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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Zhorina YuV, Abramovskikh OS, Ignatova GL, Ploshchanskay OG

Bronchial asthma is a multifactorial disease underpinned by chronic inflammation. The atopic phenotype of BA implies the presence of similar molecular mechanisms of pathogenesis between the patients. The aim of this study was to analyze the associations between the development of atopic BA/its remission and the following polymorphisms of interleukin genes: IL4 (rs2243250; C-589T), IL10 (rs1800896; G-1082A; rs1800872; C-592A), and IL13 (rs20541; Arg130Gln). Using allele-specific polymerase chain reaction (PCR), we studied the listed SNPs in the mixed urban sample of patients with BA (n = 53) and the controls (n = 30) residing in South Ural. The analysis revealed that genotype АА of IL10 (rs1800872) occurred more frequently in the control group (23.3%) than in the patients with atopic BA (5.7%) (OR = 0.197; 95% CI [0.047–0.832]; р = 0.031). No differences in genotype frequencies were observed between the patients with atopic BA and the controls for other studied polymorphisms. Our study failed to demonstrate the association of the listed polymorphisms and BA remission.

Received: 2019-09-25

Published online: 2019-10-22

DOI: 10.24075/brsmu.2019.067

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VIEWS 3090

Kiseleva YaYu, Shishkin AM, Ivanov AV, Kulinich TM, Bozhenko VK

Adoptive immunotherapy that makes use of genetically modified autologous T cells carrying a chimeric antigen receptor (CAR) with desired specificity is a promising approach to the treatment of advanced or relapsed solid tumors. However, there are a number of challenges facing the CAR T-cell therapy, including the ability of the tumor to silence the expression of target antigens in response to the selective pressure exerted by therapy and the dampening of the functional activity of CAR T cells by the immunosuppressive tumor microenvironment. This review discusses the existing gene-engineering approaches to the modification of CAR T-cell design for 1) creating universal “switchable” synthetic receptors capable of attacking a variety of target antigens; 2) enhancing the functional activity of CAR T cells in the immunosuppressive microenvironment of the tumor by silencing the expression of inhibiting receptors or by stimulating production of cytokines.

Received: 2019-10-03

Published online: 2019-10-18

DOI: 10.24075/brsmu.2019.066

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VIEWS 3242

Maksimova MYu, Dubovitskaya YuI, Krotenkova MV, Shabalina AA

Cerebral venous sinus thrombosis (CVT) becomes the cause of stroke in less than 1% of patients. In 20-30% of patients, the cause of thrombosis remains unclear, and thrombosis is considered idiopathic. Inherited hypercoagulable conditions significantly increase the risk of CVT. The aim of the study was to evaluate the frequency of prothrombogenic polymorphic variants of hemostatic and methionine-homocysteine metabolism genes alleles and genotypes in patients with aseptic CVT. Fifty one patients aged 18–75 with aseptic CVT were examined. The control group included 36 healthy volunteers. Neuroimaging methods included brain MRI in standard modes (T1, T2, T2 d-f (FLAIR), DWI) and MR venosinusography. All patients were surveyed to identify carriers of prothrombogenic polymorphic variants of hemostatic and folate metabolism genes alleles and genotypes. Prothrombogenic polymorphic variants of hemostatic genes were detected in 94% of patients, and the variants of the methionine-homocysteine metabolism genes were observed in 86% of patients. The differences between distributions of alleles and genotypes 5G6754G of the PAI-1 gene, G103T of the FXIIIA1 gene, A66G of the MTRR gene, A2756G of the MTR gene in the group of patients with CVT and in the control group were significant. Allele 4G, genotypes 4G/4G and 5G/4G of 5G6754G polymorphism of the PAI-1 gene; allele T of G103Т polymorphism of the FXIIIA1 gene; allele G and genotype A/G of A66G polymorphism of the MTRR gene; allele G and genotype A/G of A2756G polymorphism of the MTR gene correlated with aseptic CVT. It was concluded that the gene polymorphisms 5G6754G (PAI-1), G103T (FXIIIA1), A66G (MTRR) and A2756G (MTR) carriage increased the risk of aseptic CVT and did not affect the thrombosis clinical manifestations.

