Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Balanovska EV, Petrushenko VS, Koshel SM, Pocheshkhova EA, Chernevskiy DK, Mirzaev KB, Abdullaev ShP, Balanovsky OP

The lack of information about the frequency of pharmacogenetic markers in Russia impedes the adoption of personalized treatment algorithms originally developed for West European populations. The aim of this paper was to study the distribution of some clinically significant pharmacogenetic markers across Russia. A total of 45 pharmacogenetic markers were selected from a few population genetic datasets, including ADME, drug target and hemostasis-controlling genes. The total number of donors genotyped for these markers was 2,197. The frequencies of these markers were determined for 50 different populations, comprised of 137 ethnic and subethnic groups. A comprehensive pharmacogenetic atlas was created, i.e. a systematic collection of gene geographic maps of frequency variation for 45 pharmacogenetic DNA markers in Russia and its neighbor states. The maps revealed 3 patterns of geographic variation. Clinal variation (a gradient change in frequency along the East-West axis) is observed in the pharmacogenetic markers that follow the main pattern of variation for North Eurasia (13% of the maps). Uniform distribution singles out a group of markers that occur at average frequency in most Russian regions (27% of the maps). Focal variation is observed in the markers that are specific to a certain group of populations and are absent in other regions (60% of the maps). The atlas reveals that the average frequency of the marker and its frequency in individual populations do not indicate the type of its distribution in Russia: a gene geographic map is needed to uncover the pattern of its variation.

Received: 2020-11-06

Published online: 2020-12-19

DOI: 10.24075/brsmu.2020.080

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VIEWS 3487

Volkov AA, Budnik NV, Zuban ON, Abdulaev MA, Plotkin DV, Reshetnikov MN

At the current stage of development of urology, selection of the surgical method for cases of severe obstructive diseases of the upper urinary system remains a challenge. This study aimed to explore the results of application of a buccal graft (BG) to remedy extended recurrent strictures and obliterations of the distal ureter. Seven patients with the mentioned diseases had undergone surgery: for six of them, the method of choice was complete BG ureteroplasty, one had onlay ureteroplasty. One intervention was laparoscopic, the remaining surgeries were open. The length of the replaced ureteral defect was 5–8 cm. In five cases, the flap was additionally vascularized with the iliac muscle, in one we used omentum tissue, in another — both the iliac muscle and the omentum. There were no fatalities registered, nor severe complications as per the Clavien–Dindo classification. The patients were followed-up for 4–18 months; as of today, no recurrence cases were identified. Control examinations showed complete patency of the neoureter and good vascularization of the BG. Thus, this method can be an option in cases disallowing distal ureter restoration with tissues of the patient's own urinary tract or segments of the gastrointestinal tract.

Received: 2020-10-25

Published online: 2020-12-17

DOI: 10.24075/brsmu.2020.079

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VIEWS 2769

Maltseva DV, Poloznikov AA, Artyushenko VG

Intestinal epithelial cells are constantly exposed to physiologically hypoxic environment. The further reduction of tissue oxygen delivery may result in the intestinal epithelial cells function impairment, being a sign of active inflammation. The cultivation conditions are important when performing in vitro studies, since those may affect the cells’ properties. The study was aimed to assess the integrin receptor expression in the human colon adenocarcinoma Caco-2 cell line when simulating both hypoxic condition using the cobalt chloride and microcirculation. Transcriptome analysis revealed the significantly increased expression of the integrin receptors ITGA2 and ITGA5 α2- and α5-subunit genes under hypoxic conditions, as well as the reduction of ITGA5 during incubation in the microfluidic chip. The expression of β-subunits did not change. Analysis of microRNA transcriptomes revealed the decreased expression of hsa-miR-766-3p and hsa-miR-23b-5p microRNA. One of the validated targets for both microRNAs is mRNA of gene ITGA5. It has been shown that microcirculation makes it possible to bring the intestinal epithelial cells cultivation conditions closer to physiological conditions. The possible biological significance of the detected integrin expression profile alterations and the role of microcirculation have been discussed.

Received: 2020-11-09

Published online: 2020-12-17

DOI: 10.24075/brsmu.2020.078

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VIEWS 2484

Nikulin SV, Poloznikov AA, Sakharov DA

To increase the efficiency of drug development process, it is important to improve performance of preclinical experiments. A major drawback of the currently used in vitro intestinal barrier models is that it takes a significant time to obtain functional enterocyte monolayers with formed tight junctions. In this work, we have optimized various parameters such as cell density and different coatings, for a more rapid and efficient producing Caco-2 cell monolayers suitable for further experiments. In vivo microscopy and impedance spectroscopy were used to monitor cells state under various conditions. To determine possible biological mechanisms affected by exposure to various protein substrates, the transcriptomic analysis was applied. It was shown that collagen IV coating of the cell growth substrate significantly increased the rate of proliferation and migration of Caco-2 cells. This effect allows forming a functional monolayer of epithelial cells with tight junctions within 24 hours. Optimally, the initial cell density should be 90,000 to 200,000 cells/cm2. It was observed that collagen IV was poorly expressed by Caco-2 cells while the collagen IV receptor was expressed at a relatively high level in these cells. Laminin-332, another basement membrane component, was found to have no significant effect on times of formation of functional epithelial monolayers. Thus, using the optimal parameters determined in this study allows to significantly improve efficiency of using the in vitro intestinal barrier models.

Received: 2020-11-09

Published online: 2020-12-15

DOI: 10.24075/brsmu.2020.077

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VIEWS 2354

Kovtun AS, Averina OV, Poluektova EU, Kostyuk GP, Danilenko VN

Recently much attention is paid to investigation of the gut microbiome impact on children's mental health. The study was aimed to detect alterations in the taxonomic composition and content of bacterial genes encoding key enzymes involved in the metabolism of neuroactive compounds in the metagenomes of healthy young children and adolescents. The whole metagenome sequencing was used to obtain the metagenomic data of the faecal specimens. The bioinformatics algorithm developed and the catalogue of homologs created were used to identify the changes in abundance of bacterial genes and metagenomic signatures in the studied metagenomes. The core neurometabolic signature of the healthy children gut microbiota included the Bacteroides uniformis, Faecalibacterium prausnitzii and Lachnospiraceae bacterium species, as well as genes involved in production of acetic, propionic and butyric acids, glutamate and enzymes possessing antioxidant activity. Comparison of metagenomes in children of different age groups revealed significant (p < 0.1) changes in the average abundance for 3 bacterial genera and 18 species. The higher alpha diversity of the adolescents’ microbiota was observed both at the genus and species level. Furthermore, in the adolescents’ microbiota metagenomes the increased average relative abundances for the genes encoding enzymes involved in production of SCFAs, glutamate, tryptophan and compounds with antioxidant properties, histidine degradation and linoleic acid conjugation were observed (p < 0.1). The study results support the evidence that healthy gut microbial communities become more diverse and functional as their human hosts become older.

Received: 2020-11-13

Published online: 2020-12-11

DOI: 10.24075/brsmu.2020.076

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VIEWS 2604

Akhmadullina DR, Konovalov RN, Shpilyukova YuA, Grishina DA, Berdnikovich ES, Fomenko SS, Fedotova EYu, Illarioshkin SN

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by language and behaviour deficits, which is considered the second most common cause of early-onset dementia. Detection of brain atrophy patterns is important for FTD diagnosis. However, the visual assessment of magnetic resonance imaging data may not be sensitive enough requiring the use of objective gray matter (GM) volume determination method. The study was aimed to assess the GM atrophy pattern in patients with FTD compared to control group patients using voxel-based morphometry (VBM). The study included 16 patients with FTD (12 patients with nonfluent agrammatic variant primary progressive aphasia (nfvPPA), three patients with behavioral variant of FTD, and one patient with logopenic variant PPA) and 10 healthy volunteers. VBM of patients with FTD and healthy controls revealed three significant (pFWE-corr < 0.05) atrophy areas in the left inferior frontal, left fusiform, and left supramarginal gyri. Taking into account the predominance of patients with nfvPPA in the group of FTD patients, the additional VBM of this group and control group was carried out, which revealed a distinct atrophy pattern: the reduced GM volume was detected in the left inferior frontal and left middle frontal gyri (pFWE-corr < 0.05). The results obtained indicate that regardless of the clinical variant, there is a certain atrophy pattern characteristic of FTD, which involves both frontotemporal areas and parietal lobe. The example of nfvPPA shows that each variant of the disease is associated with distinct localization of atrophy.

Received: 2020-10-21

Published online: 2020-12-08

DOI: 10.24075/brsmu.2020.075

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VIEWS 2505

Nersisyan SA, Galatenko AV, Maltseva DV, Ushkaryov YuA, Tonevitsky AG

Hypoxia accompanies various pathophysiological processes, including progression of tumors and metastasis. One of the mechanisms of molecular response of cells to hypoxia implies recruitment of specific miRNAs that regulate the expression of their target genes. This study aimed to evaluate the hypoxia-induced change in expression of miRNAs and their target genes in the HT-29 human colorectal adenocarcinoma cell line with the help of integrated miRNA and mRNA sequencing. To simulate hypoxia, the cells were treated with cobalt (II) chloride. We registered a significant change in expression of sixteen human miRNAs. Six of them (hsa-miR-18a-5p, hsa-miR-22-3p, hsa-miR-27a-5p, hsa-miR-182-5p, hsa-miR-215 -5p, hsa-miR-425-5p) had a significant proportion of target genes that had the expression changing in the opposite direction. Based on the bioinformatic analysis of interactions between differentially expressed transcription factors and miRNAs, we built a possible regulatory network with its main hubs being HIF-1α, p65, с-Myc, and Egr1 (encoded by the HIF1A, RELA, MYC and EGR1 genes).

Received: 2020-10-26

Published online: 2020-12-07

DOI: 10.24075/brsmu.2020.074

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VIEWS 2450

Molchanova EE, Polunina VV, Polyaev BA, Plotnikov VP, Lobov AN, Parastaev SA

Stroke remains one of the leading causes of disability; therefore, it is important to investigate factors that might affect the quality of life of stroke patients and refine rehabilitation technologies for better functional gains. The aim of this paper was to study possible factors that determine the quality of life in the residual ischemic stroke period. The MOS SF-36 health survey was completed by 210 patients undergoing early rehabilitation at a stroke care unit. The study revealed a significant decline in some quality of life indicators correlated with advancing age and severity of the condition (correlation coefficient –0.5; р < 0.01). Both physical and mental component summary scores were lower in women than in men (p < 0.01 and p < 0.001, respectively). High scores on the majority of the applied subscales were observed in the patients with a vertebrobasilar stroke, as compared with those who had suffered a carotid stroke (p < 0.05). The early rehabilitation regimen complemented with acupuncture in the acute stroke period and the subsequent rehabilitation program at the Rehabilitation Hospital significantly contributed (р < 0.05) to improving the quality of life of stroke patients in the residual stroke period.

Received: 2020-10-20

Published online: 2020-12-05

DOI: 10.24075/brsmu.2020.073

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VIEWS 2503