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Vol 74, No 6 (2019)

OBSTETRICS AND GYNAECOLOGY: CURRENT ISSUES
The evolution of technologies in microbiology is the key to creating new opportunities for surveillance and prevention of infections in obstetrics
Priputnevich T.V., Zubkov V.V., Trofimov D.Y., Shevyreva M.P., Maryin G.G., Tutelyan A.V., Akimkin V.G., Briko N.I., Kostenko N.A., Baibarina E.N., Sukhikh G.T.

Abstract

The main direction of improving the quality of medical care for pregnant women, mothers and newborns is to improve the diagnosis and prevention of inflammatory infections, including healthcare-associated infections (HAI). A huge number of types of causative agents of opportunistic infections in women and newborns significantly complicates the etiological diagnosis and timely, adequate treatment at all stages of medical care. Recently, we have seen the emergence and spread of multi-resistant strains: bacteria from the ESKAPE-pathogens group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeroginosa, Enterobacter cloacae); as well as coagulase-negative staphylococci and yeasts, which easily realize their pathogenic potential for immunocompromised patients. The changed epidemiological situation requires the creation and functioning of a local system of surveillance of opportunistic infections in obstetrics and neonatology, primarily for the HAI, which will quickly monitor changes occurring in the etiological, intraspecific, strain structure of pathogens and respond to them in a timely manner. The evolution of technologies in microbiology allows introducing new approaches to the diagnosis, prevention and treatment of infections. Active use of modern methods of etiological diagnostics, development and application of innovative antimicrobial drugs in combination with coordinated work of physicians, microbiologists, clinical pharmacologists, epidemiologists and specialists in the field of molecular biology and bioinformatics is the key to the formation of new opportunities for epidemiological surveillance and prevention of infections in childbirth.

Annals of the Russian academy of medical sciences. 2019;74(6):364-370
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ANAESTHESIOLOGY AND CRITICAL CARE MEDICINE: CURRENT ISSUES
Prediction of the effectiveness of spontaneous breathing in patients with brain damage of various etiologies
Kiryachkov Y.Y., Petrova M.V., Parfenov A.L., Loginov A.A., Skvortsov A.E.

Abstract

BACKGROUND: Long-term respiratory support is a severe disabling factor and is accompanied by a long stay of patients in intensive care units.

AIMS: The analysis of the predictors of the success of disconnection from mechanical ventilation on the basis of clinical and diagnostic criteria in patients with brain damage of various etiologies.

METHODS: The study included 53 patients (husband ― 28, women ― 25; cf. age 53.69 ± 2.34) who are in 2019 with the consequences of traumatic brain injury (TBI) (n = 18; 33.9%); consequences of acute cerebrovascular accident (n = 24; 45.3%); the effects of anoxic brain damage (n = 3; 5.7%); consequences of subarachnoid hemorrhage (n = 8; 15.1%).

RESULTS: The statistically significant predictor of recovery of spontaneous breathing in the 1st and 2nd groups of patients were preserved chemoreflex sensitivity (IPCS), the sensitivity and specificity of IPCS was 78.57% [95 % DI 49.2−95.26] and 83.3 % [95 % CI 62.6−95.26]. The index of peripheral chemoreflex sensitivity (IPCS) was calculated using the formula: IPCS = [RRe / RRi] × [Vt(e) / Vt(i)] × [VE(e) / VE(i)] × [Vt(e) × VE(i)], where IPCS is the index of peripheral chemoreflex sensitivity in l/min; RRi and RRe; Vt(i) and Vt(e); VE(e) and VE(i) ― respiratory rate (RR, breaths/min), tidal volume (Vt), minute ventilation (VE), (l/min) of the starting point ― (i) before carrying out a functional stress test and (e) ― during a functional test of normobaric hypoxia with SpO2 in the range of 90−80 %.

CONCLUSIONS: The most significant clinical parameters statistically reliably hampering the process of successful recovery of spontaneous breathing in addition to chemoreflex sensitivity are the presence of severe heart failure, pneumonia, autonomic dysfunction, level of consciousness, age, higher levels of inspiratory and expiratory pressure mounted on a respirator.

