Репозиторий Университета

© Kolosova et al. P62/SQSTM1, a multi-domain protein that regulates inflammation, apoptosis, and autophagy, has been linked to age-related pathologies. For example, previously we demonstrated that administration of p62/SQSTM1- encoding plasmid reduced chronic inflammation and alleviated osteoporosis and metabolic syndrome in animal models. Herein, we built upon these findings to investigate effect of the p62-encoding plasmid on an agerelated macular degeneration (AMD), a progressive neurodegenerative ocular disease, using spontaneous retinopathy in senescence-accelerated OXYS rats, as a model. Overall, the p62DNA decreased the incidence and severity of retinopathy. In retinal pigment epithelium (RPE), p62DNA administration slowed down development of the destructive alterations of RPE cells, including loss of regular hexagonal shape, hypertrophy, and multinucleation. In neuroretina, p62DNA prevented gliosis, retinal thinning, and significantly inhibited microglia/macrophages migration to the outer retina, prohibiting their subretinal accumulation. Taken together, our results suggest that the p62DNA has a strong retinoprotective effect in AMD.

Copyright © 2018. All rights reserved. Objective: Evaluate growth in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ) for up to 2 years in a phase III trial. Methods: Patients with pcJIA lasting at least 6 months and inadequate response to methotrexate received open-label TCZ intravenously every 4 weeks (randomly assigned to 8 or 10 mg/kg if they weighed < 30 kg; received 8 mg/kg if they weighed ≥ 30 kg) for 16 weeks. Patients with JIA American College of Rheumatology 30 response at Week 16 were randomly assigned to TCZ or placebo for 24 weeks, with an open-label extension through Week 104. Mean ± SD height velocity (cm/yr) and World Health Organization (WHO) height SD score (SDS) were measured in patients receiving ≥ 1 dose of TCZ who did not receive growth hormone and in patients whose baseline Tanner stage was ≤ 3. Results: The study included 187 of 188 patients (99.5%) with mean WHO height SDS -0.5 ± 1.2, which was unrelated to age or disease duration (Spearman rank correlations r = 0.08 and r = -0.12, respectively). There were 123 patients at Tanner stage ≤ 3 at baseline, among whom 103 completed the study with 2 years of height SDS data. Mean height SDS increased from baseline to year 2 (+0.40, p < 0.0001). In 74 of 103 patients (72%), height SDS was greater than at baseline, and mean height velocity was 6.7 ± 2.0 cm/year. Conclusion. Among patients with pcJIA at Tanner stage ≤ 3 at baseline, 72% (74/103) had increased height SDS at the end of the study.

© 2018 WILEY-VCH Verlag GmbH  &  Co. KGaA, Weinheim Nature has long inspired scientists and engineers. As one ubiquitous example of this, nature has provided all with several clever methods to absorb, repel, and/or allow both sunlight and water to pass through surfaces. Moth's eyes (highly antireflective) and lotus leaves (highly hydrophobic and self-cleaning) represent durable natural surfaces which exhibit nearly ideal physical and optical properties. Man-made transparent surfaces must also be able to cope with water and dust while reaching the maximum possible light transmission for solar collectors, displays, and other optical devices. To explore the link between these – particularly for transparent surfaces – this review puts the physics, progress, and limitations of synthetic materials in context with natural materials. This perspective reveals that there is still much more to learn (and implement) if it is hoped to match the multifunctionality and resilience of natural materials.

© 2018 The American Society of Gene and Cell Therapy Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments. Implantation of bone marrow cells into mouse hearts after myocardial infarction is therapeutic, but if the cells are from donors that are older or post-MI (mimicking autologous cell therapy), they are less effective. This report presents evidence that a decrease in B lymphocytes is responsible for the reduced therapeutic response.

© 2018 The Author(s). Background: The approaches to the diagnosis and treatment of chronic spontaneous urticaria (CSU) differ in various parts of the world. We sought to determine the adherence to international and national urticaria guidelines as well as the motives to deviate from the guidelines among physicians worldwide. Methods: A web-based questionnaire was created and launched via e-mail by the World Allergy Organization (WAO) to representatives of all WAO Member Societies, the members of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the members of the WAO Junior Members Group (JMG), regardless of the specialty, affiliation, or nationality in March 2017. Results: We received 1140 completed surveys from participating physicians from 99 countries. Virtually all participants (96%) were aware of at least one urticaria guideline and reported that they follow a guideline. However, one in five physicians who follow a guideline (22%) reported to deviate from it. Reliance on own clinical experience is the most frequent reason for deviation from guidelines or not following them (44%). Young (< 40 years) and less experienced physicians more often follow a guideline and less often deviate than older and experienced ones. Physicians who follow a urticaria guideline showed higher rates of routinely ordering a complete blood count, the erythrocyte sedimentation rate, C-reactive protein, anti-thyroid antibodies, and thyroid-stimulating hormone and of performing the autologous serum skin test as compared to those who do not. Physicians who follow a urticaria guideline showed higher rates of using second generation antihistamines as their first-line treatment of CSU (p = 0.001) and more frequently observed higher efficacy of these drugs (or had more confidence that it would work, p < 0.019) as compared to those who do not follow the guidelines. Conclusions: Physicians' characteristics (e.g. age, clinical experience, and specialty) and country specifics and regional features (e.g. availability of drugs for CSU treatment) importantly influence adherence to urticaria guidelines and CSU patient care and should be addressed in more detail in future research.

© 2017 Informa UK Limited, trading as Taylor  &  Francis Group. The objective of this article is to attract the attention of clinical physicians to the rare but extremely relevant clinical pathology of mesenchymal dysplasias (Marfan syndrome, Ehlers–Danlos syndrome, hereditary hemorrhagic telangiectasia) and especially specific characteristics of such diseases during pregnancy. Connective tissue pathology can cover different organs and systems, symptoms of the same disease can vary in different patients thus making diagnostics significantly difficult. Here clinical diagnostic criteria and methods of molecular diagnostics of diseases are described. The pathogenesis of mesenchymal dysplasias is not currently well understood. For the patients with mesenchymal dysplasias pregnancy is fraught with high risk of life-threatening complications. The preferred delivery method for such patients is caesarean section.

© 2018, The Author(s). Introduction: Trimetazidine (TMZ) has been shown to reduce angina symptoms and to increase exercise capacity in randomized clinical trials, but more extensive data would be useful to assess its effects in real-world clinical practice and in patients with different durations of disease. Methods: CHOICE-2 was a Russian, multicenter, 6-month, open-label, prospective observational study that assessed the effect of adding TMZ modified release 35 mg bid to antianginal treatment in a real-world setting. The present analysis of CHOICE-2 results explored the effects of adding TMZ to background antianginal therapies with regard to the duration of stable angina. Results: A total of 741 patients with known durations of disease were divided into four groups according to stable angina pectoris (AP) duration, ranging from less than 1 year to more than 9 years. Addition of TMZ led to a significant decrease in the frequency of angina attacks and in the use of short-acting nitrates in all groups. In patients with recently diagnosed angina (AP duration < 1 year), the average number of angina attacks per week decreased significantly from 3.75 ± 4.63 to 0.67 ± 1.51 and in those with advanced disease (AP duration > 9 years) from 5.63 ± 5.24 to 1.32 ± 2.07. Angina-free walking distance also improved significantly. Addition of TMZ also improved patient well-being. Results were achieved rapidly (within 2 weeks), were maintained over 6 months, and were obtained in all patient groups regardless of angina duration. Conclusion: TMZ added to other antianginal therapies proved to be effective for reducing angina attacks and short-acting nitrate use, increasing angina-free walking distance, and improving patient well-being in a real-life setting, irrespective of angina duration, including patients with recently diagnosed angina. This provides an opportunity for intensification of treatment early on in the disease process, with the aim of decreasing angina burden and improving patient quality of life. Funding: Servier. Trial Registration: ISRCTN identifier ISRCTN65209863. Plain Language Summary: Plain language summary available for this article.

