[The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases].

AIM: To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology. MATERIALS AND METHODS: In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course. RESULTS: The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment. CONCLUSION: Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.

[Audiodiagnostics in examination of patients with internal TMJ derangement].

The aim of the study was to assess the efficacy of audiodiagnostics in dysfunctional TMJ disorders. Thirty-four patients were included in the study. The analysis of phonograms revealed correlation of adverse sound effects with varying degrees of internal TMJ-disorder seen by MRI imaging. The study results confirm the advantages of electronic registration of TMJ sound phenomena.

[Actual problems of hemorrhagic fever with renal syndrome].

From 2000 to 2011 85 600 cases of hemorrhagic fever with renal syndrome (HFRS) were registered in Russian Federation. Epidemically active foci of HFRS infection are located generally in temperate latitudes of the European part and the Far East. In the Far East regions whose fraction of all the HFRS disease cases in Russia is around 2%, the causative agents of the infection are Hantaan, Amur, Seoul hantaviruses, the natural reservoir for those are striped field mouse, Korean field mouse and brown rat. In the European part of Russia the causative agent of the infection are Puumala hantavirus as well as 2 genetic subtypes of Dobrava virus, the main reservoirs of those in the nature are bank vole, striped field mouse and Black Sea field mouse, respectively. 9 strain of Puumala and 10 strains of Dobrava virus were isolated. Based on sequencing of Dobrava virus strains significant differences were detected between Dobrava virus strains isolated from Black Sea field mouse from Sochi and striped field mouse from Lipetsk Region. Cultural inactivated vaccine against HFRS was developed and completed preclinical trials.

[Hemorrhagic fever with renal syndrome group outbreak caused by Sochi virus.]

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) occupies a leading place among natural focal human diseases in the Russian Federation. Sporadic incidence of HFRS-Sochi has been annually recorded in the Krasnodar Territory since 2000. The group outbreak of the HFRS-Sochi was first registered in Gelendzhik in the fall of 2013. METHODS: Serological methods were used: indirect immunofluorescence, enzyme immunoassay, FRNT in Vero cells, and methods for the viral RNA detection: PCR and RT-PCR. RESULTS: Data of clinical, epidemiological, immunological and molecular studies of 3 out of 4 cases in HFRS-Sochi outbreak are presented. Severity of the disease correlated with early gastrointestinal disorders appearance. Patient MA gastrointestinal disorders were joined on day 3 of a fever. Clinical and laboratory studies revealed signs of kidneys, liver, pancreas damage, bilateral hydrothorax, bilateral polysegmental pneumonia and polyneuropathy. As a result of long-term treatment, the patient recovered. Patient AA had gastrointestinal disturbances the next day after fever onset. The patient was not saved, despite early hospitalization. Hantavirus antigen and RNA were detected in the lung tissues 2 out of 10 Black-Sea field mice captured in the affected area, as well as in the organs of deceased patient. The most severe clinical course of the disease in close relatives, son and father, with a fatal outcome in the latter case may be the result of genetic features. The severity and outcome of the disease was not depend on day of hospitalization and correlated with the early manifestations of gastrointestinal disorders. CONCLUSIONS: Presented data confirm high virulence and pantropism of the Sochi virus, as well as the epidemiological role of Black-Sea field mouse (Apodemus ponticus) as the host of the Sochi virus and the source of human infection.

[Discovery, clinical and etiological characteristic of hemorrhagic fever with renal syndrome in the subtropical zone of Krasnodar region].

Twenty-six patients with hemorrhagic fever with renal syndrome (HFRS) were revealed as a result of serological examination of 582 patients with fever living around Sochi town. Etiologic role of Dobrava virus subtype as the cause of HFRS was assessed by immunofluorescent and ELISA assays, and neutralization test. The principal host of this virus and source of infection for humans is Caucasian forest mouse Apodemus ponticus. HFRS morbidity was sporadic and not dependent from patients' occupation and season. Comparative analysis of clinical and laboratory data from HFRS cases caused by DOB/Sochi and DOB/Lipetsk subspecies, as well as Puumala virus showed higher proportion of severe forms of disease in patients with HFRS from Sochi.

[Vilon effect on consequences of repeated radioactive and mercuric impact in small doses].

