[ANTIRETROVIRAL THERAPY AND THE RISK OF LIVER FIBROSIS PROGRESSION IN HIV/HCV COINFECTED PATIENTS].

The purpose of the study is to determine the nature of the impact of antiretroviral therapy on the development of liver fibrosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), depending on the order of pathogens acquisition. The fact is that the HIV/HCV coinfection is one of the most common pathological conditions worldwide and liver disease is a major cause of death for these patients. We have previously described the phenomenon, according to which the order of viral pathogens acquisition in HIV/HCV coinfected patients has a significant impact on the degree of progression of liver fibrosis. Introduction to clinical practice of antiretroviral therapy greatly increased the life expectancy of HIV-infected patients, however, the impact of ART on a progressive course of liver fibrosis in HIV/HCV coinfected patients have not yet been definitively established.

[MOLECULAR BIOLOGY OF HEPATITIS B VIRUS AND IMMUNOPATHOGENESIS OF CHRONIC VIRAL HEPATITIS B].

Chronic hepatitis B belongs to a category of socially significant diseases due to its wide abundance in the world and high frequency of unfavourable outcomes of this disease. Features of interaction of hepatitis B virus with human immune system, accompanying development of mechanisms of escape from immunological control, is the basis of development of chronic hepatitis B. Molecular-biological features of hepatitis B virus are the basis of the indicated mechanisms, and the content of this review is their examination. Herewith, stages of immunopathogenesis of this disease is the basis of characteristics of interaction of viral proteins with cells of immune system, and isolation of those is accepted in contemporary foreign literature.

[MECHANISMS OF INTERACTION OF VIRAL CAUSATIVE AGENTS IN PATIENTS CO-INFECTED WITH HUMAN IMMUNODEFICIENCY AND HEPATITIS C VIRUSES].

In patients infected with human immunodeficiency virus (HIV) in 20 - 30% of cases co-in- fection with hepatitis C virus (HCV) is observed, that is associated with common routes of transmis- sion for these causative agents. The main cause of lethal outcome for co-infected patients is liver damage. Thus, analysis of mechanisms of mutual influence of HIV and HCV under the conditions of co-infection gains special attention, that can be examined from both standpoints of direct inter- molecular interaction of 2 viral causative agents, as well as from the position of their immune- mediated effect. Negative effect of HIV on the course of fibrosis process in liver during HCV infection is associated with the feature of this virus to cause deep alteration in the immune system by direct damage of CD4+ cells, disruption of mechanisms of immunological memory, suppression of functions of liver fraction of NK and NKT, as well as its ability of co-receptor interaction with hepatocytes and stellate cells, enhancing progress of fibrosis alterations and HCV replication in liver. HCV.is also established to effect replication of HIV, stimulate infection of macrophages with this virus. All these events facilitate the rise in lethality during HIV and HCV co-infection.

VKORC1 polymorphisms and warfarin maintenance dose in population of Sakha (Yakuts).

BACKGROUND: Vitamin K antagonists are effective in the prevention and treatment of thromboembolic disorders. Warfarin is one of the most widely prescribed vitamin K antagonists in the world [1, 2]. It has a narrow therapeutic range and a given dose may result in a large inter-individual variation of response. Insufficient dose may fail to prevent thromboembolism, while an overdose increases the risk of bleeding. Patient-specific factors (e.g., age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dosage, but genetic factors influencing warfarin response explain a significantly higher proportion of this variability [3]. Molecular analysis of the gene that encodes the target enzyme vitamin K epoxide reductase complex 1 (VKORC1) strongly suggests that its genetic variations greatly affect the individual response to oral anticoagulants [4-7]. OBJECTIVE: To evaluate effects of VKORC1 polymorphisms on warfarin dose excess anticoagulation (INR >4.0) in the population of Sakha (S) patients. METHODS: 53 patients (29-women, 24-men) with atrial fibrillation (68%), congestive heart failure (60%), hypertension (49%) and cardiac valve replacement (26%) were recruited. The age range was 26-80 years, with a mean age of 62.87 ± 12.57 years.International normalized ratio and plasma warfarin concentrations were determined. Genotyping was carried out by RT-PCR (real-time PCR). The three genetic polymorphisms of the gene VKORC1 G3673A (rs9923231) were studied: normal (GG), heterozygous (GA) and homozygous (AA). Fisher exact probability test and chi-square test (with Yates correction) were applied to compare data among the AA and GG + GA groups; also Mann-Whitney test was used. RESULTS: The median maintenance daily dose of warfarin among AA carriers was 3.0 mg/day [1.25-7.5 mg], while in GG and GA patients it was 3.13 mg/day [1.88-7.92 mg]. The mean daily warfarin dosage was higher in GG and GA genotype carriers 4.05 mg/day (SD ± 1.7) than in patients with AA genotype 3.13 (SD ± 1.5). Differences are of borderline significance (p = 0.054). Of the 41 patients who required warfarin doses of less than 5 mg, 28 (63%) were found to be AA carriers and 14 (37%) were GG, GA carriers. Differences were not quite significant (p = 0.072). Among 31 homozygous polymorphism carriers 2 (4%) patients developed overanticoagulation (INR >4.0), while among 22 normal and heterozygous polymorphisms carriers only 3 (6%) patients developed overanticoagulation (INR >4.0). Differences were not statistically significant (p = 0.36). CONCLUSIONS: No significant association between VKORC1 polymorphisms and the frequency of excess anticoagulation (INR >4.0) was found. This may be explained by the number of cases included. AA polymorphisms compared to other polymorphisms shows borderline difference in the warfarin dose. The results can be used for the development of a pharmacogenetic-guided warfarin dosing algorithm.

Evidence-based pharmacogenetics: Is it possible?

BACKGROUND: For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person's health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers [1]. On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: "The Ministry of Health and the Russian Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies" [2]. A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia [3]. But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs [4]. OBJECTIVE: To assess the extent of genetic testing use for improving use of medicines. METHODS: PubMed and E-Library searches for the period of 2004-2015. RESULTS: The number of publications retrieved in PubMed search for the term "pharmacogenetics" for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term "pharmacogenetics" for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing interest not only among scientists, but also among practitioners. However evidence that is actually available on some key topics may not be of sufficiently high quality to support confident conclusions. As a rule, retrospective cohort studies, also known as historical cohort studies, are carried out. The number of randomized, prospective studies is not large, though in recent years, there has been an increase in their number. However, surrogate outcomes are commonly used in the mentioned studies as trial end points. The main reason for this is the lack of sponsorship. Quite often studies are not interesting for pharmaceutical companies and are carried out within the confines of the small grants. Nevertheless, systematic reviews and meta-analyses of some pharmacogenetic tests provide the high level of evidence (pharmacogenetic testing for clopidogrel, abacavir and antineoplastic drugs) so they appear even in clinical guidelines with the evidence level IIb. It is important to mention that for certain drugs FDA has already approved pharmacogenetic testing [5]. CONCLUSIONS: Evidence is often inconsistent. This leads to the fact that clinical use of pharmacogenetic testing seems to be most appropriate for the management of patients with high risk of adverse drug reactions.

[Bronchial asthma pathogenesis and genetic prognosis development].

The review is dedicated to an actual problem--genetic prognosis of risk of bronchial asthma development that is quite a complex aspect of studies from a methodological viewpoint. Bronchial asthma--heterogeneous disease by both etiology and clinical characteristics. At the same time genetic prognosis is based on the unity of pathogenetic mechanisms of development, though in immunological reactions that are the base of this disease, alternative variants are possible. The aim of this review is carrying out parallels between modern achievements in the field of deciphering trigger mechanisms of bronchial asthma pathogenesis and object of genetic studies based on these mechanisms. Among the examined conceptions--role of epithelial tissue in trigger mechanisms of bronchial asthma, variants of key role of immune system cells, first of all, T-helpers of various types for further development of inflammatory-effector reactions with damage characteristic for this disease. Compliance of contemporary approaches of genetic studies and novel concepts of bronchial asthma pathogenesis is shown.

[Association between expression of lectin type receptors by natural killers and intensity of liver fibrosis during chronic hepatitis C].

AIM: To study functional activity of natural killers on different stages of fibrosis during chronic hepatitis C. MATERIALS AND METHODS: Functional activity of CD3-/CD56+/CD16+ lymphocytes measured as expression of natural killers receptors (NKR) and natural cytotoxicity receptors (NCR) was assessed by flow cytometry. RESULTS: At stage I of fibrosis, decrease of number of CD3-/CD56+/NKG2D+ cells was observed, whereas at precirrhotic stage III--sharp decrease of CD3-/CD56+/CD94+ and CD3-/ CD56+/NKG2D+ populations, and at cirrhotic stage--decrease of number of CD3-/CD56+/ NKG2D+ cells and increase of cytolytic activity of natural killers carrying CD107a marker compared to precirrhotic stage. CONCLUSION: Obtained data demonstrate that natural killers during chronic hepatitis C receive regulatory signals mainly through lectin type receptors (CD94 and NKG2D).

[Hepatitis B virus: biology, immunopathogenesis, NK/NKT system in viral persistence].

In this review, the problem of hepatitis B is considered as related to the recent data on the biology of the viral agent, on the pathogenesis of disturbances that it causes in an organism as well as on accompanying deviations in its immune system. Special attention is paid to mechanisms of hepatitis B virus (HBV) persistence and the role of regulatory lymphocytes of NK/NKT system in this process. Some problems in further studies are specified.

[Effectiveness and safety of clopidogrel bisulfate in complex therapy of patients with acute coronary syndrome with ST segment elevation].

UNLABELLED: Efficacy of clopidogrel in acute myocardial infarction (AMI) was studied only in two trials. However efficacy and safety of loading dose of this drug and its long-term effectiveness were not studied in these trials. AIM: To assess effects of clopidogrel loading dose and long term therapy in addition to standard treatment on death, re-infarction, recurrence of angina and bleedings rate in patients with ST segment elevation acute coronary syndrome. METHODS: Patients (n=107) with AMI who met the criteria for thrombolytic therapy (TLT) were assigned randomly into either clopidogrel group A (n=51) or conventional therapy group B (n=56). Group A received loading dose of clopidogrel (300 mg) in addition to conventional therapy (TLT, aspirin, statin, ACE inhibitor and beta-blocker). Group B received only conventional therapy. The follow-up was 6 months after inclusion during which patients in group A continued to receive clopidogrel (75 mg/day after Day 2 of the study). Primary endpoint included death, re-infarction, recurrence of angina and bleedings. In addition, changes of ST segment after TLT and local contractility were assessed. RESULTS: During 30 days of follow-up rates of primary endpoint were 2.0 and 41.1% in groups A and B, respectively (p=0.003). Subgroup analyses showed that this difference depended on the rate of angina recurrence (2.4 and 36.1% in groups A and B, respectively, p=0.002). These differences were maintained during all follow-up period. Odds ratios for clopidogrel were 0.235 for primary endpoint (95% CI 0.104-0.528, p=0.0003), 0.078 for angina recurrence (95% CI 0.022-0.279, p=0,0001). No significant differences were obtained for mortality, re-infarction and bleeding rate. TLT in group A was more effective. ST depression 90 min after TLT was 86.23+/-4.38 and 61.00+/-6.97% (p=0.010), reperfusion arrhythmia rate - 72.6+/-3.27 and 33.9+/-2.78% (p=0.005) in groups A and B, respectively. CONCLUSION: The use of clopidogrel in addition to standard therapy for AMI is safe and effective. Long-term clopidogrel treatment decreases angina recurrence rate.

[Hepatitis C virus: biology, immunopathogenesis, and NK/NKT cells during viral persistence].

Data on immunological changes that accompanied HCV infection are analyzed. Role of various viral proteins in induction of immune alterations leading to HCV persistence is reviewed. Possibility of association between pathogenic mechanisms (and outcomes) of hepatitis C and alteration of aminergic regulation mechanisms in the immune system as well as perspectives of further studies assessing the role NK and NKT cell in this process.

