Chalcone hybrids and their antimalarial activity

Malaria, one of the most striking, re-emerging infectious diseases caused by the genus Plasmodium, places a huge burden on global healthcare systems. A major challenge in the control and eradication of malaria is the continuous emergence of increasingly widespread drug-resistant malaria, creating an urgent need to develop novel antimalarial agents. Chalcone derivatives are ubiquitous in nature and have become indispensable units in medicinal chemistry applications due to their diverse biological profiles. Many chalcone derivatives demonstrate potential in vitro and in vivo antimalarial activity, so chalcone could be a useful template for the development of novel antimalarial agents. This review covers the recent development of chalcone hybrids as antimalarial agents. The critical aspects of the design and structure–activity relationship of these compounds are also discussed.     

Identification of new sub-genotypes of virulent Newcastle disease virus with potential panzootic features

Virulent Newcastle disease virus (NDV) isolates from new sub-genotypes within genotype VII are rapidly spreading through Asia and the Middle East causing outbreaks of Newcastle disease (ND) characterized by significant illness and mortality in poultry, suggesting the existence of a fifth panzootic. These viruses, which belong to the new sub-genotypes VIIh and VIIi, have epizootic characteristics and do not appear to have originated directly from other genotype VII NDV isolates that are currently circulating elsewhere, but are related to the present and past Indonesian NDV viruses isolated from wild birds since the 80s. Viruses from sub-genotype VIIh were isolated in Indonesia (2009–2010), Malaysia (2011), China (2011), and Cambodia (2011–2012) and are closely related to the Indonesian NDV isolated in 2007, APMV1/Chicken/Karangasem, Indonesia (Bali-01)/2007. Since 2011 and during 2012 highly related NDV isolates from sub-genotype VIIi have been isolated from poultry production facilities and occasionally from pet birds, throughout Indonesia, Pakistan and Israel. In Pakistan, the viruses of sub-genotype VIIi have replaced NDV isolates of genotype XIII, which were commonly isolated in 2009–2011, and they have become the predominant sub-genotype causing ND outbreaks since 2012. In a similar fashion, the numbers of viruses of sub-genotype VIIi isolated in Israel increased in 2012, and isolates from this sub-genotype are now found more frequently than viruses from the previously predominant sub-genotypes VIId and VIIb, from 2009 to 2012. All NDV isolates of sub-genotype VIIi are approximately 99% identical to each other and are more closely related to Indonesian viruses isolated from 1983 through 1990 than to those of genotype VII, still circulating in the region. Similarly, in addition to the Pakistani NDV isolates of the original genotype XIII (now called sub-genotype XIIIa), there is an additional sub-genotype (XIIIb) that was initially detected in India and Iran. This sub-genotype also appears to have as an ancestor a NDV strain from an Indian cockatoo isolated in1982. These data suggest the existence of a new panzootic composed of viruses of subgenotype VIIi and support our previous findings of co-evolution of multiple virulent NDV genotypes in unknown reservoirs, e.g. as recorded with the virulent NDV identified in Dominican Republic in 2008. The co-evolution of at least three different sub-genotypes reported here and the apparent close relationship of some of those genotypes from ND viruses isolated from wild birds, suggests that identifying wild life reservoirs may help predict new panzootics.     

A coxsackievirus B5‐associated aseptic meningitis outbreak in Shandong Province,China in 2009

In 2009, a major outbreak of aseptic meningitis was noted in Linyi city, Shandong province, China. From June to September 2009, a total of 2,104 cases were involved in this outbreak, and 98.6% of patients were <16 years of age. To determine the pathogen of the outbreak, 42 cerebrospinal fluid specimens collected from aseptic meningitis cases were tested for cell culture, and 17 (40.5%) enteroviruses were isolated and identified as Coxsackievirus B5 (CVB5). Homologous comparison indicated that these isolates had 0–7.7% nucleotide divergence with each other. Phylogenetic reconstruction showed global CVB5 could be separated into four genogroups, and all Linyi CVB5 isolates belonged to the genogroup C which had been circulating for recent 27 years in Asia and Europe. Interestingly, two distinct lineages were observed for the 17 isolates in the phylogenetic tree, indicating that at least two different transmission chains of CVB5 were responsible for this outbreak. This study showed that CVB5‐associated aseptic meningitis is an emerging concern in China. J. Med. Virol. 85:483–489, 2013. © 2012 Wiley Periodicals, Inc.     

