Vol 76, No 3 (2021)


The Role of Extracellular Vesicles of Various Origins in the Development of Preeclampsia

Nikolaeva M.G., Terekhina V.U., Kudinov A.V., Momot A.P.


Pre-eclampsia is a clinically unfavorable pregnancy outcome that determines the main indicators of maternal and/or perinatal morbidity and mortality. According to modern concepts, the placenta plays a central role in the development of PE, while intercellular and intervesicular communications involving extracellular vesicles (EVs, extracellular vesicles) initiate a cascade of various biological effects, determining the mechanisms of ontogenesis of the gestational process in normal and pathological conditions. Achievements in studies of extracellular vesicles (EVs, extracellular vesicles) are of particular interest both to clinicians and to researchers studying the pathophysiology of gestational complications. Extracellular vesicles (EVs) in preeclampsia are produced both by scintiotrophoblast and the maternal body - blood cells (platelets, red blood cells, white blood cells) and the cardiovascular (vascular endothelium, smooth muscle) system. Changes in the concentration of these EVs can contribute to the implementation of preeclampsia, enhancing the pro-inflammatory and procoagulant states inherent in the gestation process. This review focuses on freely available information on the possible interactions between placental and maternal EVs. Understanding the contribution of EVs to the development of preeclampsia can help to deepen knowledge about the pathogenesis of this pathology and determine the diagnostic and prognostic significance of extracellular vesicles as biomarkers.

Annals of the Russian academy of medical sciences. 2021;76(3):237-243
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Predicting the Development of Great Obstetric Syndromes Based on Multilocus Genetic Analysis: Results of a Retrospective Comparative Cohort Study

Kudryavtseva E.V., Kovalev V.V., Baranov I.I., Ugarov I.V.


Background. Great obstetric syndromes are pathological conditions, related to the level of maternal, perinatal and infant morbidity and mortality. There is a genetic component in the development of pregnancy complications, as evidenced by numerous clinical observations and research results. Purpose — to study the frequency characteristics of the occurrence of polymorphic variants of various genes and their combinations in patients who underwent pregnancy complicated by great obstetric syndromes in comparison with women whose pregnancy proceeded without complications and successfully ended with the birth of a live full-term baby. Methods. A retrospective comparative cohort study was conducted. Molecular genetic research was carried out in 391 women: 279 women who underwent one of the verified clinical forms related to great obstetric syndromes (main group), 112 women were included in the control group. 37 polymorphisms in 33 genes were studied (FGB, F2, F5, F7, F13, GPIa, GPIIIa, GPVI, PROC, PAI1, PLAT, MTHFR, MTHFD, MTRR, MTR, SLC19A1, CBS, NOS3, END1, ACE, ADD1, AGT , CYP11B2, GSTM, GSTT, GSTP1, MnSOD, GPX1, IL1β, TNF-a, ESR1, ESR2, PGR). Results. The most significant polymorphisms and their combinations were identified. In the main group, the following combinations were more common: ACE Alu I/D ID + AGT А704G GG, AGT А704G GG + MTRR A66G AG, F7 G10976A GG + AGT А704G GG, F7 G10976A GG + F13 G103A GG, F7 G10976A GG + GPIa С807T CC, F7 G10976A GG + MTHFR C677T CC, CYP11B2 G-344A GA + IL1β G+3953A GA, PAI1-657 5G/4G 5G4G + IL1β G+3953A AA, PAI1-657 5G/4G 4G4G + IL1β G+3953A AA, in control group — AGT A704G AA + MTRR A66G AG, AGT A704G AG + MTRR A66G AG (the differences are statistically significant). To simplify the practical application of the analysis for genetic polymorphisms, a computer program named GOS RISK was created to assess the risk of pregnancy complications. The sensitivity and specificity were 70.8% and 78.8%, the efficiency of the method — 74.8%. Conclusion. Analysis of individual polymorphic variants of genes indicates their role in the discussed pathology. Creation of computer programs based on multilocus genome analysis increases the predictive value of molecular genetic studies.

Annals of the Russian academy of medical sciences. 2021;76(3):244-253
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DERMATOLOGY and VENEROLOGY: current issues

Methotrexate Safety in Psoriasis: An Overview

Asoskova A.V., Sychev D.A., Kubanov A.A.


Methotrexate is a highly efficacious treatment for psoriasis, but the use of methotrexate may be limited by concerns regarding its adverse reactions. On average, 28.3 % of patients with psoriasis treated by methotrexate develop adverse reactions. The occurrence of adverse drug reactions in some cases leads to the therapy discontinuation, which may be accompanied by psoriasis exacerbation. The purpose of this article is to provide an extensive review of the methotrexate efficacy, safety and tolerability as well as provide a comprehensive understanding of methotrexate pharmacokinetics and pharmacodynamics, methotrexate side effects pathogenesis, approaches to methotrexate safety monitoring, situations in which it is necessary to be vigilant when prescribing methotexate. We also outline current data concerning methotrexate molecular mechanism of action, including new data on its anti-inflammatory activity, that allow us to explain the pathogenesis of a number of adverse drug reactions, as well as discuss possible ways of predicting the methotrexate toxicity, especially focusing on recent advances in the field of pharmacogenetics of methotrexate-induced toxicity and personalized approach to psoriasis treatment.

Annals of the Russian academy of medical sciences. 2021;76(3):254-267
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The Effect of Various Types of Anticoagulant Therapy on the Reduction of Mortality in COVID-19

Makatsariya A.D., Slukhanchuk E.V., Bitsadze V.O., Khizroeva J.K., Tretyakova M.V., Shkoda A.S., Elalamy I., Di Renzo G., Rizzo G., Pyatigorskaya N.V., Solopova A.G., Grigoreva K.N., Nakaidze I.A., Mitryuk D.V.


Coronavirus disease 2019 (COVID-19) is a viral infection that, in severe course, leads to the development of a cytokine storm, systemic inflammatory response and coagulopathy. Unlike other sepsis-associated disseminated intravascular coagulopathy, COVID-19 induced coagulopathy is realized mainly in thrombosis. Researchers around the world are currently developing adequate diagnostic, monitoring and anticoagulant therapy approaches to safely and effectively manage patients with severe COVID-19. The need to develop laboratory monitoring is due to the fact that 20% of patients have changes in hemostasis indicators, while in patients with a severe form of the disease, they are present in 100% of cases. In case of deaths from COVID-19, there is an increase in the concentration of D-dimer and fibrinogen degradation products. Thus, the severity of hemostasis disorders has an important prognostic value. Anticoagulant therapy is included in the list of all recommendations as an effective means of reducing mortality from COVID-19. The questions of the recommended groups and doses of anticoagulant drugs are still open. The approach to the choice of an anticoagulant should be based not only on risk factors, characteristics of the course of the disease, anamnesis, but also on the wishes of the patient during long-term therapy at the post-hospital stage.

Annals of the Russian academy of medical sciences. 2021;76(3):268-278
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QRS-Fragmentation: Perspectives for Use in Clinical Practice

Fedulaev Y.N., Makarova I.V., Pinchuk T.V., Chuvarayan G.A.


The current article provides a detail review of foreign publications, discussing the opportunities and the benefits of evaluation of the QRS-fragmentation (fQRS) — a new electrocardiographic (ECG) parameter in patients with coronary artery disease (CAD). Diagnostic criteria for narrow and wide QRS-complexes are defined. Main results of the comparative and correlation analysis, evaluating fQRS and electrocardiographic (pathologic Q-waves), echocardiographic (left ventricular ejection fraction), angiographic settings are described. There is a discussion of the prognostic role of fQRS in stable CAD as well as in patients presented with acute myocardial infarction. fQRS is an available ECG-marker of local myocardial fibrosis. It seems to be a useful negative predictor in individuals with CAD, indicating an increased risk of life-threatening ventricular arrhythmias and recurrent cardiac events. The presence of fragmented QRS-complexes is associated with an increased in-hospital and long term (overall as well as cardiovascular) mortality. Routine evaluation of fQRS in standard ECG leads does not require additional resources, and will contribute to an improvement in diagnostics and risk stratification of stable CAD as well as myocardial infarction. Assessment of fQRS can be included in noninvasive diagnostic algorithm concerning CAD.

Annals of the Russian academy of medical sciences. 2021;76(3):279-286
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Mechanisms of Damage to the Cardiovascular System in COVID-19

Fisun A.Y., Lobzin Y.V., Cherkashin D.V., Tyrenko V.V., Tkachenko K.N., Kachnov V.A., Kutelev G.G., Rudchenko I.V., Sobolev A.D.