[Isolation of a specific inhibitor of microbial serine proteinase from kidney bean seeds]. / Vydelenie iz semian fasoli spetsificheskogo ingibitora serinovykh proteinaz mikroorganizmov.

A protein acting as a specific inhibitor of microbial serine proteinases was isolated from kidney bean seeds. The purification procedure included complex formation between the inhibitor and Aspergillus oryzae proteinase. The protein with a Mr approximately 10 000 inhibits subtilisin and Asp. oryzae proteinase but does not affect trypsin and chymotrypsin. The inhibitor molecule contains no half-cystine residues.

[Identification of the reactive sites of kidney bean proteinase inhibitor]. / Stroenie reaktivnykh tsentrov belka - ingibitora serinovykh proteinaz iz fasoli.

The protein proteinase inhibitor from kidney bean (isoinhibitor, pI 4.3) is a double-headed inhibitor with independent reactive sites for trypsin and chymotrypsin. The reactive site of the inhibitor for trypsin is Lys (22)- Ser (23) in the sequense ...-Lys-Ser-Ile-Pro-Ala-Glx-Cys-Arg-..., the reactive site for chymotrypsin is Leu (64)-Ser (65) in the sequence ...-Thr-Leu-Ser-Ile-Pro-Ala-Glx-Cys-Arg-... .

[Comparative study of preparations of hirudin and "pseudohirudin"]. / Sravintel'noe izuchenie girudina i "psevdogirudina".

In contrast to hirudin, "pseudohirudin", which is practically devoid of the antithrombin activity, is represented as associates of di- and trimers. The molecular weight of the "pseudohirudin" monomer is by 2000 less than that for hirudin. This corresponds to the 20 amino acid residues difference calculated from the total number of the amino acid residues. Changes in the amino acid composition consist in a higher content of dicarboxylic amino acids, isoleucine, lysine, tyrosine and cystein in the hirudin preparations.

A specific inhibitor of Colletotrichum lindemuthianum protease from kidney bean (Phaseolus vulgaris) seeds.

A specific protein-an inhibitor of Colletotrichum lindemuthianum protease-was isolated from kidney bean seeds in a homogeneous form. The purification procedure included gel filtration, isoelectric focusing and affinity chromatography on trypsin-Sepharose column. The latter was introduced to separate the fungal protease inhibitor from closely related trypsin and chymotrypsin inhibitors present in kidney bean seeds.

[Physico-chemical properties of a protein-inhibitor of serine proteinases from the potato]. / Izuchenie fiziko-khimicheskikh svoistv belka--inhibitora serinovykh proteinaz iz kartofelia

Serine proteases inhibitor with pl-7.3, isolated from potatoe tubers by isoelectric focusing procedure as described previously (V.V. Mosolov et al., Bioorganic Chem., 1, 1449, 1975), was homogeneous under ultracentrifugation, having sedimentation coefficient S20,w 2.8S. Its molecular weight, investigated by sedimentation equilibrium and gel filtration through Sephadex G-100, was found to be 32500 and 31500 respectively. The Stokes radius R and frictional ratio f/fo were found to be 24 A and 1.14. The molecular weight of the inhibitor as determined by sodium dodecylsulfate polyacrylamide electrophoresis was twice as low as determined in ultracentrifuge and by gel filtration procedure. It is suggested that the inhibitor is dimer and consists of two protomers of equal molecular weight.

[Study of thermostable proteins in potatoes by isoelectric focusing]. / Izuchenie termostabil'nykh belkov kartofelia metodom izoelektricheskogo fokusirovaniia

With the aid of the method of isoelectric focusing eight thermostable proteins with isoelectric points of 3.6, 3.9, 4.u, 5.1, 5.8, 6.6, 7.2 and 10.0 were found in the extract from potato tubers of the Lyubimets variety. All the proteins had inhibitory activity in relation to alpha-chymotrypsin and trypsin.