The purpose of the study was to determine the efficacy of vilon administration in rats after reiterated exposure to ecotoxicants (mercury in concentration near to maximum allowable one and gamma-radiation in small dose). In 24 hours after repeated radioactive and mercuric impact (RMI) and for 30 consecutive days the animals reported lymphopenia. At the same time the indices of DNA leucocytes content and structure did not differ from the parameters of intact animals, this could evidence the development of adaptation reactions. Vilon administration led to the normalization of the lymphocytes number by the 30th day after repeated irradiation (contrary to the radioactive- chemical control), while the number of granulocytes in the test group was higher than that in the intact control group. Study of the survival rate in rats revealed that Vilon reduced morbidity of rats in the course of 15 months after RMI.

Carcinogenesis and aging. IV. Effect of low-molecular-weight factors of thymus, pineal gland and anterior hypothalamus on immunity, tumor incidence and life span of C3H/Sn mice.

The low-molecular-weight polypeptide factors were obtained from bovine thymus (TF), pineal gland (PF) and anterior hypothalamus (AHF). Both TF and PF administration enhanced the rejection of skin allograft and stimulated the immunological response to sheep erythrocytes in adult CBA mice. Treatment of CBA mice with AHF increased the graft survival and inhibited antibody formation to sheep erythrocytes. Chronic TF or PF administration decreased spontaneous tumor development and prolonged the life span of female C3H/Sn mice. Administration of AHF failed to influence the life span and the tumor incidence of female C3H/Sn mice. The role of immunity and hormonometabolic shifts in mechanisms of both aging and the age-associated increase in cancer incidence are discussed.

Effect of low-molecular-weight factors of thymus and pineal gland on life span and spontaneous tumour development in female mice of different age.

Female SHR mice, aged 3.5 or 12 months, were exposed monthly to 5-day long courses of subcutaneous injections of 0.1 mg thymus-derived or pineal gland-derived polypeptide factors (TF and PF, respectively) or 0.9% sodium chloride solution (control). PF treatment increased life span of both young and middle-aged mice by 20% and 17%, respectively, and TF increased the life span only in young mice. Both factors when administered to young mice caused a decrease in both overall tumour incidence and incidence of mammary adenocarcinomas (TF, 1.8-fold decrease; PF, 2.6-fold decrease). TF administration to mature mice did not produce any antitumour effect, whereas PF possessed certain anti-tumour activity, but the response was far less pronounced than in young animals. The results obtained give additional evidence of the geroprotective and anti-tumour effect of thymus and pineal gland-derived peptide factors. The mechanisms of action of TF and PF and perspectives of clinical use of these agents as geroprotectors are discussed.

Short-time dynamics with initial correlations.

The short-time dynamics of correlated systems is strongly influenced by initial correlations, giving rise to an additional collision integral in the non-Markovian kinetic equation. Exact cancellation of the two integrals is found if the initial state is thermal equilibrium, which is an important consistency criterion. Analytical results are given for the time evolution of the correlation energy, which are confirmed by comparisons with molecular dynamics simulations.

[Influence of the polypeptide preparations cortexin and encephalin on the transplacental carcinogenic effect of N-nitroso-N-ethylurea in rats]. / Vliianie polipeptidnykh preparatov korteksina i éntsefalina na transplatsentarnyi kantserogennyi éffekt N-nitrozo-N-étilmocheviny u krys.

The polypeptide preparations cortexin and encephalin from grey and white substances of the cattle brain injected in the postnatal period are studied for their effect on the development of the nervous system and kidney tumours in rats induced transplacentally by N-nitroso-N-ethylurea. The two preparations decreased both the incidence and multiplicity of the brain tumours. It is supposed that the anticarcinogenic effect of these preparations is due to their normalizing action on the differentiation and proliferation of the brain glia cells.

[Effect of polypeptide factors of the thymus, pineal gland, bone marrow and anterior hypothalamus on the realization of transplacental carcinogenesis]. / Vliianie polipeptidnykh faktorov timusa, épifiza, kostnogo mozga i perednego gipotalamusa na realizatsiiu transplatsentarnogo kantserogeneza.

