In Search of Optimal Criteria for Iron Deficiency in CHF Patients. Post-hoc Analysis of the Study "Prevalence of Iron Deficiency in Patients With Chronic Heart Failure in the Russian Federation (ID-CHF-RF)".

AIM: Comparative analysis of clinical, anamnestic, and laboratory and instrumental data of patients with chronic heart failure (CHF) and iron deficiency (ID) diagnosed according to the AHA/ESC/RSC criteria, and CHF patients diagnosed with ID based on decreased transferrin saturation (TSAT) ≤19.8% or serum iron (Fe) ≤13 µmol/l. MATERIAL AND METHODS: An additional analysis of the ID-CHF-RF study was performed. The analyzed population included 498 patients (198 women) with CHF. In addition to the ID criteria provided by the protocol (AHA/ESC/RSC criteria: ferritin <100 µg/l or ferritin from 100 to 299 µg/l and TSAT<20%), concentrations of ID biomarkers were assessed, which showed high sensitivity and specificity for the diagnosis of ID compared to the morphological picture of the bone marrow (TSAT<19.8% or Fe ≤13 µmol/l). Subgroups of patients with ID determined only by the AHA/ESC/RSC criteria, only by the TSAT≤19.8% and Fe ≤13 µmol/l criteria, and by both were analyzed. RESULTS: ID diagnosed by the AHA/ESC/RSC criteria was found in 83.1% of patients. The TSAT ≤19.8% and Fe ≤13 µmol/l criteria revealed ID in 74.5% of patients. In 341 patients (76.8%), ID was diagnosed using both criteria. Patients with ID diagnosed by the TSAT≤19.8% and Fe≤13 µmol/l criteria, compared with patients with ID diagnosed by the AHA/ESC/RKO criteria, had a 50% lower Fe (9.8 µmol/l vs. 19.4 µmol/l) and a higher incidence of anemia (43.3% vs. 23.3%) and diabetes mellitus (DM) (36.7% and 24.7%). Also, these patients had higher values of body mass index (BMI) and NT-proBNP concentration (2317 [1305;9092] vs. 1691 [709;3856] pg/ml), and lower LV EF values (41.5 [29.0;54.5]% vs. 45.0 [34.0;54.0]%), respectively. The most severe course of CHF and the greatest changes in laboratory tests associated with ID and anemia were observed in patients with ID determined by two criteria. Patients in this group were older, with a higher BMI, more frequent presence of atrial fibrillation, and higher NT-proBNP (4182 [1854;9341] pg/ml). CONCLUSION: Patients with isolated low ferritin are characterized by less severe clinical and functional impairment compared to patients with low TSAT or Fe. At the same time, patients with ferritin higher than 300 µg/l and low TSAT and/or Fe were characterized by very severe CHF and a low functional status, although this may not be related with ID. Thus, the use of the ferritin-based criteria of ID may lead to overdiagnosis of ID in some patients and, at the same time, miss some of the most "severe" patients who likely require the ID correction. Patients with ID who show a decrease in all three parameters are likely to benefit most from Fe supplementation. It is advisable to perform additional studies on the effect of Fe supplements on the course and prognosis of the disease in this cohort of patients.

Anti-Inflammatory Effect of Technologically Processed Antibodies to the Molecules of the Major Histocompatibility Complex in a Model of Acute Inflammation In Vivo.

The anti-inflammatory effect of technologically processed antibodies (TPA) to immune targets (MHC I and MHC II) was assessed in the carrageenan-induced rat paw edema model. The parameters "increase in edema" and "suppression of edema" significantly decreased (p<0.05) against the background of treatment with TPA and the reference drug indomethacin compared to the placebo group. The tested TPA produced an anti-inflammatory effect.

Hypolypidemic Activity of L-Rhamnopyranosyl-6-O-Methyl-D-Galacturonan, a Polysaccharide Isolated from Birch Leaves (Betula pendula L.).

In male Syrian hamsters fed a synthetic high-fat diet enriched with cholesterol (0.3%), administration of a polysaccharide from birch leaves L-rhamnopyranosyl-6-O-methyl-D-galacturonan (3 g/100 g of diet) resulted in a decrease in total cholesterol levels, mainly due to the LDL fraction, triglycerides, and bile acids in blood serum; the content of triglycerides and cholesterol in the liver also decreased, while excretion of bile acids with feces increased. Thus, the lipid-lowering effect of L-rhamnopyranosyl-6-O-methyl-D-galacturonan is related to its ability to bind bile acids in the intestine and interrupt their enterohepatic circulation.

Prevention of the Genotoxic Effects of Doxorubicin with Anthocyanin-Containing Complex from Sorbus aucuparia L. Fruit.

We studied the effect of an anthocyanin-containing complex from the fruits of S. aucuparia L. on doxorubicin-induced genotoxicity in bone marrow cells of C57BL/6 mice. The complex reduced the genotoxic effect doxorubicin in metaphase plates of bone marrow cells in 24, 48 h, and 10 days after the administration of the cytostatic. The mean number of single fragments and the fraction of cells with gaps and aberrant metaphases also decreased.

Female and Male Phenotypes of Iron Deficiency in CHF. Additional analysis of the «The Prevalence of Iron Deficiency in Patients With Chronic Heart Failure in the Russian Federation (J-CHF-RF)¼ study.

Aim    To evaluate the incidence of iron deficiency (ID) in men and women with chronic heart failure (CHF) and to compare clinical and functional indexes in patient with and without ID depending on the gender.Material and methods    An additional analysis of the study "Prevalence of Iron Deficiency in Patients With Chronic Heart Failure in the Russian Federation (ID-CHF-RF)" was performed. The study included 498 (198 women, 300 men) patients with CHF, in whom, in addition to iron metabolism, the quality of life and exercise tolerance (ET) were studied. 97 % of patients were enrolled during their stay in a hospital. ID was defined in consistency with the European Society of Cardiology (ESC) Guidelines. Also, and additional analysis was performed according to ID criteria validated by the morphological picture of the bone marrow.Results    ID was detected in 174 (87.9 %) women and 239 (79.8 %) men (p=0.028) according to the ESC criteria, and in 154 (77.8 %) women and 217 (72.3 %) men (p=0.208) according to the criteria validated by the morphological picture of the bone marrow. Men with ID were older and had more severe CHF. They more frequently had HF functional class (FC) III and IV (63.4 % vs. 43.3 % in men without ID); higher concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower ET. HF FC III increased the probability of ID presence 3.4 times (p=0.02) and the probability of HF FC IV 13.7 times (p=0.003). This clinical picture was characteristic of men when either method of determining ID was used. In women, ID was not associated with more severe CHF.Conclusion    Based on the presented analysis, it is possible to characterize the male and female ID phenotypes. The male ID phenotype is associated with more severe CHF, low ET, and poor quality of life. In females of the study cohort, ID was not associated with either the severity of CHF or with ET.

Erythropoiesis-Stimulating Properties of Anthocyanin-Containing Complex from Sorbus aucuparia L. in Cytostatic Anemic Syndrome in Mice with Lewis Lung Carcinoma.

The results of studying the effect of the anthocyanin-containing complex from Sorbus aucuparia L. on the main indicators of erythropoiesis in the blood and bone marrow of mice with Lewis lung carcinoma against the background of doxorubicin administration were presented. It was shown that administration of the anthocyanin-containing complex from S. aucuparia L. to animals with the tumor prevented the development of anemic syndrome by promoting regeneration of the erythropoiesis after its depletion caused by single administration of a cytostatic agent.

Antinociceptive Effect of Ethowurtzine, a New Compound from the Class of Hexaazaizowurzitane.

Analysis of specific pharmacological activity evaluated high antinociceptive efficacy of the first synthesized compound 10-di(ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane (ethowurtzine) in models of somatogenic pain of different genesis (thermal, visceral pain, mechanical compression of paw).The new molecule from the class of hexaazaisowurtzitane effectively blocks nociceptive reactions at the supraspinal and peripheral levels of pain sensitivity organization. The effect of ethowurtzine was comparable or exceeded the effect of tramadol. The obtained results prove the possibility of creating new pharmacologically active molecules based on the high-energy substance hexaazaisowurtzitane.

Restructuring of the Optokinetic Reflex during Metamorphosis in Pelobates fuscus Laur.

The restructuring of the gaze stabilization system in Pelobates fuscus was investigated by quantitative analysis of the optomotor response using video imaging. Gaze stabilization is an important component in the system of neural mechanisms of visual depth perception. It was shown that the optomotor response in aquatic tadpoles of P. fuscus is similar to that of fish (movement of the animal in the direction of the visual background movement and eye nystagmus consisting of a fast and a slow phase). During metamorphosis (transition from the aquatic to the terrestrial lifestyle), froglets of P. fuscus responded to the movement of the visual background by eyes and head movements. One year after metamorphosis, P. fuscus responded to movement of the visual background as adult Anura: only by head movements (a slow and a fast phase), while eye movements were absent. Possible causes of the loss of active eye movements by Anura amphibians in the process of evolution are discussed.

[Iron deficiency in Russia heart failure patients. Observational cross-sectional multicenter study].

Aim    To evaluate the prevalence of iron deficiency (ID) in Russian patients with heart failure (HF).Material and methods    Iron metabolism variables were studied in 498 (198 women, 300 men) patients with HF. Data were evaluated at admission for HF (97 %) or during an outpatient visit (3 %). ID was determined according to the European Society of Cardiology Guidelines.Results    83.1 % of patients had ID; only 43.5 % of patients with ID had anemia. Patients with ID were older: 70.0 [63.0;79.0] vs. 66.0 years [57.0;75.2] (p=0.009). The number of patients with ID increased in parallel with the increase in HF functional class (FC). Among patients with ID, fewer people were past or current alcohol users (p=0.002), and a greater number of patients had atrial fibrillation (60.1 vs. 45.2 %, p=0.016). A multiple logistic regression showed that more severe HF (HF FC) was associated with a higher incidence of ID detection, whereas past alcohol use was associated with less pronounced ID. An increase in N-terminal pro-brain natriuretic peptide (NT-proBNP) by 100 pg/ml was associated with an increased likelihood of ID (odds ratio, 1.006, 95 % confidence interval: 1.002-1.011, p=0.0152).Conclusion    The incidence rate of HF patients is high in the Russian Federation (83.1 %). Only 43.5 % of these patients had anemia. The prevalence of ID in the study population increased with increases in HF FC and NT-proBNP.

Erythropoesis-Stimulating Properties of Anthocyanin-Containing Complexes in Cytostatic Anemic Syndrome.

We studied the effect of an anthocyanin-containing complex from Sorbus aucuparia L. on the main indicators of erythropoiesis in the blood and bone marrow of mice against the background of doxorubicin treatment. It was shown that administration of an anthocyanincontaining complex from S. aucuparia L. prevented the development of anemic syndrome by stimulating regeneration of the erythroid lineage of hematopoiesis after its devastation by single administration of the cytostatic.

[Study of the structure and microflora of urethral tissues in urethral pain syndrome].

Urethral pain syndrome (UPS) is characterized by the occurrence of persistent or recurrent pain in the urethra in the absence of a confirmed infection and other obvious local pathological changes. The study of its pathogenetic aspects is important first of all for understanding the causes of the disease, to prescribe effective treatment, specific recommendations for the prevention and treatment of this disease are also absent. This paper presents the advanced experience of our research group on the study of the urethral state by the in vivo cross-polarization optical coherence tomography (CP OCT) method, and also the results of the microbiota analysis in the urethral tissues. The purpose of the study is to search for the risk factors for UPS and the character of changes in the urethral tissues, using the data of: 1) concomitant pathology, 2) structural changes in the urethral wall in UPS in comparison with chronic cystitis of bacterial etiology 3) studying the microbiota of urethral tissues. MATERIALS AND METHODS: The condition of the urethra was studied in 109 patients: 55 of them with UPS (group "US"), without clinical manifestations of inflammation; 41 - with chronic inflammation of the lower urinary tract of various origins (group "Inf"); in 14 patients with stones of the upper urinary tract without pyelonephritis, the urethra was taken as the norm (group "N"). All performed a clinical minimum of studies, also cystoscopy with the study of the bladder triangle, the neck of the bladder and the urethra by the method of in vivo tissue imaging - CP OCT. The device "OCT-1300U" with wavelength of 1300 nm is used. To determine the possible role of UPS disease background, the analysis of concomitant pathology preceding the development of UPS was performed. To analyze the relationship of changes in the urethral tissues with the composition of its microbiota, a PCR study of biopsies from the proximal segment of the urethra was performed in 13 patients with UPS. RESULTS: Qualitative comparison of the thickness and character of the OCT signal of the urethral wall layers observed using CP OCT in the studied groups of patients allowed us to establish that the state of the epithelium and connective tissue structures of the mucous membrane in patients with UPS is not the norm, changes are similar to those in chronic inflammation. Changes in the character of the OCT signal were recorded in all parts of the urethra, but in the middle third they are most pronounced and most critical. In UPS, there is a brightly pronounced reorganization of the connective tissue stroma components. Pronounced fibrosis of subepithelial structures (increased signal brightness in the cross-channel compared to the norm) with their thickening was recorded in 48.2% of cases, and thinning/lack of visualization of the epithelial layer was detected in 20.5%, and in chronic inflammation 55.5% and 40.6% of cases, respectively. According to the results of PCR, only one patient had significant total bacterial contamination of the biopsy (TB=104.7). In all other cases, the total bacterial mass of the biopsies was at the level of negative control. CONCLUSIONS: In patients with UPS, the presence of several concomitant, often chronic, diseases was revealed, which may be a premorbid background and one of the risk factors for the occurrence and maintenance of UPS. Pilot PCR studies of biopsies from the proximal segment of the urethra indicate that low values of bacterial contamination in the majority of patients with UPS do not exclude the possible role of bacteria in the development of the disease in some patients. The CP OCT method used in this study is currently the only one in vivo method of visualization of the urethral mucosa, which provides real-time images of structural changes in the epithelial (atrophy or hyperplasia) and connective tissue (active or latent inflammation with cellular infiltration or fibrosis) layers of the urethra, allowing better understanding of the pathogenesis of the disease and monitoring of therapy.

[Social health of the citizens of the States of the Eurasian Economic Union in the context of the COVID-19 pandemic].

Based on the results of sociological research, the article considers the consequences of the pandemic on the social health of citizens of the Eurasian Economic Union (EAEU) states. A comparative analysis is carried out between groups of labor migrants from the EAEU states in Moscow and Russian citizens of the same age. The paper discusses the measures taken by the EАEU, for the maintenance of social health in terms of the COVID-19 pandemic crisis.

[The social health of citizen of the Eurasian Economic Union in conditions of COVID-19 pandemic].

The article considers, on the basis of results of sociological research, consequences of pandemic impact on social health of citizens of the Eurasian Economic Union states. The comparative analysis was applied to two groups of labor migrants from the EAEU states in Moscow and Russian citizens of the same age. The measures taken by the EАEU to maintain population social health in conditions of COVID-19 pandemic are considered.

Semaphorin-3A Inhibits Proliferation, but Does Not Affect Apoptosis of Mouse Thymocytes In Vitro.

Neuronal factor semaphorin-3A is viewed as immune suppressant of peripheral T lymphocytes, but it can also negatively affect activity of the thymus, the central organ of the immune system. The study examined the effects of this factor on proliferative activity and apoptosis of mouse thymocytes in vitro. Semaphorin-3A inhibited spontaneous and mitogen-stimulated proliferative activity of thymocytes producing no effect on the development of apoptosis in these cells. Flow cytometry revealed expression of semaphorin-3A receptors neuropilin-1 and plexin-A1 on thymocyte membranes. Approximately 13% thymocytes simultaneously expressed both receptors. The study suggests that semaphorin-3A, which is constitutively synthesized in thymic stroma in vivo, can play the role of inhibitory factor during thymocyte maturation.

[Thrombosis of the inferior vena cava and right portions of the heart in a relapsing retroperitoneal malignant tumour]. / Tromboz nizhnei poloi veny i pravykh otdelov serdtsa pri retsidivnoi zabriushinnoi zlokachestvennoi opukholi.

Presented herein is a clinical case report regarding successful treatment of a female patient with a relapsing malignant retroperitoneal tumour complicated by disseminated thrombosis of the inferior vena cava, right atrium and right ventricle of the heart. A relapse of the malignant uterine tumour had developed 3 years after the primary operation and was represented by a large-size mass ingrowing into the infrarenal segment of the inferior vena cava, aorta, as well as jejunum. Additional examination revealed the presence of a tumorous thrombus extending from the primary tumorous node in the lumen of the inferior vena cava to the right atrium and ventricle. The procedures performed consisted in removal of the tumour with resection of the inferior vena cava, aorta, and jejunum, followed by thrombectomy from the right portions of the heart under extracorporeal circulation. The postoperative period turned out uneventful, with no complications observed. The woman was discharged on POD 15. Twelve-month postoperative follow up revealed neither relapse nor progression of the disease. Currently, the patient continues undergoing specific treatment (second-line chemotherapy). Also discussed in the article are current challenges concerning both the classification of tumour thrombosis of the inferior vena cava in retroperitoneal sarcomas, and the choice of optimal strategy and policy of treatment.

Semaphorin 3A Negatively Affects Proliferation of Mouse Thymus Epithelial Cells In Vitro.

We studied effects of semaphorin 3A, keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and their combinations on the proliferative activity of cortical (cTEC1-2) and medullary (mTEC3-10) thymus epithelium cell lines. Semaphorin 3A inhibited the proliferative activity of epithelial cells, while HGF and KGF, in contrast, exerted a stimulating effect. The effect of KGF and semaphorin 3A on different cell lines depended on the expression of receptors for these two factors. When the combination of two factors was used, semaphorin 3A was able to neutralize the stimulating effect of HGF and KGF. It can be assumed that semaphorin 3A synthesized in the thymus stroma, can act as a functional antagonist of HGF and KGF and have an inhibitory effect when these drugs are administered into the body for the therapeutic purpose of restoring thymus functions.

Analgesic Activity of Hexaazaisowurtzitane Derivatives.

Pronounced analgesic activity of the innovative compound 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo[5,5,0,03, 11,05, 9] dodecane (thiowurtzine) was observed in the thermal nociceptive hot plate test and in the acute visceral and somatic deep pain model (acetic acid writhing test). In these experimental models, naloxone-sensitive thiowurtzine-induced analgesia was revealed. The absence of tropism to peripheral opioid receptors in the acetic acid writhing test was demonstrated using naloxone methiodide. Course administration of low-toxic thiowurtzine in effective doses was not associated with ulcerogenic damage to the gastric mucosa in experimental animals.

Mitochondria with Morphology Characteristic for Alzheimer's Disease Patients Are Found in the Brain of OXYS Rats.

Growing evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of sporadic Alzheimer's disease (AD). One of the key contributors to various aspects of AD pathogenesis, along with metabolic dysfunction, is mitochondrial dynamics, involving balance between fusion and fission, which regulates mitochondrial number and morphology in response to changes in cellular energy demand. Recently, Zhang et al. ((2016) Sci. Rep., 6, 18725) described a previously unknown mitochondrial phenotype manifesting as elongated chain-linked mitochondria termed "mitochondria-on-a-string" (MOAS) in brain tissue from AD patients and mouse models of AD. The authors associated this phenotype with fission arrest, but implications of MOAS formation in AD pathogenesis remain to be understood. Here we analyze the presence and number of MOAS in the brain of OXYS rats simulating key signs of sporadic AD. Using electron microscopy, we found MOAS in OXYS prefrontal cortex neuropil in all stages of AD-like pathology, including manifestation (5-month-old rats) and progression (12-18-month-old rats). The most pronounced elevation of MOAS content (8-fold) in OXYS rats compared to Wistar controls was found at the preclinical stage (20 days) on the background of decreased numbers of non-MOAS elongated mitochondria. From the age of 20 days through 18 months, the percentage of MOAS-containing neuronal processes increased from 1.7 to 8.3% in Wistar and from 13.9 to 16% in OXYS rats. Our results support the importance of the disruption of mitochondrial dynamics in AD pathogenesis and corroborate the existence of a causal link between impaired mitochondrial dynamics and formation of the distinctive phenotype of "mitochondria-on-a-sting".

Inactivation of M111 Protein Gene Modifies Streptococcus Pyogenes Interactions with Mouse Macrophages In Vitro.

Immunomodulatory properties of S. pyogenes protein M111 were studied on the model of Gurov strain and its isogenic mutant not expressing M protein. Mouse resident peritoneal macrophages were incubated with bacteria and generation of nitroxide and superoxide anions and production of IL-6, IL-10, and IL-17 were evaluated. Protein M111 modified macrophage response: it exhibited antiphagocytic activity, prevented ROS formation, and stimulated the production of anti-inflammatory cytokine IL-10. The results suggested that this protein could serve in the bacteria as a factor suppressing the host defense forces and promoting the realization of the strategy beneficial for pathogens - escape from the host immune defense.

[The value of optical coherence tomography and morphometry in evaluating the peripancreatic adipose tissue in infected pancreatic necrosis]. / Znachenie opticheskoi kogerentnoi tomografii i morfometrii dlia otsenki sostoianiia parapankreaticheskoi zhirovoi kletchatki pri infitsirovannom pankreonekroze.

OBJECTIVE: To investigate the morphometric and optical coherence tomography (OCT) characteristics of the microstructure of retroperitoneal peripancreatic adipose tissue during passive drainage and active perfusion-aspiration drainage for infected pancreatic necrosis. MATERIAL AND METHODS: The authors analyzed 74 samples of peripancreatic adipose tissue obtained from 37 patients with passive (Group 1) and active perfusion-aspiration drainage (Group 2) of a focus of peripancreatitis. The tissues were examined with OCT, then fixed in a formalin solution and underwent histological examination, including morphometric one. RESULTS: The examined groups showed qualitative and quantitative differences in the tissue microstructure. In Group 1 samples, the proportion (median (upper quartile; lower quartile)) of interlobular connective tissue was 5.6 (3.9; 6.1)%; and that of adipocytes was 44.6 (41.2; 51.6)%. Necrotic tissue occupied 46.2 (35.6; 56.1)% of the area of specimens. The OCT images of necrotic tissue displayed a preponderance of unstructured regions with a high signal level while the parenchymal areas showed a cellular structured pattern. In Group 2 samples, the proportion of interlobular connective tissue was 16.2 (11.4; 19.7)%, and that of adipocytes was 68.5 (59.7; 71.2)%. At the same time, Group 2 exhibited necrosis - 14.4 (11.5; 19.2%) that was 3.2 times less than in Group 1. The OCT images of Group 2 samples showed a preponderance of cellular structured regions characteristic of the parenchyma, with pronounced stromal elements, which corresponded to the histological pattern. CONCLUSION: Active perfusion-aspiration drainage of peripancreatic adipose tissue versus passive drainage is associated with a smaller proportion of necrotic tissue (14.4% versus 46.2%; p≤0.05) and a larger proportion of a stromal vascular component (16.2% vs. 5.6%; p≤0.05). OCT could qualitatively distinguish viable fat tissue parenchyma from necrotic areas, without specially preparing the samples, which was confirmed by histomorphometric results.