A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacologic therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. Clinical Trial Registration - http://clinicaltrials.gov Unique identifier: NCT01873950

FEE EXPENSES CORRELATION IN THE FIELD OF LAW AND OTHER EXPENSES ON FINANCIAL RESULT OF THE RUSSIAN ENTERPRISES

Purpose: to determine features of interrelation and influence of expenses by fee in the field of law and other expenses on financial result of the Russian enterprises. Methods: general-logical methods of knowledge, correlation and regression analysis, comparative analysis, graphic analysis. Results: in article features of interrelation and influence of fee expenses in the field of law and other expenses on financial result of the Russian enterprises are investigated. The general characteristic of subject relevance is given. The modern scientific works considering questions of interrelation and various factors influence on financial result are analyzed. Despite rather large number of publications on the matter, we revealed lack of works of the expenses of the enterprises on external legal services considering influence on their financial result. For elimination of this gap, as the first of steps, we generalized data on proceeds from sales, profits before the taxation, prime costs, fee expenses in the field of law, fee expenses of science, fee of education, fee expenses of audit organizations. Specific weight of the presented expenses in prime cost is calculated. This statistics is presented from 2011 for 2016 in a section of the federal districts of Russia. Further the coefficients of correlation and factors which are most closely interconnected with revenue and profit were defined. The regression model of the resulting sign (proceeds from sales) and factorial signs is constructed (fee expenses in the field of law and fee expenses of science). An assessment of quality of the received regression equation is in conclusion given. Scientific novelty: in article on the basis of the regression analysis an assessment of interrelation and to influence of fee expenses in the field of law for proceeds from sales is given. Practical importance: the main results, provisions and conclusions of article can be used when developing strategy of the enterprises, at decision-making in the field of management of expenses. The data obtained in article will be useful to scientists-economists, scientific and pedagogical workers to expansion and better understanding of subject domain. The methodological base of article can act as an example when forming research competences of students, undergraduates and graduate students

Women Derivative Names with Suffix -Чиц (А) / -Щиц(А) in the Russian Media Space

ABSTRACT The article is devoted to functioning in the modern russian language word-formation type with the suffix -чиц (а)/-щиц (а) as a means of expressing the derivational category of femininity. The language material of the study is represented by 459 lexemes with the suffix -чиц (а)/-щиц (а), functioning in modern contexts. The semantic and stylistic characteristics of the considered word-formation type are given. The conclusion is made about the productivity and universality of the feminitives -чиц (а)/-щиц (а) in modern Russian, which allows them to remain in the center of the word-formation category of femininity.RESUMEN El artículo está dedicado a funcionar en el tipo moderno de formación de palabras en ruso con el sufijo –чиц (а) / - щиц (а) como un medio para expresar la categoría derivada de la feminidad. El material lingüístico del estudio está representado por 459 lexemas con el sufijo –чиц (а) / - щиц (а), que funciona en contextos modernos. Se dan las características semánticas y estilísticas del tipo considerado de formación de palabras. Se llega a la conclusión sobre la productividad y la universalidad de las feminitivas –чиц (а) / - щиц (а) en el ruso moderno, lo que les permite permanecer en el centro de la categoría de feminidad de formación de palabras.

Matrix metalloproteinases and their inhibitors

Metalloproteinase was discovered by Gross and Lapierre in 1962 for the first time. Since then, more than 20 enzymes of this family have been characterized, and their functions have been studied in detail. Metalloproteinases take part in blood pressure regulation, the cell matrix extension and remodeling, anesthesia, multiple sclerosis, blood coagulation, wound healing, tumor transformation and metastasis, etc. This review covers structure of matrix metalloproteinases, their mechanism of action, as well as MMP's endogenous and exogenous inhibitors. A special place is occupied by analysis of approaches to matrix metalloproteinases synthetic inhibitors and their activity. This review demonstrates the perspectivity of new selective matrix metalloproteinase inhibitors design

Polycystic ovary syndrome

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.Robert J Norman, Ruijin Wu and Marcin T Stankiewic

The preparation of the Ti-Al alloys based on intermetallic phases

This article deals with a method of obtaining materials in the Ti-Al system. Research was carried out in accordance with the phase diagram of the system state. It was established, that both single-phase and multiphase systems, containing finely dispersed intermetallic compositions of phases Ti3Al, TiAl and TiAl3, are formed. Additionally, it was found that the pure finely dispersed (coherent-scattering region (CSR) up to 100 nm) intermetallic compound TiAl3 is formed at molar ratio of Ti:Al = 1:3. Experimentally proved the possibility of produce the complex composition of alloys and intermetallic compounds and products based on them

Role of salicylic acid in acclimation to low temperature

Low temperature is one of the most important limiting factors for plant growth throughout the world. Exposure to low temperature may cause various phenotypic and physiological symptoms, and may result in oxidative stress, leading to loss of membrane integrity and to the impairment of photosynthesis and general metabolic processes. Salicylic acid (SA),phenolic compound produced by a wide range of plant species, a may participate in many physiological and metabolic reactions in plants. It has been shown that exogenous SA may provide protection against low temperature injury in various plant species, while various stress factors may also modify the synthesis and metabolism of SA. In the present review, recent results on the effects of SA and related compounds in processes leading to acclimation to low temperatures will be discussed

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005

Vaginal dysbiosis as a factor contributing to the development of recurrent lower urinary tract infections

Introduction. It is known that women are significantly more likely to suffer from lower urinary tract infections (LUTIs) than men. Nowadays, there is growing evidence to demonstrate the impact of vaginal microbiota on the development of recurrent LUTIs.Objectives. To demonstrate the impact of vaginal microbiota disorders on the development of recurrent lower urinary tract infections.Materials & methods. Seventy-five women with recurrent LUTIs 19 – 76 years old were enrolled in this study. The examination was performed according to the algorithm developed in the Department of Urology and Surgical Andrology, Russian Medical Academy of Continuous Professional Education. Real-time PCR of vaginal epithelial cell scrapings (Femoflor 16) was performed to comprehensively evaluate the vaginal microbiota.Results. Vaginal dysbiosis was detected in 47/75 (62.7%) women with recurrent UTIs: moderate vaginal dysbiosis was detected in 25/75 (33.3%) women and severe dysbiosis — in 22/75 (29.3%) women. A moderate correlation between the presence/absence of vaginal dysbiosis and the number of LUTI recurrences over 6 months was found (r = 0.310; p = 0.007). Vaginal dysbiosis was significantly more common among peri- and postmenopausal women with recurrent LUTIs than reproductive women (OR = 4.85; 95% CI = 1.45 – 16.17).Conclusion. Vaginal dysbiosis contributes to the development of recurrent LUTIs with more relapses. Vaginal microbiota disorders and, consequently, recurrent LUTIs are more common in peri- and postmenopausal women than reproductive women

Матриксные металлопротеиназы и их ингибиторы

Metalloproteinase was discovered by Gross and Lapierre in 1962 for the first time. Since then, more than 20 enzymes of this family have been characterized, and their functions have been studied in detail. Metalloproteinases take part in blood pressure regulation, the cell matrix extension and remodeling, anesthesia, multiple sclerosis, blood coagulation, wound healing, tumor transformation and metastasis, etc. This review covers structure of matrix metalloproteinases, their mechanism of action, as well as MMP's endogenous and exogenous inhibitors. A special place is occupied by analysis of approaches to matrix metalloproteinases synthetic inhibitors and their activity. This review demonstrates the perspectivity of new selective matrix metalloproteinase inhibitors design.В 1962 г. Gross J и Lapierre C впервые была обнаружена металлопротеиназа. С тех пор было охарактеризовано более 20 ферментов этого семейства, а также подробно изучены их функции. Металлопротеиназы учавствуют в регуляции кровяного давления, развитии и ремоделировании клеточного матрикса, обезболивании, рассеянном склерозе, процессе свертывания крови, заживления ран, в процессах опухолевой трансформации и метастазирования и др. Настоящий обзор посвящён рассмотрению представлений о структуре матриксных металлопротеиназ, механизме их действия, а так же эндогенным и экзогенным ингибиторам матриксных металлопротеиназ. Особый акцент сделан на анализе подходов к дизайну синтетических ингибиторов матриксных металлопротеиназ и их активности. Представленный обзор демонстрирует перспективность конструирования новых селективных ингибиторов матриксных металлопротеиназ