Evaluation of the Hepatoprotective Effect of L-Ascorbate 1-(2-Hydroxyethyl)-4,6-Dimethyl-1,2-Dihydropyrimidine-2-One Upon Exposure to Carbon Tetrachloride.

Hepatoprotective properties of a new pyrimidine derivative - L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropyrimidine-2-one, synthesized on the basis Xymedon, were assessed in white rats exposed to CCl4. The compound under study administered prior to exposure to CCl4 reduced the deviation of biochemical parameters from reference values and severity of structural and morphological changes in liver, when compared to the control. Hepatoprotective properties of the studied compound were more pronounced than those of Xymedon.

New Xymedon Analogues for Stimulation of Posttraumatic Regeneration of the Spinal Cord in Rats.

Effect of systemic administration of synthetic pyrimidine derivatives, xymedon and compounds 29D and 34D, was studied in rats with experimental dosed contusion spinal cord injury. Xymedon promoted recovery of motor function after injury. Compounds 29D and 34D more effectively restored the parameters of open-field and Rotarod tests in comparison with xymedon. Compound 29D more effectively than xymedon maintained the number of Olig2+ oligodendrocytes in the corticospinal tract and NG2 cells in all investigated areas of the white matter. In the group treated with compound 34D, the differences in the number of NG2+ cells were revealed only in the anterior funiculi, where the number of these glial cells was 2-fold higher than in the xymedon-treated group. Obtained results suggest that the studied xymedon analogs, compounds 29D and 34D, can exert their therapeutic action through different molecular and cellular pathways.

[The awareness and attitude of population of Kazakhstan to inoculation against human papilloma virus].

The vaccines against human papilloma virus are a potential tool for prevention of cervix cancer and particular other types of cancer. The high inclusion of target group in applied vaccination program is economically effective and successful activity depending in many instances on reliable knowledge and positive attitude of population to inoculation. The cross-sectional study was carried out using previously developed anonymous questionnaires for various groups of population in four pilot regions of Kazakhstan where national ministry of health proposes for inoculation of girls aged 9-13 years two vaccines against human papilloma virus (four- and two-valence) The data base was organized using software Microsoft Access. The materials were integrated and processed using variation statistics techniques in software IBM SPSS Statistics 19 and applying Student criterion and calculating correlation dependences. Out of all respondents, 66% were aware about existence of human papilloma virus/ the main portion of parents 'female adolescents learned about vaccination against human papilloma virus from Internet and medical workers. The most significant factor preventing implementation of vaccination and the proper perception by respondents was absence of confidence in safety of vaccine. About 54% of parents of female adolescents and 75% of teachers consider vaccine as unsafe. And only 72% of medical workers consider vaccine as safe. Despite known effectiveness of vaccination against human papilloma virus, number of problems exist related to implementation of program. The level of awareness and understanding of different groups of population concerning the role of vaccination in development of oncologic pathology and possibility of prevention of cancer at the expense of vaccination. The intersectoral relationships are to be developed between medicine and education system. The significance of information activities of medical control organs and organizations is to be enhanced.

THE INCIDENCE OF COLORECTAL CANCER IN KAZAKHSTAN.

The purpose of the study is to examine the situation and to ascertain the features of incidence and mortality of colorectal cancer (CRC) in Kazakhstan in 2004-2013 and to give a forecast until 2020. MATERIALS AND METHODS: The data of new cases and deaths, which are available in the Cancer Registry of Research Institute of Oncology and Radiology of the Republic of Kazakhstan, were applied. in the analyzes the modern methods of variation statistics were applied to determine the average relative number, the study of time series, standard errors of means and other indicators. RESULTS: The average 10-year CRR incidence was 15.5?0.31 cases per 100 000 population, and the rate of increase reached 2.04% per year where higher rates (+2.28%) were typical for colon cancer. Age is one of the most important factors in the development of CRC. In 30-39 years, the incidence rate increased 11.5 times relative to the age grouping up to 30 years, in 50-59 and 60-69 years, the incidence increases 3.2 and 2.5 times respectively, relative to the previous level. In the group older than 70 years the incidence is 121.1?4.04. On the average during the study period the CRR incidence among females is 1.2 times higher than among males. CONCLUSION: The high correlation of developing CRC by age and sex was determined. The death rate from CRC was 9.6?0.25 cases per 100 000. According to the forecast for 2020 the CRC incidence will increase by 11%, and the mortality will not significantly change.