The review article is devoted to the analysis of the literature on the various mechanisms of damage to the cardiovascular system in COVID-19. The article briefly outlines the epidemiology and urgency of the COVID-19 problem, describes the features of the clinical picture of heart muscle damage in COVID-19. The pathophysiology, morphology and pathogenetic mechanisms of myocardial involvement in cases of SARS-CoV-2 lesion are considered in detail. The authors present a diagram of various mechanisms of myocardial damage in COVID-19, which includes mediated damage to the heart muscle through angiotensin-converting enzyme 2, myocardial damage caused by hypoxemia, microvascular heart damage, and systemic inflammatory response syndrome. A detailed scheme of cardiomyocyte infection with the involvement of cytokines, which ultimately leads to myocardial remodeling and dilated cardiomyopathy, is presented. The pathophysiological foundations of the development of sudden cardiac death in COVID-19, which include the mechanisms of life-threatening arrhythmias, acute coronary syndrome, and heart failure, are considered. The authors analyzed scientific studies of the toxic effects of COVID-19 drug treatment on the heart muscle, in particular, antiviral, antibacterial, antimalarial agents. Their potential benefits and harms, as well as the likelihood of developing cardiovascular events, in particular sudden cardiac death, were assessed.

Annals of the Russian academy of medical sciences. 2021;76(3):287-297
pages 287-297 views

The Effect of Angiotensin Receptor Inhibitors and Neprilysin on Aortic Stiffness in Patients with Heart Failure and Reduced Ejection Fraction

Ryazanov A.S., Shikh E.V., Kapitonov K.I., Makarovskaya M.V., Kudryavtsev A.A.


Background. Compared with enalapril, sacubitril/valsartan reduces mortality from cardiovascular diseases and the number of hospitalizations for heart failure in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling. The aim of the study is to determine the effect of sacubitril/valsartan on aortic stiffness and cardiac remodeling compared with enalapril in HFrEF. Materials and methods. In this long-term outpatient study, 100 patients with HFrEF received sacubitril/valsartan or enalapril. The primary endpoint was the change in arterial impedance (aortic stiffness characteristic) over a 12-month follow-up. Secondary endpoints included changes in N-terminal cerebral natriuretic propeptide (NT-proBNP), ejection fraction, left atrial volume index, E/e’ index, left ventricular end-systolic and end-diastolic volumes; left ventricular-arterial index (Ea/Ees). Results. During 12 months of follow-up, 100 patients showed significant differences between the groups with respect to changes in arterial impedance, which decreased from 224.0 to 207.9 dynes × s/ cm5 in the sacubitrile/valsartan group and increased from 213.5 to 214.1 dyne × s/cm5 in the enalapril group (difference between groups: –9.3 dynes × s/ cm5; 95% CI: from –16.9 to 12.8 dynes × s/cm5; p = 0.69). Also, there were intergroup differences in the change in left ventricular ejection fraction and Ea/Ees index. NT-proBNP level, left ventricular end-diastolic and systolic volume index, left atrial volume index, E/e’ index were reduced in the sacubitril/valsartan group. Conclusions. Treatment with sacubitril/valsartan compared with enalapril resulted in a significant reduction in aortic stiffness in HFrEF.

Annals of the Russian academy of medical sciences. 2021;76(3):298-306
pages 298-306 views


Prospects for the Etiotropic Treatment of Dysferlinopathy

Ivanova A.V., Smirnikhina S.A., Lavrov A.V.


Dysferlinopathies belong to a phenotypically heterogeneous group of neuromuscular diseases caused by mutations in the DYSF gene, which disrupt the expression of dysferlin protein in human skeletal muscle cells. These pathologies are of an autosomal recessive inheritance pattern, their prevalence is 1: 200000. Dysferlinopathies include diseases such as Miyoshi myopathy with primary lesion of the distal fragments of the lower extremities and limb-gridle muscular dystrophy type 2B with primary lesion of the proximal fragments of both the lower and upper limbs, also distal myopathy with anterior tibial onset (DMAT). Nowdays, there are various pathogenetic and symptomatic treatments for hereditary muscular dystrophies but there are very few registered drugs for the etiological treatment of these diseases. This review discusses the main modern methods of gene therapy that can be used to treat dysferlinopathies, such as stop-codon passing, exon skipping, overexpression of other genes, gene transfer, splicosome-mediated trans-splicing, and also describes the latest experimental studies using these methods. In conclusion, exon-skipping and trans-splicing have been identified as the most optimal approaches in the treatment of muscular dystrophies, in particular dysferlinopathies.

Annals of the Russian academy of medical sciences. 2021;76(3):307-316
pages 307-316 views


Innovative Approach to Surgical Treatment for Locally Advanced Cancer of Paranasal Sinus and Nasal Cavity

Kit O.I., Reshetov I.V., Engibaryan M.A.


