Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes

Aims: To investigate the value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in a cohort of a community’s residents who were diagnosed as pre-diabetes, and to evaluate the association of VAT and SAT with insulin resistance.

Methods: This study was based on cross-sectional analysis of data from 107 adults. VAT and SAT were assessed by computed tomography. Insulin resistance was defined by homeostasis model assessment of insulin resistance >2.69. The relationship of VAT and SAT with insulin resistance were examined by linear regression. Logistic regression was used to analyze the association of VAT and SAT with insulin resistance.

Results: A total of 87 subjects had VAT ≥100?cm². Thirty-six out of 107 (33.6%) subjects were detected to have insulin resistance, 71 were normal (66.4%), and all had insulin resistance with VAT ≥100?cm². VAT (r?=?0.378, p?r?=?0.357, p?p?=?.003), but that of SAT was lost.

Conclusion: Pre-diabetic subjects with insulin resistance had elevated levels of VAT. VAT was more strongly associated with insulin resistance than SAT in Chinese subjects with pre-diabetes.     

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

Purpose

This article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical.

Methods

After establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development.

Results

This article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case.

Conclusions

Developers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.

     

Empirical treatment of lower urinary tract infections in the face of spreading multidrug resistance: in vitro study on the effectiveness of nitroxoline

The spread of antimicrobial resistance challenges the empirical treatment of urinary tract infections (UTIs). Among others, nitrofurantoin is recommended for first-line treatment, but acceptance among clinicians is limited due to chronic nitrofurantoin-induced lung toxicity and insufficient coverage of Enterobacteriaceae other than Escherichia coli. Nitroxoline appears to be an alternative to nitrofurantoin owing to its favourable safety profile, however data on its current in vitro susceptibility are sparse. In this study, susceptibility to nitroxoline was tested against 3012 urinary clinical isolates (including multidrug-resistant bacteria and Candida spp.) by disk diffusion test and/or broth microdilution. At least 91% of all Gram-negatives (n?=?2000), Gram-positives (n?=?403) and yeasts (n?=?132) had inhibition zone diameters for nitroxoline ≥18?mm. Except for Pseudomonas aeruginosa, nitroxoline MIC₉₀ values were ≤16?mg/L and were 2- to >16-fold lower compared with nitrofurantoin. In extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus (MRSA), MIC₉₀ values of nitroxoline were two-fold higher compared with non-ESBL-producing enterobacteria and methicillin-susceptible S. aureus (MSSA). The in vitro efficacies of nitroxoline and nitrofurantoin against ATCC strains of E. coli, Enterococcus faecalis and Proteus mirabilis were compared by time–kill curves in Mueller–Hinton broth and artificial urine. Nitroxoline was non-inferior against E. coli, P. mirabilis and E. faecalis in artificial urine. In conclusion, nitroxoline showed a broad antimicrobial spectrum, with inhibition zone diameters and MICs of nitroxoline well below the EUCAST breakpoint for E. coli for most organisms, and thus may also be a target for therapy of uncomplicated UTIs.     

Effects of high-dose baclofen on cue reactivity in alcohol dependence: A randomized,placebo-controlled pharmaco-fMRI study

Increased functional brain response towards alcohol-associated stimuli is a neural hallmark of alcohol dependence and a promising target for pharmacotherapy. For the first time, we assessed the effects of individually titrated high-dose baclofen on cue reactivity and functional connectivity in alcohol-dependent (AD) patients in a randomized controlled trial (RCT).We investigated 23 recently detoxified AD patients and 23 matched healthy controls (HC) with a cue reactivity functional magnetic resonance imaging task. Patients were further scanned at baseline without medication and during treatment with high-dose baclofen/placebo (30–270 mg/d). Analyses were conducted for alcohol cue-elicited brain response, alcohol cue-modulated and stimulus-independent functional connectivity with left ventral tegmental area (VTA) as seed region.At baseline, AD patients (N?=?23) showed increased cue-elicited brain activation in the ventral striatum (VS) compared to HC (N?=?23), which was decreased at the second scanning session compared to baseline. Patients receiving baclofen (N?=?10) showed a significant stronger decrease in cue-elicited brain activation in left orbitofrontal cortex (OFC), bilateral amygdala and left VTA than patients receiving placebo (N?=?13). Treatment with baclofen further led to a decrease in alcohol cue-modulated functional connectivity between left VTA and left anterior cingulate cortex (ACC) as well as left medial prefrontal cortex (MPFC). Regarding clinical outcome, significantly more patients of the baclofen group remained abstinent during the high-dose period.Baclofen specifically decreased cue-elicited brain responses in areas known to be involved in the processing of salient (appetitive and aversive) stimuli. Treatment with high-dose baclofen seems to provide a pharmacological relief of this neural “warning signal” evoked by alcohol-related cues, thereby possibly supporting patients in remaining abstinent.Trial Registration Identifier of the main trial [BACLAD study] at clinicaltrials.gov: NCT01266655.     

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.     

An enzyme-linked immunosorbent assay for monoester-type aconitic alkaloids and its application in the pharmacokinetic study of benzoylhypaconine in rats

A new enzyme-linked immunosorbent assay (ELISA) method for quantitative determination of monoester-type aconitic alkaloids was developed. The antibodies derived from the immunogen of benzoylmesaconine (BM) could be electively affined to benzoylaconitine-type alkaloids with an ester bond (14-benzoyl-), especially to benzoylhypaconine (BH, 140.02% of cross-reactivity). The effective working range of BH was 1 ng/ml to 5 μg/ml; the lower limit of detection and the quantification were 0.35 and 0.97 ng/ml, respectively. The values of CV for intra-day and inter-day assays and recovery ratios were in acceptable ranges. The results of stability experiments were also satisfactory. This validated method was employed for pharmacokinetic study of BH in rats and the bioavailability orally administered was estimated to be 16.3%.     

急性莠去津中毒三例救治体会

近年来随着百草枯被禁用,其他类型除草剂中毒的患者开始增多。莠去津是国内广泛使用的一种低毒类的农药,自服莠去津自杀是常见的中毒原因。近来我院连续收治了3例莠去津中毒合并多脏器功能障碍(MODS)的患者。现将其临床特点总结如下。     

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。