Sainte Justine Hospital Research Center
Sainte Justine Hospital Research Center
Charfi I.,Sainte Justine Hospital Research Center |
Charfi I.,University of Montréal |
Audet N.,McGill University |
Bagheri Tudashki H.,Sainte Justine Hospital Research Center |
And 3 more authors.
British Journal of Pharmacology | Year: 2015
Opioids activate GPCRs to produce powerful analgesic actions but at the same time induce side effects and generate tolerance, which restrict their clinical use. Reducing this undesired response profile has remained a major goal of opioid research and the notion of 'biased agonism' is raising increasing interest as a means of separating therapeutic responses from unwanted side effects. However, to fully exploit this opportunity, it is necessary to confidently identify biased signals and evaluate which type of bias may support analgesia and which may lead to undesired effects. The development of new computational tools has made it possible to quantify ligand-dependent signalling and discriminate this component from confounders that may also yield biased responses. Here, we analyse different approaches to identify and quantify ligand-dependent bias and review different types of confounders. Focus is on δ opioid receptor ligands, which are currently viewed as promising agents for chronic pain management. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity © 2014 The British Pharmacological Society.
Lataster J.,Maastricht University |
Collip D.,Maastricht University |
Ceccarini J.,Catholic University of Leuven |
Haas D.,Maastricht University |
And 7 more authors.
NeuroImage | Year: 2011
Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D 2/3 PET radioligand [ 18F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [ 18F]fallypride. Psychosocial stress was initiated at 100min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [ 18F]fallypride displacement. Voxel-based statistical maps, representing specific D 2/3 binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone. © 2011 Elsevier Inc..
Ndiaye C.,University of Montréal |
Ndiaye C.,Sainte Justine Hospital Research Center |
Mena M.,Catalan Institute of Nanoscience and Nanotechnology |
Alemany L.,Catalan Institute of Nanoscience and Nanotechnology |
And 11 more authors.
The Lancet Oncology | Year: 2014
Background: We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis. Methods: We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16INK4a). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity. Findings: 148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82.2% (95% CI 77.7-86.4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45.8% (95% CI 38.9-52.9) for oropharynx, 22.1% (16.4-28.3) for larynx (including hypopharynx), and 24.2% (18.7-30.2) for oral cavity. The percent positivity of p16INK4a positive cases in HPV-positive oropharyngeal cancer cases was 86.7% (95% CI 79.2-92.9) and of E6/E7 mRNA positive cases was 86.9% (73.2-96.8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39.8% and of p16INK4a was 39.7%. Of subsites, tonsils (53.9%, 95% CI 46.4-61.3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption. Interpretation: The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines. Funding: European Commission. © 2014 Elsevier Ltd.
Kadoury S.,Philips |
Labelle H.,Sainte Justine Hospital Research Center |
Paragios N.,École Centrale Paris |
Paragios N.,French Institute for Research in Computer Science and Automation
Medical Image Analysis | Year: 2011
In this paper, we introduce a novel and efficient approach for inferring articulated 3D spine models from operative images. The problem is formulated as a Markov Random Field which has the ability to encode global structural dependencies to align CT volume images. A personalized geometrical model is first reconstructed from preoperative images before surgery, and subsequently decomposed as a series of intervertebral transformations based on rotation and translation parameters. The shape transformation between the standing and lying poses is achieved by optimizing the deformations applied to the intervertebral transformations. Singleton and pairwise potentials measure the support from the data and geometrical dependencies between neighboring vertebrae respectively, while higher-order cliques (groups of vertebrae) are introduced to integrate consistency in regional curves. Local vertebra modifications are achieved through a constrained mesh relaxation technique. Optimization of model parameters in a multimodal context is achieved using efficient linear programming and duality. Experimental and clinical evaluation of the vertebra model alignment obtained from the proposed method gave promising results. Quantitative comparison to expert identification yields an accuracy of 1.8 ± 0.7. mm based on the localization of surgical landmarks. © 2011 Elsevier B.V.
Nagi K.,Sainte Justine Hospital Research Center |
Nagi K.,University of Montréal |
Pineyro G.,Sainte Justine Hospital Research Center |
Pineyro G.,University of Montréal
Methods | Year: 2016
Signaling bias makes reference to the capacity of G-protein coupled receptor (GPCR) ligands to direct pharmacological stimuli to a subset of effectors among all of those controlled by the receptor. This new signaling modality has added texture to the classical notion of efficacy. In doing so, it has opened new avenues for the development of therapeutic GPCR ligands that specifically modulate signals underlying desired effects while sparing those that support undesired drug actions. Essential to taking advantage of this texture is the ability to identify, quantify and represent bias in a reliable and intuitive manner that ensures comparison among ligands. Here, we present a practical guide on how the operational model may be used to evaluate ligand efficiency to induce different responses, how differences in response may be used to estimate bias and how quantitative information derived from this analysis may be graphically represented to recreate a drug's unique signaling footprint. The approach used is discussed in terms of data interpretation and limitations that may influence the conclusions drawn from the analysis. © 2015 Elsevier Inc.
Pacis A.,Sainte Justine Hospital Research Center |
Pacis A.,University of Montréal |
Nedelec Y.,Sainte Justine Hospital Research Center |
Nedelec Y.,University of Montréal |
And 2 more authors.
Current Opinion in Immunology | Year: 2014
The response of host immune cells to microbial stimuli is dependent on robust and coordinated gene expression programs involving the transcription of thousands of genes. The dysregulation of such regulatory programs is likely to significantly contribute to the marked differences in susceptibility to infectious diseases observed among individuals and between human populations. Although the specific factors leading to a dysfunctional immune response to infection remain largely unknown, we are increasingly appreciating the importance of genetic variants in altering the expression levels of immune-related genes, possibly via epigenetic changes. This review describes how recent technological advances have profoundly contributed to our current understanding of the genetic architecture and the epigenetic rules controlling immune responses to infectious agents and how genetic and epigenetic data can be combined to unravel the mechanisms associated with host variation in transcriptional responses to infection. © 2014 Elsevier Ltd.
Laprise C.,University of Montréal |
Laprise C.,Sainte Justine Hospital Research Center |
Baril J.-G.,Clinique Medicale du Quartier Latin |
Dufresne S.,Clinique Medicale du Quartier Latin |
And 2 more authors.
AIDS Patient Care and STDs | Year: 2013
Hyperbilirubinemia is common among patients exposed to atazanavir (ATV), but its long-term significance is not well documented. The objective was to analyze hyperbilirubinemia (incidence, regression, determinants, and outcome) among 1150 HIV-positive patients followed-up in a prospective cohort between 2003 and 2012. Cumulative incidence of hyperbilirubinemia grades 3-4 and its probability of regression were estimated using Kaplan-Meier method. Cox proportional hazards model was used to study the determinants. Generalized estimating equation (GEE) regression was used to evaluate the association between hyperbilirubinemia grades 3-4 and adverse health outcome. Eight years cumulative incidence of hyperbilirubinemia was 83.6% (95% CI:79.0-87.7) and 6.6% (95% CI:4.7-9.2) among ATV users and non-users, respectively. This clinical outcome fluctuated considerably, as most patients exposed to ATV (91%) regressed, transiently, to lower grade at some point during follow-up. Determinants were atazanavir (HR=147.90, 95% CI: 33.64-604.18), ritonavir (HR=5.18, 95% CI:2.33-11.48), zidovudine (HR=2.62, 95% CI:1.07-6.46), and age (HR=1.04 95% CI:1.01-1.08). Alcohol consumption and others non-antiretroviral medications including hepatotoxic and recreational drugs were not available for analyses. Incidence of hyperbilirubinemia was very high among ATV users and, although regression to lower grade was frequent in the clinical follow-up of these patients, this was usually transient as the mean level of bilirubin stayed at a relatively high level. Importantly, long-term hyperbilirubinemia was not associated with adverse health outcome. © Copyright 2013, Mary Ann Liebert, Inc.
Brinkworth J.F.,Sainte Justine Hospital Research Center |
Brinkworth J.F.,University of Montréal |
Barreiro L.B.,Sainte Justine Hospital Research Center |
Barreiro L.B.,University of Montréal
Current Opinion in Immunology | Year: 2014
Chronic inflammatory and autoimmune diseases have been the focus of many genome-wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review. © 2014 Elsevier Ltd.
Kadoury S.,Philips |
Labelle H.,Sainte Justine Hospital Research Center
European Spine Journal | Year: 2012
Purpose Understanding how to classify and quantify three-dimensional (3D) spinal deformities remains an open question in adolescent idiopathic scoliosis. The objective of this study was to perform a 3D manifold characterization of scoliotic spines demonstrating thoracic deformations using a novel geometric and intuitive statistical tool to determine patterns in pathological cases. Methods Personalized 3D reconstructions of thoracic (T)/ lumbar (L) spines from a cohort of 170 Lenke Type-1 patients were analyzed with a non-linear manifold embedding algorithm in order to reduce the high-dimensionality of the data, using statistical properties of neighbouring spine models. We extracted sub-groups of the data from the underlying manifold structure using an unsupervised clustering algorithm to understand the inherent distribution and determine classes of pathologies which appear from the low-dimensional space. Results For Lenke Type-1 patients, four clusters were detected from the low-dimensional manifold of 3D models: (1) normal kyphosis (T) with hyper-lordosis (L) and high Cobb angles (37 cases), (2) low kyphosis (T) and normal lordosis (L), with high rotation of plane of maximum curvature (55 cases), (3) hypo-kyphotic (T) and hyperlordosis (L) (21 cases) and (4) hyper-kyphotic (T) with strong vertebral rotation (57 cases). Results show the manifold representation can potentially be useful for classification of 3D spinal pathologies such as idiopathic scoliosis and serve as a tool for understanding the progression of deformities in longitudinal studies. Conclusions Quantitative evaluation illustrates that the complex space of spine variability can be modeled by a low-dimensional manifold and shows the existence of an additional hyper-kyphotic subgroup from the cohort of 3D spine reconstructions of Lenke Type-1 patients when compared with previous findings on the 3D classification of spinal deformities. © 2011 Springer-Verlag.
Kaufman G.N.,Sainte Justine Hospital Research Center |
Zaouter C.,Sainte Justine Hospital Research Center |
Valteau B.,Sainte Justine Hospital Research Center |
Sirois P.,IPS Therapeutique Inc. |
And 2 more authors.
Arthritis Research and Therapy | Year: 2011
Introduction: Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.Methods: Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.Results: Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.Conclusions: BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management. © 2011 Kaufman et al.; licensee BioMed Central Ltd.