Randomised controlled trial: effect of metformin add-on therapy on functional cure in entecavir-treated patients with chronic hepatitis B

Introduction and ObjectivesHepatitis B surface antigen (HBsAg) clearance, indicating functional cure or resolved chronic hepatitis B (CHB), remains difficult to achieve via nucleos(t)ide analogue monotherapy. We investigated whether metformin add-on therapy could help achieve this goal in entecavir-treated patients with hepatitis B e antigen (HBeAg)-negative CHB.Patients and MethodsPatients with HBeAg-negative CHB who met eligibility criteria (entecavir treatment for > 12 months, HBsAg < 1000 IU/mL) were randomly assigned (1:1) to receive 24 weeks of either metformin (1000 mg, oral, once a day) or placebo (oral, once a day) add-on therapy. The group allocation was blinded for both patients and investigators. Efficacy and safety analyses were based on the intention-to-treat set. The primary outcome, serum HBsAg level (IU/mL) at weeks 24 and 36, was analysed using mixed models.ResultsSixty eligible patients were randomly assigned to the metformin (n = 29) and placebo (n = 31) groups. There was no substantial between-group difference in the HBsAg level at week 24 (adjusted mean difference 0.05, 95% confidence interval -0.04 to 0.13, p = 0.278) or week 36 (0.06, -0.03 to 0.15, p = 0.187), and no significant effect of group-by-time interaction on the HBsAg level throughout the trial (p = 0.814). The occurrence of total adverse events between the two groups was comparable (9 [31.0%] of 29 vs. 5 [16.1%] of 31, p = 0.227) and no patient experienced serious adverse events during the study.ConclusionAlthough it was safe, metformin add-on therapy did not accelerate HBsAg clearance in entecavir-treated patients with HBeAg-negative CHB.     

济南市2011年急性脑膜炎/脑炎症候群病例哨点监测分析

目的了解济南市2011年急性脑膜炎/脑炎症候群（Acute Meningitis/Encephalitis Syndrome,AMES）哨点监测病例的主要病毒性病原及其流行病学特征。方法在济南市选取省、市、县级各2所医院作为哨点医院,收集2011年AMES病例血清和脑脊液（Cerebrospinal Fluid,CSF）标本,采用酶联免疫吸附试验对4种病毒特异性免疫球蛋白（Immunoglobilin,Ig）M进行血清学诊断。结果济南市2011年报告的AMES病例集中在5-9月,高峰出现在6-8月,峰值出现在7月,但≥15岁的病例数无季节性高峰。所有病例的血清和CSF标本均检测了流行性乙型脑炎病毒（Japanese Encephalitis Virus,JEV）IgM,阳性率为7.1%（46/647例）,比2008-2010年明显下降,其差异有统计学意义（χ2=12.6,P〈0.05）。其余血清标本IgM检测结果为：人类肠道病毒（Human Enterovirus,HEV）阳性率为18.5%（61/330例）,流行性腮腺炎病毒（Mumps Virus,MuV）阳性率为13.9%（46/330例）,单纯疱疹病毒（Herpes Simplex Virus,HSV）阳性率为13.0%（43/330例）。不同年龄组病例的主要病原存在差异,〈5岁以HEV感染为主,而≥15岁则以HSV为主。与其他3种病毒的季节分布不同,MuV感染全年无明显差异（χ2=5.4,P=0.36）。4种病毒中,仅HSV感染有明显的性别差异（χ2=5.1,P=0.02）,女性感染较多。结论济南市2011年6所哨点医院AMES病例的主要病毒性病原体依次为HEV、MuV、HSV、JEV。由于不同病毒的流行病学特征不同,需针对病毒的特性制定个性化监测方案,并加强实验室检测。     

