Vol 73, No 6 (2018)


Peculiarities of Changing Bioregulators and Organic Acids in the Serum of Blood and Amniothic Fluid of Women with Spontaneous Preterm Labor

Krukier I.I., Avrutskaya V.V., Levkovich M.A., Narezhnaya E.V., Smolyaninov G.V., Yerdzhanyan L.L., Nikashina A.A.


Background: Premature birth is currently a serious problem for obstetrician-gynecologists. Most researcher consider this problem from the standpoint of metabolome disturbances.

Aims: determination of the level of bioactive regulators and organic acids with physiological and complicated pregnancy, ending in timely and spontaneous preterm labor, in blood serum and amniotic fluid and revealing the presence of their relationship for the development of premature birth and the condition of newborns.

Materials and methods: 72 women were examined, 40 of them with a physiological pregnancy (control group) and 32 with premature labor (the main group). All studies were carried out in the blood serum and amniotic fluid of women of these groups. The content of TGFβ was determined by the method of solid-phase enzyme immunoassay. Identification and quantitative determination of citric and succinic acids were carried out by the method of capillary electrophoresis.

Results: TNFα production in the blood serum of women with preterm labor, decreased by 38%, and the level of citric and succinic acids by 33 and 30%, respectively, compared with the control group. In the amniotic fluid the level of TNFα was increased 2.5 times and TGFβ ― 2.2 times, citric acid ― 79%.

Conclusions: The revealed imbalance in the level of cytokines and organic acids studied in that biological fluids can evidently affect the fetal condition, which can be considered as possible markers of perinatal injuries and prognostic indicators of the state of the newborn.

Annals of the Russian academy of medical sciences. 2018;73(6):361-367
pages 361-367 views


Association of SNPs in the Promoter Regions of VEGF (rs699947 и rs2010963), ICAM1 (rs281437) and ET-1 (rs1800541) with Serum Levels of Related Proteins and Alcoholic Liver Cirrhosis Risk

Ivanov A.S., Garmasch I.V., Arisheva O.S., Markova M.A., Melnik A.S., Terebilina N.N., Baronets V.Y., Peregud D.I., Tarasenko E.V., Kobalava Z.D.


Background: Uncontrolled use of alcohol can lead to the development of cirrhosis of the liver, which is manifested by fibrosis with the formation of regenerative nodes, an increase in pressure in the portal vein system and impaired liver function. Hepatic endothelium dysfunction during the formation of portal hypertension is accompanied by an increase in the level of protein molecules involved in the functioning of the endothelium: vascular endothelial growth factor A (VEGF-A), a soluble form of the intercellular adhesion molecule (s-ICAM-1) and endothelin-1 (ET -one). It is assumed that elevated levels of VEGF-A, s-ICAM-1 and ET-1 in alcoholic liver cirrhosis (AHC) may be interconnected with the structure of polymorphic loci, the promoter regions of the respective genes, which in turn may be a genetic risk factor for developing cirrhosis.

Aims: Investigate the relationship of carriage of variant forms of polymorphic loci located in the promoter regions of VEGF-A, ICAM-1 and ET-1 with the level of the corresponding proteins in the blood serum and the risk of AHC.

Materials and methods: The main group consisted of patients with pathological dependence on alcohol, aggravated by cirrhosis of the liver (AHC, n=60). The control group consisted of persons suffering from alcohol abuse, without liver pathology (AA, n=24). The observation period was the period of hospitalization. The serum levels of VEGF-A, s-ICAM-1 and ET-1 were evaluated by enzyme immunoassay. The distribution of variant forms of polymorphic loci located in the promoter regions of the VEGF-A genes (rs699947 and rs2010963), ICAM1 (rs281437) and ET-1 (rs1800541) in the studied sample was performed by real-time PCR.

