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© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Cluster headache is a disorder with increased hereditary risk. Associations between cluster headache and polymorphism rs2653349 of the HCRTR2 gene have been demonstrated. The less common allele (A) seems to reduce disease susceptibility. The polymorphism rs5443 of the GNB3 gene positively influences triptan treatment response. Carriers of the mutated T allele are more likely to respond positively compared to C:C homozygotes, when treated with triptans. DNA was extracted from buccal swabs obtained from 636 non-related Southeastern European Caucasian individuals and was analyzed by real-time PCR. Gene distribution for the rs2653349 was G:G = 79.1%, G:A = 19.2%, and A:A = 1.7%. The frequency of the wild-type G allele was 88.7%. The frequencies for rs5443 were C:C = 44.0%, C:T = 42.6%, and T:T = 13.4%. The frequency of the wild-type C allele was 65.3%. The frequency distribution of rs2653349 in the Southeastern European Caucasian population differs significantly when compared with other European and East Asian populations, and the frequency distribution of rs5443 showed a statistically significant difference between Southeastern European Caucasian and African, South Asian, and East Asian populations. For rs2653349, a marginal statistically significant difference between genders was found (p = 0.080) for A:A versus G:G and G:A genotypes (OR = 2.78), indicating a higher representation of male homozygotes for the protective mutant A:A allele than female. No statistically significant difference was observed between genders for rs5443. Cluster headache pathophysiology and pharmacotherapy response may be affected by genetic factors, indicating the significant role of genotyping in the overall treatment effectiveness of cluster headaches.

© 2018, The Author(s). Efficacy and safety of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, were demonstrated in juvenile idiopathic arthritis (JIA) with polyarticular course (pJIA) in the CHERISH trial. This observational, III phase study evaluated long-term treatment of TCZ in pJIA patients was conducted by members of the Pediatric Rheumatology International Trials Organization (PRINTO) from Poland and Russia. Forty-one patients, who had completed the CHERISH core study (104 weeks), were extensionally treated with TCZ (8 mg/kg, intravenous infusion every 4 weeks). Total treatment time was from 131 to 193 weeks. The long-term safety (the primary endpoint) and efficacy were evaluated. All patients achieved ACR70 response in the core study and continued to achieve at least ACR50 response up to week 24 of this study. The safety population comprised 46.41 patient-years (PY). Rates per 100 PY of adverse (AEs) and serious events (SAEs) were 181.0 and 6.46, respectively. Pharyngitis and respiratory tract infections were the most common AEs. Except one AE (severe neutropenia), all others were classified as mild (24.4%) or moderate (29.3%). The incidence of SAEs was low (7.3%). No new safety findings were observed. The safety profile of over 2.5-year treatment with TCZ is consistent with the pre-marketing CHERISH clinical trial. Presented data and continued efficacy response support the use of TCZ in pJIA. EUDRACT No: 2011-001607-12. https://clinicaltrials.gov/ct2/show/study/NCT01575769?term=ML27783.

© 2018 American Society for Microbiology.  The discovery of highly diverse nonprimate hepatoviruses illuminated the evolutionary origins of hepatitis A virus (HAV) ancestors in mammals other than primates. Marsupials are ancient mammals that diverged from other Eutheria during the Jurassic. Viruses from marsupials may thus provide important insight into virus evolution. To investigate Hepatovirus macroevolutionary patterns, we sampled 112 opossums in northeastern Brazil. A novel marsupial HAV (MHAV) in the Brazilian common opossum (Didelphis aurita) was detected by nested reverse transcription- PCR (RT-PCR). MHAV concentration in the liver was high, at 2.5 × 10 9 RNA copies/g, and at least 300-fold higher than those in other solid organs, suggesting hepatotropism. Hepatovirus seroprevalence in D. aurita was 26.6% as determined using an enzyme-linked immunosorbent assay (ELISA). Endpoint titers in confirmatory immunofluorescence assays were high, and marsupial antibodies colocalized with anti- HAV control sera, suggesting specificity of serological detection and considerable antigenic relatedness between HAV and MHAV. MHAV showed all genomic hallmarks defining hepatoviruses, including late-domain motifs likely involved in quasienvelope acquisition, a predicted C-terminal pX extension of VP1, strong avoidance of CpG dinucleotides, and a type 3 internal ribosomal entry site. Translated polyprotein gene sequence distances of at least 23.7% from other hepatoviruses suggested that MHAV represents a novel Hepatovirus species. Conserved predicted cleavage sites suggested similarities in polyprotein processing between HAV and MHAV. MHAV was nested within rodent hepatoviruses in phylogenetic reconstructions, suggesting an ancestral hepatovirus host switch from rodents into marsupials. Cophylogenetic reconciliations of host and hepatovirus phylogenies confirmed that hostindependent macroevolutionary patterns shaped the phylogenetic relationships of extant hepatoviruses. Although marsupials are synanthropic and consumed as wild game in Brazil, HAV community protective immunity may limit the zoonotic potential of MHAV.

