Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10−3). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the diseas

July 2017 ENCALS statement on edaravone

Peer reviewe

A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118

A prospective study to evaluate the impact of ³¹P-MRS to determinate mitochondrial dysfunction in skeletal muscle of ALS patients

Impaired mitochondrial energy production probably plays a role in motor neuron death in amyotrophic lateral sclerosis (ALS) and has been found not only in motor neurons but also in skeletal muscle of patients with ALS. 31P magnetic resonance spectroscopy (31P-MRS) has the potential to reflect the energy metabolism of skeletal muscle in vivo. We sought to determine whether an altered mitochondrial energy metabolism of the muscle cell in patients with SALS can be detected by 31P-MRS, and to this end we recorded 31P-MR spectra of the gastrocnemius muscle of patients with ALS under a standardized isometric muscle exercise protocol. In a prospective setting we compared ten patients with sporadic ALS and 38 age-matched controls. The patients were characterized by a disease duration of approximate 18 months and classified as having probable to definite ALS by means of the revised El Escorial criteria. The time constant of oxidative PCr recovery after aerobic (tau1) and ischaemic muscle contraction (tau2) was used to determine the capacity of mitochondrial ATP formation. We found that mitochondrial impairment in skeletal muscle of patients with ALS could not be confirmed by 31P-MRS and therefore cannot be used as a surrogate factor of the diseas

Sulfides of Argysuksky gabbro massif (Northwest of Eastern Sayan)

Актуальность работы обусловлена необходимостью детального петрологического исследования многочисленных потенциально рудоносных мафит-ультрамафитовых массивов Канской глыбы Восточного Саяна с целью совершенствования региональных схем корреляции, а также выявления в них Pt-Cu-Ni оруденения. Цель работы: комплексное изучение сульфидной минерализации габброидов Аргысукского массива с целью оценки степени потенциальной перспективности интрузива на обнаружение в нем промышленного медно-никелевого оруденения. Методы исследования: изучение рудной минерализации в аншлифах с использованием поляризационного микроскопа Axio Scope Carl Zeiss; диагностика химического состава рудной минерализации методом рентгеноспектрального микроанализа с применением электронного сканирующего микроскопа Tescan Vega II LMU, оборудованного энергодисперсионным спектрометром (с полупроводниковым Si (Li) детектором INCA x-sight) INCA Energy 450 и волнодисперсионным спектрометром INCA Wave 700. Результаты. Впервые в габброидах Аргысукского массива проведена детальная диагностика сульфидной минерализации, которая увеличилась до 12 минеральных разновидностей. Изученная минерализация обнаруживает высокое сходство по своей специализации, минеральному набору и особенностям химизма с сульфидами из габброидов Талажинского массива, что также подтверждает ранее сделанное предположение о высоком сходстве этих объектов и их единой формационной природе. Типоморфизм и химические особенности сульфидов указывают на то, что их кристаллизация в габброидах происходила из исходного высокожелезистого сульфидного расплава в условиях повышенной фугитивности серы и значимой роли меди в рудной системе. Полученные результаты наряду с петрологическими особенностями позволяют предполагать высокую перспективность исследуемого массива на обнаружение Cu-Ni оруденения.The relevance of the work is caused by the need in detailed petrological studies of numerous potentially mineralized mafic-ultramafic massifs of the Kan block of the Eastern Sayan to improve the correlation of regional schemes, and to identify Pt-Cu-Ni mineralization in them. The main aim of the research is a complex study of sulfide mineralization of gabbroides of the Argysuksky massif in order to assess the degree of potential prospect of intrusion for detecting commercial copper-nickel mineralization in it. The methods: study of ore mineralization in polished sections using a polarizing microscope AxioScope Carl Zeiss; determination of chemical composition of ore mineralization by the method of X-ray spectrum microanalysis using scanning electron microscope Tescan Vega II LMU, equipped with energy-dispersive spectrometry (with a semiconductor Si (Li) detector INCA x-sight) INCA Energy 450 and wave-dispersive spectrometer INCA Wave 700. The results. The detailed diagnosis of sulfide mineralization was carried out in gabbroides of Argysuksky massif. The miniralization increased to 12 mineral varieties. The studied mineralization shows high similarity on specialization, mineral recruitment and chemistry with sulfides from gabbros of Talazhinsky massif, which further confirms the earlier assumption made about the high similarity of these objects and their assignment to a single formation type. Typomorphic and chemical features of sulphides indicate that their crystallization in gabbros occurred from the original high-iron sulfide melt at high sulfur fugacity and significant role of copper in ore system. The results obtained, along with petrological features, point out on great promise of the test massif for detection of Cu-Ni ores