© 2018, Pleiades Publishing, Ltd. Phospholipase D (PLD; EC 3.1.4.4) is one of the key enzymes catalyzing hydrolysis of cell membrane phospholipids. This review considers and summaries current knowledge about six human PLD isoforms, their structure and a role in physiological and pathological processes. Comparative analysis of PLD isoforms structure is presented. The review considers the mechanism of hydrolysis and transphosphatidylation performed by PLD, the role of PLD1 and PLD2 in the pathogenesis of some types of cancer, infectious, thrombotic, and neurodegenerative diseases is analyzed. The prospects of development of PLD isoformselective inhibitors are considered in the context of their clinical use and inclusion into various therapeutic schemes; the latter is especially important in the case of already developed PLD inhibitors. Phosphatidylethanol (PEth) formed in the human body during phospholipid transphosphatidylation catalyzed by PLD is considered as an alcohol abuse biomarker.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. An express technique for isolation and quantitative determination of water-soluble polysaccharides from roots of Taraxacum officinaleWigg. was developed and allowed the assay time to be shortened to 3.5 h. The developed technique was validated for precision, accuracy, robustness, and linearity and was demonstrated to be precise under repeatable conditions, accurate, and robust. The precipitate mass was strictly linearly dependent on the analyzed raw-material mass for gravimetric determination of water-soluble polysaccharides from roots of T. officinale. The technique could be used for express quality control of T. officinale roots and for commercial production of inulin from this raw material.

The prevalence of habitual miscarriage varies depending on territories of the Russian Federation and other countries. The rate of premature delivery in the Moscow Zelenograd administrative okrug in 2013-2015 in average made up to 4.5%-4.7%. The percentage of habitual miscarriage made up to 3.6% that is a rather low indicator as compared with other Moscow okrugs and national average indices. The article considers three-level model of evaluation of medical, economic and social efficiency of obstetric gynecologic care support of population at the out-patient stage.

© 2018, International Journal of Pharmaceutical Quality Assurance. All rights reserved. Filipendula ulmaria (L.) Maxim. (Meadowsweet) is known in traditional medicine as anti-inflammatory, wound-healing, astringent and antibacterial remedy. However recent studies show that it also has neurotropic activity. In Russia meadowsweet flowers are used as crude herbal drugs (temporary pharmacopoeial monograph 42-1777-87), also leafs and herb are used in the traditional medicine. Objective of the study was to carry out comparative investigation of composition and content of major biologically active compounds (BAC) in Filipendula ulmaria herb, flowers and leafs by thin-layer chromatography, differential spectrophotometry with aluminum chloride reagent (total flavonoids in terms of rutoside), gravimetry (total extractives, extracted by water), permanganatometric titration (total tannins in terms of tannin). Rutoside, tannin, gallic acid and salicylic acid were identified in Filipendula ulmaria herb, flowers and leafs by TLC. Also we analyzed content of substances extracted by water, flavonoids and tannins. Total extractives, extracted by water in F. ulmaria herb is 13.12±0.10%, in leafs - 13.98±0.37%, in flowers - 18.09±0.17%. Total tannins in F. ulmaria herb is 11.87±0.47%, in leafs - 12.06±0.18%, in flowers - 12.26±0.29%. Total flavonoids in F. ulmaria herb 4.34±0.17%, in leafs - 6.98±0.23%, in flowers - 11.75±0.57%. The obtained data will be used for development of a pharmacopoeial monograph project “Filipendula ulmaria (L.) Maxim., herba” for inclusion in the State Pharmacopoeia of the Russian Federation.

© 2018, Allerton Press, Inc. The effect of medium pH and ion strength on the thermal stability of formate dehydrogenases (EC 1.2.1.2, FDH) from model plant Arabidopsis thaliana (AthFDH) and soybean Glycine max (SoyFDH) are studied. The dependence of the residual activity on time is described by the kinetics of the reaction of the first order in all the experimental conditions. The dependence of the first order thermal inactivation constants on phosphate buffer concentration has the form of a bell-shaped curve. It was found that an increase in the pH value resulted in an increase and decrase of inactivation rate constans for SoyFDH and AthFDH, respectively. The activation parameters of the thermal inactivation process, ΔH≠ and ΔS≠ are calculated from the experimental data at different medium pH values and phosphate buffer concentrations.

© 2018, The Author(s). Purpose of Review: The aim of this article is to discuss how allergen-specific immunotherapy (AIT) can be improved through molecular approaches. We provide a summary of next-generation molecular AIT approaches and of their clinical evaluation. Furthermore, we discuss the potential of next generation molecular AIT forms for the treatment of severe manifestations of allergy and mention possible future molecular strategies for the secondary and primary prevention of allergy. Recent Findings: AIT has important advantages over symptomatic forms of allergy treatment but its further development is limited by the quality of the therapeutic antigen preparations which are derived from natural allergen sources. The field of allergy diagnosis is currently undergoing a dramatic improvement through the use of molecular testing with defined, mainly recombinant allergens which allows high-resolution diagnosis. Several studies demonstrate that molecular testing in early childhood can predict the development of symptomatic allergy later on in life. Summary: Clinical studies indicate that molecular AIT approaches have the potential to improve therapy of allergic diseases and may be used as allergen-specific forms of secondary and eventually primary prevention for allergy.

© 2018 John Wiley  &  Sons Australia, Ltd This research is designed to test the hypothesis that elevated homocysteine (Hcy) levels in vivo, caused by a deficit in vitamin B complex, promote changes in cardiac function and redox status that lead to heart failure. In order to conduct the study, we used adult male Wistar albino rats (n = 30; 4 weeks old; 100 ± 15 g body weight). Hyperhomocysteinaemia (HHcy) in these animals was achieved by dietary manipulation. For 4 weeks, the animals were fed with a standard rodent chow (control, CF), a diet enriched in methionine with no deficiency in B vitamins (i.e., folic acid, B6 and B12) (HMNV) or a diet enriched in methionine and deficient in B vitamins (HMLV). After 28 days of dietary manipulation, all animals were killed. The rat hearts were isolated and retrogradely perfused according to the Langendorff technique at a gradually increasing perfusion pressure. We found a negative correlation between elevated serum Hcy and total body and heart weight. The maximum rate of left ventricular pressure development was significantly increased in the HMNV group compared with in the other groups. Systolic left ventricular pressure was significantly changed in all groups. HHcy induces remodelling of the cardiac tissues, as moderate HHcy is associated with more prominent interstitial and perivascular fibrosis. Our results suggest that a high methionine diet without vitamin B complex causes profound negative effects associated with HHcy.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Results from experiments conducted for the parameter Residual Organic Solvents during the course of developing a draft regulation for the drug substance of the innovative pharmacological agent thrombaptanib are reported. The structure of the compound is given. Its pharmacological action is described. A list of potential residual organic solvents was compiled by analyzing the synthetic scheme and manufacturing technology. A separate part of the work describes in detail a developed GC-MS procedure for determining residual organic solvents. Validation results of the procedure for Specificity, Linearity, Accuracy, Precision, and Reproducibility are presented. The validation protocol for the procedure at the time of the studies followed domestic guides for validation that were written based on existing international documents because there was no existing GPM for validation in the current edition of the SP RF. A test sample of thrombaptanib was analyzed using the developed procedure for Residual Organic Solvents. The developed procedure was included in the Residual Organic Solvents section of the draft regulation.

© 2018 Elsevier B.V. Development of efficient biodegradable, environmentally responsive, biocompatible and non-toxic delivery system is needed for efficient gene delivery. As well known, properties of the vehicle are determined by the structure of carrier components. The aim of the current study was to estimate in vitro transfection efficacy of aliphatic di-, tri- and tetrapeptide-based cationic lipoplexes loaded with siRNA in function of a number of cationic groups using 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Physicochemical properties and cytotoxicity of the liposomes were found to be dependent upon a number of amino acid derivatives in an amphiphilic polar head. Uptake of liposomes loaded with nucleic acid (lipoplexes) and their localization in HEK293T cells was studied by confocal microscopy. The liposomes based on lipotripeptides had the highest transfection efficiency which was 20-fold higher than those fabricated from lipotetrapeptides.

© 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 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.