High Average Gradient in a Laser-Gated Multistage Plasma Wakefield Accelerator.

Plasma wakefield accelerators driven by particle beams are capable of providing accelerating gradient several orders of magnitude higher than currently used radio-frequency technology, which could reduce the length of particle accelerators, with drastic influence on the development of future colliders at TeV energies and the minimization of x-ray free-electron lasers. Since interplasma components and distances are among the biggest contributors to the total accelerator length, the design of staged plasma accelerators is one of the most important outstanding questions in order to render this technology instrumental. Here, we present a novel concept to optimize interplasma distances in a staged beam-driven plasma accelerator by drive-beam coupling in the temporal domain and gating the accelerator via a femtosecond ionization laser.

[Pathogenic TSHR variants in children with thyroid dysgenesis].

BACKGROUND: Loss-of-function mutations in the TSH receptor gene (TSHR) (NP_000360.2) are the potential causes of thyroid dysgenesis in patients with congenital hypothyroidism. Heterozygous variants of the TSHR gene lead to partial resistance to TSH, homozygous and compound heterozygous variants have been shown to cause CH due to thyroid hypoplasia or TSH resistance. Recently more and more articles in this field have appeared in the international literature sources, while local publications are limited. The studies are necessary to understand the etiology, pathogenesis of the disease, to improve the management of these patients. AIM: To assess the frequency of incidence of pathogenic variants of the TSHR gene in children with CH due to thyroid dysgenesis. To study inheritance and phenotypic patterns of CH in families. MATERIALS AND METHODS: In this single-center interventional one-stage non-comparative study a group of CH patients was examined. The patients underwent neck ultrasound and radionuclide imaging. The examination was performed 14 days after hormone replacement therapy suspension or prior to its initiation. The structure of thyroid dysgenesis was estimated, genetic testing for mutations in the TSHR gene was performed using the NGS method. RESULTS: The study included 95 children with primary CH (75 girls; 20 boys). The patients' median age at the time of examination was 6.2 years [4.5; 8.9], the median level of neonatal TSH was 157.5 mU/l [60.9; 257.2]. Ectopic thyroid was found in 52% of children, aplasia in 36%, hypoplasia and hemiagenesis in 10% and 2%, respectively. In 5.4% of cases (in 5 out of 95 patients), different variants of the TSH gene were detected. Two children had heterozygous p.R450H and p.D487N variants in TSHR gene, two patients was homozygous for the p.S49Afs * 9 variant, one child had compound heterozygous variants (p.A485D and p.R450H). According to ultrasound imaging, all patients had thyroid hypoplasia of varying severity. Three children underwent thyroid scintigraphy, which revealed decreased 99mТc pertechnetate uptake (0.3-0.9%). CONCLUSION: In our study, the incidence of different variants in the TSHR gene in children with CH was 5.3%. Our analysis uncovered two previously undescribed variants. Genetic testing may be able to help with making the diagnosis, patient's management, and genetic counseling.

[Primary hyperparathyroidism in children].

BACKGROUND:  Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) with upper-normal or elevated blood calcium levels due to primary thyroid gland pathology. PHPT is a rare pathology in children, with a prevalence of 2-5:100,000 children according to the literature. Due to the non-specificity of clinical manifestations at onset (nausea, vomiting, abdominal pain, emotional lability), the disease may remain undiagnosed for a long time. AIM:  To study the features of the course and molecular genetic basis of primary hyperparathyroidism in children. MATERIALS AND METHODS:  Retrospective observational study of 49 patients diagnosed with primary hyperparathyroidism. All patients underwent a comprehensive laboratory-instrumental and molecular genetic study at the Institute of Pediatric Endocrinology, Endocrinology Research Center of Russia in the period 2014-2022. RESULTS:  The first clinical symptoms of PHPT were noted at the age of 13.8 years [10.6; 1 5.2], among which fatigue, headaches, dyspepsia, lower limb pain, and fractures were the most common. The age of diagnosis was 15.81 years [13.1; 16.8], all children were found to have high levels of PTH, total and ionized calcium, with hypophosphatemia in 93.9% of patients (n=46) and hypercalciuria in 43% (n=21). Five out of 49 patients (10.2%) were found to have ectopy of the thyroid: 3 showed an intrathyroidal location, 2 in the mediastinal region. Molecular genetic study revealed mutations in 32.7% of patients (n=16, CI (21; 47)), mutations in MEN1 being the most frequent (n=11). Pathogenic variants in CDC73 were detected in 3 patients, RET - in 2. Among the operated 39 patients, adenoma of the thyroid was detected in 84.6% of cases (n=33), hyperplasia in 7.7% (n=3), atypical adenoma in 5.1% (n=2), carcinoma in 5.1% of cases (n=2). CONCLUSION:  The paper presents the peculiarities of the course and the results of molecular genetic study of pediatric PHPT. This sample is the largest among those published in the Russian Federation.

[Hydrogen effect on the mechanisms of mucosal immunity in patients with COVID-19].

AIM: To study the inhalation of an active form of hydrogen effect to mucosal and system immunity in a rehabilitation program for health workers. MATERIALS AND METHODS: The study involved patients that survived COVID-19 after therapy with inhaled hydrogen for 90 minutes (n=30), and a control group of patients treated according to standard protocol for managing patients that survived COVID-19 during the rehabilitation period (n=30). Biomaterial was carried out in 2 stages: on the first day of the study, before the accepted therapy and on the 10th day of the study. The indicators of humoral and cellular immunity were studied. The levels of secretory immunoglobulin A (sIgA) and IgG were investigated using the method of enzyme-linked immunosorbent assay. Phagocytosis was assessed on a Beckman Coulter FC-500 flow cytometer. Statistical data processing was carried out in the GraphPad Prism 7.00 software using nonparametric methods. RESULTS: It was shown that the phagocytic index (PI) of monocytes in nasal scrapings after inhaled hydrogen treatment did not significantly change relative to the first day of treatment and control, while the PI of granulocytes in nasal scrapings significantly increased relative to the first day by 2.5 times (p=0.000189), as well as relative to the control by 1.1 times (p=0.047410). PI of monocytes in pharyngeal scrapings showed a significant increase relative to the first day of treatment by 2.8 times (p=0.041103), however, did not differ relative to the control. PI of granulocytes of pharyngeal scraping did not differ significantly relative to the first day and control. PI of granulocytes and blood monocytes of the studied group did not change significantly. PI of granulocytes and monocytes of peripheral blood relative to control during therapy did not change. The sIgA level in nasal scrapings significantly increased by 2.9 times, while in pharyngeal scrapings the level of sIgA significantly decreased by 2 times. Сonclusion. We have shown an increase in granulocytes PI in the nasal cavity and oral monocytes, as well as in the level of sIgA in the nasal cavity during therapy with active hydrogen. The data obtained indicate the effectiveness of therapy, which can be used both in the treatment of COVID-19, and in post-COVID syndrome as an additional therapy. The absence of changes in blood parameters, as well as individual links in nasal and pharyngeal scrapings, requires further study to develop ways to overcome treatment tolerance.

Metastatic cardiac tumors: literature review and own observation of testicular tumor metastasis in the right ventricle of the heart.

BACKGROUND: Tumors of the heart are uncommon and usually benign (in 93% cases myxomas are observed). More often secondary, metastatic tumors are detected in the heart, as a rule, at pronounced progression of the malignant neoplasm with multiple lesions of other internal organs (lung, pleura, liver, etc.). Literature review on cardiac metastases of different tumors is given. CASE REPORT: Own observation of a young man with rare single metastasis of malignant testicular germ cell tumor with predominance of embryonic carcinoma in the right ventricle of the heart is presented; the primary tumor was detected after metastasis revealing. The diagnostic algorithm using routine histological study supplemented with immunohistochemistry, including detection of cytokeratin pan, cytokeratin 5/6, cytokeratin 7, CD30, OCT4, TTF-1, hCG, and AFP markers expression, is described.

Mitochondria-Targeted Antioxidant SkQR1 Reduces TNF-Induced Endothelial Permeability in vitro.

Prolonged or excessive increase in the circulatory level of proinflammatory tumor necrosis factor (TNF) leads to abnormal activation and subsequent damage to endothelium. TNF at high concentrations causes apoptosis of endothelial cells. Previously, using mitochondria-targeted antioxidants of SkQ family, we have shown that apoptosis of endothelial cells is dependent on the production of reactive oxygen species (ROS) in mitochondria (mito-ROS). Now we have found that TNF at low concentrations does not cause cell death but activates caspase-3 and caspase-dependent increase in endothelial permeability in vitro. This effect is probably due to the cleavage of ß-catenin - an adherent junction protein localized in the cytoplasm. We have also shown that extracellular matrix metalloprotease 9 (MMP9) VE-cadherin shedding plays a major role in the TNF-induced endothelial permeability. The mechanisms of the caspase-3 and MMP9 activation are probably not related to each other since caspase inhibition did not affect VE-cadherin cleavage and MMP9 inhibition had no effect on the caspase-3 activation. Mitochondria-targeted antioxidant SkQR1 inhibited TNF-induced increase in endothelial permeability. SkQR1 also inhibited caspase-3 activation, ß-catenin cleavage, and MMP9-dependent VE-cadherin shedding. The data suggest that mito-ROS are involved in the increase in endothelial permeability due to the activation of both caspase-dependent cleavage of intracellular proteins and of MMP9-dependent cleavage of the transmembrane cell-to-cell contact proteins.

[Influence of the Potassium Channels Activator Nicorandil to the Quality of Life in Patients With Ishemic Heart Disease and Stable Angina Pectoris].

The aim of the study to assess the influence of medicamentous therapy to the quality of life of ischemic heart disease patients with stable angina pectoris by activator potassium channels nicorandil in comparison with traditional therapy by isosorbide dinitrate. The study included 84 ischemic heart disease patients. Authors consider quality of life as an estimated category of state of the subject in an illness situation. The dynamic of physical and psychological components of quality of life are compared in ischemic heart disease patients under the treatment by nicorandil and isosorbide dinitrate. Indicators of quality of life, defined on the basis of a questionnaires of SAQ and GHQ supplementing an illness picture, are an multiple-factor criterion of an assessment of a condition of this category of patients. The benefits of nicorandil in influence on quality of life indicators were revealed in the study.

[ACTUAL QUESTIONS OF TEACHING PALLIATIVE CARE IN A SYSTEM OF FURTHER PROFESSIONAL EDUCATION.]

In response to the introduction ofpalliative care as a new kind of medical care in Russian Federation (Federal law No.323 from 21.11.2011), Russian Federation Health Ministry has taskedfurther educational institutions with teaching doctors about this new kind of care. I.M Sechenov First Moscow State Medical University has answered this plea in 2015 by introducing a new course focused on palliative care. The program of education was prepared in accordance with rec- ommendations of World Health Organization (WHO) and European Association for Palliative Care (EAPC). A special attention was paid to the pain relief communication skills and organization ofpalliative care for adults in ambulatory and stationary treatment. The program integrates different teaching methods including eLearning, trainings on pain relief and practical trainings on communication skills for interaction with palliative patients and their relatives using the technology of <>.

[Comparative Assessment of Effects of Isosorbide Dinitrate, Isosorbide-5-Mononitrate and Nicorandil on the Frequency of Angina Attacks and Vasoregulating Endothelial Function in Patients With Ischemic Heart Disease].

AIM: to compare effects of isosorbide dinitrate, isosorbide-5-mononitrate and nicorandil on frequency of angina attacks and vasoregulating endothelial function in patients with ischemic heart disease (IHD). MATERIAL AND METHODS. In 117 patients with stable II-III functional class angina we analyzed frequency of angina attacks, exercise tolerance, data of 24-hour Holter ECG monitoring and brachial artery Doppler study. RESULTS. Patients with IHD had impaired endothelium-dependent vasodilation in the form of reduced endothelial response to increase of "shear stress" during test with reactive hyperemia. Long-term therapy with isosorbide dinitrate, isosorbide-5-mononitrate, and nicorandil was associated with normalization of endothelium-dependent vasodilation of the brachial artery. This effect was more pronounced during therapy with nicorandil.

Low Concentrations of Uncouplers of Oxidative Phosphorylation Prevent Inflammatory Activation of Endothelial Cells by Tumor Necrosis Factor.

In endothelial cells, mitochondria play an important regulatory role in physiology as well as in pathophysiology related to excessive inflammation. We have studied the effect of low doses of mitochondrial uncouplers on inflammatory activation of endothelial cells using the classic uncouplers 2,4-dinitrophenol and 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole, as well as the mitochondria-targeted cationic uncoupler dodecyltriphenylphosphonium (C12TPP). All of these uncouplers suppressed the expression of E-selectin, adhesion molecules ICAM1 and VCAM1, as well as the adhesion of neutrophils to endothelium induced by tumor necrosis factor (TNF). The antiinflammatory action of the uncouplers was at least partially mediated by the inhibition of NFκB activation due to a decrease in phosphorylation of the inhibitory subunit IκBα. The dynamic concentration range for the inhibition of ICAM1 expression by C12TPP was three orders of magnitude higher compared to the classic uncouplers. Probably, the decrease in membrane potential inhibited the accumulation of penetrating cations into mitochondria, thus lowering the uncoupling activity and preventing further loss of mitochondrial potential. Membrane potential recovery after the removal of the uncouplers did not abolish its antiinflammatory action. Thus, mild uncoupling could induce TNF resistance in endothelial cells. We found no significant stimulation of mitochondrial biogenesis or autophagy by the uncouplers. However, we observed a decrease in the relative amount of fragmented mitochondria. The latter may significantly change the signaling properties of mitochondria. Earlier we showed that both classic and mitochondria-targeted antioxidants inhibited the TNF-induced NFκB-dependent activation of endothelium. The present data suggest that the antiinflammatory effect of mild uncoupling is related to its antioxidant action.

[Comparative Assessment of Effects of Isosorbide Dinitrate, Isosorbide-5-Mononitrate and Nicorandil on the Frequency-of Angina Attacks and Vasoregulating Endothelial Function in Patients With Ischemic Heart Disease].

AIM: to compare effects of isosorbide dinitrate, isosorbide-5-mononitrate and nicorandil on frequency of angina attacks and vasoregulating endothelial function in patients with ischemic heart disease (IHD). MATERIAL AND METHODS: In 117 patients with stable II-III functional class angina we analyzed frequency of angina attacks, exercise tolerance, data of 24-hour Holter ECG monitoring and brachial artery Doppler study. RESULTS: Patients with IHD had impaired endothelium-dependent vasodilation in the form of reduced endothelial response to increase of "shear stress" during test with reactive hyperemia. Long-term therapy with isosorbide dinitrate, isosorbide-5-mononitrate, and nicorandil was associated with normalization of endothelium-dependent vasodilation of the brachial artery. This effect was more pronounced during therapy with nicorandil.

[Performance of fragmenting operation for restoration of a correct rhythm while treating the isolated failure of a mitral valve].

Possibilities of application of the proposed procedure for intraoperative restoration of the sinus rhythm while the mitral valve prosthesis (MVP) were studied up. In 161 patients, suffering the isolated mitral valve failure stage IV, a surgical treatment was conducted in Department of surgical treatment of acquired heart failures. The left atrium plasty was conducted in 119 (73.9%) of them with the objective to reduce its size and eliminate the re-entry waves passability. Fragmentation in left atrium was conducted in lowradiofrequency regime of diathermy (25-35 W) in accordance to variant (cut and sew) of operations Maze - 3 and Maze - 4. On a hospital stage 3 patients died (hospital lethality 1.9%). MVP in combination with Maze operation in a lowradiofrequency regime have permitted to restore successfully a correct rhythm in 80.2% of patients on a hospital stage and to stabilize it during 1 year postoperatively.

[Plasty of the left atrium in the isolated mitral valve prosthesis implantation].

Possibilities of the procedures conduction of the left atrium (LA) plasty in a mitral valve prosthesis (MVP) were studied. There were examined 553 patients, in whom surgical treatment in the clinic was conducted. In all the patients MVP was conducted for isolated mitral valve failure and dilatation of LA. In 371 patients (the main group) MVP and LA plasty were conducted, in 182 (control group)--LA was not corrected. Morphometric indices of left cardiac cameras, survival, stability of the operation good results in late terms have witnessed high efficiency of MVP with LA reduction in comparison with such in a control group. Late results of MVP in conjunction with LA reduction exceed such in a control group, witnessing expediency of the proposed methods of surgical treatment application.

Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage.

Increased serum level of tumor necrosis factor α (TNFα) causes endothelial dysfunction and leads to serious vascular pathologies. TNFα signaling is known to involve reactive oxygen species (ROS). Using mitochondria-targeted antioxidant SkQR1, we studied the role of mitochondrial ROS in TNFα-induced apoptosis of human endothelial cell line EAhy926. We found that 0.2 nM SkQR1 prevents TNFα-induced apoptosis. SkQR1 has no influence on TNFα-dependent proteolytic activation of caspase-8 and Bid, but it inhibits cytochrome c release from mitochondria and cleavage of caspase-3 and its substrate PARP. SkQ analogs lacking the antioxidant moieties do not prevent TNFα-induced apoptosis. The antiapoptotic action of SkQR1 may be related to other observations made in these experiments, namely SkQR1-induced increase in Bcl-2 and corresponding decrease in Bax as well as p53. These results indicate that mitochondrial ROS production is involved in TNFα-initiated endothelial cell death, and they suggest the potential of mitochondria-targeted antioxidants as vasoprotectors.

[On the use of statins in patients with chronic cardiac insufficiency].

Today, the necessity to use hypolipidemic agents belonging to the group of statins as means of primary and secondary prevention of coronary artery disease (CAD) and its complications is not doubted. The results of numerous large studies conducted in many different countries during the last 10 to 15 years confirm this statement. The appropriateness of statin application to patients with chronic cardiac insufficiency (CCI) is still under discussion, because there are no sufficient data on whether hypolipidemic therapy is able to improve the prognosis in this category of patients. The authors conducted a long-term research into the use of statins in combination with basic combined therapy in patients with CCI complicating the course of CAD. A reverse correlation between the levels of total cholesterol, low-density protein cholesterol, and the degree of CCI severity was demonstrated. Long-term continuous therapy of CCI patients with a combination of medications including statins did not worsen the clinical symptoms. However, hypolipidemic therapy should be administered to CCI patients on a differentiated basis, taking into account the initial state of lipid profile and the severity of the underlying disease.

[Treatment of patients with three-atrium heart].

Typical three-atrium heart constitute a rare inborn heart failure, in which pulmonary veins drain into the proximal additional camera of the left atrium, separated from distal left pericardium cavity of it own by diaphragm, in which there is one or more restrictive apertures. Of 6770 patients, consecutively operated on by one surgeon, in 15 (0.21%) ageing from 7 mo to 30 years the three-atrium heart was revealed. In all the patients the surgical correction of the failure was accomplished using artificial blood circulation. The early diagnosis and surgical treatment of the patients, suffering three-atrium heart failure, secures good late results and quality of life.