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2018 year, number 3

1.
SEARCH FOR ARE REGULATORY SEQUENCES IN GENES OF MASTER REGULATORS OF AUTOPHAGY AND LYSOSOMAL BIOGENESIS TFEB AND TFE3

Anton Vladimirovich CHECHUSHKOV, Elena Bronislavovna MENSHCHIKOVA
Research Institute for Experimental and Clinical Medicine of Federal Research Center for Fundamental and Translational Medicine
Keywords: система Keap1/Nrf2/ARE, лизосомальный биогенез, аутофагия, TFEB, TFE3

Abstract >>
Transcription factors TFEB and TFE3 are the master regulators of lysosomal biogenesis and autophagy and control most of the protein genes involved in the formation of lysosomes by interacting with the promoters of these genes containing the regulatory motif CLEAR. Their activation is strictly regulated and occurs in response to the violation of lysosomal homeostasis and cell damage. Such effects are accompanied by activation of redox processes and by induction of the redox-sensitive signal system Keap1/Nrf2/ARE, the main purpose of which is to maintain internal homeostasis in apoptosis-inducing, carcinogenic and stressful influences. Thus, the question arises about the existence of regulatory loops between the Keap1/Nrf2/ARE and TFEB(TFE3)/CLEAR signaling systems. To search for the ARE sequence in the TFEB and TFE3 genes, a position frequency matrix was generated based on the 57 functional ARE sequences described in the literature. ARE-like sequences were labeled in the UCSC genome browser for analysis of evolutionary conservation, colocalization with various functional DNA and chromatin modifications, as well as with other regulatory elements. In the human TFEB gene, 15 ARE-like motifs were found. Of these, the sequence located in the first intron is conserved across vertebrates. In the mouse Tfeb gene, 15 ARE-like motifs were also found; one of them is conserved, but is located in the coding exon. Human and mouse transcription factor TFE3 genes contain less ARE-like sequences, among them the sequence conserved across vertebrate is noteworthy, which is located in the second intron. Using the ChIP-seq data from the ENCODE database, the histone landscape in the respective regions of the genome was analyzed and it was established that the evolutionarily conserved ARE regulatory element located in the TFE3 enhancer region likely play a functional role.



2.
CHARACTERISTICS OF BINDING TYROXINE WITH FRACTIONS OF HIGH DENSITY LIPOPROTEINS AND APOLIPOPROTEIN A-I

Lev Mikhaylovich POLYAKOV, Roman Aleksandrovich KNYASEV, Aleksandr Vladimirovich RYABCHENKO, Nataliya Viktorovna TRIFONOVA, Mariya Vladimirovna KOTOVA
Institute of Biochemistry of Federal Research Center for Fundamental and Translational Medicine
Keywords: липопротеины высокой плотности, тироксин, аполипопротеин А-I

Abstract >>
The aim of the study was to study the binding of various fractions of human blood plasma lipoproteins (VLDL, LDL, HDL2 and HDL3) with thyroxine (T4). Chromatography on Sepharose CL-2B showed that a significant portion of the labeled 125I-thyroxine eluted in the volume of the output of the HDL fraction, which may indicate the possibility of formation of HDL-T4 complexes. The process was reversible, since the introduction of an excessive amount (10-6-10-7 M) of unlabeled T4 into the system resulted in the displacement of 125I-T4 from complexes with HDL, which indicates a «protein - ligand» type interaction. The effect of environmental conditions on the formation of complexes of T4 with HDL is investigated. An increase in temperature to 40 °C resulted in a more than 50 % decrease in the release of radioactivity with a fraction of HDL. Complexation decreased at 4 °C, however, the complexes showed the greatest stability. The main physicochemical characteristics of the interaction of T4 with subfractions of HDL2 and HDL3 were obtained by quenching tryptophan fluorescence. The complexation constants of HDL with T4 were of the order of 106-107 M-1. The greatest affinity for T4 was found for particles of subfraction of HDL3. It was established that the main protein component of HDL ─ apolipoprotein A-I takes part in complexation with T4, on which has one binding center.



3.
BIOSIMILARS, PRODUCED USING THE RECOMBINANT DNA TECHNOLOGY

Zhanna Il’darovna AVDEEVA, Vladimir Petrovich BONDAREV, Vadim Anatol’evich MERKULOV, Yuriy Vital’evich OLEFIR
Scientific Center for Expert Evaluation of Medicinal Product of Minzdrav of Russia
Keywords: биоподобные препараты («biosimilars»), биотехнологические препараты, оценка качества, доклинические исследования, клинические исследования, экстраполяция, безопасность, взаимозаменяемость

Abstract >>
The review presents materials on the scientific principles underlying the development, preclinical and clinical research, registration and control of the safety of biosimilar medicines produced using genetic engineering techniques. The number of biosimilars used in the clinic, defined as «biosimilars», is steadily increasing. The features of biotechnological preparations are presented, that requires a special approach to assessing the newly developed preparation evidence of similarity with the original (reference) preparation. To ensure the effectiveness and safety of their use, the procedure for registration of such medicines is determined by the regulatory framework governing the requirements for proof of similarity with previously approved biological medicinal products. The data concerning the differences in the nature and scope of studies at the stages of quality assessment, preclinical and clinical development of biosimilar and original drugs are performed. The issues related to extrapolation of clinical trial results and the issues of medicines interchangeability are reported. The modern information on international experience of biosimilar medicines registration, scientific achievements and regulatory requirements concerning evidence of similarity in assessing the quality, effectiveness and safety of biosimilar biotechnological medicines («biosimilars») has been reported.



4.
INVESTIGATION OF THE ANTIVIRAL ACTIVITY OF AN ORAL DRUG PREPARATION BASED ON IMMOBILIZED INTERFERON λ-1

Dmitriy Nikolaevich KINSHT1,2, Pavel Gennad’evich MADONOV3,2, Galina Vadimovna KOCHNEVA4, Tatyana Sergeevna TARTYNOVA1, German Igorevich BAYKALOV1
1Novosibirsk State Medical University of Minzdrav of Russia
2«Scientific Future Management» company
3Novosibirsk State Medical University of Minzdrav of Russia «Scientific Future Management» company Novosibirsk State Medical University of Minzdrav of Russia
4State Research Center of Virology and Biotechnology «Vector»
Keywords: интерферон λ-1, гепатотропные вирусы, вирусный гепатит C, иммобилизация, электронно-лучевая иммобилизация, иммобилизированный интерферон λ-1

Abstract >>
Despite the success in developing direct-acting antiviral drugs, in routine clinical practice the use of interferons remains relevant. Parenteral administration of interferons is accompanied by systemic side effects and presents significant inconveniences for patients. A drug based on interferon λ-1, which has high enteric bioavailability and ensures its high concentration in the liver, is promising for the effective treatment of hepatotropic viruses. The aim of the investigation was to study the antiviral activity of an oral medicine based on interferon λ-1 immobilized on polyethylene glycol-1500 by electron-beam synthesis technology. Materials and methods: Real time PCR, Western blot and immunohistochemical method were used to study antiviral activity of tested medicine against hepatitis C virus. Results and discussion: The tested medicine retains antiviral activity against hepatitis C virus. All obtained results are consistent with each other. A 50 % inhibitory dose is in the range of 0.008-0.08 ng/ml. Conclusion: IFN λ-1 immobilized on polyethylene glycol with the help of radiation synthesis technology can be considered as a prototype of an oral drug for the treatment of viral hepatitis, in particular hepatitis C.



5.
PATHOMORPHOLOGICAL ANALYSIS OF ERBIUM LASER APPLICATION TO CORRECTION OF STRESS URINARY INCONTINENCE IN WOMEN

Galina Anatolevna LAPIY1, Asya Yurevna YAKOVLEVA1, Natig Arifogly ABDULLAEV1, Aleksandr Izrailevich NEYMARK2
1Institute of Molecular Pathology and Pathomorphology of Federal Research Center for Fundamental and Translational Medicine
2Altaic State Medical University
Keywords: стрессовое недержание мочи, Er:YAG-лазер, лазерная технология IncontiLase, биопсия влагалища, морфология, морфометрия, иммуногистохимия

Abstract >>
The aim of the investigation is to study the pathomorphological changes in the anterior vaginal wall in women with stress urinary incontinence, who received correction using an erbium laser Fotona. Material and methods. The complex pathomorphological analysis of the biopsy specimens of the vaginal mucosa (VM) in women with stress urinary incontinence (SUI) before and after exposure Er-YAG-laser was performed. Results. It is shown that the main signs of remodeling of VM during SUI are disorganization of fibrillar structures (collagen and elastic fibers) of the intercellular matrix, microcirculation disorders, dystrophic and atrophic changes in the epithelium. After application of laser technology IncontiLase in the VM, signs of stimulation of neocollagenogenesis and neoelastogenesis processes, enhancement of neoangiogenesis, replenishment of a population of synthetically active fibroblasts, increased proliferation (an increase in the index of Ki-67-positive epitheliocytes by 67 %) and improvement of the structure of the vaginal epithelium are revealed. Conclusion. The use of an Er-YAG laser in the correction of SUI in women potentiates the restoration of the morphofunctional organization of VM.



6.
ASSESSMENT OF HEART RATE VARIABILITY IN INTERRELATIONSHIP WITH EATING BEHAVIOR DISORDERS IN WOMEN WITH DIFFERENT TYPE OF OBESITY AND TYPE 2 DIABETES

Iraida Georgievna MOKHOVA, Boris Borisovich PINKHASOV, Vera Georgievna SELYATITSKAYA
Research Institute of Experimental and Clinical Medicine of Federal Research Center for Fundamental and Translational Medicine
Keywords: типы распределения жировой ткани, ожирение, сахарный диабет 2 типа, вариабельность ритма сердца, пищевое поведение

Abstract >>
Objective: to research features of vegetative regulation and their relation to eating behavior in women with different types of obesity and type 2 diabetes. Methods. 106 women were examined; survey of women included anthropometric measurements, study and calculation of heart rate variability were performed with “VNS-micro” (Neurosoft, Russia); recording of food consumption in 24hs were assessed. The types of eating disorders (ED) were detected with DEBQ. Results and discussion. Adipose tissue topography (ATT) among women is associated with vegetative regulation, as well with ED. So, the spectrum of both high-frequency (HF) and low-frequency (LF) oscillations are increased in women with gynoid type of ATT. Conversely, android type of ATT is characterized by overall decline of LF and HF oscillations with residual dominance of the sympathetic part. An increase in the relative contribution to the total power of the very low-frequency (VLF) spectrum among women has been revealed. Emotional and compulsive eating behavior disorders were prevalent in women with gynoid type of ATT, external type of ED prevailed among women with android type of ATT. Women with android type of ATT and type 2 diabetes had minimal severity of eating behavior disorders. The increase in activity of the sympathetic and parasympathetic parts of the autonomic nervous system in women with gynoid type of ATT was combined with sympathoadrenal and vagoinsular reactions, which is confirmed by a positive correlation of emotional ED with HF and LF, and there was a negative correlation of restrictive ED with LF. A negative correlation of emotional ED with VLF among women with android type ATT was detected. There are no correlation of ED indices and activity of the autonomic nervous system among women with android type of ATT and type 2 diabetes. It can be associated with manifestations of diabetic vegetative neuropathy.