The postnatal action of low-molecular polypeptide factors of thymus (FT), pineal gland (FP), bone marrow (FRM) and anterior hypothalamus (FAH) on transplacental carcinogenic effect of N-nitroso-N-ethylurea in rats was studied. Both FT and FP administrations decreased incidence and multiplicity of tumours and prolonged their mean latent periods. These drugs inhibited mainly the development of tumours of the spinal cord, kidneys and peripheral nervous system but not those of the brain. Both FBM and FAH had no significant influence on transplacental carcinogenesis. FT and FP anticarcinogenic effect is supposed to be due to their normalizing action on hormonal metabolic and immunological shifts arising in the body after transplacental administration of the carcinogen.

[Inhibiting effect of thymogen on the development of tumors of the esophagus and forestomach induced by N-nitrososarcosine ethyl ester in rats]. / Ingibiruiushchii éffekt timogena na razvitie opukholei pishchevoda i predzheludka, indutsirovannykh étilovym éfirom N-nitrozosarkozina u krys.

Immunostimulating synthetic peptide thymogen being an analog of the thymus polypeptide drug thymalin was studied for its effect on carcinogenesis of the esophagus and forestomach in male rats. Rats received N-nitrososarcosine ethyl ester (NSEE) per os in the daily dose of 100 mg/kg of body weight during 8 weeks. After cessation of the carcinogen administration rats were treated with thymogen (the daily dose of 10 micrograms per rat) or immune-inactive polypeptide drug pulmolin from the alveolar tissue of lung (the daily dose of 0.5 mg per rat) during the following 32 weeks. Animals were killed 40 weeks after the experiment beginning. NSEE induced the esophagus and forestomach tumours, mainly papillomas and rarely carcinomas, practically in all rats, more than 5 tumours per rat, on the average. Thymogen decreased the tumour incidence by 12% and made tumour multiplicity 1.7 times as low. Pulmolin did not influence development of these tumours.

[Achievements and prospects in the development of the St. Petersburg Institute of Bioregulation and Gerontology of the Northwestern Branch of the Russian Academy of Medical Sciences]. / Dostizheniia i perspektivy razvitiia Sankt-Peterburgskogo Instituta Bioreguliatsii i Gerontologii SZO RAMN (k 10-letiiu so dnia osnovaniia).

The article presents the results of the 10-years' long activity of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences founded to fulfill the basic and applied aims in the sphere of bioregulation and gerontology and to integrate with medical practice new methods of preventing premature ageing and age-related pathology by means of pharmaceuticals based upon peptide bioregulators. Among the Institute main achievements are the theoretical developments in the field of peptide regulation of ageing, creation of a new medical domain--bioregulation therapy, and foundation of the Russian school of biogerontology.

[Geroprotective effect of thymalin and epithalamin]. / Geroprotektornaia éffektivnost' timalina i épitalamina.

Researchers of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences and the Research Institute of Gerontology of the Ukrainian Academy of Medical Sciences (Kiev) clinically assessed the geroprotective effects of thymic and epiphyseal peptide bioregulators (Thymalin and Epithalamin, correspondingly) in 266 elderly and older persons during 6-8 years (the bioregulators were applied for the first 2-3 years of observation). The obtained results convincingly confirmed the ability of the bioregulators to normalize the basic functions of the human organism, i.e. to improve the indices of the cardiovascular, endocrine, immune, and nervous systems, homeostasis, and metabolism. The restoration of homeostasis in the patients was accompanied by a 2.0-2.4-fold decrease in acute respiratory disease incidence, reduced incidence ischemic heart disease clinical manifestations, hypertension, deforming osteoarthrosis, and osteoporosis, as compared to the control group. Such a significant improvement in the somatic state of the peptide-treated patients corresponded to a decrease in their mortality rate during the observation period: 2.0-2.1-fold among the Thymalin-treated patients, 1.6-1.8-fold--in the Epithalamin-treated group, and 2.5-fold--in the patients treated with Thymalin combined with Epithalamin, as compared to the control group. A separate group of patients was treated with Thymalin combined with Epithalamin annually for 6 years. We registered a 4.1-fold mortality decrease in this group as compared to the control level. The results of our research confirmed the conclusion on the high geroprotective efficacy of Thymalin and Epithalamin and the expediency of their application in medicine and social care as the means of health maintenance and age-related pathology prevention in persons over 60 years old enabling the prolongation of the active period of their lives.

[Molecular physiology of aging]. / Molekuliarnaia fiziologiia stareniia.

The article is dedicated to the analysis of the peptide bioregulators role in molecular mechanisms of ageing and age-related pathology development. There has been put forward the concept of peptide regulation of ageing based on the priority data of authors long-term investigations on inhibition of involution processes in organs and tissues developed with age and restoration of specific proteins synthesis in cells under the influence of natural and synthetic peptide bioregulators. The prospects of peptide bioregulators employment in gerontological practice are being discussed in the paper with the purpose of treatment and prevention of age-associated pathology and human longevity increase.

[The effect of brain peptides on nerve tissue cells in vitro]. / Vliianie peptidov golovnogo mozga na kletki nervnoi tkani in vitro.

The effect of cortexin and epithalamin on the cell growth rate was investigated in the organotypic tissue culture of dorsal root ganglia (DRG), and of cortex and subcortical structures of 10-11-day old chick embryos. Cortexin in concentrations of 20 and 100 ng/ml is active, inducing a more intensive neurite outgrowth in DRG, compared to the control. Epithalamin was active in concentrations 20 and 200 ng/ml. Cortexin (100 ng/ml) was active in the cortex tissue culture, but inhibited the neurite growth in the subcortical structures culture. The stimulation of this culture to development was evident after using 200 ng/ml epithalamin. The neurite stimulating effect of cortexin and epithalamin is presumably associated with neurotrophic factors.

[The use of DNA polymerase from Thermus thermophilus]. / Primenenie DNK-polimerazy iz Thermus termophilus.

National DNA polymerase from Thermus thermophilus was used in polymerase chain reaction (PCR). The synthetic oligonucleotides (primers) to the basic structural HIV genes GAG, ENV, the genome DNA of donor peripheral blood lymphocytes were used, and the controls included the plasmid DNA with cloned HIV genome and the genome DNA of peripheral blood lymphocytes from HIV-infected persons confirmed by ELISA and Western blot analysis. The PCR technique and evaluation of the obtained results are described. The expediency of using PCR for different contingents is discussed.

[Changes in the histologic structure of the organs of immunogenesis during treatment with immunomodulators]. / Izmenenie gistologicheskoi struktury organov immunogeneza pri vozdeistvii immunomoduliatorov.

The effect of levamisole as well as thymic (thymalin and bone marrow (hemalin) immunomodulators on the immunogenesis organs in practically healthy animals were studied. The comparison of multiple parameters of morphological changes developing in the immunocompetent organs under the influence of immunomodulators was performed by means of so called "similarity ratio". Morphological changes in the central organs of immunogenesis were more severe after the administration of hemalin than after levamisole. The influence of immunomodulators on the peripheral organs of immunogenesis were more uniform. The results obtained in the experiments on healthy animals may serve the basis for a further morphological analysis of the immunomodulators effects under the conditions of the immune homeostasis disturbance.

[The diagnostic value of different test systems for the screening determination of antibodies to the human immunodeficiency virus]. / Diagnosticheskaia tsennost' razlichnykh test-sistem dlia skriningovogo opredeleniia antitel k virusu immunodefitsita cheloveka.

Evaluation of the quality of enzyme immunoassay (EIA) systems by their sensitivity and specificity is inadequate, mainly due to the impossibility of detecting early or latent HIV infection in humans as it manifests by seroconversion only to a few HIV proteins. The additional evaluation criterion (confirmation rate) has been introduced, and an original method for the integral evaluation of the quality of assay systems intended for the diagnosis of HIV infection by EIA techniques has been proposed.

[Effect of substances of a polypeptide nature isolated from the thymus and cerebral cortex on the primary immune response of mice to thymus-dependent and thymus-independent antigen]. / Vliianie veshchestv polipeptidnoi prirody, vydelennykh iz timusa i kory golovnogo mozga, na pervichnyi immunnyi otvet u myshei k timuszavisimomu i timusnezavisimomu antigenu.

The study of the effect of low molecular polypeptides on the primary immune response induced in CBA mice by the injection of thymus-dependent antigen (SRBC) and thymus-independent Vi-antigen showed that the injection of the preparation obtained from the cerebral cortex (cortexin) or the thymus (thymarin) for 5 days before and for 3 days after SRBc immunization stimulated the production of both direct (IgM) and indirect (IgG) antibody-producing cells, as well as the production of hemagglutinins. At the same time the production of antibody-producing cells and antibodies to Vi-antigen was suppressed. The preparations of white cerebral tissue and red bone marrow produced no effect on immune response in the animals.