Association of interleukins genes polymorphisms with multi-drug resistant tuberculosis in Ukrainian population

Introduction: Multi-drug resistant tuberculosis (MDR TB) is a significant health problem in some parts of the world. Three major cytokines involved in TB immunopathogenesis include IL-2, IL-4 and IL-10. The susceptibility to MDR TB may be genetically determined. The aim of the study was to assess the association of IL-2, IL-4, IL-10 gene polymorphisms with multi-drug resistant tuberculosis (MDR TB) in Ukrainian population. Material and methods: We observed 140 patients suffering from infiltrative pulmonary tuberculosis (PT) and 30 apparently healthy subjects. The patients were assigned to two groups whether they suffer or do not suffer from pulmonary MDR TB. Interleukin gene (IL) polymorphisms, particularly T330G polymorphism in the IL-2 gene, C589T polymorphism in the IL-4 gene and G1082A polymorphism in the IL-10 gene were studied through polymerase chain reaction. Circulating levels of IL-2, IL-4 and IL-10 in venous blood were estimated using ELISA. Results: Prior to treatment, patients with PT showed significant increase of IL-2 levels and decrease of IL-4 and IL-10 levels compared to apparently healthy subjects. Circulating IL-4 and IL-10 levels were significantly decreased whilst serum IL-2 level was significantly increased in patients with MDR TB compared to non-MDR TB. Low IL-4 and IL-10 secretion and considerable IL-2 alterations were shown to be significantly associated with mutations of homozygous and heterozygous genotypes affecting C589T polymorphism in the IL-4 gene, G1082A polymorphism in the IL-10 gene and T330G polymorphism in the IL-2 gene in patients with PT. Conclusions: Heterozygous genotype and mutations homozygous genotypes gene in polymorphisms determining specified cytokines’ production is a PT risk factor and may lead to disease progression into chronic phase. Heterozygous genotype of aforementioned cytokine genetic polymorphisms was significantly the most frequent in patients with MDR TB

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration–time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.publishedVersio

Endothelial Dysfunction in Children with Clinically Stable and Exacerbated Asthma

Introduction: In children with asthma, endothelial dysfunction signs are observed, and their extent depends on the severity of the disease. These changes are also present in remission. High level of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) expression causes active adhesion of inflammatory cells and can indicate direct endothelium participation in development and supporting of chronic inflammation. Bronchial asthma (BA) is characterised by airways chronic inflammation. A special role in this inflammatory process formation is played by development of endothelial dysfunction. The aim of the study was to evaluate endothelial state in children with clinically stable and exacerbated asthma. Material and methods: 91 children with persistent asthma were examined. Among them there were 40 patients with mild persistent (group I), 34 subjects with moderate persistent (group II) and 17 individuals with severe persistent (group III) asthma. 20 healthy children were selected as controls. The serum levels of sVCAM-1 were determined by enzyme-linked immunosorbent assay (ELISA). The ultrasound assessment of endothelium-dependent flow-mediated dilation of the brachial artery (FMD%) has been made. Ultrasonography has been used for investigation of the intima-media thickness (I-M) complex. Data analysis was performed with the Statsoft Statistica Version 8 (Tulsa, OK). Results: The serum levels of sVCAM-1 were significantly increased in the patients with asthma exacerbation (p < 0.001) and remission (p < 0.001), compared with the controls. The index of FMD% was significantly diminished in the patients of I, II, III group with exacerbation (p < 0.001) and stayed lower in the subjects with asthma in remission (p < 0.001), compared with the controls. The thickness of I-M complex was significantly increased in the patients of I, II, III group, compared with the controls (p < 0.001). The endothelium parameter levels: sVCAM-1 (H = 56.11, p = 0.0001), FMD% (H = 43.20, p = 0.0000), the thickness of I-M complex (H = 49.37, p = 0.0000) depend on the severity of the disease. Correlations between the endothelium and pulmonary function parameters were proved (p < 0.05). Conclusions: Endothelial dysfunction in children with asthma was determined. Dependence of severity of the disease on functional state of the vascular endothelium was proved

Are level of IL-13 and IL-4 predictive for formation of chronic inflammation in children with asthma?

Introduction: Asthma diagnosis in young children may represent a clinical challenge. There are no standard prognostic and dia-gnostic methods. The aim of the study was to evaluate the clinical and prognostic assessment of IL-4 and IL-13 concentrations in children with recurrent wheezing.Material and methods: The study included 96 children with recurrent wheezing. 81 patients were diagnosed as transient wheezing, 15 patients with asthma, and 25 healthy children were selected as controls. The concentrations of IL-4 and IL-13 were analyzed in exhaled breath condensate (EBC) using an enzyme-linked immunosorbent assay (ELISA). Data analysis was performed using Statsoft Statistica Version 8 (Tulsa, OK) and the statistical program MedCalc version 17.2.Results: Both IL-4 and IL-13 concentrations were significantly higher in DDA (21.13 pg/mL, 26.13 pg/mL, respectively) and TW (13.86 pg/mL, 18.3 pg/mL, respectively) groups as compared to healthy controls (3.37 pg/mL, 16.35 pg/mL, respectively; p < 0.001), and the highest rates were observed in children with diagnosed asthma (p < 0.001, DDW vs TW, respectively). IL-4 concentration higher than 18.45 pg/mL (with sensitivity 86.7% and specificity 80%) and IL-13 concentration higher than 20.17 pg/ /mL (with sensitivity 100% and specificity 76.7%) in EBC in children with wheezing recurrence can be considered as a possible predictor of asthma development.Conclusions: The concentration of the anti-inflammatory cytokines IL-4 and IL-13 were significantly increased in children with recurrent wheezing and the highest rates were found in asthma developing children. The concentrations of IL-4 and IL-13 in chil-dren with wheezing can be considered as a possible predictor of asthma development

Are Level of IL-13 and IL-4 Predictive for Formation of Chronic Inflammation in Children with Asthma?

Introduction: Asthma diagnosis in young children may represent a clinical challenge. There are no standard prognostic and dia-gnostic methods. The aim of the study was to evaluate the clinical and prognostic assessment of IL-4 and IL-13 concentrations in children with recurrent wheezing. Material and methods: The study included 96 children with recurrent wheezing. 81 patients were diagnosed as transient wheezing, 15 patients with asthma, and 25 healthy children were selected as controls. The concentrations of IL-4 and IL-13 were analyzed in exhaled breath condensate (EBC) using an enzyme-linked immunosorbent assay (ELISA). Data analysis was performed using Statsoft Statistica Version 8 (Tulsa, OK) and the statistical program MedCalc version 17.2. Results: Both IL-4 and IL-13 concentrations were significantly higher in DDA (21.13 pg/mL, 26.13 pg/mL, respectively) and TW (13.86 pg/mL, 18.3 pg/mL, respectively) groups as compared to healthy controls (3.37 pg/mL, 16.35 pg/mL, respectively; p < 0.001), and the highest rates were observed in children with diagnosed asthma (p < 0.001, DDW vs. TW, respectively). IL-4 concentration higher than 18.45 pg/mL (with sensitivity 86.7% and specificity 80%) and IL-13 concentration higher than 20.17pg/ /mL (with sensitivity 100% and specificity 76.7%) in EBC in children with wheezing recurrence can be considered as a possible predictor of asthma development. Conclusions: The concentration of the anti-inflammatory cytokines IL-4 and IL-13 were significantly increased in children with recurrent wheezing and the highest rates were found in asthma developing children. The concentrations of IL-4 and IL-13 in chil-dren with wheezing can be considered as a possible predictor of asthma development

Interrelationship of endothelial function parameters in children with bronchial asthma in exacerbation and remission

Introduction: In children with asthma, endothelial dysfunction signs are observed, and their extent depends on the severity of the disease.These changes are also present in remission. High level of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) expression causes activeadhesion of inflammatory cells and can indicate direct endothelium participation in development and supporting of chronic inflammation.Bronchial asthma (BA) is characterised by airways chronic inflammation. A special role in this inflammatory process formationis played by development of endothelial dysfunction.The aim of the study was to evaluate endothelial state in children with clinically stable and exacerbated asthma. Material and methods: 91 children with persistent asthma were examined. Among them there were 40 patients with mild persistent(group I), 34 subjects with moderate persistent (group II) and 17 individuals with severe persistent (group III) asthma. 20 healthy childrenwere selected as controls. The serum levels of sVCAM-1 were determined by enzyme-linked immunosorbent assay (ELISA). The ultrasoundassessment of endothelium-dependent flow-mediated dilation of the brachial artery (FMD%) has been made. Ultrasonography has been usedfor investigation of the intima-media thickness (I-M) complex. Data analysis was performed with the Statsoft Statistica Version 8 (Tulsa, OK). Results: The serum levels of sVCAM-1 were significantly increased in the patients with asthma exacerbation (p < 0.001) andremission (p < 0.001), compared with the controls. The index of FMD% was significantly diminished in the patients of I, II, IIIgroup with exacerbation (p < 0.001) and stayed lower in the subjects with asthma in remission (p < 0.001), compared with thecontrols. The thickness of I-M complex was significantly increased in the patients of I, II, III group, compared with the controls(p < 0.001). The endothelium parameter levels: sVCAM-1 (H = 56.11, p = 0.0001), FMD% (H = 43.20, p = 0.0000), the thicknessof I-M complex (H = 49.37, p = 0.0000) depend on the severity of the disease. Correlations between the endothelium andpulmonary function parameters were proved (p < 0.05). Conclusions: Endothelial dysfunction in children with asthma was determined. Dependence of severity of the disease on functionalstate of the vascular endothelium was proved

Semi-Refined Carrageenan Attenuates Lipopolysaccharide-Induced Reactive Oxygen Species Production in Peripheral Blood Mononuclear Cells and Cell Membrane Alterations in Leukocytes

Aim: To assess the effects of semi-refined carrageenan (E407a) on lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) generation in peripheral blood mononuclear cells (PBMCs) and LPS-mediated cell membrane alterations in leukocytes. Methods: Blood samples collected from 8 intact rats were incubated with E407a (10 mg/ml), E407a (50 mg/ml), LPS (1 µg/ml), E407a (10 mg/ml) + LPS (1 µg/ml), E407a (50 mg/ml) + LPS (1 µg/ml) and without those compounds (controls) for 2 h in RPMI 1640 medium enriched with 5% fetal bovine serum. ROS generation in PBMCs obtained from the incubated samples was estimated by flow cytometry using 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) staining. The impact of E407a, LPS and their mixture on leukocyte cell membranes was evaluated spectrofluorimetrically using the fluorescent probe 2-(2¢-hydroxy-phenyl)-5-phenyl-1,3-oxazole. Results: Expectedly, incubation with LPS induced ROS generation in PBMCs and decreased the lipid order of cell membranes in leukocytes. E407a alone was found to alter neither ROS production in PBMCs, nor membrane lipid order in leukocytes. Semi-refined carrageenan partially reduced LPS-mediated ROS overproduction in PBMCs and cell membrane alterations in leukocytes. Conclusion: E407a attenuates LPS-induced alterations of redox homeostasis in rat PBMCs and LPS-mediated modifications of cell membrane lipid order in leukocytes

ECONOMETRIC MODELING OF MANAGERIAL DECISIONS AT THE MACRO AND MICRO LEVELS

The theoretical and practical aspects of the application of the econometric approach to making managerial decisions in a crisis at the micro and macro levels are highlighted. Theoretical aspects determine the basic categories of the research problem: managerial decision, stages of managerial decision-making to determine the feasibility of using econometric methods, crisis and crisis phenomena, econometric approach. The specifics of making managerial decisions in a crisis at the micro and macro levels have been determined; the characteristic features, areas of problem solving and methods for solving managerial problems are considered, depending on the level of their formalization. Practical aspects highlight the rationale for the use of econometric methods at the stage of problem identification: identification of crisis phenomena in the relevant areas; a quantitative analysis of the crisis made it possible to identify and determine the imbalances. The advantages and disadvantages of the econometric approach to managerial decision-making are determined; general econometric methods of substantiating managerial decisions and their consequences are described. The features and advantages of Data-driven decision-making over Highest Paid Person's Opinion are determined; the types of information and analytical support of managerial decisions and the methods used for its formation are determined. The author's understanding of the concepts "econometric approach to managerial decision making", "information and analytical support of managerial decisions" is proposed. Practical aspects highlight the feasibility of using econometric methods and at the stage of justifying managerial decisions – the use of econometric methods in accordance with the scope of application, taking into account its specificity and state: a matrix "economic security – standard of living – innovative development" has been developed to justify the decision on the application of strategies to ensure economic security through changes in the level of innovative development and the standard of living of the population of the region (transformation strategy, innovative development strategy, human development strategy and growth strategy) on the basis of correlation-regression analysis, calculation of partial elasticity coefficients, a potentially most effective variant of reconfiguring the functional components of the innovation infrastructure was established; a model of authentic management of the development of the Ukrainian tourist services market has been developed, which assumes the use of specific mechanisms of authentic management and accounting for the authenticity of the cultural and historical resources of local tourism markets, the asymmetry of infrastructural and socio-economic development of markets, the spatial polarization of the location of climatic and recreational factors of local tourist markets; based on the results of the taxonomic analysis of the state of the hotel and restaurant industry, managerial solutions were proposed for the implementation of the strategy for the development of the hotel and restaurant industry for the coming period, including activities at the national level and at the level of individual business entities; an algorithm for making optimal decisions based on the development of the innovative potential of personnel has been developed: defining the problems of enterprise development; search for the reasons for the retardation of the development of the enterprise; determination of the reasons for the retardation of the development of the enterprise; determination of optimal solutions depending on the formulated problem; development of recommendations for achieving strategic goals, based on the construction of a "tree of opportunities"; a cognitive map (graph) of the process of making strategic decisions in the sphere of making strategic changes at mining and processing enterprises was built taking into account the influence of the following concepts: goals of strategic changes; the goals of the enterprise strategy implementation; the duration of the change lag; the level of encouragement of the team of changes; threshold opportunities for strategic change; unique opportunities for strategic change; average opportunities for strategic change; sufficiency of the potential for strategic changes; resistance to change; fiduciary corporate culture