6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aß production and clearance, resulting in increased amount of Aß in various forms [2]. Reduction of Aß production and increasing clearance of Aß pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Aß fibrils in vitro and Aß plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Aß and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Aß-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. OBJECTIVE: To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease. METHODS: In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Aß1-40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer's disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls.To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials.For ß-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test. RESULTS: We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 ± 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 ± 1%. Compound 35 at 10 nM, exhibited a significant (35 ± 9%) inhibitory activity toward human AChE-induced Aß aggregation.Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit.Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice.Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of ß-amyloid peptide (ßAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of ßAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced ßAP load in cerebral cortex but not in dentate gyrus and CA3 area. CONCLUSIONS: Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Aß plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD.

[Monitoring of influenza and other respiratory diseases causative agents in children, hospitalized with community-acquired pneumonia in 2012-2013 epidemic season].

AIM: Study the circulation of respiratory viruses in children with community-acquired pneumonia (CAP) during the period from October 2012 to May 2013. MATERIALS AND METHODS: 136 children with CAP aged from 3 months to 16 years with ARI symptoms at the disease debut were studied. RNA/DNA of influenza A, B, parainfluenza (PI); adeno-, rhino-, RS-viruses, corona-, metapneumo- (MPV) and bocaviruses were detected in nasopharynx smears by PCR with hybridization-fluorescent detection in real time. Antibodies against influenza viruses A/H1N1/pdm09 California/07/09, epidemic reference strains of influenza viruses A/H1N1/Brisbane/59/07, A/ H3N2/Victoria/361/201 1, B/Wisconsin/1/10, against PI viruses type 1, 2, 3 were determined in paired sera by HAI. RESULTS: In February-March 2013 the number of children protected by antibodies against influenza decreased, and circulation of influenza viruses A/H3N2 and A/H1N1/ pdm09 was detected. Rhinoviruses and PI viruses were determined throughout the epidemic season, bocavirus and adenoviruses--during the autumn-winter period, RS-virus and MPV--during winter-spring. Coronaviruses were not detected. The peak of virus detection was established in February when the threshold of influenza and ARI morbidity was exceeded. The main pathogens of children of the first 3 years of life are rhinoviruses, RS-virus, PI viruses and bocavirus. RS-virus infection at the debut of CAP in children younger than 3 years in 55.5% of cases is associated with the development of broncho-obstructive syndrome. Bocavirus infection in 50% of cases progresses with laryngo-tracheitis and bronchiolitis. CONCLUSION: The fraction of viruses in etiologic structure ofARI in children varies depending on immune layer, season and age of children. Etiology of viral infection at the debut of CAP could only be proven using specialized laboratory studies.

Amphiphilic macrocycles bearing biofragment: molecular design as factor controlling self-assembly.

Two novel macrocyclic 6-methyluracilic amphiphiles (uracilophanes) with four (UP1) and two (UP2) uracil moieties and ammonium groups have been synthesized. Tetracationic multi-uracilophane is composed of two macrocyclic units bridged each other with an external methylene spacer, while in the cryptand-like dicationic uracilophane pyrimidinic moieties are connected with an internal methylene spacer. This internal spacer provided a conformational rigidity to the macrocycle. The self-assembly of the uracilophanes is studied and compared with a reference dicationic uracilophane (UP3) with no spacer fragment. Compounds UP1 and UP3 are capable of aggregating, which is characterized by the analogous critical micelle concentration of 1mM, although the former has four decyl tails versus two decyl tails in UP3 molecule. NMR self-diffusion, fluorimetry and DLS techniques revealed that bimodal size distribution occurs in the UP1 solution, with small (≤2nm) and large (ca. 30-50 nm) aggregates contributed. Unexpectedly, the cryptand-like uracilophane UP2 with the same hydrophobicity as UP3 does not form aggregates. The balance of the geometry and energetic factors was analyzed and compared with those contributing to the aggregation of the reference compound UP3. It was established that it is the geometry that controls the packing of the cryptand-like uracilophanes upon aggregation, while hydrophobic effect plays a minor role. In contrast, both factors control the aggregation of oligomeric macrocycle, with energetic factor prevailing. These findings are of importance for (i) the understanding the diverse structural behavior of bioamphiphiles that have very similar chemical structure, but different conformations; and (ii) the design of amphiphiles with controlled model of self-assembly. Supramolecular systems studied can be recommended for biotechnological applications.

Study of hepatoprotective effects of xymedon.

Xymedon (1-(ß-oxyethyl)-4,6-dimethyl-1,2-dihydro-2-oxopyrimidine), a regeneratory and wound-healing drug, exhibited hepatoprotective activity in laboratory animals with experimental toxic hepatitis. Oral drug reduced the severity of toxic involvement of the liver induced by CCl4 and reduced animal mortality. Xymedon promoted recovery of the blood biochemical parameters characterizing the liver status.

[Molecular-epidemiological monitoring of enterovirus circulation in the Far East and Zabaikalye].

