Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms

Gaucher disease, the most prevalent sphingolipidosis, is caused by the deficient activity of acid beta-glucosidase, mainly due to mutations in the GBA gene. Over 200 mutations have been identified worldwide, more than 25 of which were in Spanish patients. In order to demonstrate causality for Gaucher disease, some of them: c.662C>T (p.P182L), c.680A>G (p.N188S), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1093G>A (p.E326K), c.1289C>T (p.P391L), c.1292A>T (p.N392I), c.1322T>C (p.I402T), and the double mutants [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), were expressed in Sf9 cells using a baculovirus expression system. Other well-established Gaucher disease mutations, namely c.1226A>G (p.N370S), c.1342G>C (p.D409H), and c.1448T>C (p.L444P), were also expressed for comparison. The levels of residual acid beta-glucosidase activity of the mutant enzymes produced by the cDNAs carrying alleles c.662C>T (p.P182L), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1289C>T (p.P391L), and c.1292A>T (p.N392I) were negligible. The c.1226A>G (p.N370S), c.1322T>C (p.I402T), c.1342G>C (p.D409H), c.1448T>C (p.L444P), and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]) alleles produced enzymes with levels ranging from 6 to 14% of the wild-type. The three remaining alleles, c.680A>G (p.N188S), c.1093G>A (p.E326K), and [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]), showed higher activity (66.6, 42.7, and 23.2%, respectively). Expression studies revealed that the c.1093G>A (p.E326K) change, which was never found alone in a Gaucher disease-causing allele, when found in a double mutant such as [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), decreases activity compared to the activity found for the other mutation alone. These results suggest that c.1093G>A (p.E326K) should be considered a "modifier variant" rather than a neutral polymorphism, as previously considered. Mutation c.680A>G (p.N188S), which produces a mutant enzyme with the highest level of activity, is probably a very mild mutation or another "modifier variant."     

神经性厌食症患者体重指数的对照分析

目的 :探讨神经性厌食症患者体重指数 (BMI)的特点及疾病的临床特征。方法 :采用进食障碍调查问卷 (EDI-1)对 3 0名神经性厌食症患者和 3 0名正常对照者进行评定 ,计算EDI -1量表分、BMI。结果 :根据期望BMI和目前BMI的差值 ,厌食症患者可分为追求更瘦组和不追求更瘦组。不追求更瘦组的目前BMI最低 ,追求更瘦组的目前BMI次之 ,正常对照组目前BMI最高 ,差异具有显著性 (F =5 4 15 ,P <0 0 1) ;两病例组间期望BMI没有差异 (P >0 0 5 ) ,但都低于正常对照组。追求更瘦组EDI -1量表总分最高、不追求更瘦组次之、对照组最低 ,差异具有显著性 (P <0 0 1)。结论 :体重过低的厌食症患者可能希望体重增加。但无论患者是否希望体重增加 ,期望体重指数都低于正常 ,实际上都是怕胖的。追求更瘦的患者可能预后较差 ,这可能与患者较严重的认知偏差以及某些心理特征有关。     

精神分裂症病人及家属受歧视状况

目的：了解精神分裂症病人及其家属受歧视状况，探讨歧视对精神分裂症病人及其家属的影响。方法：应用自编问卷在北京地区对精神分裂症病人(N=225)、精神分裂症病人家属(N=230)、社区居民(N=257)和精神科医护人员(N=283)进行调查。结果：42％的病人报告他们受到了单位不公正对待，受到同事或同学歧视，被邻居看不起，并导致恋爱或婚姻失败。56%的家属报告为避免歧视把病人患精神病的事对外保密。全部4组受试中85％以上的人相信歧视会降低病人的自信心，75％以上的人相信歧视给家属造成很大的心理压力，70％以上的人相信歧视严重影响病人的生活，60％以上的人相信歧视使病人的家庭成员减少了他们应有的社交活动。与其他三组人群比较，精神科医护人员更同意精神病人及其家属受歧视是常见的现象，更相信歧视会给他们的生活带来严重影响。与病人和家属比较，对歧视现象的存在社区居民的认同较低，但他们同样认为歧视对病人和家属有消极影响。结论：精神分裂症病人遭遇到的歧视突出地表现在与个人基本社会生活密切有关的工作、婚姻和人际交往三个方面。社会歧视对病人及其家属的心理和社会生活产生了严重影响。     

A reversed-phase high-performance liquid chromatographic assay for the determination of N-acetylcysteine in aqueous formulations

A stability-indicating assay is described for the determination of N-acetylcysteine in aqueous pharmaceutical formulations. The sample is diluted to an appropriate concentration with dilute aqueous orthophosphoric acid. An aliquot of the solution, containing added l-tyrosine as an internal standard, is chromatographed using a 10-mum C(18) stationary phase with dilute orthophosphoric acid (pH 2.0) containing 0.5% w/v of sodium perchlorate as the mobile phase. The assay, which has a relative standard deviation of about 0.8%, can also be used as a test for related impurities in N-acetylcysteine. It is also suitable for determining the N-acetylcysteine content of the drug substance.     

Clinical methods in psychiatric genetics. II. The high risk approach

The study of individuals at "high" risk for developing psychiatric disorders is useful in confirming that a biological trait marker identified in patient populations is also present in genetically susceptible individuals who have never been ill, and predicts the future onset of illness. We outline a systematic method for deciding which variables to choose and how many individuals are required in order for a study to have sufficient power. We demonstrate how these decisions depend on the assumptions that can be made with regard to the mode of inheritance of the biological trait, the relationship of the biological trait to illness, and the magnitude of the mean difference observed between patients and controls. We also quantify the increased power of studying offspring of two affected parents rather than offspring of one affected parent.     

