Sialic acid as the potential link between lipid metabolism and inflammation in the pathogenesis of atherosclerosis.

In the modern world, cardiovascular diseases have a special place among the most common causes of death. Naturally, this widespread problem cannot escape the attention of scientists and researchers. One of the main conditions preceding the development of fatal cardiovascular diseases is atherosclerosis. Despite extensive research into its pathogenesis and possible prevention and treatment strategies, many gaps remain in our understanding of this disease. For example, the concept of multiple low-density lipoprotein modifications was recently stated, in which desialylation is of special importance. Apart from this, sialic acids are known to be important contributors to processes such as endothelial dysfunction and inflammation, which in turn are major components of atherogenesis. In this review, we have collected information on sialic acid metabolism, analyzed various aspects of its implication in atherosclerosis at different stages, and provided an overview of the role of particular groups of enzymes responsible for sialic acid metabolism in the context of atherosclerosis.

Radiomics in Determining Tumor-to-Normal Brain SUV Ratio Based on 11C-Methionine PET/CT in Glioblastoma.

Modern methodology of PET/CT quantitative analysis in patients with glioblastomas is not strictly standardized in clinic settings and does not exclude the influence of the human factor. Methods of radiomics may facilitate unification, and improve objectivity and efficiency of the medical image analysis. The aim of the study is to evaluate the potential of radiomics in the analysis of PET/CT glioblastoma images identifying the relationship between the radiomic features and the 11С-methionine tumor-to-normal brain uptake ratio (TNR) determined by an expert in routine. Materials and Methods: PET/CT data (2018-2020) from 40 patients (average age was 55±12 years; 77.5% were males) with a histologically confirmed diagnosis of "glioblastoma" were included in the analysis. TNR was calculated as a ratio of the standardized uptake value of 11C-methionine measured in the tumor and intact tissue. Calculation of radiomic features for each PET was performed in the specified volumetric region of interest, capturing the tumor with the surrounding tissues. The relationship between TNR and the radiomic features was determined using the linear regression model. Predictors were included in the model following correlation analysis and LASSO regularization. The experiment with machine learning was repeated 300 times, splitting the training (70%) and test (30%) subsets randomly. The model quality metrics and predictor significance obtained in 300 tests were summarized. Results: Of 412 PET/CT radiomic parameters significantly correlated with TNR (p<0.05), the regularization procedure left no more than 30 in each model (the median number of predictors was 9 [7; 13]). The experiment has demonstrated a non-random linear correlation (the Spearman correlation coefficient was 0.58 [0.43; 0.74]) between TNR and separate radiomic features, primarily fractal dimensions, characterizing the geometrical properties of the image. Conclusion: Radiomics enabled an objective determination of PET/CT image texture features reflecting the biological activity of glioblastomas. Despite the existing limitations in the application, the first results provide a good perspective of these methods in neurooncology.

Sialic acid as the potential link between lipid metabolism and inflammation in the pathogenesis of atherosclerosis

In the modern world, cardiovascular diseases have a special place among the most common causes of death. Naturally, this widespread problem cannot escape the attention of scientists and researchers. One of the main conditions preceding the development of fatal cardiovascular diseases is atherosclerosis. Despite extensive research into its pathogenesis and possible prevention and treatment strategies, many gaps remain in our understanding of this disease. For example, the concept of multiple low-density lipoprotein modifications was recently stated, in which desialylation is of special importance. Apart from this, sialic acids are known to be important contributors to processes such as endothelial dysfunction and inflammation, which in turn are major components of atherogenesis. In this review, we have collected information on sialic acid metabolism, analyzed various aspects of its implication in atherosclerosis at different stages, and provided an overview of the role of particular groups of enzymes responsible for sialic acid metabolism in the context of atherosclerosis.

[Radiological biomarkers of brain gliomas]. / Radiologicheskie biomarkery gliom golovnogo mozga.

The most important objective of modern neuroimaging is comparison of data on genotype and phenotype of brain gliomas. Radiogenomics as a new branch of science is devoted to searching for such relationships based on MRI and PET/CT parameters. The 2021 WHO classification of tumors of the central nervous system poses the most important tasks for physicians in assessment of biological behavior of tumors and their response to combined treatment. The review demonstrates the possibilities and prospects of preoperative MRI and PET/CT with amino acids in assessing the genetic profile of brain gliomas.

Molecular Pathogenesis and the Possible Role of Mitochondrial Heteroplasmy in Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is a life-threatening condition associated with high mortality, in which the aortic wall is deformed due to congenital or age-associated pathological changes. The mechanisms of TAA development remain to be studied in detail, and are the subject of active research. In this review, we describe the morphological changes of the aortic wall in TAA. We outline the genetic disorders associated with aortic enlargement and discuss the potential role of mitochondrial pathology, in particular mitochondrial DNA heteroplasmy, in the disease pathogenesis.

[Dynamic11C-methionine PET/CT in differential diagnosis of brain gliomas]. / Dinamicheskaya PET/KT s 11S-metioninom v differentsial'noi diagnostike glial'nykh opukholei golovnogo mozga.

OBJECTIVE: To evaluate the possibilities of dynamic preoperative 11C-methionine (MET) PET/CT in differential diagnosis of various types of brain gliomas in adults. MATERIAL AND METHODS: The study included 74 patients aged 48±14 years with supratentorial gliomas: Grade IV - glioblastoma (GB, n=33), Grade III - anaplastic oligodendroglioma (AOD, n=10) and anaplastic astrocytoma (AA, n=12), Grade II - diffuse astrocytoma (DA, n=13) and oligodendroglioma (OD, n=6). All patients underwent standard MRI and dynamic MET PET/CT within 20 minutes after intravenous injection of radiopharmaceutical. Then, we compared MRI and PET/CT data and comprehensively analyzed the early stages of time-activity curve using 2 parameters: the first pass peak (FPP) and the first peak of maximum uptake (Pmax). RESULTS: We have significantly distinguished high-grade tumors (GB and AA+AOD) and certain benign gliomas (DA and OD) (p<0.05). AUC was over 0.7 and 0.8 for FPP and Pmax in differential diagnosis of various gliomas, respectively. We found that difficulties in differential diagnosis of gliomas arise mainly if oligodendrogliomas are included in the control group. CONCLUSION: Dynamic PET/CT with analysis of FPP and Pmax increases specificity of differential diagnosis of various gliomas compared to standard static imaging. These data are valuable for choice of optimal treatment strategy, as well as fundamental research of metabolic processes and vascularization of various tumors.

[Intracellular pH measurement in glioblastoma cells: the possibilities of phosphorus-31 MR spectroscopy]. / Izmerenie vnutrikletochnogo vodorodnogo pokazatelya glioblastom: vozmozhnosti fosfornoi magnitno-rezonansnoi spektroskopii.

OBJECTIVE: To analyze intracellular pH measurement with phosphorus-31 MR spectroscopy in glioblastoma cells and to compare these data with intracellular pH in healthy volunteers. MATERIAL AND METHODS: There were 10 patients aged 41 - 67 years with supratentorial glioblastomas. Intracellular pH in glioblastoma cells was compared with pH in healthy persons. RESULTS: We found a tendency to increased intracellular pH in glioblastoma cells in comparison with pH in intact brain tissue. CONCLUSION: Intracellular pH in brain tissue can be used as a potential marker of early abnormalities which could not be detected by conventional MRI. Moreover, these data may be valuable to estimate the efficacy of chemotherapy. The study was supported by Russian Science Foundation (grant No. 18-15-00337).

[Positron emission tomography with 11C-methionine in primary brain tumor diagnosis]. / Primenenie PET-KT s 11C-metioninom v pervichnoi diagnostike gliom.

OBJECTIVE: To investigate the variations in 11C-methionine uptake in the intact brain tissue and in glial brain tumors of different types. MATERIAL AND METHODS: Forty patients (21 men, 19 women) with gliomas, Grade I-IV, underwent 11C-methionine PET-CT and contrast-enhanced MRI. Standardized uptake value (SUV), tumor-to-normal (T/N) ratios and tumor volume were analyzed. RESULTS: The high inter-subject variability was detected in the intact brain tissue (SUV in the frontal lobe (FL) varies from 0.47 to 1.73). Amino acid metabolism was more active in women than in men (FL SUV 1.32±0.22 and 1.05±0.24, respectively). T/N ratio better differentiates gliomas by the degree of anaplasia compared to SUV. Gliomas of Grade III (T/N=2.64±0.98) were significantly different (p<0.05) from those of Grade IV (T/N=3.83±0.75). The lowest level of methionine uptake was detected in diffuse astrocytomas (T/N=1.52±0.57), which was lower than with anaplastic astrocytomas (T/N=2.34±0.77, p<0.05). CONCLUSIONS: 11C-methionine PET-CT was informative in the high/low degree of malignancy differentiation (T/N 1.66±0.71 for Grade I-II and 3.18±1.06 for Grade III-IV, p<0.05). The method was also useful in separating astrocytomas of Grade II and III. The considerable variation of SUV in the intact brain tissue as well as the difference in uptake between selected areas of the brain were revealed.

Experimental Study of the Biodistribution of New Bone-Seeking Compounds Based on Phosphonic Acids and Gallium-68.

We investigate biodistribution of gallium-labeled hydroxyethylidenediphosphonic acid (68Ga-HEDP) and diethylenetriaminepentakis(methylenephosphonic acid) (68Ga-DTPMP) in intact Wistar rats. It was shown that 68Ga-DTPMP accumulated mainly in the bone tissue providing high femur/blood and femur/muscle ratios and had high stability in vivo. In contrast, 68Ga-HEDP was characterized by low stability and high uptake of radioactivity in blood throughout the study. So 68Ga-DTPMP can be considered as a new prospective radiotracer in oncology for imaging bone tissue metastasis by positron emission tomography.

[Inflammatory infiltrates, vasa vasorum, and endothelial NO synthase in the wall of thoracic aortic aneurysm]. / Vospalitel'nye infil'traty, vasa vasorum i NO-sintaza éndoteliia v stenke anevrizmy grudnogo otdela aorty.

OBJECTIVE: To elucidate whether there is a relationship between inflammation of the wall of aortic aneurysm and the number of vasa vasorum in it. MATERIAL AND METHODS: The investigation material was aortic aneurysm wall segments obtained during surgery. Among the patients, there were 20 men and 5 women. The patients' age ranged from 33 to 69 years. The investigation used monoclonal antibodies to macrophages (CD68), T cells (CD3, CD4, and CD8) and antibodies to von Willebrand factor, endothelial NO synthase, and alpha smooth muscle actin. A morphometric study was conducted. RESULTS: Calculation of the number of vasa vasorum (including newly formed vessels) in the adventitia of aortic aneurysm revealed that there was a statistically significant difference between the number of vasa vasorum in patients with an active inflammatory response (Group 1) versus Group 2 patients with a moderate inflammatory process in the aneurysm wall (p≤0.05) and a statistically significant difference between Groups 1 and 3 (without inflammatory infiltrates) (p≤0.05). Endothelial vasa vasorum heterogeneity was found in case of an immune response to NO synthase. At the same time individual vasa vasorium did not contain NO synthase, this enzyme was identified in the endothelium in a number of nearby vessels. CONCLUSION: The increase in the number of vasa vasorum in the aneurysm wall in patients with abundant inflammatory infiltrates is due to the fact that some of the inflammatory cytokines of T-cells and macrophages also contribute to angiogenesis.

[Phosphorus (P) magnetic resonance spectroscopy for evaluation of brain tissue metabolism and measuring non-invasive pH. A study involving 23 volunteers. Part I]. / Fosfornaia (R) MR-spektroskopiia v otsenke énergeticheskogo metabolizma mozgovoi tkani i neinvazivnom izmerenii pH. Issledovanie 23 dobrovol'tsev. Chast' I.

Evaluation of brain metabolism is an important part in examination of brain lesions. Phosphorus magnetic resonance spectroscopy opens up great opportunities for studying the energy metabolism and allows noninvasive examination of metabolic processes occurring both in healthy and in pathologic brain tissue by obtaining a spectrum of phosphorus-containing metabolites involved in the turnover of cell membrane phospholipids. The technique presented in this paper was used to conduct 31P MR spectroscopy and to estimate the ratio between the peaks of the main metabolites and intracellular pH of the healthy brain tissue of 23 volunteers in the age group under 30 years old in clinical settings. Based on the recorded stable phosphorus spectra of metabolites of the healthy brain tissue, the value of intracellular pH (6.963±0.044) and the ratio of the main PME/PDE peaks (1.17±0.20) were calculated. The database was created to subsequently analyze the metabolic changes in brain tissue spectra in norm and in pathology, as well as the intracellular pH variations that have diagnostic and prognostic value.

[Gigantic aneurysm of the coronary artery]. / Gigantskaia anevrizma koronarnoi arterii.

The paper describes a clinical case of gigantic aneurysm of one of the coronary arteries. It considers the morphological and immunohistochemical characteristics of the wall of the blood vessel with the detected signs of coronaritis. The authors have determined that Kawasaki disease could be retrospectively diagnosed in early childhood.

[The heteroplasmy level of some mutations in gene MT-CYB among women with asymptomatic atherosclerosis].

Atherosclerosis is a polygenic socially significant disease whose risk factors include coronary heart disease, diabetes, hypertension, and myocardial infarction. According to the literature, mutations m.14846G>A (G34S), m.15762G>A (G339Q), m.15084G>A (W113Ter), and m.15059G>A (G190Ter) of cytochrome B gene (MT-CYB) are associated with mitochondrial myopathies, myoglobinuria, and exercise intolerance. Preliminary studies carried out by the authors made it possible to discover an association of certain mitochondrial genome mutations with atherosclerotic lesions of aortic intima in people who died as a result of an accident or sudden death. The most interesting seemed to be the data on the association of mutations m.14846G>A and m.15059G>A of the cytochrome B gene with lipofibrous aortic plaques, because these mutations affect the mitochondrial respiratory chain enzyme. Defects in the given chain may be the reason for the launch of pathogenic mechanisms in the human body. Owing to the fact that mutations in the mitochondrial genome are inherited by the maternal type, it was decided to analyze cytochrome B gene mutations in a sample of female volunteers from Moscow oblast. According to the findings, mutations m.14846G>A and m.15059G>A are highly significantly associated with atherosclerotic lesions of the carotid arteries: m.14846G>A is antiatherogenic and m.15059G>A is proatherogenic.

[Analysis of mitochondrial haplogroups in persons with subclinical atherosclerosis based on high-throughput mtDNA sequencing].

Genetic predisposition plays an important role among other risk factors in multifactorial socially significant diseases such as atherosclerosis and its clinical manifestations. This pilot study was aimed to identify the relationship between the type of mitochondrial haplogroup and the risk of subclinical atherosclerosis in humans. For accurate detection of mitochondrial haplogroups, high-throughput sequencing of the mitochondrial genome using the Roche 454 technology was carried out. The results have shown that in Russian population, the belonging to haplogroup H is associated with an increased risk of atherosclerosis, but belonging to haplogroups T and U--with reduced risk. The data obtained can be used to assess individual risk of atherosclerosis and for further studies on the role of mitochondrial genome mutations in the development of atherosclerosis and its clinical manifestations.

[Direct human DNA damage by unfavorable environmental and climatic factors].