6 year molecular-biological monitoring of enteroviruses in the Far East and Zabaikalye was carried out. Nucleotide sequence of 125 strains was determined from 2006 to 2011. Molecular analysis was carried out in VP1 virus genome region. Phylogenetic interactions for ECHO-6, ECHO-30, ECHO-11, Coxsackie B-5 (CB-5), Coxsackie B-1 (CB-1) and Coxsackie A-9 (CA-9) were analyzed. Highly dynamic epidemiology was shown to be inherent for ECHO-6 and ECHO-30 viruses and is characterized by genetic heterogeneity and consequent change of virus variants. On the contrary a relative stability of circulating genotypes is intrinsic for CB-1, CB-5 and ECHO-11 enteroviruses. The results of molecular-biological studies indicate frequent introduction of new enterovirus variants from countries of Europe and Asia.

Synthesis and antimycobacterial activity of novel 1,3-dimethylisocyanurate derivatives.

A series of novel 1,3-dimethylisocyanurates has been synthesized as potential inhibitors of ß-ketoacyl synthase in mycobacteria. Most of the 25 compounds described and tested for their activity against M. tuberculosis have a bacteriostatic effect, comparable and even higher that of first-line antituberculosis drugs. These compounds are nontoxic, species-specific, exhibiting no activity against other bacterial species.

[Correlation between the receptor specificity of pandemic influenza A (H1N1)pdm09 virus strains isolated in 2009-2011 and the structure of the receptor-binding site and the probability of fatal primary viral pneumonia].

The receptor specificity (RS) of pandemic influenza A(H1N1) pdm09 virus strains deposited into the State Collection of Viruses of the Russian Federation, D. I. Ivanovsky Research Institute of Virology, Ministry of Health and Social Development of Russia, in the 2009-2010 and 2010-2011 epidemic seasons to a panel of 9 sialoglycopolymers (SGP). The strains were divided into 3 groups according to the W(3/6) index proposed by the authors, which was equal to the amount of reactivities to unbranched alpha2-3-SGP to that of reactivities to unbranched alphal-6-SGP: W(3/6) < or = 1.0; 1.0 < W(3/6) < or = 1.5. The W(3/6) < or = 1.5 group showed a predominance of a2-3-RS, attended by the high incidence of fatal primary viral pneumonias (FPVP) (60.0%) and amino acid replacements in the HA1 receptor-binding site (RBS) (80.0%): D222{G, N} and Q223R. The 1.0 < W(3/6) < or = 1.5 group was characterized by mixed alpha2-3/alpha2-6-RS with the incidence of FPVP (29.7%) and amino acid replacements in the HA1 RBS (40.5%) (D222{G, N, V} and Q223), respectively. In the W(3/6) < or = 1.0 group, alpha2-6-RS was prevalent, FPVPs were absent and amino acid replacements in HA1 RBS (D222{G, E}) were seen only in 6.0% of cases. The number of strains with increased specificity to alpha2-3-sialosides increased in the 2010-2011 epidemic season as compared to the previous season. With their further spread among the population, there may be a rise in cases of severe primary viral pneumonias with possible fatal outcomes, which can be, however, accompanied by a decrease in the capacity of mutants to air-dropwise transmission.

[A possible association of fatal pneumonia with mutations of pandemic influenza A/H1N1 sw1 virus in the receptor-binding site of the HA1 subunit].

The paper gives the results of sequence analysis of 150 positive samples in real-time RT-PCR, including 47 autopsy materials from patients (including 10 pregnant women), who died from fatal pneumonia mainly in November-December 2009, in whom the lifetime etiological diagnosis had not been made and hence no early etiotropic therapy performed. 70% of the primary materials from the deceased patients were found to have pandemic influenza A(H1N1) v mutants in the lung tissue with D222G (15%), D222N (15%), D222E (2%) substitutions, as well as a mixture of mutants (38%). Nasopharyngeal lavages from 3 Chukotka deceased patients exhibited only consensus (nonmutant) D222 virus variants; there was a mixture of consensus and mutant virus variants in the trachea and a mixture of mutant ones in the lung. Preliminary data from the study of the interaction of the hemagglutinin of two strains having D222G and D222N mutations with 9 oligosaccharides imitating the variants of cell receptors for influenza A virus suggest that there is a double receptor specificity for alpha2'-3' and alpha2'-6'-sialosides with a preponderance of alpha2'-3'-specificity. Further spread of the mutants that have acquired a high virulence and preserved their capacity for the respiratory route of human infection may lead to the situation similar to that seen in the 1918-1919 pandemic. Another scenario for evolution of the virus is to preserve its receptor specificity for alpha2'-3'-sialosides and high virulence with losses of alpha2'-6' specificity and capacity for aerosol transmission, by damping the pandemic.