Results: The development of alcoholic cirrhosis was accompanied by a significant increase in the concentration of VEGF-A, s-ICAM-1 and ET-1 in serum. At the same time, direct correlations between the concentrations of VEGF-A, s-ICAM-1 and ET-1 in serum and the diameter of the portal vein in persons with liver cirrhosis were revealed. Patients with AHC are often carriers of the G allele of rs1800541 locus, located in the promoter of the ET-1 gene, compared with individuals suffering from control without liver pathology, which is associated with an increased risk of developing cirrhosis in alcohol dependence. The carriage of the C allele rs699947, as well as the C allele rs2010963 located in the promoter of the VEGF gene was associated with an increased level of VEGF-A in the AHC compared to carriers of this allele in the AA group. In addition, in the group of patients with AHC, carriers of allele C, homozygous CC genotype and heterozygous GC genotype of rs2010963 locus compared with carriers of G allele or homozygous GG genotype, respectively, were characterized by elevated serum VEGF-A levels.

Conclusion: Carrier allele G of the rs1800541 locus (ET-1) is a risk factor for liver cirrhosis with alcohol abuse. The carriage of the C allele rs699947, as well as the C allele rs2010963 located in the promoter of the VEGF gene, can determine the elevated serum VEGF-A level in the AHC.

Annals of the Russian academy of medical sciences. 2018;73(6):368-377
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Microvesicles of leukocyte origin

Markova K.L., Kogan I.U., Sheveleva A.R., Mikhailova V.A., Selkov S.A., Sokolov D.I.


Microvesicles are a new field of biological research. They are subcellular structures ranging in size from 100 to 1000 nm and found in practically all human biological fluids. Their sources are different cells. Microvesicles have a diverse internal composition and carry a wide spectrum of molecules on their surface, which determines their participation in physiological and pathological processes. Their assumed role of biological markers of diseases has aroused great interest. At the present time, there is a lot of data in the world literature about microvesicles of platelets and endothelial cells, and there is practically no data about microvesicles of leukocytes. In this regard, the purpose of the given review was to summarize the data about microvesicles of leukocytes. The review presents data about source cells, internal and superficial composition of leukocytes’ microvesicles, their interaction with various cells, and involvement in physiological and pathological processes. Further study of microvesicles will make it possible to clarify their role in normal and pathological conditions, the possibility of using them as vectors of diseases and carriers of various biologically active molecules.

Annals of the Russian academy of medical sciences. 2018;73(6):378-387
pages 378-387 views


Perspective Nerve Conduits for Stimulation of Regeneration of Damaged Peripheral Nerves

Miroshnikova P.K., Lyundup A.V., Batsalenko N.P., Krasheninnikov M.E., Zhang Y., Feldman N.B., Beregovykh V.V.


Nerve damage is a common severe trauma caused by a complete or partial disruption of the integrity of the nerve trunk and appropriate dissociation of the CNS and denervated tissue. «Golden standard» in the treatment of extensive injuries of peripheral nerves is the use of autografts of nerve fibers, but when they are used, pathological disturbances appear in the donor zone and the results of surgical treatment are not always satisfactory. Currently, an alternative to the traditional method is the use of nerve conduits (conductors) for directed regeneration of axons. In this work, the results of the application of nerve conductors from various materials and with various biologically active components in preclinical and clinical studies, as well as conduits used in clinical practice, were analyzed. The efficiency of regeneration was compared, on the basis of the analysis the conductor most suitable for successful nerve regeneration was selected, including approaches for creating innervated tissue engineered constructs. In this work, we have collected research on nerve conductors from various materials with various prescribed properties using certain factors used to treat damage to the peripheral nervous system, showing all the advantages and disadvantages of their use, which makes it possible to develop and create a conduit that meets all the requirements of modern regenerative medicine.

Annals of the Russian academy of medical sciences. 2018;73(6):388-400
pages 388-400 views

Optimization of Surgical Care and Anesthesia in the Treatment of Multilevel Degenerative Diseases of the Lumbar Spine in Patients with Overweight and Obesity

Byvaltsev V.A., Kalinin A.A., Goloborodko V.Y.


Background: The provision of surgical care in the treatment of degenerative diseases of the lumbar spine in patients with obesity and obesity is associated with significant risks of anesthesia and the development of perioperative complications. Aims: to analyze the results of the introduction of a combination of surgical procedures and anesthesia in the treatment of multilevel degenerative diseases of the lumbar spine in patients with excessive body weight and obesity.