Background. Despite the rapid oncology development, the problem of surgical treatment for locally advanced tumors of the paranasal sinus and nasal cavity is still relevant. The search and development of ways to improve the surgical approach, including modern endovascular methods, appears necessary. Aims — development and evaluation of the effectiveness of an innovative approach to the surgical treatment of malignant tumors of the nasal cavity and paranasal sinus with superselective intra-arterial embolization as a preparatory stage. Materials and methods. The study is based on the treatment outcomes of 52 patients with cancer of the nasal cavity and paranasal sinus. The main group included 21 patients receiving treatment with our developed approach including preoperative superselective intra-arterial embolization as a preparatory stage for surgical treatment. The control group included 31 patients receiving standard surgical treatment with traditional ligation of the external carotid artery at the first stage. Estimation of the amount of intraoperative blood loss with gravimetric analysis was considered the primary endpoint of the study. Post-embolization syndrome manifestations were analyzed by evaluating the pain intensity with a visual analogue scale and thermometry. Results. Intraoperative blood loss in patients of the main group varied from 100 to 400 ml, being on average 231.9±100.58 ml. In the control group, the blood loss varied from 300 ml to 1000 ml, on average 630.97±190.23. The data analysis proved demonstratively the effectiveness of the developed approach to surgical treatment of locally advanced tumors of the nasal cavity and paranasal sinus, since it statistically significantly reduced the amount of intoperative blood loss (p < 0.005). Conclusions. Our developed approach to the treatment for malignant tumors of the paranasal sinus and nasal cavity optimized the results of surgical treatment and statistically significantly reduced the amount of intoperative blood loss, compared to the traditional ligation of the external carotid artery, from 630.97±190.23 to 231.9±100.58 ml (p < 0.005), with minimal manifestations of post-embolization syndrome.

Annals of the Russian academy of medical sciences. 2021;76(3):317-323
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A Randomized Safety Study of 13-Valent Pneumococcal Conjugated Vaccine and Post-Vaccination Immune Response to Streptococcus pneumoniae Serotypes in Adult Patients with Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Kostinov M.P., Protasov A.D., Zhestkov A.V., Yastrebova N.E., Kostinov A.M., Vlasenko A.E., Polishhuk V.B., Kostinova A.M., Korovkina E.S., Ryzhov A.A., Shmit'ko A.D.


Background. Vaccination against pneumococcal infection is one of the priorities in improving the quality of treatment and prevention measures in adults with various pathologies. The effectiveness of vaccination is directly related to the individual’s ability to form an adequate specific immunity. Aims — the aim of the study was to assess the level of post-vaccination antibodies to capsular polysaccharides of S. pneumoniae in adult patients with bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD) after administration of 13-valent conjugated pneumococcal vaccine (PCV13). Materials and methods. The ELISA method was used to determine the level of IgG antibodies to 12 capsular polysaccharides serotypes 1, 3, 4, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F of S. pneumoniae that are part of PCV13, and 2 serotypes — 9N, 15B — that are not part of the vaccines using research test systems developed on the basis of the I.I. Mechnikov Research Institute of Vaccines and Sera. Groups of adult patients — 32 patients with BA and 33 with COPD who received basic treatment according to accepted international standards. The comparison group consists of 20 healthy patients who do not have comorbidities. In patients, vaccination was performed outside the acute period of the disease using PCV13. Results. Vaccination of PCV13 patients with BA and COPD does not lead to the development of exacerbations of the underlying disease, while unusual symptoms in the post-vaccination period, provided for by the drug’s instructions, can rarely develop. A comparative analysis of changes in IgG antibodies conducted after 6 weeks relative to the initial level of IgG antibodies to S. pneumoniae capsular polysaccharides in adult patients and healthy vaccinated PCV13 showed the same increase in specific antibodies to 12 serotypes of pneumococcus. The difference was found only in relation to IgG antibodies to a mixture of polysaccharides included in the PCV13 vaccine, which were registered higher in patients with BA and COPD in the post-vaccination period (p < 0.001) than in healthy patients. Conclusions. PCV13 vaccination of patients with BA and COPD is safe and is accompanied by the synthesis of IgG antibodies to capsular polysaccharides serotypes of S. pneumoniae similarly to the healthy group.

Annals of the Russian academy of medical sciences. 2021;76(3):324-334
pages 324-334 views


Reviews: F.I. Ershov. “History of Virology from D.I. Ivanovskay to the present day ”. Popular science edition. GEOTAR-Media, 279 p., 2020

Galegov G.A., Pronin A.V.


A review for the book by F.I. Ershova “History of Virology from D.I. Ivanovsky to the present day”, publishing house GEOTAR-Media, 2020.

Annals of the Russian academy of medical sciences. 2021;76(3):335-336
pages 335-336 views

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