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To date, it has been established that in the progression of cardiovascular (CV) disorders, an increase in the level of homocysteine (HC) and hypovitaminosis D play an important role. According to the latest recommendations, the modern clinician should consider risk factors not as a diagnostic sign, but as a prognostic, contributing factor, which to some extent can lead to destructive changes in the vascular wall. The aim. To study the morphological changes of the vascular wall depending on the degree of hyperhomocysteinemia and hypovitaminosis D. Materials and methods. We analyzed data from 54 patients who, in addition to determining the level of HC and vitamin D, underwent morphological studies of fragments of the great saphenous vein and aorta. Samples were obtained during coronary artery bypass grafting. Depending on the degree of hyperhomocysteinemia and the level of vitamin D, the patients were divided into 3 groups. Results. Morphological examination of the great saphenous vein and aorta showed normal structure of the vascular wall in patients with normal levels of HC and vitamin D (78.5% and 71.4%, respectively). Patients from the groups 2 and 3 with hyperhomocysteinemia had more pronounced changes in the venous wall, regardless of the level of vitamin D. These data suggest a probable association of HC levels with the changes in the vascular wall. It was also noted that the patients of group 3 had more pronounced inflammatory infiltration of the vascular wall. Conclusions. Hyperhomocysteinemia and hypovitaminosis D are independent predictors of CV disorders and have a detrimental effect on the vascular wall and blood coagulation system, creating conditions for the progression of atherosclerosis. The higher is the level of HC, the more pronounced are morphological changes in the vascular wall of the vein, leading to hypertrophy of all layers, regardless of the level of vitamin D.

Purpose of the study. to study the morphological changes of long-functioning kidney transplants and determine the main causes of transplant dysfunction. Materials and methods. A total of 52 recipients aged 20 to 70 years were analyzed retrospectively at different times after transplant surgery (5 to 22 years).Morphological changes in the kidney transplant are comparable according to light microscopy. The morphological changes in the graft were studied in the initial and long-term period. Morphological studies were conducted in monitoring mode. Results. In the early period after transplantation, ischemic injuries, primary graft function, and episodes of acute rejection were taken into account. In the distant period, morphological changes were evaluated in accordance with the recommendations of the Banff-classification. When analyzing long-term results, antigendependent (immune) and antigen-independent (visible) factors that affect the renal transplant are distinguished. The main clinical and laboratory indicators of allografts dysfunction are increased creatinine and proteinuria. In antigen-dependent forms (cellular, humoral and mixed rejection), humoral rejection is the most common (25%) allografts dysfunction. Antigen-independent forms of dysfunction (streptococcal infection 25%, inflammatory diseases 19,2%, recurrent pathology 3,8%, signs of cyclosporine nephrotoxicity in combination with other forms was found in 59,2%, nephrosclerosis 65,4%). Conclusions. The data obtained suggest that antigen-dependent (immune) factors, and in particular humoral rejection, are the most common cause of allografts dysfunction, and antigenindependent factors contribute to the progression of chronic rejection and the development of nephrosclerosis.

For many years, cardiovascular diseases have been a major cause of morbidity and mortality worldwide. In modern society these have become one of the most pressing medical and social problems. To date, progression of coronary heart disease (CHD) and its complications is strongly associated with increased homocysteine (HC) level and hypovitaminosis D. However, medical literature does not sufficiently cover the issues of drug treatment of patients with metabolic disorders after coronary artery bypass grafting, therefore, more detailed study of this problem is required. The aim. To develop a differentiated approach to the medical treatment of CHD patients before and after direct myocardial revascularization. Materials and methods. The study analyzed the data of 133 patients, 117 (87.96%) men and 16 (12.03%) women, diagnosed with CHD. In these patients, the levels of homocysteine and vitamin D were evaluated. Depending on the levels of hyperhomocysteinemia and vitamin D, the patients were divided into 3 groups. Results. About 70% of the patients examined had elevated blood homocysteine levels greater than 15 ¤mol/L. Based on selective CAG (MSCT CA) findings and complete examination, myocardial revascularization was indicated in 133 patients, as recommended by the 2018 ESC/EACTS Guidelines on myocardial revascularization. In 95% of cases (126 patients), direct myocardial revascularization was performed. All the patients received standard therapy preoperatively, and after getting results of HC and vitamin D tests, metabolic therapy, including folic acid, vitamins B6, B12 and D, depending on HC and vitamin D levels, was prescribed. Conclusions. Hyperhomocysteinemia and hypovitaminosis D provoke impaired endothelial vasomotor function and activate neointimal hyperplasia. Patients with hyperhomocysteinemia and vitamin D deficiency should receive metabolic therapy based on folic acid, vitamins B 6 and B12, and vitamin D, both preoperatively and postoperatively. The first control of HC and vitamin D levels is carried out within 3 months after the treatment initiation.