Materials and methods: The results of surgical treatment of 86 patients were studied, 2 groups were identified. In the study group (SG, n=37), minimally invasive surgical techniques and original surgical approach, paravertebral musculature infiltration with bupivacaine with epinephrine, and multimodal anesthesia with dexmedetomidine were used. The comparison group (CG, n=49) consisted of patients who used the technique of traditional open transpedicular fixation in combination with the posterior interbody fusion without the above combination of surgical procedures and anesthesia. Observation and clinical evaluation was performed in the early (during hospitalization) and in the distant (on average 36 months) postoperative periods.

Results: In SG there were no changes in hemodynamics and better results were obtained on the speed of recovery of psychomotor functions. The use of local anesthetics significantly reduced the local pain syndrome (p<0.05) and the need for analgesics (p=0.002). Comparative analysis in the main group revealed significantly better results in indices of the duration of the operation [SG 145 (105; 155) min, CG 185 (100; 205) min; p=0.02], the volume of blood loss [SG 110 (90; 140) ml, CG 510 (390; 640) ml; p<0.001], the activation time [SG 1 (1; 2) days, CG 3 (3; 4) days; p=0.01], the length of hospitalization [SG 10 (9; 11) days, CG 13 (12; 15) days; p=0,03], remote clinical parameters of the pain syndrome level from the visual analogue scale in the lower extremities [SG 3 (1; 4) mm, CG 9 (6; 14) mm; p=0.006] and the lumbar spine [SG 6 (4; 9) mm, CG 16 (11; 21) mm; p=0.001], functional state according to ODI [SG 8 (6; 10) points, CG 16 (12; 24) points; p=0.008], subjective satisfaction with the operation performed on the Macnab scale (p=0.01). The number of postoperative complications in SG was 8%, in CG ― 18% (p=0.006).

Conclusions: Analysis of the results of the introduction of a combination of surgical and anesthetic support methods in the treatment of multilevel degenerative diseases of the lumbar spine in patients with overweight and obesity, including minimally invasive surgical techniques, infiltration of paravertebral muscles with bupivacaine and epinephrine, multimodal anesthesia with dexmedetomidine showed its high perioperative safety, low number of complications, as well as better and clinical outcomes in the early and late postoperative periods.

Annals of the Russian academy of medical sciences. 2018;73(6):401-410
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Influence of CYP3A Activity on the Efficacy and Safety of Fluvoxamine in Patients Depressive Disorders and Comorbid Alcohol Use Disorder

Zastrozhin M.S., Smirnov V.V., Sorokin A.S., Grishina E.A., Ryzhikova K.A., Bedina I.A., Shipitsyn V.V., Savchenko L.M., Buzik O.Z., Koporov S.S., Bryun E.А., Sychev D.A.


Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens adversely affects the prognosis of the course of both diseases and their outcomes. For the treatment of DD, drugs from the group of selective serotonin reuptake inhibitors, whose representative is fluvoxamine, are used. Fluvoxamine therapy is often associated with a risk of development is shown to be ineffective, and a part of patients develop dose-dependent adverse drug reactions (ADR) and pharmacoresistance.

Objective: To study the effects of CYPD6 isoenzyme activity on the efficacy and safety of fluvoxamine therapy in patients with depressive disorders, comorbid with alcoholism.

Methods: The study was conducted on 117 Russian patients with DD, alcohol-dependent comorbid. For the purpose of correction of depressive disorders within the framework of cyclothymia, fluvoxamine (Fevarin) was administered to patients at a dosage of 50−150 mg/day. Genotyping was carried out by the method of polymerase chain reaction in Real-time mode with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of ADR. To evaluate the activity of CYP2D6, the method of high performance liquid chromatography with mass spectrometry was used to measure the urinary content of the endogenous substrate of this isoenzyme and its metabolite, the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.

Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was statistically significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.0; 5.0] (p<0.001); safety indicator, estimated on a UKU scale: 3.0 [2.0; 4.0], (GA) 4.0 [4.0; 4.2] (p<0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.0] (p<0.001); safety indicator, estimated on a UKU scale: (GG) 9.0 [9.0; 10.0], (GA) 6.0 [6.0; 7.0] (p<0.001). The calculation of the correlation coefficients between the difference in the number of scores on psychometric scales and the metabolic ratio showed a statistically significant inverse correlation of the average power degree between the efficiency index estimated by the HAMD scale (r=-0.467, p<0.05). There was no connection with the difference on the UKU scale (r=0.173, p>0.05).

Conclusion: In a study of a group of 117 patients with DD, comorbid with alcohol dependence, the effect of CYP2D6 activity, estimated by the ratio of the endogenous substrate concentrations of pinolin and its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, on the efficacy of fluvoxamine therapy. This effect was also shown using the results of genotyping. The results of genotyping also showed the existence of a difference in the safety index in patients with different genotypes from the polymorphic marker CYP2D6 1846G>A.

Annals of the Russian academy of medical sciences. 2018;73(6):411-419
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Epidemiology and Providing of Healthcare for Patients with Inherited Epidermolysis Bullosa in the Russian Federation

Kubanov A.A., Karamova A.A., Chikin V.V., Bogdanova E.V., Monchakovskaya E.S.


Background: Inherited epidermolysis bullosa is a group of genetic skin disorders. In most severe forms, such as junctional and dystrophic subtypes, quality of life and life expectancy are significantly decreased. Therapeutic approaches include wound care and complication treatment.

Aims: To evaluate the incidence and prevalence of inherited epidermolysis bullosa in the Russian Federation, sociodemographic characterisrics and provision of healthcare.

Methods: To conduct the research forms summarizing demographic, medical and social information on inherited epidermolysis bullosa patients were developed. The forms were sent to state outpatient dermatologic clinics in federal subject of the Russian Federation. Data on inherited epidermolysis bullosa patients from outpatient dermatologic clinics were obtained within the period of 2014−2016 by extracting information from their medical charts. A confirmed inherited epidermolysis bullosa diagnosis was considered as an inclusion criterion for the research. Based on the collected data prevalence and incidence rate were estimated.

Results: Data on 439 patients from 70 federal subject at year-end 2014, 404 patients from 59 federal subject at year-end 2015 and 417 patients from 60 federal subject at year-end 2016 were collected. In 2014 EB simplex was diagnosed in 19.6% patients, dystrophic EB — in 11.6% patients. In most patients (66%) EB type was not diagnosed. In 2016 patients with EB simplex (48%) and dystrophic EB (24.2%) prevailed. In 25% patients an EB type was not specified. In 2014 the prevalence rates were estimated as 3.6 (in 70 federal subject), in 2015 — 3.8 (in 59 federal subject), in 2016 — 3.9 per 1 million population (in 60 federal subject). The incidence rates were estimated as 0.22 and 0.33 per 1 million population in 2015 and 2016 respectively.

Conclusions: In 2016 the percent of patients with established EB type has increased in comparison to 2014. No significant changes in prevalence rates has been registered.

Annals of the Russian academy of medical sciences. 2018;73(6):420-430
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SNP Association with Risk for Sporadic Papillary Thyroid Carcinoma in Kazakh Population

Krykpayeva A.S., Nakashima M., Espenbetova M.Z., Mussazhanova Z., Azizov B.S.


Background: The recent genome-wide association studies (GWAS) including FOXE1 and NKX2-1 genes have represent associations for well differentiated thyroid carcinoma. Replication studies in geographically distinct populations identified strong associations of rs965513 (9q22.33) and rs944289 (14q13.3) SNPs with papillary thyroid cancer. This work is the first to characterise the associations of SNPs in a population-based Kazakh cohort.

Aims: To study association of SNPs with risk for sporadic papillary thyroid carcinoma (PTC) in Kazakh population.

Materials and methods: A total of 298 patients with histologically confirmed PTC and 742 controls of Kazakh origin were recruited. All participants donated a peripheral venous blood sample which was used to isolate genomic DNA. Genotyping was performed using TaqMan Genotyping on a Light Cycler 480 (Roche, Indianapolis, IN).

Results: Significant associations: rs965513 (p=3.24 E-16; OR=2.05, 95% CI 1.82−2.11) and rs944289 (p=1.38 E-06; OR=1.39, 95% CI 1.21−1.52) were found in the multiplicative model of inheritance adjusted for age and sex.

Conclusions: Our study unambiguously confirms the existence of genetic determinants of susceptibility to PTC in Kazakh population.

Annals of the Russian academy of medical sciences. 2018;73(6):431-435
pages 431-435 views

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