Prevalence of mental disorder in an urban population in central Sweden

The principal reason for this epidemiological study was the lack of psychiatric morbidity studies in a predominantly urban population, by psychiatrists in direct interviews. The psychiatric examination, covering 1970-71, included a representative selection of 2,283 persons, 18-65 years old from "former" Stockholm County, and the 12-month prevalence of mental disorders was measured. The total of non-participants was 12%. Forty-seven percent had a psychiatric diagnosis - significantly more women (54%) than men (40%). Excluding the psychosomatic diagnoses, 31% of the population received a psychiatric diagnosis, which agrees closely with other contemporary studies of mental disorder in the Nordic countries. The primary diagnoses were: neuroses 26%, psychosomatic diagnoses 16%, schizophrenic/paranoid conditions or other psychoses 0.6%, affective disorders 0.2%, psychoorganic syndromes 1.2%, psychopathy 0.2%, character neurosis 1%, drug dependence 0.2% (as a primary or a secondary diagnosis 0.6%), alcoholism 1.4% (as a primary or a secondary diagnosis 3.1%) and mental retardation 0.4% (as a primary or a secondary diagnosis 0.8%).     

Associations Between Thyroid Hormone Levels and Urinary Concentrations of Bisphenol A,F, and S in 6-Year-old Children in Korea

ObjectivesBisphenol A (BPA) is used in the electrical, mechanical, medical, and food industries. Previous studies have suggested that BPA is an endocrine disruptor. Regulation of BPA has led to increased use of bisphenol F (BPF) and bisphenol S (BPS). However, few studies have investigated the associations of BPF and BPS with thyroid dysfunction in children. Our study investigated the associations of prenatal BPA and early childhood BPA, BPF, and BPS exposure with thyroid function in 6-year-old children.MethodsPrenatal BPA concentrations were measured during the second trimester of pregnancy in an established prospective birth cohort. We measured urinary BPA, BPF, and BPS concentrations and thyroid hormone levels (thyroid-stimulating hormone, total T₃, and free T₄) in 6-year-old children (n=574). We examined the associations between urinary bisphenol concentrations and percentage change of thyroid hormone concentrations using multivariate linear regression. We also compared thyroid hormone levels by dividing the cohort according to BPA, BPF, and BPS concentrations.ResultsThe associations between prenatal BPA and total T₃ levels were statistically significant in all models, except for girls when using a crude model. The associations between urinary BPA and BPS concentrations and levels of all thyroid hormones were not statistically significant. However, we observed that lower free T₄ levels (−1.94%; 95% confidence interval, −3.82 to −0.03) were associated with higher urinary BPF concentrations in girls only.ConclusionsOur findings identified significant associations between prenatal BPA exposure and total T₃ levels in all children and between BPF exposure and free T₄ levels in girls only.     

Polyphenols and Human Health: The Role of Bioavailability

Polyphenols are a group of phytochemicals with potential health-promoting effects. They are classified as flavonoid (flavonols, flavanols, flavones, flavanones, isoflavones, and anthocyanins) and non-flavonoid molecules (phenolic acids, hydroxycinnamic acids, lignans, stilbenes, and tannins). Although an increasing number of trials have shown a correlation among polyphenol consumption and a reduction in risk factors for chronic diseases, discrepancies in explaining their positive effects have been found in terms of the bioavailability. In fact, polyphenols show a low bioavailability due to several factors: interaction with the food matrix, the metabolic processes mediated by the liver (phase I and II metabolism), intestine and microbiota. On the other hand, the biological activities of phenol compounds may be mediated by their metabolites, which are produced in vivo, and recent studies have confirmed that these molecules may have antioxidant and anti-phlogistic properties. This review discusses the studies performed in vivo, which consider the polyphenol bioavailability and their different food sources. Factors influencing the biological effects of the main classes of polyphenols are also considered.     

Trends in Vitamin C Consumption in the United States: 1999–2018

Low intakes of fruits and vegetables have resulted in suboptimal intakes of several micronutrients, including vitamin C. This cross-sectional study used data from 84,902 children/adults (≥1 y) who completed a 24-h dietary recall as part of the United States National Health and Nutrition Examination Survey (1999–2018). Mean vitamin C intakes from foods/beverages were calculated as were trends in major food/beverage sources of vitamin C. Percentages below the Estimated Average Requirement (EAR) were estimated. Overall, mean vitamin C consumption declined by 23% (97–75 mg/d; p-value for trend < 0.001). 100% fruit juice was the leading source of vitamin C (25.6% of total or 21.7mg/d), but this declined by 48% (25–13 mg/d; p-value for trend < 0.001). Whole fruit increased among children/adolescents (+75.8%;10–17 mg/d; p-value for trend < 0.001), but not adults, while the vegetable contribution was generally unchanged. The proportion of the population below the EAR increased by 23.8% on a relative scale or 9 percentage points on an absolute scale (38.3–47.4%). Declines in vitamin C intake is driven largely by decreases in fruit juice coupled with modest increases in whole fruit. Due to associations between vitamin C intake and numerous health outcomes these trends warrant careful monitoring moving forward.