Репозиторий Университета

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Promising directions for the discovery of universal carriers for active pharmaceutical ingredients (APIs) are reviewed. Transdermal delivery of the APIs in medicines is attracting increasing attention from designers of drug formulations. A transdermal therapeutic system (TTS) is a dosage form for external use as controlled-release patches or films. TTSs are classified depending on the mode of API incorporation into several basic types such as reservoir, adhesive, matrix, and microreservoir. Methods for developing TTSs based on microemulsions are described in the review.

© 2018 Peptide and protein neurotoxins, such as α-conotoxins from Cone snails and α-neurotoxins from snake venoms, are excellent tools to identify distinct nicotinic acetylcholine receptor (nAChR) subtypes. Here we compared the rat/human species specificity of α7 nAChR towards peptide and protein neurotoxins and found that α-conotoxin analogues [K11A]TxIB and [H5D]RegIIA are much more potent on the rat versus human α7 receptor expressed in Xenopus oocytes. In the hope to determine the key residue responsible for the difference in α-conotoxin analogues affinities, ten single mutants of rat α7 nAChR were obtained because there are 10 differences in the extracellular ligand-binding domains of these species, and only K185R mutation decreased the affinity for α-conotoxins [K11A]TxIB and [H5D]RegIIA, down to their low affinities for human α7 nAChR. On the other hand, the reverse mutation R185K in human α7 nAChR resulted in the greatest increase in the affinity for both conotoxins, while a double mutation hα7[S183N, R185K] made the potency of the receptor for them as high as that of rat α7 nAChR. The effects of mutations at position 185 were investigated also with some other α-conotoxins and cobra venom α-cobratoxin and found to have similar but much less pronounced effects on their species specificity. Molecular modeling provided possible explanation for the high species selectivity of [K11A]TxIB and [H5D]RegIIA towards α7 nAChR, opening the new way for design of their analogues with improved affinity to the human receptor.

© 2018, Pleiades Publishing, Ltd. Solubilization with pluronic F-127 gave water-soluble forms of hydrophobic photosensitizers—steroid derivatives of pyropheophorbide a. Solubilization was performed by evaporating the chloroform co-solutions of photosensitizer and pluronic (triple block copolymer of ethylene and propylene oxide) and subsequently dissolving the resulting dry residue in water. The concentration ratios of modified pyropheophorbide–pluronic at which the photosensitizer completely passed into the aqueous phase were determined. Among the starting hydrophobic photosensitizers, pyropheophorbide–dihydrotestosterone possessed the highest activity in photosensitized oxidation of anthracene with singlet oxygen in chloroform, while after solubilization, pyropheophorbide–testosterone was most active in the test (for photodynamic therapy) oxidation of tryptophan in aqueous solutions.

The article considers the results of sociological survey of medical personnel of the Moscow oblast. The purpose of study is to analyze attitude of medical personnel to the system of mandatory medical insurance in modern conditions. The sociological survey carried out according standard methodology using originally developed questionnaire. The public opinion of medical personnel of medical municipal organizations of the Moscow oblast was investigated in 2013 (n = 632) and 2017 (n = 798). It was established that, 25 years later from the moment of organization of the system of mandatory medical insurance, not all medical personnel is oriented in it. The percentage of those who consider it as a false and over bureaucratized one increased. The number of respondents considering that medical insurance organizations protect interests of patients decreased and those who feel no impact of mandatory medical insurance foundations on activities of medical organizations increased up to 35%. The most of respondents consider functions of medical insurance organizations and mandatory medical insurance foundations exclusively as controlling ones. In both surveys less than 30% of respondents supported actual system of mandatory medical insurance. The general results of the sociological survey testify the necessity of changing policy of relationship between the system of mandatory medical insurance and medical personnel, including activization of activities concerning explanation of tasks, functions and authorities of mandatory medical insurance foundations and medical insurance organizations and also consensual consideration of opinions of all participants of the mandatory medical insurance system.

© 2018 Elsevier Inc. Background: Corticotrophin-releasing hormone receptor-1 gene (CRHR1) variants have been implicated in mental health. However, little is known of the effects of CRHR1 on long-term mental health and behavior in presence of environmental stressors. We assess the effects of CRHR1 variant (rs17689918)-by-environment interactions on emotionality and behavioral traits, including anxiety, depression, aggression and antisocial behaviors. We also determine effects of rs17689918-by-environment-by-sex interactions on the above-mentioned outcomes. Methods: Genotypic assessments were carried out in 564 children (mean age 10 years, 52.5% females) from the ongoing longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). Information on stressful life events and family relationships were available at baseline and information on behavioral and mental health outcomes (self- and parent-reports) were available at follow-up ages of 18 and 25 years. ANOVAs were used to determine associations of two-way CRHR1-by-environment and three-way CRHR1-by-sex-by-environment interactions on behavioral and mental health outcomes. Results: Two-way CRHR1 interaction effects showed associations between low familial warmth and hostility in individuals with the GG genotype. Associations of low familial warmth with aggression, of higher number of stressful life events with aggression, and of stressful live events with anxious-depressive symptoms were noted in male A-allele carriers and female GG homozygotes. Conclusion: CRHR1-by-familial environment interactions influence both outwardly-directed aggression as well as mood and anxiety disorder symptoms in a sex-specific manner. The type of environmental stressor can also influence effects of CRHR1 on behavioral and mental health outcomes.

© 2018 IEEE. Modern laser technologies have a wide range of scientific, commercial, medical and other applications. In medicine, lasers are used both for diagnostic, therapeutic, and surgical purposes. Safety of laser radiation in assisted reproductive technologies is discussed in the paper. Efficiency of using femtosecond (fs) laser pulses to perform noncontact embryo biopsy as well as laser-assisted hatching is shown. First results on femtosecond laser marking on the surface of embryo outer shell for individual embryo tagging are also presented. Question of safety of THz radiation for living objects (starting at the cellular level and ending with the organism in whole) is still a matter of controversy and requires further study. Experimental study of high-power THz pulses effect on living 2D cell culture is presented. MSC cells are exposed to multiple (from 80 to 100) THz pulses with intensities up to 1 MV/cm. No short-term damage effects are observed during first hours post cell irradiation.

© 2018 The Author(s). Background: Amphibian trypanosomes were the first ever described trypanosomatids. Nevertheless, their taxonomy remains entangled because of pleomorphism and high prevalence of mixed infections. Despite the fact that the first species in this group were described in Europe, virtually none of the trypanosomes from European anurans was analyzed using modern molecular methods. Methods: In this study, we explored the diversity and phylogeny of trypanosomes in true frogs from Europe using light microscopy and molecular methods. Results: A comparison of observed morphotypes with previous descriptions allowed us to reliably identify three Trypanosoma spp., whereas the remaining two strains were considered to represent novel taxa. In all cases, more than one morphotype per blood sample was observed, indicating mixed infections. One hundred and thirty obtained 18S rRNA gene sequences were unambiguously subdivided into five groups, correspondent to the previously recognized or novel taxa of anuran trypanosomes. Conclusions: In this work we studied European frog trypanosomes. Even with a relatively moderate number of isolates, we were able to find not only three well-known species, but also two apparently new ones. We revealed that previous assignments of multiple isolates from distant geographical localities to one species based on superficial resemblance were unjustified. Our work also demonstrated a high prevalence of mixed trypanosome infections in frogs and proposed a plausible scenario of evolution of the genus Trypanosoma.

© 2018 Wiley Periodicals, Inc. A new approach to making a photopolymeric composition was first elaborated in this work based on the use of poly-N,N′-(m-phenylene)isophtalamide as the heterochain polymer matrix together with 4,4′-diphenyl oxide diacrylamide as the crosslinking agent. Reproducible three-dimensional (3D) objects have been formed using a laser stereolithograph completed with a laser with wavelength of 405 nm. According to the thermogravimetric analysis, the thermal stability of the formed objects could be changed through a control from 260 to 405 °C. Moreover, it was proven that the tensile strength of samples of the crosslinked films reached 90.1 ± 3.2 MPa at the elongation at break of 12.4 ± 2.3%, depending on the forming parameters of such samples. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 46463.

© 2018 by Turkish Association of Urology. Objective: Surgical site infection (SSI) is defined as infection at or near surgical incisions within 30 days of an operative procedure and classified either incisional superficial and deep or organ/space. The aim of the study is to report and compare the incidence and management of SSIs after robot-assisted laparoscopic radical prostatectomy (RALP) and retropubic radical prostatectomy (RRP). Material and methods: Within the last 4 years, we identified 285 patients that underwent RRP, n=187 (66%) or RALP, n=98 (34%). We reviewed the frequency, types and way of management of SSI complications. Results: A significant difference was found between RALP and RRP (2/98, 2% vs. 27/187, 14.4%; p<0.0001) as for SSIs. The time interval between the time of surgery and diagnosis of SSIs was longer in RALP relative to RRP (median 13.5 vs. 12.9 days, p=0.761). Conclusion: All types of SSIs could be developed after RP, however RALP patients only experienced organ or space SSIs and have a lower rate of SSIs and shorter treatment time.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Technology development for solid dosage forms with a solid dispersion of diclofenac is a crucial problem in pharmaceutical science and practice. The goal of the work was science-based and experimental technology development for tablets containing a solid dispersion of diclofenac with improved biopharmaceutical indicators as an equivalent to the substance. The obtained granulates and tablets had indicators that met the corresponding standards of the Russian SP XIIIth Ed. Almost 100% of the diclofenac was released from the developed tablets. This was 1.3 times greater than from commercial tablets. The recommended shelf life under these conditions is two years. The proposed technology could not only increase the bioavailability of the slightly soluble non-salt form of diclofenac but also facilitate further development of new medicinal preparations with improved bioavailability.

© 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 Elsevier Ltd The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. When reaching a critical length, these intermediate species aggregate laterally to transform into fibers arranged into branched fibrin network. We combined multiscale modeling in silico with atomic force microscopy (AFM) imaging to reconstruct complete atomic models of double-stranded fibrin protofibrils with γ-γ crosslinking, A:a and B:b knob-hole bonds, and αC regions—all important structural determinants not resolved crystallographically. Structures of fibrin oligomers and protofibrils containing up to 19 monomers were successfully validated by quantitative comparison with high-resolution AFM images. We characterized the protofibril twisting, bending, kinking, and reversibility of A:a knob-hole bonds, and calculated hydrodynamic parameters of fibrin oligomers. Atomic structures of protofibrils provide a basis to understand mechanisms of early stages of fibrin polymerization. Zhmurov et al. used 27 relevant crystal structures to computationally reconstruct the full-atomic models of fibrin oligomers and protofibrils, which correlate with high-resolution atomic force microscopy images. The structures contain much valuable information for understanding the early stages of fibrin polymerization.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Solid dispersions (SDs) of indomethacin with polyethylene glycol 1500 (PEG-1500) were studied to determine their effect on indomethacin solubility. Production of SDs increased the solubility and dissolution rate of indomethacin in H2O. The solubility and dissolution rate of indomethacin from SDs increased by 1.8 – 2.2 and 3.1 – 4.4 times, respectively. Indomethacin became less crystalline and then amorphous during preparation of the SDs. Dissolution of the SDs solubilized indomethacin and formed colloidal solutions.

© 2018 Elsevier Ltd  Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53 + cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i. e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53 + H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53 +/+ HCT116 cells in much lower concentration range compared to p53 −/− HCT116 cells.

© 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, Pleiades Publishing, Inc. DNA isolation is a routine procedure when performed in laboratory environment, yet in the field it may still remain problematic. This is especially true of some crop species bred for useful metabolites that may also hinder DNA extraction. Here we compare the efficiency of DNA extraction protocols and commercial DNA isolation kits when used on samples from Helianthus and Allium. Since extraction of DNA is known to be compromised by co-extraction of PCR-inhibiting metabolites, the isolation of DNA was followed by PCR as a testing procedure for the isolation step. The MagnoPrime Fact and MagnoPrime Uni DNA isolation kits were better suited for field work due to faster processing times and smaller required amount of starting material (20 mg fresh/0.5 mg dry). In all cases the subsequent PCR managed to amplify the DNA fragments of interest well enough to be useful in further research.

