Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis

A microRNA profile of human CD8(+) regulatory T cells and characterization of the effects of microRNAs on Treg cell-associated genes.

Recently, regulatory T (Treg) cells have gained interest in the fields of immunopathology, transplantation and oncoimmunology. Here, we investigated the microRNA expression profile of human natural CD8(+)CD25(+) Treg cells and the impact of microRNAs on molecules associated with immune regulation. We purified human natural CD8(+) Treg cells and assessed the expression of FOXP3 and CTLA-4 by flow cytometry. We have also tested the ex vivo suppressive capacity of these cells in mixed leukocyte reactions. Using TaqMan low-density arrays and microRNA qPCR for validation, we could identify a microRNA 'signature' for CD8(+)CD25(+)FOXP3(+)CTLA-4(+) natural Treg cells. We used the 'TargetScan' and 'miRBase' bioinformatics programs to identify potential target sites for these microRNAs in the 3'-UTR of important Treg cell-associated genes. The human CD8(+)CD25(+) natural Treg cell microRNA signature includes 10 differentially expressed microRNAs. We demonstrated an impact of this signature on Treg cell biology by showing specific regulation of FOXP3, CTLA-4 and GARP gene expression by microRNA using site-directed mutagenesis and a dual-luciferase reporter assay. Furthermore, we used microRNA transduction experiments to demonstrate that these microRNAs impacted their target genes in human primary Treg cells ex vivo. We are examining the biological relevance of this 'signature' by studying its impact on other important Treg cell-associated genes. These efforts could result in a better understanding of the regulation of Treg cell function and might reveal new targets for immunotherapy in immune disorders and cancer

Experience and analyses of results in open and laparoscopic partial nephrectomy

Renal cancer takes the 10th place on incidence among malignant new growths, and on the level of an increase concedes only to a prostate cancer. Today surgical treatment remains by the single efficient method of treatment of the localized renal tumors. In recent years low-invasive surgical interventions at new growths of renal began to be applied more often. In this article experience of realization of 74 operations executed by laparoscopic and open access on the basis of USMU chair of urology in the urological department of MAI "City Clinical Hospital №40" during the 2013-2018 years is explained. The comparative analysis of partial nephrectomy depending on access is carried out. The analysis of 35 patients treatment is made.Рак почки занимает 10 место по уровню заболеваемости среди злокачественных новообразований, а по уровню роста уступает только раку предстательной железы. На сегодняшний день хирургическое лечение остается единственным эффективным методом лечения локализованного рака почки. В последние годы малоинвазивные хирургические вмешательства при новообразованиях почек стали применяться чаще. В данной статье изложен опыт выполнения 74 операций, выполненных лапароскопическим и открытым доступами на базе кафедры урологии УГМУ в отделении урологии МАУ "Городская клиническая больница №40" за 2013-2018 года. Проведен сравнительный анализ резекций почек в зависимости от доступа на основании изучения данных наблюдений за пациентами в течение 5 лет. Выполнен анализ отдаленных результатов лечения 35 пациентов

Urological tactics in cases of gestational pyelonephritis

Gestational pyelonephritis is a state of the art in practice of urological, gynecological, microbiogical, dermatovenerological and immunological departments. Firstly it’s related with gestational pyelonephritis in a past medical history: complications in pre- and postnatal periods, miscarriage of pregnancy and stillbirth, progression of chronical desease that leading to woman disability. In addition, gestational pyelonephritis has a negative affection on a fetus status and child health. These problems are loom large in social and medical domain.Острый гестационный пиелонефрит вновь и вновь обращает на себя внимание врачей многих специальностей: урологов, акушеров-гинекологов, микробиологов, дерматовенерологов, иммунологов. В первую очередь, это обусловлено проблемами, которые имеют причинно-следственную связь с перенесенным гестационным пиелонефритом: осложнения в дородовом и послеродовом периодах, невынашивание беременности и мертворождение, развитие хронических заболеваний у женщин, порой приводящих к инвалидизации. Несомненно, гестационный пиелонефрит влияет на состояние плода и соответственно на здоровье ребенка. Эти проблемы относятся к категории чрезвычайно важных социальных и медицинских вопросов

Laparoscopic surgery in urology and complications

Laparoscopic surgeon was recommended in urological treatment of diseases for a long time ago not only among Russian urologists but also among the world. From 2002 in our department were completed more than 1500 laparoscopic procedures concerning: idiopathic varicocele, renal cysts, renal and prostate cancer, hydronephrosis, Ormond desease, vesicovaginal fistula and laparoscopic treatment of urolithiasis in cases? When we could not use endoscopic treatment. In the present work we are summarize not only operation experiences but specify possible complications as well to which we have confronted in the last 15 years.Видеолапароскопическая хирургия в лечении урологических заболеваний давно зарекомендовала себя с хорошей стороны не только среди урологов России, но и мира. С 2002 года в нашем отделении проводятся лапароскопические операции по поводу: варикоцеле, кист почек, рака почки и рака простаты, гидронефроза, болезни Ормонда, пузырно-влагалищных свищах, а также конкрементов почки и мочеточника, которые невозможно прооперировать эндоскопическим путём. В данной работе мы суммируем не только опыт 1500 лапароскопических операций, но и освещаем возможные осложнения, с которыми мы сталкивались на протяжении последних 15 лет

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed similar to 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.Peer reviewe

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016

Species structure of entomopathogenic fungi in the soil of Jata Nature Reserve

Study determines the species composition and frequency of entomopathogenic fungi in the soil of Jata Nature Reserve (E Poland). Fungi were isolated from soil samples by 'insect bait method' with Galleria mellonella and Tenebrio molitor larvae. We found five species of entomopathogenic fungi: Beauveria bassiana, Isaria farinosa, I. fumosorosea, Metarhizium anisopliae and Lecanicillium lecanii. The two most common species M. anisopliae and I. farinosa comprised 50.1% and 21.8% of the total number of the infected insects, respectively. Species composition of entomopathogenic fungi in the examined stands and the number of infected insects differed significantly depending on the sampling season and insect used as bait

The optimal time for hematopoietic stem cell translantation for Hodgkin's lymphoma. International guidelines and real practic in Russia and former USSSR countries (Part II)

The influence of previous antitumor therapy the efficacy and tolerability of high-dose chemotherapy with autologous hematopoietic progenitor cells transplantation (HCST) in 369 patients with Hodgkin, s lymphoma in the clinics of Russia and CIS countries was analyzed. Longterm treatment results of patients who have received 1 or 2 therapy lines before deciding about HCST were comparable (5‑year overall survival (OS) – 67 ± 3.8 % and 71 ± 5.0 %; freedom from treatment failure survival (FFTF) – 52.6 ± 3.9 % and 61 ± 5.0 %, respectively). The worst results (p &lt; 0.05) are in patients who have received &gt; 2 lines of therapy prior HSCT (5‑year OS – 46 ± 9.7 %, FFTF – 38.4 ± 9.0 %). The negative impact of previous treatment on the efficiency of hematopoietic material collection and hematopoiesis reconstitution as well observed in patients who received &gt; 2 lines of therapy. Therefore, if the delay of HSCT in patients who achieved remission on secondline therapy was caused by organizational problems, for optimum results is necessary to conduct HSCT not later than second relapse while maintaining tumor chemosensitivity (third disease remission). However, when remission is not achieved after second-line therapy, is necessary to change the treatment regimen and performing HSCT only at confirmation of tumor chemosensitivity, because regardless of prior therapy line number, this approach leads to better results than earlier performing HSCT without remission.</p