Annals of the Russian academy of medical sciences. 2019;74(6):371-377
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MOLECULAR MEDICINE AND GENETICS: CURRENT ISSUES
Genome-editing techniques to increase the therapeutic efficacy of monoclonal antibodies
Firstova V.V., Shemyakin I.G., Dyatlov I.A.

Abstract

The review presents a general description of therapeutic monoclonal antibodies, cell lines used to obtain them, characterizes the reasons for the immunogenicity of recombinant antibodies, and approaches used to eliminate the side effects of therapeutic monoclonal antibodies. The focus is on resolving the immunogenicity problems of fully human therapeutic monoclonal antibodies. The most attention are concentrated on the data of antibody-producing cell genomic editing to increase the yield of the product, the stability of expression of the recombinant protein and reduce its immunogenicity. Modern methods of site-directed modification (zinc finger method, TALEN and CRISPR/CAS9) for editing the genome of the CHO cell line are analyzed. The strategies of genomic editing choice carrying out taking into account the advances of omix technologies are discussed. Approaches to increase the life span of producer cells are considered, including an increase in the expression of anti-apoptotic signals and the deletion of proapoptotic genes, an increase in the duration of the cell cycle of cells in the G0/G1 phase. The approaches used to regulate the posttranslational modification of monoclonal antibodies are considered. Significant part of the review are devoted to the discussion of the spesificity and differences of glycosylation, galactosylation and sialization of monoclonal antibodies in different expression systems and the associated different degree of immunogenicity of monoclonal antibodies. The main approaches to the regulation of the synthesis of monoclonal antibodies at the stage of translation using non-coding RNA are considered.

Annals of the Russian academy of medical sciences. 2019;74(6):378-387
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INFECTIOUS DISEASES: CURRENT ISSUES
A study of serum miRNA-122 in hepatitis C and associated hepatocellular carcinoma
Yushchuk N.D., Malov S.I., Malov I.V., Dvornichenko V.V., Rasulov R.I., Marche P., Decaens T., Macek-Jilkova Z., Stepanenko L.A., Ogarkov O.B., Orlova L.S.

Abstract

BACKGROUND: The discovery of a cluster of short non-coding RNAs called microRNAs (miRNAs) has become an important event in molecular biology. One of its representatives, miR-122 plays a large role in regulating the expression of genes involved in carbohydrate, lipid metabolism, and iron metabolism in the body. In experimental studies it was shown that in addition to regulatory functions, miR-122 is involved in the pathogenesis of hepatitis C, providing the life cycle of the virus in the cell. The shift of emphasis in the study of miR-122 from basic research into clinical medicine seems to be a promising area of personalized medicine.

AIMS: to determine the clinical significance of miR-122 in acute and chronic hepatitis C and associated hepatocellular carcinoma.

MATERIALS AND METHODS: A total of 407 people were examined, including 17 patients with acute hepatitis C (AHC), 158 patients with chronic hepatitis C (CHC) and 62 patients with HCC associated with hepatitis C. Comparison groups consisted of 84 healthy individuals and 62 patients with clinically pronounced cirrhosis of a non-infectious etiology. In each cohort, the relative miR-122 level was determined in the blood of patients. The analysis was performed in PCR using the Qubit microRNA Assay Kit -100 for the quantitative determination of microRNAs (Thermo Fisher Scientific, USA). Relative miR-122 expression values were calculated by the formula 2 -ΔΔCT using U6 snRNA as a reference RNA.

RESULTS: The highest miR-122 level in serum was found in patients with AHC at the height of the icteric period. The level of miR-122 showed a direct correlation with the activity of hepatic transaminases in patients with AHC (r = 0.72) and CHC (r = 0.44). An analysis of miR-122 level relative to the degree of liver fibrosis in patients with chronic hepatitis C showed that, as liver fibrosis progresses, the level of miR-122 expression decreases. The decrease in miR-122 expression in patients with severe fibrosis was universal and did not depend on the etiology of the disease. The development of HCC in the presence of chronic hepatitis C was accompanied by a decrease in the level of miR-122 by 10 times on average compared to patients with chronic hepatitis C.