© 2018 Elsevier Ltd Biological effects of hormones in both plants and animals are based on high-affinity interaction with cognate receptors resulting in their activation. The signal of cytokinins, classical plant hormones, is perceived in Arabidopsis by three homologous membrane receptors: AHK2, AHK3, and CRE1/AHK4. To study the cytokinin–receptor interaction, we used 25 derivatives of potent cytokinin N6-benzyladenine (BA) with substituents in the purine heterocycle and/or in the side chain. The study was focused primarily on individual cytokinin receptors from Arabidopsis. The main in planta assay system was based on Arabidopsis double mutants retaining only one isoform of cytokinin receptors and harboring cytokinin-sensitive reporter gene. Classical cytokinin biotest with Amaranthus seedlings was used as an additional biotest. In parallel, the binding of ligands to individual cytokinin receptors was assessed in the in vitro test system. Quantitative comparison of results of different assays confirmed the partial similarity of ligand-binding properties of receptor isoforms. Substituents at positions 8 and 9 of adenine moiety, elongated linker up to 4 methylene units, and replacement of N6 by sulfur or oxygen have resulted in the suppression of cytokinin activity of the derivative toward all receptors. Introduction of a halogen into position 2 of adenine moiety, on the contrary, often increased the ligand activity, especially toward AHK3. Features both common and distinctive of cytokinin receptors in Arabidopsis and Amaranthus were revealed, highlighting species specificity of the cytokinin perception apparatus. Correlations between the extent to which a compound binds to a receptor in vitro and its ability to activate the same receptor in planta were evaluated for each AHK protein. Interaction patterns between individual receptors and ligands were rationalized by structure analysis and molecular docking in sensory modules of AHK receptors. The best correlation between docking scores and specific binding was observed for AHK3. In addition, receptor-specific ligands have been discovered with unique properties to predominantly activate or block distinct cytokinin receptors. These ligands are promising for practical application and as molecular tools in the study of the cytokinin perception by plant cells.

© 2018 Walter de Gruyter GmbH, Berlin/Boston 2018. The paper proposes a stable time-splitting method for the numerical simulation of free-surface viscous flows. The key features of the method are a semi-Lagrangian scheme for the level-set function transport improved with MacCormack predictor-corrector step with limiting strategy and an adaptive volume-correction procedure. The spatial discretization is done by a hybrid finite volume/finite difference method on dynamically adaptive hexahedral meshes. Numerical verification is done by comparing full-scale 3D numerical simulations of the sloshing tank and the coastal wave run-up with other numerical and experimental results known from the literature.

© 2018, Pediatria Ltd. All rights reserved. Clinical guidelines for the selection and use of antibiotics (AB) for common and most important community-acquired infections are aimed at increasing the treatment efficacy and overcoming growth of bacterial pathogens resistance to AB. They are based on the principle of positive ratio of «benefit/risk» of AB and selection of primary and alternative drugs. The article presents Russian and foreign data on pediatricians preferences in the choice of AB for ARI in children, on the level of Streptococcus pneumoniae resistance to penicillins and macrolides and other respiratory bacterial pathogens to macrolides in Russia (including the pediatric population) and abroad, which led to similar changes in grouping of AB in the Eurasian clinical recommendations and WHO recommendations. It demonstrates a significant coincidence of the AB choice for community-acquired pneumonia and acute bacterial rhinosinusitis in children in comparable recommendations with the recognition of amoxicillin as the first choice drug and the general tendency to restrict the use of macrolides. It also points on the need to control the AB use.

© 2018, Pleiades Publishing, Ltd. A rapid method is developed for the quantitative determination of 5–35 g/L of isonicotinic hydrazide (INH, isoniazide) in aqueous media. The method is based on the formation of copper(I) oxide in the reaction of isonicotinic hydrazide with copper ions on the surface of indicator tablets and the subsequent recording of the analytical signal by reflectance spectrophotometry and colorimetry. Aluminum oxide is proposed as a solid-phase substrate for the production of indicator tablets. Isonicotinic hydrazide can be determined in the tablet form of the Isoniazid preparation.