Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice

Resistance to drug treatment of acromegaly and ways to overcome it

Acromegaly is a severe disabling neuroendocrine disease caused by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The problem of resistance to drug therapy in patients with acromegaly is quite common in clinical practice and requires a personalized approach, considering various predictors of sensitivity to the choice of the treatment method. To date, first-generation somatostatin analogues are first-line drugs in the medical treatment of acromegaly, but up to 50% of patients do not achieve biochemical remission of the disease. The prognosis of sensitivity to somatostatin analogues is of great importance and the selection of patients in whom this therapy will be not successful provides invaluable assistance in choosing the optimal treatment approach. This review summarizes potential predictors of sensitivity and resistance to existing drug treatment of acromegaly, discusses possible ways to overcome the resulting resistance to therapy, suggests options for a personalized approach to choosing a treatment strategy in the absence of disease control against the background of monotherapy with somatostatin analogues, including «off-label» combinations. Timely addition of growth hormone receptor antagonist (pegvisomant) avoids repeated neurosurgical intervention, radiation therapy or prescribing excessively high doses of somatostatin analogues. Optimal use of mono- or combination therapy contributes to the achievement of biochemical remission in most resistant patients

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Clinical features of the myasthenic syndrome arising from mutations in GMPPB

BACKGROUND: Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission. METHODS: Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity. RESULTS: All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol. CONCLUSIONS: Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment

Изучение влияния лечебно–профилактических паст на состояние гигиены полости рта

Метою дослідження було визначення стану гігієни ротової порожнини і вивчення впливу лікувально-профілактичних паст на стан гігієни, шляхом проведення порівняльного аналізу та вибору найбільш оптимальної лікувальнопрофілактичної пасти для підтримання хорошого рівня гігієни. Було проведено клінічні дослідження, в яких приймали участь 45 пацієнтів. Проведена оцінка стану гігієни порожнині рота. Пацієнти розділені на 3 групи по 15 у кожній. Першій групі пацієнтів були рекомендовані пасти с фторидом і комплексом триклозан/сополімер, другій групі рекомендована паста, яка містить такі основні компоненти, як розчинний фторид, стабілізоване олово та гексаметафостат, третя група використовувала зубну пасту, яка включає у склад кальцію гідроксіапатит. По закінченню строку використання зубних паст кожній групі пацієнтів була проведена повторна оцінка гігієни ротової порожнини.According to the data of WHO, all over the world 60-90 % of school-aged children and 100 % of adults have caries. Speaking generally, in whole, about 30 % of people at the age of 65-75 have no natural teeth. The development of such kind of diseases directly depends on: the hygiene of oral cavity, which is unsatisfactory for the most number of the patients, and on the correct prophylaxis/prevention, where the leading role is given to the medical prophylactic toothpastes. The main aim of the investigation was defining of the state of oral cavity hygiene and studying the influence of the therapeutic preventive pastes on the cavity hygiene condition by the means of comparative analysis and the choice of the optimum toothpaste for the support of the high level of the hygiene.Целью исследования являлось определение состояния гигиены полости рта и изучение влияния лечебно-профилактических паст на состояние гигиены полости рта, путем проведения сравнительного анализа и выбора наиболее оптимальной лечебно-профилактической пасты для поддержания хорошего уровня гигиены. Проведены клинические исследования, в которых принимало участие 45 человек. Проведена оценка состояния гигиены полости рта. Пациенты разделены на группы по 15 человек. Первой группе пациентов были рекомендованы пасты с фторидом и комплексом триклозан/сополимер, второй группе рекомендована паста которая содержит такие основные компоненты, как растворимый фторид, стабилизированное двухвалентное олово и гексаметафосфат, третья группа использовала зубную пасту, включающую в состав кальция гидроксиапатит. По истечению срока использования зубных паст каждой группе пациентов была проведена повторная оценка гигиены полости рта

THE PREVENTION, DIAGNOSIS, AND TREATMENT OF VITAMIN D AND CALCIUM DEFICIENCIES IN THE ADULT POPULATION OF RUSSIA AND IN PATIENTS WITH OSTEOPOROSIS (ACCORDING TO THE MATERIALS OF PREPARED CLINICAL RECOMMENDATIONS)

The paper presents data on the role of vitamin D and calcium in the function of many human organs and tissues. Lifestyle, dietary preferences, and insufficient physical activity contribute to the high prevalence of vitamin D and calcium deficiencies in the adult population of Russia, causing different diseases and abnormalities. The authors have worked out recommendations for the preventive use of vitamin D and calcium in healthy population, give consumption rates for these substances, and describe the clinical and laboratory signs of vitamin D deficiency and indications for screening. They also propose treatment regimens for vitamin D deficiency and depict the signs of intoxication inoverdose. Particular emphasis is laid on the place of vitamin D and calcium in the therapy of osteoporosis

Применение алгоритма искусственного интеллекта для оценки минеральной плотности тел позвонков по данным компьютерной томографии

Goal: To develop a method for automated assessment of the volumetric bone mineral density (BMD) of the vertebral bodies using an artificial intelligence (AI) algorithm and a phantom modeling method.Materials and Methods: Evaluation of the effectiveness of the AI algorithm designed to assess BMD of the vertebral bodies based on chest CT data. The test data set contains 100 patients aged over 50 y.o.; the ratio between the subjects with/without compression fractures (Сfr) is 48/52. The X-ray density (XRD) of vertebral bodies at T11-L3 was measured by experts and the AI algorithm for 83 patients (205 vertebrae). We used a recently developed QCT PK (Quantitative Computed Tomography Phantom Kalium) method to convert XRD into BMD followed by building calibration lines for seven 64-slice CT scanners. Images were taken from 1853 patients and then processed by the AI algorithm after the calibration. The male to female ratio was 718/1135.Results: The experts and the AI algorithm reached a strong agreement when comparing the measurements of the XRD. The coefficient of determination was R2=0.945 for individual vertebrae (T11-L3) and 0.943 for patients (p=0.000). Once the subjects from the test sample had been separated into groups with/without Сfr, the XRD data yielded similar ROC AUC values for both the experts – 0.880, and the AI algorithm – 0.875. When calibrating CT scanners using a phantom containing BMD samples made of potassium hydrogen phosphate, the following averaged dependence formula BMD =0.77*HU-1.343 was obtained. Taking into account the American College Radiology criteria for osteoporosis, the cut-off value of BMD<80 mg/ml was 105.6HU; for osteopenia BMD<120 mg/ml was 157.6HU. During the opportunistic assessment of BMD in patients aged above 50 years using the AI algorithm, osteoporosis was detected in 31.72% of female and 18.66% of male subjects.Conclusions: This paper demonstrates good comparability for the measurements of the vertebral bodies’ XRD performed by the AI morphometric algorithm and the experts. We presented a method and demonstrated great effectiveness of opportunistic assessment of vertebral bodies’ BMD based on computed tomography data using the AI algorithm and the phantom modeling.Цель работы: разработать методику автоматизированной оценки объемной минеральной плотности кости (МПК) тел позвонков с помощью алгоритма искусственного интеллекта (ИИ) и метода фантомного моделирования.Материалы и методы: Для оценки эффективности алгоритма ИИ, проводящего измерение МПК тел позвонков по данным КТ органов грудной клетки (ОГК), подготовлен набор данных: 100 пациентов старше 50 лет и отношением с/без компрессионных переломов (КП) 48/52. Из них у 83 алгоритмом ИИ и экспертами была измерена рентгеновская плотность (РП) тел позвонков на уровне Th11-L3 (205 позвонков). Для перевода РП (HU) в МПК применялась разработанная ранее методика ККТ ФК (Количественная компьютерная томография фантом калиевый) с построением калибровочных прямых для семи 64-срезовых КТ сканеров. После проведения калибровки были выполнены и обработаны алгоритмом ИИ КТ ОГК 1853 пациентов в соотношении мужчин и женщин составило 718/1135.Результаты: В ходе оценки эффективности алгоритма ИИ получено хорошее соответствие при сравнении измерений МПК по данным экспертов и алгоритма ИИ. Коэффициент детерминации составил R2= 0,945 для отдельных позвонков (Th11-L3) и 0,943 для пациентов (р=0,000). При разделении пациентов из тестовой выборки на группы с/без КП по данным РП были получены сходные показатели ROC AUC для экспертной разметки 0,880 и по данным алгоритма ИИ 0,875. При калибровке КТ сканеров с помощью фантома, содержащего образцы МПК на основе гидрофосфата калия, получена усредненная формула зависимости МПК=0,77*HU-1,343. С учетом критериев American College Radiology для остеопороза граничное значение МПК<80 мг/мл составило 105,6HU для остеопении МПК<120 мг/мл – 157,6HU. При оппортунистическом определении МПК у пациентов старше 50 лет по данным алгоритма ИИ было установлено, что остеопороз выявлен у 31,72% женщин и 18,66% мужчин.Вывод: Продемонстрирована хорошая сопоставимость результатов определения РП тел позвонков по данным морфометрического алгоритма ИИ и при экспертной разметке. Предложена методика и продемонстрирована эффективность оппортунистического определения МПК тел позвонков по данным КТ с помощью алгоритма ИИ и использования фантомного моделирования