7.
EFFECTIVENESS OF MONONUCLEAR LEUKOCYTE SUSPENSION APPLICATION IN BULLOUS KERATOPАTHY SURGERY

Ekaterina Olegovna FILIPPOVA, Olga Ivanovna KRIVOSHEINA
Siberian Medical State University of Minzdrav of Russia
Keywords: эндотелиально-эпителиальная дистрофия, аутологичные мононуклеары крови, цитокины, эндотелий, пролиферация

Abstract >>
The aim of the research was to study the effectiveness of bullous keratopаthy surgical treatment by modified method of operative intervention including intra-chamber injection of autologous blood mononuclear cells suspension with subsequent layering on the inner surface of the cornea. Material and methods. Clinical studies were conducted among 44 patients who comprised two groups: the main group (21 patients) and comparison group (23 patients). The treatment of the main group was carried out by a new method. The treatment of the comparison group was traditional pharmacotherapy. Results and discussion. The cornea hydration reduction in the main group was noted during the first 5 days after surgical treatment. The moderate decrease of corneal oedema in the comparison group started on 10-12 days. The pachymetry index decreased by 11 % in the main group and by 3.1 % in the comparison group after 1 month of treatment. Visual acuity increased fivefold in the main group and twofold in the comparison group. Conclusion. The use of the modified surgical treatment of the bullous keratopаthy promotes a faster decrease in the cornea hydration and stable improvement in visual acuity in the postoperative period compared with the course of conservative treatment.



8.
STRUCTURAL AND FUNCTIONAL FEATURES OF THE LIVER WITH MARKERS OF HCV- AND HBV-INFECTION AND OF GASTRIC MUCOSA FOR VARYING DEGREES OF Helicobacter pylori COLONIZATION

David L’vovich NEPOMNYASHCHIKH1, Olga Alexeevna POSTNIKOVA1, Elena Ivanovna MIGUS’KINA2, Ekaterina Eduardovna ABRAMOVA1
1Novosibirsk State Medical University of Minzdrav of Russia
2Novosibirsk Regional Clinical Hospital
Keywords: хронические HCV- и HBV-инфекции, гепатопатия, гастропатия, Helicobacter pylori

Abstract >>
The aim of the investigation was to study the structural features of the liver cell populations and gastric mucosa at varying intensity of Helicobacter pylori colonization in patients with HCV and HBV infection markers. Material and methods. The clinical and morphological study of 95 patients with markers of HCV and HBV infection and with gastric dysfunction (52 men and 43 women aged 16 to 66 years) and 56 patients with chronic gastritis has been carried out. The results have been compared to the degree of H. pylori infection. Results and discussion. It is shown that in all patients with chronic hepatitis the gastric mucosa is involved in the pathological process while the fibrosing form of lesions - gastropathy predominated. The significant correlation between structural changes and the hepatitis activity degree as well as with the presence of H. pylori has not been revealed. Analysis of the stomach structural changes in patients with chronic gastritis, depending on the presence of H. pylori and the infection intensity showed that the catarrhal-fibrotic process predominates in gastric mucosa in case of high degree of H. pylori activity and fibrosing changes predominate in the absence of H. pylori .



9.
CONTENTS OF SOME OSTEOTROPIC GROWTH FACTORS AND OSTEOGENESIS MARKERS IN BLOOD OF PATIENTS WITH OSTEOGENESIS IMPERFECTa AND HYPOPHOSPHATEMIC RICKETS

Evgeniya Petrovna VYKHOVANETS, Svetlana Nikolaevna LUNEVA, Nataliya Viktorovna NAKOSKINA, Eduard Rifovich MINGAZOV, Arnold Vasilyevich POPKOV
Russian Ilizarov Scientific Center «Restorative Traumatology and Orthopaedics» of Minzdrav of Russia
Keywords: сыворотка крови, факторы роста и их рецепторы, несовершенный остеогенез, фосфат-диабет, остеосинтез аппаратом Илизарова