山东省≤15岁人群感染乙型肝炎病毒“a”抗原决定簇变异株的流行病学特征分析

目的了解山东省≤15岁人群感染的乙型肝炎（乙肝）病毒（Hepatitis B Virus,HBV）中,＂a＂抗原决定簇变异株流行强度及分布特征,探讨其流行与乙肝疫苗（Hepatitis B Vaccine,HepB）免疫的关系。方法对2009年国家法定传染病报告系统报告的山东省≤15岁乙肝病例进行个案调查和血标本采集,采用巢式聚合酶链反应方法扩增其血清HBV S基因,测序后与基因数据库中的标准序列进行比对分析。结果山东省2009年共报告≤15岁乙肝326例,对302例（92.64%）进行了个案调查和血标本采集,对其中158份标本进行HBV-脱氧核糖核酸提取,扩增HBV S基因并成功测序137份。14份标本检出＂a＂抗原决定簇变异株,检出率为10.22%;有HepB免疫史和无HepB免疫史者检出率分别为10.66%和6.67%,差异无统计学意义（χ2=0.23,P=0.63）;未发现不同性别、地区、接种HepB种类和母亲乙肝病毒表面抗原携带状态者间检出率的差异有统计学意义（P〉0.05）。14份标本共检出＂a＂抗原决定簇6个氨基酸位点发生9种变异,其中126位点和144位点检出率较高,分别为4.38%（6/137）和2.92%（4/137）,但差异无统计学意义（χ2=7.39,P=0.19）。结论目前山东省≤15岁乙肝病例中,HBV＂a＂抗原决定簇变异株流行率较低,存在多种变异形式,尚未出现强变异株;尚未发现其流行与HepB免疫有关。     

Molecular typing and drug susceptibility of Mycobacterium tuberculosis isolates from Chongqing Municipality,China

China’s tuberculosis (TB) burden is second only to that of India worldwide. In Chongqing, the largest municipality in southwestern China, although the prevalence of both TB and drug-resistant TB is higher than in other municipalities, the molecular characteristics and drug susceptibility phenotypes are poorly known. In this study, 297 Mycobacterium tuberculosis isolates from Chongqing were genotyped with spacer oligonucleotide typing (spoligotyping) and 28-locus MIRU-VNTR (24-locus MIRU-VNTR scheme and 4 other loci). Spoligotyping results were compared with drug-resistant profiles. Patients who showed clustering by both spoligotyping and 28-locus MIRU-VNTR were interviewed to investigate their detailed contact history. Our data demonstrated that the Beijing genotype was the most prevalent genotype, and ST1 was the most predominant lineage in Chongqing. The Beijing genotype was significantly associated with ethambutol resistance and multidrug-resistant phenotypes. A combination of the 10 most polymorphic loci permitted to achieve higher discriminatory power than 24-VNTR. In addition, a presumed transmission pathway was observed in a cluster of patients with the same MIRU-VNTR profile. The 10-VNTR locus set is suitable for genotyping of Mycobacterium tuberculosis in Chongqing.     

Methicillin-resistant Staphylococcus aureus ST30-SCCmec IVc clone as the major cause of community-acquired invasive infections in Argentina

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have become a major concern worldwide. We conducted a prospective multicenter study of invasive CA-MRSA to evaluate clinical features and genotype of strains causing invasive infections in Argentina. A total of 55 patients with invasive CA-MRSA infections were included. Most patients (60%) had bloodstream infections, 42% required admission to intensive care unit and 16% died. No CA-MRSA isolates were multiresistant (resistant ⩾3 classes of antibiotics). All isolates carried Panton-Valentine leukocidin (PVL) genes and staphylococcal cassette chromosome (SCCmec) type IV. The majority CA-MRSA strains belonged to ST30 and had identical pulsed-field gel electrophoresis (PFGE) patterns, qualifying as a clonal dissemination of a highly transmissible strain. The main clone recovered from patients with CA-MRSA invasive infections was genotyped as pulsed-field gel electrophoresis type C-ST30, SCCmec type IVc-spa type 019, PVL positive. It has become predominant and replaced the previously described CA-MRSA clone (PFGE type A, ST5, SCCmec type IV, spa type 311).