Received: 2019-08-19

Published online: 2019-10-16

DOI: 10.24075/brsmu.2019.065

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VIEWS 3094

Kalashnikova LA, Gulevskaya TS, Sakharova AV, Chaykovskaya RP, Gubanova MV, Danilova MS, Shabalina AA, Dobrynina LA

The causes of internal carotid artery (ICA) and vertebral artery (VA) dissection, as well as its provoking factors, remain understudied. The aim of this paper was to explore morphological changes in the ICA/VA walls, factors provoking dissection, clinical signs and biomarkers of connective tissue (CT) damage. A total of 271 patients were examined, of whom 54% were women. The mean age of the participants was 37.0 ± 10 years. Clinical signs and biomarkers of CT damage (matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1, hydroxyproline, sulphated glycosaminoglycans) were analyzed in 82 patients and 40 healthy volunteers. Histologic examination of dissected and seemingly intact arteries conducted in 5 cases revealed signs of arterial wall dysplasia similar to those characteristics of fibromuscular dysplasia: thinning and splitting of the internal elastic membrane, areas of fibrosis, irregular orientation of myocytes, and their necrosis in the tunica media. Clinical signs and biomarkers of CT dysplasia (CTD) were more pronounced in patients with arterial dissection than in the controls. The major provoking factors were head turns and physical activity (42%), minor head injury (10%), and acute respiratory infection in the month preceding arterial dissection (14%). We conclude that arterial wall dysplasia is a predisposing factor for ICA/VA dissection, both spontaneous and provoked. The analysis of CTD biomarkers and clinical signs suggests connective tissue pathology in patients with ICA/VA dissection.

Received: 2019-09-03

Published online: 2019-10-04

DOI: 10.24075/brsmu.2019.064

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VIEWS 3382

Priputnevich TV, Isaeva EL, Muravieva VV, Gordeev AB, Zubkov VV, Timofeeva LA, Mesyan MK, Shubina J, Makarov VV, Yudin SM

Currently, there are no criteria allowing to adequately assess composition and volume of the newborns' gut microbiota, which prevents early detection of the pathological processes and appropriate intervention. This study aimed to apply the methods of culturomics, proteomics and molecular genetic technologies to investigate the development of gut microbiota in healthy newborns delivered in the city of Moscow both vaginally and through a cesarean section. We examined 66 children, 33 of them delivered vaginally and 33 by cesarean section. The luminal bacterial flora samples were collected on the 1st, 7th and 30th days of life. There were 136 species of microorganisms belonging to 40 genera identified. We established that cesarean section slows down normal development of the gut microflora: through the follow-up period (1 month of life), gut microbiocenosis in such children did not yield the results on par with those registered in children born vaginally. Bifidobacteria were significantly more common in the vaginal delivery group: 84% of 109–1012 CFU/g versus 33% of 105–1012 CFU/g in the cesarean section group. At the same time, the former group had significantly less clostridia (33.3% and 65.4%, respectively) and lactose-negative Escherichia coli strains (2.4 and 19.4%, respectively) than the latter group.

Received: 2019-08-28

Published online: 2019-09-28

DOI: 10.24075/brsmu.2019.063

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VIEWS 3426

Fedotova EYu, Abramycheva NYu, Nuzhny EP, Ershova MV, Klyushnikov SA, Illarioshkin SN

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia associated with the non-coding GAA tandem repeats expansion in the FXN gene. Transcription impairment and frataxin protein deficiency are the key features of the disease pathogenesis. Our research was aimed to study the FXN gene mRNA expression as well as to carry out the clinical, genetic and epigenetic correlation analysis in a group of patients with homozygous expansion, in a group of their relatives with heterozygous expansion and in a control group. The FXN mRNA level was determined using the real-time polymerase chain reaction. Methylation pattern of CpG sites was evaluated by direct bisulfite sequencing. As a result of the study, the threshold values were obtained between the FRDA patients group, the group of heterozygous carriers and the control group (15 and 79%, respectively). The clinical and genetic features comparison with the FXN expression level revealed no significant correlation. When comparing gene expression with an epigenetic profile, it was found that hypermethylation of a number of CpG sites upstream of the trinucleotide repeats and some non-CpG sites downstream of the region of repeats inhibited expression. Thus, the identified methylated sites may be considered as a target for epigenome editing to increase the FXN transcription and, consequently, for target therapy of the disease.

Received: 2019-08-22

Published online: 2019-09-26

DOI: 10.24075/brsmu.2019.062

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VIEWS 3320

Fokin VF, Ponomareva NV, Konovalov RN, Krotenkova MV, Medvedev RB, Lagoda OV, Tanashyan MM

One of the methods of assessment of cognitive functions in patients with chronic ischemic cerebrovascular disease — CICD (dyscirculatory encephalopathy) implies studying connectivity of neural networks through the analysis of rest functional magnetic resonance imaging (rest fMRI) data. The main objective of this study was to assess the relationship between working memory (WM) characteristics and connectivity of various parts of the brain in patients diagnosed with CICD. The study involved 22 female CICD patients; they were divided into two groups, one with satisfactory level of WM and the other with compromised WM. We assessed intra-brain connectivity with the help of rest fMRI, using the SPM-12 and CONN18b software applications in Matlab platform. The other aspects evaluated were the gray to white matter ratio and the association of this indicator with WM. Significant differences in the intra-brain connectivity were registered in both the satisfactory WM group and the compromised WM group. The brain parts where those differences were found are left parahippocampal area and right supramarginal gyrus; right cerebellar hemisphere and left parietal, as well as left frontal areas; right cingular and left lingual gyri. In addition, we detected significant differences in the ratio in the gray and white matter volumes in both groups (p = 0.007). The results obtained indicate that memory deterioration in CICD patients is concomitant with deteriorating connectivity between the cortical areas, as well as between cerebellum and cortex, which may be associated with a more significant loss of the white matter.

Received: 2019-08-19

Published online: 2019-09-22

DOI: 10.24075/brsmu.2019.061

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VIEWS 3231

Berezhnoy DS, Fedorova TN, Kulikova OI, Stavrovskaya AV, Abaimov DA, Gushchina AS, Olshansky AS, Voronkov DN, Stvolinsky SL

The late stage of Parkinson’s disease is characterized by massive neuronal loss in the substantia nigra (SN) and degeneration of the dopaminergic innervation in the striatum. There is a need to assess the neuroprotective effect of antioxidants (AO) at this stage of the disease. The aim of our study was to assess the efficacy of two AO, carnosine and lipoic acid (LA), in the rat model of late-stage parkinsonism. The pathology was induced by a unilateral injection of 6-hydroxydopamine (6-OHDA) into the SN of the right brain hemisphere. AO were administered 4 times, starting on day 14 following the injection of the toxin. We investigated the effect of the injected drugs on the behavior of rats, the loss of neurons in the SN and the metabolism of biogenic neurotransmitter amines. Both AO dampened the development of 6-OHDA-induced neurological and behavioral symptoms. 6-OHDA induced a 90% drop (p = 0.01) in the levels of dopamine (DA) and its metabolites in the right striatum and caused death of over 95% of neurons (p = 0.01) in the SN of the right hemisphere (p = 0.01). AO did not have a significant effect on the number of neurons in the SN but caused an increase in the levels of DA metabolites, as compared to their levels in the animals exposed to 6-OHDA. Elevated DA (a 5.8-fold increase, p = 0.007) was observed only in the animals treated with carnosine. LA stimulated a 23% decline in serotonin levels (p = 0.06) and a 36% increase (p = 0.009) in its metabolite, 5-hydroxyindolacetic acid (5-HIAA). We conclude that although carnosine and LA did not have a direct neuroprotective effect, they could relieve the symptoms. This suggests that these AO could be used as an adjunctive component to antiparkinsonian therapy.

Received: 2019-08-12

Published online: 2019-09-18

DOI: 10.24075/brsmu.2019.060

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VIEWS 3199