Chronic Idiopathic Cough: A Discrete Clinical Entity?

STUDY OBJECTIVES: Despite the success of specialist cough clinics, there is increasing recognition of a subgroup of chronic coughers in whom a diagnosis cannot be made even after thorough, systematic investigation. We call this condition chronic idiopathic cough (CIC). The aim of this study is to compare the clinical characteristics of CIC patients with those of coughers in whom a diagnosis has been established (non-CIC) to see if there is a recognizable clinical pattern that distinguishes CIC from non-CIC. DESIGN: Retrospective analysis of the medical records of chronic cough patients. SETTING: The Royal Brompton Hospital Chronic Cough Clinic, London. PATIENTS: One hundred patients with chronic cough referred to the Royal Brompton Hospital Cough Clinic between October 2000 and February 2004. RESULTS: Seventy-one percent of all patients were female. Median age was 57 years (range, 19 to 81 years), with a median duration of symptoms of 48 months (range, 2 to 384 months). The primary diagnoses were CIC (42%), postnasal drip syndromes (22%), gastroesophageal reflux disease (16%), asthma (7%), and others (13%). In CIC patients, the median age at referral, age at onset of cough, and proportion of females did not differ significantly from non-CIC patients. CIC patients had a longer median duration of cough (72 months vs 24 months, p = 0.002), were more likely to report an upper respiratory tract infection (URTI) as the initial trigger of their cough (48% vs 24%, p = 0.0014), and had a significantly lower cough threshold in response to capsaicin (log concentration of capsaicin required to induce five or more coughs, - 0.009 vs 0.592, p = 0.032) than non-CIC patients. CONCLUSIONS: Patients with CIC commonly describe a URTI that initiates their cough, which then lasts for many years, and they demonstrate an exquisitely sensitive cough reflex. We believe that CIC may be a distinct clinical entity with an as-yet unidentified underlying pathology.     

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2016–17 season: Comparison with the 2010–11 to 2015–16 seasons

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2016–17 Japanese influenza season, we measured the 50% inhibitory concentration (IC₅₀) of these NAIs for influenza virus isolates from patients and compared them with the results from the 2010–11 to 2015–16 seasons.Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC₅₀ was determined by a neuraminidase inhibition assay using a fluorescent substrate.A total of 276 virus isolates, 6 A (H1N1)pdm09 (2.2%), 249 A (H3N2) (90.2%), and 21 B (7.6%), had the IC₅₀ measured for the four NAIs. B isolates included 11 (52.4%), 9 (42.9%), and one (4.8%) of the Victoria, Yamagata, and undetermined strains, respectively.No A (H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2016–17 season. No isolate with highly reduced sensitivity to the four NAIs have been found for A (H3N2) or B from the 2010–11 to 2016–17 seasons. No significant trend of increase or decrease was found in the geometric mean IC₅₀s of the four NAIs during the seven studied seasons.These results indicate that the sensitivity to the four commonly used NAIs has been maintained and that any change in the effectiveness of these NAIs would be minute. Common usage of NAIs for patient treatment has not been a driving force in the selection of NAI resistant viruses.     

Evaluation of anthrax vaccine safety in 18 to 20 year olds: A first step towards age de-escalation studies in adolescents

Background/objectivesAnthrax vaccine adsorbed (AVA, BioThrax^®) is recommended for post-exposure prophylaxis administration for the US population in response to large-scale Bacillus anthracis spore exposure. However, no information exists on AVA use in children and ethical barriers exist to performing pre-event pediatric AVA studies. A Presidential Ethics Commission proposed a potential pathway for such studies utilizing an age de-escalation process comparing safety and immunogenicity data from 18 to 20 year-olds to older adults and if acceptable proceeding to evaluations in younger adolescents. We conducted exploratory summary re-analyses of existing databases from 18 to 20 year-olds (n = 74) compared to adults aged 21 to 29 years (n = 243) who participated in four previous US government funded AVA studies.MethodsData extracted from studies included elicited local injection-site and systemic adverse events (AEs) following AVA doses given subcutaneously at 0, 2, and 4 weeks. Additionally, proportions of subjects with ≥4-fold antibody rises from baseline to post-second and post-third AVA doses (seroresponse) were obtained.ResultsRates of any elicited local AEs were not significantly different between younger and older age groups for local events (79.2% vs. 83.8%, P = 0.120) or systemic events (45.4% vs. 50.5%, P = 0.188). Robust and similar proportions of seroresponses to vaccination were observed in both age groups.ConclusionsAVA was safe and immunogenic in 18 to 20 year-olds compared to 21 to 29 year-olds. These results provide initial information to anthrax and pediatric specialists if AVA studies in adolescents are required.     

Toxicology of 3-epi-deoxynivalenol,a deoxynivalenol-transformation product by Devosia mutans 17-2-E-8

Microbial detoxification of deoxynivalenol (DON) represents a new approach to treating DON-contaminated grains. A bacterium Devosia mutans 17-2-E-8 was capable of completely transforming DON into a major product 3-epi-DON and a minor product 3-keto-DON. Evaluation of toxicities of these DON-transformation products is an important part of hazard characterization prior to commercialization of the biotransformation application. Cytotoxicities of the products were demonstrated by two assays: a MTT bioassay assessing cell viability and a BrdU assay assessing DNA synthesis. Compared with DON, the IC₅₀ values of 3-epi-DON and 3-keto-DON were respectively 357 and 3.03 times higher in the MTT bioassay, and were respectively 1181 and 4.54 times higher in the BrdU bioassay. Toxicological effects of 14-day oral exposure of the B6C3F₁ mouse to DON and 3-epi-DON were also investigated. Overall, there were no differences between the control (free of toxin) and the 25 mg/kg bw/day or 100 mg/kg bw/day 3-epi-DON treatments in body and organ weights, hematology and organ histopathology. However, in mice exposed to DON (2 mg/kg bw/day), white blood cell numbers and serum immunoglobulin levels were altered relative to controls, and lesions were observed in adrenals, thymus, stomach, spleen and colon. Taken together, in vitro and in vivo studies indicate that 3-epi-DON is substantially less toxic than DON.     