CONCLUSIONS: The determination of the expression level of miR-122 in serum can be used in laboratory monitoring of the management of patients with HC as an indicator of the severity of liver damage in AHC and the rate of formation of liver fibrosis in CHC. Evaluation of possibility of using miR-122 as a predictor of the development of HCC in the outcome of HC requires additional studies of the specificity and sensitivity of the test and comparison of the obtained data with the results of using generally accepted protein tumor markers.

Annals of the Russian academy of medical sciences. 2019;74(6):388-395
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CARDIOLOGY AND CARDIOVASCULAR SURGERY: CURRENT ISSUES
Ischemic cardiomyopathy: blood monocytes and mediators of their differentiation
Chumakova S.P., Shipulin V.M., Urazova O.I., Pogonchenkova D.A., Vince M.V., Pryakhin A.S., Kolobovnikova Y.V., Churina E.G., Novitskiy V.V.

Abstract

BACKGROUND: The three-year survival rate of patients with ischemic cardiomyopathy (ICMP) is 5−35 %; its pathogenesis is poorly understood. Violation of cytokine-dependent differentiation of monocytes/macrophages involved in atherogenesis may play an important role in the development of ICMP.

AIMS: To characterize the disorders of monocytes subpopulation composition and mediators spectrum of blood in patients with coronary heart disease (CHD), associated with the development of ICMP.

METHODS: A one-stage, clinical, controlled (case-control) study was conducted from February 2017 to December 2018. 45 patients with CHD (all men), who were in a cardiac surgery hospital, were examined before coronary bypass surgery: 19 people suffering from ICMP, and 26 people who do not suffer from ICMP, as well as 14 healthy men. In the blood of the examined individuals CD14++CD16-, CD14++CD16+, CD14+CD16++ and CD14+CD16- monocytes were determined with respect to all CD14-positive cells by flow cytometry, in blood plasma ― concentration of galectin 2 and 9, IL-4, IL-10, IFN-γ, M-CSF, HIF-1α by enzyme-linked immunosorbent assay (ELISA).

RESULTS: The development of the ICMP accompanied by deficiency of HIF-1α and CD14+CD16++ monocytes (0.037 [0.020; 0.045] ng/ml, p = 0.019, and 5.05 [4.08; 6.58] %, p = 0.011) in combination with an excess of IL-10 (30.05 [24.75; 33.50] ng/ml, p = 0.042) in the blood. It is shown in blood of patients without ischemic cardiomyopathy the increase in the content of CD14++CD16+ cells and lack of CD14+CD16- monocytes (25.27 [15.78; 31.39] %, p = 0.038, and 2.68 [2.63; 4.09] %, p = 0.027) at normal concentration of IL-10 and HIF-1α. In patients with CHD and ischemic cardiomyopathy and without ICMP in the blood the concentration of M-CSF and galectin-2 (2.00 [1.21; 3.24] pg/ml, p = 0.028, and 0.40 [0.12; 2.37] ng/ml, p = 0.004; 3.00 [1.90; 4.05] pg/ml, p = 0.003, and 3.20 [2.07; 4.00] ng/ml, p = 0.002, respectively) is reduced at normal content of galectin-9, and CD14++CD16- monocytes. IL-4 and IFN-γ in blood plasma are not determined (zero values).

CONCLUSIONS: The development of ICMP is associated with excess of IL-10 and HIF-1α deficiency, which is accompanied by inhibition of CD14+CD16++ monocytes maturation.

Annals of the Russian academy of medical sciences. 2019;74(6):396-404
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ONCOLOGY: CURRENT ISSUES
Data analysis of a pilot screening program for the early detection of esophageal and gastric cancers: retrospective study
Smailova D.S., Ibrayev S.E., Muzafarov S.N., Samarova U.S., Khismetova Z.A., Rakhimzhanova F.S., Fabbro E.

Abstract

BACKGROUND: According to the WHO, in 2018 stomach cancer was the fifth and esophageal cancer seventh most common cancer in the world. In 2011 the National Screening Program for the Early Detection of Breast, Cervical, and Colorectal Cancer was introduced in Kazakhstan. In 2013 a pilot screening program for the early detection of esophageal and stomach cancers was introduced in Kazakhstan in some regions where there is a low detectability.

AIM: Determination of the main causes of low detection of esophageal and stomach cancers in the framework of a pilot screening program in Pavlodar region (Kazakhstan).

METHODS: According to the Ministry of Healthcare of the Republic of Kazakhstan, the target group for screening to detect esophageal and stomach cancers was men and women at the aged of 50, 52, 54, 56, 58 and 60 who were not registered as a cancer patient. A retrospective analysis was carried out according to the newly diagnosed cases of esophageal and stomach cancers in Pavlodar region for 2013−2017. All cases of esophageal and stomach cancers were analyzed to determine the proportion of new cases detected as part of a pilot screening program.

RESULTS: 1114 new cases of esophageal and stomach cancers are registered from 2013 to 2017 in Pavlodar region. According to the data in Pavlodar region the average age of newly diagnosed patients with esophageal and stomach cancers was 66 years, M = 65.92 (95 % CI: 65.24−66.59) SD = 11.495. During pilot screening program, 135 042 participants were examined; various pathological processes of the esophageal and stomach cancers were detected among 1678 patients, including 97 cancer cases. The detectability of esophageal and stomach cancers from the total number of participants was 0.07 %. Out of 1114 all registered new cases of esophageal and stomach cancers, only 97 new diagnosed cases detected as part of a pilot screening program, reaching 8.7 %, which is considered low.

CONCLUSIONS: The main reasons for low detection are administrative barriers. The main barrier of the pilot screening program was the selection of the target group at the age of 50, 52, 54, 56, 58, 60 years old only. Therefore, 15.5 % of newly diagnosed cases of esophageal and stomach cancers were missed due to existing intervals. The second barrier was the use of endoscopes which did not support the function of photo and video archiving of the conducted procedures.

Annals of the Russian academy of medical sciences. 2019;74(6):405-412
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PHTHISIOLOGY: CURRENT ISSUES
New technologies for the diagnosis of drug-resistant tuberculosis
Ergeshov A.E., Chernousova L.N., Andreevskaya S.N.

Abstract

Widespread drug-resistant tuberculosis is a global challenge that has a potential to have a negative impact on the global TB situation. Rapid TB diagnosis and early initiation of effective treatment based on the individualized chemotherapy regimens underpin efforts in prevention of further spread of tuberculosis. Microbiological methods of TB diagnosis that provide evidence of the TB process etiology and identify drug susceptibility of the pathogen play a very important role. The review covers the current and emerging methods of the microbiological TB diagnosis including conventional microbiological (microscopy of diagnostic material, cultural studies on solid media and culture fluids) and modern molecular genetic tests (DNA strips, biological microchips, multiplex PCR, GeneXpert and diagnostic systems of the new generation and point-of-care tests) and demonstrates the role of the described methods in the diagnostic TB laboratory algorithm. The example of the Microbiology Department of the Central TB Research Institute illustrates the effectiveness of modern developments in the diagnosis of drug-resistant tuberculosis and their impact on improving treatment success in the clinical departments of the CTRI. The review presents further prospects of drug-resistant TB diagnosis in relation to the new technologies such as Next Generation Sequencing. The conclusion summarizes information on the current state of microbiological diagnosis of drug-resistant tuberculosis and emphasizes the importance of developing and introducing new technologies into the diagnostic process.

Annals of the Russian academy of medical sciences. 2019;74(6):413-422
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ENDOCRINOLOGY: CURRENT ISSUES
Immune status markers dynamics during rotational diet therapy in obesity
Gapparova C.M., Chekhonina Y.G., Sentsova T.B., Vorozhko I.V., Lapik I.A.

