Репозиторий Университета

© 2018 Denisenko et al. Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (p=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (p=0.018), and in multiple comparison Kruskal–Wallis test (p=0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs.

© 2018 IEEE. The work is focused on the research of urea elimination possibilities out of the waste dialysis solution by its electro-oxidation on the surface of platinum group metals and carbon materials. The work includes findings of experimental tests of various electrode materials for the specific urea elimination rate in a model solution.

© 2018, University of Kragujevac, Faculty of Science. All rights reserved. Two sets of reactants for modelling neurogenesis (SRMN) were developed based on the designed and tested genetic structures of lentiviral vectors. SRMN-1 contains the genetic construct LVV-GFAP-GCaMP3 and is intended for cellspecific transduction in astroglia cells. SRMN-2 contains the genetic construct LVV-PRSx8-TN-XXL and is intended for the phenotype-specific transduction in neurons. The present study examined SRMN-1 and SRMN-2 samples and assessed their efficiency in vitro and in vivo in Norvegicus rats. Specificity to particular cell types for all SRMN samples exceeded 97%. The number of induced signalling cascades was determined via activation of intracellular ingsignalling cascades in neurons and astrocytes (purinergic receptors and β-adrenoceptors). The results demonstrated dynamic recording of fluorescent signals and a two-fold increase in intensity after addition of the activator in all samples. The experimental SRMN samples revealed successful and stable transfection of catecholaminergic neurons and astrocytes, data on transfection efficiency, specificity of the developed genetic structures of SRMN, and calcium dynamics in transfected neurons and astrocytes.

© 2018 Elsevier GmbH Background: The non-healing wound is a characteristic clinical sign in recessive dystrophic epidermolysis bullosa (RDEB). Methods: Six patients with recessive dystrophic epidermolysis bullosa were injected with suspension of allogeneic fibroblasts into erosion margins. Erosions (>1 month old) with surface area between 2 cm2 and 28 cm2 were selected for treatment. The patients were administered with 1 mL suspension of allogeneic fibroblasts with concentration 5 × 106 cells/ml, 10 × 106 cells/ml and 20 × 106 cells/ml. Paired erosions were injected with vehicle solution alone. All erosions were assessed for healing rate and biopsied at baseline and at two weeks after treatment. Immunofluorescence antigen mapping (IFM) was performed to detect C7 expression. Results: An increase of healing rate was detected 14 days after fibroblasts and vehicle alone injections, in some cases with complete erosion closure. The results of the IFM in patients treated with allogeneic fibroblasts and vehicle solution demonstrated the increase of collagen VII expression in dermo-epidermal junction, more intensive in patients injected with 20 × 106 cells/ml. Conclusions: Intradermal administration of allogeneic fibroblasts is a safe and effective method of treatment of non-healing wounds in recessive dystrophic epidermolysis bullosa.

© 2018 Elsevier B.V. Recombination is a common event in RNA viruses; however, in the rabies virus there have been only a few reports of isolated recombination events. Comprehensive analysis found traces of recent recombination events within Arctic, Arctic-like and Africa 1b rabies virus groups, as well as recombination between distinct lyssaviruses. Recombination breakpoints were not linked to gene boundaries and could be detected all over the genome. However, there was no evidence that recombination is an important factor in the genetic variability of the rabies virus. It is therefore likely that recombination in the rabies virus is limited by ecological factors (e.g., rare co-circulation of distinguishable lineages and a narrow window for productive coinfection in most carnivore hosts), rather than molecular barriers (e.g., incompatibility of genome fragments).

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Changes in the biochemical composition of the tear film is a critical risk factor for the development of chronic perioperative dry eye syndrome, because increasing the duration of general anesthesia did not affect the dynamics of tear secretion recovery, but slowed down normalization of its structure and antioxidant activity in the post-anesthetic period.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Oxidative kidney injury was compared in newborn and adult rats under conditions of ischemia/reperfusion and in experimental model of systemic inflammation induced by endotoxin (LPS of bacterial cell wall) administration. Oxidative stress in the kidney accompanied both experimental models, but despite similar oxidative tissue damage, kidney dysfunction in neonates was less pronounced than in adult animals. It was found that neonatal kidney has a more potent regenerative potential with higher level of cell proliferation than adult kidney, where the level proliferating cell antigen (PCNA) increased only on day 2 after ischemia/reperfusion. The pathological process in the neonatal kidney developed against the background of active cell proliferation, and, as a result, proliferating cells could almost immediately replace the damaged structures. In the adult kidney, regeneration of the renal tissue was activated only after significant loss of functional nephrons and impairment of renal function.

© 2018, Pleiades Publishing, Inc. Hemophilia A is a recessive X-linked hereditary disease, so its manifestation in women is extremely rare and can be a result of an asymmetric X-chromosome inactivation or, even more rarely, of a presence of mutations in both FVIII gene alleles. We conducted a mutation screening of the FVIII gene in two female patients with clinical hemophilia A manifestation in this study. One patient had a hereditary disease; the second one was diagnosed with acquired hemophilia A as an adult. Both patients carried the same missense mutation His2026Arg. The patient with the hereditary form of the disease also had previously known microinsertion c.4379_4380 insA (p.Asn1460Lys-fs*1). We found no additional aberrations by sequencing of all functionally significant parts of the factor VIII gene of the patient with acquired hemophilia but showed clear asymmetric inactivation of X-chromosomes. Therefore, one of the possible explanations for the emergence of the hemophilic syndrome in this case can be the delayed manifestation of the FVIII gene germline mutation owing to the enhancement of hematopoiesis clonality with age.

© 2018 IOP Publishing Ltd. One of the essential goals in regenerative medicine is microvascularization which enables an effective blood supply within de novo constructed tissues and organs. In our study, we used two common multipotent mesenchymal stromal cell (MMSC) sources (subcutaneous adipose tissue and Wharton's jelly of the umbilical cord) where is a subpopulation of endothelial precursors. In the medium supplemented with VEGF, the 3D cultures of UC MMSCs and ADSCs promoted the endothelial cell differentiation. To evaluate their ability to form a capillary-like network, we encapsulated spheroids within non-modified and PEGylated fibrin hydrogels. The PEGylated hydrogel supported better the formation of multibranched cords than the pure fibrin gel. Analysis of tubule growth rate, length, and branching showed that the differentiated ADSCs had higher angiogenic potential than the differentiated hUC MMSCs. Our study can be a basis for the development of new strategies in tissue engineering and treatment of vascular diseases.

© 2018, Pediatria Ltd.. All rights reserved. Therapy with genetically engineered biological preparations (GEBP) significantly improved the prognosis and quality of life of patients with juvenile idiopathic arthritis (JIA). However, primary or secondary in efficiency, the development of undesirable phenomena require switching to another GEBP. Objective of the research – to determine optimal GEBP preparations when selecting and switching therapy based on the analysis of prescribed GEBP in real practice, depending on the clinical version of the JIA and the presence of uveitis. Materials and methods: the study included 322 patients with JIA on GEBP therapy, observed in the Pediatric Rheumatology Department of Children's Clinical Hospital of the I.M. Sechenov First Moscow State Medical University from Jan. 1, 2015 to Dec. 31, 2017. Retrospective, continuous observational clinical study. Of 322 patients, 70 (21,74%) had systemic JIA, 155 patients (48,14%) had polyarterial seronegative for rheumatoid factor (RF–) variant of JIA, 9 patients (2,8%) – polyarticular seropositive for rheumatoid factor RF+) variant of JIA, 55 patients (17,08%) – oligoarticular (persistent and spreading) variant of JIA, 26 patients (8,07%) – enthesitis (juvenile spondylitis), 7 patients (2,17%) – psoriatic variant of JIA. Results: as the first biological preparation were prescribed: etanercept to 177 (54,97%) patients; adalimumab to 51 (15,84%); tocilizumab to 44 (13,66%); abatacept to 39 (12,11%); infliximab to 11 (3,42%) patients. Transition to the second line of biological therapy was performed in 51 patients (in 15,8% of cases), on the third line of therapy in 13 patients (in 4,04% of cases), on the fourth line in 3 patients (in 0,93% of cases). As the second-line GEBP adelimumab was prescribed in 22 cases (43,14%), tocilizumab in 13 (25,49%), etanercept in 11 (21,57%), abatacept in 5 (9,8%). GEBP inefficiency was the reason for switching to the second line in 32 cases (9,9%). Of these, secondary inefficiency in 22 cases (6,8%); primary inefficiency – in 4 (1,3%), low efficiency – in 6 (1,9%), development/exacerbation of uveitis – in 7 patients (2,2%), in 6 cases (1,9%) due to insufficient compliance, drug shortage in the community, etc. Adverse effects caused switching in 5 patients (1,6%), incl. in 4 children – infusion reactions, in one – tuberculosis. Analysis of GEBP choice depending on the disease form and the presence of uveitis, was performed in 3 groups. Group 1 (n=70) consisted of patients with systemic JIA. Group 2 (n=53) included patients with articular form of JIA and concomitant uveitis. Group 3 (n=199) included patients with articular form of JIA without concomitant uveitis. Patients with systemic JIA as the first-line GEBP tocilizumab was prescribed significantly more often – to 38 patients out of 70 (54,29±5,96%) than etanercept – to 19 patients (27,14±10,19%) (t=2, 3, p<0,05), and other drugs in total (infliximab, abatacept, adalimumab) – to 13 (18,57±10,88%) (t=2,9, p<0,05). Switching to GEBP second line in this group was performed in 20 patients (28,57%). Tocilizumab was the final choice drug (after 3 years of follow-up) at the time of samples collection in 50 patients (71,43%) with systemic JIA. In patients with articular forms of JIA and concomitant uveitis as the first-line GEBP, adalimumab was prescribed significantly more often – in 34 of 53 cases (64,15±8,23%) than other drugs (abatacept, etanercept, infliximab) in total – 19 of 53 cases (35,85±11,01%) (t=2,06, p<0,05). Adalimumab was the drug final choice at the time of sample collection for 43 (81,13%) patients with JIA and uveitis. Most patients with articular form without uveitis received etanercept as first-line GEBP, 150 of 199 (75,38±3,54%), and etanercept prescription frequency was significantly higher than that of other drugs (abatacept, adalimumab, tocilizumab, infliximab) in total – 49 of 199 (24,62±6,19%) (t=7,1, p<0,01). In this group, the switching frequency was the smallest and amounted only 8,54%. The number of patients who received etanercept at the end of the study actually remained unchanged – 148 patients (74,37%).

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Our study confirmed the capacity of S. pyogenes strains to form biofilms on abiotic surfaces. Chains of streptococci surrounded by bluish film were seen under a microscope after alcian blue staining of the preparations grown on slides. On ultrathin sections in transmission electron microscope, the extracellular matrix (indicator of biofilm maturity) became visible after staining with alcian blue. Microscopy of the sections shows structures characteristic of a biofilm in spaces between the cells. Scanning electron microscopy also demonstrates the presence of a biomembrane. Importantly that type 1M strain forming in fact no membranes when cultured on plastic plates (Costar) formed biofilms on the glass. It seems that the conditions for the biofilm formation on the plastic and on the glass differ, due to which the exopolymeric matrices formed on different surfaces vary by biochemical composition.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Objective. To study the association between the kynurenine-3-monooxygenase (KMO) gene and depression. Materials and methods. Polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) of the KMO gene were studied in patients with depression (study group) and mentally healthy subjects of comparable gender and age (control group). Results and conclusions. The rs2275163 polymorphism was not associated with depression. An association between the rs1053230 polymorphism and depression was found. The frequency of the GG genotype, linked with lower KMO activity and increased kynurenic acid levels in patients with endogenous psychoses, was greater in the study group than the control group (p = 0.001, OR 2.8 (95% CI 1.73–4.24). thus, the GG genotype can be regarded as a risk allele for developing depression.

© 2018, © International Headache Society 2018. Background: Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is being evaluated for migraine prevention. Methods: In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3. Results: Patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% CI) treatment difference of −1.0 (−1.6, −0.5) (p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) (p = 0.010). Migraine-specific medication treatment days were reduced by −1.2 (erenumab) and −0.6 (placebo) days, a treatment difference of −0.6 (−1.0, −0.2) (p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary – Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) (p = 0.13) and in Migraine Physical Function Impact Diary – Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) (p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis. Conclusions: As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen). Trial registration: ClinicalTrials.gov, NCT02483585.

© 2018, Copyright © Kazan (Volga region) Federal University. The syntheses of a series of novel derivatives of stilbazole and their azo-analogs bearing the phenylalkenyl and phenyldiazenyl substituents at position 6 of the pyridoxine ring are reported. The observed cis/trans regioselectivity in the Wittig reaction between triphenylbenzylphosphonium chloride and carbonyl derivatives of pyridoxine ketal is discussed with respect to transition state intermediates, nature of base used in the reaction, and resonance transformations in the pyridoxine system. The azo-derivatives are obtained by azocoupling of the diazonium salts of sulfanilic or 4-aminophenyl-1,3-disulfonic acids with the corresponding pyridoxine acetals. Nine compounds from the obtained experimental series are capable of emitting second harmonic generation light, although with a reduced efficiency as compared to well known KH2PO4 or LiIO3 perovskite crystals, but with excellent beam resistance under laser irradiation, which makes them potential starting points for the development of novel nonlinear optical materials.

© 2018 Taylor  &  Francis Group, LLC. The mechanism of the molecular circadian clocks is currently understood as a transcription/translation feedback loop involving more than ten genes. Genetic variation at some of loci in these genes has been shaped by adaptation to environmental factors. In particular, latitudinal clines in allele frequency were documented in several animal species, but the contradictory conclusions were drawn from the results of rare human studies. Here we tested whether the out-of-African dispersal of human populations to higher latitudes of the Eurasian continent was associated with latitude-dependent shifts in allele frequency at polymorphic loci in genes of three (reference, circadian and skin pigmentation) groups. In order to detect the genetics-based signatures left by latitude-driven adaptation and to distinguish them from the confounding effects of population demographic history, we analyzed allele frequencies in 1594 individuals from 5 African and 11 Eurasian populations of the 1000 Genomes Project Phase 3. Up to 80 polymorphisms with global minor allele frequency > 0.2 were sampled from each of 36 genes (1665 polymorphisms in total). As expected, percentage of polymorphisms demonstrating both significantly enlarged differentiation of Eurasian populations on allele frequency and significant correlation between latitude and allele frequency was significantly higher in pigmentation genes compared to circadian genes and in circadian genes compared to reference genes. We also showed that the latitude-driven adaptation can be separated from genetic consequences of demographic perturbations by comparison of results obtained for the whole set of 16 African and Eurasian populations with results for only Eurasian populations that share the common demographic history. The revealed latitudinal clines in allele frequency seemed to be shaped by polygenic selection occurring by small allele frequency shifts spread across many loci in circadian and non-circadian genes. The present results provided a rationale for necessity to facilitate candidate gene studies by prioritizing genetic markers of chronotype.

© 2017 Elsevier B.V. KISS1 tumor suppressor protein regulates cancer cell invasion via MMP9 metalloproteinase. Downregulation of KISS1 gene expression promotes progression of breast cancer and melanoma, resulting in the development of distant metastases. In the current study, we investigated whether restoration of KISS1 expression in KISS1-deficient human metastatic breast cancer cells holds potential as an advanced anticancer strategy. To this end we engineered an infectivity-enhanced conditionally-replicative human adenovirus type 5 encoding KISS1 as an “arming” transgene in the Ad5 E3 region for an ectopic KISS1 expression in transduced cancer cells. The oncolytic potential of the vector was examined using brain-invading metastatic clones of CN34 and MDA-MB-231 breast cancer cells, which supported high levels of AdKISS1 replication, correlating with a robust CRAd-mediated cytotoxicity. Secretion of cellular factors responsible for tumor angiogenesis, cell-to-cell communication and anti-tumoral immune responses upon KISS1 expression in breast cancer cells was analyzed by a RayBiotech Kiloplex Quantibody array. Overall, our results indicate that KISS1 transgene expression provides an important benefit for CRAd-mediated cytotoxicity in breast cancer cells and holds potential as an anticancer treatment in conjunction with oncolytic virotherapy of breast and other metastatic cancers.

© 2018, Pediatria Ltd. All rights reserved. The article presents results of the study of glutathione-S-transferase GSTM1 and GSTT1 genes polymorphism in children with an isolated form of esophageal atresia (EA) with tracheoesophageal fistula and without fistula. Study materials and methods: 130 children were examined, including 39 children with EA and 91 children without EA, whose mothers did not consume tobacco or alcohol during pregnancy. All children belong to the Russian ethnic group. Samples of DNA for further analysis were obtained from buccal epithelial cells. Typing of allelic polymorphism of GSTM1 and GSTT1 genes was performed by Real-time PCR and quantitative PCR. Results: in children with an isolated EA the study revealed a statistically significant increase in the frequency of heterozygous genotypes (+/del) for GSTM1 in comparison with the frequency estimate in the control group (χ2=6,74 df=1, p<0,001). Conclusion: the association of EA with the heterozygous genotype of GSTM1 gene was first established, which may indicate a higher risk of pathology development for carriers of this genotype. The authors believe that EA formation depends on the cumulative effect of mother and newborn genotypes, leading to a decrease in GSTM1 enzyme catalytic activity. To determine the hereditary predisposition to EA development in a fetus it is reasonable to determine the glutathione-S-transferase genes polymorphisms in pregnant women who smoke and consume alcohol, as well as pregnant women living in ecologically unfavorable regions.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The possible interchangeability of eye drops was analyzed using glaucoma medicines containing latanoprost as examples. It was shown that the reference and generic drugs could be identical with respect to composition of active ingredients when manufactured from the same pharmaceutical substance but could differ in the excipient composition, in particular, have a different buffer and osmolality that could produce differences in their clinical effects. An analysis of the literature showed that the therapeutic efficacy and safety could vary for pharmaceutically equivalent drugs. The lack of therapeutic equivalence on the background of pharmaceutical equivalence could be caused by the use of different packaging and different dosing systems. Therefore, results from clinical trials must be compared to confirm the interchangeability of eye drops.

© 2018 Paediatrician Publishers, LLC. All Rights Reserved. The article provides the characteristic of a tumor from cells of cartilaginous tissue - chondroblastoma. Current data on etiology, key links of pathogenesis, types of tumor, General clinical manifestations, approaches to diagnosis and treatment in children are analyzed.

© 2018, Dynasty Publishing House. All rights resvered. The objective. A comparative study of components of the quality of life of parturient women, whose pregnancy developed both after in vitro fertilisation (with the use of donor or own oocytes) or spontaneously. Patients and methods. We assessed the quality of life of 160 parturient women. In 40 women pregnancy developed after IVF with the use of donor eggs, in 40 women – after IVF with own eggs, 40 patients participated in the programme «Surrogate motherhood», and 40 women had a spontaneous pregnancy. The standard SF-36 questionnaire was used. Results. Surrogate mothers demonstrate a somewhat higher self-assessment of their physical condition, underestimate their limitations on physical activities (daily self-care, walking, climbing stairs, carrying heavy objects, etc.), estimate their health at the moment of the survey higher than respondents of other groups and overestimate their mental health (mood, absence of depression and anxiety, the general index of positive emotions) as compared with respondents of other groups. Conclusion. Preventive psychological diagnostics, psychological follow-up of women during preparation to pregnancy, during carrying a baby and in the postpartum period have favourable effects on the successful outcome of the «Surrogate motherhood» programme.