[Hereditary afibrinogenemia: A literature review and clinical observations]. / Nasledstvennaia afibrinogenemiia: obzor literatury i klinicheskie nabliudeniia.

Afibrinogenemia is a rare congenital coagulopathy that leads to life-threatening bleeding. In afibrinogenemia, plasma fibrinogen levels are less than 0.1 g/L. The clinical manifestations of the disease can be both bleeding and thromboses of different localizations, which is determined by the multifunctional role of fibrinogen in hemostasis. The described cases demonstrate different clinical phenotypes of the disease. In both cases the diagnosis was confirmed by genetic examinations that revealed homozygous mutations in the fibrinogen A genes. The nature of the mutations assumes consanguineous marriages, as confirmed by the results of a genealogical analysis. Fibrinogen preparations are promising in treating afibrinogenemia in Russia.

[Atherogenesis in human - clinical aspects of circulating immune complexes].

It has been suggested that circulating immune complexes containing low density lipoproteins (LDL-CIC) play a role in atherogenesis and are involved in the formation of early atherosclerotic lesions. The complexes, as well as anti-LDL antibody were found in the blood of patients with atherosclerotic process in various cardiovascular diseases, well as in the blood of animals with experimentally modulated atherosclerosis. One can assume that the presence anti-LDL antibodies in blood is a result of an immune response that is induced by modification of lipoproteins. LDL-CIC differ from native LDL in many aspects. They have much lower levels of sialic acid, a smaller diameter and a higher density electronegativity than native LDL. The fraction of the LDL-CIC in serum is an important manifestation of the atherosclerotic process. LDL-CIC, unlike the native LDL is able to induce intracellular accumulation of neutral lipids, especially esterified cholesterol in cell cultures obtained from healthy human aortic intima and macrophages in culture. After removal of the LDL-CIC, the serum of CHD-patients loses its atherogenic properties. The titer of the LDL-CIC in the blood serum significantly correlate with the progression of atherosclerosis and in vivo has the highest diagnostic yield of measured among other lipid parameters. Increasing CIC- cholesterol could also increase the risk of coronary artery atherosclerosis.

Modern state of problem of delivery of medicines with use of erythrocytes as cell-carriers.

Erythrocytes are prospective carriers of wide range of medicines and other biologically active agents. Main peculiarity and advantage of erythrocytes as carriers of medicines is their absolute bio-compatibility and ability for long circulation in an organism. While growing old these cells undergo natural process of biodegradation. Relatively inactive endocellular environment protects carried medicine from being inactivated by different endogenous factors. At the present time different methods of loading medicines in erythrocytes are used: electroporation, induced endocytosis, osmotic pulse hematolysis, hypotonic hematolysis. Most of these methods are based on the ability of these cells for reversible deformation of the surface without changing area of surface. Introduction of medicines in erythrocytes can be conducted in natural way as a result of their sorption on cell membrane. Different medicines can be used as the objects for targeted transport: antibiotics, antineoplastic drugs, corticosteroids, peptides, enzymes etc. extracorporeal pharmacotherapy with use of erythrocytes as carriers can be applied in the treatment of different diseases. Range of used medicines and provided possibilities is quite wide at a present time, but further development of this direction is very prospective. The aim of the authors was to outline a common concept of the potential of erythrocytes as universal transportation means of medicines for therapy of different pathological conditions.

[Structural and Functional Properties of Vascular Endothelium].

We have summarized in this paper main conceptions on structure and function of vascular endothelium with special attention to the role of caveolae both in regulation of function of endothelium itself and transvesicular transport of metabolic substrates. We have also described the role of shear stress in activation of vascular endothelium and putative mechanisms of its action.

[Structural and Functional Properties of Vascular Endothelium].

We have summarized in this paper main conceptions on structure and function of vascular endothelium with special attention to the role of caveolae both in regulation of function of endothelium itself and transvesicular transport of metabolic substrates. We have also described the role of shear stress in activation of vascular endothelium and putative mechanisms of its action.

[Use of anti-B-cell therapy in case of antisynthetase syndrome as the severest subtype of polymyositis/dermatomyositis].

