Chronopharmacological Characteristics of the Effect of Hepatoprotectors in Experiment?

We studied circadian rhythms of activity of hepatoprotectors (Antral, Carsil, and glutargin) under conditions of acute paracetamol-induced hepatitis simulated in the morning, afternoon, evening, and at night (09.00, 15.00, 21.00, and 03.00). Antral and Carsil exhibited similar chronoprofiles with the maximum hepatoprotective activity at 09.00 and 21.00, while glutargin exhibited circadian pattern opposite and its activity was maximum at 15.00 and 03.00.

HMGB1 in the pathogenesis of ultraviolet-induced ocular surface inflammation.

High-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein as well as a crucial cytokine that regulates inflammation. This study demonstrated that secretion of HMGB1 due to ultraviolet (UV) radiation inducing ocular surface inflammation-mediated reactive oxygen species (ROS) production. After treating conjunctival epithelial cells with UV radiation, HMGB1 was translocated from the nucleus to the cytoplasm and then eventually to the extracellular space. HMGB1 played a crucial role in UV-induced conjunctival neutrophil infiltration, which subsided when mice were pretreated with the HMGB1 inhibitors soluble receptor for advanced glycation endproducts (sRAGEs) and HMGB1 A box protein. In case of using ROS quencher, there was decrease in UV-induced HMGB1 secretion in conjunctival epithelial cells and mice. Considering that UV-induced chronic inflammation causes ocular surface change as pterygium, we have confirmed high HMGB1 translocation and ROS expression in human pterygium. Our findings therefore revealed a previously unknown mechanism of UV-induced ocular inflammation related to ROS and HMGB1 suggesting a new medical therapeutic target.

[Markers of effectiveness of preoperative taxane-based chemotherapy for locally advanced breast cancer].

The absolute sensitivity signs of breast cancer to the drug have not yet been developed. Data from clinical trials on the study of experimental laboratory predictive markers of chemosensitivity: TOP2alpha (topoisomerase 2-alpha), beta-tubulin (subunit of dimeric protein tubulin), and BRCA1 (breast cancer 1) are contradictory and not numerous. Analysis of the results by the end of the clinical trial will allow examining the correlation between the effectiveness of preoperative taxane-chemotherapy and the level of experimental and standard molecular markets that is important for development of algorithm of treatment tactics for patients with locally advanced breast cancer.

[The effectiveness of ultrasound and sonoelastography in the diagnosis of palpable and non-palpable breast lesions].

The purpose of this study was to analyze the causes of false results in the ultrasound (US) and sonoelastography (SEG) examination of non-palpable and palpable lesions of the breast. The efficacy of diagnosis of non-palpable and palpable lesions by US and SEG was compared. 211 women with histologically confirmed focal breast lesions (146 non-palpable and 65 palpable) were included in the group. Women had a mean age of 52.0 +/- 13.6 years. The diameter of non-palpable lesions was less than 2 cm. Local mastopathy and medullar carcinoma were the reason of false results in most US. SEG allowed differentiating of these lesions. We found that SEG increased the specificity of diagnostics of non-palpable breast lesions by 19%.

[Clinical and morphological features and treatment for lobular breast cancer].

The study presents data on the treatment of lobular breast cancer. On the basis of the studied morphological and molecular-biological characteristics there were substantiated types of treatment that improved the survival of patients with invasive lobular carcinoma. It was showed the efficacy of systemic treatment for lobular breast cancer and also studied long-term outcomes of lobular breast cancer depending on the morphological and biological features.

[Formation of focus of West Nile fever on the territory of Saratov Region].

AIM: Detection of circulation of West Nile virus (WNV) on the territory of Saratov Region and prerequisites for formation of natural focus of West Nile fever (WNF), determination of the role of WNV in infectious pathology on the territory of the region. MATERIALS AND METHODS: of organs of small mammals, birds, blood-sucking arthropods for the presence of WNV markers (antigens and/or RNA) were studied. Clinical material from patients with symptoms not excluding WNF was studied. Donor blood sera samples were analyzed with the aim of detection of immune layer against WNV in population of Saratov Region. RESULTS: In 2010 WNV antigens were detected by EIA in 12 samples (7.1%) of mammal organ suspensions. In 2012 by using RT-PCR and EIA, markers of WNV were detected in 6 samples of bird brain suspensions (6.3%) and 1 sample of mammal organ suspension. Immune layer of population against WNV was 4% in 2011, 2.8% in 2012. In 2012 in 11 of 27 examined patients IgM against WNV in diagnostic titers and/or serconversion of IgG in paired sera were detected. In addition in 5 individuals virus RNA was detected in blood. Based on clinical, laboratory data and epidemiologic anamnesis 11 patients were diagnosed with WNF. CONCLUSION: The results obtained give evidence on the circulation of WNV on the territory of Saratov Region in 2010 - 2012. With the development of complications of WNF epidemiologic situation in 2012 an expansion of WNV areal onto the territory of the region took place and the process of formation of WNF natural foci is ongoing.

Reproducible effects of the mitochondria-targeted plastoquinone derivative SkQ1 on Drosophila melanogaster lifespan under different experimental scenarios.

Previously, extremely low, nanomolar concentrations of the mitochondria-targeted plastoquinone derivative SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) were shown to prolong the lifespan of male and female Drosophila melanogaster by about 10 % (Anisimov et al., Biochemistry (Moscow) 73:1329-1342, 2008). Using long-term monitoring of SkQ1 effects on the Drosophila lifespan, we analyzed different integral parameters of Drosophila survival and mortality under SkQ1 treatment. Meta-analysis was used to evaluate the average SkQ1 effect measured in terms of standard deviation. The effect appeared to be 0.25 for females and 0.18 for males, which corresponds to a low effect by Cohen's "Rules-of-Thumb". The SkQ1 effects on the Drosophila lifespan were reproducible over six years and showed no relationship to fluctuations in the mean lifespan of the w(1118) line used in the experiments, methods of preparation and administration of the drug, seasons, or calendar years. Adding SkQ1 to fly food was associated with a reduction in early mortality and a decrease in random variation in lifespan. All survival curves were fitted by Gompertz function. Analysis of the Gompertz function parametric plane demonstrated significant differences between points corresponding to experimental and control cohorts. The Strehler-Mildvan correlations for 11 experiments with females and for 7 experiments with males were calculated. The significant increase in the slope of the regression lines indicated that feeding flies SkQ1 reduced the rate of fall of fly vitality and, consequently, slowed aging. These findings indicated that the SkQ1 effect on lifespan was associated with both elevation of life quality and slowing of aging.

[Sonoelastography in the diagnosis of breast tumors smaller than 2 cm].

This is an analysis of the use of sonoelastography as part of complex instrumental diagnostic procedure (mammography, gray-scale and Doppler ultrasonography) for small breast tumors. A total of 126 patients with breast lesions below 20 mm in diameter were divided into two groups depending on lesion size. The first group consisted of women with 5-10 mm lesions (21 patients with carcinoma and 20 patients with benign tumors), the second group was characterized by 11-20 mm lesions (69 carcinoma patients and 16 patients with benign lesions). According to analysis results the diagnostic complex of gray-scale ultrasonography and sonoelastography is most sensitive, the sensitivity is higher in the second group (89.1% and 97.7% respectively). The complex ultrasonography procedure yielded better overall results than mammography in both patients' groups.

[The 2009 pandemic influenza in Russia. I. Diagnosis and molecular biological characteristics of the virus].

The analysis of 1558 clinical samples revealed influenza virus A(H1N1v) RNA in 339 patients with influenza and 163 fatal cases,which was made in May to December 2009. Data on the antigenic properties of more than 250 of pandemic virus strains isolated at the Research Institute of Influenza and the molecular genetic characteristics of 31 strains are presented. All the test isolates were found to have the S203 substitution in hemagglutinin, which was characteristic of one of 5 minor genome A(H1N1v) virus variants found in the United States and Mexico in 2009. All the test strains contain the S31N substitution in the M2 protein, which determines viral resistance to adamantine, and have no H275Y substitution in neuraminidase, which determines oseltamivir resistance. The substitution of amino acid residue of Asp to Gly at position 222 of HA was found in 8 (73%) of 11 isolates from postmortem lung and trachea samples and in 2 (10%) of 20 isolates from nasopharyngeal swabs. The determination of the pathogenic role of this substitution calls for further investigations.

[Preclinical studies of live intranasal H5N1 influenza vaccine with the deleted HS1 gene].

The paper gives the results of evaluating the efficiency of deINS1 pandemic H5N1 vaccine candidate VN1203delNS1 which was constructed by reverse genetics on the basis of influenza virus strain A/Vietnam/1203/04. The safety, immunogenicity and cross-protection of the vaccine strain against different H5N1 virus clades were demonstrated in mouse and macaque models. The results showed the possibility of designing a new-generation replication-deficient intranasal influenza vaccine, by applying an approach to deleting the NS1 pathogenicity factor, an antagonist of the interferon system.

Mitochondria-targeted plastoquinone derivative SkQ1 increases early reproduction of Drosophila melanogaster at the cost of early survival.

It was previously found that 20 pM SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) solution increased lifespan of virgin females and males of the fruit fly Drosophila melanogaster with maximal and highly reproducible effect on early survival of females. In this paper we demonstrate that SkQ1 solution of the same concentration does not increase lifespan of mated females and males, early effect on female survival being absent, whereas early fertility and the total number of progeny are elevated in treated flies. Increase in fertility observed in young mated females instead of increase of survival typical for young virgin females might illustrate the trade-off between the fly's lifespan and reproduction.

[Syndrome of premature ageing in ataxia-telangiectasia patients].

Ataxia-telangiectasia (AT), a genetic disorder due to mutation of gene atm characterized by progressive neurological abnormalities in combination with oculocutaneous telangiectasias, immunodeficiency, and increased frequency of malignant formations, is inherited according to autosome recessive mechanism. Cells of the patients with AT show increased radio sensitivity and some markers of premature ageing. The telomere lengths are sharply shortened in these cells already from the birth. We studied radio sensitivity (at the dose 2 Gy) and manifestations of premature ageing markers in cultured skin fibroblasts obtained from two unrelated AT patients and their heterozygous parents. We have shown that all the markers studied, that is HP1-gamma, phosphorylation of the histone variant H2AX (gamma-H2AX), and focuses 53BP1, indicate premature ageing of both the patients' and their blood relatives' cells. However, cells of the heterozygous carriers express premature ageing to a less extent. Investigation of the repair process characteristics (the amount of gamma-H2AX and the deal of cells with focuses 53BP1 in their nuclei) after X-ray irradiation has given following results: the patients' cells complete repair only half even in 24 after irradiation, while the healthy donor's cells complete repair in 24 h. Heterozygous cells also reliably differ from healthy donor's cells. Only in the case of apoptosis marker, p21, heterozygous cells do not differ from normal cells, whereas the patients' cells differ significantly. It has been noted that the mutation of gene atm is related to suppression of DNA double-strand breaks (DSBs) repair systems, which, in its turn, is in accordance with the increased radio sensitivity and premature ageing at the cell level in the AT families.

[Detection of arbovirus antigens in the mosquitoes and ticks inhabiting the Saratov Region].

The paper gives the results of a study dealing with the detection of the antigens of arboviruses of West Nile, Sindbis, Batai, Crimean-Congo hemorrhagic fever, a serocomplex of Californian encephalitis in the field material gathered in the Saratov Region in 2000-2006. The bloodsucking arthropods inhabiting the region were shown to be actively involved in the circulation of arboviruses in natural biotopes. The conclusion that it is expedient to organize an annual monitoring of arbovirus-induced infections in the areas where positive findings have been notified is justified.

[Regularory elements of the copia retrotransposon determine different levels of expression in different organs of males and females of Drosophila melanogaster].

Using a model system in which the expression of the reporter gene lacZ is under the control of five deleted variants of the copia retrotransposon regulatory region, which includes the 5'-long terminal repeat (LTR) and the 5'-untranslated region (5'-UTR), their contribution to the control of retrotransposon activity in different organs of males and females of Drosophila melanogaster was analyzed. The whole regulatory region provides expression of the reporter gene at the embryonic stage, and in larvae and adult flies only in generative organs. The 5'-end of LTR harbors a positive regulator that determines expression of the retrotransposon in organs of all types. The 3'-end of LTR harbors a negative regulator, which is sex- and time-specific: it represses copia expression in generative organs of males at all stages of development, and only at the imaginal stage in somatic tissues, without any effect on the expression of the retrotransposon in females. 5'-UTR contains a negative regulator of copia expression: it decreases the expression in embryos and generative organs and blocks it in somatic tissues. It may be suggested that a complex set of regulatory elements was formed in the course of the evolution of the retrotransposon, which made it possible to maintain a certain level of its expression in different types of cells and tissues and at different stages of development and, thus, to limit the harm caused to the host and provide the possibility for the retrotransposon to exist in the host genome over many generations.

Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 5. SkQ1 prolongs lifespan and prevents development of traits of senescence.

Very low (nano- and subnanomolar) concentrations of 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) were found to prolong lifespan of a fungus (Podospora anserina), a crustacean (Ceriodaphnia affinis), an insect (Drosophila melanogaster), and a mammal (mouse). In the latter case, median lifespan is doubled if animals live in a non-sterile vivarium. The lifespan increase is accompanied by rectangularization of the survival curves (an increase in survival is much larger at early than at late ages) and disappearance of typical traits of senescence or retardation of their development. Data summarized here and in the preceding papers of this series suggest that mitochondria-targeted antioxidant SkQ1 is competent in slowing down execution of an aging program responsible for development of age-related senescence.

[Method SiteGA for the recognition of transcription factor binding sites].

A new approach, SiteGA, for the prediction of functional transcription factor binding sites has been developed. The approach is based on the detection of locally positioned dinucleotides by the genetic algorithm and discriminant analysis. The approach has been applied to recognize transcription factor binding sites involved in the regulation of immune responses and cell growth (AP-1, IRF1, ISGF3, NFkappaB, STAT1), obesity and lipid metabolism (HNF4, PPAR, SREBP), and the expression of steroidogenesis genes (SF-1). SiteGA is far superior in accuracy to the traditionally used method of position weight matrices. The approach was implemented in the web tool, SiteGA http://wwwmgs2. bionet.nsc.ru/mgs/programs/sitega.

[The manifestation of necrophagy in the populations of rodents carrying the virus of hemorrhagic fever with renal syndrome].

The role of necrophagy in the epizootic manifestations of hemorrhagic fever with renal syndrome (HFRS) is first shown. By analyzing a great body of data obtained in the Saratov Region in 1982-2000, it has been established that the frequency of manifestations of necrophagy depends on many factors, the most important of which are a season, the size (density) of populations of small mammals, their species composition and the type of biotopes inhabited by these animals. Necrophagy is ascertained to be of great importance in HFRS foci as one of the alimentary routes of infection transmission in the parasitic systems. The presence or absence of necrophagy may serve as a preliminary test for the activity of HFRS foci.

[The ecology and prevalence of arboviruses on the territory of the Saratov Region].

The territorial spread of Tahyna, Batai, Sindbis, West Nile fever and Crimean-Congo hemorrhagic fever viruses throughout the Saratov region in 1998 - 2000 was analyzed. The characteristics of the epizootic activity of the natural foci of these arboviruses in different landscape zones (temperate forest-steppes, steppes and semi-deserts) were calculated. The species composition of small mammals, the natural reservoirs of the causative agents of arbovirus infections, was determined.