Pronostic d'éveil et de non éveil dans le coma (étude de faisabilité)

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Translation termination efficiency modulates ATF4 response by regulating ATF4 mRNA translation at 5' short ORFs

International audienceThe activating transcription factor 4 (ATF4) promotes transcriptional upregulation of specific target genes in response to cellular stress. ATF4 expression is regulated at the translational level by two short open reading frames (uORFs) in its 5′-untranslated region (5′-UTR). Here, we describe a mechanism regulating ATF4 expression in translation termination-deficient human cells. Using microarray analysis of total RNA and polysome-associated mRNAs, we show that depletion of the eucaryotic release factor 3a (eRF3a) induces upregulation of ATF4 and of ATF4 target genes. We show that eRF3a depletion modifies ATF4 translational control at regulatory uORFs increasing ATF4 ORF translation. Finally, we show that the increase of REDD1 expression, one of the upregulated targets of ATF4, is responsible for the mTOR pathway inhibition in eRF3a-depleted cells. Our results shed light on the molecular mechanisms connecting eRF3a depletion to mammalian target of rapamycin (mTOR) pathway inhibition and give an example of ATF4 activation that bypasses the signal transduction cascade leading to the phosphorylation of eIF2α. We propose that in mammals, in which the 5′-UTR regulatory elements of ATF4 mRNA are strictly conserved, variations in translation termination efficiency allow the modulation of the ATF4 response

Parkinsonian central pain is linked to the connectivity of the nucleus accumbens and the anterior insula

International audiencePain is a frequent and disabling non-motor symptom of Parkinson’s Disease (PD). Yet, no treatment to date can efficiently reduce this pain. This article investigates the brain functional connectivity of PD patients with central pain and the effects of levodopa and oxycodone on this connectivity.Thirty-eight PD patients received either levodopa, oxycodone, or a placebo during an eight-week period. Pain intensity was evaluated using the Visual Analogue Scale and resting-state functional connectivity was measured before and after treatments. PD patients were also separated into two groups: responders and non-responders.At baseline, the intensity of pain was correlated with the connectivity between the anterior insula and the posterior cingulate cortex and between the nucleus accumbens, the brainstem, and the hippocampus. Levodopa and oxycodone had no specific effects on functional connectivity. Responders had a decrease in connectivity between the anterior insula and the posterior cingulate cortex, while non-responders showed an increase in connectivity.The correlation between pain intensity and specific brain connectivity may represent a “hyper-awareness” of pain and a distortion of learning and memory systems in PD patients with central pain, leading to a state of chronic pain. The placebo effect could explain the changes in connectivity that are associated with a potential reduction in pain awareness

Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial

International audienceBackground: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. Objectives We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone‐ prolonged‐release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP.Methods: OXYDOPA was a randomized, double‐blind, double‐dummy, placebo‐controlled, multicenter parallel‐group trial run at 15 centers within the French NS‐Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone‐PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add‐on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week‐10 based on modified intention‐to‐treat analyses.Results: Between May 2016 and August 2020, 66 patients were randomized to oxycodone‐PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was −17 ± 18.5 on oxycodone‐PR, −8.3 ± 11.1 on levodopa/benserazide, and −14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was −1.54 (97.5% confidence interval [CI], −17.0 to 13.90; P = 0.8) on oxycodone‐PR and +7.79 (97.5% CI, −4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all‐cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone‐PR (39%) than levodopa/benserazide (5%) or placebo (15%).Conclusions: The present trial failed to demonstrate the superiority of oxycodone‐PR or a higher dose of levodopa in patients with PCP, while oxycodone‐PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Trial of Lixisenatide in Early Parkinson’s Disease

International audienceBackground: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease.Methods: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent.Results: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%.Conclusions: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial

IntroductionPolyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.MethodsWe assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores.ResultsThe mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests.ConclusionsSpecially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017

Amantadine use in the French prospective NS-Park cohort

International audienceObjective: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD).Background: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres.Methods: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis).Results: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users.Conclusions: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs