Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.     

小柴胡颗粒配合奥司他韦治疗小儿流感的临床效果

目的 分析奥司他韦配合小柴胡颗粒治疗小儿流感的效果与预后状况。方法 选取2018年1月~2019年1月我院收治的90例流感患儿,随机分成对照组和研究组,每组45例。对照组采用奥司他韦胶囊治疗,研究组在对照组基础上联合小柴胡颗粒治疗。对比两组症状缓解时间、临床疗效及不良反应。结果 研究组发热、咳嗽、扁桃体肿大缓解时间分别为（2.05±0.43）d、（3.02±0.93）d、（2.73±0.77）d,短于对照组的（4.31±1.63）d、（4.99±1.62）d、（3.98±1.32）d,差异具有统计意义（P＜0.05）,而两组鼻塞缓解所用的时间比较,差异无统计学意义（P＞0.05）。两组治疗总有效率及不良反应总发生率比较,差异无统计学意义（P＞0.05）。结论 采用奥司他韦联合小柴胡颗粒治疗小儿流感,能缩短病程,且用药安全性高。     

The development and genetic diversity of H5N1 influenza virus in China, 1996-2006

Since it was first detected in 1996, the Goose/Guangdong/1/1996 (Gs/GD) H5N1 influenza virus and its reassortants have spread to over 60 countries, with over 20 distinct genetic reassortants previously recognized. However, systematic analysis of their interrelationship and the development of genetic diversity have not been explored. As each of those reassortants was first detected in China, here 318 full-length H5N1 virus genomes isolated from 1996 to 2006 in this region were phylogenetically analyzed. Our findings revealed two major group reassortment events in 2001 and 2002 that were responsible for the generation of the majority of the 44 distinct Gs/GD genotypes identified, excepting those 1997 variants. Genotype replacement and emergence occurred continually, with 34 transient genotypes detected while only 10 variants were persistent. Two major replacements of predominant genotypes were also observed: genotype B replaced by Z in 2002 and then genotype Z replaced by the now predominant genotype V in 2005.     

Avian influenza virus isolates from wild birds replicate and cause disease in a mouse model of infection

The direct transmission of highly pathogenic avian influenza (HPAI) viruses to humans in Eurasia and subsequent disease has sparked research efforts leading to better understanding of HPAI virus transmission and pathogenicity in mammals. There has been minimal focus on examining the capacity of circulating low pathogenic wild bird avian influenza viruses to infect mammals. We have utilized a mouse model for influenza virus infection to examine 28 North American wild bird avian influenza virus isolates that include the hemagglutinin subtypes H2, H3, H4, H6, H7, and H11. We demonstrate that many wild bird avian influenza viruses of several different hemagglutinin types replicate in this mouse model without adaptation and induce histopathologic lesions similar to other influenza virus infections but cause minimal morbidity. These findings demonstrate the potential of wild avian influenza viruses to directly infect mice without prior adaptation and support their potential role in emergence of pandemic influenza.     

Postmortem findings of pulmonary lesions of older datum in intravenous drug addicts

Summary At post-mortem examination the lungs of 30 intravenous narcotic addicts were compared to two groups of 30 age- and sex-matched controls with no history of narcotic abuse. A distinctly uneven distribution of pulmonary pathology among the two groups was found, with various non-acute, non-granulomatous lesions dominating in the addict group. Microscopically, the typical pattern consisted of focally thickened fibrotic and hypercellular alveolar septa, accumulation of haemosiderin-laden macrophages in alveolar walls as well as in the lumina of alveoli and respiratory passages, and vascular lesions with full-thickness fibrosis of arterial walls. An attempt at quantitative scoring of the changes indicated that the extent of pulmonary pathology increases with the addict's age or duration of narcotic abuse and with the degree of social deterioration. The same changes could also be demonstrated in some control cases with a history of salicylate or alcohol abuse, or with known heart/lung disease.The addict group also exhibited myocardial alterations in 28 of 30 cases. Typical findings were myofibrillar degeneration and fatty infiltration.In 15 of 30 addicts morphological and toxicological examination did not yield a definitive cause of death. However, the present demonstration of cardiopulmonary pathology suggests that narcotic addicts may be prone to acute circulatory and/or respiratory derangement even if no overdose of drugs is taken.     

口服避孕药失效的药理分析与合理使用

目的科学认识口服避孕药的不良反应,明确药物避孕失败的药理学原因,指导合理用药,提高人口素质,达到优生优育的目的。方法通过临床用药经验,总结口服避孕药的主要不良反应、本类药物与其他药物之间的相互作用,并给出一些合理的用药建议。结果口服避孕药的主要不良反应包括早期的类早孕反应,严重的不良反应主要体现在增加心脑血管系统疾病的风险方面,但发生率较低,本类药物与肝药酶诱导剂、抗生素、抗结核病药以及抗癫痫药等合用,可导致避孕失败,指导合理使用本类药物可以增加用药的有效性和依从性。结论使用口服避孕药时需要避免与导致避孕失败的药物合用,同时积极指导本类药物的合理使用,开展健康教育,对广大育龄妇女正确、合理选择使用口服避孕药避孕具有积极意义。     

H9N2禽流感病毒反向遗传系统的构建和鉴定

目的 建立H9N2亚型禽流感病毒反向遗传系统,为人禽流感疫苗研制以及传播和致病机制等方面的研究提供技术平台.方法 使用RT-PCR方法获得禽流感H9N2亚型病毒A/Guangzhou/333/99(H9N2)的8条全长基因节段,然后克隆到双表达载体pCI-pol Ⅰ中,获得H9N2禽流感病毒的8个基因节段的8质粒系统.将构建好的8质粒共转染293T细胞后,收获上清接种鸡胚,然后对鸡胚尿囊液进行鉴定;对拯救的病毒进行鉴定.结果 8质粒系统转染293T细胞后可以成功拯救出H9N2禽流感病毒,血凝效价可达到29/50μl,生长特性与野生型病毒类似.结论 成功建立了H9N2禽流感病毒反向遗传系统.     

Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail

ObjectiveTo describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole.MethodsWe studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs.ResultsA total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8–43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths.ConclusionsTreatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.     

2017~2018年成都市三区县外环境禽流感监测分析

目的 监测四川省成都市三区县外环境中禽类流行性感冒（禽流感）病毒的分布状况,为人禽流感防控提供参考依据。方法 我中心在2017年5月~2018年5月采用实时荧光定量PCR检测成都市三区县外环境中甲型流感通用病毒,再将阳性标本进行H5、H7、N9和H9分型,采用χ2检验比较定性资料。结果 在497份样本中,甲型流感病毒阳性标本87份,检出率为17.91%;分型实验中,H5、H7、N9和H9分别检出7份、6份、12份和41份,其阳性检出率依次为1.41%、1.21%、2.41%、8.25%,未分型成功23份,占总样本的4.63%。结论 成都市三区县外环境存在禽流感病毒污染,有人感染禽流感风险;需加强对外环境及高危人群禽流感监测,并规范对市场的管理机制,落实消毒和检疫准入等预防措施。     

Generation and characterisation of monoclonal antibodies specific to avian influenza H7N9 haemagglutinin protein

Introduction: Emerging virulent strains of influenza virus pose a serious public health threat with potential pandemic consequences. A novel avian influenza virus, H7N9, breached the species barrier from infected domestic poultry to humans in 2013 in China. Since then, it has caused numerous infections in humans with a close contact to poultry. Materials and Methods: In this study, we describe the preliminary characterisation of five murine monoclonal antibodies (MAbs) developed against recombinant haemagglutinin (rHA) protein of avian H7N9 A/Anhui/1/2013 virus by their Western blot and enzyme-linked immunosorbent assay (ELISA) reactivity and binding affinity. Results: Of the five MAbs, four were highly specific to H7N9 HA and did not show any cross-reactivity in ELISA with rHA protein from pandemic as well as seasonal H1N1, H2N2, H3N2, H5N1 and influenza virus B (B/Brisbane/60/2008). However, one of the MAbs, MA-24, in addition to HA protein of H7N9 also reacted strongly with HA protein of H3N2 and weakly with HA of pandemic and seasonal H1N1 and H2N2. All the five MAbs also reacted with H7N9 rHA in Western blot. The MAbs bound H7N9 rHA with an equilibrium dissociation constant (K_D) ranging between 0.14 and 25.20 nM, indicating their high affinity to HA. Conclusions: These antibodies may be useful in developing diagnostic tools for the detection of influenza H7N9 virus infections.     