Abstract

BACKGROUND: Сhronic immune inflammation in obesity is pathogenetically associated with the development insulin resistance and the metabolic syndrome. However, there are a number of works devoted to the relationship of obesity and allergic diseases, in which data were obtained on models of bronchial asthma and allergic rhinitis. In obesity against a background of chronic immune inflammation, a more severe course of concomitant allergic disease is observed, accompanied by an increase in pro-inflammatory cytokine levels. In this regard, obesity and food allergies should be considered from the standpoint of comorbidity, and the study of immune status markers dynamics in obese patients with concomitant food allergies at the background of diet therapy will create prerequisites for determining the criteria of the effectiveness of the treatment.

AIM: To study the of immune status markers dynamics on the background of rotational diet therapy for obesity.

METHODS: A single-site, randomized controlled trial was conducted. The duration of observation of the patients was 14 days. There were 68 patients with obesity, aged 47.4 ± 5.4 years, randomly divided into 2 homogeneous groups. Levels of allergen-specific IgG to 90 food allergens were measured to all patients of the main group by enzyme immunoassay method. The comparison group received a standard low-calorie diet. In both groups, the levels of pro-inflammatory markers (IL-1β, TNFα, IL-6) were determined using commercial Biosource kits (Belgium).

RESULTS: In evaluating of the cytokine status and the level of non-specific markers of inflammation at the initial stage of the study, patients with a body mass index above 35 showed a significant increase in concentrations of C-reactive protein, IL-1β, and IL-6. Analysis of allergen-specific IgG to 90 food allergens showed that food intolerance was found often to milk, dairy products, gluten. Analyzing the dynamics of the level of pro-inflammatory markers during treatment, a significant decrease in the level of CRP, IL-6, IL-1β was detected in the main group 15 % (p < 0.05), 14 % (p < 0.05), 10 % respectively, while in the comparison group the decrease in the level of IL-6 was 9 %, IL-1β by 6 %,CRP by 10 % (p < 0.05).

CONCLUSION: In patients with obesity with concomitant food intolerance there are changes in the immune status in the form of increased levels of pro-inflammatory markers. During the observation a more significant decrease was found in the studied parameters in the main group was detected at the background of rotational diet therapy in relation to the comparison group. The decrease in the concentrations of the studied markers in the serum during the study is an indicator of the effectiveness of rotational diet therapy.

Annals of the Russian academy of medical sciences. 2019;74(6):423-429
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Predictive biomarkers in the treatment of acromegaly: a review of the literature
Przhiyalkovskaya E.G., Osmanova P.O., Mamedova E.O., Lutsenko A.S., Belaya Z.E., Melnichenko G.A.

Abstract

In the era of personalized medicine treatment of acromegaly requires the individual selection of optimal treatment based on the measured parameters. Following the standard algorithm for the management of patients with acromegaly with the choice of neurosurgical treatment as the main and somatostatin analogues as the first line of drug therapy with ineffective surgery prevents the achievement of remission in patients resistant to these types of therapy. The introduction of predictive biomarkers in clinical practice will allow to achieve remission of the disease faster and reduce the financial costs of ineffective treatments. We collected information of possible predictive biomarkers in acromegaly from literature. This review presents data from studies of potential predictive biomarkers in different treatments of acromegaly. According to the analysis of publications, the greatest number of results is devoted to the prediction resistance to somatostatin analogues. Reliable biomarkers predicting the inefficiency of somatostatin analogues include low immunoexpression of somatostatin receptors type 2 and AIP protein, rarely granular type of pituitary adenoma and hyperintensive signal on T2-weighted images in magnetic resonance imaging of the pituitary gland. At the same time, the search for predictors of the effectiveness of pegvisomant is focused on the study of the receptor of growth hormone and opens up new opportunities for pharmacogenomic research. Thus, it is necessary to expand the search of predictive biomarkers for different methods of acromegaly’s treatment. It is especially important to identify biomarkers that do not require mandatory removal of the tumor. Of great interest is the study of epigenetic biomarkers, in particular miRNAs, which carry out post-transcriptional regulation of gene expression. The study of circulating blood microRNAs in acromegaly opens up prospects for the introduction of a personalized approach in the treatment of this disease.

Annals of the Russian academy of medical sciences. 2019;74(6):430-440
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