© 2018 Scandinavian Physiological Society. Published by John Wiley  &  Sons Ltd Aim: During early post-natal development, arterial contraction depends less on Ca2+-signalling pathways but more on changes in Ca2+-sensitivity compared to adult animals. Whether this difference is related to Rho-kinase, one of the major players affecting Ca2+-sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho-kinase critically contributes to the higher Ca2+-sensitivity of contraction in intact arteries of 1-week-old rats. Methods: We studied 1-week-old, 4- to 5-week-old and 10- to 12-week-old rats performing isometric myography, Ca2+-fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia. Results: In 10- to 12-week-old rats, methoxamine (MX) produced vasoconstriction associated with an increase in [Ca2+]i and Ca2+-sensitivity. In contrast, in 1-week-old rats these contractions were accompanied only by an increase in Ca2+-sensitivity. All MX-induced effects were reduced by the Rho-kinase inhibitor Y-27632; this reduction was complete only in 1-week-old rats. The Rho-kinase specific site Thr855 on MYPT1 was increasingly phosphorylated by MX in vessels of 1-week-old, but not 10- to 12-week-old rats; this effect was also inhibited completely by Y-27632. The Rho-kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4- to 5-week-old rats reduced it considerably in 1-week-old rats. Conclusion: Our results suggest that the higher Ca2+-sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.

© 2018, EDP Sciences, SIF, Springer-Verlag GmbH Germany, part of Springer Nature. For advanced applications in modern industry, it is very important to reduce the volume of ferroelectric nanoparticles without serious deterioration of their polar properties. In many practically important cases, the fixed volume (rather than the fixed size) corresponds to realistic technological conditions of nanoparticles fabrication. The letter is focused on the theoretical study of the behavior of ferroelectric polarization, paramagnetoelectric coefficient and phase diagrams of semi-ellipsoidal nanoparticles with a fixed volume V. Our approach combines the Landau-Ginzburg-Devonshire phenomenology, the classical electrostatics, and the elasticity theory. Our results show that the size effects on the phase diagrams and polarization of semi-ellipsoidal BiFeO3 nanoparticles nontrivially depend on V. These findings provide a path to optimize the polar properties of nanoparticles by controlling their phase diagrams at a fixed volume.

© 2018 Background: Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation. Methods: A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion. Results: A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis. Conclusions: These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life.

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. Objectives. The objective of this study was to assess the effect that triple therapy (anticoagulation plus CS plus plasma exchange and/or IVIGs) has on the mortality risk of patients with catastrophic APS (CAPS) included in the CAPS Registry. Methods. Patients from the CAPS Registry were grouped based on their treatments: triple therapy; drugs included in the triple therapy but in different combinations; and none of the treatments included in the triple therapy. The primary endpoint was all-cause mortality. Multivariate logistic regression models were used to compare mortality risk between groups. Results. The CAPS Registry cohort included 525 episodes of CAPS accounting for 502 patients. After excluding 54 episodes (10.3%), a total of 471 patients with CAPS were included [mean (S.D.) age 38.5 years (17); 68.2% female primary APS patients 62%]. Overall, 174 (36.9%) patients died. Triple therapy was prescribed in 189 episodes (40.1%), other combinations in 270 (57.3%) and none of those treatments in 12 episodes (2.5%); the mortality rate in the three groups was 28.6, 41.1 and 75%, respectively. Triple therapy was positively associated with a higher chance of survival when compared with non-treatment [adjusted odds ratio (OR) = 9.7, 95% CI: 2.3, 40.6] or treatment with other combinations of drugs included in the triple therapy (adjusted OR = 1.7, 95% CI: 1.2, 2.6). No statistical differences were found between patients that received triple therapy with plasma exchange or IVIGs (P = 0.92). Conclusion. Triple therapy is independently associated with a higher survival rate among patients with CAPS.

© 2017 IEEE. The article analyzes the process of development of electronic industry in the USSR in the late 1950s and 1960-ies. It's based on documents of the CPSU Central Committee. The authors argue that in these years Soviet electronics were developing rapidly in military and research areas related to space exploration and nuclear energy. Gradual introduction of computers in civil engineering was stated at the same time. But USSR still conceded significantly United States in the growth of the computing machinery. However, in the 1960-ies ideas of universal computerization of the USSR and formation of communism on this basis appeared.

© 2017 IEEE. This paper describes the early period in the development of Soviet digital computers and R&D policy in this field (late 1940s - mid 1950s). The authors focus on the Soviet scientists and economic executives' awareness of the new types of computing machines, their initial application area - the Soviet Atomic Project, and the conditions in which the first computers were made. The Atomic Project leaders realized the value of the new machines but were planning to use only the limited number of them.

