EXPRESSION OF TLR2, TLR3, TLR4 AND PROINFLAMMATORY TNF AND IL-6 CYTOKINES IN LIVER BIOPSIES OF NONALCOHOLIC FATTY LIVER DISEASE PATIENTS

Non-alcoholic fatty liver disease (NAFLD) is a group of conditions closely associated with obesity that are among the most common and socially significant liver diseases in the modern Western world. The emergence and progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis with the subsequent development of fibrosis are the leading factors in the pathogenesis of a significant proportion of the most severe liver pathologies, such as cirrhosis and hepatocellular carcinoma, as well as extrahepatic metabolic complications of NAFLD, such as insulin resistance and type 2 diabetes mellitus. The inflammatory component is one of the most important factors in the pathogenesis of NAFLD, particularly in the context of the progression of simple steatosis to non-alcoholic steatohepatitis. At the same time, the role of the most important mediators of the inflammatory response, innate immunity receptors and the Toll-like receptors in particular, in the pathogenesis of NAFLD has been poorly studied. In the present work, we first used the bioinformatics analysis of the publicly available gene expression databases to demonstrate that only TLR1, TLR2, TLR3 and TLR4 were significantly expressed in the healthy human liver. We then used the reverse transcription PCR to measure the mRNA expression levels of TLR2, TLR3, and TLR4, as well as those of the important pro-inflammatory mediators tumor necrosis factor (TNF) and interleukin-6 (IL-6), in the liver biopsy specimens obtained from 20 patients with NAFLD (simple steatosis, n = 10; non-alcoholic steatohepatitis, n = 10), as well as from 4 obese patients with clinical suspicion for NAFLD but no histological signs of NAFLD in their liver biopsies. We found a significant increase in the expression of TLR2, TLR3 and TLR4 mRNA in liver biopsy samples obtained from patients with non-alcoholic steatohepatitis as compared to those obtained from controls without histological signs of NAFLD. We were also able to demonstrate the association between the hepatic levels of TLR2, TLR3 and TLR4 mRNAs with the histological degree of liver damage as evidenced by the degree of steatosis and balloon dystrophy of hepatocytes, as well as with the plasma levels of uric acid, the important endogenous stimulator of innate immunity. Our data indicate the possible involvement of innate immunity, particularly the Toll-like receptors, in the pathogenesis of NAFLD

Capabilities of the GAMMA-400 gamma-ray telescope to detect gamma-ray bursts from lateral directions

The currently developing space-based gamma-ray telescope GAMMA-400 will measure the gamma-ray and electrons + positrons fluxes using the main top-down aperture in the energy range from ~20 MeV to several TeV in the highly elliptic orbit (without shadowing the telescope by the Earth and outside the radiation belts) continuously for a long time. The instrument will provide fundamentally new data on discrete gamma-ray sources, gamma-ray bursts (GRBs), sources and propagation of Galactic cosmic rays and signatures of dark matter due to its unique angular and energy resolutions in the wide energy range. The gamma-ray telescope consists of the anticoincidence system (AC), the converter-tracker (C), the time-of-flight system (S1 and S2), the position-sensitive and electromagnetic calorimeters (CC1 and CC2), the top and bottom scintillation detectors of the calorimeter (S3 and S4) and lateral detectors of the calorimeter (LD). In this paper, the capabilities of the GAMMA-400 gamma-ray telescope to measure fluxes of GRBs from lateral directions of CC2 are analyzed using Monte-Carlo simulations. The analysis is based on second-level trigger construction using signals from S3, CC2, S4 and LD detectors. For checking the numerical algorithm the data from space-based GBM and LAT instruments of the Fermi experiment are used, namely, three long bursts: GRB 080916C, GRB 090902B, GRB 090926A and one short burst GRB 090510A. The obtained results allow us to conclude that from lateral directions the GAMMA-400 space-based gamma-ray telescope will reliably measure the spectra of bright GRBs in the energy range from ~10 to ~100 MeV with the effective area of about 0.13 m2 (for each of the four sides of CC2) and total field of view of about 6 sr.Comment: 19 pages, 18 figures, the paper will be submitted to Advances in Space Researc

Consensus position of endocrinologists and pathologists on coding causes of death in patients with diabetes mellitus (expert opinion)

Coding of the causes of death of patients with diabetes mellitus (DM) in the Russian Federation is one of the long-discussed problems, due to the comorbidity of diabetes and cardiovascular diseases (CVD) and a number of contradictions in the key regulatory documents regulating the statistics of mortality in this category of patients, which acquires particular relevance in the context of the coronavirus pandemic, due to its negative impact on the outcomes of the course of COVID-19 and mortality risks. In pursuance of the decisions of the Minutes of the meeting of the working group under the project committee of the National Project «Health» on identifying patterns in the formation of mortality rates of the population dated January 20, 2021 No. 1, chaired by Deputy Prime Minister of the Russian Federation T.A. Golikova, experts of two directions - endocrinology and pathological anatomy, prepared a Draft of agreed recommendations on the Rules for coding the causes of death of patients with diabetes, causing the greatest problems in terms of the use of ICD-10 when choosing the initial cause of death, including in the case of death from CVD and COVID-19

Puzzles of Dark Matter - More Light on Dark Atoms?

Positive results of dark matter searches in experiments DAMA/NaI and DAMA/LIBRA confronted with results of other groups can imply nontrivial particle physics solutions for cosmological dark matter. Stable particles with charge -2, bound with primordial helium in O-helium "atoms" (OHe), represent a specific nuclear-interacting form of dark matter. Slowed down in the terrestrial matter, OHe is elusive for direct methods of underground Dark matter detection using its nuclear recoil. However, low energy binding of OHe with sodium nuclei can lead to annual variations of energy release from OHe radiative capture in the interval of energy 2-4 keV in DAMA/NaI and DAMA/LIBRA experiments. At nuclear parameters, reproducing DAMA results, the energy release predicted for detectors with chemical content other than NaI differ in the most cases from the one in DAMA detector. Moreover there is no bound systems of OHe with light and heavy nuclei, so that there is no radiative capture of OHe in detectors with xenon or helium content. Due to dipole Coulomb barrier, transitions to more energetic levels of Na+OHe system with much higher energy release are suppressed in the correspondence with the results of DAMA experiments. The proposed explanation inevitably leads to prediction of abundance of anomalous Na, corresponding to the signal, observed by DAMA.Comment: Contribution to Proceedings of XIII Bled Workshop "What Comes beyond the Standard Model?

Canagliflozin: from glycemic control to improvement of cardiovascular and renal prognosis in patients with type 2 diabetes mellitus. Resolution of Advisory Board

Inhibitors of the sodium-glucose cotransporter type 2 (SGLT2i) are a modern class of antihyperglycemic drugs with an insulin-independent mechanism of action. Due to its ability to effectively lower blood glucose levels, improve a number of other cardiometabolic parameters (body weight, blood pressure, uric acid), as well as reduce cardiovascular and renal risks, SGLT2i have become drugs of choice for many of patients with type 2 diabetes mellitus (T2DM). Meanwhile, along with the generally recognized classes-effects of this group of drugs, there are intragroup features, including those associated with their different selectivity in sodium-glucose cotransporters of types 1 and 2 (SGLT1 and SGLT 2). For example, one of the most studied SGLT2i, canagliflozin, in addition to its inhibitory activity against SGLT2, can also moderately block SGLT1 in the intestine and kidneys that could give a maximum efficiency in the control glycemia and others cardiometabolic parameters. In addition, canagliflozin improves not only cardiovascular, but also renal prognosis in patients with T2DM, which is reflected in the corresponding indications in the summary of product characteristics of the drug. This document summarize the established and new data regarding the efficacy and safety of canagliflozin, as well as its place in the treatment of T2DM

Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease

Aim: present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points. Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion. Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients