Rustam S. Khapaev

Impaired intrarenal hemodynamics is one of the links in the pathogenesis of chronic kidney disease in type 2 diabetes (T2D); correction of these disorders is the target of drugs with nephroprotective activity, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors. The aim of our study was to evaluate the effect of the SGLT2 inhibitor empagliflozin on intrarenal blood flow parameters in patients with T2D. Material and methods . In an open prospective cohort singlecenter study, clinical and laboratory data were monitored before the start of treatment, on the 7th, 28th, 90th, and 180th day of taking empagliflozin 10 mg/day. The study of renal blood flow parameters was carried out using Doppler ultrasonography, peak systolic (PSV), end-diastolic, and mean velocity (MV) of blood flow, as well as resistance index (RI) of intrarenal arteries were assessed. Results and discussion . Forty patients with T2D and chronic kidney disease, chronic heart failure and/or atherosclerotic cardiovascular disease were included, 17 men and 23 women, aged 43 to 76 years. In the arteries of the cortex, on the 90th day of empagliflozin administration, a decrease in PVR and MV was observed compared to the period before the start of treatment (p < 0.001 and p = 0.004, respectively). This dynamics was maintained on the 180th day (p < 0.001). The lowest values of RI in the arteries of the renal cortex were observed on the 180th day (all p < 0.01 compared to the periods before treatment, on the 7th and 28th days of empagliflozin administration). IR of blood flow in the medulla decreased from the 7th to the 90th day (p = 0.003). The revealed changes in intrarenal hemodynamics were associated with the dynamics of serum creatinine and glycated hemoglobin A1c content, as well as of albuminuria. Conclusions . In patients with T2D, a decrease in intravascular resistance and blood flow rates in the kidney is observed on the 90–180th day of empagliflozin use. Changes in intrarenal blood flow are associated with the hemodynamic and metabolic response to empagliflozin.

Progression of lymphedema as pathologic condition characterized first of all by accumulation of high-protein fluid in the interstitial space. The another component of the affected body region volume is adipose tissue hypertrophy, and fibrosis. On the other hand, obesity may be one of the causes of lymphedema. In particular, obesity is a risk factor for increased upper extremity volume secondary to lymphedema after breast cancer treatment. In addition, it is believed that due to excessive amounts of adipose tissue, lymphatic vessel stasis occurs, which serves as a cause of impaired lymphatic transport from the limb. Some experimental studies testifies about lymphatic fluid stasis gradients regulate the expression of some proteins and the expression of these molecules correlates with fat deposition in response to lymphatic fluid stasis. The aim of this study is to search for genes involved in the pathogenesis of adipogenesis as well as lymphedema using bioinformatic approaches related to the analysis of molecular genetic networks. For this one the association gene network of lymphedema and adipogenesis was reconstructed using ANDSystem. The intersection of these two networks included 7 genes and 22 proteins simultaneously involved in the development of both lymphedema and adipogenesis. Result of the bioinformatics analysis, it was shown that most of the proteins involved in the process of adipogenesis are significantly associated with the development of lymphedema.

Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

The aim of the study: to determine the association of various Hp phenotypes (Hp1-1, Hp1-2 and Hp2-2) with the severity of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2D). Materials and Methods: One hundred and thirty-six patients (84 women and 52 men) with T2D were examined. Assessment of diabetes complications, comorbidities and metabolic parameters was performed. All patients underwent duplex ultrasound of the carotid arteries with measurement of intimamedia thickness (IMT). Hp variants (Hpl-l, Hpl-2 and Hp2-2) were determined by ELISA. Results: Hp1-1 variant was detected in 8 (14%) patients, Hp1-2 was revealed in 23 (39%), and Hp2-2 in 28 individuals (47%). Patients with different Hp phenotypes demonstrated no differences in age, duration of T2D, parameters of lipid metabolism and glycemic control. Carotid atherosclerosis was detected in 60% of patients with Hp1-1, 75.9% of those with Hp1-2 and in 68.3% of patients with Hp2-2. IMT values in the right carotid common artery (CCA) were the smallest in the Hp1-1 group (0.9 (0.7; 1.6) mm vs. 1.6 (0.8; 2.7) and 1.2 (0.8; 2.2) mm). The IMT of the left CCA showed similar trends (0.9 (0.7; 1.5) mm vs. 1.5 (0.9; 2.0) and 1.2 (0.8; 2.2) mm, p =0.09). The incidence of carotid artery stenosis in the study groups was 26.7%,39.7% and 31.7%, respectively. Conclusion: in T2D patients the Hp1-1 haptoglobin phenotype may be a protective factor against carotid atherosclerosis.

The development of the excess subcutaneous fat and fibrosis is usual for the late stages of lymphedema. Some experimental investigations confirm this by morphological findings on the mouse-model lymph-fluid stasis. On the other hand, the obesity poses deleterious consequences on every organ system, particularly on the lymphatic network. Interactions between adipogenesis, fibrosis and fluid exchange are very interesting for mathematical modelling of the lymphatic flow disturbance. The mathematical modeling of the interaction between adipogenesis and fibrosis is based on the idea of using the Kahn-Hilliard equation, since experimental results show that adipogenesis is a mechanism generated predominantly by diffusion. Application of the Kahn-Hilliard equations to the phenomenological model of adipogenesis allows us to calculate the fractions of lipid droplets and their amounts.

BACKGROUND: Carotid atherosclerosis (CA) and lower extremity peripheral artery disease (PAD) is a common and potentially life-threatening comorbidity in diabetes.AIM: to determine risk factors and biomarkers of the association of CA and PAD in patients with type 2 diabetes.MATERIALS AND METHODS: A single-center cross-sectional comparative study was carried out. Three hundred ninety one patients with type 2 diabetes were included. Duplex ultrasound of carotid and low limb arteries, screening/monitoring of diabetic complications and associated diseases, and assessment of glycemic control, biochemical and coagulation parameters were performed. Factors involved in vascular wall remodeling, including calponin-1, relaxin, L-citrulline, matrix metalloproteinase-2 and -3, were measured in blood serum by ELISA.RESULTS: The signs of CA and PAD were observed in 330 and 187 patients respectively. In 178 patients, both CA and PAD were revealed. The risk of combined involvement of carotid and lower extremity arteries was higher in patients with diabetic retinopathy (OR=2.57, pCONCLUSION: In subjects with type 2 diabetes, carotid and lower extremity atherosclerotic disease is associated with age, diabetes duration, abdominal obesity, microvascular and macrovascular complications, glucose variability, and high serum levels of L-citrulline.

Among the reasons of primary lymphedema development, a certain role belongs to genetic factors. The specific molecular products participate in remodeling of blood and lymphatic vascular networks. Vascular endothelial growth factors (VEGFs) are key regulators of endothelial functions of the cells, which are responsible for lympho- and vasculogenesis. Moreover, matrix metalloproteinases (ММР) may act as regulators of both lymphangiogenesis, and angiogenesis. Since the regulatory regions of VEGFA gene, as well as of ММР genes are polymorphic, one may suggest, that their different expression level, determined by these polymorphisms, could be associated with development of swellings typical for lymphedema.We have analyzed gene polymorphisms in two regulatory regions of vascular endothelial growth factor-A VEGF-A (rs 699947 and rs 3025039), and matrix metalloproteinase genes MMP2 (rs 2438650), MMP3 (rs 3025058), MMP9 (rs 3918242), and their combinations in the patients with primary lymphedema.A group of patients with primary lymphedema included 72 subjects (55 women and 17 men) at the age of 18 to 81 years. Control group included 526 inhabitants of Novosibirsk (153 men, 373 women) without chronic diseases, comparable for age with lymphedema patients. We have performed typing of regulatory regions in VEGF (rs 699947, rs 3025039), ММР2 (rs 2438650), ММР3 (rs 3025058), ММР9 genes (rs 3918242). Fifteen complex genotypes have been revealed that were positively associated with disease. Analysis of the gene network topology has outlined the main intergenic interactions upon primary lymphedema development. MMP2 -1306 CC, MMP9 -1562CC and VEGF +936CC arrange the basic knots in the gene network (53% of total interactions). A number of significantly different complex genotypes was revealed at patients with primary lymphedema with normal body mass index (BMI < 25) and obesity (BMI < 30). Hence, frequency of complex genotype VEGF +936 CC: MMP3 -1171 5А6А:MMP9 -1562 CC in the patients with obesity is increased more 5.5-fold compared to the patients with normal BMI.The data obtained may presume a certain value of the analyzed gene polymorphisms in pathogenesis of primary lymphedema. Topological analysis of gene networks allows to study the structural and functional organization of gene-gene interactions for development of approaches to individyal preventive maintenance and therapy of the disease.

The basic principles of an Doppler ultrasound of the blood-vascular system are described. The methods possibilities and restrictions are considered. The main quantitative indices and their practical importance are discussed.