Center Hospitalier Of Luniversitede Montreal

Montréal, Canada

Center Hospitalier Of Luniversitede Montreal

Montréal, Canada
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Schneider R.,Center Hospitalier Of Luniversitede Montreal | Mohebiany A.N.,Center Hospitalier Of Luniversitede Montreal | Ifergan I.,Center Hospitalier Of Luniversitede Montreal | Beauseigle D.,Center Hospitalier Of Luniversitede Montreal | And 5 more authors.
Journal of Immunology | Year: 2011

Multiple lines of evidence suggest that CD8 T cells contribute to the pathogenesis of multiple sclerosis (MS). However, the sources and involvement of cytokines such as IL-15 in activating these cells is still unresolved. To investigate the role of IL-15 in enhancing the activation of CD8 T cells in the context of MS, we determined cell types expressing the bioactive surface IL-15 in the peripheral blood of patients and evaluated the impact of this cytokine on CD8 T cell cytotoxicity and migration. Flow cytometric analysis showed a significantly greater proportion of B cells and monocytes from MS patients expressing IL-15 relative to controls. We established that CD40L activation of B cells from healthy donors increased their IL-15 levels, reaching those of MS patients. We also demonstrated an enhanced cytotoxic profile in CD8 T cells from MS patients upon stimulation with IL-15. Furthermore, we showed that IL-15 expressed by B cells and monocytes is sufficient and functional, enhancing granzyme B production by CD8 T cells upon coculture. Exposure of CD8 T cells to this cytokine enhanced their ability to kill glial cells as well as to migrate across an in vitro inflamed human blood-brain barrier. The elevated levels of IL-15 in patients relative to controls, the greater susceptibility of CD8 T cells from patients to IL-15, in addition to the enhanced cytotoxic responses by IL-15-exposed CD8 T cells, stresses the potential of therapeutic strategies to reduce peripheral sources of IL-15 in MS. Copyright © 2011 by The American Association of Immunologists, Inc.

Rathore K.I.,McGill University | Berard J.L.,McGill University | Redensek A.,McGill University | Chierzi S.,McGill University | And 5 more authors.
Journal of Neuroscience | Year: 2011

Lipocalin 2 (Lcn2) plays an important role in defense against bacterial infection by interfering with bacterial iron acquisition. Although Lcn2 is expressed in a number of aseptic inflammatory conditions, its role in these conditions remains unclear. We examined the expression and role of Lcn2 after spinal cord injury (SCI) in adult mice by using a contusion injury model. Lcn2 expression at the protein level is rapidly increased 12-fold at 1 d after SCI and decreases gradually thereafter, being three times as high as control levels at 21 d after injury. Lcn2 expression is strongly induced after contusion injury in astrocytes, neurons, and neutrophils. The Lcn2 receptor (Lcn2R), which has been shown to influence cell survival, is also expressed after SCI in the same cell types. Lcn2-deficient (Lcn2 -/-) mice showed significantly better locomotor recovery after spinal cord contusion injury than wild-type (Lcn2 +/+) mice. Histological assessments indicate improved neuronal and tissue survival and greater sparing of myelin in Lcn2 -/-mice after contusion injury. Flow cytometry showed a decrease in neutrophil influx and a small increase in the monocyte population in Lcn2 -/-injured spinal cords. This change was accompanied by a reduction in the expression of several pro-inflammatory chemokines and cytokines as well as inducible nitric oxide synthase early after SCI in Lcn2 -/-mice compared with wild-type animals. Our results, therefore, suggest a role for Lcn2 in regulating inflammation in the injured spinal cord and that lack of Lcn2 reduces secondary damage and improves locomotor recovery after spinal cord contusion injury. © 2011 the authors.

Le Page C.,Center Hospitalier Of Luniversitede Montreal | Le Page C.,Institute Du Cancer Of Montreal | Kobel M.,University of Calgary | De Ladurantaye M.,Center Hospitalier Of Luniversitede Montreal | And 34 more authors.
Biopreservation and Biobanking | Year: 2013

Human biological specimens are important for translational research programs such as the Canadian Ovarian Experimental Unified Resource (COEUR) funded by the Terry Fox Research Institute. Sample quality is an important consideration, as it directly impacts the quality of ensuing research. The aim of the present study was to determine the quality of tissues collected from different sites contributing to the COEUR cohort. Samples from high-grade serous ovarian tumors (fresh frozen and corresponding paraffin-embedded tissues) were provided by nine participating Canadian biobanks. All samples were shipped to a central site using a Standard Operating Protocol (SOP). DNA and RNA extraction was conducted by the quality control division of the Canadian Tumor Repository Network (CTRNet). DNA quality was determined by ß-globin gene PCR amplification, and RNA quality by the RNA integrity number (RIN), as measured by the Agilent BioAnalyzer. DNA of acceptable quality had at least three bands of ß-globin amplified from DNA (n = 115/135), and a RIN number ‡ 7 was considered very good for RNA (n = 80/135). Sample preparation and storage time had little effect on RNA or DNA quality. Protein expression was assessed on tissue microarray by immunohistochemistry with antibodies against p53, WT1, E-cadherin, CK-7, and Ki67 from formalin fixed-paraffin embedded (FFPE) tissues. As seen with a nonhierarchical clustering statistical method, there was no significant difference in immunostaining of paraffin tissues among specimens from different biobanks. Interestingly, patients with worse outcome were highly positive for p53 and weak for WT1. In conclusion, while there was no common SOP for retrospectively collected material across Canadian biobanks, these results indicate that specimens collected at these multiple sites are of comparable quality, and can serve as an adequate resource to create a national cohort for the validation of molecular biomarkers in ovarian cancer. © 2013, Mary Ann Liebert, Inc.

Ryerson C.J.,University of British Columbia | Camp P.G.,University of British Columbia | Eves N.D.,University of British Columbia | Schaeffer M.,University of British Columbia | And 24 more authors.
Annals of the American Thoracic Society | Year: 2016

Rationale: Pulmonary rehabilitation improves dyspnea and exercise capacity in idiopathic pulmonary fibrosis (IPF); however, it is unknown whether breathing high amounts of oxygen during exercise training leads to further benefits. Objectives: Herein, we describe the design of the High Oxygen Delivery to Preserve Exercise Capacity in IPF Patients Treated with Nintedanib study (the HOPE-IPF study). The primary objective of this study is to determine the physiological and perceptual impact of breathing high levels of oxygen during exercise training in patients with IPF who are receiving antifibrotic therapy. Methods: HOPE-IPF is a two-arm double-blind multicenter randomized placebo-controlled trial of 88 patients with IPF treated with nintedanib. Patients will undergo 8 weeks of three times weekly aerobic cycle exercise training, breathing a hyperoxic gas mixture with a constant fraction of 60% inhaled oxygen, or breathing up to 40% oxygen as required to maintain an oxygen saturation level of at least 88%. Measurements and Main Results: End points will be assessed at baseline, postintervention (Week 8), and follow-up (Week 26). The primary analysis will compare the between-group baseline with posttraining change in endurance time during constant work rate cycle exercise tests. Additional analyses will evaluate the impact of training with high oxygen delivery on 6-minute walk distance, dyspnea, physical activity, and quality of life. Conclusions: The HOPE-IPF study will lead to a comprehensive understanding of IPF exercise physiology, with the potential to change clinical practice by indicating the need for increased delivery of supplementaloxygenduringpulmonary rehabilitationin patients with IPF. Clinical trial registered with (NCT02551068). Copyright © 2016 by the American Thoracic Society.

Zakrzewski-Jakubiak H.,University of Montréal | Doan J.,University of Montréal | Lamoureux P.,University of Montréal | Singh D.,University of Montréal | And 3 more authors.
American Journal Geriatric Pharmacotherapy | Year: 2011

Background: Polypharmacy increases the risk of cytochrome P450-based drugdrug interactions (CYP450-DDIs), leading to decreased therapeutic efficacy or increased drug toxicity. Objective: The aims of this study were to investigate the utility of a new CYP450-DDI software, InterMED-Rx, in aiding pharmacists in detecting CYP450-DDIs in hospitalized elderly patients and to ascertain pharmacists' agreement on how to intervene for each CYP450-DDI. Methods: A consensus panel of geriatric pharmacists first established guidelines for managing clinically relevant pharmacokinetic CYP450-DDIs. A prospective study was then conducted of patients newly admitted to a geriatric hospital whose pharmaceutical profile underwent analysis with InterMED-Rx. Rates and types of interventions were recorded. Results: Pharmacists' interrater agreement on how to manage CYP450-DDIs was initially only moderate (Cohen's κ, 0.51; 95% CI, 0.390.62), but improved subsequent to deliberation (Cohen's κ, 0.79; 95% CI, 0.700.88). Persistent disagreement involved interactions between 2 drugs with similar affinities for the same cytochrome. One hundred patients with polypharmacy (≥5 medications) aged 82.3 years (range, 65-96), with a mean (SD) of 12.2 (4.1) drugs (range, 527) were recruited for the prospective study. Eighty percent of patients had at least 1 CYP450 DDI detected with InterMED-Rx. A total of 238 CYP450-DDIs were identified involving CYP3A4 (70.2%), CYP2D6 (22.7%), and CYP2C9 (3.4%) substrates or inhibitors. Nineteen percent of patients received immediate medication adjustment, and 39% required follow-up of clinical signs, symptoms, and laboratory tests to determine whether future modification was needed. More than one half (56%) of all patients who required clinical follow-up had further medication adjustment prior to discharge. Conclusions: Use of the InterMED-Rx software identified elderly patients at risk for pharmacokinetic interactions and facilitated interventions aimed at reducing adverse drug events. Although consensus can be reached among pharmacists on how to intervene for many CYP450-DDI scenarios, certain situations allow for multiple intervention strategies. © 2011 Elsevier HS Journals, Inc. All rights reserved.

Pignol J.-P.,Erasmus University Rotterdam | Vu T.T.T.,Center Hospitalier Of Luniversitede Montreal | Mitera G.,University of Toronto | Bosnic S.,University of Toronto | And 2 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2015

Purpose: To prospectively capture acute toxicities and pain associated with postmastectomy radiation therapy (PMRT), to analyze patient and treatment risk factors for severe side effects. Methods and Materials: Women referred for PMRT were prospectively enrolled and assessed weekly during and after radiation therapy. The endpoint included severe National Cancer Institute Common Terminology Criteria for Adverse Effects grade 3 moist desquamation, other skin symptoms, and pain. Results: Of 257 patients, 73 (28.4%) experienced extensive moist desquamation, 84 (32.7%) Common Terminology Criteria for Adverse Effects skin toxicity grade 3, and 57 (22.2%) a pain impacting on daily life activities. Among symptoms only grade 3 moist desquamation was significantly associated with severe pain ( P <.001). On multivariate analysis, smoking, high-energy photons, and skin bolus were significantly associated with severe moist desquamation. Skin toxicity doubled for smokers, with 40% severe pain, 48% grade 3 moist desquamation, and 64% grade 3 skin toxicity. Without skin bolus 4.2% had severe pain, none moist desquamation, and 2.1% grade 3 skin toxicity. When skin bolus was used on alternate days, the frequency increased to 15% for pain, 22% for moist desquamation, and 26% for grade 3 skin toxicity. When bolus was used daily, 32% had pain, 41% moist desquamation, and 47% grade 3 skin toxicity. Symptoms peaked 1 to 2 weeks after the end of PMRT. Conclusions: The present cohort study suggests excessive radiation toxicity after PMRT. Among factors associated with an increase of toxicity are smoking habits and the use of skin bolus. © 2015 Elsevier Inc.

Gentric J.C.,Center Hospitalier Of Luniversite Of Montreal | Gentric J.C.,University of Western Brittany | Darsaut T.E.,University of Alberta | Makoyeva A.,Center Hospitalier Of Luniversite Of Montreal | And 3 more authors.
American Journal of Neuroradiology | Year: 2014

BACKGROUND AND PURPOSE: Flow diverters are designed to occlude aneurysms while preserving flow to jailed arterial branches. We postulated that treatment success depended on the size of the aneurysm ostium or defect in the parent artery.MATERIALS AND METHODS: Flow diverter expansion and deformation were studied in silicone tubes with wall apertures of various sizes. Large and giant canine sidewall aneurysms, featuring a branch located immediately opposite the aneurysm, and a smaller 6- to 8-mm (group A, n = 6) or a larger 10- to 16-mm (group B, n = 6) ostium were created to study the effects of ostium size on aneurysm or branch occlusion by flow diverters. Angiographic results after deployment and at 3 months were scored by using an ordinal scale. The amount of neointima formation on the segment of the device overlying the aneurysm or the branch ostia was determined by specimen photography.RESULTS: The fusiform deformation of flow diverters was maximal with larger defects in silicone tubes. At 3 months, group B aneurysms showed worse angiographic results than group A aneurysms, with larger residual aneurysm volumes (P = .002). Neointimal coverage of the aneurysm ostia was more complete in group A compared with group B (P = .002).CONCLUSIONS: The effects of flow diversion may vary with the size of the aneurysm ostium.

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