Platelet Serotonin Level Predicts Survival in Amyotrophic Lateral Sclerosis

International audienceBACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown. METHODOLOGY: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects. PRINCIPAL FINDINGS: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. CONCLUSIONS/SIGNIFICANCE: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease

Construction and first tests of a PET-like detector for hadrontherapy beam ballistic control

International audienceWe present the first results obtained with a detector, called Large Area Pixelized Detector (LAPD), dedicated to the beam ballistic control in the context of hadrontherapy. The purpose is to control the ballistics of the beam delivered to the patient by in-beam and real time detection of secondary particles, emitted during its irradiation. These particles could be high energy photons (prompt γ), or charged particles like protons, or 511 keV γ from the annihilation of a positron issued from the β+ emitters induced in the patient tissues along the beam path. These methods require being able to detect with a huge efficiency, and with a minimum dead time, these secondary particles emitted when the beam hits the patient. The LAPD is similar to a conventional Positron Emission Tomography camera. The 511keV γ are detected and the reconstructed line of responses allow to measure the β+ activity distribution. Nevertheless, when trying to use γ from positron annihilations for the ballistic control in hadrontherapy, the large γ prompt background should be taken into account and properly rejected. This detector is made of two half-rings of 120 channels each. Each channel consists of a 13*13*15 mm3 LYSO crystal glued to a PMT. The PMT signal is sent to an Analog Sampling Module (ASM board). ThisVME 6U board is based on the DRS4 chip technology (Switch Capacitor Array) from the Paul Sherrer Institute and was specially designed for the LAPD detector. This board receives up to 24 differential analog input signals, with maximum amplitude of 600 mV, digitized by 12 bits - 33 MHz ADC. The sampling rate varies between 1 and 5 GHz, for a maximum buffer size of 1024 samples. The first part of the talk is devoted to the description of the detector and its electronics. Then, we describe the various trigger strategy, and the on-going upgrade of the VME-based acquisition system to a μTCA-based technology. The selection of the coincident 511 keV γ is also discussed, and the reconstruction using aniterative MLEM algorithm is presented. In the last part of the talk, few results from an experiment with one third of the detector, using proton and carbon ion beams at the Heidelberg Ion-Beam Therapy Center in 2014, are also described, and the Coincidence Resolution Time and energy resolution are given. First reconstruction results, obtained with a phantom filled with a high intensity FDG source at the cancer research center of Clermont-Ferrand in 2015 are also shown. This detector is now characterized, and will be installed at the Lacassagne hadrontherapy center (Nice, France), on the 65 MeV line (Medicyc) in December 2015 first, and on the future 230 MeV line (S2C2 from IBA) in 2016. The capability of this detector and its associated electronics to measure the ballistic of the proton beam in real clinical conditions with a sufficient precision will be evaluated

Mutation spectrum in the large GTPase dynamin 2, and genotype–phenotype correlation in autosomal dominant centronuclear myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 ( DNM2 ), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM‐related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice‐site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue‐specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. Hum Mutat 33:949–959, 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92087/1/22067_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/92087/2/humu_22067_sm_SuppInfo.pd

Search for Scalar Diphoton Resonances in the Mass Range 65−60065-600 GeV with the ATLAS Detector in pppp Collision Data at s\sqrt{s} = 8 TeVTeV

A search for scalar particles decaying via narrow resonances into two photons in the mass range 65–600 GeV is performed using $20.3\text{}\text{}{\mathrm{fb}}^{-1}$ of $\sqrt{s}=8\text{}\text{}\mathrm{TeV}$ $pp$ collision data collected with the ATLAS detector at the Large Hadron Collider. The recently discovered Higgs boson is treated as a background. No significant evidence for an additional signal is observed. The results are presented as limits at the 95% confidence level on the production cross section of a scalar boson times branching ratio into two photons, in a fiducial volume where the reconstruction efficiency is approximately independent of the event topology. The upper limits set extend over a considerably wider mass range than previous searches