The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity

Parkinson's disease (PD) is the most common motor disorder affecting the elderly. PD is characterized by the formation of Lewy bodies and death of dopaminergic neurons. The mechanisms underlying PD are unknown, but the discoveries that mutations in alpha-synuclein can cause familial PD and that alpha-synuclein accumulates in Lewy bodies suggest that alpha-synuclein participates in the pathophysiology of PD. Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T, or A30P alpha-synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain alpha-synuclein and ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the amount of alpha-synuclein expressed and the type of alpha-synuclein expressed, with the amount of alpha-synuclein aggregation following a rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation, alpha-synuclein also appears to induce toxicity. BE-M17 neuroblastoma cells overexpressing alpha-synuclein show up to a fourfold increase in vulnerability to toxicity induced by iron. The vulnerability follows the same rank order as for aggregation. These data raise the possibility that alpha-synuclein acts in concert with iron and dopamine to induce formation of Lewy body pathology in PD and cell death in PD

DONOR-TRANSMITTED CORONARY ATHEROSCLEROSIS

Aim. To estimate opportunities, prospects and safety of using heart transplants from aged donors who are at high risk of coronary atherosclerosis.Materials and methods. Over the period from March 1987 to May 2014450 heart transplantations (HTx) were performed in V.I.Shumakov Federal Research Center of Transplantology and Artifi cial Organs. During the fi rst month after HTx coronarography was made to 152 (37,8%) recipients inorder to exclude/confi rm donor-transmitted coronary atherosclerosis (DTCA) and to identify tactics of treatment. Coronary atherosclerosis was detected among 16 patients (3,6% of total number of HTx), 15 (93,8%) men and 1 (6,2%) women. Mean age of recipients with DTCA at the moment of HTx was 48,3 ± 13,1 years.Results. Hemodynamically relevant coronary atherosclerosis was not detected and percutaneous coronary intervention (PCI) was not made in the group of patients with the mean age of 42,24 ± 8,91 years. Using heart transplants from aged donors is connected with increasing risk of DTCA among the recipients. DTCA-dependent PCI is not connected with coronary mortality. Actuarial survival rate of patients who underwent PCI is comparable with the same one in the total population of HTx recipients and is equal to 87,5% at 5 years and less.Conclusion. Hearts from aged donors (older than 50 years) may be used for HTx with suffi cient level of safety. Due to high level of DTCA using of hearts from such donors is preferable for completing urgent HTx to recipients 1А–В UNOS

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

ТРОМБОЗОМ ЛЕВЫХ ОТДЕЛОВ СЕРДЕЧНОГО ТРАНСПЛАНТАТА, РАЗВИВШИМСЯ НА ФОНЕ ПРИМЕНЕНИЯ ВЕНО-АРТЕРИАЛЬНОЙ ЭКСТРАКОРПОРАЛЬНОЙ МЕМБРАННОЙ ОКСИГЕНАЦИИ

We present a case report of a 16-year-old man with venoarterial extracorporeal membrane oxygenation (VA-ECMO) for primary graft failure after orthotopic heart transplantation who developed left atrium and left ventricular thrombosis despite systemic anticoagulation. The surgical thrombectomy was performed and the patient was successfully weaned off the extracorporeal support on the first day thereafter.Представлен клинический случай успешного лечения реципиента сердца с тотальным тромбозом левого предсердия и левого желудочка, развившимся в ранние сроки после трансплантации на фоне применения периферической ВА ЭКМО как метода механической поддержки кровообращения при острой правожелудочковой недостаточности пересаженного сердца. Пациенту успешно выполнили хирургическую тромбэктомию, и ВА ЭКМО прекращена на первые сутки после операции

НАРУШЕНИЕ МАКРОМОЛЕКУЛЯРНОЙ СТРУКТУРЫ КАРДИОМИОЦИТОВ АЛЛОТРАНСПЛАНТАТА СЕРДЦА КАК ПРИЗНАК ХРОНИЧЕСКОГО ОТТОРЖЕНИЯ

Chronic rejection, especially cardiac allograft vasculopathy, is a major limiting factor for long-term transplant survival. This process affects not only the blood vessels, but also cardiomyocytes. However, there are extremely few reports on the evaluation of their macromolecular structure state. The aim of the study was to evaluate the structural proteins of cardiomyocytes (actin, myosin, troponin I, titin, desmin, vinculin) of heart allografts in different periods after the operation (from 6 days to 15 years). Major changes of macromolecular structure were revealed in late period after transplantation (6 months – 15 years). The contribution of humoral immune response in the process of chronic cardiac allograft rejection was observed: in eight of twelve recipients episodes of acute humoral rejection had been repeatedly registered; disorders of the expression of 5 proteins out of 6 characterized were found in recipients with recurrent and persistent antibody-mediated rejection. Хроническое отторжение, и прежде всего болезнь коронарных артерий, является основным лимитирую- щим фактором длительной функции аллотрансплантата сердца. Данный процесс затрагивает не только со- суды, изменениям также подвержены и кардиомиоциты. Однако сообщений, касающихся оценки состоя- ния их макромолекулярной структуры, крайне мало. Целью нашей работы явилось исследование состояния структурных белков кардиомиоцитов (актин, миозин, тропонин I, титин, десмин, винкулин) аллотрансплан- тата сердца в разные периоды после операции (от 6 дней до 15 лет). Основные изменения макромолекуляр- ной структуры выявлены в подгруппе позднего периода (6 мес.–15 лет). Продемонстрирован вклад гумо- рального звена иммунного ответа в процесс хронического отторжения аллотрансплантата сердца: у восьми из двенадцати реципиентов данной подгруппы неоднократно регистрировали эпизоды острого антитело- опосредованного отторжения; нарушения экспрессии пяти белков из шести охарактеризованных были об- наружены у реципиентов с возвратным и персистирующим антителоопосредованным отторжением.

ТРАНСМИССИВНЫЙ АТЕРОСКЛЕРОЗ КОРОНАРНЫХ АРТЕРИЙ ТРАНСПЛАНТАТА

Aim. To estimate opportunities, prospects and safety of using heart transplants from aged donors who are at high risk of coronary atherosclerosis.Materials and methods. Over the period from March 1987 to May 2014450 heart transplantations (HTx) were performed in V.I.Shumakov Federal Research Center of Transplantology and Artifi cial Organs. During the fi rst month after HTx coronarography was made to 152 (37,8%) recipients inorder to exclude/confi rm donor-transmitted coronary atherosclerosis (DTCA) and to identify tactics of treatment. Coronary atherosclerosis was detected among 16 patients (3,6% of total number of HTx), 15 (93,8%) men and 1 (6,2%) women. Mean age of recipients with DTCA at the moment of HTx was 48,3 ± 13,1 years.Results. Hemodynamically relevant coronary atherosclerosis was not detected and percutaneous coronary intervention (PCI) was not made in the group of patients with the mean age of 42,24 ± 8,91 years. Using heart transplants from aged donors is connected with increasing risk of DTCA among the recipients. DTCA-dependent PCI is not connected with coronary mortality. Actuarial survival rate of patients who underwent PCI is comparable with the same one in the total population of HTx recipients and is equal to 87,5% at 5 years and less.Conclusion. Hearts from aged donors (older than 50 years) may be used for HTx with suffi cient level of safety. Due to high level of DTCA using of hearts from such donors is preferable for completing urgent HTx to recipients 1А–В UNOS.Цель: оценить вклад трансмиссивного атеросклероза коронарных артерий трансплантата в непосредственный исход трансплантаций и определение перспективности использования трансплантатов с предсуществующим коронарным атеросклерозом.Материалы и методы. В ФГБУ «ФНЦ трансплантологии и искусственных органов имени академика В.И. Шумакова» с марта 1987 г. по май 2014 г. выполнено 450 трансплантаций сердца (ТС). В пределах первого месяца после ТС 152 (37,8%) реципиентам была выполнена коронарография для исключения/подтверждения трансмиссивного атеросклероза коронарных артерий трансплантата (ТАКАТ) и определения тактики лечения. Поражение коронарных артерий было выявлено у 16 пациентов (3,6% от общего количества трансплантаций), 15 (93,8%) мужчин и 1 (6,2%) женщины. Средний возраст реципиентов с ТАКАТ на момент выполнения ТС составил 48,3 ± 13,1 года.Результаты. В группе пациентов, у которых не было выявлено гемодинамически значимого поражения коронарного русла и чрескожное коронарное вмешательство (ЧКВ) не выполнялось, средний возраст донора составил 42,24 ± 8,91 года, в группе с ТАКАТ и последующей ЧКВ – 47,94 ± 5,38 года (р = 0,013). Использование трансплантатов от возрастных доноров сопряжено с повышенным риском ТАКАТ у реципиентов. Выполнение ЧКВ по поводу ТАКАТ не сопровождается коронарогенной летальностью. Актуриальная выживаемость пациентов, перенесших ЧКВ по поводу ТАКАТ, сопоставима с таковой в общей популяции реципиентов и на сроке до 5 лет составляет 87,5%.Заключение. Сердца от возрастных доноров (старше 50 лет) могут быть с достаточной степеньюбезопасности использованы для трансплантации. Ввиду высокого риска ТАКАТ использование таких трансплантатов предпочтительно при выполнении ургентных трансплантаций у реципиентов статуса 1А–В UNOS

SUCCESSFUL TREATMENT OF A RECIPIENT WITH MASSIVE THROMBOSIS OF HEART TRANSPLANT LEFT CHAMBERS DURING EXTRACORPOREAL MEMBRANE OXYGENATION

We present a case report of a 16-year-old man with venoarterial extracorporeal membrane oxygenation (VA-ECMO) for primary graft failure after orthotopic heart transplantation who developed left atrium and left ventricular thrombosis despite systemic anticoagulation. The surgical thrombectomy was performed and the patient was successfully weaned off the extracorporeal support on the first day thereafter

Heart transplantation waiting list of V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs. Trends from 2010 to 2017

The aim: to analyze the waiting list for heart transplantation from 2010 to 2017 and to characterize recipients with chronic heart failure III–IV NYHA Class.Methods. The study comprised 997 patients (139 [14%] females and 858 [86%] males) included in the waiting list for heart transplantation the period from January 2010 to December 2017. The average age of patients on the waiting list was 49.0 ± 12.0 (from 10 to 78 years). Before making a decision on inclusion in the waiting list, all patients underwent clinical and instrumental examination, including general clinical studies, echocardiography, measurement of central hemodynamic parameters using a Swan–Gans catheter, computer and/or magnetic resonance imaging of the chest, abdominal and brain.Results. Heart transplantation was performed on 728 patients (99 females – 13.6% and 629 males – 86.4%) including 18 children aged 12 to 17 years (14.18 ± 2.07 years). Mortality in the waiting list in 2010 was 16.1%, compared with 3.2% in 2017