© 2018 The implementation of novel therapeutic interventions has improved the survival rates of melanoma patients with metastatic disease. Nonetheless, only 33% of treated cases exhibit long term responses. Circulating tumor cell (CTC) measurements are currently of clinical value in breast, prostate and colorectal cancers. However, the clinical utility of melanoma CTCs (MelCTCs) is still unclear due to challenges that appear intrinsic to MelCTCs (i.e. rarity, heterogeneity) and a lack of standardization in their isolation, across research laboratories. Here, we review the latest developments, pinpoint the challenges in MelCTC isolation and address their potential role in melanoma management.

© 2018 Walter de Gruyter GmbH, Berlin/Boston. The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups. The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction. In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency. The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.

© 2018 Walter de Gruyter GmbH, Berlin/Boston. Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam's metabolic liver pathways and other pharmacokinetic features. To determine phenazepam's metabolic pathways, the study was divided into three stages: In silico modeling, in vitro experiment (cell culture study), and in vivo confirmation. In silico modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The in vitro study was performed using a hepatocytes' cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam's metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients. According to in silico and in vitro analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the in vivo study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94-4.65] to 2.79 [95% CI: 2.02-3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam. Experimental in silico and in vivo studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.

© 2018 American Association for the Advancement of Science. All rights reserved. Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

© Am J Case Rep, 2018.  Objective: Unusual setting of medical care Background: Noninvasive assessment of the fractional flow reserve (FFR) in patients with coronary artery disease plays an important role in determining the need for revascularization. It is particularly relevant for patients with a borderline stenoses and painless myocardial ischemia. Our article describes the first clinical experience in the Russian Federation of using an automated method of noninvasive assessment of the fractional flow reserve (FFR ct ) with a one-dimensional (1-D) mathematical model in a patient with painless myocardial ischemia. Case Report: A 58-year-old male patient who underwent stent implantation in the left circumflex coronary artery (LCX) due to an acute non-ST-elevation posterior myocardial infarction had borderline stenoses of the left anterior descending artery (LAD). After stent implantation, there were no relapse angina symptoms on drug treatment, and according to our examination guideline for patients with borderline stenoses, a treadmill test was performed. The test was positive; therefore, FFR assessment was recommended, with coronary multi-slice CT being performed. The following results were obtained: FFR ct LAD – 0.57; FFR ct LCX – 0.88. An invasive assessment of FFR was also performed as a reference standard and revealed: FFR LAD – 0.6; FFR LCX – 0.88, and simultaneously a LAD percutaneous coronary intervention (PCI) was performed. Three months later, the patient underwent a stress test, which revealed no evidence of induced ischemia. Conclusions: Our method of noninvasive assessment of FFR has shown encouraging results, but we believe that larger-scale studies are needed to establish it as common clinical practice.

© 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 Wiley Periodicals, Inc. Herein the stereoselective two-step synthesis of pure exo-5-trimethylsilylnorbornene is reported. The monomer proved to be highly reactive in both metathesis and addition polymerization. ROMP polymerization was catalyzed by the first-generation Grubbs catalyst. High-molecular-weight saturated addition polymers were prepared using nickel or palladium complexes as precatalysts and Na+[B(3,5-(CF3)2C6H3)4]− and/or MAO as cocatalysts. The obtained addition polynorbornenes are highly gas permeable and microporous materials possessing large free volume and BET surface area (up to 540 m2/g). The influence of the substituent orientation (exo- vs. exo-/endo-mixture) on polymer properties was established. The metathesis polymer based on exo-isomer exhibits 1.5- to 2-fold increase of permeability coefficients for all gases in comparison to the similar polymer based on the mixture of exo- and endo-isomers. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1234–1248.

© 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 IEEE. A hybrid mock circulatory loop (MCL) intended for training and study of engineers and physicians involved into ventricular assist devices design and development is described in this paper. Represented hybrid MCL allow to simulate different cardiovascular conditions including normal and heart failure states.

© 2018 IEEE. The paper presents an algorithm of system identification for implantable rotary blood pumps. The algorithm allows to build mathematical models in accordance with the quality metric introduced to assess the effectiveness of identification. The quality metric was set as an error of pump flow estimation. In the result the mathematical models were identified using experimental dataset for two different rotary blood pumps Sputnik. The identified model of Sputnik 1 characterizes by the mean error about 0.12 L on the control set, the identified model of updated pump-Sputnik 2-mean error about 0.14 L. The identified models intended for control of pump flow during in vitro trials.

© 2018 IEEE. The possibility of noninvasive detection of magnetic particles in biological objects has been investigated. It has been found that magnetic particles, including magnetite, hematite, and catalytic iron particles in carbon nanotubes, can be detected by ultrasensitive magnetic field sensors with resolutions of 10-8-10-14 T. This research direction is shown to be promising for noninvasive monitoring of organs, implants, prosthesis, and other elements of biological systems.