Abstract >>
In recent years there is intensive growth of the number of genetic diseases such as imperfect osteogenesis and hypophosphatemic rickets. Treatment of this category of patients includes surgical intervention, however in many cases there are recurrences of the disease and the patients have to undergo multiple surgeries. It is known that study of concentration of growth factors and regulatory polyproteins can help in understanding of pathogenetic course of genetic diseases. Material and methods. We studied growth factors and their receptors, bone markers and vitamin D by enzyme-linked immunoassay in blood serum of patients with hypophosphatemic rickets and osteogenesis imperfecta during surgical treatment. The analysis was carried out according to technique from manual to sets eBioscience (TGF-β1, TGF-β2, VEGF-A, VEGF-R2, VEGF-R3), Immunodiagnostic systems (IGF-1, osteocalcin, vitamin D, β-CrossLaps), Invitrogen (VEGF), RayBiotech Inc. (FGF-1, FGF-2, TGF-α, SCF, SCFsR), Mediagnost (IGF-2), QULDEL (pyridinoline), Enzo (DKK-1). Results. It has been established that concentration of growth factors IGF-1, VEGF, FGF-2, TGF-β1, TGF-β2 and their receptors VEGF-R3, SCFsR, bone markers osteocalcin, pyridinoline, as well as vitamin D in blood of patients of different groups at different stages of treatment varied. However, concentration of IGF-1, VEGF-R2 before surgery and ТGF-α on the 60th day, SCF on the 60th day in patients with hypophosphatemic rickets and osteogenesis imperfecta did not differ.



10.
CUMULATIVE FLUID BALANCE OF INFUSION THERAPY OF NEWBORNS WITH NECROTIZING ENTEROCOLITIS

Igor’ Alekseevich AL’YANOV1, Kristina Vladimirovna BUDAROVA2, Sergey Ivanovich SIROTA3, Aleksey Nikolaevich SHMAKOV1,4
1Novosibirsk State Medical University of Minzdrav of Russia
2City Children’s Clinical Emergency Hospital
3Children City Clinical Hospital № 1
4State Novosibirsk Regional Clinical Hospital
Keywords: кумулятивный баланс, некротический энтероколит, инфузионная терапия, критическое состояние, гиповолемия

Abstract >>
The aim of the research is to study the connection between the five-day cumulative fluid balance and the outcome of a critical condition in the surgical group of newborns. Material and methods. The study involved 30 newborns with necrotizing enterocolitis in stage IIIB according to Walsh - Kliegman. Groups were formed by the criterion of outcome. Analyzed parameters were age and body weight of participants, hematocrit number; the cumulative five-day fluid balance expressed as a percentage of the initial body weight. The data were carried out by nonparametric statistics. Results and discussion. The only independent factor determining the probability of death from necrotizing enterocolitis of newborns is the gestational age and the body weight as its derivative. The likelihood of an unfavorable outcome in necrotizing enterocolitis of the newborn doesn’t depend on the five-day cumulative fluid balance.



11.
CERVICAL DYSTONIA: HISTORICAL AND MODERN ASPECTS (REVIEW)

Oksana Arkadyevna DRUZHININA1, Larisa Pavlovna SHPERLING2, Nataliya Grigorevna ZHUKOVA3
1City Polyclinic № 1
2Regional Center for Extrapyramidal Diseases with Botulinum Therapy Room
3Siberian State Medical University of Minzdrav of Russia
Keywords: цервикальная дистония, эпидемиология, мультифакториальность, классификация, ботулинотерапия

Abstract >>
Dystonia is hyperkinesis characterized by involuntarily repetitive muscle contractions in one or more body areas. It leads to the appearance of a pathological posture and disruption of arbitrary movements. This definition is the most common, but not completely exhaustive, because of the phenotypic polymorphism of the disease. There is not unitary methodology for epidemiological research. Also the disease clinical symptoms are very polymorphic. These reasons make the results of the study incomplete and inaccurate. Implementation mechanism of dystonic hyperkinesia is still insufficiently studied. At the present time the disease multifactorial nature is the leading hypothesis whereby the genetic determinacy can be realized under the influence of exogenous factors. The diagnosis of the cervical dystonia is clinical and sets on the manifestations of the pathological posture of the head and neck. The disease begins at the active working age and proceeds with the functional deficit formation leading to difficulties of domestic and professional nature. This leads to psychological, social dysaptation and disability of patients. The proven effective treatment for the cervical dystonia is the use of botulinum toxin of type A (the grade of recommendation A).



12.
DISTANT VISION SCREENING OF SCHOOLCHILDREN AS A PRACTICAL METHOD OF APPLYING TELEMEDICINE TO OPHTHALMOLOGY: RESULTS AND PROSPECTS

Valeriy Vyacheslavovich CHERNYKH, Igor Leonidovich PLISOV, Natalya Gennadievna ANTSIFEROVA, Varvara Borisovna PUSHCHINA
The S.N. Fyodorov Eye Microsurgery Complex, Novosibirsk branch
Keywords: телемедицина, скрининг зрения, оптотипы Ландольта, острота зрения, миопия, косоглазие, амблиопия

Abstract >>
Early detection of children sight disturbances allows ophthalmologists to prescribe in time preventive activities and treatment, to stop developing pathology, and to prevent complications initiation. The purpose of our study was to elaborate and introduce into practice a method of distant screening examinations of schoolchildren using telecommunication facilities. Material and methods. We developed an interactive computer program for distant examination of visual acuity, long or short sight shift in refraction , diagnostics of astigmatism and pathology of macular area. The results of the examination were automatically recorded in a computer database. The program was hosted on the clinic website. Examination was performed simultaneously for up to 5 schoolchildren sitting in a computer class of their schools. The examination lasted from 4 to 8 minutes for the group depending on the quantity of the invoked tests. Results and discussion. 28,983 schoolchildren underwent the distant screening of vision. Visual acuity of 1.0-0.9 was revealed in 14345 people (49.5 %), 0.8-0.2 - in 11187 people (38.6 %) and less than 0.1 - in 3451 people (11.9 %). The test is not specific in terms of the type of pathology, but it allows us to conclude that more than half of schoolchildren have a reduced vision. A method of distant screening vision examinations is reliable and high-performance. Database of the examination results is helpful to diagnose pathology at early stage, to track its dynamics and to inform parents in time on whether an expanded investigation and ophthalmological treatment of their children is necessary.



13.
EVALUATION OF NEUROLOGICAL DEFICIENCY IN PATIENTS WITH INSULT WORKING IN THE CONDITIONS OF EXPOSURE TO HARMFUL PRODUCTION FACTORS

Maria Viktorovna YASHNIKOVA1,2
1Novosibirsk State Medical University of Minzdrav of Russia
2City Clinical Emergency Hospital № 1
Keywords: инсульт, мужчины, шкала NIHSS, неврологический дефицит, производственные факторы

Abstract >>
The question on the peculiarities of stroke course in persons working under the influence of unfavorable occupational factors has not been sufficiently studied. The aim of the study was to assess the severity of stroke and the severity of the neurological deficit in the acute period of stroke in men exposed to occupational factors of physical and chemical nature. The analysis of the recovery dynamics in the acute period of stroke in 241 patients (the main group) exposed to harmful occupational factors (general vibration, production noise, electromagnetic radiation (EMR), toxic-dust factor) was carried out. The comparison group consisted of 76 patients with stroke who did not work under the influence of harmful occupational factors. To objectify the severity of the condition and assess the severity of the neurological deficit, the National Institutes of Health Stroke Scale (NIHSS) was used in the scores for admission and dynamics of an acute stroke on day 21 of the disease (NIHSS 1 and NIHSS 2). An initially expressed deficit (NIHSS 1 scale) in patients with stroke in the main group was established, compared with the comparison group, and the highest indicator was found in men who contacted EMR. Significant differences between the indices of the initial neurological deficit of the main group and the comparison group were revealed only among young men who had contact with EMR, as well as with the toxic-dust factor. The best dynamics of recovery in the acute period of stroke was found in the comparison group, and in the main group among young people, except for the production group with the influence of the toxic-dust factor. In patients with ischemic stroke, the minimal neurological deficit to the end of the acute period was in the comparison group, and in the main group - in young men who had the influence of general vibration, as well as noise. The severe course of hemorrhagic stroke was established in the comparison group, and in the main group - among patients who had contact with EMR. The elderly of the main group had the maximum severity of the neurological deficit, with the exception of patients who had the effect of a toxic-dust factor.