Antisynthetase syndrome encompassing a symptom complex with severe interstitial lung disease is the severest subtype of polymyositis and dermatomyositis. The characteristic feature of antisynthetase syndrome is the insufficient efficiency of traditional therapy with glucocorticosteroids and cytostatics, which determines the prognosis of the disease and the need for new therapeutic approaches to treating these patients.

[Prognostication of immunological reactivity and the choice of the variant of reflexotherapy for a newborn infant].

AIM: The objective of the present study was to determine the classification differences in immunological reactivity and to identify its predictors in the newborn infants. MATERIAL AND METHODS: The study involved 115 full-term newborn infants presenting with grade 3 prenatal hypoxic ischemic encephalopathy in the late neonatal period. The features of immunological reactivity under the influence of acupuncture were examined. Statistical processing was carried out by means of discriminant analysis. RESULTS: The assessment and prediction of the effectiveness of acupuncture in the neonates suffering from cerebral ischemia are based on the index of immunological reactivity and the leukocyte index of intoxication, as well as on the ratio of monocytes to band neutrophils content. For generation of the group classifier of immunological predictors in a newborn infant and development of indications for reflex therapy, nine parameters of interest were measured. The group specificity of the child was determined by three variables, viz. leukocyte index of intoxication, monocyte and band neutrophil counts with values of the Fisher's exact test (F) and reliability (Wilks Lambda 0.90894; approximation F (3.144) = 4.809; p < 0.0032). The partial Wilks Lambda values showed that the greatest contribution was provided by the leukocyte index of intoxication and monocytes. Prediction accuracy of the classification matrix in the standard treatment group reached 30.8% and 91.7% respectively when reflex therapy was included in the combined rehabilitation treatment. Overall, classification accuracy amounted to 70.3%. The presence of distinctive changes in the subgroups preconditioned a personalized approach to the prescription of reflex therapy to the newborn infants and the choice of the treatment modality on an individual basis (parent, child, or both) in the "mother-newborn" system. The variant of treatment was determined by comparing the values of the results of the formulas. The newborns were referred to the subgroup with the highest value of the classification function. The predictors made it possible to reliably distinguished the second (p = 0.032) and the third (p = 0.022) subgroups from the first one, with some degree of overlapping between the edge zones of centroids of the second and third subgroups (p = 0.073). Therefore, the sensitivity of classification in the individual subgroups was lower than in the group model and was estimated at 34.4, 71.9, and 65.6% for the first, second and third groups, respectively. CONCLUSION: The mathematical models can discriminatebetween the immunological characteristics and predict them in individual newborn infants; also, they can be helpful for preventing the disruption of their adaptation process.

[On the issue of optimizing protein and energy supply for patients with acute cerebrovascular accident]. / K voprosu ob optimizatsii belkovogo i energeticheskogo obespecheniya patsientov s ostrym narusheniem mozgovogo krovoobrashcheniya.

OBJECTIVE: To study the severity of systemic metabolic dysfunction in various types of stroke and determine the parameters of optimal energy and protein supply for this category of patients in the presence of severe neurological deficit (National Institutes of Health Stroke Scale - NIHSS score of 15 points or more) during different periods of the disease. MATERIAL AND METHODS: The retrospective study included 512 patients with acute cerebrovascular accident (ACVA) who received nutritional support (NS) for 10 days or more: 367 (71.7%) people with ischemic stroke (IS) and 145 (28.3%) - with hemorrhagic stroke (HS). The course of stroke in all patients included in the study was accompanied by severe and extremely severe neurological disorders (15 points or more on the NIHSS scale). Energy expenditure and the severity of the catabolic reaction of the body were studied by dynamic assessment of indirect calorimetry indicators and actual nitrogen losses. RESULTS: More than 99% of patients received tube feeding. Using the method of indirect calorimetry, the ranges of energy expenditure during stroke were determined: for IS - 1600-2100 kcal/day (24-26 kcal/kg/day), for HS - 1900-2600 kcal/day (26-30 kcal/kg/day) in depending on the period of the disease. The average nitrogen losses at all stages of the disease in patients with IS and HS were comparable. In IS, these amounts were 19 g/day (0.25 g/kg/day), which corresponds to 119 g/day of protein (1.56 g/kg/day of protein), and in HS patients lost an average of 18.9 g/day of nitrogen (0.24 g/kg/day) or 118 g/day of protein (1.5 g/kg/day of protein). The maximum nitrogen losses were observed in the period from 10 to 20 days of illness and amounted to 24.7 g/day in patients with HS (0.31 g/kg/day or 1.93 g/kg/day protein), and in patients with IS - 24.5 g/day (0.29 g/kg/day or 1.81 g/kg/day protein). CONCLUSION: An identified trend towards a decrease in mortality in patients with acute stroke with energy supply in the amount of 27-28 kcal/kg/day and protein consumption in the amount of 1.3-1.4 g/kg/day compared with patients receiving 20-21 kcal/kg /day and 1-1.2 g/kg/day of protein requires further prospective randomized studies.

Quantitative aspects of RNA silencing in metazoans.

Small regulatory RNAs (microRNAs, siRNAs, and piRNAs) exhibit several unique features that clearly distinguish them from other known gene regulators. Their genomic organization, mode of action, and proposed biological functions raise specific questions. In this review, we focus on the quantitative aspect of small regulatory RNA biology. The original nature of these small RNAs accelerated the development of novel detection techniques and improved statistical methods and promoted new concepts that may unexpectedly generalize to other gene regulators. Quantification of natural phenomena is at the core of scientific practice, and the unique challenges raised by small regulatory RNAs have prompted many creative innovations by the scientific community.

[Recombinant activated factor VII use for the bleeding implications prevention during central venous catheterization in pediatric patients with acute leucosis and thrombocytopenia].

UNLABELLED: Research objective was to develop an algorithm of the recombinant activated Factor VII (rFVIIa) prophylactic use for the bleeding implications prevention during central venous catheterization in Pediatric patients with acute leucosis and thrombocytopenia. METHODS: 30 Pediatric patients with acute leucosis and thrombocytopenia received rFVIIa 30-120 microg kg(-1) before the internal jugular vein catheterization with ultrasound control. Comparative group 1 included 39 Pediatric patients without preventive haemostatic treatment; comparative group 2 included 30 patients received platelet concentrate. RESULTS: the first attempt catheterization numbers increased, the time of the catheterization was reduced, platelet aggregation was improved and the bleeding implications frequency was 6.6% in patients received rFVIIa before the internal jugular vein catheterization. 23.1%--in the comparative group 1; 26.7% in the comparative group 2. CONCLUSION: Ultrasound navigation and rFVIIa preventive use together improve internal jugular vein catheterization results.

Mechanisms of human DNA methylation, alteration of methylation patterns in physiological processes and oncology.

DNA methylation is one of the epigenetic modifications of the genome, the essence of which is the attachment of a methyl group to nitrogenous bases. In the eukaryote genome, cytosine is methylated in the vast majority of cases. About 98% of cytosines are methylated as part of CpG dinucleotides. They, in turn, form CpG islands, which are clusters of these dinucleotides. Islands located in the regulatory elements of genes are in particular interest. They are assumed to play an important role in the regulation of gene expression in humans. Besides that, cytosine methylation serves the functions of genomic imprinting, transposon suppression, epigenetic memory maintenance, X- chromosome inactivation, and embryonic development. Of particular interest are the enzymatic processes of methylation and demethylation. The methylation process always depends on the work of enzymatic complexes and is very precisely regulated. The methylation process largely depends on the functioning of three groups of enzymes: writers, readers and erasers. Writers include proteins of the DNMT family, readers are proteins containing the MBD, BTB/POZ or SET- and RING-associated domains and erasers are proteins of the TET family. Whereas demethylation can be performed not only by enzymatic complexes, but also passively during DNA replication. Hence, the maintenance of DNA methylation is important. Changes in methylation patterns are observed during embryonic development, aging, and cancers. In both aging and cancer, massive hypomethylation of the genome with local hypermethylation is observed. In this review, we will review the current understanding of the mechanisms of DNA methylation and demethylation in humans, the structure and distribution of CpG islands, the role of methylation in the regulation of gene expression, embryogenesis, aging, and cancer development.

