Berry-Kravis E.,Rush University Medical Center |
Des Portes V.,University of Lyon |
Des Portes V.,French National Center for Scientific Research |
Hagerman R.,University of California at Davis |
And 12 more authors.
Science Translational Medicine | Year: 2016
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstreameffect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebocontrolled, parallel-group studies of mavoglurant in FXS, designed to confirmthis result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with fewadverse events. Therefore, under the conditions of our study, we could not confirmthemGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predictmavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.
Mollaei F.,Center for Research on Brain |
Mollaei F.,McGill University |
Shiller D.M.,Center for Research on Brain |
Shiller D.M.,Sainte Justine Research Center |
And 4 more authors.
Movement Disorders | Year: 2013
The basal ganglia are involved in establishing motor plans for a wide range of behaviors. Parkinson's disease (PD) is a manifestation of basal ganglia dysfunction associated with a deficit in sensorimotor integration and difficulty in acquiring new motor sequences, thereby affecting motor learning. Previous studies of sensorimotor integration and sensorimotor adaptation in PD have focused on limb movements using visual and force-field alterations. Here, we report the results from a sensorimotor adaptation experiment investigating the ability of PD patients to make speech motor adjustments to a constant and predictable auditory feedback manipulation. Participants produced speech while their auditory feedback was altered and maintained in a manner consistent with a change in tongue position. The degree of adaptation was associated with the severity of motor symptoms. The patients with PD exhibited adaptation to the induced sensory error; however, the degree of adaptation was reduced compared with healthy, age-matched control participants. The reduced capacity to adapt to a change in auditory feedback is consistent with reduced gain in the sensorimotor system for speech and with previous studies demonstrating limitations in the adaptation of limb movements after changes in visual feedback among patients with PD. © 2013 Movement Disorder Society.
Dave V.P.,Institute Of Recherches Cliniques Of Montreal Ircm |
Hajjar F.,Institute Of Recherches Cliniques Of Montreal Ircm |
Dieng M.M.,Sainte Justine Research Center |
Haddad E.,Sainte Justine Research Center |
And 3 more authors.
Retrovirology | Year: 2013
Background: Vpu is a multifunctional accessory protein that enhances the release of HIV-1 by counteracting the entrapment of nascent virions on infected cell surface mediated by BST2/Tetherin. Vpu-mediated BST2 antagonism involves physical association with BST2 and subsequent mislocalization of the restriction factor to intracellular compartments followed by SCF(β-TrCP) E3 ligase-dependent lysosomal degradation. Apart from BST2 antagonism, Vpu also induces down regulation of several immune molecules, including CD4 and SLAMF6/NTB-A, to evade host immune responses and promote viral dissemination. However, it should be noted that the multiple functions of Vpu have been studied in cell-based assays, and thus it remains unclear how Vpu influences the dynamic of HIV-1 infection in in vivo conditions.Results: Using a humanized mouse model of acute infection as well as CCR5-tropic HIV-1 that lack Vpu or encode WT Vpu or Vpu with mutations in the β-TrCP binding domain, we provide evidence that Vpu-mediated BST2 antagonism plays a crucial role in establishing early plasma viremia and viral dissemination. Interestingly, we also find that efficient HIV-1 release and dissemination are directly related to functional strength of Vpu in antagonizing BST2. Thus, reduced antagonism of BST2 due to β-TrCP binding domain mutations results in decreased plasma viremia and frequency of infected T cells, highlighting the importance of Vpu-mediated β-TrCP-dependent BST-2 degradation for optimal initial viral propagation.Conclusions: Overall, our findings suggest that BST2 antagonism by Vpu is critical for efficient early viral expansion and dissemination during acute infection and as such is likely to confer HIV-1 increased transmission fitness. © 2013 Dave et al.; licensee BioMed Central Ltd.
Herman K.M.,McGill University |
Sabiston C.M.,University of Toronto |
Mathieu M.-E.,University of Montréal |
Mathieu M.-E.,Sainte Justine Research Center |
And 2 more authors.
Preventive Medicine | Year: 2014
Objectives: Sedentary behavior (SB) is distinct from physical inactivity. Children's guidelines recommend ≤. 2. h/day screen time and ≥. 60. min/day moderate-to-vigorous physical activity (MVPA). This study describes SB in children at elevated risk of obesity, including the possibility of high SB in otherwise active children. Methods: Participants were 534 children from Quebec, Canada, aged 8-10. years with ≥. 1 obese parent in 2005-2008. SB and MVPA were measured by accelerometer and specific SBs by self-report, and height and weight were directly measured. Results: Overweight/obese children were significantly more sedentary overall and reported higher screen time than normal weight children. About 19% of boys and 46% of girls met screen time but not PA guidelines; 28% of boys and 5% of girls met PA but not screen time guidelines. About 46% of overweight/obese children met neither guideline (32% normal weight); only 5% overweight/obese children met both (21% normal weight). Reported behaviors contributed 60%-80% of total SB time; the most sedentary children had the most unaccounted for SB time. Conclusions: Overweight/obese children are more sedentary overall and report higher screen time than normal weight children. Public health efforts targeting PA and SB in children must consider sex and weight status while being cognizant that being sufficiently active is not exclusive of high levels of SB. © 2014 Elsevier Inc.
Elbared J.,Sainte Justine Research Center
Pharmacogenomics Journal | Year: 2015
Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8–12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.The Pharmacogenomics Journal advance online publication, 8 September 2015; doi:10.1038/tpj.2015.63. © 2015 Macmillan Publishers Limited
Patten S.A.,Sainte Justine Research Center |
Moldovan F.,University of Montréal
Medical Hypotheses | Year: 2011
Adolescent idiopathic scoliosis (AIS) is a condition characterized by a three-dimensional structural deformity of the spine. It is the most common type of spine deformity occurring in children aged 10 to maturity. Although the etiology of AIS still remains unknown, the role of genetic factors in the development of idiopathic scoliosis is widely accepted. However, to date no causative genes of AIS have been identified. Recently, the semicircular canals, which are part of the inner ear, were found to be morphologically abnormal in idiopathic scoliosis patients. Here we hypothesized that genetic predisposition to inner ear anomalies in AIS patients may be a strong factor in the generation of idiopathic scoliosis. The proposed idea is that gene defects could impair the development of the semicircular canals. A malformation of semicircular canals might affect the transmission of sensory signal about rotational movement of the body to the central nervous system; leading to an alteration in the neuronal circuit of balance. This will in turn affect body posture and results in the initiation of the curvature of the spine. This hypothesis may provide new insights in the understanding of the pathophysiologic mechanisms of idiopathic scoliosis. It can also offer hopes for potential early prediction of scoliosis. © 2010.
Arabkhari M.,University of Toronto |
Bunda S.,University of Toronto |
Wang Y.,University of Toronto |
Wang A.,University of Toronto |
And 2 more authors.
Glycobiology | Year: 2010
We recently established that the subunit of cell surfaceresiding elastin receptor, neuraminidase-1 (Neu1), can desialylate adjacent insulin-like growth factor 1 receptors (IGF-1R) of arterial smooth muscle cells, thereby quenching their proliferative response to insulin-like growth factor II. In this study, we explored whether Neu1 would also desialylate the insulin receptors (IR), as well as the IGF-1R on rat skeletal L6 myoblasts, and whether desialylation of IR and IGF-1R would affect a netproliferativeeffectofinsulin. First, we found that physiological (0.5-1 nM) and high therapeutic (10 nM) insulin concentrations induced a modest increase in proliferation rate of cultured L6 myoblasts. While IR kinase inhibitor could abolish the mitogenic effect of these insulin concentrations, the observed more pronounced proliferative response to supraphysiological concentration (100 nM) of insulin could be eliminated only by specific inhibition of IGF-1R. Then, we found that treatment of L6 cells with mouse-derived Neu1 or with Clostridium perfringens neuraminidase caused desialylation of IR, which coincided with a significant increase of their proliferative response to lower (0.5-10 nM) concentrations of insulin. In contrast, experimental desialylation of IGF-1R coincided with elimination of the heightened proliferative response of L6 myoblasts to 100 nM insulin. Importantly, we also found that inhibition of endogenous Neu1 abolished the increase in proliferation of L6 cells induced by 1 and 10 nM of insulin, but amplified the proliferative effect of 100 nM insulin. We therefore conclude that desialylation of both IR and IGF-1R by Neu1 controls the net proliferative response of skeletal myoblasts to insulin. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Pshezhetsky A.V.,Sainte Justine Research Center |
Pshezhetsky A.V.,University of Montréal |
Pshezhetsky A.V.,McGill University |
Hinek A.,University of Toronto
Glycoconjugate Journal | Year: 2011
Terminal sialic acid residues are found in abundance in glycan chains of glycoproteins and glycolipids on the surface of all live cells forming an outer layer of the cell originally known as glycocalyx. Their presence affects the molecular properties and structure of glycoconjugates, modifying their function and interactions with other molecules. Consequently, the sialylation state of glycoproteins and glycolipids has been recognized as a critical factor modulating molecular recognitions inside the cell, between the cells, between the cells and the extracellular matrix, and between the cells and certain exogenous pathogens. Sialyltransferases that attach sialic acid residues to the glycan chains in the process of their initial synthesis were thought to be mainly responsible for the creation and maintenance of a temporal and spatial diversity of sialylated moieties. However, the growing evidence also suggests that in mammalian cells, at least equally important roles belong to sialidases/neuraminidases, which are located on the cell surface and in intracellular compartments, and may either initiate the catabolism of sialoglycoconjugates or just cleave their sialic acid residues, and thereby contribute to temporal changes in their structure and functions. The current review summarizes emerging data demonstrating that neuraminidase 1 (NEU1), well known for its lysosomal catabolic function, can be also targeted to the cell surface and assume the previously unrecognized role as a structural and functional modulator of cellular receptors. © Springer Science+Business Media, LLC 2011.