北京市1例人感染H9N2禽流感病例的流行病学调查与分析

目的 分析北京市人感染H7N9禽流感疫情强化监测中发现的1例人感染H9N2禽流感病例流行病学调查情况,为今后科学防控人感染H9N2禽流感疫情提供参考.方法 采用现场流行病学和实验室检测相结合的方法,收集病例流行病学资料,采集并检测病例、暴露环境和密切接触者等标本,分析流行病学特征和可能的感染来源.结果 病例发病第3日和第7日咽拭子标本检测均为H9N2禽流感病毒核酸阳性.病例发病前10天内无禽类接触史,但病例平时活动有暴露于H9N2禽流感病毒污染环境的可能.密切接触者在医学观察期内均未出现流感样症状.结论 该病例为北京市首例成人感染H9N2禽流感确诊病例,同时也是北京市第二例H9N2禽流感确诊病例.医疗机构加强流感样病例监测是及时发现人感染H9N2禽流感病例的重要手段.     

流感/禽流感病毒及其致病力鉴别的基因芯片技术研究

目的 建立流感/禽流感病毒及其致病力鉴别的基因芯片检测技术.方法 以血凝素(HA)、神经氨酸酶(NA)、核蛋白(NP)基冈作为靶片段,设计病毒检测和致病力特异性鉴别探针,建立基因芯片鉴别检测技术,采用单引物扩增法(SPA)处理样本核酸,分别对此芯片进行特异性、敏感性和符合率评价.结果 此芯片能够特异性的检测H1N1、H3N2、B型流感病毒及H5N1、H9N2禽流感病毒,敏感性分别为8HAU、16HAU、32HAU及8HAU、8HAU.致病力鉴别探针敏感性为32HAU.同RT-PCR方法比较,检测灵敏度为83.9%.结论 建立的常见流感病毒检测基因芯片特异性高、敏感性高、灵敏度高,更能够对致病力进行有效甄别,可作为临床诊断、传染病防控等方面的有益补充.     

Impact of clinical pharmacist in an Indian Intensive Care Unit

Background and Objectives:

A critically ill patient is treated and reviewed by physicians from different specialties; hence, polypharmacy is a very common. This study was conducted to assess the impact and effectiveness of having a clinical pharmacist in an Indian Intensive Care Unit (ICU). It also evaluates the clinical pharmacist interventions with a focus on optimizing the quality of pharmacotherapy and patient safety.

Materials and Methods:

The prospective, observational study was carried out in medical and surgical/trauma ICU over a period of 1 year. All detected drug-related problems and interventions were categorized based on the Pharmaceutical Care Network Europe system.

Results:

During the study period, average monthly census of 1032 patients got treated in the ICUs. A total of 986 pharmaceutical interventions due to drug-related problems were documented, whereof medication errors accounted for 42.6% (n = 420), drug of choice problem 15.4% (n = 152), drug-drug interactions were 15.1% (n = 149), Y-site drug incompatibility was 13.7% (n = 135), drug dosing problems were 4.8% (n = 47), drug duplications reported were 4.6% (n = 45), and adverse drug reactions documented were 3.8% (n = 38). Drug dosing adjustment done by the clinical pharmacist included 140 (11.9%) renal dose, 62 (5.2%) hepatic dose, 17 (1.4%) pediatric dose, and 104 (8.8%) insulin dosing modifications. A total of 577 drug and poison information queries were answered by the clinical pharmacist.

Conclusion:

Clinical pharmacist as a part of multidisciplinary team in our study was associated with a substantially lower rate of adverse drug event caused by medication errors, drug interactions, and drug incompatibilities.     

Production and diagnostic application of monoclonal antibodies against influenza virus H5

Nine monoclonal antibodies (mAbs) against avian influenza virus (AI) H5 subtype from mice immunized with inactivated virus H5N1 (A/Turkey/ON/6213/66) were produced. Upon testing, the results indicated that the binding epitopes of eight out of the nine mAbs were conformational, while one mAb (#7) reacted with denatured H5N1 only. Two mAbs #10 and #11 reacted with all of the thirteen H5 strains tested indicating that the binding epitopes of these mAbs were conserved among these H5 subtypes.Possible applications of these mAbs in rapid tests for H5 antigen were explored. Double antibody sandwich (DAS) ELISAs were developed using two selected mAbs #10 and #11. This DAS ELISA detects specific H5 viruses and is able to identify all thirteen H5 strains tested. Three mAbs showed reactivity with AI H5 antigen for both immunofluorescence (IF) and immunohistochemistry. A cELISA used to screen chickens that had been infected with an H5 virus was developed with mAb #9 and recombinant H5 antigen. The sera from chickens that have been infected with an H5N1 virus were examined using the cELISA. 80% of the sera from H5 infected chickens showed a positive H5 specific antibody response at 7 days post-infection (dpi) and remained positive until the end of the experiment on day 30 (>40% inhibition). This panel of the AI H5 specific mAbs is valuable for the development of various immunoassays.     

