Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

ObjectivesPolymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects.MethodsAn open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics.ResultsOne female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively.ConclusionsThis study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.     

Ca2+-binding activity of a COOH-terminal fragment of the Drosophila BK channel involved in Ca2+-dependent activation

Mutational and biophysical analysis suggests that an intracellular COOH-terminal domain of the large conductance Ca(2+)-activated K(+) channel (BK channel) contains Ca(2+)-binding site(s) that are allosterically coupled to channel opening. However the structural basis of Ca(2+) binding to BK channels is unknown. To pursue this question, we overexpressed the COOH-terminal 280 residues of the Drosophila slowpoke BK channel (Dslo-C280) as a FLAG- and His(6)-tagged protein in Escherichia coli. We purified Dslo-C280 in soluble form and used a (45)Ca(2+)-overlay protein blot assay to detect Ca(2+) binding. Dslo-C280 exhibits specific binding of (45)Ca(2+) in comparison with various control proteins and known EF-hand Ca(2+)-binding proteins. A mutation (D5N5) of Dslo-C280, in which five consecutive Asp residues of the "Ca-bowl" motif are changed to Asn, reduces (45)Ca(2+)-binding activity by 56%. By electrophysiological assay, the corresponding D5N5 mutant of the Drosophila BK channel expressed in HEK293 cells exhibits lower Ca(2+) sensitivity for activation and a shift of approximately +80 mV in the midpoint voltage for activation. This effect is associated with a decrease in the Hill coefficient (N) for activation by Ca(2+) and a reduction in apparent Ca(2+) affinity, suggesting the loss of one Ca(2+)-binding site per monomer. These results demonstrate a functional correlation between Ca(2+) binding to a specific region of the BK protein and Ca(2+)-dependent activation, thus providing a biochemical approach to study this process.     

Transgenic alteration of Toll immune pathway in the female mosquito Aedes aegypti

Reverse genetics is a powerful tool for understanding gene functions and their interactions in the mosquito innate immunity. We took the transgenic approach, in combination with the RNA interference (RNAi) technique, to elucidate the role of mosquito REL1, a homolog of Drosophila Dorsal, in regulation of Toll immune pathway in the mosquito Aedes aegypti. By transforming the mosquitoes with DeltaREL1-A or a double-stranded RNA construct of REL1 driven by the female fat body-specific vitellogenin (Vg) promoter with the pBac[3xP3-EGFP, afm] vector, we generated two different transgenic mosquito strains, one with overexpressed AaREL1 and the second with AaREL1 knockdown. Both strains had a single copy of the respective transgene, and the expression in both transgenic mosquitoes was highly activated by blood feeding. Vg-DeltaREL1-A transgenic mosquitoes activate Toll immune pathway in the fat body by blood feeding. The overexpression of both isoforms, AaREL1-A and AaREL1-B, in Vg-DeltaREL1-A transgenic mosquitoes resulted in the concomitant activation of Aedes Sp?tzle1A and Serpin-27A, independent of septic injury. The same phenotype was observed in the mosquitoes with RNAi knockdown of an Aedes homolog to Drosophila cactus, an IkappaB inhibitor of Drosophila Toll pathway. The effect of the transgenic RNAi knockdown of AaREL1 on mosquito innate immunity was revealed by increased susceptibility to the entomopathogenic fungus Beauveria bassiana and the reduced induction of Spz1A and Serpin-27A gene expression after fungal challenge. These results have proven that AaREL1 is a key downstream regulator of Toll immune pathway in the mosquito A. aegypti.     

Daptomycin therapy in 6 cases of left-sided infective endocarditis and literature review北大核心CSCD

Objective To evaluate the efficacy of daptomycin in the treatment of left-sided infective endocarditis after failing to respond to vancomycin. Methods A retrospective analysis was conducted for 6 cases of infective endocarditis. Results Five of the six infective endocarditis patients were complicated with paravalvular abscess (artificial valve in 3 cases, native valve in 2 cases). Their disease deteriorated even under vancomycin treatment. Four of these patients received emergency valve replacement surgery but still febrile after operation. The antimicrobial therapy was switched to daptomycin at dose of 6 mg/kg daily for 2 to 4 weeks. The patients responded satisfactorily to daptomycin. The infection was controlled to some extent in the fifth patient after switching to daptomycin, but recurred later, and died suddenly on day 21 after reoperation. The sixth patient had infective endocarditis of native valve, and had treated with piperacillin-tazobactam for 2 weeks and vancomycin for 3 weeks, but responded poorly. The patient still had fever and enlarged vegetation. Switching to daptomycin reduced the body temperature and vegetation. Serum creatine kinase elevated moderately in one patient, and normal in the other 5 patients. No other apparent adverse reaction was reported. One patient died and the other five patient survived well for 18 months to 5 years. Conclusions Preliminary observation demonstrates the efficacy of daptomycin salvage treatment in a few cases of left-sided infective endocarditis after failing to respond to vancomycin therapy. © 2018, Editorial Department of Chinese Journal of Infection. All rights reserved.     

The Associations of Month of Birth With Body Mass Index,Waist Circumference,and Leg Length: Findings From the China Kadoorie Biobank of 0.5 Million Adults

Background

Season of birth (SoB) has been linked with various health outcomes. This study aimed to examine the associations between month of birth (MoB) and adult measures of leg length (LL), body mass index (BMI), and waist circumference (WC).

Methods

We analysed survey data from 10 geographically diverse areas of China obtained through the China Kadoorie Biobank. Analysis included 487 529 adults with BMI ≥ 18.5 kg/m². A general linear model was used to examine the associations between MoB and adult measures of LL, BMI, and WC, adjusted for survey site, sex, age, education level, smoking habit, alcohol consumption, physical activity level, sedentary leisure time, height (only for WC and LL), and hip circumference (only for LL).

