HLA-linked genes and leprosy: a family study in Karigiri, South India.

The evidence for a genetic determination of susceptibility to leprosy is reviewed. To test the hypothesis that an HLA (histocompatibility leukocyte antigen)-linked gene is associated with such susceptibility, the association between the distribution of leprosy within a family and the segregation of HLA haplotypes was investigated among 72 families who lived in Karigiri, Tamil Nadu State, South India. A statistically significant association was found for families in which siblings had tuberculoid leprosy and in which neither parent had leprosy. The findings from the data of this study agree with those of two previous studies carried out among smaller populations is Surinam and Wardha, Maharashtra State, India. Such an agreement suggests that a genetic determinant which is linked to the major HLA locus on chromosome 6 and which is probably recessive affects susceptibility to tuberculoid leprosy in humans.     

Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.     

Appropriateness and clinical outcome of chest computed tomography without intravenous contrast: A study conducted in Pakistan

Background

Chest computed tomography (CT), including high-resolution CT (HRCT), has become an integral part of modern healthcare. It enables the physician to arrive at a diagnosis using a noninvasive approach. Our practice has shown that various chest CT scans without intravenous (IV) contrast, including HRCT, have no proper clinical indication. For the same reason, we have assessed the appropriateness of chest CT without IV contrast based on the evidence-based American College of Radiology (ACR) appropriateness criteria.

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

BACKGROUND: Abdominal obesity and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) increase cardiovascular risk. The very low-density lipoprotein (VLDL) is a triglyceride (TG)-rich particle. Frequent variations in the genes coding for enzymes and proteins involved in the VLDL catabolism have already been documented. The epistatic effect of such variants on the risk profile associated with abdominal obesity remains to be elucidated. OBJECTIVE: This study aims to assess the effect of combinations of frequent single-nucleotide polymorphisms (SNPs) in the VLDL catabolic pathway on the relation between abdominal obesity and fasting TG. METHOD: Only gene variants in the lipoprotein lipase, apolipoprotein (apo) CIII, hepatic lipase and apo E genes known to be frequent in the general population (allele frequency>5%) were included in this study. The presence of selected SNPs was detected by polymerase chain reaction-restriction fragment length polymorphism in a sample of 640 non-diabetic French Canadians at high cardiovascular risk (405 obese, 235 non-obese). RESULTS: Carrying more than two frequent gene variants involved in the VLDL catabolic pathway significantly increased the risk of hyperTG (odds ratio of TG>1.7 mmol/l=4.15; P=0.001). This effect was proportional to the number of SNPs and genes involved and was significantly amplified by the presence of abdominal obesity defined on the basis of waist circumference. CONCLUSION: When combined with abdominal obesity, epistasis in the VLDL pathway has a deleterious effect on fasting TG and coronary artery disease risk profile according to the TG threshold (1.7 mmol/l) used in medical guidelines for the assessment of the metabolic syndrome and associated risk.     

血浆白介素-37水平与冠心病的相关性研究

目的：探讨急性冠脉综合征（Acute Cornary Syndrome,ACS）患者血浆白介素-37 (Interleukin-37,IL-37）水平, 与白介素-18（Interleukin-18,IL-18）、C反应蛋白（C Reactive Protein,CRP）水平及冠脉病变程度的关系。方法：2016年1月至2016年12月因胸闷、胸痛等症状就诊于河北医科大学第二医院并行冠脉造影的患者作为研究对象,分为对照组、稳定型心绞痛及不稳定型心绞痛患者以及急性心肌梗死患者,每组30例。收集血液标本常规检测患者的生化指标,用酶联免疫吸附法（ELISA）检测血浆IL-37、IL-18,行心脏超声明确左室舒张末径（LVEDD）、左室射血分数（LVEF）,行冠脉造影术评估的冠脉Gensini评分。结果：心梗组的左室射血分数（LVEF)较对照组、稳定组、不稳定组降低（P<0.05）;而心梗组左室舒张末径（LVEDD）、脑钠肽（BNP）、肌钙蛋白I（TNI）、Gensini评分、肌酸激酶同工酶（CK-MB）较对照组、稳定组、不稳定组明显升高（P<0.05）。心梗组较不稳定组、对照组、稳定组的IL-37和 IL-18血浆水平明显升高（P<0.05）,不稳定组较对照组与稳定组IL-37 和IL-18血浆水平均明显升高（P<0.05）,稳定组较对照组IL-37和IL-18血浆水平升高（P<0.05）。心梗组的CRP水平较对照组、稳定组、不稳定组明显升高（P<0.05）。相关性分析显示,IL-37浓度与BNP,TNI,Cr,CK-MB,LVEDD,CHOL,TG,LDL,Gensini评分无明显相关,与CRP之间具有正相关性（r=0.532, P<0.01）,与LVEF之间具有负相关性（r=-0.442, P<0.01）,血浆IL-37与IL-18具有正相关性（r=0.808, P<0.01）。结论：ACS患者血浆IL-37明显升高,而且与血浆IL-18、CRP水平呈正相关性,与LVEF之间具有负相关性,提示IL-37可能成为ACS患者诊断和预后的一种新型炎症标志物。     