[Trends in the spread of pandemic influenza A(H1N1) swl in the Far East in 2009].

The paper describes the trend in the spread of pandemic influenza A(H1N1) swl virus in the Far East, which started in this region 2-3 months later than that in the European part of Russia. By mid-October seasonal epidemic influenza was practically displaced by pandemic one.

Compounds with the dioxopyrimidine cycle inhibit cholinesterases from different groups of animals.

We firstly synthesized derivatives of 6-methyluracil, alloxazine, and xanthine, containing omega-tetraalkylammonium (TAA) groups at the N(1) and N(3) atoms in a pyrimidine cycle and assayed their anticholinesterase activities. Compounds with triethylpentylammoniumalkyl groups behaved as typical reversible inhibitors of acetylcholinesterase (AChE) (pI(50) 3.20-6.22) and butyrylcholinesterase (BuChE) (pI(50) 3.05-5.71). Compounds, containing two ethyl residues and a substituted benzyl fragment in the tetraalkylammonium group at N(3) atoms or two similar TAA groups at N(1) and N(3) atoms, possessed very high anticholinesterase activity. Although these compounds displayed the activity of typical irreversible AChE inhibitors (a progressive AChE inactivation; k(i) 7.6 x 10(8) to 3.5 x 10(9)M(-1)min(-1)), they were reversible inhibitors of BuChE (pI(50) 3.9-6.9). The efficiency of AChE inhibition by some of these compounds was more than 10(4) times higher than the efficiency of BuChE inhibition. Several synthesized TAA derivates of 6-methyluracil reversibly inhibited electric eel and cobra venom AChEs and horse serum BuChE. However, depending on their structure, the tested compounds possessed the time-progressing inhibition of mammalian erythrocyte AChE, typically of irreversible inhibitors. As shown upon dialysis and gel-filtration, the formed mammalian AChE-inhibitor complex was stable. Thus, a new class of highly active, selective, and irreversible inhibitors of mammalian AChE was described. In contrast to classical phosphorylating or carbamoylating AChE inhibitors, these compounds are devoid of acylating functions. Probably, these inhibitors interact with certain amino acid residues at the entrance to the active-site gorge.

[Molecular epidemiology of ECHO 6 virus, the causative agent of the 2006 outbreak of serous meningitis in Khabarovsk].

A total of 3194 cases of enterovirus meningitis were notified in the Russian Federation in 2005, of them there were 1434 cases in the Khabarovsk Territory. Enteroviruses were isolated from 1020 out of the virologically studied 1362 patients from the Khabarovsk Territory. Viruses E6 and E30 were isolated in 80 and 14.7% of cases, respectively. E1, E3, E7, E33, Coxsackie virus B1, B4, B5, and A10 were sporadically detected. The E6 strains isolated in Komsomolsk-on-Amur were identical while E6 strains isolated in Khabarovsk belonged to two different genotypes and greatly differed from those isolated in Konsomolsk-on-Amur. The virus E30 strains isolated in Khabarovsk and Komsomolsk-on-Amur had a 1% difference in VP1 genome nucleotide sequence and belonged to E30 subtype that circulated in Russia and Kazakhstan in 2004-2005.

[Epidemiologic and etiologic characteristic of enterovirus infections in Khabarovsk region].

Results of epidemiologic, virologic, and serologic studies of enterovirus infections in Khabarovsk region from 1975 to 2006 were analyzed. Patterns of epidemic process of these infections were established: periodic change of dominating type of pathogen in the population; onset of the large epidemic peaks of incidence during emergence of circulation of new for the given area serotypes of enteroviruses; possibility of realization of several routes of virus transmission. Role of water factor in the progress of the epidemic process was revealed. Etiology of the large epidemic rise of aseptic meningitis incidence in Khabarovsk region in 2006 was established--the leading pathogens were ECHO viruses serotypes E6 and E30.

[The effect of melamine salt of bis(oxymethyl)phosphinic acid (melafen) on the growth processes and cytoplasmic membrane function in potato tuber cells].

The effects of a new synthetic growth regulator, preparation melafen, on the growth processes in potato plant tubers and the H+ -ATPase activity in cell plasmalemma were studied. It was demonstrated that melafen could both stimulate and inhibit the growth of potato tubers depending on its concentration and the physiological state of the tubers. It is likely that one of the manifestations of melafen action is its influence on the division and extension of apical meristem cells. The growth stimulation caused by melafen is connected with modifications of the plasmalemma of potato tuber cells, namely, the activation of H+ -ATPase and increase in the membrane proton permeability.