The alternative complement pathway in ANCA-associated vasculitis: further evidence and a meta-analysis.

We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses. The median concentrations of MAC, C5a, C3a and factor B were higher in active AAV patients (P < 0·001). Achievement of remission was associated with reductions in C3a (P = 0·005), C5a (P = 0·035) and factor B levels (P = 0·045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression or disease severity on complement levels. A total of 1122 articles were screened, and five studies, including this report, were entered into the meta-analysis. Plasma MAC, C5a and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.

[Risk factors for the early development of septic shock in patients with severe COVID-19].

AIM: In a retrospective study, we evaluated factors associated with the early development of septic shock in patients with severe COVID-19. MATERIALS AND METHODS: We collected medical records of the intensive care unit patients submitted by the local COVID-19 hospitals across Russia to the Federal Center for the Critical Care at the Sechenov First Moscow State Medical University (Sechenov University). Septic shock in crticially ill patients requiring mechanical ventilation was defined as a need in vasopressors to maintain blood pressure. RESULTS: We studied 1078 patients with severe COVID-19 who were admitted to the intensive care units for respiratory support. There were 611 males and 467 females. The mean age was 61.013.7 years. Five hundred twenty five medical records (48.7%) were received from the Moscow hospitals, 159 (14.7%) from the Moscow region, and 394 (36.5%) from the hospitals located in 58 regions of the Russian Federation. In 613 (56.9%) patients, diagnosis of SARS-CoV-2 infection was confirmed by PCR, and in the other cases it was established on the basis of the clinical picture and the results of the chest CT scan. Septic shock developed in 214 (19.9%) of 1078 patients. In the logistic regression model, the risk of septic shock in patients older than 50 years was higher than in patients of a younger age (OR 2.34; 95% CI 1.533.67; p0.0001). In patients with more severe SARS-CoV-2 infection, there was an increase in the prevalence of cardiovascular diseases, including coronary heart disease and atrial fibrillation, type 2 diabetes and malignant tumors. The risk of septic shock in patients with three or more concomitant diseases was higher than in patients without any concomitant chronic diseases (OR 1.76; 95% CI 1.762.70). CONCLUSION: The risk of septic shock in patients with acute respiratory distress syndrome induced by SARS-CoV-2 is higher in patients older than 50 years with concomitant diseases, although a severe course of the disease is also possible in younger patients without any concomitant disorders.

[Sympathetic Nervous System Activation in Pathogenesis of Development of Essential Hypertension and Its Role in Target-Organs Damage in Young and Middle Aged Adults: the Cardioprotective Capabilities of Bisoprolol].

The article discusses various mechanisms of developmentt and progression of arterial hypertension in young and middle aged adults. It emphasizes the predominant role of hypersympathicotonia in the development of the disease in this category of patients. Various mechanisms are considered, by means of which the increase of activity of the sympathetic nervous system leads to elevation of arterial pressure and potentiates early damage of target organs, first of all, damage of the heart. The data of numerous studies demonstrating pronounced cardioprotective effects of a highly selective representative of the class of ß-blockers bisoprolol in young and middle aged hypertensive patients are presented.

The modern therapy of systemic vasculitides: perspectives and challenges.

Systemic vasculitis is a heterogeneous group of inflammatory diseases, which are classified according to the diameter of the affected vessels. The treatment of systemic vasculitis is no longer empirical, because of increasing number of randomized clinical trials in this field. In recent years, there was a trend to limit the cumulative dose of glucocorticosteroids and immunosuppressive drugs, partially through biological drugs usage. However, biologic therapy is not always superior to combination of glucocorticosteroids and cytotoxic drugs. The efficacy of different biologic drugs varies in patients with different forms of systemic vasculitis, which creates the ground for personalized therapy of these diseases. Another serious problem is the absence of strict criteria to immunosuppressive therapy intensification, especially in vasculitis, affecting large vessels, due to the lack of reliable laboratory markers of disease activity. The article reviews modern approaches to the treatment of some types of systemic vasculitis, including ANCA-associated vasculitides, giant cell arteritis, Takayasu`s arteritis and cryoglobulinemic vasculitis.

Relationship between serologic profile (ANCA type) and clinical features of renal involvement in ANCA-associated vasculitides.

AIM: To compare the frequency, clinical features and outcomes of renal involvement in ANCA-associated vasculitides (AAV) in patients with antibodies against proteinase-3 (pr3-ANCA) and myeloperoxidase (MPO-ANCA). MATERIALS AND METHODS: In our retrospective study we enrolled 264 patients, 94 males and 170 females, median age 53 [36; 62] years. Among them 157 were pr3-ANCA positive and 107 were MPO-ANCA positive. AAV was diagnosed according to ACR criteria and Chapel Hill consensus conference definition (2012). Median follow up was 44 [18; 93] months. We assessed baseline BVAS and VDI by the end of the follow up. Serum creatinine (sCr), estimated glomerular filtration rate (eGFR), hematuria and daily proteinuria were estimated. Diagnosis and stage of chronic kidney disease (CKD) and acute kidney injury (AKI) were established according to KDIGO guidelines (2012) and Scientific Society of Russian Nephrologists (2016). RESULTS: Renal involvement was present in 181 (68.6%) patients, and its frequency was similar in pr3-ANCA and MPO-ANCA subgroups. Patients with MPO-ANCA developed rapidly progressive glomerulonephritis and hypertension significantly more often than patients with pr3-ANCA: 50.7% vs 35.6% (p=0.049) and 46.1% vs 29.8% (p=0.029) respectively. At disease onset, median sCr was significantly higher and eGFR was significantly lower in patients with MPO-ANCA (p<0.05). 1-year and 5-year renal survival rates were similar in pr3-ANCA-positive (93.9% and 87.4% respectively) and MPO-ANCA positive patients (87.4% and 83.1% respectively). Median BVAS and VDI scores were significantly higher in pr3-ANCA subgroup. The number of patients who developed AAV relapse during 1-year follow up was also significantly higher in pr3-ANCA subgroup. The frequency of eye and ENT involvement was significantly higher in pr3-ANCA positive patients than in MPO-ANCA-positive patients. CONCLUSION: The frequency of extrarenal manifestations, clinical features of renal involvement and relapse rate are associated with AAV serotype.

IMMUNOGENIC PROPERTIES OF RECOMBINANT MOZAIC PROTEINS BASED ON ANTIGENS NS4A AND NS4B OF HEPATITIS C VIRUS.

The aim of the study was to investigate immunogenic properties of mosaic recombinant proteins constructed on the data of hepatitis C virus NS4A and NS4B antigens. Four mosaic recombinant proteins, containing the T and B epitopes of the NS4A and NS4B antigens, were created by genetic engineering methods in the E. coli system. To enhance the immune response they were linked in different variations to the nucleotide sequences of murine interleukin-2 (IL-2), the Neisseria meningiditis lipopeptide, and the T helper epitope of the core protein of hepatitis C virus. The immunogenic properties of these recombinant proteins were analyzed by immunoblotting, ELISA and ELISpot using sera from immunized mice and patients infected with hepatitis C virus. Recombinant proteins specifically reacted with the sera of immunized mice and infected patients in immunoblotting. According to the ELISA data, the predominant formation of antibodies to NS4B was observed when mice were immunized with the recombinant proteins containing both antigens. Analysis of gamma-interferon production by T-lymphocytes upon contact with activated dendritic cells showed in ELISpot that the maximum production of this cytokine was detected when adjuvant components were located at the N- and C-ends of the recombinant protein. The highest level of gamma-interferon production during stimulation with this drug was detected in lymphocytes from the bone marrow and lymph nodes. The recombinant protein containing the T and B epitopes of NS4A and NS4B, murine IL-2 and the lipopeptide Neisseria meningiditis had the greatest immunostimulate effect among the four constructions. This recombinant protein formed nanoparticles of 100-120 nm in size.

Investigation of the effects of GABA receptor agonists in the differentiation of human induced pluripotent stem cells into dopaminergic neurons.

The influence of GABA receptor agonists on the terminal differentiation in vitro of dopaminergic (DA) neurons derived from IPS cells was investigated. GABA-A agonist muscimol induced transient elevation of intracellular Ca2+ level ([Ca2+] i ) in the investigated cells at days 5 to 21 of differentiation. Differentiation of cells in the presence of muscimol reduced tyrosine hydroxylase expression. Thus, the presence of active GABA-A receptors, associated with phenotype determination via Ca2+-signalling was demonstrated in differentiating human DA neurons.

Experimental therapy of graft-versus-host disease by mesenchymal stromal cells grown on oxide nanocoatings.

Immune aggression to transplanted allogeneic bone marrow, i.e. the graft-versus-host disease (GVHD), could be decreased by the suppression of effector and/or activation of T- regulatory cells (Treg). This task could be solved by co-transplantaiton of allogeneic bone marrow and mesenchymal stromal cells (MSCs). This study demonstrated the elevated immune modulating activity of MSCs by their culturing in vitro on Al203 oxide nanocoatings. Introduction of the cells to the animals with GVHD resulted in an increased content of Treg in the spleen of bone marrow recipients, reduced severity of the pathology, and higher survival of animals. Thefindings could be the basis for developing the new approaches to optimize the GVHD treatment methods involving the oxide nanocoating cultured MSCs.

[Renoprotecion With Metabolic Syndrome: the Possibility of Receptor Agonist Imidazoline Moxonidine].

The article is devoted to the of prevalence, diagnosis, and prognostic significance of renal damage in metabolic syndrome. The pathogenetic mechanisms of development and progression of chronic kidney disease in individuals with obesity, including the role of increased activity of the sympathetic nervous system is discussed. Approaches to the choice of antihypertensive drugs with an emphasis on metabolic and renal protection properties are given. The advantages of imidazoline receptors in neuroprotective of moxonidine in patients with arterial hypertension, metabolic syndrome, and diabetes mellitus is discussed in detail. number of mechanisms of renal protection actions of the agonists of imidazoline receptors is described.

[Prognostic value of renal resistance index in estimating the progression of chronic kidney disease].

AIM: To study a relationship between main renal and intraparenchymal renal arterial resistance indices (RIs) measured by Doppler ultrasonography and clinical and laboratory parameters and to determine their prognostic value in estimating the progression of chronic kidney disease (CKD). SUBJECTS AND METHODS: The investigation enrolled 53 CKD patients divided into groups: glomerular and interstitial diseases. Glomerular filtration rate (GFR) calculated using the CKD-EPI formula, proteinuria (PU) severity, kidney sizes, renal parenchyma thickness, parenchyma/collecting index, and main and intrarenal vessel RIs were determined at the first hospitalization. The mean follow-up was 14 ± 2.64 months. The rate of GFR decline was estimated at the rehospitalization. RESULTS: Main renal and intrarenal vessel RIs depend on patient age and pulse pressure. The RIs are associated with GFR and PU in the group of glomerular diseases and with kidney sizes and structure in that of interstitial diseases. The interlobar arterial RI is the most sensitive predictor for worsening renal function with a threshold of 0.65, which is comparable to the prognostic value of PU. CONCLUSION: The main renal and intrarenal vessel RIs may be considered as a predictor for worsening renal function.

[Hormonal and Metabolic Differences in Patients With Coronary Artery Disease].

OBJECTIVE: To prove the involvement of the autonomic nervous system in the formation of thrombotic status of the patients. 24 patients with myocardial infarction were enrolled in the study. Catecholamines levels were compared duing pain episodes and at rest. Patients were divided in to 2 groups according to the level of norepinephrine during the pain episode: Group 1-12 persons with the level of norepinephrine more than 500 pg/ml, and group 2-12 persons with a level below 500 pg/ml. Patients in group 1 the level of beta thromboglobulin and thromboxane were elevated, as well as there are changes of cAMP and cGMP, indicating increased thrombogenic activity. Particular attention was paid to the 8 patients in Group 1, in which the level of norepinephrine is maintained above 500 pg/ml both during pain and at rest (disseminated intravascular coagulation).

[The Results of Long-Term Observation of Patients Who Participated in the ADVANCE Trial].

We present in this article data on the prevalence and risk of complications in patients with diabetes and hypertension. From the standpoint of current guidelines on the management of arterial hypertension we consider problems of target blood pressure levels and choice of antihypertensive drugs in patients with diabetes, including those with diabetic nephropathy. We also present results of long-term observation of participants of the ADVANCE trial that have shown that reduction of mortality achieved because of antihypertensive therapy in the randomized study persisted throughout follow-up. Discussion of possible mechanisms of this phenomenon and the advantages of fixed perindopril/indapamide combination is presented as well.

[Value of Fatty acids in formation of thrombotic status in patients with ischemic heart disease].

Interrelation between fatty acids and platelet aggregation has been a subject of interest for cardiologists in the terms of thrombogenic status. In order to study this problem we observed 42 patients with ischemic heart disease and 30 healthy persons. In patients we found elevation of arachidonic acid and lowering of docosahexaenic acid levels. Hypoxemic assay revealed in these patients lowering of prostacyclin and antithrombin III levels. In the pathogenesis of disturbances of platelet aggregation in patients with ischemic heart disease alteration of structure of platelets with increased quantity of phosphatidyl ethanolamine and corresponding change of thrombocyte asymmetry resulted in conformational reorganization of proteins and lipids.

[Blood viscosity in patients with ischemic heart disease].

AIM: To elucidate relation of blood viscosity to development of a hypoxic state of microcirculation in patients with ischemic heart disease (IHD). MATERIAL AND METHODS: We examined 42 patients with postmyocardial infarction cardiosclerosis and 30 healthy persons (control group). Measurements were made by rotatory viscometer at shear rates 1 - 10 s(-1). RESULTS: In patients with IHD we found increased blood viscosity and lowering of blood fluidity limit. Pathogenesis of increased blood viscosity in patients with IHD involves elevated blood fibrinogen, enhanced aggregation ability of erythrocytes, and accelerated formation of fine and large erythrocyte aggregates.

[Possibilities for early diagnosis and monitoring of age-related macular degeneration].

High prevalence of age-related macular degeneration (AMD) among older adults and treatment difficulties at later stages make early diagnosis and disease monitoring an actual problem of ophthalmology. Although methods for identification of gene-positive groups are now available, genetic studies are not sufficiently widespread in our country to ensure screening for AMD risk. In this regard there remains a need to determine the earliest objective sings of the degenerative process and progression criteria. This paper reviews anatomically oriented functional methods of retinal examination at the onset of AMD and later in the course of the disease. Analysis of collected material will provide systematic understanding of current possibilities for early diagnosis and functional monitoring of AMD patients prior to the decrease of their visual acuity.

[Antipsychotic drugs and their influence on the carbohydrate metabolism in patients with schizophrenia-spectrum disorders].

The effect of antipsychotic drugs, typical and atypical neuroleptics, is described in the following sections of this paper: antipsychotic drugs and carbohydrate metabolism, prevention and risk factors, pharmacoepidemiology, treatment. It is concluded that neuroleptic treatment increases the risk of metabolic impairment. Mechanisms of this effect are not clear so far. Ethnicity, sex, age and features of the therapy may play a role. Clozapine, olanzapine, ziprasidone, sertindole and some typical neuroleptics are risk factors as well. Common glucose-reducing drugs as well as prevention of metabolic impairment and special behavioral training,including the control over the level of glycemia, are used in treatment of diabetes mellitus induced by neuroleptics.

The use of nanocomposite coatings with various physicochemical properties in tissue engineering.

We studied the effect of nanocomposite coatings with various physicochemical properties on the structural and functional properties (adhesion potential, phenotype, gene expression) of mesenchymal stem cells. Of all tested nanocoatings (Al2O3, ZrO2, Ta2O5), oxide coating Al2O3 enriched in vitro monolayer bone marrow cell culture with cells carrying mesenchymal stem cells phenotype markers and stimulated expression of ido gene, which can confer new therapeutic potencies to these cells and extend their application in clinical practice.

[Dynamics of morphological structures of platelets in patients with ischemic heart disease in dependence on blood levels of fatty acids].

Levels of fatty acids in platelets of ischemic heart disease (IHD) patients (n = 39) has been compared with those in healthy subjects (n = 12). Increased content of arachidonic acid and thromboxane A2 in platelets of IHD patients forms thrombogenic picture of IHD. High level of fibrinogen and decrease in heparin and antithrombin III in IHD patients facilitates formation of blood clots. Morphological examination of platelets in IHD patients has demonstrated an increase of levels of discocytes and spherocytes as well as appearance of small and large platelet-erythrocyte aggregates promoting blood slot formation.