Designing in vitro Blood-Brain Barrier Models Reproducing Alterations in Brain Aging

Blood-brain barrier (BBB) modeling in vitro is a huge area of research covering study of intercellular communications and development of BBB, establishment of specific properties that provide controlled permeability of the barrier. Current approaches in designing new BBB models include development of new (bio) scaffolds supporting barriergenesis/angiogenesis and BBB integrity; use of methods enabling modulation of BBB permeability; application of modern analytical techniques for screening the transfer of metabolites, bio-macromolecules, selected drug candidates and drug delivery systems; establishment of 3D models; application of microfluidic technologies; reconstruction of microphysiological systems with the barrier constituents. Acceptance of idea that BBB in vitro models should resemble real functional activity of the barrier in different periods of ontogenesis and in different (patho) physiological conditions leads to proposal that establishment of BBB in vitro model with alterations specific for aging brain is one of current challenges in neurosciences and bioengineering. Vascular dysfunction in the aging brain often associates with leaky BBB, alterations in perivascular microenvironment, neuroinflammation, perturbed neuronal and astroglial activity within the neurovascular unit, impairments in neurogenic niches where microvascular scaffold plays a key regulatory role. The review article is focused on aging-related alterations in BBB and current approaches to development of “aging” BBB models in vitro

Pilot Project «All-Russian Registry of Patients with Severe Bronchial Asthma.» The First Results in a Children’s Group of Patients (Moscow’s Observation Program)

The article presents the first results of the pilot observation program «The All-Russian Severe Asthma Patient Registry» which was started in Moscow. Objectives. The objective of this initiative is the accumulation of clinical data on patients with severe bronchial asthma in the Russian Federation. Methods. The chosen method was a registry, the rights holders of which were 3 professional associations — Interregional Public Organization «Russian Respiratory Society», Public Organization «Union of Pediatricians of Russia», All-Russian Public Organization «Association of Allergologists and Clinical Immunologists». Results. The results of the pilot project are presented by the data analysis of electronic case report forms of 36 children (totally, the project included 100 patients, 64 adults and 36 children) enrolled in the program from June to December 2016. Using the registry, a detailed analysis of the clinical characteristics of a group of children with severe atopic bronchial asthma was carried out, the results of a pharmacoepidemiological evaluation of therapy were given. Obtained by the researchers, a high frequency of the assignment of a genetically engineered biologic drug of omalizumab meets the international recommendations but does not reflect the all-Russian reality and can be explained by inclusion in the registry of pediatric patients observed only in the Federal State Autonomous Institution «National Scientific and Practical Center of Children’s Health» of the Ministry of Health of the Russian Federation. Conclusion. To determine true indicators that characterize bronchial asthma in children in the Russian Federation it is necessary, undoubtedly, to expand the geography of project participants

Assessment of physicians’ and senior medical students’ knowledge in treatment of patients with community acquired pneumonia: Current results of the KNOCAP project

Introduction. Community-acquired pneumonia (CAP) remains one of the most acute problems of bronchopulmonary pathology being the 4th in the mortality structure (after cardiovascular, cerebrovascular diseases and malignant neoplasms) and the 1st among all fatalities from infectious diseases. Thanks to the scientific progress achieved in the antibiotic therapy and vaccine prophylaxis, the death toll has decreased four times compared to its rate during the “pre-antibiotic era“. However, nowadays there is a steadily increasing trend in the pneumonia mortality rate in Russia. The only possible way to increase efficacy of CAP treatment is timely initiated rational antibiotic therapy, considering the possible etiologies, risk factors and the severity of the patient’s condition. Materials and methods. The article represents the results of anonymous prospective surveys within the framework of the KNOCAP multi-centered research project aimed at accessing the knowledge on the fundamental issues in diagnosis and treatment of community-acquired pneumonia. The survey involved 222 students in their fifth- and sixth years in medical institute from Belgorod, Dnepr (Dnipro), Voronezh, Kiev (Kyiv) and Saratov and 110 physicians from Krasnodar, Saratov, Belgorod and Dnepr.Results and discussion. According to the results of the survey, such levels of correct answers were given by doctors and students, respectively: the inadmissibility of antimicrobial therapy (AMT) delay in CAP - 82% and 59%; the main criterion for withholding AMT - 56% and 37%; “sequential therapy” - 61% and 59%. At the same time, only 24% of the students and 23% of the physicians surveyed correctly reported typical mistakes in the treatment of a non-severe CAP with 50% or more accuracy; and in case of initial treatment, the number of correct responses was less than 28% for students and 45% for doctors. Conclusion. The survey showed that both senior medical students majoring in Medical Care and general practitioners had a low level of knowledge in CAP treatment. Hence, curricula need to be adjusted both in medical universities and in health institutions for practitioners in order to inform them and, thus, improve the quality of their knowledge in this field

Assessment of physicians’ and senior medical students’ knowledge in treatment of patients with community-acquired pneumonia: Current results of the KNOCAP project

Community-acquired pneumonia (CAP) remains one of the most acute problems of bronchopulmonary pathology being the 4th in the mortality structure (after cardiovascular, cerebrovascular diseases and malignant neoplasms) and the 1st among all fatalities from infectious diseases. Thanks to the scientific progress achieved in the antibiotic therapy and vaccine prophylaxis, the death toll has decreased four times compared to its rate during the “pre-antibiotic era“. However, nowadays there is a steadily increasing trend in the pneumonia mortality rate in Russia. The only possible way to increase efficacy of CAP treatment is timely initiated rational antibiotic therapy, considering the possible etiologies, risk factors and the severity of the patient’s condition

Pregnancy Outcomes in Women After Arterial Switch Operation for Transposition of the Great Arteries: Results From ROPAC (Registry of Pregnancy and Cardiac Disease) of the European Society of Cardiology EURObservational Research Programme

Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate

Пилотный проект «Общероссийский регистр пациентов с тяжелой бронхиальной астмой». Первые результаты в детской группе пациентов (наблюдательная программа г. Москвы)

The article presents the first results of the pilot observation program «The All-Russian Severe Asthma Patient Registry» which was started in Moscow. Objectives. The objective of this initiative is the accumulation of clinical data on patients with severe bronchial asthma in the Russian Federation. Methods. The chosen method was a registry, the rights holders of which were 3 professional associations — Interregional Public Organization «Russian Respiratory Society», Public Organization «Union of Pediatricians of Russia», All-Russian Public Organization «Association of Allergologists and Clinical Immunologists». Results. The results of the pilot project are presented by the data analysis of electronic case report forms of 36 children (totally, the project included 100 patients, 64 adults and 36 children) enrolled in the program from June to December 2016. Using the registry, a detailed analysis of the clinical characteristics of a group of children with severe atopic bronchial asthma was carried out, the results of a pharmacoepidemiological evaluation of therapy were given. Obtained by the researchers, a high frequency of the assignment of a genetically engineered biologic drug of omalizumab meets the international recommendations but does not reflect the all-Russian reality and can be explained by inclusion in the registry of pediatric patients observed only in the Federal State Autonomous Institution «National Scientific and Practical Center of Children’s Health» of the Ministry of Health of the Russian Federation. Conclusion. To determine true indicators that characterize bronchial asthma in children in the Russian Federation it is necessary, undoubtedly, to expand the geography of project participants.В статье представлены первые результаты пилотной наблюдательной программы «Общероссийский регистр пациентов с тяжелой бронхиальной астмой», стартовавшей в Москве. Цель данной инициативы — аккумуляция клинических сведений о больных тяжелой бронхиальной астмой в Российской Федерации. Методы. Методом был выбран регистр, правообладателями которого стали 3 профессиональные ассоциации — Межрегиональная общественная организация «Российское респираторное общество», Общественная организация «Союз педиатров России», Всероссийская общественная организация «Ассоциация аллергологов и клинических иммунологов». Результаты пилотного проекта, представлены анализом данных электронных индивидуальных регистрационных карт 36 пациентов детского возраста (всего в проект было включено 100 больных, из них 64 взрослых и 36 детей), прошедших регистрацию в программе с июня по декабрь 2016 г. С использованием регистра проведен подробный анализ клинической характеристики группы детей с тяжелой атопической бронхиальной астмой, даны результаты фармакоэпидемиологической оценки терапии. Полученная исследователями высокая частота назначения генно- инженерного биологического препарата омализумаба соответствует международным рекомендациям, однако не отражает общероссийской действительности и может быть объяснена включением в регистр пациентов детского возраста, наблюдающихся только в ФГАУ «ННПЦЗД» Минздрава России. Заключение. Для определения истинных показателей, характеризующих бронхиальную астму у детей в Российской Федерации, несомненно, необходимо расширение географии участников проекта.

Влияние ферментозаместительной терапии на обструкцию верхних дыхательных путей у детей с мукополисахаридозами: ретроспективное когортное исследование

Background. Data on the efficacy of enzyme replacement therapy (ERT) in relation to the pathology of ENT organs and respiratory performance in sleep in children with mucopolysaccharidosis (MPS) is poorly presented in the literature. Our aim was to assess the effect of ERT on the upper respiratory tract in children with MPS. Methods. According to the case histories, we studied treatment results of children with MPS type I and II who received ERT in the Research Center of Children’s Health from January 2007 to November 2016. The severity of upper airway obstruction and its change during ERT was assessed according to indices of apnea-hypopnea and desaturation (SpO2), average/minimal SpO2, duration of SpO2 episodes < 90%, and hypertrophy degree of palatine tonsils and adenoids. Results. The severity of the obstructive sleep apnea syndrome did not progress in children (n = 15) with MPS against the background of ERT with a median duration of 38 (23; 48) months: initially, the apnea-hypopnea index was 3 (1.3; 7.7), while the repeated study — 2.6 (0.9; 13.5) (p = 0.507). There was also no statistically significant change in cardiorespiratory monitoring values. Conclusion. Long-term ERT in children with MPS type I and II interferes with the progression of airway obstruction.Обоснование. Данные об эффективности ферментозаместительной терапии (ФЗТ) в отношении патологии ЛОР- органов и показателей дыхания во сне у детей с мукополисахаридозом (МПС) в литературе представлены скудно.Цель исследования — оценить влияние ФЗТ на состояние верхних дыхательных путей у детей с МПС.Методы. По историям болезни изучали результаты лечения детей с МПС I и II типов, получавших ФЗТ в Научном центре здоровья детей (ныне ФГАУ «НМИЦ здоровья детей» Минздрава России) с января 2007 по ноябрь 2016 г. Выраженность обструкции верхних дыхательных путей и ее изменение на фоне ФЗТ оценивали по индексам апноэ-гипопноэ и десатурации (SpO2), средней/минимальной SpO2, продолжительности эпизодов SpO2< 90% и степени гипертрофии небных миндалин и аденоидов.Результаты. У детей (n=15) с МПС на фоне ФЗТ продолжительностью (медиана) 38 (23; 48) мес тяжесть синдрома обструктивного апноэ сна не прогрессировала: исходно индекс апноэ-гипопноэ составил 3 (1,3; 7,7), при повторном исследовании — 2,6 (0,9; 13,5) (р=0,507). Также не установлено статистически значимого изменения показателей кардиореспираторного мониторинга.Заключение. Длительная ФЗТ у детей с МПС I и II типов препятствует прогрессированию обструкции дыхательных путей.КОНФЛИКТ ИНТЕРЕСОВ Л.С. Намазова-Баранова — получение исследовательских грантов от фармацевтических компаний Пьер Фабр, Genzyme Europe B. V., ООО «Астра зенека Фармасьютикалз», Gilead / PRA «Фармасьютикал Рисерч Ассошиэйтс СиАйЭс», Bionorica, Teva Branded Pharmaceutical products R&D, Inc / ООО «ППД Девелопмент (Смоленск)», «Сталлержен С. А.» / «Квинтайлс ГезмбХ» (Австрия). Л.М. Кузенкова, А.К. Геворкян, Т.В. Подклетнова, Н.Д. Вашакмадзе читают лекции для компаний «Санофи Джензайм», «Шайер», «Биомарин». Остальные авторы подтвердили отсутствие конфликта интересов, о котором необходимо сообщить

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years