlighted within the latest triennium report. This article describes some common obstetric emergencies with which the anaesthetist will become involved. It emphasizes management related to some deficiencies identified in the Centre for Maternal and Child Enquiries report as well as highlighting a multidisciplinary approach throughout. Good communication between team members is paramount in all aspects of medical care, but this approach should be fostered routinely to ensure that rapid and appropriate decisions are made in a safe and timely manner.     

Social and economic inequalities in fatal opioid and cocaine related overdoses in Luxembourg: A case–control study

BackgroundTo investigate social and economic inequalities in fatal overdose cases related to opioid and cocaine use, recorded in Luxembourg between 1994 and 2011.MethodsCross-examination of national data from law enforcement and drug use surveillance sources and of forensic evidence in a nested case–control study design. Overdose cases were individually matched with four controls, when available, according to sex, year of birth, drug administration route and duration of drug use. 272 cases vs 1056 controls were analysed. Conditional logistic regression analysis was performed to assess the respective impact of a series of socioeconomic variables.ResultsBeing professionally active [OR = 0.66 (95% CI 0.45–0.99)], reporting salary as main legal income source [OR = 0.42 (95% CI 0.26–0.67)] and education attainment higher than primary school [OR = 0.50 (95% CI 0.34–0.73)] revealed to be protective factors, whereas the professional status of the father or legal guardian of victims was not significantly associated to fatal overdoses.ConclusionsSocioeconomic inequalities in drug users impact on the occurrence of fatal overdoses. Compared to their peers, users of illicit drugs with lower socioeconomic profiles show increased odds of dying from overdose. However, actual and self-referred socioeconomic characteristics of drug users, such as educational attainment and employment, may have a greater predictive value of overdose mortality than the parental socioeconomic status. Education, vocational training and socio-professional reintegration should be part of drug-related mortality prevention policies.     

Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05 mg/kg day is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350 μg/L is proposed using a default relative source contribution for water of 20%.     

流感嗜血菌及卡他布兰汉菌感染的临床特征与药敏分析

目的分析厦门地区流感嗜血菌和卡他布兰汉菌的临床特征及其耐药性,为临床治疗提供依据。方法对2008年1月-2012年12月分离580株流感嗜血菌和185株卡他布兰汉菌进行分析,细菌鉴定采用VITEK-2Compact全自动分析系统,药敏检测采用ATBTM HAEMO药敏条,β-内酰胺酶检测采用Cefinase纸片,数据采用WHONET 5.6软件进行分析。结果流感嗜血菌与卡他布兰汉菌主要来自儿科住院患儿,以≤4岁儿童为主,流感嗜血菌和卡他布兰汉菌的高发季节分别为春季和冬季;流感嗜血菌产β-内酰胺酶率为47.1%、流感嗜血菌对氨苄西林耐药率高达52.1%,对头孢克洛、磺胺甲噁唑/甲氧苄啶、四环素耐药率≥15.0%;流感嗜血菌的产β-内酰胺酶菌株和非产β-内酰胺酶菌株均对环丙沙星、左氧氟沙星、头孢噻肟、阿莫西林/克拉维酸的敏感率≥80.0%;卡他布兰汉菌产β-内酰胺酶率为52.9%,对氨苄西林耐药率为10.8%,其对阿莫西林/克拉维酸、氯霉素、头孢呋辛、头孢噻肟、利福平、头孢克洛、左氧氟沙星、四环素、磺胺甲噁唑/甲氧苄啶的耐药率均≤5.0%。结论流感嗜血菌和卡他布兰汉菌主要来自儿科患儿,检出率受季节变化影响;其对氨苄西林的耐药率较高;流感嗜血菌有较高的β-内酰胺酶检出率,但对临床常用药物阿莫西林/克拉维酸、四环素的敏感性较高。     

老年肺部感染患者病原菌分布及耐药性研究

目的分析老年肺部感染患者病原菌分布特点及耐药性,旨在为临床合理用药提供参考依据。方法对2011年12月-2012年12月158例老年肺部感染患者的痰标本进行细菌培养、鉴定、药物敏感试验,试验菌株均采用全自动微生物鉴定分析仪进行鉴定,药敏试验采用纸片扩散法(K-B),数据采用SPSS16.0统计软件进行分析。结果 158例老年肺部感染患者的痰标本检出144株病原菌,其中革兰阴性菌102株占70.83%,革兰阳性菌40株占27.78%,真菌2株占1.39%;革兰阴性杆菌对亚胺培南/西司他丁耐药率最低为1.96%,其次为美罗培南、哌拉西林/他唑巴坦,耐药率分别为3.92%、13.73%,革兰阳性球菌对青霉素G、红霉素、氧氟沙星的耐药率较高,分别为87.50%、80.00%、77.50%。结论及时了解病原菌的分布及耐药趋势有利于合理选择抗菌药物,制定有效治疗方案,不仅可降低老年患者感染的发生及病死率,而且能够减少耐药菌株的产生。     

多潘立酮片门诊用药评价及智能化知识库的作用

背景　多潘立酮为胃肠促动力药，自2012年起连续载入《国家基本药物》。鉴于2012-2014年加拿大、美国、英国等指出多潘立酮有导致心源性猝死及突发室性心律失常的风险，特别是年龄超过60岁、每天用药超过30 mg的患者。2016年9月，我国原国家食品药品监督管理总局（CFDA）发布了《关于修订多潘立酮制剂说明书的公告》，提出对多潘立酮说明书内容进行重新修订的要求。此后，多潘立酮生产厂家对多潘立酮说明书“不良反应、禁忌、注意事项、用法用量”等项进行修订，更新后的药品说明书载入了相关警示及风险提示内容。目的　了解多潘立酮片门诊治疗各种疾病的情况，为临床安全、合理用药提供参考。方法　选取2019年3-8月上海市闵行区吴泾社区卫生服务中心门诊医师开具的单一诊断，使用多潘立酮片的处方515张，统计患者的性别、年龄、临床诊断、用法用量等。构建契合社区医疗卫生机构用药特点的知识库智能管理系统。结果　515例使用多潘立酮片患者中，男197例（38.3%），女318例（61.7%）；年龄26~98岁，平均年龄（72.0±12.4）岁，以60 岁及以上的老年患者为主〔86.0%（443/515）〕。单一诊断涉及的疾病有19种，其中消化不良、消化性溃疡、慢性胃炎、胃食管反流病居前4位，占81.4%（419/515）。所有患者的每日剂量符合药品说明书规定。结论　门诊多潘立酮片使用基本合理。借助知识库利用信息技术能为患者用药“保驾护航”。