Peculiar effects of muscarinic M1, M2, and M3 receptor blockers on cardiac chronotropic function in neonatal rats.

The effects of muscarinic M(1), M(2), and M(3) cholinergic receptor blockade on the regulation of chronotropic function of the heart were studied in vivo in 7-day-old rat pups. Intravenous injection of M(2) receptor blocker gallamine produced no changes in cardiac chronotropy. In contrast, M(1) receptor blocker pirenzepine and M(3) receptor blocker 4DAMP provoked bradycardia. These data attest to the involvement of M(1) and especially M(3) cholinergic receptors in the regulation of cardiac chronotropy in rat pups, which confirms the view on pronounced species-specific and age-related peculiarities in the heart control mechanisms.

Protective effect of transplantation of neonatal liver cell nuclei on the model of acute toxic hepatitis.

We present the results of comparative analysis of functional and morphological changes in the liver of animals with experimental CCl(4)-induced hepatitis under conditions of transplantation of neonatal liver cells and nuclei. It was found that transplantation of neonatal liver cell nuclei in acute toxic hepatitis provides better functional and structural state of the target organ.

[Hygienic evaluation of educational conditions and health status in junior pupils from rural schools].

Clinical and epidemiological examinations were made in rural junior (8-10-year-old) schoolchildren from the Vyazma District, Smolensk Region. The clinical findings were compared with the results of evaluation of sanitary-and-hygienic school welfare (SGW), made by the regional branch of the Russian Inspectorate for the Protection of Consumer Rights and Human Welfare, and with those of a sociological survey of school directors and teachers. In the rural schools referred to as Group III morbidity, the incidence of diseases was ascertained to be significantly higher and their patterns had its peculiarities as compared to good hygienic and social educational institutions. There was evidence that the worse schooling conditions, the more children suffered from chronic diseases, chronic mental diseases and physical malformations in particular.

White matter hyperintensity in different migraine subtypes.

The diagnostic value of white matter hyperintensities (WMH) in different types of migraineare unknown. To evaluate the WMH pattern of different subtypes in migraine patients with no vascular risk factors. 92 migraine patients (73 females, mean age 34.6 ± 8.9; 61 episodic migraine, 31 chronic migraine, 36 migraine with aura, 56 migraine without aura) without vascular risk factors underwent brain MRI (3 T). We also included a matched healthy control group with no migraine (n = 24). The prevalence of WMH in different types of migraine was similar and ranged from 38.7 to 44.4%; the control group showed no WMH at all. Lesions were located within frontal, parietal and temporal lobes (in order of decreasing incidence) in juxtacortical and/or deep white matter. WMH appeared as round or slightly elongated foci with a median size of 2.5 mm [1.5; 3]. Total number, size and prevalence of WMH by lobes and white matter regions were similar between groups, and no interaction with age or sex was found. The number of lesions within the frontal lobe juxtacortical white matter correlated with the age of patients (r = 0.331, p = 0.001) and the duration since migraine onset (r = 0.264, p = 0.012). Patients with different migraine subtypes and without vascular risk factors are characterized by a similar pattern of WMH in the absence of subclinical infarctions or microbleedings. Therefore, WMH have no relevant prognostic value regarding the course of migraine and vascular complications. WMH pattern may be used to differentiate migraine as a primary disorder and other disorders with migraine-like headache and WMH.

[Interhemisphere asymmetry of regulation of the local brain blood flow in patients with dyscirculatory encephalopathy].

Patients with dyscirculatory encephalopathy (DE) were examined to elucidate interhemisphere relationships by recording brain constant potential (CP) and perfusion CT. Electrophysiological characteristics were shown to relate to local brain blood flow. Dispersion of intrehemisphere CP level in DE patients proved more pronounced than in healthy subjects. Interhemisphere CP difference in temporal region significantly (p < 0.001) correlated with the time needed to reach maximum concentration of contrast agent in the frontal and temporal cortex, basal ganglia, and thalamus. Left temporal CP level positively correlated with contrast agent concentration in the above brain structures of both hemispheres and negatively with that in the right hemisphere. It is concluded that intertemporal relationships may influence vegetative nervous system that in turn changes cardiovascular function.