Circulating intercellular adhesion molecule 1 predicts non-specific elevation of α1-fetoprotein

Molecules governing cellular interactions have been suggested to be involved in the spurious elevation of 1-fetoprotein (AFP) in non-neoplastic liver disease. To explore this controversial issue, we measured AFP, circulating intercellular adhesion molecule 1 (cICAM-1), and common liver function tests in 111 patients (71 male, 40 female). Eighty-four patients had non-neoplastic chronic liver disease and 27 had hepatocellular carcinoma. The concentration of cICAM-1 was determined immunoenzymatically. In patients with non-neoplastic chronic liver disease, univariate analysis demonstrated a significant correlation between AFP and cholinesterase (R=–0.397,P<0.001), aspartate aminotransferase (R=0.421,P<0.001), bilirubin (R=0.231,P<0.05) and cICAM-1 (R=0.430,P<0.001). Multivariate analysis among these variables and AFP indicated cICAM-1 to be the strongest independent predictor of AFP. We conclude that cICAM-1 compares favourably with liver function tests in predicting non-specific AFP variations in non-neoplastic chronic liver disease, suggesting a link between targeting of the inflammatory damage to the hepatocyte and development of neoplasia.Abbreviations AFP 1-fetoprotein - cICAM-1 circulating intercellular adhesion molecule 1     

Modified osmotic fragility test for the laboratory diagnosis of hereditary spherocytosis

A modified osmotic fragility test, based on measurement of hemolysis in four hypotonic NaCl solutions and logarithmic linearization of osmotic fragility curve is, like the "Pink test," a specific and sensitive test for the laboratory diagnosis of hereditary spherocytosis.     

Subcostal echocardiography to determine right ventricular pacing catheter position and control advancement of electrode catheters in intracardiac electrophysiologic studies: M mode and two dimensional studies

To assess the value of subcostal echocardiography in determining the position of a right ventricular pacing catheter, M mode and two dimensional echocardiography was performed from four different locations in 30 patients. Subcostal M mode echocardiography had a higher detection rate of the pacing catheter than did the precordial M mode examination. However, with M mode echocardiography it was not possible to determine the position of the pacing catheter from any of the locations. The subcostal two dimensional echocardiography demonstrated the full length of the pacing catheter in the right heart chambers and its anatomic position in all patients and proved superior to the precordial approach. This technique allowed the detection of complications related to pacing catheters. A pacing catheter ejected from the ventricular cavity was found in the inferior vena cava. Perforation of the ventricular septum with a bipolar electrode for temporary pacing was also diagnosed.

Subcostal two dimensional echocardiography was used in 20 patients as an additional technique for controlling the advancement of electrode catheters in right heart intracardiac electrophysiologic studies. The electrode catheters were successfully positioned at all routine sites in all patients except one. Thus, subcostal two dimensional echocardiography has advantages over fluoroscopy in the determination of pacing catheter position and in controlling the advancement of electrode catheters in intracardiac electrophysiologic studies.     

泻白散及其主药体外抗氧化活性研究

目的 建立泻白散和方中3味主药甘草、地骨皮、桑白皮的体外抗氧化活性测定方法,并对31批药材和10批泻白散煎液的抗氧化活性进行测定。方法 采用紫外可见分光光度法检测一定浓度的药材提取液引起DPPH溶液吸光度（A）值降低,考察波长为517 nm,分别探索3味药材抗氧化活性成分的提取条件;并进行不同溶剂的吸收考察、专属性考察、DPPH线性考察、药材提取液线性考察、精密度试验、重复性试验、耐用性考察等方法学验证;以清除DPPH自由基的半抑制浓度（IC₅₀）作为评价指标,对泻白散和方中3味药材的体外抗氧化活性进行考察。结果 地骨皮、甘草、桑白皮和泻白散提取液的IC₅₀均值为0.31、1.24、1.49和0.91 g/L,泻白散提取工艺对方中药物抗氧化活性的保留均值为56%。结论 建立的抗氧化活性测定方法可用于泻白散及方中主药的抗氧化活性测定,为多维度评价中药和中药材质量提供新思路。     

遗传性凝血因子Ⅴ缺乏症九例基因分析

目的分析9例遗传性凝血因子Ⅴ（FⅤ）缺乏症患者的临床表现及分子致病机制。方法对1999年4月至2019年9月就诊于中国医学科学院血液病医院的9例遗传性FⅤ缺乏症患者进行回顾性分析：应用活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）及FⅤ促凝活性（FⅤ∶C）测定进行表型诊断；使用高通量靶向测序筛查F5基因变异，Sanger测序验证并分析双亲携带情况；Swiss-model进行三维结构分析，ClustalX-2.1软件进行同源保守性分析。结果9例患者的FⅤ∶C为0.1～10.6 U/dl，其中8例患者有出血病史，以皮肤/黏膜出血最为多见（3例），其余1例未发生出血事件。所有患者中纯合子5例，复合杂合子4例，共检测到12个致病或疑似致病F5基因突变，其中c.6100C>A/p.Pro2034Thr、c.6575T>C/p.Phe2192Ser、c.1600_1601delinsTG/p.Gln534*、c.4713C>A/p.Tyr1571*和c.952+5G>C为首次报道。结论该研究新发现的基因突变丰富了与遗传性FⅤ缺乏症相关F5基因突变谱，高通量测序方法可以有效检测F5基因突变。