Results

MoB was independently associated with both BMI and WC. Birth months in which participants had higher measures of adiposity were March–July for BMI and March–June for WC. The peak differences were 0.14 kg/m² for BMI and 0.47 cm for WC. The association between MoB and LL depended on survey site. Participants who were born in February–August in four sites (Harbin, Henan, Gansu, and Hunan) had the shortest LL (all P < 0.01). The peak difference in mean LL was 0.21 cm. No statistically significant association between MoB and LL was noted in the other sites (Qingdao, Suzhou, Sichuan, Zhejiang, Liuzhou, and Haikou).

Conclusions

These findings suggest that MoB is associated with variations in adult adiposity measures and LL among Chinese adults. Low exposure to ultraviolet B radiation and subsequent reduced levels of vitamin D during the late second and early third trimesters may be involved in these phenomena.Key words: month of birth, BMI, waist circumference, leg length, vitamin D deficiency     

以数据挖掘为核心的医院数据管理平台建设初探

以建设基于精细化管理的医院决策支持系统为目的,利用数据仓库等信息化技术对各业务系统数据进行采集、清洗、整合,建立数据中心进行综合管理,保证数入一门、数出一门。有效消除信息孤岛、解决数据混乱状态、缓解信息化应用瓶颈。以数据挖掘为手段以病种为核心着重分析医疗核心指标及医保的总额预付管理两个主题,通过深入分析明确管理目标、缩小管理范畴、抓住主要矛盾,提高医院科学管理水平。     

眼科诊断用接触镜的消毒现状及消毒效果比较

目的：调查国内医院对眼科诊断用接触镜的消毒现状,评估其消毒效果。方法：采用方便抽样的方法对10所医院进行调查,发现氯霉素滴眼液冲洗、75%乙醇搽拭和0.05%的二氯异氰尿酸钠( NaDCC)浸泡是目前我国临床最常用的眼科诊断用接触镜消毒方法。将被金黄色葡萄球菌、表皮葡萄球菌或铜绿假单胞菌污染的眼科检查用接触镜,用上述三种消毒剂按照以下方式进行消毒：1)擦拭;2)浸泡消毒5min;3)浸泡消毒10min,n=9.然后镜面采样,对细菌群落培养并计数以评估细菌量,观察消毒效果。同时评估消毒后镜头的清晰度。结果：细菌负荷量为1×108/mL×50μL/镜头等于5×106/镜头。 NaDCC或乙醇消毒显著降低了细菌量;擦拭消毒时,75%的乙醇和NaDCC的消毒效果与氯霉素滴眼液比较差异显著(P≤0.01),但不能达到临床消毒要求,仍然存在交叉感染的风险。浸泡消毒效果与时间正相关,75%的乙醇和NaDCC浸泡10 min最有效,能完全达到临床消毒要求,氯霉素滴眼液浸泡10 min仍然不能达到临床要求。但乙醇会影响镜头的清晰度。结论：NaDCC浸泡消毒10 min 或更长时间是一种简单有效的眼科诊断用接触镜消毒方法。     

Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3β pathway

Background and Purpose

Recent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects of salidroside on diabetic mice and to explore the underlying mechanisms.

Experimental Approach

The therapeutic effects of salidroside on type 2 diabetes were investigated. Increasing doses of salidroside (25, 50 and 100 mg·kg⁻¹·day⁻¹) were administered p.o. to db/db mice for 8 weeks. Biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. Primary cultured mouse hepatocytes were used to further explore the underlying mechanisms in vitro.

Key Results

Salidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Hypolipidaemic effects and amelioration of liver steatosis were observed after salidroside administration. In vitro, salidroside dose-dependently induced an increase in the phosphorylations of AMPK and PI3K/Akt, as well as glycogen synthase kinase 3β (GSK3β) in hepatocytes. Furthermore, salidroside-stimulated AMPK activation was found to suppress the expression of PEPCK and glucose-6-phosphatase. Salidroside-induced AMPK activation also resulted in phosphorylation of acetyl CoA carboxylase, which can reduce lipid accumulation in peripheral tissues. In isolated mitochondria, salidroside inhibited respiratory chain complex I and disturbed oxidation/phosphorylation coupling and moderately depolarized the mitochondrial membrane potential, resulting in a transient increase in the AMP/ATP ratio.

Conclusions and Implications

Salidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria-related AMPK/PI3K/Akt/GSK3β pathway     

Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells

The therapeutic goal of cancer treatment is now geared towards triggering tumour‐selective cell death with autophagic cell death being required for the chemotherapy of apoptosis‐resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3‐II to LC3‐I in a time‐ and dose‐dependent manner but had no effect on the levels of autophagy‐related protein ATG6 and ATG13 expression. Autophagy inhibitors, 3‐methyladenine (3‐MA), chloroquine and bafilomycin A1, or ATG genes silencing in HepG2 cells significantly inhibited CA‐induced autophagic cell death. The CA treatment decreased the levels of phosphorylated Akt and mTOR without any effects on PI3K or PTEN. Most importantly, overexpression of Akt and knockdown of PTEN attenuated autophagy induction in CA‐treated cells. Taken together, our results indicated that CA induced autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. These findings suggest that CA has a great potential for the treatment of hepatoma via autophagic induction. Copyright © 2014 John Wiley & Sons, Ltd.     

Dickkopf-1 perpetuated synovial fibroblast activation and synovial angiogenesis in rheumatoid arthritis

Clinical Rheumatology - Dickkopf-1 (Dkk-1), a regulatory molecule of the Wnt pathway, is elevated and leads to bone resorption in patients with RA. This study is aimed to investigate the...