AIM: To study the impact of simulated climatic conditions of the 2010 summer in Moscow on the telomere repeats of chromosomes in human blood cells. MATERIALS AND METHODS: The climatic conditions of July-August 2010 in Moscow were simulated at the Medical Technical Complex, Institute of Biomedical Problems, Russian Academy of Sciences. The relative length of the telomeric repeats of blood cell chromosomes from 6 apparently healthy volunteers was measured by quantitative real-time polymerase chain reaction. RESULTS: These conditions were ascertained to lead to a statistically significant decline in the length of telomere repeats in the terminal portions of chromosomes by 15%. CONCLUSION: Environmental changes and abnormal temperature rises may result in oxidative stress accompanied by telomere shortening, which can be, in turn, a factor of premature aging.

[Primary aorto-intestinal fistulas (review of the literature and description of clinical case reports)].

The article contains a review of the literature dedicated to a rare complication of an abdominal aortic aneurysm, i.e., an aortic-intestinal fistula, and a report of two clinical cases illustrating different tactical approaches to management of this pathology in the settings of a referral department.

[Prolongation of enoxaparin therapy to one month promotes recanalization of the occlusively thrombosed deep veins].

AIM: To compare effects of prolongation of the treatment with therapeutic doses of enoxaparin to 1 month on recanalization of occlusively thrombosed deep veins (OTDV) of the limbs with results of standard therapy with unfractionated heparin (UFH). Both treatments were followed by warfarin administration. MATERIAL AND METHODS: Thirty patients were selected from 111 patients with a history of deep vein thrombosis (DVT) and/or pulmonary artery embolism according to the following criteria: the presence of occlusive thrombosis of one deep vein minimum; the absence of DVT for 12 months of follow-up. Patients of group 1 (n = 15) received standard therapy (UFH for at least 5 days) with switch to warfarin. Patients of group 2 (n = 15) received therapeutic doses of enoxaparin (1 mg/kg each 12 hours) for 30 days minimum with switch to warfarin. Follow-up was 12 months. Ultrasonic duplex angioscanning of the limbs was made at baseline, 1, 3, 6 and 12 months after treatment start. RESULTS: After follow-up month 1, 3 and 6 number of patients with occlusive DVT was significantly less in group 2. All the patients given enoxaparin achieved recanalization of OTDV within 3 months of treatment. OTDV recanalization was not achieved in 20% patients of group 1 even 12 months after treatment start. CONCLUSION: Prolongation of enoxaparin treatment to 1 month followed by warfarin treatment is superior to standard UFH treatment followed by warfarin in providing recanalization of OTDV within 3 months of treatment. Moreover, this treatment predicts persistence of recanalization within 12 months of anticoagulant therapy.

[Hybrid operating room: a new horizon in cardiovascular surgery].

Creating hybrid operating rooms (OR) is a new stage of the development of present-day cardiovascular surgery, with the need for these operating suites having evolved resulting from rapid implementation of novel techniques of treating cardiovascular diseases, combining elements of «open¼ and endovascular surgery. Despite widespread interest in this problem, there are virtually no systematized works properly describing the specificity of designing and organization of the hybrid OR's work. The present work was aimed at compiling the literature data and sharing own experience gained in organization of the hybrid OR, designation of indispensable technical and organizational requirements for performing hybrid interventions, studying the basic problems related to designing and building such operating rooms, as well as organization and management of the personnel.

[Polymorphisms of genes CYP2C9 and VKORC1 in patients with venous thromboembolic complications in Moscow population: effects on stability of anticoagulant therapy and frequency of hemorrhage].

AIM: To investigate frequency of carriage of genetic polymorphisms CYP2C9 and VKORC1 in patients with venous thromboembolic complications (VTEC) in Moscow population given warfarin treatment and effects of this carriage on stability of anticoagulation and frequency of hemorrhagic complications (HC) in warfarin treatment. MATERIAL AND METHODS: The study included 111 patients with the history of deep vein thrombosis and/ or pulmonary artery thromboembolism. All the patients received non-fractionated or low-molecular heparin for at least 5 days, then warfarin (target INR 2.0-3.0). Warfarin dose was selected empirically. Gene CYP2C9 and VKORC1 polymorphisms were studied. HC were endpoints. RESULTS: Genotype CYP2C9*1/*1 (a "wild" type) was detected in 94 (84.7%) patients. Of other genotypes - heterozygotes CYP2C9*1/*2 (4.5%) and CYP2C9*1/*3 (10.8%). Genotyping by VKORC1 detected genotype GG (a wild type) in 42.3%, genotype GA--in 48.6%, genotype AA--in 9.1% patients. A mean warfarin dose, supporting an adequaite INR, was asspciated with both genotype CYP2C9 and VKORC1. Warfarin doses were highest in carriers of wile genotypes CYP2C9 and VKORC1 (6,9 and 8,8 mg/day), the lowest--in patients with genotypes CYP2C9*1/*3 and VKORC1 (4,5 and 4,0 mg/day). The carriers of polymorphisms CYP2C9*1/*3 and VKORC1 showed less stable anticoagulation vs carriers of allele variants CYP2C9*1/*1, CYP2C9*1/*2 and genotypes GG, GA VKORC1. An HC rate depended, as a rule, on carriage of genotypes CYP2C9*1/*3 and AA VKORC1. The highest risk of HC was associated with genotype CYP2C9*1/*3. The results of multifactorial regression analysis also indicated that carriage of genotype CYP2C9*1/*3, a female gender and the range of INR in warfarin treatment > or = 2,66 are independent predictors of HC in VTEC patients on warfarin treatment. CONCLUSION: Carriage of gene CYP2C9 and VKORC1 polymorphisms affects suppoting dose of warfarin and rate of hemorrhage in patients with VTEC in Moscow population. Frequency of HC is the highest in carriers of genotypes CYP2C9*1/*3 and AA VKORC1, they need minimal supporting dose of warfarin. Carriage of genotype CYP2C9*1/*3 in line with a female gender and instability of INR is an independent predictor of HC in VTEC patients in Moscow population on warfarin treatment.

[Thrombin-activated inhibitor of fibrinolysis and efficacy and safety of long-term warfarin treatment in patients with venous thromboembolic complications].

AIM: To study effects of thrombin-activated fibrinolysis inhibitor (TAFI) on efficacy and safety of long-term anti-coagulant treatment in patients with venous thromboembolic complications (VTEC). MATERIAL AND METHODS: A total of 111 patients with a history of an episode of deep vein thrombosis (DVT) and/or pulmonary artery thromboembolism (PATE) entered the study. All the patients received unfractionated or low-molecular heparin for at least 5 days than switch on warfarin (target values of INR 2.0-3.0). Baseline blood levels of TAFI were measured. The patients were followed up for 18 months. Recurrent (DVT/TAFI and hemorrhagic complications (HC) were endpoints. Also, frequency of complete lysis of deep vein thrombi was assessed after 12 months of treatment. RESULTS: A TAFI level varied from 50 to 217% (median 106%, interquartile rage 90-133%). TAFI concentration positively correlated with fibrinogen and thromb size. The patients were divided into two groups depending on TAFI content: group 1 patients had low TAFI (under 25th percentile; < 90%); patients of group 2 had high TAFI (above 25th percentile; > 90%). Group 1 patients were characterized by less stable anticoagulation. This association did not depend on genetic characteristics which determine sensitivity to warfarin (CYP2C9 and VKORC1). Low TAFI was associated with reduced risk of DVT for 18 months and higher probability of complete lysis of the thrombi after 12 months of anticoagulant therapy compared to VTEC patients with high TAFI. No differences were found by TAFI level in patients with HC and without HC, but in HC patients low TAFI was associated with spontaneous hemorrhages and bleeding in therapeutic INR values. CONCLUSION: The results of this pilot study evidence that a TAFI level can be one of the factors influencing efficacy and safety of long-term anticoagulant therapy in patients with VTEC on warfarin treatment.