Nanоbiocomposite based on dihydroquercetin and arabinogalactan in the form of a gel for external use as a means for the treatment of chronic venous insufficiency in an experiment

Background. Due to the high prevalence of chronic venous insufficiency among the population, with a decrease in the quality of life of patients and their early disability, there is a need to develop modern effective and safe means for the prevention and treatment of this pathology. We have developed the optimal composition and technology of a gel for external use based on a nanobiocomposite of dihydroquercetin and arabinogalactan, which has a venoprotective effect. The article presents data on the results of a preclinical study of the safety and specific activity of the gel.The aim. To study the specific activity (decongestant, antitranssudative action) and safety of a gel for external use based on nanobiocomposite of dihydroquercetin and arabinogalactan used for the treatment of chronic venous insufficiency in the framework of preclinical studies.Materials and methods. The object of the study was a gel for external use based on dihydroquercetin and arabinogalactan nanobiocomposite. The study was conducted on 32 white male rats of the same age, for 15 days. The study of the pharmacological activity of a gel based on a nanobiocomposite of dihydroquercetin and arabinogalactan, was carried out on a model of acute venous stagnation in the tail of a rat (edema of non-inflammatory genesis), the dynamics of tail volume growth in the experimental and control group of animals was evaluated. The irritant effect of the gel on the skin of animals was also determined, the permeability of the capillaries of the skin was determined.Results. When studying the pharmacological activity of the gel on a model of acute venous stagnation in the tail, it was shown that a soft dosage form for external use developed on the basis of nanobiocomposite of dihydroquercetin and arabinogalactan has decongestant and antitranssudative activity. The presence of a locally irritating effect in the gel under study has not been established in the framework of the experiment.Conclusion. In the course of preclinical study of the gel of the nanobiocomposite dihydroquercetin and arabinogalactan on laboratory animals, its antitranssudative activity and safety have been proven

Проксимальная спинальная мышечная атрофия 5q в Республике Северная Осетия – Алания: популяционно-генетические особенности, проблемы диагностики и перспективы лечения

This study presents the structure and population data of spinal muscular atrophy 5q in the Republic of North Ossetia – Alania. The number of newborns for the period 2000–2020 was 195 954, and the prevalence of spinal muscular atrophy 5q among newborns was 1:24 494, or 4.08 per 100.000. That corresponds to data on other populations of the Russian Federation and the world. We also describe intermediate results of the clinical efficacy of treatment of three spinal muscular atrophy 5q patients. Gene replacement therapy was used in two cases and combined pathogenetic and gene replacement therapy was used in the third case. No clinically significant decrease in the CHOP INTEND score from the baseline level was found in any patient during follow‑up. Clinical improvement was noted both during treatment with nusinersen and after administration of onasemnogene abeparvovec. Described clinical cases demonstrate the importance of early diagnosis and initiation of antisense oligonucleotide and/or gene replacement therapy, which is possible only when spinal muscular atrophy 5q is included in the neonatal screening program.Представлен анализ структуры спинальной мышечной атрофии 5q в Республике Северная Осетия – Алания, описаны молекулярно‑генетические и популяционные характеристики данной патологии в регионе. Число новорожденных за период 2000–2020 гг. составило 195 954 ребенка, распространенность спинальной мышечной атрофии 5q составила 1:24 494, или 4,08 на 100 тыс. новорожденных, что несколько ниже, чем в других популяциях РФ и мира. Приводятся примеры промежуточной оценки эффективности лечения 3 пациентов. В 2 случаях применялась генозаместительная терапия, а в 3‑м – комбинированная патогенетическая и генозаместительная терапия. Ни у одного пациента при наблюдении в динамике не было зарегистрировано клинически значимого уменьшения оценки по шкале CHOP INTEND относительно исходного уровня. Положительный терапевтический эффект отмечен как на фоне лечения нусинерсеном, так и после введения онасемноген абепарвовека. Приведенные клинические наблюдения демонстрируют необходимость раннего выявления и начала лечения антисмысловыми олигонуклеотидами и/или генозаместительной терапии, что возможно только при включении спинальной мышечной атрофии 5q в программу неонатального скрининга

A large meteoritic event over Antarctica ca. 430 ka ago inferred from chondritic spherules from the Sør Rondane Mountains

Large airbursts, the most frequent hazardous impact events, are estimated to occur orders of magnitude more frequently than crater-forming impacts. However, finding traces of these events is impeded by the difficulty of identifying them in the recent geological record. Here, we describe condensation spherules found on top of Walnumfjellet in the Sør Rondane Mountains, Antarctica. Affinities with similar spherules found in EPICA Dome C and Dome Fuji ice cores suggest that these particles were produced during a single-asteroid impact ca. 430 thousand years (ka) ago. The lack of a confirmed crater on the Antarctic ice sheet and geochemical and 18O-poor oxygen isotope signatures allow us to hypothesize that the impact particles result from a touchdown event, in which a projectile vapor jet interacts with the Antarctic ice sheet. Numerical models support a touchdown scenario. This study has implications for the identification and inventory of large cosmic events on Earth

Stochastic Inversion of P-to-S Converted Waves for Mantle Composition and Thermal Structure: Methodology and Application

We present a new methodology for inverting P‐to‐S receiver function (RF) waveforms directly for mantle temperature and composition. This is achieved by interfacing the geophysical inversion with self‐consistent mineral phase equilibria calculations from which rock mineralogy and its elastic properties are predicted as a function of pressure, temperature, and bulk composition. This approach anchors temperatures, composition, seismic properties, and discontinuities that are in mineral physics data, while permitting the simultaneous use of geophysical inverse methods to optimize models of seismic properties to match RF waveforms. Resultant estimates of transition zone (TZ) topography and volumetric seismic velocities are independent of tomographic models usually required for correcting for upper mantle structure. We considered two end‐member compositional models: the equilibrated equilibrium assemblage (EA) and the disequilibrated mechanical mixture (MM) models. Thermal variations were found to influence arrival times of computed RF waveforms, whereas compositional variations affected amplitudes of waves converted at the TZ discontinuities. The robustness of the inversion strategy was tested by performing a set of synthetic inversions in which crustal structure was assumed both fixed and variable. These tests indicate that unaccounted‐for crustal structure strongly affects the retrieval of mantle properties, calling for a two‐step strategy presented herein to simultaneously recover both crustal and mantle parameters. As a proof of concept, the methodology is applied to data from two stations located in the Siberian and East European continental platforms.This work was supported by a grant from the Swiss National Science Foundation (SNF project 200021_159907). B. T. was funded by a Délégation CNRS and Congé pour Recherches et Conversion Thématique from the Université de Lyon to visit the Research School of Earth Sciences (RSES), The Australian National University (ANU). B. T. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 79382

Эффективность и безопасность препарата нусинерсен в рамках программы расширенного доступа в России

Introduction. Spinal muscular atrophy is a severe neuromuscular disease characterized by rapid progression of muscle weakness and early death. Pathogenetic therapy with nusinersen can significantly change the course of the disease and enable the patient to acquire new skills. The study of the efficacy and safety of nusinersen therapy in patients with type 1 spinal muscular atrophy should be continued. The aim of the study was to assess the safety and efficacy of nusinersen therapy in patients with type 1 spinal muscular atrophy for 6 months as part of an expanded access program at federal and regional healthcare facilities. Materials and methods. Patients with type 1 spinal muscular atrophy received nusinersen therapy under the expanded access program (NCT02865109). Patients were evaluated before starting treatment and 6 months after starting treatment. Overall motor development and motor function was assessed using the Hammersmith Infant Neurological Status Scale Part 2 and the Philadelphia Pediatric Hospital Neonatal Motor Scale. Results. 41 children aged 6 to 38 months received nusinersen therapy between July 2019 and March 2020. At the time of analysis, all patients were alive and continued treatment. The average improvement on the Hammersmith Hospital Neurological Status Scale was 3.7 points after 6 months of therapy compared to baseline (n = 39, p <0.001). The mean improvement on the Children’s Hospital of Philadelphia Scale for the Diagnosis of Motor Function in Newborns was 9.8 after 6 months of therapy from baseline (n = 30, p <0.001). Conclusion. The efficacy and safety of nusinersen have been demonstrated in real clinical practice in Russia in the treatment of early-onset spinal muscular atrophy.Введение. Спинальная мышечная атрофия – тяжелое нервно-мышечное заболевание, характеризующееся быстрым прогрессированием мышечной слабости, ранним летальным исходом. Применение патогенетической терапии нусинерсеном может существенно изменить течение болезни и дать возможность пациенту приобрести новые навыки. Изучение эффективности и безопасности терапии нусинерсеном у пациентов со спинальной мышечной атрофией 1-го типа неообходимо продолжать. Цель исследования – оценить безопасность и эффективность терапии нусинерсеном пациентов со спинальной мышечной атрофией 1-го типа в течение 6 мес в рамках клинической практики в лечебно-профилактических учреждениях федерального и регионального уровней. Материалы и методы. Пациенты со спинальной мышечной атрофией 1-го типа получали терапию препаратом нусинерсен в рамках программы расширенного доступа (NCT02865109). Оценка пациентов проводилась до начала лечения и через 6 мес после начала лечения. Оценивали общее двигательное развитие, моторную функцию – с помощью Шкалы оценки неврологического статуса больницы Хаммерсмит у детей раннего возраста, часть 2, и Шкалы детской больницы Филадельфии для диагностики двигательных функций у новорожденных. Результаты. Терапию препаратом нусинерсен получил 41 ребенок в возрасте от 6 до 38 мес в период с июля 2019 по март 2020 г. На момент анализа все пациенты были живы и продолжали лечение. Среднее улучшение по Шкале оценки неврологического статуса больницы Хаммерсмит составило 3,7 балла через 6 мес терапии по сравнению с исходным уровнем (n = 39, р <0,001). Среднее улучшение по Шкале детской больницы Филадельфии для диагностики двигательных функций у новорожденных составило 9,8 балла через 6 мес терапии по сравнению с исходным уровнем (n = 30, р <0,001). Заключение. Продемонстрированы эффективность и безопасность нусинерсена в условиях реальной клинической практики в России при терапии спинальной мышечной атрофии 1-го типа с ранним началом

Strong variability in the thermal structure of Tibetan Lithosphere

We present a model of thermal lithospheric thickness (the depth where the geotherm reaches a temperature of 1300°C) and surface heat flow in Tibet and adjacent regions based on a new thermal-isostasy method. The method accounts for crustal density heterogeneity, is free from any assumption of a steady-state lithosphere thermal regime, and assumes that deviations from crustal Airy-type isostasy are caused by lithosphere thermal heterogeneity. We observe a highly variable lithospheric thermal structure which we interpret as representing longitudinal variations in the northern extent of the subducting Indian plate, southward subduction of the Asian plate beneath central Tibet, and possible preservation of fragmented Tethyan paleo-slabs. Cratonic-type cold and thick lithosphere (200-240 km) with a predicted surface heat flow of 40-50 mW/m2 typifies the Tarim Craton, the northwest Yangtze Craton, and most of the Lhasa Block that is likely refrigerated by underthrusting Indian lithosphere. We identify a ‘North Tibet anomaly’ with thin (80-100 mW/m2). We interpret this anomaly as the result of removal of lithospheric mantle and asthenospheric upwelling at the junction of the Indian and Asian slabs with opposite subduction polarities. Other parts of Tibet typically have intermediate lithosphere thickness of 120-160 km and a surface heat flow of 45-60 mW/m2, with patchy anomalies in eastern Tibet. While different uplift mechanisms for Tibet predict different lithospheric thermal regimes, our results in terms of a highly variable thermal structure beneath Tibet suggest that topographic uplift is caused by an interplay of several mechanisms. Key Points Thick Tibetan lithosphere defines the longitudinally variable northern extent of the Indian plate The ‘North Tibet Anomaly’ with a hot mantle marks the junction of the Indian and Asian slabs Tethyan paleo-slabs explain variable lithosphere thickness in eastern Tibe