A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones

Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norfloxacin for clinical strains of S. aureus including VISA. Development of resistance against IMRG4 alone and in combination with norfloxacin was low and IMRG4 prolongs the post-antibiotic effect of norfloxacin. These virtues combined with the low toxicity of IMRG4, assessed by MTT assay and haemolysis, makes it an ideal candidate to enter drug development pipeline against S. aureus.     

质子泵抑制剂对慢性肝病患者肠道微生态的影响

目的探究质子泵抑制剂(PPIs)对慢性肝病患者肠道微生态的影响。方法选取郑州市第六人民医院2018年12月至2019年3月诊断及拟行PPIs治疗的慢性肝病患者31名,使用奥美拉唑进行治疗,20 mg/次,2次/d,疗程4周,检测治疗前后肠道菌群的构成。结果治疗前后患者肠道菌群构成差异显著:治疗后患者肠道菌群在Shannon指数(4.61±0.62 vs 5.01±0.83;t=2.889,P=0.005)、Simpson指数(0.89±0.09 vs 0.95±0.11;t=3.159,P=0.002)显著低于治疗前;治疗前患者肠道菌群中Coriobacteriaceae、Eggerthella、Ruminococcus、Anaerotruncus、Dorea、Turicibacter、Paraprevotella的相对丰度显著高于治疗后,治疗后肠道菌群中Veillonellaceae、Campylobacter、Haemophilus、Streptococcus、Streptococcaceae、Lactobacillus、Lactobacillaceae的相对丰度显著高于治疗前(均P<0.05)。结论PPIs可改变慢性肝病患者肠道菌群的构成。     

硬膜外腔麻醉对妊娠血小板减少症患者凝血功能的影响

目的:探讨硬膜外腔麻醉对妊娠血小板减少症患者凝血功能的影响。方法:选择陆军军医大学大坪医院麻醉科(我院)2018年6月至2019年6月收治的妊娠血小板减少症患者86例,按照随机数字表法分为研究组和对照组,每组各43例。研究组给予硬膜外腔麻醉,对照组给予全麻,观察和比较两组产妇麻醉前后凝血系统各项指标的变化情况。结果:研究组产妇在麻醉前、麻醉后0.5 h、术后0.5 h、术后24 h、术后48 h激活凝血酶时间(Activated partial thromboplastin time,APTT)长于对照组(P<0.05)。两组产妇麻醉后纤维蛋白原(Fibrinogen, FIB)和D-二聚体水平(D-dimer,D-D)较麻醉前显著升高,且对照组明显高于研究组(P<0.05)。两组产妇手术时间比较差异无统计学意义(P>0.05),研究组产妇术后平均出血量和术后24 h平均出血量均明显少于对照组(P<0.05)。两组新生儿出生1 min、5 min的Apgar评分比较差异无统计学意义(P>0.05)。结论:硬膜外腔麻醉对妊娠血小板减少症产妇的凝血功能影响较小,但麻醉起效快、效果确切,且可一定程度减少患者手术和术后出血量。     

血必净注射液联合静脉胰岛素泵入治疗糖尿病酮症酸中毒的效果及对氧化应激反应的影响

目的:探讨血必净注射液联合静脉胰岛素泵入治疗糖尿病酮症酸中毒的效果及对氧化应激反应的影响。方法:选择2016年8月至2018年8月我院收治的糖尿病酮症酸中毒患者80例,根据随机数表法分为观察组(n=41)和对照组(n=39)。对照组给予胰岛素泵治疗,观察组在对照组的基础上采用血必净注射液治疗。比较两组患者的临床疗效、治疗前后单核细胞趋化蛋白(MCP)、空腹血糖(FBG)、餐后血糖(PBG)、丙二醛(MDA)、超氧化物歧化酶(SOD)、总抗氧化能力(TAC)水平的变化及临床症状改善时间。结果:治疗后,两组单核细胞趋化蛋白水平均较治疗前显著下降,且观察组明显低于对照组(P0.05)。治疗后,观察组MDA低于对照组,SOD、TAC水平均显著高于对照组(P0.05);观察组血糖达标、尿酮体转阴、PH恢复时间及胰岛素用量均显著低于对照组(P0.05)。结论:血必净注射液联合胰岛素泵治疗糖尿病酮症酸中毒患者的效果显著明显优于单用血必净治疗,可能与其有效提高机体的抗氧化能力有关。     

B超声引导下肋锁间隙与喙突入路连续臂丛神经阻滞对Barton骨折术后镇痛效果比较

目的:比较超声引导下肋锁间隙与喙突两种入路连续臂丛神经阻滞对Barton骨折手术患者术后的镇痛效果。方法:选择择期行Barton骨折手术患者60例,随机分为肋锁间隙入路连续臂丛神经阻滞组(A组,n=30)和喙突入路连续锁骨下臂丛神经阻滞组(B组,n=30)。两组均在超声引导下进行臂丛神经阻滞,同时留置神经阻滞导管,麻醉后2小时经神经阻滞导管连接无线电子镇痛泵。记录手术过程中神经深度、麻醉操作时间,并评估麻醉效果;记录术后第一次追加药物时间;记录麻醉后6 h、12 h、18 h、24 h、36 h、48 h静息及运动状态VAS评分;记录术后第一天和第二天镇痛泵有效按压次数及补救镇痛情况;记录患者满意度及并发症发生情况。结果:与B组相比,A组神经深度明显减浅(P<0.05),麻醉操作时间显著缩短(P<0.05),术后第一次追加药物时间延长(P<0.05),麻醉后12 h、18 h、24 h、36 h静息及运动状态VAS评分较低(P<0.05),术后第一天有效按压次数明显减少(P<0.05),患者满意度评分高(P<0.05),误穿血管发生率明显减少(P<0.05)。结论:超声引导下肋锁间隙入路与喙突入路连续锁骨下臂丛神经阻滞均可安全有效用于Barton骨折手术术后镇痛;但肋锁间隙连续臂丛神经阻滞术后镇痛效果更好,且具有神经阻滞深度浅、操作时间更短、阻滞效果更好、患者满意度更高及并发症更少等优点。     

Australasian sky islands act as a diversity pump facilitating peripheral speciation and complex reversal from narrow endemic to widespread ecological supertramp

The Australasian archipelago is biologically extremely diverse as a result of a highly puzzling geological and biological evolution. Unveiling the underlying mechanisms has never been more attainable as molecular phylogenetic and geological methods improve, and has become a research priority considering increasing human‐mediated loss of biodiversity. However, studies of finer scaled evolutionary patterns remain rare particularly for megadiverse Melanesian biota. While oceanic islands have received some attention in the region, likewise insular mountain blocks that serve as species pumps remain understudied, even though Australasia, for example, features some of the most spectacular tropical alpine habitats in the World. Here, we sequenced almost 2 kb of mitochondrial DNA from the widespread diving beetle Rhantus suturalis from across Australasia and the Indomalayan Archipelago, including remote New Guinean highlands. Based on expert taxonomy with a multigene phylogenetic backbone study, and combining molecular phylogenetics, phylogeography, divergence time estimation, and historical demography, we recover comparably low geographic signal, but complex phylogenetic relationships and population structure within R. suturalis. Four narrowly endemic New Guinea highland species are subordinated and two populations (New Guinea, New Zealand) seem to constitute cases of ongoing speciation. We reveal repeated colonization of remote mountain chains where haplotypes out of a core clade of very widespread haplotypes syntopically might occur with well‐isolated ones. These results are corroborated by a Pleistocene origin approximately 2.4 Ma ago, followed by a sudden demographic expansion 600,000 years ago that may have been initiated through climatic adaptations. This study is a snapshot of the early stages of lineage diversification by peripatric speciation in Australasia, and supports New Guinea sky islands as cradles of evolution, in line with geological evidence suggesting very recent origin of high altitudes in the region.     

C-2 phenyl replacements to obtain potent quinoline-based Staphylococcus aureus NorA inhibitors

Abstract

NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of “selectivity index” in comparison to 1.