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.     

Effects of squalene on expression of LDLR in HepG2 cells and its mechanism北大核心CSCD

Aim To investigate the effect of squalene on LDLR expression in HepG2 cells and its mechanism of down-regulated cholesterol. Methods The proliferation of HepG2 cells exposed to squalene at different concentrations was measured by MTT assay. The effect of squalene on the expression of LDLR in HepG2 cells was measured by flow cytometry and fluorescence mi-croscopy. The effect of different concentrations of squalene on the interaction between SCAP and Insig2, two key protein molecules of SREBP pathway, was assayed by FRET technology. Results MTT results showed that squalene had inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner. Flow cytometry and fluorescence microscopy results showed that squalene enhanced LDLR expression in HepG2 cells compared with the control group. The results of FRET technology revealed that compared with model control group, the YFP fluorescence value in Squalene group dramatically declined, and the YFP fluorescence value of each drug group decreased with the range of 5-25 |xmol L1 squalene concentration. Conclusions Squalene may promote the expression of LDLR in HepG2 cells through inhibiting the interaction between SCAP and Insig2 proteins in SREBP pathway, which may confirm that squalene is a potential novel drug for the down-regulation of cholesterol level. © 2018 Publication Centre of Anhui Medical University. All rights reserved.     

I Am Quite Mellow But I Wouldn't Say Everyone Else Is”: How UK Students Compare Their Drinking Behavior to Their Peers'

Background: Excessive drinking is commonplace at UK Universities. Individuals may misperceive how much they drink compared to others and are less likely to think that they will suffer adverse consequences. Young people often distance themselves and their friends from ‘problem drinkers’. Objectives: The aim of the study was to explore how student drinkers compared their own drinking behaviors to the drinking behaviors of others. Methods: An online survey was completed by 416 students aged 18–30 (68.5% female). They were asked ‘how do you think your drinking compares with other people like you?' and ‘how do you think your behavior when you drink compares with other people like you?’ Answers were subjected to thematic analysis. Results: The first main theme was about ‘identification as a ‘good’ drinker’. Participants suggested their own behavior when drinking was similar to their sober behavior. Further, they viewed themselves as more able to maintain a balance between staying in control and having fun while drinking. The second main theme was about ‘distancing from being a ‘bad’ drinker. Participants distanced themselves from negative prototypical drinkers, such compulsive or anti-social drinkers. They also attributed their own drinking behaviors to situational factors, but described other people as intentionally violent or aggressive. Conclusions/Importance: These findings may explain the failure of some health messages to change drinking behaviors. If drinkers perceive that their behavior when they drink is better than other people's then they may discount intervention messages. Targeting these biases could be incorporated into future interventions.     

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。