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.

[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 <>.

[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.

[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.