Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

BACKGROUND: More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa. OBJECTIVES: The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone. METHODS: In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. RESULTS: After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P<O.01 v placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (P<0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (P<0.05), "on" time increased by 21.3% (P<0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (P<0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100 mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhea. CONCLUSION: Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy

Validation of the Multiple Sclerosis International Quality of Life questionnaire

This study aims to validate the Multiple Sclerosis (MS) International Quality of Life (MusiQoL) questionnaire, a multi-dimensional, self-administered questionnaire, available in 14 languages, as a disease-specific quality of life scale that can be applied internationally. A total of 1992 patients with different types and severities of MS from 15 countries were recruited. At baseline and day 21 ± 7, each patient completed the MusiQoL, a symptom checklist and the short-form (SF)-36 QoL questionnaire. Neurologists also collected socio-demographic, MS history and outcome data. The database was randomly divided into two subgroups and analysed according to different patient characteristics. For each model, psychometric properties were tested and the number of items was reduced by various statistical methods. Construct validity, internal consistency, reproducibility and external consistency were also tested. Nine dimensions, explaining 71% of the total variance, were isolated. Internal consistency and reproducibility were satisfactory for all the dimensions. External validity testing revealed that dimension scores correlated significantly with all SF-36 scores, but showed discriminant validity by gender, socio-economic and health status. Significant correlations were found between activity in daily life scores and clinical indices. These results demonstrate the validity and reliability of the MusiQoL as an international scale to evaluate QoL in patients with MS. © 2008 SAGE Publications

Supplementary Material for: Modelling and Prediction of 25-Hydroxyvitamin D Levels in Norwegian Relapsing-Remitting Multiple Sclerosis Patients

<b><i>Background/Aim:</i></b> 25-Hydroxyvitamin D (25(OH)D) levels are suggested to influence the susceptibility and risk of disease progression in multiple sclerosis (MS). Seasonal fluctuation of 25(OH)D levels may differ in magnitude between individuals. The purpose of this paper was to model the seasonal fluctuation of vitamin D in Norwegian MS patients and to examine to which extent one single 25(OH)D measurement predicts the level at other time points throughout the year. <b><i>Methods:</i></b> During December 2004 and July 2008, 762 serum samples were collected from 92 Norwegian relapsing-remitting MS patients. Time series analysis and multivariate modelling techniques were used to model seasonal fluctuations and intra- and inter-individual variations in 25(OH)D values. <b><i>Results:</i></b> Most patients reached their lowest 25(OH)D level in March/April and the highest in July/August. There were substantial intra-individual variations in the extent of seasonal fluctuation, with 36.6% of explainable variation in seasonally adjusted 25(OH)D levels (on a logarithmic scale) attributable to the patient level. The remaining 63.4% could be accounted for by sources of inter-individual variation. Both the total and inter-individual variabilities were lowest in February, and the prediction interval in this month was up to 26% narrower compared to other months. The prediction intervals would be at least 21% wider with only one observation available per patient. <b><i>Conclusions:</i></b> The seasonal fluctuations of 25(OH)D levels in Norwegian relapsing-remitting MS patients are subject to pronounced intra- and inter-individual variation. The most representative measurements of 25(OH)D levels are taken in February

Prospects for a survey of the Galactic plane with the Cherenkov Telescope Array

International audienceApproximately one hundred sources of very-high-energy (VHE) gamma rays are known in the Milky Way. A survey of the entire Galactic Plane in the energy range from a few tens of GeV to a few hundred TeV has been proposed as a Key Science Project for the upcoming Cherenkov Telescope Array Observatory (CTAO). This article presents the status of the studies towards the Galactic Plane Survey (GPS). We build and make publicly available a sky model that combines data from observations of known gamma-ray emitters with state-of-the-art physically-driven models of synthetic populations of the main classes of established Galactic VHE sources, as well as of interstellar emission from cosmic-ray interactions in the Milky Way. We also perform an optimisation of the observation strategy. We use the improved sky model and observation strategy to simulate GPS data that are analysed using the methods and software tools under development for real data. We show that the GPS has the potential to increase the number of known Galactic VHE emitters by almost a factor of five. This corresponds to the detection of more than two hundred pulsar wind nebulae and a few tens of supernova remnants at average integral fluxes one order of magnitude lower than in the existing sample above 1 TeV, therefore opening the possibility to perform unprecedented population studies. The GPS also has the potential to provide new VHE detections of binary systems and pulsars, and to identify any bright PeVatrons. Furthermore, the GPS will constitute a pathfinder for deeper follow-up observations of these source classes. Finally, we show that we can extract from GPS data an estimate of the contribution to diffuse emission from unresolved sources, and that there are good prospects of detecting interstellar emission and statistically distinguishing different scenarios. (Abridged

Prospects for a survey of the Galactic plane with the Cherenkov Telescope Array

International audienceApproximately one hundred sources of very-high-energy (VHE) gamma rays are known in the Milky Way. A survey of the entire Galactic Plane in the energy range from a few tens of GeV to a few hundred TeV has been proposed as a Key Science Project for the upcoming Cherenkov Telescope Array Observatory (CTAO). This article presents the status of the studies towards the Galactic Plane Survey (GPS). We build and make publicly available a sky model that combines data from observations of known gamma-ray emitters with state-of-the-art physically-driven models of synthetic populations of the main classes of established Galactic VHE sources, as well as of interstellar emission from cosmic-ray interactions in the Milky Way. We also perform an optimisation of the observation strategy. We use the improved sky model and observation strategy to simulate GPS data that are analysed using the methods and software tools under development for real data. We show that the GPS has the potential to increase the number of known Galactic VHE emitters by almost a factor of five. This corresponds to the detection of more than two hundred pulsar wind nebulae and a few tens of supernova remnants at average integral fluxes one order of magnitude lower than in the existing sample above 1 TeV, therefore opening the possibility to perform unprecedented population studies. The GPS also has the potential to provide new VHE detections of binary systems and pulsars, and to identify any bright PeVatrons. Furthermore, the GPS will constitute a pathfinder for deeper follow-up observations of these source classes. Finally, we show that we can extract from GPS data an estimate of the contribution to diffuse emission from unresolved sources, and that there are good prospects of detecting interstellar emission and statistically distinguishing different scenarios. (Abridged

Prospects for a survey of the Galactic plane with the Cherenkov Telescope Array

International audienceApproximately one hundred sources of very-high-energy (VHE) gamma rays are known in the Milky Way. A survey of the entire Galactic Plane in the energy range from a few tens of GeV to a few hundred TeV has been proposed as a Key Science Project for the upcoming Cherenkov Telescope Array Observatory (CTAO). This article presents the status of the studies towards the Galactic Plane Survey (GPS). We build and make publicly available a sky model that combines data from observations of known gamma-ray emitters with state-of-the-art physically-driven models of synthetic populations of the main classes of established Galactic VHE sources, as well as of interstellar emission from cosmic-ray interactions in the Milky Way. We also perform an optimisation of the observation strategy. We use the improved sky model and observation strategy to simulate GPS data that are analysed using the methods and software tools under development for real data. We show that the GPS has the potential to increase the number of known Galactic VHE emitters by almost a factor of five. This corresponds to the detection of more than two hundred pulsar wind nebulae and a few tens of supernova remnants at average integral fluxes one order of magnitude lower than in the existing sample above 1 TeV, therefore opening the possibility to perform unprecedented population studies. The GPS also has the potential to provide new VHE detections of binary systems and pulsars, and to identify any bright PeVatrons. Furthermore, the GPS will constitute a pathfinder for deeper follow-up observations of these source classes. Finally, we show that we can extract from GPS data an estimate of the contribution to diffuse emission from unresolved sources, and that there are good prospects of detecting interstellar emission and statistically distinguishing different scenarios. (Abridged