Efficacy and Tolerability of a 20-mg Dose of Methylphenidate for the Treatment of Daytime Sleepiness in Adult Patients With Myotonic Dystrophy Type 1: A 2-Center, Randomized, Double-Blind, Placebo-Controlled, 3-Week Crossover Trial
Puymirat J.,University of Quebec |
Bouchard J.-P.,Hopital de lEnfant Jesus |
Mathieu J.,Neuromuscular Clinic
Clinical Therapeutics | Year: 2012
Background: Despite the fact that excessive daytime sleepiness (EDS) is one of the most common manifestations in patients with myotonic dystrophy type 1 (DM1), no treatment is yet available. Methylphenidate is being studied for prospective use in the treatment of EDS. Objective: The aim of this investigator-initiated study was to evaluate the efficacy and tolerability of a single 20-mg morning dose of methylphenidate for the treatment of EDS in adults with DM1. Methods: This randomized, double-blind, placebo-controlled, 3-week crossover trial was conducted at 2 sites in Quebec. French-Canadian patients with DM1 with an Epworth Sleepiness Scale score ≥10 were invited to participate in this crossover trial of 20 mg/d of methylphenidate versus placebo, with 3 weeks in each arm of the study separated by a 2-week washout period. The primary efficacy end points were the Daytime Sleepiness Scale and the Epworth Sleepiness Scale at week 3. Secondary end points included the energy/vitality scale of the RAND 36-Item Health Survey, the Profile of Mood States questionnaire, and the mean sleep latency test. Assessment of tolerability profile included a physical examination, measurement of blood pressure, standard 12-lead ECG, and laboratory tests. Adverse event assessments were recorded based on patient reporting at each visit on clinical report forms. Results: In a total of 24 patients (12 men, 12 women; mean [SD] age, 46  years), 17 completed the study. Treatment with methylphenidate showed a significant change in median scores on the Daytime Sleepiness Scale (-3.0 vs -0.5; . P = 0.003) and the Epworth Sleepiness Scale (-3.0 vs -1.5; . P = 0.039). The Profile of Mood States and the energy/vitality scale from the RAND 36-Item Health Survey showed no significant changes. Likewise, there was no significant change in mean sleep latency test results. One patient died during the trial, but the autopsy results eliminated methylphenidate as cause of death. Three patients discontinued methylphenidate due to treatment-emergent adverse events (1, diarrhea; 2, nervousness and irritability). Loss of appetite, nausea, and palpitations were the most common adverse events reported by more patients treated with methylphenidate than those receiving placebo. Conclusion: A single 20-mg dose of methylphenidate significantly reduced daytime sleepiness in this small selected population of patients with DM1. . ClinicalTrials.gov identifier: . NCT01421992. © 2012 Elsevier HS Journals, Inc.
Zhao J.,University of Quebec |
Dupre N.,Hopital de lEnfant Jesus |
Puymirat J.,Unite de recherche genetique humaine |
Chahine M.,University of Quebec
Journal of Physiology | Year: 2012
M1476I, a French Canadian founder mutation of Na+ channel Nav1.4, causes potassium-aggravated myotonia, with cold-induced myotonia as the most distinctive clinical feature. Mexiletine, a class 1B local anaesthetic, relieves the myotonic symptoms of patients carrying the M1476I mutation. We used the patch-clamp method to investigate the functional characteristics of this mutation by heterologous expression in tsA201 cells. The M1476I mutation caused an increased persistent Na+ current, a 2- to 3-fold slower fast inactivation, a 6.4 mV depolarizing shift in the midpoint of steady-state inactivation, and an accelerated recovery from fast inactivation compared to the wild-type (WT) channel. Cooling slowed the kinetics of both channel types and increased the amplitude of the persistent current in M1476I channels. Mexiletine suppressed the persistent Na+ current generated by the M1476I mutation and blocked both WT and M1476I channels in a use-dependent manner. The inactivation-deficient M1476I channels were less susceptible to mexiletine during repetitive pulses. The decreased use-dependent block of M1476I channels might have resulted from the slower onset of mexiletine block, and/or the faster recovery from mexiletine block, given that the affinity of mexiletine for the inactivated state of the WT and mutant channels was similar. Increased extracellular concentrations of potassium had no effect on either M1476I or WT currents. These results indicated that cooling can augment the disruption of the voltage dependence of fast inactivation by M1476I channels. The therapeutic efficacy of mexiletine in M1476I carriers may be partly due to the open-channel block targeting the persistent Na+ currents generated by M1476I channels. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.
Chaleat-Valayer E.,Center Medico Chirurgical Of Readaptation Des Massues |
Mac-Thiong J.-M.,University of Montreal |
Paquet J.,Hopital de lEnfant Jesus |
Berthonnaud E.,University of Lyon |
And 2 more authors.
European Spine Journal | Year: 2011
Introduction: The differences in sagittal spino-pelvic alignment between adults with chronic low back pain (LBP) and the normal population are still poorly understood. In particular, it is still unknown if particular patterns of sagittal spino-pelvic alignment are more prevalent in chronic LBP. The current study helps to better understand the relationship between sagittal alignment and low back pain. Materials and methods: To compare the sagittal spino-pelvic alignment of patients with chronic LBP with a cohort of asymptomatic adults. Sagittal spino-pelvic alignment was evaluated in prospective cohorts of 198 patients with chronic LBP and 709 normal subjects. The two cohorts were compared with respect to the sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), lumbar lordosis (LL), lumbar tilt (LT), lordotic levels, thoracic kyphosis (TK), thoracic tilt (TT), kyphotic levels, and lumbosacral joint angle (LSA). Correlations between parameters were also assessed. Results: Sagittal spino-pelvic alignment is significantly different in chronic LBP with respect to SS, PI, LT, lordotic levels, TK, TT and LSA, but not PT, LL, and kyphotic levels. Correlations between parameters were similar for the two cohorts. As compared to normal adults, a greater proportion of patients with LBP presented low SS and LL associated with a small PI, while a greater proportion of normal subjects presented normal or high SS associated with normal or high PI. Conclusion: Sagittal spino-pelvic alignment was different between patients with chronic LBP and controls. In particular, there was a greater proportion of chronic LBP patients with low SS, low LL and small PI, suggesting the relationship between this specific pattern and the presence of chronic LBP. © 2011 Springer-Verlag.
English S.W.,Ottawa Hospital |
English S.W.,Ottawa Hospital Research Institute |
McIntyre L.,Ottawa Hospital |
McIntyre L.,Ottawa Hospital Research Institute |
And 9 more authors.
Journal of Clinical Epidemiology | Year: 2016
Objective We derived and validated a method to screen all hospital admissions for 1° subarachnoid hemorrhage (SAH) by retrospectively implementing recognized diagnostic criteria. Study Design and Setting A screen for 1° SAH was developed using two previously created registries. Screen-positive cases underwent diagnosis confirmation with primary record review. A review of all patient hospital encounters with the diagnostic code for 1° SAH, and cross-referencing with an existing SAH registry was undertaken to identify missed cases. Results Three subscreens were combined to form the 1° SAH screen (sensitivity: 98.4% [95% CI: 91.7-99.7%], specificity: 93.4% [95% CI: 90.4-95.4%], n = 455 patients in validation sample). From 1,699 screen-positive admissions between July 1, 2002 and June 30, 2011, we identified 831 true cases of SAH of which 632 patients had 1° SAH from ruptured aneurysm/arteriovenous malformation (sensitivity: 96.5% [95% CI: 94.8-97.8%], specificity: 40.3% [95% CI: 38.1-42.6%]). A review of all encounters with a diagnostic code for 1° SAH yielded additional 22 true cases. Conclusion When positive, our 1° SAH screen significantly increases the probability of this diagnosis in a particular hospitalization. The addition of patient hospitalizations encoded with the diagnostic code for 1° SAH improved sensitivity. Together, these methods represent the best way to retrospectively identify all cases of 1° SAH within an extensive sampling frame. © 2016 Elsevier Inc.
Jean J.,University of Quebec |
Jean J.,Laval University |
Soucy J.,Hopital de lEnfant Jesus |
Pouliot R.,University of Quebec |
Pouliot R.,Laval University
Tissue Engineering - Part A | Year: 2011
Psoriasis is a skin disease characterized by the presence of red plaques on the skin. This pathology is well-known to be a retinoid-sensitive disease. Previous investigations have shown that retinoids can modulate epidermal proliferation with an antiproliferative potential in hyperproliferative skins. The aim of this study was to compare the development of psoriatic substitutes cultured in a retinoic acid supplemented medium with those cultured in medium receiving no supplement, to define the effects of this growth factor on keratinocyte proliferation and differentiation. The self-assembly method was used to create substitutes. Characterization of the psoriatic substitutes was performed by histological and immunolabeling analyses. Results showed that psoriatic keratinocyte substitutes cultured with retinoic acid have a thinner epidermis compared with psoriatic keratinocyte substitutes cultured without this supplement. Further, the expression of all tested cell differentiation markers was restored in psoriatic keratinocyte substitutes cultured in presence of retinoic acid. No significant change in epidermal thickness or in the expression of late differentiation markers was observed in healthy keratinocyte substitutes cultured with or without retinoic acid; however, some changes were reported for proliferation and early differentiation markers. Results suggest that retinoic acid can modulate epidermal differentiation and proliferation with an antiproliferative potential in psoriatic substitutes such as observed in psoriatic skin in vivo. © Copyright 2011, Mary Ann Liebert, Inc.