To date, it has been established that in the progression of coronary artery disease (CAD) and its complications, an increase in the level of homocysteine and hypovitaminosis D are essential. However, medical publications do not adequately cover the study of the effects of hyperhomocysteinemia and vitamin D deficiency on the course of atherosclerosis and the functional state of the myocardium, and requires more detailed research of this problem. Objective. To study the functional state of the myocardium depending on the degree of hyperhomocysteinemia and hypovitaminosis D in patients with CAD. Materials and methods. The study analyzed data from 69 diagnosed with CAD. Depending on the degree of hyperhomocysteinemia and the level of vitamin D, patients were divided into 3 groups. Results. In all patients, speckle-tracking echocardiography revealed a decrease in longitudinal and circular myocardial deformation. Patients with hyperhomocysteinemia and vitamin D deficiency had significantly lower myocardial deformity. Comparing the data of echocardiography, it was found that in patients of all three groups – no significant difference in hemodynamic parameters was found, despite the difference in the level of HC and vitamin D. Conclusions. Hyperhomocysteinemia and hypovitaminosis D are risk factors for the development of CAD. It was revealed that the higher level of homocysteine and the pronounced deficiency of vitamin D, are associated with more pronounced changes in the functional state of the myocardium.

We studied the effectiveness of anti-tuberculosis vaccination with BCG in mice of inbred strains and F1 hybrids (highly resistant to tuberculosis infection) that represent a wide range of genetically determined differences in susceptibility to infection with virulent Mycobacterium tuberculosis. The greatest relative effect was found in susceptible mice, with the exception of highly susceptible I/St mice that were practically not protected by vaccination. Despite significant effect of vaccination in inbred mice, their resistance to M. tuberculosis infection did not exceed that of non-vaccinated highly resistant F1 hybrids.

The objective: to study the quantity and variability of bacterial microbiota in lower gut, the prevalence of microorganisms resistant to antibacterial drugs among microorganisms isolated from the bronchi of pulmonary tuberculosis patients receiving chemotherapy. Subjects and methods . Microorganisms of the bacterial microbiota from lower gastrointestinal tract isolated from respiratory tuberculosis patients were studied. 178 patients were examined retrospectively and 53 patients were examined prospectively. Diagnostic specimens obtained from the bronch i/l ungs (sputum, bronchoalveolar lavage fluid, aspirate, etc.) of respiratory tuberculosis patients were tested. Bacteriological tests complying with current regulatory documents were used. Results . It was found out that gut microbiota varied in tuberculosis patients of various age groups at different stages of treatment and in addition to that, the microbiota was characterized by certain pronounced manifestations of dysbiosis. In cases when clinically significant microorganisms were isolated from bronchi of respiratory tuberculosis patients, a relatively high prevalence of microorganisms resistant to the most important antibacterial drugs was detected.

An actual problem in surgical practice is paresis of the gastrointestinal tract, the main manifestation of which is constipation after surgical treatment. Treatment of postoperative gastrointestinal paresis, which is manifested primarily by constipation, should be comprehensive and, if necessary, patients are shown taking laxatives to stimulate bowel function.Sodium picosulfate is one of the most commonly used and effective drugs, belongs to the group of synthetic stimulant laxatives. The above review noted the safety and effectiveness of sodium picosulfate for atonic constipation, for regulating stool (hemorrhoids, proctitis, anus cracks), for preparing for surgical operations, instrumental and radiological examinations.The presence of picosulfate in the clinic and hospital surgeon’s arsenal makes it possible to optimize the drug therapy in surgical patients with constipation syndrome at the hospital and outpatient treatment stage.

For experimental modeling of tuberculosis, animals of various species are used, each of which has its own advantages and disadvantages. Specific characteristics of animal genetics and immunology during the development of tuberculosis in the experiment were studied in sufficient detail. In addition, mice, guinea pigs, and primates are widely used to test new vaccines and candidate drugs. Modeling of tuberculosis of reproductive organs of females has been developed much worse, since artificial approaches to reproducing genital tuberculosis which do not correspond to the real development of pathology in humans, are more often used. The review describes aspects of modeling tuberculosis as systemic and local infectious process including the study of disorders in the reproductive system of female animals during the development of pulmonary tuberculosis.

Анемии – группа заболеваний, характеризующихся уменьшением количества циркулирующих эритроцитов и/или гемоглобина в единице объема крови ниже нормального для данного возраста и пола. Чаще (80–95% всех анемий) в реальной клинической практике встречается хроническая же-лезодефицитная анемия (ЖДА). ЖДА нередко встречается в практике гастроэнтеролога и у пациентов хирургических отделений. В представленном обзоре обсуждаются наиболее значимые аспекты диагностики и лечения ЖДА в практике гастроэнтеролога и хирурга. Парентеральные препараты железа показаны в тех случаях, когда есть противопоказания к применению пероральных препаратов или они неэффективны. В хирургической практике (при необходимости быстрого восполнения железа в организме) и в гастроэнтерологии (язвенная болезнь желудка и двенадцатиперстной кишки, указания в анамнезе на оперативные вмешательства на желудочно-кишечном тракте, болезнь Крона, язвенный колит, синдром мальаб-сорбции) парентеральные препараты железа рассматриваются в качестве препаратов выбора. Результаты многочисленных международных и рос-сийских исследований свидетельствуют об эффективности и безопасности железа (III) гидроксида олигоизомальтозата в качестве препарата вы-бора для лечения абсолютных или функциональных железодефицитных состояний при отсутствии эффективности пероральных препаратов железа и при необходимости быстрого восполнения железа. Ключевые слова: железодефицитная анемия, гастроэнтерология, хирургия, диагностика, лечение, препараты железа, железа (III) гидроксид оли-гоизомальтозат, Монофер. Для цитирования: Трухан Д.И., Деговцов Е.Н., Никоненко В.А., Самойлов Д.В. Железодефицитная анемия в практике гастроэнтеролога и хирурга: актуальные аспекты диагностики и лечения. Consilium Medicum. 2020; 22 (8): 71–77. DOI: 10.26442/20751753.2020.8.200357

We have demonstrated that long-term exposure of intact mice to rifampicin (6 months) induces resistance to this drug, which manifested in inability of rifampicin to suppress the growth of Mycobacterium tuberculosis in the lungs and spleen during subsequent infection. It the same time, isoniazid is still effective in these mice. In this case, the phenomenon of somatic resistance to rifampicin in mice was observed if the treatment was started in a short period (within 4 days) after infection with M. tuberculosis. If the interval between infection and rifampicin administration was longer (3 weeks), the resistance disappeared.

Chronic myelomonocytic leukosis (CMML) is rarely diagnosed and amounts to 1 per 100 thousand of adults per year, more often in men over 60 years. The clinical case of the rare, prolonged course of myelodysplastic chronic myelomonocytic leukosis (MD-CMML) in a middle-aged woman with rapid transformation into acute monocytic leukemia (AMoL-M5в) with the atypical fulminant course is presented. A retrospective analysis of the course of the disease drew attention to the severe vasculitis suffered by the patient 19 years ago, which could be regarded as the debut of CML in the presence of characteristic pathological changes in the hemogram. Non-pronounced clinical manifestations in the form of moderate cervical lymphadenopathy, skin lesions in the form of transient erythema, spotty eruptions over the next 10 years, fit into the clinical picture of MD-CMML. A detailed picture of the disease was observed after viral infection, bronchitis, antibiotic therapy. Absence of significant blastemia and severe inhibition of normal hematopoiesis with expressed extramedular manifestations of the disease in the patient were not typical for the course of AMoL-M5b in this case. The progression of skin lesions was noteworthy, which gave reason for unfavorable prognosis. For several weeks, the spread of erythematous elements was observed throughout the body with itching, not controlled by antihistamines and corticosteroid drugs; the appearance of maculopapular rashes, merging in places; small-point hemorrhages like vasculitis over the entire surface of the skin. Notable was the development of severe hemorrhagic syndrome without severe thrombocytopenia, significant changes in the coagulogram, as a manifestation of early severe coagulopathy.

Infectious process even at the initial stage after aerosol infection with Mycobacterium tuberculosis induced rapid changes in vaginal microbiota in mice. Rapid decrease in both the quantity and diversity of microbiota was noted, and then, partial recovery of normal flora was observed. Changes in vaginal microbiota was detected as soon as in 3-7 days after lung infection, while inflammatory changes appeared by day 35. At the early stage of infection, no signs of inflammation were observed, neither M. tuberculosis nor its DNA were detected in mouse genital organs.

Pulmonary embolism (PE) is a major life-threatening illness which remains one of the main causes of sudden death throughout the world. The analysis of diagnosis and treatment of 472 patients with acute pulmonary embolism for a period of 10 years was performed. High efficiency of diagnosis using multispiral computer angiopulmonography (MSCT APG) has been established, thus this method completely supersedes the traditional selective angiopulmonography. Seventeen (3.6 %) patients died due to PE recurrence, another 8 (1.7 %) patients died due to the bleeding after using fibrinolytics and anticoagulants, and 14 (2.9 %) died due to progression of organs failure. This emphasizes the need to improve measures aimed to prevent PE recurrence and identify sources of possible bleeding and refrain from aggressive fibrinolytic therapy. The use of differentiated approach to the treatment with thrombolytic therapy and anticoagulants enabled to achieve recovery in 433 (91.7 %) patients who were discharged for outpatient treatment. New oral anticoagulants were prescribed to 94 (21.7 %) patients after discharge.

Novel continuous-flow cascade reactions are developed for producing 1,4-diaryl-disubstituted dipolar γ-carbolines 2 that contain a carboxylate group and their two pentacyclic precursors 6, 7 from hemiindigos 1. The nucleophilic and pro-electrophilic chemistry described is new to the hemiindigos 1, and it led to the discovery of antimycobacterial scaffold characteristic of rimino-type pentacycles 6, 7 and potent drug clofazimine. The new scaffold like clofazimine appears to be useful in developing lead agents active against drug-resistant/dormant TB.

Swelling is an important property of charged gels and membranes. The size of pores and, therefore, membrane properties such as conductivity, diffusion and hydraulic permeability, permselectivity depend on water content and degree of swelling. In this paper we propose a simple model for equilibrium swelling of an ion-exchange membrane, allowing calculation of water content and membrane thickness as functions of the concentration and pH of the bathing solution. The model parameters include the equivalent volume of dry polyelectrolyte gel, the volume fraction of macropores and others. Three types of ion-exchange functional groups, namely, the secondary, tertiary and quaternary amino groups in an anion-exchange membrane are taken into account. The osmotic pressure exerted by micro- and mesopores, appearing in the gel when swelling, is expressed using the Gregor equation, which employs the mole fractions of free and bound water. The equilibria between protonated and deprotonated amino groups are assumed as well as the Donnan and ion-exchange equilibria between the membrane and bathing solution. The results of calculations are compared with experimental data on the membrane thickness and effective exchange capacity obtained for two heterogeneous anion-exchange membranes MA-40 and MA-41 (Shchekinoazot) differed by the composition of functional groups. The procedure of determining membrane structural and thermodynamic parameters is described. A good quantitative agreement between the theory and experiment is found for both membranes using the same set of ion hydration numbers and chemical equilibrium constants for secondary and tertiary amino groups. In particular, it is shown that with increasing pH of the bathing solution, the membrane thickness (and, hence, water content) pass through a local maximum and a local minimum. The simplicity of the model, which does not reduce adequacy, would enable it to be included later in other models describing the transport of ions and water to account for the swelling and change in the membrane structure with a change in pH and concentration of the bathing solution.

The research methodology of electric vehicles electromechanical systems consisting of synchronous electric drives and hybrid energy storages is developed. The simulation platform for investigation of the complete electromechanical system is validated on the base of separate experimental tests of the hybrid energy storage system and vector-controlled interior permanent magnet synchronous motor drive. The simulation testing results of the most spread topologies of energy storage for electric vehicles based on batteries and supercapacitors are given. The load for energy storages is calculated based on the experimental transients of a drive system. The integrals of squared battery current and its rate of change are compared to analyze the battery ageing characteristics.

The degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinson’s disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons results in locomotor impairments and mitochondrial abnormality in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modelling and treating PD.

SummaryReliable delivery of presynaptic material, including active zone and synaptic vesicle proteins from neuronal somata to synaptic terminals is prerequisite for faithful synaptogenesis and neurotransmission. However, molecular mechanisms controlling the somatic assembly of presynaptic precursors remain insufficiently understood. Here we show that in mutants of the small GTPase RAB2 active zone and synaptic vesicle proteins accumulated in the neuronal somata at the trans-Golgi network and were consequently depleted at synaptic terminals, provoking neurotransmission deficits. The ectopic presynaptic material accumulations consisted of heterogeneous vesicles and short tubules of 40×60 nm and segregated in subfractions either positive for active zone proteins or co-positive for synaptic vesicle proteins and LAMP1, a lysosomal membrane protein. Genetically, rab2 behaved epistatic over arl8, a lysosomal adaptor controlling axonal export of precursors. Collectively, we here identified a Golgi-associated assembly sequence in presynaptic precursor vesicle biogenesis controlled by RAB2 dependent membrane remodelling and protein sorting at the trans-Golgi.

Today the common view of the Neosepta membranes is that their material is electrically homogeneous, i.e. it does not include heterogeneities (except reinforcing fabric). However, there are a few publications, according to which their surface is not homogeneous geometrically and this fact has an important impact on the mass transfer rate. In this paper, we thoroughly study geometric heterogeneity of four commercial homogeneous Neosepta cation-exchange (CMX and CMX-Sb) and anion-exchange (AMX and AMX-Sb) membranes by applying optical microscopy, scanning electron microscopy, scanning electrochemical microscopy (SECM) and digital micrometer. It is found that the surface of all membranes is undulated: there are repeating hills and valleys due to the waved reinforcing fabric. The amplitude of undulation increases when swelling: in the case of dry samples, it varies from 10 (AMX-Sb) to 30 (CMX-Sb) microns, while for swollen samples, from 20 (AMX-Sb) to 55 (CMX) microns. These values are comparable to the diffusion layer thickness in industrial electrodialyzers, hence might make an essential impact in enhancement of mass transfer. The period of undulation is several hundreds of microns. Despite common use of micrometer, it gives overestimated membrane thickness since its measuring faces are applied only to the tops of the hills.

The article presents clinical examples of the application of methods of multi-segment osteotomy of upper jaw at the level of Le Fort I, as a preparatory stage before the prosthesis on dental implants in 6 patients with dysgnathias complicated edentulous upper jaw. We examined and operated on 6patients agedfrom 28 to 55 years with designtime complicated edentulous maxilla, c complete growth of the facial skeleton. The average period of postoperative follow-up was 24 months. The method of multi-segment osteotomy of upper jaw at the level of Le Fort I, used in the treatment of such patients, allowed to normalize the ratio of the alveolar bases of the upper and lower jaws and to create the conditions to achieve functional and stable result of implantation and prosthetics.

Objective: to study the efficacy of anti-tuberculosis (TB) therapy in dependence of genetics of the host. Introduction: Dependence of anti-TB drugs’ performance upon genetics of the host remains very poorly studied, and the question about possible influence of genetic susceptibility to infection on the efficacy of treatment remains unanswered. Methods: Highly TB susceptible I/St, resistant C57BL/6 and (I/St x C57BL/6) F1 female mice were infected via aerosol with M. tuberculosis H37Rv. Three or 8 weeks after infection of mice we initiated therapy with isoniazid (INH), rifampicin or Bedaquiline. Treatment duration was 2 months. Efficacy of therapy was evaluated by CFU counts in lungs and spleens as well as by lung pathology. Results: All 3 drugs were more effective in genetically susceptible I/St mice if treatment was initiated in 3 weeks of infection. When therapy was initiated at week 8 of infection the picture was the opposite - the least effect was achieved in I/St mice. Unlike other mouse strains, I/St mice by week 8 of infections develop necrotic and hypoxic granulomas in the lungs. This may be the cause of reduced metabolic state of mycobacteria in such granulomas and difficult access of drugs to them. Conclusions: Efficacy of TB-drug therapy depends on genetic susceptibility of the host to TB infection. Necrotic and hypoxic lung granuloma in susceptible host can significantly abrogate drug efficacy.

The rising incidence of thyroid cancer observed after the Chernobyl accident of 1986 in Ukraine necessitates improving early diagnostics of the disease. Respective diagnostic criteria used currently in FNA cytology have a limited specificity. They usually lack a monocausal relation to the medical condition they represent. These limitations are evident in the identification of radiation-related thyroid cancers. In this chapter, a strategy for the search of new FNA indicators for thyroid malignancy is proposed. Cancers are known to evolve by a reiterative process of clonal expansion, genetic diversification, and clonal selection. Yet insufficient attention is given to FNA features reflecting multiclonal nature of thyroid malignancy. Several new FNA indicators providing diagnostically relevant information on early events of an invasive/metastatic process are proposed. They include specific patterns observed in epithelial cell sheets as well as cells of two unusual phenotypes that form such patterns. These enlarged and pleomorphic cells of epithelial origin demonstrate 100% specificity in the identification of the PTC. The conclusion was made that FNA markers reflecting core aspects of an invasive/metastatic process show a higher specificity in the identification of the disease. The strategy to search for cytologic indicators of diagnostic value should account for this fact.

At present time, the death rate from cardiovascular disease occupies leading position in the structure of total mortality worldwide. The opportunity to conduct non-invasive studies of the coronary arteries has appeared through the development and implementation of multislice computed tomography (MSCT) into medical practice, which carry 64 or more sections. Aim. The purpose of this research is the identification of diagnostic capabilities of 64-slice MSCT in the verification of the severity of coronary artery lesions in patients with proven coronary artery disease. Methods and results. The study has been conducted on a 64-slice CT scanner Optima 660 (GE, USA). The degree of stenosis and calcification of the coronary arteries and also central hemodynamics have been studied. The analysis of survey results of 65 patients with coronary heart disease (30.8% of patients had a history of myocardial infarction) has been carried out. The average age of patients in observation group was 60.2 ± 10.56 years. Male patients were dominated (75.4%). According to the 64-slice MSCT it has been found that coronary artery stenosis occurs ≥ 50% in 90.0% of patients with myocardial infarction, and in 32.5% of patients with symptomatic coronary artery disease. Conclusion. Therefore, MSCT has sufficient specificity in the diagnosis of occlusive and stenotic lesions of the coronary arteries, and can be used for screening patients with suspected coronary artery disease.

We describe the design, synthesis, and in vitro antimycobacterial activity of a series of novel simple hybrid hydrazides and hydrazide-hydrazones combining indole and pyridine nuclei. The compounds are derivatives of 1-acetylindoxyl or substituted indole-3-carboxaldehydes tethered via a hydrazine group by simple C-N or double C=N bonds with 3- and 4-pyridines, 1-oxide 3- and 4-pyridine carbohydrazides. The most active of 15 compounds showed MICs values against an INH-sensitive strain of Mycobacterium tuberculosis H37Rv equal to that of INH (0.05-2 μg/mL). Five compounds demonstrated appreciable activity against the INH-resistant M. tuberculosis CN-40 clinical isolate (MICs: 2-5 μg/mL), providing justification for further in vivo studies.

This paper presents data on morphological changes in the wall of abdominal aortic aneurysms in order to study the importance of the inflammatory response in the development of an aneurysm. It is found that chronic inflammation plays a major role in the pathogenesis of abdominal aortic aneurysm formation. In the wall of the aneurysm revealed extensive inflammatory infiltrates of lymphocytes, macrophages, which are the main source of metalloproteinases that cause degeneration of elastin and collagen, which leads to the destruction of the wall structure and dilatation of the aorta.

Background and objectives : The nucleus is a complex and dynamic organelle enclosing the major part of the cell's genome. A growing body of evidence suggests that changes in the shape of this organelle can influence cell activities. The other way around, altered nuclear shape may be indicative of impaired cell function. Symmetry is an important aspect of nuclear shape not receiving the attention it merits. We address this problem by presenting a software tool allowing to quantify nuclear shape asymmetry in light microscopy images. Methods : The software named nPAsym is written in Scala and implemented as a plugin to ImageJ making possible to use it in combination with other ImageJ tools. The plugin works with 8-bit images segmented into black nuclear masks and white background. It performs a number of operations allowing to analyze multiple objects within a single image, removing some segmentation artefacts, filtering out objects incomplete and below a specified size. The feature of interest is quantified using the notion of point asymmetry. The performance of nPAsym was tested in a small-scale study comparing nuclear shapes for cells of nodular goiter, follicular thyroid adenoma and papillary thyroid carcinoma. Results : We present nPAsym, the ImageJ plugin, that measures nuclear shape asymmetry. It works with digital microscopic images segmented using either a raster graphics editor or built-in ImageJ functions. nPAsym is packaged in a single .jar file and does not require installation as well as configuration. It has proved effective in distinguishing between some of the nuclear shape phenotypes. Conclusions : nPAsym is the user-friendly, platform-independent and open-source software tool allowing to quantify nuclear shape asymmetry in digital images captured from cytologic and histologic preparations. It has a potential to become useful for both experimental research and diagnostics.

Panels of congenic mouse strains that differ by the alleles of a certain chromosomal segment and by the level of susceptibility to tuberculosis (TB) infection is a precise tool for adequate dissection of host TB genetics, immunology and pathology, as well as the efficacy of TB-vaccines and drugs. Here we present two H2-congenic strains on the C3H genetic background, C3H.JK (H2j) and C3H/HeDiSn (H2k) which differ profoundly in TB susceptibility, and a new I.B6 panel of H2-congenic strains on the well-characterized TB-susceptible I/St H2j genetic background. H2j haplotype determines a high level of TB susceptibility. After inoculation with a high dose of Mtb, I/St, C3H/HeDiSn and C3H.JK mice displayed similar mortality curves. Gradual dose reduction, leading to less severe TB manifestations, allowed identification the C3H/HeDiSn strain as the most TB-susceptible in terms of survival time, lung CFU counts and lung pathology. For further studying the role of the H2 and background genes in TB control, we now perform segregation genetic analysis (F2 dissection) of relevant phenotypes.

TB infection in mice develops relatively rapidly which interferes with experimental dissection of immune responses and lung pathology features that differ between genetically susceptible and resistant hosts. Earlier we have shown that the M. tuberculosis strain lacking four of five Rpf genes (ΔACDE) is seriously attenuated for growth in vivo. Using this strain, we assessed key parameters of lung pathology, immune and inflammatory responses in chronic and reactivation TB infections in highly susceptible I/St and more resistant B6 mice. ΔACDE mycobacteria progressively multiplied only in I/St lungs, whilst in B6 lung CFU counts decreased with time. Condensed TB foci apeared in B6 lungs at week 4 of infection, whilst in I/St their formation was delayed. At the late phase of infection, in I/St lungs TB foci fused resulting in extensive pneumonia, whereas in B6 lungs pathology was limited to condensed foci. Macrophage and neutrophil populations characteristically differed between I/St and B6 mice at early and late stages of infection: more neutrophils accumulated in I/St and more macrophages in B6 lungs. The expression level of chemokine genes involved in neutrophil influx was higher in I/St compared to B6 lungs. B6 lung cells produced more IFN-γ, IL-6 and IL-11 at the early and late phases of infection. Overall, using a new mouse model of slow TB progression, we demonstrate two important features of ineffective infection control underlined by shifts in lung inflammation: delay in early granuloma formation and fusion of granulomas resulting in consolidated pneumonia late in the infectious course.

In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-) ) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV(+) ) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV(+) interneurons were reduced with age in CHL1(-/-) mice, from a surplus of +27% at 1 month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV(+) interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short- and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9 months of age in CHL1(-/-) mice. This deficit could be abrogated by a GABAA receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity. Close homolog of L1-deficient (CHL1(-/-) ) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3-CA1 excitatory synapses. Furthermore, adult CHL1(-/-) mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans.

The most investigations of the biomarkers of renal allograft dysfunction (RAD) are limited by early post-operational period and are aimed at diagnosis of acute rejection of renal transplant. This work has aimed to establish additional characteristics of chronic RAD by using non-invasive biomarkers of the blood serum and urine.Materials and methods. 79 patients aged 16 to 59 years (47 men and 32 women) took part in our retrospective study. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamil transferase (GGT), alkaline phosphatase (ALP), N-acetyl-β-D-glucosaminidase (NAG); interleukins (IL-2, IL-8, IL-10) and beta-2-microglobulin were evaluated.Results. Increased IL-10 and β2-MG serum concentration, and increased urinary concentration and activity of β2-MG, IL-2, IL-8, NAG, AP, AST, GGT were typical for chronic RAD. Only NAG was independently significantly associated with chronic RAD in multivariate regression. From the area under ROC-curves were derived, that β2-MG level in serum and urine, and the activity of NAG in urine had the excellent and good power to classify patients with satisfactory function and chronic RAD.Conclusions. The increase of β2-MG in serum and urine may indicate glomerular and tubular dysfunction, respectively. An increase of urinary NAG indicates the ongoing damage of the tubules. The increase of IL-2 and IL-8 in the urine and IL-10 in serum may indicate the etiology of chronic RAD.

The nucleus of an eukaryotic cell is a membrane-bound organelle containing a major part of the cellular genome. Nuclear shape is controlled by forces generated in the cytoskeleton, nuclear envelope and matrix of the nucleus and may change when the balance of these forces is disturbed. In certain cases, such changes may be indicative of cell pathology. Nuclear shape feature is being commonly addressed in both experimental research and diagnostics; nevertheless its symmetry-related aspects receive little attention. This article introduces a technique allowing to estimate nuclear shape asymmetry in digital images captured from cyto- or histological preparations. Implemented in a software package, this technique quantifies the asymmetry using two scenarios. The first one presumes the identification of nuclear pixels laying outside the largest inscribed circle. According to the second scenario, the algorithm searches for nuclear pixels lacking pixel-partners symmetric with respect to the nuclear area's centroid. In both cases, the proportion of "asymmetric" pixels is used to estimate the feature of interest. The technique was validated on images of cell nuclei having distinctive shape phenotypes. A conclusion was made that shape asymmetry feature may be useful accessory to the toolbox of nuclear morphometry.

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-β or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Among 230 target-synthesized indole-based compounds, seven 3-triazenoindoles showed MICs of 0.2 to 0.5 μg/ml against Mycobacterium tuberculosis strain H37Rv and isoniazid-resistant human isolate CN-40. The TU112 compound was active also against a dormant form of M. tuberculosis . Some of these triazenoindoles were active against Mycobacterium avium , with MICs of 0.05 to 0.5 μg/ml. The selectivity indices (SI) for M. tuberculosis and M. avium were significantly higher than 10, making these compounds acceptable for the next testing step.

Operando μ-Raman spectroscopy is used to probe the water distribution across Nafion® and Aquivion™ membranes in the operating fuel cell. The through-plane water concentration profile is obtained with μm resolution at the middle of the active surface, both at the gas distribution channel and at the under-lands areas. Depth-resolved measurements carried out at room temperature show that the water content of both membranes increases with the increase of the feed gas relative humidity and decreases with the increase of stoichiometry. At given relative humidity and stoichiometry conditions, the water content first increases at the fuel cell start-up and, then, decreases progressively with the increase of the current density delivered by the cell. The water loss is due to the concomitant rise of pressure drops and of the cell inner temperature, the latter giving the larger contribution. Pressure drops are related to the increase of the feed gases fluxes while temperature rise is due to increasing ohmic losses and heat from the electrochemical reaction. Compared to Nafion, Aquivion exhibits larger water content, but similar dehydration rate as a function of ohmic losses, and larger water accumulation at the under-lands area compared to channel.

Tuberculosis (TB) treatment is confounded by the range of metabolic states displayed by Mycobacterium tuberculosis, by the long duration required and by the increasing prevalence of drug-resistant strains. Latent TB infection is especially difficult to treat due to the phenotypic antibiotic resistance of non-replicating M. tuberculosis. Therefore, the development of new drugs effective against both active and latent TB infection is needed. New 1-hydroxy-2-thiopyridine derivatives were synthesized and found to be highly effective in vitro against both actively growing and dormant non-culturable M. tuberculosis. Such compounds are leads for the development of new drugs for all forms of TB including latent infection. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

The question about possible influence of genetic susceptibility to Tuberculosis (TB) infection on the efficacy of its antibiotic treatment remains unanswered, and the results of scarce studies on the topic look contradictory. In the present work we studied the efficacy of short-term INH therapy against M. tuberculosis in hyper-susceptible I/St, relatively resistant BALB/c and highly resistant (I/St x BALB/c) F1 mice by comparing lung and spleen CFU counts and lung histopathology after 1- and 2-mo therapy. Our results indicate that the efficacy of INH therapy, as evaluated at the early phase of infection, is more effective in genetically susceptible hosts. Possible reasons for contradictions between studies applying early VS. late evaluation of the efficacy of treatment are discussed.

The studies of neuronal cell-glycosaminoglycan interactions indicate an increasing interest in the question of how heparin can mediate adhesion properties of the cell. We have found that high levels of both N-CAM concentration and heparin-binding activity were noticed in the early stages of brain formation. According to electron microscopy data, an elevation of free heparin in the substratum leads to a decrease of the N-CAM content and changing of its distribution on the membrane of cultured hippocampal neurons. Spatial arrangement of immunogold labelled N-CAM molecules in plasma membrane profiles of cultured neurones was quantified with image analysis software using an interlabel distance estimate. To convert these estimates into two dimensional (2D) quantities, namely the 2D pattern and density of labelling, a computer simulation technique was used. Heparin added to the substratum in a concentration of 40 microg/ml decreased the 2D N-CAM labelling density by 50% - 39.8 labels/microm(2) compared with the control values of 88.9 labels/microm(2).