Nail involvement in leprosy: a study of 300 patients

Three hundred leprosy patients were recruited to study the pattern and frequency of nail changes. Nail changes, like longitudinal ridging in finger nails, transverse striations involving both finger and toe nails etc. which occurred with similar frequency in the PB and MB patients in comparison with the control group, were excluded from the analysis. Out of a total number of 150 PB patients, 84 (56%) showed nail changes. Fifty-eight (38.6%) patients showed changes in the finger nails, with an average of 3.2 involved nails per patient. Fifty-three (35.3%) patients showed changes in the toe nails, with an average of 3.0 nails per patient. The most common change observed was longitudinal melanonychia (32.4%) in the finger nails and longitudinal ridging (46.3%) in the toe nails.In comparison, 131/150 (87.3%) MB patients showed nail changes. Finger nail changes were seen in 102 (68%) patients with an average of 5.5 nails affected per patient. Changes in toe nails were seen in 116 (77.3%) patients, with an average of 6.0 nails involved per patient. The most common nail change observed was longitudinal melanonychia in 89/523, (17%) of the total involved finger nails and subungual hyperkeratosis in 164/702, (23.4%) of the total toe nails involvement. Out of a total of 32 colony patients, 31 (96.9%) showed nail changes both in finger and toe nails with an average of 7.9 and 8.4 affected nails per patient, respectively. The most common nail change observed was rudimentary nail(s) on fingers (29%) and toes (21.1%). Among MB patients, a significantly higher number had finger nail involvement in LL group. The frequency of nail involvement for both fingers and toes was significantly greater in LL as compared to BL group of patients. The frequency of nail involvement was significantly more in patients having disease for more than 5 years and in those having trophic changes secondary to loss of sensations and impaired circulation.     

Effect of levamisole on clinical outcome and DNCB conversion in leprosy patients. A long term study

Fifteen patients of lepromatous leprosy within first 6 months of diagnosis were studied. 7 controls received standard DDS treatment and placebo while 8 patients received cyclical levamisole treatment (150 mg daily for 3 days repeated after a gap of 2 weeks), in addition to standard DDS treatment. Patients were followed up clinically for lepra reactions, serial B.I. and DNCB test for 2 years. We observed that ENL reactions were more common and more severe in levamisole treated group while an upgrading type reaction occurred only in one of the control patients. B I. remained same in both groups throughout, while DNCB score was higher in control rather than levamisole treated groups. Thus, levamisole treatment does not seem to have caused stimulation of CMI in our patients as judged by DNCB reaction while it may have caused stimulation of humoral immunity as seen by higher incidence of ENL reaction. This may be undesirable in lepromatous patients.     

Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform

OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.     

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.     

基于细胞色素b和内转录间隔区基因序列的4个棕脊足螨地理种群遗传变异分析

目的　分析不同地理种群棕脊足螨（Gohieria fusca）遗传多样性和遗传分化。方法　自安徽省芜湖市（WH）、蚌埠市（BB）、亳州市（BZ）和浙江省嘉兴市（JX）等4个地区采集螨虫标本并筛选出棕脊足螨,采用PCR技术扩增棕脊足螨线粒体细胞色素b（cytochrome b, Cytb）和核糖体DNA内转录间隔区（internal transcribed spacer, ITS）基因并对扩增产物测序。采用Chromas 2和DNASTAR 1.00软件进行序列校对和拼接,采用DnaSP 5.10.00软件计算各种群单倍型多样性（Hd）、核苷酸多态性（Pi）,应用MEGA 10.2软件包计算遗传分化指数（Fst）和基因流（Nm）。采用Arlequin 3.1软件计算Tajima’s D和Fu’s FS值,并进行中性检验和分子方差分析;采用Network 10.2软件基于Median⁃joining法构建单倍型网络图。结果　棕脊足螨样本Cytb基因序列长度为372 bp、ITS基因序列长度为1 301 ~ 1 320 bp。基于线粒体Cytb基因和核糖体ITS基因序列分析发现,4个棕脊足螨地理种群均表现出较高遗传多样性（Hd = 0.804,Pi = 0.006 91）。分子方差分析发现,4个棕脊足螨地理种群间存在遗传分化（Fst = 0.202 40, P < 0.05）,且遗传变异主要来自种群内（79.76%）。基因流分析发现,4个棕脊足螨地理种群间局部存在高水平基因流（Nm > 1）。基于Cytb基因的中性检验发现,棕脊足螨WH种群Tajima’s D值和Fu’s FS值分别为-1.796 31和-3.293 98（P均< 0.05）,表明WH种群可能发生过历史扩张。单倍型网络图和系统发育树分析结果一致,均表明不同棕脊足螨地理种群无明显地理分布格局。基于ITS基因序列分析发现,4个棕脊足螨地理种群单倍型多样性（Hd）与核苷酸多态性（Pi）均较高,整体值分别为0.985和0.011 97,具有较高遗传多样性。分子方差分析发现,棕脊足螨Fst值为0.104 62（P < 0.05）,种群间存在中等程度遗传分化。基于ITS基因的中性检验发现,棕脊足螨整体Tajima’s D值和Fu’s FS值分别为-6.088 20和-1.935 99（P均> 0.05）,无明显历史扩张。结论　4个棕脊足螨地理种群遗传多样性较高,存在显著遗传分化。由于不同棕脊足螨地理种群间局部发生高水平基因流,未发现其明显地理分布格局。     

