Management of the ataxias : towards best clinical practice

This document aims to provide recommendations for healthcare professionals on the diagnosis and management of people with progressive ataxia. The progressive ataxias are rare neurological conditions, and are often poorly understood by healthcare professionals. Diagnosis has generally been a long process because of the rarity and complexity of the different ataxias1. In addition, many healthcare professionals are unsure how best to manage the conditions and there is sometimes a feeling that little can be done for these patients1,2 Although there are no disease-modifying treatments for the majority of the progressive ataxias, there are many aspects of the conditions that are treatable and it is thus important that this is recognised by the relevant healthcare professionals. The diagnosis and management of the few treatable causes is also of paramount importance. All this highlights the importance of producing these guidelines: in order to increase awareness and understanding of these conditions, and lead to their improved diagnosis and management. With new developments in genetic technologies and the discovery of more genes, diagnosis is improving and has great scope to continue to do so. In addition, research is advancing and many human trials to test medications are taking place, making us more optimistic that disease-modifying treatments will be found for the progressive ataxias

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Interrelation between arterial inflammation in acute coronary syndrome and circadian variation

At present, the study into inflammatory markers has become a new tool which is most useful for establishing the prognosis of patients with acute coronary syndrome. The inflammatory substrate involved is acute coronary syndrome is extremely complex, with a large number of factors involved both in its activation and its modulation. It is known that C-reactive protein play a key role in the physiopathology of the atherosclerosis. Furthermore, scientific literature reports that the existence of a circadian rhythm in the triggering of cardiovascular accidents can suggest the implication of, or association with these physiological rhythms that show activity peaks at particular times of the day or night. Keeping in mind the potential association between inflammation and circadian rhythm, a better understanding of the kinetics of said markers could lead to improvements in their use in cardiovascular diseases. Considering the diversity of the diurnal variations in the intrinsic properties of the cardiovascular system, these should be kept in mind during the design of in vivo experimental studies. As such, the information available reinforces our opinion when suitably validating the biomarkers and the need to demonstrate their reliability, stability, and lack of variability and standardise the methodology of their measurement

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Underlying Event measurements in pp collisions at s=0.9 \sqrt {s} = 0.9 and 7 TeV with the ALICE experiment at the LHC

We present measurements of Underlying Event observables in pp collisions at s√=0.9 and 7TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p T,LT in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p T thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2–3 between the lower and higher collision energies, depending on the track p T threshold considered. Data are compared to Pythia 6.4, Pythia 8.1 and Phojet. On average, all models considered underestimate the multiplicity and summed p T in the Transverse region by about 10–30%

Underlying Event measurements in pp collisions at root s=0.9 and 7 TeV with the ALICE experiment at the LHC

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)We present measurements of Underlying Event observables in pp collisions at root s = 0 : 9 and 7 TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p(T),L-T in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p(T) thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2-3 between the lower and higher collision energies, depending on the track p(T) threshold considered. Data are compared to PYTHIA 6.4, PYTHIA 8.1 and PHOJET. On average, all models considered underestimate the multiplicity and summed p(T) in the Transverse region by about 10-30%.7Calouste Gulbenkian Foundation from LisbonSwiss Fonds Kidagan, ArmeniaConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Financiadora de Estudos e Projetos (FINEP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)National Natural Science Foundation of China (NSFC)Chinese Ministry of Education (CMOE)Ministry of Science and Technology of China (MSTC)Ministry of Education and Youth of the Czech RepublicDanish Natural Science Research CouncilCarlsberg FoundationDanish National Research FoundationEuropean Research Council under European CommunityHelsinki Institute of PhysicsAcademy of FinlandFrench CNRS-IN2P3Region Pays de LoireRegion AlsaceRegion AuvergneCEA, FranceGerman BMBFHelmholtz AssociationGeneral Secretariat for Research and Technology, Ministry of Development, GreeceHungarian OTKANational Office for Research and Technology (NKTH)Department of Atomic EnergyDepartment of Science and Technology of the Government of IndiaIstituto Nazionale di Fisica Nucleare (INFN) of ItalyMEXT, JapanJoint Institute for Nuclear Research, DubnaNational Research Foundation of Korea (NRF)CONACYTDGAPA, MexicoALFA-ECHELEN Program (High-Energy physics Latin-American-European Network)Stichting voor Fundamenteel Onderzoek der Materie (FOM)Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), NetherlandsResearch Council of Norway (NFR)Polish Ministry of Science and Higher EducationNational Authority for Scientific Research - NASR (Autoritatea Nationala pentru Cercetare Stiintifica - ANCS)Federal Agency of Science of the Ministry of Education and Science of Russian FederationInternational Science and Technology Center, Russian Academy of SciencesRussian Federal Agency of Atomic EnergyRussian Federal Agency for Science and InnovationsCERN-INTASMinistry of Education of SlovakiaDepartment of Science and Technology, South AfricaCIEMATEELAMinisterio de Educacion y Ciencia of SpainXunta de Galicia (Conselleria de Educacion)CEADENCubaenergia, CubaIAEA (International Atomic Energy Agency)Swedish Reseach Council (VR)Knut & Alice Wallenberg Foundation (KAW)Ukraine Ministry of Education and ScienceUnited Kingdom Science and Technology Facilities Council (STFC)The United States Department of EnergyUnited States National Science FoundationState of TexasState of OhioFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq