[Molecular genetics in diagnosis of Coats disease: combination of oligogenic variants associated with different forms of hereditary retinal dystrophy]. / Molekulyarno-geneticheskie nakhodki pri diagnostike bolezni Koatsa: sochetanie oligolokusnykh izmenenii, svyazannykh s raznymi nozologicheskimi formami nasledstvennoi retinopatii.

Coats disease (OMIM 300216) is a form of hereditary retinal dystrophy, which occurs due to congenital abnormality of retinal vessels and features unilateral exudative vitreoretinopathy. Coats disease mostly occurs sporadically; its genetic cause is still undetermined. Molecular genetic research including whole exome sequencing by the NGS method was used to define a genetic cause of the observed phenotype. Two heterozygous variants in different genomic loci associated with other forms of hereditary retinal dystrophy were detected, a rare variant in the HMCN1 gene c.9571C>T, p.(Arg3191Cys), and a known pathogenic variant in the NPHP4 gene c.2930C>T, p.(Thr977Met). The HMCN1 gene is responsible for dominant age-related macular degeneration (OMIM 603075), pathogenic variants in the NPHP4 gene cause recessive Senior-Løken syndrome 4 (OMIM 266900). These genes encode the proteins that are involved in the regulation of integrity of the blood-retinal barrier in the vascular endothelium (NPHP4) and retinal pigment epithelium (HMCN1). The identified mutation in the NPHP4 gene could lead to decreased function of the NPHP4 protein and contribute to the development of retinal degeneration, potentially of oligogenic nature.

SNP-Based Chromosomal Microarray Analysis for Detecting DNA Copy Number Variations in Fetuses with a Thickened Nuchal Fold.

The aim of the study was to assess the diagnostic potential of SNP-based chromosomal microarray analysis for detecting pathogenic copies number variations (CNVs) in fetuses with a normal karyotype, in which an increase in the nuchal translucence of >2.5 mm was detected by ultrasound at a gestational age of 11 weeks to 13 weeks 6 days. Materials and Methods: The study included 225 pregnant women who underwent invasive prenatal diagnostic procedures following the detection of an isolated thickening of the fetal nuchal fold. The fetal material obtained was examined using a cytogenetic test; if a normal karyotype was confirmed, chromosomal microarray analysis was performed as a second-line test. Results: Pathogenic CNVs were detected in 22 of 225 fetuses (9.8%) with a normal karyotype. Of these 22 fetuses, pathogenic CNVs not classified as syndromes were detected in 14 cases (63.6%), and those previously described as syndromes - in 8 cases (36.4%). In 9 fetuses (41%), CNVs in two non-homologous chromosomes were determined; these findings indicated a high likelihood of carrying balanced translocations in the parents. Indeed, when analyzing the parent's karyotype, in 8 out of 9 couples, balanced translocations were found in one of the parents. Conclusion: Using chromosomal microarray analysis in fetuses with a thickened nuchal fold makes it possible to increase the ability to detect chromosomal imbalances, including those caused by pathological meiotic segregation of parental reciprocal translocation.

[Epigenomic variations manifesting as a loss of heterozygosity affecting imprinted genes represent a molecular mechanism of autism spectrum disorders and intellectual disability in children]. / Épigenomnye variatsii v vide poteri geterozigotnosti, zatragivaiushchei imprintirovannye geny, kak molekuliarnyi mekhanizm rasstroistv autisticheskogo spektra i umstvennoi otstalosti u detei.

AIM: Long continuous stretches of homozygosity (LCSH) are regularly detected in studies using molecular karyotyping (SNP array). Despite this type of variation being able to provide meaningful data on the parents' kinship, uniparental disomy and chromosome rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Despite their direct relationship to imprinting, LCSH in imprinted loci have not been considered in terms of pathogenicity. The present work is aimed at studying LCSH in chromosomal regions containing imprinted genes previously associated with disease in children with idiopathic intellectual disability, autism, congenital malformations and/or epilepsy. MATERIAL AND METHODS: Five hundred and four patients with autism spectrum disorders and intellectual disability were examined. RESULTS: LCSH affecting imprinted loci associated with various diseases were identified in 40 (7.9%) individuals. Chromosomal region 7q21.3 was affected in twenty three cases, 15q11.2 in twelve, 11p15.5 in five, 7q32.2 in four. Four patients had 2 LCSH affecting imprinted loci. Besides one LCSH in 7q31.33q32.3 (~4 Mbp) region, all LCSH were 1-1.6 Mbp. Clinically, these cases resembled the corresponding imprinting diseases (e.g. Silver-Russell, Beckwith-Wiedemann, Prader-Willi, Angelman syndromes). Parental kinship was identified in 8 cases (1.59%), which were not affected by LCSH at imprinted loci. CONCLUSION: The present study shows that LCSH affecting chromosomal regions 7q21.3, 7q32.2, 11p15.5 and 15p11.2 occur in about 7.9% of children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations is obviously common in a group of children with neurodevelopmental disorders. LCSH less than 2.5-10 Mbp are usually ignored in molecular karyotyping (SNP array) studies and, therefore, an important epigenetic cause of intellectual disability, autism or epilepsy with high probability remains without attention.

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

[BRAF-positive paucicellular variant of anaplastic carcinoma in the presence of tall cell variant papillary thyroid cancer]. / BRAF-pozitivnyi malokletochnyi variant anaplasticheskoi kartsinomy na fone papilliarnogo raka shchitovidnoi zhelezy iz vysokikh kletok.

To paper describes a case of paucicellular anaplastic cancer in the presence of tall cell variant papillary thyroid carcinoma. Microscopic examination showed that the differentiated component of the tumor was composed of papillary structures with tall cells, the height of which exceeded 3-4 times the width. Its anaplastic component consisted of fibrous tissue with occasional spindle-shaped cells and focal lymphocytic infiltration to the extent of 70%. The spindle-shaped cells expressed cytokeratins, ß-catenin, p53, and vimentin. The tumor cells and lymphocytes showed an association with Epstein-Barr virus. Molecular genetic study of the tumor revealed the following mutations: BRAF p.Val600Glu (p.V600e was), HRAS p.His27His (p.H27H), PIK3CA p.Glu545Lys (p.E545K), TP53 p.Arg248Gln (p.R248Q).

[Structural variations of the genome in autistic spectrum disorders with intellectual disability]. / Strukturnye variatsii genoma pri autisticheskikh rasstroistvakh s umstvennoi otstalost'yu.

AIM: To analyze structural variations in the genome in children with autism and intellectual disability. MATERIAL AND METHODS: Using high-resolution karyotyping (AffymetrixCytoScan HD Array) and original bioinformatic technology, 200 children with autism and intellectual disability were studied. RESULTS AND CONCLUSION: Data on structural variations in the genome in children with autism and intellectual disability are provided. Causative genomic pathology (chromosome abnormalities and copy number variations - CNV) was determined in 97 cases (48.5%). Based on these RESULTS: 24 candidate genes for autism with intellectual disability were selected. In 16 cases (8%), the chromosome mosaicism manifested as aneuploidy of whole autosomes and sex chromosomes (gonosomes) was identified. In 87 children (43.5%), there were genomic variations, which are characteristic of the so-called «grey zone¼ of genetic pathology in mental illnesses. Bioinformatic analysis showed that these genomic variations had a pleiotropic effect on the phenotype.

[Von Hippel-Lindau disease type 2-related pancreatic neuroendocrine tumor and adrenal myelolipoma].

The paper describes a case of von Hippel--Lindau-related pancreatic neuroendocrine tumor and adrenal myelolipoma in a 44-year-old woman. The pancreatic tumor and a left retroperitoneal mass were removed in the women in July 2014 and May 2015. Histological examination of the pancreatic tumor revealed that the latter consisted of clear cells forming tubular and tubercular structures showing the expression of chromogranin A, synaptophysin, and cytokeratins 18 and 19 and a negative response to CD10 and RCC. The adrenal medullary mass presented as clear-cell alveolar structures with inclusions of adipose tissue mixed with erythroid, myeloid, and lymphoid cells. The clear-cell component of the adrenal gland expressed neuroendocrine markers with a negative response to cytokeratins, CD10, and RCC. Molecular genetic examination yielded a signal corresponding to two copies of the VHL gene. No deletions or amplifications of the gene were detected. Cases of von Hippel--Lindau disease concurrent with adrenal pheochromocytoma and myelolipoma and simultaneous pancreatic involvement were not found in the literature.

[15-year experience of moxifloxacin in the treatment of patients with bacterial rhinosinusitis].

The article summarizes 15 years of experience of the use of moxifloxacin (Avelox) in Russia in patients with acute bacterial rhinosinusitis. Emphasize its high bactericidal activity against a broad spectrum of microorganisms- from basic agents to the atypical and anaerobic microflora. The results of these studies suggest the continued effectiveness of the dosage of 400 mg a short course (7 days) over 15 years of practical use of the drug, which in its clinical efficacy is superior to amoxicillin/clavulanate, cefuroxime axetil and levofloxacin. The safety profile of moxifloxacin, studied at the population level is not associated with an increased risk of adverse effects in compliance with the dosing regimen, taking into account the indications and contraindications.

Association of non-invasive prenatal testing and chromosomal microarray analysis for prenatal diagnostics.

The purposes of this study is to examine possibility to use combination of non-invasive prenatal testing (NIPT) and chromosomal microarray analysis (CMA) for prenatal diagnostics and their advantages between combined first-trimester screen with confirmation by karyotyping of CVS or amniocytes. A total of 1968 pregnant women, in this study, have undergone prenatal screening and/or diagnostic tests. NIPT is more suitable and efficient for the detection of aneuploidy. However, this test has limitations for detection deletions/duplications. Use of CMA for confirmation of some NIPT findings or as first test for women with ultrasound abnormalities can detect small imbalances in chromosomes. Combination of NIPT and CMA allows a higher prenatal detection of chromosomal abnormalities.

[Therapeutic modalities for the management of cough associated with acute respiratory viral infection, effective in an otolaryngologist's practice].

The objective of the present study was to evaluate the effectiveness ascoril therapy in comparison with the treatment using the mucoactive agent lasolvan in the adult patients suffering from productive cough associated with acute viral respiratory infection. Patients and methods. The study included 120 patients suffering from productive cough associated with acute viral respiratory infection. They were divided into two groups. The patients comprising group 1 (n=6.) were treated with ascoril, those in group 2 (n=60) were given lasolvan. Results. The effectiveness of the treatment of cough in group 1 was found to be higher compared with that in group 2 (p<0.05); moreover, it was associated with better dynamics of certain indicators of the quality of life, such as the social activity level, vitality, and general health (p<0.05). The safety of the proposed treatment was confirmed by the absence of the adverse events throughout the entire treatment period.

[Postinfectious cough - a modern view to the pathogenesis and treatment options].

The paper presents a literature review regarding the pathogenesis and therapy options of postinfectious (PI) cough.It was shown that the pathogenesis of PI cough may be multifactorial, and in general, the state is of a great interest for otolaryngologists, because on the one hand, there is a large number of patients with PI cough, and on the other hand, it is unclear practical solution. In this regard, since the pharmacological viewpoint of the largest positive effect can be expected with combination of medications with synergistic actions. One of them is Ascoril expectorant whose effectiveness in both children and adults with respect to the dynamics of cough has been demonstrated in many studies.

[Antisense oligonucleotides: a new class of biologically active molecules]. / Antismyslovye oligonukleotidy--printsipial'no novyi klass aktivnykh molekul.

Data available in literature on the biological activity of antisense oligonucleotides are reviewed with emphasis on the results of tests of the related antitumor and antiasthmatic preparations and the basic novelty of these drugs.

[The effect of endogenous opioid peptides and their synthetic analogs on T-cell immunity]. / Vliianie éndogennykh opioidnykh peptidov i ikh sinteticheskikh analogov na T-kletochnyi immunitet.

The effects of the endogenous opioid peptides met- and leu-enkephalins and their synthetic analogs such as DAGO, DADLE, dalargin on the formation and activity of cytolytic T lymphocytes in response to alloantigen stimulation were studied in the unidirectional mixed culture of lymphocytes. It was shown that the maximum stimulating effect of the opioids manifested itself on their addition 24-48 hours after the initiation of incubation and on addition of suboptimal concentrations of an antigen to the culture. The selective opioid receptor ligands mu- and delta-types + (DAGO and DADLE) have a heterodirectional effect on the formation of specific T killer cells in the mixed culture of lymphocytes.

[The effect of endogenous opioid peptides and their synthetic analogs on the activity of natural killer cells]. / Vliianie éndogennykh opioidnykh peptidov i ikh sinteticheskikh analogov na aktivnost' estestvennykh killernykh kletok.

Met- and leu-enkephalins and their synthetic analogs DAGO, DADLE, and dalargin were tested for their effects on the activity of natural killer cells. The endogenous opioid peptides and dalargin were shown to be able to enhance the cytolytic activity of natural killer cells.

[The beta-carotene stimulation of cellular immunity reactions in mice]. / Stimuliatsiia beta-karotinom reaktsii kletochnogo immuniteta u myshei.

The immunomodulating properties of synthetic beta-carotene were studied in C57Bl/6 and BALB/c mice using the tests of proliferative, cytotoxic and suppressor activity, and evaluating the adhesive capacity of macrophage lineage cells. Long-term feeding of C57Bl/6 mice with beta-carotene microgranules (0.1-0.5 mg of active substance per mouse) led to enhanced T cell proliferative response to ConA, which lasted for 15-45 days. Administration of beta-carotene oil solution to BALB/c mice previously immunized with alloantigens (0.17-0.34 mg of beta-carotene per mouse) enhanced T-cell cytotoxicity against L-929 and YAC-1 cells and macrophage cytotoxicity against L-929 cells. The treatment also reduced T-suppressor activity as shown in the assays of inhibition of the lymphocyte blast transformation reaction and mixed lymphocyte culture. The treatment with both preparations of beta-carotene enhanced the adhesive properties of macrophages and related cells, and induced the increased production of oxygen active radicals by these cells.

[The effect of synthetic beta-carotene on the primary immune response of CBA strain mice]. / Vliianie sinteticheskogo beta-karotina na pervichnyi immunnyi otvet myshei linii CBA.

Synthetic beta-carotene was studied for its effect on a primary humoral immune response to thymus-dependent antigen of sheep red cells. beta-Carotene was demonstrated to have immunomodulatory action. The effect depended on the dose of the agent and its administration time after immunization. The agent could produce both stimulant and suppressive effects.

[The effect of beta-carotene on interleukin-2 production and mitogen-induced proliferation of T-lymphocytes]. / Vlianie beta-karotina na produktsiiu interleikina-2 i mitogenindutsirovannuiu proliferatsiiu T-limfotsitov.

Interleukin-2 (IL-2) production followed by with aftereffect of the immunosuppressive agent hydrocortisone and mitogen-induced proliferation of T lymphocytes were studied in the presence of artificial beta-carotene. Treatment of CBA mice with the drug was performed within various periods. beta-Carotene was found to elevate IL-2 secretion and the effect was both time- and dose-dependent. The drug removed immunosuppression developed after intraperitoneal administration of hydrocortisone. At the same time, beta-carotene stimulated mitogen-induced proliferation of T cells, which was dose-dependent.