Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates

Ecotoxicology - Exposure patterns in ecotoxicological experiments often do not match the exposure profiles for which a risk assessment needs to be performed. This limitation can be overcome by...     

Enzymatic synthesis of glucuronidated metabolites of two neurological active agents using plant glucuronosyltransferases

Abstract

Glucuronidation is an important and popular metabolic reaction in vivo of drugs. The further evaluation of biological activity and toxicity of glucuronides is necessary in the course of the drug research and development. However, the synthesis of glucuronides is limited by the lack of efficient approach. Herein, we have developed a new glucuronide synthesis method using plant uridine diphosphate-dependent glucuronosyltransferases (UGTs), UGT88D4, UGT88D7, and EpGT8, enabling the convenient preparation for corresponding O-glucuronide metabolites (1a, 2a, 3a, and 3b) in milligram scale of two neurological active agents, IMM-H004 (1) and FLZ (2). Their structures were characterized by spectroscopic data analyses.     

Application of prioritization approaches to optimize environmental monitoring and testing of pharmaceuticals

Pharmaceuticals are ubiquitous in the natural environment with concentrations expected to rise as human population increases. Environmental risk assessments are available for a small portion of pharmaceuticals in use, raising concerns over the potential risks posed by other drugs that have little or no data. With >1900 active pharmaceutical ingredients in use, it would be a major task to test all of the compounds with little or no data. Desk-based prioritization studies provide a potential solution by identifying those substances that are likely to pose the greatest risk to the environment and which, therefore, need to be considered a priority for further study. The aim of this review was to (1) provide an overview of different prioritization exercises performed for pharmaceuticals in the environment and the results obtained; and (2) propose a new holistic risk-based prioritization framework for drugs in the environment. The suggested models to underpin this framework are discussed in terms of validity and applicability. The availability of data required to run the models was assessed and data gaps identified. The implementation of this framework may harmonize pharmaceutical prioritization efforts and ensure that, in the future, experimental resources are focused on molecules, endpoints, and environmental compartments that are biologically relevant.     

Extracellular vesicles released in response to respiratory exposures: implications for chronic disease

Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter-based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies.     

Chemical constituents from Canarium album Raeusch and their anti-influenza A virus activities

Journal of Natural Medicines - Two new dyhydrophaseic acid glucoside isomers, (1′S, 3′R, 5′S, 8′R, 2Z, 4E)-dihydrophaseic acid-3′-O-β-d-glucopyranoside (2) and...     

Mechanism of acid production and secretion by osteoclasts]

Osteoclasts are primary cells responsible for bone resorption. The most characteristic feature of osteoclasts is the presence of ruffled borders and clear zones. The resorbing area under the ruffled border of osteoclasts is acidic, which favors dissolution of bone mineral. In bone-resorbing osteoclasts, hydrogen ions are provided by carbonic anhydrase II, which catalyzes the hydration of CO2 to H2CO3. Recently, it has been shown that the proton pump of the vacuolar H(+)-ATPase type exists in the ruffled border membranes of osteoclasts. Secretion of hydrogen ions by osteoclasts generates an equal amount of cytoplasmic base equivalents, principally as HCO3-. Osteoclasts have a chloride/bicarbonate exchanger, which normalizes the intracellular pH when osteoclasts actively resorb bone. In this paper, we review the mechanism of the acid secretion by osteoclasts.     

Enhanced terminal room disinfection and acquisition and infection caused by multidrug-resistant organisms and Clostridium diffcile(the Benefits of Enhanced Terminal Room Disinfection study):a cluster-randomised,multicentre,crossover study

中文:背景患者入院后可从不当消毒的环境表面获得多药耐药菌和艰难梭菌。本文确定了3种强化的终末消毒(入住同一病房的两名患者之间的消毒)策略,对感染耐甲氧西林金黄色葡萄球菌(MRSA)、耐万古霉素肠球菌(VRE)、艰难梭菌(CD)和多重耐药不动杆菌的影响。方法本文在美国东南部的9家医院开展了一项务实的、集群-随机、交叉研究。凡曾有感染或定植目标细菌感染患者居住过的病房,患者出院后随机采取4种消毒策略中的一种方法进行终末消毒:对照(季胺盐类消毒剂消毒,但凡遇到CD采用含氯消毒剂);UV(季胺盐类+UV-C消毒,但凡遇到CD采用含氯消毒剂+UV-C);含氯消毒剂;含氯消毒剂+UV-C。凡入住目标病房的患者被列为暴露人群。这4种终末消毒方法分别在每家医院连续实施7个月的周期。本文随机设计这几种消毒策略在每家医院内的实施顺序(1:1:1:1)。主要产出的结果是,观察暴露患者中目标细菌的感染的发生或定植情况,以及ITT人群中暴露患者CD感染发生率。本研究ClinicalTrials.gov注册编号:NCT01579370。结果共有31 226名患者暴露,其中21 395(69%)符合标准,包括4 916名对照组,5 178名UV组,5 438名含氯消毒剂组,以及5 863名含氯消毒剂+UV组。在对照组中,22 426个暴露日中有115名患者发生目标细菌的感染(51.3/10000暴露日)。在标准清洁策略的基础上增加UV消毒的暴露患者,其目标细菌感染的发生率明显较低(n=76;33.9/10 000暴露日;RR:0.70,95%CI:0.50～0.988;P=0.036)。含氯消毒剂组(n=101;41.6/10 000暴露日;RR:0.85,95%CI:0.69～1.04;P=0.116),或含氯消毒剂+UV组患者(n=131;45.6/10 000暴露日;RR:0.91,95%CI:0.76～1.09;P=0.303)的目标细菌的感染率,其差异无统计学意义。同样,在含氯消毒剂的基础上增加UV消毒,暴露患者中CD感染率也没有发生改变((n=38 vs 36;30.4 vs 31.6/10 000暴露日;RR:1.0,95%CI:0.57-1.75;P=0.997)。解释污染的医疗机构环境是获得病原微生物的重要来源;强化终末消毒可以降低这一风险。     

El Registro de Gemelos de Murcia. Un recurso para la investigación sobre conductas relacionadas con la salud

Genetically informative designs and, in particular, twin studies, are the most widely used methodology to analyse the relative contribution of genetic and environmental factors to inter-individual variability. These studies basically compare the degree of phenotypical similarity between monozygotic and dizygotic twin pairs. In addition to the traditional estimate of heritability, this kind of registry enables a wide variety of analyses which are unique due to the characteristics of the sample. The Murcia Twin Registry is population-based and focused on the analysis of health-related behaviour. The observed prevalence of health problems is comparable to that of other regional and national reference samples, which guarantees its representativeness. Overall, the characteristics of the Registry facilitate developing various types of research as well as genetically informative designs, and collaboration with different initiatives and consortia.