FCGR3A和FCGR3B基因拷贝数变异对HBV感染转归的影响

目的 探讨FCGR3A和FCGR3B基因拷贝数变异与HBV感染后不同转归和疾病进展的相关性。方法 收集2014年1月—2018年12月安徽医科大学第一附属医院和第二附属医院感染病科住院和门诊841例慢性HBV感染者和296例自限性HBV感染者外周血标本,并将慢性HBV感染者根据病情进展程度进一步分为慢性乙型肝炎（CHB）组、肝硬化（LC）组、肝细胞癌（HCC）组。采用AccuCopy技术定量分析两组患者外周血FCGR3A和FCGR3B基因拷贝数变异。计量资料两组间比较采用独立样本t检验,多组间比较采用单因素方差分析和Kruskal-Wallis H检验;计数资料组间比较采用χ²检验。同时采用χ²检验分析FCGR3基因CNV在不同组间的分布差异。应用年龄和性别校正的logistic回归模型综合分析CNV对HBV感染慢性化的影响。结果 慢性HBV感染组与自限性HBV感染组的FCGR3A、FCGR3B 拷贝数变异频率分布差异均有统计学意义（χ²值分别为11.406、19.143,P值均<0.05）。在慢性HBV感染后疾病...     

Transmission of leprosy: a study of skin and nasal secretions of household contacts of leprosy patients using PCR

It is generally held that dissemination of Mycobacterium leprae is from nasal mucosa and not through the skin of infected patients. In this study, we evaluated M. leprae in the unbroken skin and nasal secretions of multibacillary (MB) leprosy patients and their contacts. Specimens were examined by direct microscopy and polymerase chain reaction (PCR) for M. leprae DNA. Results showed that 60% of untreated MB leprosy patients examined histologically had acid-fast bacilli in the keratin layer. By PCR studies it was found that 80% of the patients had M. leprae DNA in skin washings and 60% had M. leprae DNA on swabs obtained from the nasal mucosa. Ninety-three contacts of the untreated MB cases were also tested for exposure to M. leprae by analyzing skin washings and nasal secretions by PCR. PCR analysis showed significant skin (17% positive) and nasal muscosal (4%) exposure in contacts before instituting treatment of the index cases. After 2 months of treating the index cases, all contacts tested were negative for M. leprae DNA. These data suggested that both skin and nasal epithelia of untreated MB leprosy patients contribute to the shedding of M. leprae into the environment and contacts of untreated MB cases are at risk for contact with M. leprae through both the nasal mucosa and exposed surfaces of their skin.     

Effect of BCG on the risk of leprosy in an endemic area: a case control study

The effect of BCG on the risk of leprosy was measured using a case-control design in an area endemic for the disease. In this study, 397 newly diagnosed cases and 669 controls matched for age, sex and locality were selected from a defined population. Information on exposure to BCG, contact with another case of leprosy, and relevant socioeconomic variables were obtained from the subjects. Having infectious (multibacillary) and noninfectious (paucibacillary) contacts in the household increased the risk of disease 11.7 times (p less than 0.001) and 2.7 times (p less than 0.001), respectively. Overall, the protection offered by BCG was not significant (odds ratio = 0.8; p = 0.17). However, BCG appeared to increase the risk for indeterminate leprosy (adjusted odds ratio = 2.7; p = 0.09) while protecting against borderline disease (adjusted odds ratio = 0.39; p = 0.03). It is possible that BCG causes a shift in the overall cell-mediated immune response, thus increasing the risk for milder and transient forms of leprosy while protecting against more serious forms. These findings may have important implications for the design and interpretation of vaccine trials. Namely, trials should be designed to measure the protective efficacy of vaccines against the more serious forms of leprosy, which have the greatest public health significance.