[Pharmacological prevention of fibrosis in dacryosurgery]. / Medikamentoznaya profilaktika fibrotizatsii v dakriokhirurgii.

Chronic inflammatory process in the lacrimal drainage system is the main etiological factor leading to dacryostenosis and consequent obliteration - partial and total nasolacrimal duct obstruction. Prevention of this process is an urgent problem in dacryology. Currently, there is very little research on the development and use of conservative methods for treating dacryostenosis using anti-inflammatory, as well as anti-fibrotic drugs. In this regard, the main method of treating lacrimal drainage obstruction is dacryocystorhinostomy. However, the problem of recurrence after this operation has not been resolved. The causes of recurrence can be cicatricial healing of dacryocystorhinostomy ostium, canalicular obstruction, formation of granulations and synechiae in its area. Surgical methods of recurrence prevention are associated with possible complications, and there is conflicting data on the feasibility of their use. Based on this, the development of pharmacological methods for the prevention of fibrosis in dacryology is promising, among which the antitumor antibiotic Mitomycin C is the most studied. However, there are no specific scientifically substantiated recommendations for the use of this drug, and the data on its effectiveness vary. This has prompted researchers to look for and study alternative anti-fibrotic agents, such as antitumor drugs, glucocorticoids, hyaluronic acid, small molecule, biological, immunological and genetically engineered drugs, as well as nanoparticles. This review presents the current data on the efficacy and prospects of the use of these drugs in dacryology.

Photosensitizing effects and physicochemical properties of chlorophyll a derivatives with hydrophilic oligoethylene glycol fragments at the macrocycle periphery.

In this work, screening studies of the cytotoxic effect of chlorins with fragments of di-, tri-, and pentaethylene glycol at the macrocycle periphery in relation to HeLa, A549, and HT29 cells were performed. It is shown that, despite different hydrophobicity, all the compounds studied have a comparable photodynamic effect. The conjugate of chlorin e6 with pentaethylene glycol, which has the lowest tendency to association among the studied compounds with tropism for low density lipoproteins and the best characteristics of the formation of molecular complexes with Tween 80, has a significant difference in dark and photoinduced toxicity (ratio IC50(dark)/IC50(photo) approximately 2 orders of magnitude for all cell lines), which allows to hope for a sufficiently large "therapeutic window". A study of the interaction of this compound with HeLa cells shows that the substance penetrates the cell and, after red light irradiation induces ROS appearance inside the cell, associated, apparently, with the photogeneration of singlet oxygen. These data indicate that photoinduced toxic effects are caused by damage to intracellular structures as a result of oxidative stress. Programmed type of cell death characterized with caspase-3 induction is prevailing. So, the conjugate of chlorin e6 with pentaethylene glycol is a promising antitumor PS that can be successfully solubilized with Tween 80, which makes it suitable for further in vivo studies.

[The main provisions of programs of medical and social rehabilitation of patients with occupational diseases of ent organs]. / Poryadok razrabotki i osnovnye razdely programmy reabilitatsii postradavshego na proizvodstve s professional'nymi otorinolaringologicheskimi zabolevaniyami.

The article discusses the main, modern provisions of the programs of medical and social rehabilitation of patients with occupational diseases of the ENT organs. The criteria of the degree of loss of professional ability to work in hearing loss and malignant neoplasms of the upper respiratory tract are presented. Rehabilitation programs and forms are developed taking into account the needs of the victim in medical, social and vocational rehabilitation, taking into account the potential capabilities and abilities of the victim to carry out professional, domestic and social activities.

[Forensic examination of air gun dart wounds]. / Sudebno-meditsinskaya otsenka ranenii drotikami, metaemymi iz dukhovykh ruzhei.

The objective was to study the mechanism of formation of experimental wounds of the human body dummy by 12 different types of common air gun darts. The impact of dart tips design features on macro- and microscopic morphological patterns of wounds was established; the description of further laboratory diagnostics of the wounds was provided.

SRPES and STM data for the model bimetallic Pd-In/HOPG catalysts: Effects of mild post-synthesis oxidative treatments.

Post-synthesis treatment of bimetallic catalysts in different gas phases resulting in the adsorption-induced segregation is among promising approaches to enhance their activity not compromising selectivity towards a number of low-temperature reactions. Our recently published paper (M.A. Panafidin, A.V. Bukhtiyarov, I.P. Prosvirin, I.A. Chetyrin, A.Yu. Klyushin, A. Knop-Gericke, N.S. Smirnova, P.V. Markov, I.S. Mashkovsky, Y.V. Zubavichus, A.Yu. Stakheev, V.I. Bukhtiyarov, A mild post-synthesis oxidative treatment of Pd-In/HOPG bimetallic catalysts as a tool of their surface structure fine tuning. Appl. Surf. Sci.) reports on Pd-In intermetallic formation regularities and their evolution after storage in air as well as during treatment in oxygen at submillibar pressures. The current paper gives an extended representation of experimental ex situ/in situ synchrotron-based photoelectron spectroscopy (SRPES) and scanning tunnelling microscopy (STM) data used to derive scientific conclusions in the paper quoted above.

[Ofatumumab - a new drug for the treatment of multiple sclerosis]. / Ofatumumab ­ novyi preparat dlya lecheniya rasseyannogo skleroza.

Recently anti-B-cell therapy has been increasingly integrated into the treatment of multiple sclerosis (MS). This review is devoted to ofatumumab, a new drug of this line. Ofatumumab, an all-human monoclonal antibody used to treat chronic leukemia, binds to a different region than the binding site of other CD20 antibodies, including both a small and large loop in the CD20 receptor structure. This monoclonal antibody provides favorable results for MS by reducing the frequency of exacerbations and the risk of disability progression, significantly more pronounced when compared with teriflunomide. The drug can be used in patients with active relapsing MS and SPMS with exacerbations, with the ineffectiveness of first-line drugs as one of the options for second-line therapy, in patients with highly active MS, especially with a high risk of PML (transfer from natalizumab), as well as if there are difficulties in organizing intravenous courses in day hospitals (produced as outpatient injections).

[Treatment of multiple sclerosis with glatiramer acetate: a new look]. / Lechenie rasseyannogo skleroza preparatami glatiramera atsetat ­ novyi vzglyad.

In recent years, the use of a new dosage (40 mg) of glatiramer acetate (GA), which is administered 3 times weekly has become widespread. In Russia, the drug Timexon (produced by the company BIOCAD) was developed and passed successful clinical trials. The final efficacy analysis included 150 patients treated for 12 months. The convenience of using a double dose of GA in 40 mg, which is registered on the territory of the Russian Federation by two manufacturing companies: CJSC BIOCAD and Teva Pharmaceutical Enterprises Ltd., has been proven.

[Visually impaired older adults as a target group of social rehabilitation: towards the issue of the peculiarities of lifestyle.]

The article presents materials of an empirical study of the peculiarities of the way of life of visually impaired older people in a social rehabilitation context. In comparison with older people without disabling visual impairment, the older blind and visually impaired, according to the results of the conducted questionnaire survey, are characterized in terms of their position in society, the preservation of the «inner core¼ of the personality, involvement in social and cultural life, the need for novelty and expansion of «spiritual and cultural spaces¼, creative activity and social and cultural communication.

Influence of surface morphology of chitosan films modified by chitin nanofibrils on their biological properties.

The paper is devoted to the study of influence of chitin nanofibrils on the structure, surface morphology, mechanical properties, and electrical conductivity of chitosan-based composite films intended for use in biomedical technologies. It was demonstrated that the optimal concentration of chitin nanofibrils in the composite film is 5 wt.%. For the films of this composition, we observed orientation of structural elements on film surface, enhanced mechanical properties as well as an increase in both specific conductivity and proliferative activity of skin fibroblasts on film surface. These results are related to the appearance of oriented structure in nanocomposites and to self-organization of chitosan macromolecules on the surface of chitin nanofibrils. It was revealed that increase in surface energy and surface hydrophilicity did not facilitate effective adhesion, viability and proliferative activity of cells during cultivation on the surface of composite films.

Association between Disturbances in Polyunsaturated Fatty Acid Metabolism and Development of Oxidative Stress during Experimental Diabetes Mellitus.

We studied the effect of streptozotocin-induced diabetes mellitus on the level of glycemia and some other indices of lipid metabolism, including fatty acid metabolism and LPO intensity, during the development of diabetes mellitus in rats. Even at the early terms of diabetes development, hypertriglyceridemia and hypercholesterolemia were accompanied by changes in the blood content of fatty acid (at the expense of ω3 and ω6 fatty acids) that persisted throughout the observation period. Intensification of LPO against the background of suppressed activity of antioxidant enzymes and reduced level of ω3 fatty acids attested to the development of oxidative stress. These data attest to antioxidant property of ω3 fatty acids, which is seen from positive correlations between these fatty acids and activity of antioxidant enzymes.

[Clinical cases of multiple sclerosis in children with cerebral palsy]. / Klinicheskie sluchai rasseiannogo skleroza u detei s detskim tserebral'nym paralichom.

The careful differential diagnosis is very important in pediatric cases of multiple sclerosis (MS). It has special difficulties, if MS started in patients with residual neurological pathology. Two cases of development of MS in children with cerebral palsy (CP) are presented. The clinical features and diagnostic difficulties in such comorbid situations are discussed .

[The risk of ischemic stroke in patients with multiple sclerosis]. / Risk razvitiia ishemicheskogo insul'ta u bol'nykh rasseiannym sklerozom.

A brief literature review on risk factors of ischemic stroke in patients with multiple sclerosis (MS) is presented. A case of ischemic stroke in a MS patient was demonstrated, and risk factors were identified.

Evaluation of the Efficiency of Lytic Mycobacteriophage D29 on the Model of M. tuberculosis-Infected Macrophage RAW 264 Cell Line.

Culture of mouse macrophages (RAW 264.7 ATCC strain) in wells of a 6-well plate was infected with M. tuberculosis in proportion of 15 mycobacteria per one macrophage and then treated with a lytic strain of mycobacteriophage D29. Antibacterial efficacy of mycobacteriophages was studied using D29 phage (activity 108 plaque-forming units/ml) previously purified by ion exchange chromatography. After single and double 24-h treatment, the lysed cultures of macrophages were inoculated onto Middlebrook 7H10 agar medium. The number of mycobacterial colonies in control and test wells (at least 3 wells in each group) was 300.178±12.500 and 36.0±5.4, respectively (p<0.01).

Enzyme-Substrate Reporters for Evaluation of Substrate Specificity of HIF Prolyl Hydroxylase Isoforms.

An organism naturally responds to hypoxia via stabilization of hypoxia-inducible factor (HIF). There are three isoforms of HIFα subunits whose stability is regulated by three isozymes of HIF prolyl hydroxylase (PHD1-3). Despite intense studies on recombinant enzyme isoforms using homogeneous activity assay, there is no consensus on the PHD isoform preference for the HIF isoform as a substrate. This work provides a new approach to the problem of substrate specificity using cell-based reporters expressing the enzyme and luciferase-labeled substrate pair encoded in the same expression vector. The cell is used as a microbioreactor for running the reaction between the overexpressed enzyme and substrate. Using this novel approach, no PHD3 activity toward HIF3 was demonstrated, indirectly pointing to the hydroxylation of the second proline in 564PYIP567 (HIF1) catalyzed by this isozyme. The use of "paired" enzyme-substrate reporters to evaluate the potency of "branched tail" oxyquinoline inhibitors of HIF PHD allows higher precision in revealing the optimal structural motif for each enzyme isoform.

Sol-gel Synthesis, Photo- and Electrocatalytic Properties of Mesoporous TiO2 Modified with Transition Metal Ions.

Mesoporous nanosized titania films modified with Co2+, Ni2+, Mn3+, and Cu2+ ions have been produced by templated sol-gel method and characterized by optical spectroscopy, X-ray diffraction (XRD), and Brunauer, Emmett, and Teller (BET) surface area measurement. Band gap energy and the position of flat band potentials were estimated by photoelectrochemical measurements. The films doped with transition metals possessed higher photocurrent quantum yield, as well as photo- and electrochemical activity compared to undoped samples. Mn+/TiO2 (M-Co, Ni, Mn, Cu) electrodes with low dopant content demonstrate high efficiency in electrocatalytic reduction of dissolved oxygen. Polarization curves of TiO2, TiO2/Ni2+, TiO2/Co2+/3+, and TiO2/Mn3+ electrodes contain only one current wave (oxygen reduction current). It means that reaction proceeds without the formation of an intermediate product H2O2.

Non-porous Iron Titanate Thin Films Doped with Nitrogen: Optical, Structural, and Photocatalytic Properties.

The synthesized undoped and nitrogen doped iron titanate films treated at 450 and 500 °C were crystallized forming pseudobrookite and landauite phase as shown by XRD patterns. The presence of urea in the synthesis procedure promoted the crystallization rate. XPS data indicated that iron ions existed in divalent and trivalent forms, and their ratio was changed for nitrogen-doped sample. The formation of the complexes between iron and urea during sol aging with the following reduction of Fe3+ to Fe2+ within calcination can be a reason not only for accumulation of iron onto the surface as shown by EDS but also for twice increase of divalent iron as registered by XPS. The iron titanate films extended the visible light absorption. Two band gap energy values for all iron-contained films were calculated. The photocatalytic response of all iron titanate films treated at 450 °C compared to pure titania films was spectacularly enhanced under UV and visible light. The slight enhance in photocatalytic activity of nitrogen-doped iron titanate films can be explained by the interstitial nitrogen incorporation rather than substitutional.

[The application of lytic micro-bacteriophage В29 for accelerated phenotype detection of sensitivity mycobacteria of tuberculosis to anti-tuberculosis medications.]

In conditions of prevalence of medicine-resistant strains of mycobacteria of tuberculosis necessity in accelerated, including phenotype techniques of detection of sensitivity of mycobacteria to anti-microbial chemotherapeutic medications in clinical samples is an actual issue. The results of application of accelerated phenotype techniques of detection of sensitivity of clinical strains of mycobacteria of tuberculosis to anti-microbial chemotherapeutic medications on the basis application of lytic mycobacteriophage D29 are presented. The principle of technique is in evaluation of reproduction of mycobacteriophage in cells of mycobacteria of tuberculosis in presence of sensitive to them anti-bacterial medications. The reproduction of mycobacteriophage is evaluated by quantitative analysis of phage DNA in polymerase chain reaction in real-time. The study used 102 clinical strains of mycobacteria of tuberculosis obtained after primary cultivation or re-cultivation in tubes of MGIT system (Bactec). After positive results of growth of mycobacteria of tuberculosis were obtained, the samples were incubated during 48 hours in CO2 incubator in the presence of critical concentrations of 10 widely applied in case of treatment tuberculosis medicinal substances in liquid nutrient medium Middlebrook 7H9 enriched with components OADC, in format of 24 well cultural plate with volume of nutrient medium 1 ml per well. Whereupon, in plate wells deposited 2x103 plaque-forming units of mycobacteriophage D29. After 24 hours a qualitative detection of phage DNA was implemented with polymerase chain reaction in real-time using reagents phage D29 ("Syntol", Russia). The increasing of threshold level of fluorescence of Ct more than to 2 cycles in samples with antibiotic as compared with control testifies sensitivity of the analyzed strain of mycobacteria of tuberculosis to antibiotic. The level of coincidence made up to 91% in comparative study with inoculation in Lowenstein-Jensen nutrient medium. The level of coincidence made up to 96% in comparative study with Bactec test-system of limited number of strains with establishment of sensitivity for 10 medications. The data was confirmed concerning inverse relationship of value ∆Ct and minimal inhibiting concentration of medication. The supposed high efficiency of possible reagents' set on the basis of presented technique on cost/quality criterion.

MOLECULAR-GENETIC PROPERTIES OF VIBRIO CHOLERAE EL TOR STRAINS CIRCULATING IN AFRICA.

The review contains some brief information on cholera epidemics in Africa. Based on the results of the whole genome sequencing of 30 clinical strains isolated in Africa in different periods of the 7th cholera pandemic (1985-2012), extensive genetic diversity has been revealed. It is demonstrated that at present cholera epidemics in Africa are caused by new variants of the agent, which emerged in South- Eastern Asia in consequence of not only new genes acquisition, but also genome alterations of pandemicity and pathogenicity islands. SNP analysis of 53 strains circulating at different times in the territory of the continent, as well as isolated in South-Eastern Asia, has been carried out. Phylogenetic relations between the majority of the African and Asian strains have been established. In addition, strains were shown to exist that are, apparently, endemic to the African region. Identified genetic diversity of the strains with varying virulence and drug resistance points out the necessity of continuous molecular monitoring of the cholera agent in Africa.

Structure-activity relationship for branched oxyquinoline HIF activators: Effect of modifications to phenylacetamide "tail".

HIF prolyl hydroxylase is a major regulator of HIF stability. Branched tail oxyquinolines have been identified as specific inhibitors of HIF prolyl hydroxylase and recently demonstrated clear benefits in various scenarios of neuronal failure. The structural optimization for branched tail oxyquinolines containing an acetamide bond has been performed in the present study using HIF1 ODD-luc reporter assay. The special attention has been paid to the length of a linker between acetamide group and phenyl ring, as well as substitutions in the phenyl ring in the other branch of the tail. The optimized version of branched tail oxyquinolines is 3-fold more potent than the original one identified before and shows a submicromolar EC50 in the reporter assay. The compounds have been studied in a "liver-on-a-chip" device to question their hepatotoxicity towards differentiated human HepaRG "hepatocytes": the absence of hepatotoxicity is observed up to 200 µM concentrations for all studied derivatives of branched tail oxyquinolines.

Detection and quantification of epithelial progenitor cell populations in human healthy and IPF lungs.

BACKGROUND: In the human lung, epithelial progenitor cells in the airways give rise to the differentiated pseudostratified airway epithelium. In mice, emerging evidence confers a progenitor function to cytokeratin 5 (KRT5(+)) or cytokeratin 14 (KRT14(+))-positive basal cells of the airway epithelium. Little is known, however, about the distribution of progenitor subpopulations in the human lung, particularly about aberrant epithelial differentiation in lung disease, such as idiopathic pulmonary fibrosis (IPF). METHODS: Here, we used multi-color immunofluorescence analysis to detect and quantify the distribution of airway epithelial progenitor subpopulations in human lungs obtained from healthy donors or IPF patients. RESULTS: In lungs from both, healthy donors and IPF patients, we detected KRT5(+)KRT14(-), KRT5(-)KRT14(+) and KRT5(+)KRT14(+) populations in the proximal airways. KRT14(+) cells, however, were absent in the distal airways of healthy lungs. In IPF, we detected a dramatic increase in the amount of KRT5(+) cells and the emergence of a frequent KRT5(+)KRT14(+) epithelial population, in particular in distal airways and alveolar regions. While the KRT14(-) progenitor population exhibited signs of proper epithelial differentiation, as evidenced by co-staining with pro-SPC, aquaporin 5, CC10, or MUC5B, the KRT14(+) cell population did not co-stain with bronchial/alveolar differentiation markers in IPF. CONCLUSIONS: We provide, for the first time, a quantitative profile of the distribution of epithelial progenitor populations in human lungs. We show compelling evidence for dysregulation and aberrant differentiation of these populations in IPF.