Detection of amantadine-resistant variants among avian influenza viruses isolated in North America and Asia

Here, we report the diversity of amantadine-resistant mutants among avian influenza A viruses with pandemic potential (H5, H6, H7, and H9 hemagglutinin subtypes). Drug-resistant variants were not detected among 1979--83 isolates, whereas 31.1% of H5 and 10.6% of H9 strains from Southeast Asia isolated in 2000-04 carried mutations in M2 protein. In North America, resistant variants occurred among H7 viruses only (16.4% of those tested). H6 viruses were amantadine-sensitive. These findings prompt concern regarding the control of pandemic influenza, the possibility that the next pandemic virus will be amantadine-resistant and the need to monitor the use of the drug in poultry.     

Vaccination of gallinaceous poultry for H5N1 highly pathogenic avian influenza: Current questions and new technology

Vaccination of poultry for avian influenza virus (AIV) is a complex topic as there are numerous technical, logistic and regulatory aspects which must be considered. Historically, control of high pathogenicity (HP) AIV infection in poultry has been accomplished by eradication and stamping out when outbreaks occur locally. Since the H5N1 HPAIV from Asia has spread and become enzootic, vaccination has been used on a long-term basis by some countries to control the virus, other countries have used it temporarily to aid eradication efforts, while others have not used it at all. Currently, H5N1 HPAIV is considered enzootic in China, Egypt, Viet Nam, India, Bangladesh and Indonesia. All but Bangladesh and India have instituted vaccination programs for poultry. Importantly, the specifics of these programs differ to accommodate different situations, resources, and industry structure in each country. The current vaccines most commonly used are inactivated whole virus vaccines, but vectored vaccine use is increasing. Numerous technical improvements to these platforms and novel vaccine platforms for H5N1 vaccines have been reported, but most are not ready to be implemented in the field.     

Evaluation of an epitope-blocking enzyme-linked immunosorbent assay for the detection of antibodies to influenza A virus in domestic and wild avian and mammalian species

An epitope-blocking enzyme-linked immunosorbent assay (bELISA) was developed for the detection of antibodies to influenza A virus in taxonomically diverse domestic and wild vertebrate species. In contrast to the bELISAs published previously that require reagent production, manipulation by the end-user, or have not been evaluated for use with both mammalian and avian species, this assay is performed using commercially available recombinant nucleoprotein antigen and corresponding nucleoprotein-specific monoclonal antibody and has been shown to work with multiple avian and mammalian species. The efficacy of the bELISA as a serum screening assay was compared to the agar gel immunodiffusion (AGID) assay using 251 serum samples obtained from experimentally infected mallards (Anas platyrhynchos) and raccoons (Procyon lotor). The concordance between the AGID assay and bELISA was 94.1% (95% CI = 89.9, 98.3) for raccoons, and 71.2% (95% CI = 63.5, 78.9) for mallards and 82.8% (95% CI = 78.2, 87.3) overall. The bELISA was more sensitive than the AGID assay as demonstrated by the detection of antibodies to influenza A virus at earlier time points in experimental infection studies and at higher serial dilutions. The efficacy of the bELISA to monitor natural influenza A virus exposure was also compared to the AGID assay using an additional 745 serum samples from six avian species and six mammalian species. This bELISA provides a rapid, reliable, and inexpensive technique for large-scale surveillance of influenza A virus exposure in taxonomically diverse vertebrate species.     

Development of rHA1-ELISA for specific and sensitive detection of H9 subtype influenza virus

A recombinant antigen-based single serum dilution ELISA was developed for simultaneous detection and subtyping of influenza viruses. Recombinant baculovirus encoding the hemagglutinin (HA₁ subunit) of H9N2 virus was generated. To evaluate the rHA1-ELISA, microplates were coated with purified HA1 protein and tested with reference control sera. Subsequently, 92 field sera collected from chickens suspected to be infected with H9N2 AIV were employed to test the efficacy of the rHA1-ELISA. The sera were tested simultaneously by HI and a commercial AIV ELISA kit. The rHA1-ELISA appeared to be highly specific and sensitive for direct detection of H9N2 antibodies in serum samples.     

Prevention and control of highly pathogenic avian influenza with particular reference to H5N1

Highly pathogenic avian influenza viruses of the H5N1 subtype emerged in Far East Asia in 1996 and spread in three continents in a period of 10 or less years. Before this event, avian influenza infections caused by highly pathogenic viruses had occurred in many different countries, causing minor or major outbreaks, and had always been eradicated.