[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.

[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.

[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.

[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.

[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.

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.

[Comprehensive approach to diagnosis and treatment of chronic generalized periodontitis]. / Kompleksnyi podkhod k diagnostike i lecheniiu khronicheskogo generalizovannogo parodontita.

The article presents the new investigation technique of parodontium examination and treatment. The trials proved the high efficacy of low molecular polyvinylpyrrolidone, antioxidantes, antihypoxants, application sorbites, low-temperature plasma flow argon and surgical interventions.

[Prospects of cytomedines application in clinical medicine and gerontology]. / Perspektivy primeneniia tsitomedinov v klinicheskoi meditsine i gerontologii.

Available are the results of experimental and clinical study of a new class of peptide bioregulators--cytomedines. Mechanism of action of these substances is considered. Cytomedines-based drugs can be used for prevention and treatment of age pathology and premature aging. A new trend in clinical medicine--bioregulation therapy--is grounded.

Effect of vilon on biological age and lifespan in mice.

Subcutaneous administration of vilon (Lys-Glu) to female CBA mice starting from the 6th month of life increased physical activity and endurance, decreased body temperature, prolonged the lifespan, and prevented the development of spontaneous neoplasms. Vilon had no effect on age-related changes of estrous function and free radical processes. Long-term administration of vilon caused no unfavourable effects on animal development. The obtained results show safety of chronic vilon administration and allow to use this preparation for geroprotection and prophylaxis of age pathology.

Effect of peptide Lys-Glu on interleukin-2 gene expression in lymphocytes.

Lys-Glu in vitro stimulated interleukin-2 gene expression in mouse spleen lymphocytes. This effect depended on peptide concentration and duration of treatment. It is hypothesized that this peptide is the shortest regulatory fragment promoting the transport of trans-acting factors into the nucleus. It can not be excluded that Lys-Glu is a structural component of trans-acting factor active centers, which are necessary for the activation of interleukin-2 gene transcription in lymphocytes.

Immunomodulatory synthetic dipeptide L-Glu-L-Trp slows down aging and inhibits spontaneous carcinogenesis in rats.

Immunomodulatory molecule L-Glu-L-Trp was isolated from natural calf thymic peptide complex Thymalin by reverse-phase high performance liquid chromatography. On the basis of the synthesized dipeptide a pharmaceutical was designed containing this compound, which later receives the brand name Thymogen. The agent activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced changes in intracellular composition of cyclic nucleotides, and activated neutrophilic chemotaxis and phagocytosis. The effect of dipeptide on survival, life span and spontaneous tumor development was studied in female rats. Seventy-six, five-month-old outbred female rats were randomly subdivided into two groups and were subcutaneously injected with 0.2 ml of normal saline (controls, 32 rats) or with 5 micrograms/rat of the dipeptide L-Glu-L-Trp, dissolved in 0.2 ml of saline (44 rats), 5 times per week for 12 months. Animals were monitored up to their natural death and all the tumors discovered were studied microscopically. Mean life span of rats in both groups was similar but that of 10% maximum survived control rats constituted 949 +/- 16.1 days, whereas in the dipeptide-treated rats this value was 1048 +/- 21.1 days (P < 0.001). Six out of 44 rats treated with the drug survived over the maximum life span of control rats (965 days). The aging rate indicated as alpha in the Gompertz equation, was 0.0071 days-1 in controls and 0.0041 days-1 in rats exposed to L-Glu-L-Trp. Total tumor incidence was 1.5 times lower (P < 0.01), malignant tumor incidence 1.7 times lower (P < 0.01), and hematopoietic malignancies (leukemias and lymphomas) 3.4 times lower (P < 0.02) in rats exposed to the dipeptide in comparison with controls. Thus, treatment with L-Glu-L-Trp delayed aging rate and decreased spontaneous tumor incidence in rats.

[Cortexin effectiveness in circulatory encephalopathy]. / Effektivnost' primeneniia korteksina pri distsirkuliatornykh éntsefalopatiiakh.

A clinical trial of cortexin, a new peptide bioregulator of cerebral functions, in combined therapy of dyscirculatory encephalopathy (DE) stage I-II was made in 76 patients. They were divided into two groups: a control group of 31 patients on standard therapy and the study group of 45 patients on standard therapy with adjuvant cortexin delivered via nasal electrophoresis (NE). The effect was estimated by clinical symptoms, psychophysiological tests, computed EEG, quantitative parameters of rehabilitation. Cortexin NE produced a positive effect on psychoemotional state, neurological status, intellectual-mnestic and CNS functions. Adjuvant cortexin aroused efficiency of rehabilitation in DE stage I and II by 22.7%. The response of intellectual-mnestic and CNS functions was the highest. Cortexin improves attention, perception, memory, thinking, cortical neurodynamic processes. It is well tolerated and has no side effects. Cortexin is recommended as a drug of choice in combined treatment of patients with DE stage I-II.

Propagation of curved activation fronts in anisotropic excitable media.

We study theoretical and numerical propagation of autowave fronts in excitable two-variable (activator-inhibitor) systems with anisotropic diffusion. A general curvature-velocity relation is derived for the case that the inhibitor diffusion is neglected. This relation predicts the break of an activation front when the front curvature exceeds a critical value, which is corroborated by computer simulations of a particular reaction-diffusion model. Some qualitative effects associated with the inhibitor diffusion are studied numerically. It is found that the critical value of curvature decreases with an increase in the inhibitor diffusion coefficient. The core of a spiral wave increases in size and turns through an angle which depends on the inhibitor diffusion coefficient. PACS Numbers: 05.50. +q, 05.70. Ln., 82.40. -g, 87.10. +e.