Amyloid properties of the yeast cell wall protein Toh1 and its interaction with prion proteins Rnq1 and Sup35.

Amyloids are non-branching fibrils that are composed of stacked monomers stabilized by intermolecular ß-sheets. Some amyloids are associated with incurable diseases, whereas others, functional amyloids, regulate different vital processes. The prevalence and significance of functional amyloids in wildlife are still poorly understood. In recent years, by applying new approach of large-scale proteome screening, a number of novel candidate amyloids were identified in the yeast Saccharomyces cerevisiae, many of which are localized in the yeast cell wall. In this work, we showed that one of these proteins, Toh1, possess amyloid properties. The Toh1-YFP hybrid protein forms detergent-resistant aggregates in the yeast cells while being expressed under its own PTOH1 or inducible PCUP1 promoter. Using bacterial system for generation of extracellular amyloid aggregates C-DAG, we demonstrated that the N-terminal Toh1 fragment, containing amyloidogenic regions predicted in silico, binds Congo Red dye, manifests 'apple-green' birefringence when examined between crossed polarizers, and forms amyloid-like fibrillar aggregates visualized by TEM. We have established that the Toh1(20-365)-YFP hybrid protein fluorescent aggregates are co-localized with a high frequency with Rnq1C-CFP and Sup35NM-CFP aggregates in the yeast cells containing [PIN+] and [PSI+] prions, and physical interaction of these aggregated proteins was confirmed by FRET. This is one of a few known cases of physical interaction of non-Q/N-rich amyloid-like protein and Q/N-rich amyloids, suggesting that interaction of different amyloid proteins may be determined not only by similarity of their primary structures but also by similarity of their secondary structures and of conformational folds.

[Biomarkers and mechanisms of early vascular damage]. / Biomarkery i mekhanizmy rannego povrezhdeniia sosudistoi stenki.

AIM: To assess the association of classic vascular risk factors, indicators of cerebral arteries wall damage and stress induction, and their role in early vascular and brain damage in middle age subjects without vascular events. MATERIAL AND METHODS: 87 patients were evaluated (49 women, 38 men, mean age 51.2±6.5). The following vascular risk factors were assessed: hypertension, diabetes, total cholesterol and low density lipoproteins levels, obesity and smoking. Patients underwent ultrasound of neck arteries, brain MRI and laboratory testing of blood parameters, probably associated with vascular wall damage: CRP, TNF-α, sICAM-1, sVCAM, HIF1-α, NO, VAP-1, VEGF-A, VEGF-C, sVEGF-R1, sVEGF-R2, TGF-ß1, general antioxidant status. RESULTS AND CONCLUSION: Mediating role of stress parameters in risk factors formation, initiation and maintenance of mechanisms of vascular damage was demonstrated. Hypercortisolemia suggested the association with age, atheromatosis, local inflammatory reactions via the TGF-ß1-HIF-1-VEGF family, systemic inflammation response via CRP, and elevated epinephrine levels were associated with TNF-α-mediated systemic inflammation. The association of TNF-α and MRI signs of cerebral small vessel disease (SVD) in non-hypertensive patients may indicate that TNF-α-mediated inflammation and increased permeability of vessel wall is an independent cause and potential biomarker of early small vessel damage. Influence of hypertension on age-dependent SVD is probably maintained by local vascular wall damage mechanisms via the TGF-ß1-HIF-1-VEGF family. However, hypertension heterogeneity and association of early cerebral vessels damage with various protective reactions require further clarification of the conditions for using these parameters as possible biomarkers of early SVD.

Association study of methylenetetrahydrofolate reductase genetic polymorphism 677C>T with schizophrenia in hospitalized patients in population of European Russia.

The purpose of the research was to investigate the association of methylenetetrahydrofolate reductase (hereinafter MTHFR) genetic polymorphism 677C>T with schizophrenia in the Russian population in comparison with the control group of healthy blood donors. Also some characteristics of schizophrenia were examined in patients with/without defective T-allele of MTHFR677C>T polymorphism. 500 patients with schizophrenia and 499 blood donors were examined for T-allele carriage of polymorphism MTHFR677C>T by PCR method. 150 archival medical records were studied (in the first patients included in the study). The carriage of T-allele of genetic polymorphism MTHFR677C>T was significantly more common in patients than in healthy donors: 255/500 versus 219/499 (p=0,0287, χ2=4,79; OR=1,33, 95%CI [1037; 1707]). The number of patients with chronic type of schizophrenia onset was significantly more among T-allele carriers (n=77) than among normal CC-genotype carriers (n=73): р=0.038. The number of "incapacitated" persons in the group of patients with defective T-allele (n=77) was significantly higher than in patients with normal genotype (n=73, p=0.0439; OR=2.878, 95%CI=1.111-7.456). The results suggest that T-allele of genetic polymorphism MTHFR677C>T in the population of European Russia may increase the risk of developing schizophrenia and its unfavorable prognosis, which requires further investigation.

EFFECT OF SOMEUNFAVORABLE FACTORS OF ENVIRONMENT ON THE SURVIVAL OF CHILDREN WITH ACUTE LEUKEMIA IN A LONG6TERM PERIOD AFTER ACCIDENT ON THE CHORNOBYL NPP. / VPLYV DEIaKYKh NESPRYIaTLYVYKh ChYNNYKIV DOVKILLIa NA VYZhYVANIST' DITEI Z GOSTRYMY LEIKEMIIaMY U VIDDALENYI PERIOD PISLIa AVARIÏ NA ChORNOBYL'S'KII AES.

OBJECTIVE: Determine of the influence of adverse environmental factors, including irradiation, on the survival ofchildren with acute leukemia in the long-term period after the Chornobyl accident (2008-2017). MATERIALS AND METHODS: Examined 74 children with acute leukemia (АL): 64 with acute lymphoblastic leukemia(ALL); 10 - acute myeloblastic leukemia (AML). The influence of negative environmental factors was assessed bythe degree of integrated pollution of the atmospheric air, surface waters and soils with pesticides, heavy metals (Pb,Cu, Ni, Cr, Mn, Zn, Fe) and cesium isotope 137Cs. These regions were ranked on a moderately polluted (1), polluted (2),very (3) and extremely (4) polluted territories. Took into account the age of children, blood test, immunophenotyp-ic of variant the acute leukemia, survival of patients and place of residence (city / village), serum ferritin level (SF). RESULTS: Exposure doses of children were in the range from 0.4 mSv to 35.0 mSv (average values were (4.25 ± 0.63 mSv)and did not affect the prognosis and variants of AL. 52 children lived in moderately and polluted territories (30 wereresidents of cities, 22 - villages). 22 patients were lived in very and extremely polluted territories (4 were residentsof cities, 18 - villages). Of 74 patients with ALL and AML 24 children died (32.4 %). The smallest number ofchildren, who died, were patients with «general type¼ В-ALL (18.7 %), most of all children with pro-В-ALL (8 out of10) and Т-ALL (3 of 4). Of the 52 patients, the inhabitants of moderately and polluted regions, 13 patients died (25%), while out of 22 patients, who lived in very and extremely polluted areas, 11 children died (50 % share)(rs = 0.39; p < 0.05). Of the 10 patients with AML, 4 children died. Most often, children died, who were residents ofvillages. Moreover, the level of SF was significantly higher in children over 6 years, the inhabitants of villages -(406.8 ± 40.6) ng/ml, compared to younger patients - (211.2 ± 32.1) ng/ml) and residents of of cities: up to 6years - (297.4 ± 52.3) ng/ml; over 6 years - (275.6 ± 29.8) ng/ml. CONCLUSIONS: The obtained data testify to the negative influence of environmental factors, including iron, and canbe the basis for understanding the mechanisms of potentiating influence of metals and their compounds on thedevelopment of malignant diseases of the blood system in children.