De Vera M.A.,University of Montréal |
De Vera M.A.,Sainte Justine Research Center |
Berard A.,University of Montréal |
Berard A.,Sainte Justine Research Center
British Journal of Clinical Pharmacology | Year: 2012
AIM Due to their effect on altering physiological interactions between vasodilator and vasoconstrictor autacoids in normal pregnancies, antidepressants may be associated with the risk of pregnancy-induced hypertension. We evaluated the impact of antidepressant use during pregnancy on the risk of pregnancy-induced hypertension. METHODS We conducted a nested case-control study within the Quebec Pregnancy Registry, built by linkage of provincial medical, pharmaceutical, hospital and birth databases. We identified 1216 women with a diagnosis of pregnancy-induced hypertension with or without pre-eclampsia and with no history of hypertension before pregnancy. We randomly selected 10 controls for each case, matched on case index date (date of diagnosis) and gestational age. Odds ratios (OR) were calculated using conditional logistic regression models, adjusting for sociodemographic characteristics, maternal depression, anxiety, other chronic conditions, medication use and health service utilization. RESULTS Among cases, 45 (3.7%) had used antidepressants during pregnancy compared with 300 (2.5%) in the control group (OR 1.52, 95% CI 1.10, 2.09). After adjusting for potential confounders, use of antidepressants during pregnancy was significantly associated with increased risk of pregnancy-induced hypertension (OR 1.53, 95% CI 1.01, 2.33). In stratified analyses, use of selective serotonin re-uptake inhibitors (OR 1.60, 95% CI 1.00, 2.55), and more specifically, paroxetine (OR 1.81, 95% CI 1.02, 3.23) was associated with risk of pregnancy-induced hypertension. CONCLUSIONS Women who use antidepressants during pregnancy are at increased risk of pregnancy-induced hypertension with or without pre-eclampsia above and beyond the risk that could be attributed to their depression or anxiety disorders. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
Willot S.,CHU Ste Justine |
Gauthier C.,Sainte Justine Research Center |
Patey N.,Sainte Justine Research Center |
Faure C.,CHU Ste Justine |
Faure C.,Sainte Justine Research Center
Neurogastroenterology and Motility | Year: 2012
Background The enteric nervous system is a complex network that includes, in the digestive mucosa, neuronal bodies and fibers interacting with the immune system and mucosal mast cells (MC). These interactions involve the secretion of messengers, such as the neurotrophin nerve growth factor (NGF), which influence colonic motility and sensitivity, both affected in irritable bowel syndrome (IBS). This study was designed to test the hypothesis that, in children with IBS, colonic mucosal innervation, NGF content, and MC infiltration are altered. We aimed to measure MC infiltration, number of neuronal bodies, distance from MC to nerve fibers, inflammation, and NGF content in rectal mucosa of pediatric patients with IBS as compared with controls. Methods Rectal biopsies from children (median age: 14years) with diarrhea-predominant IBS (n=11) and controls (n=14) were studied. MC and neuronal mucosal structures were identified by tryptase, CD117 and PGP9.5 immunoreactivity. Inflammatory cells (neutrophils, eosinophils, and lymphocytes) were counted. NGF was quantified in situ by ELISA. Key Results No mucosal inflammation was detected in IBS. MC infiltration and number of neuronal bodies were not significantly different between IBS and controls. The distance between MC and nerve fibers was not different in IBS compared with controls (5.2±0.3 vs 5.0±0.3μm). Number of MC in close proximity to nerve fibers (<5μm) was not different in the two groups. However, in IBS, NGF content was higher than controls (0.93±0.3 vs 0.62±0.3pgmg-1 protein, P<0.05) and significantly correlated with MC number. Conclusions & Inferences Regardless of inflammation, NGF content is increased in rectal mucosa of diarrhea-predominant IBS children. © 2012 Blackwell Publishing Ltd.