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Bonnelye E.,French Institute of Health and Medical Research | Reboul P.,Hospitalier Of Luniversite Of Montreal | Reboul P.,French National Center for Scientific Research | Duval N.,Pavillon des Charmilles | And 2 more authors.
Arthritis and Rheumatism | Year: 2011

Objective We reported previously that the orphan nuclear receptor, estrogen receptor-related receptor α (ERRα), is expressed in articular chondrocytes and is dysregulated in a mouse model of inflammatory arthritis. The aim of this study, therefore, was to determine whether ERRα is also dysregulated in patients with osteoarthritis (OA). Methods ERRα messenger RNA (mRNA) and protein were quantified in normal and OA cartilage samples and in OA chondrocytes in vitro, with and without short-term treatment with a variety of OA-associated factors and signaling pathway agonists and inhibitors. Results ERRα expression was lower in OA than in normal articular cartilage. Interleukin-1β (IL-1β) markedly up-regulated ERRα expression in OA chondrocytes in vitro, and agonist or inhibitor treatment indicated that the up-regulation was dependent on cyclooxygenase 2 (COX-2; NS398), prostaglandin E2, cAMP (8-bromo-cAMP), and protein kinase A (PKA; KT5720). Treatment with the ERRα inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERRα by IL-1β, suggesting autoregulation of ERRα in the IL-1β pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1β versus IL-1β alone, and the down-regulation of MMP-13 mRNA and protein observed with XCT790 alone suggests that the up-regulation of MMP-13 by IL-1β is ERRα-dependent. Conclusion We report the first evidence that ERRα expression is regulated by IL-1β in COX-2-, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERRα target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERRα may both respond to the healing signal and contribute to extracellular degradation in OA cartilage. Copyright © 2011 by the American College of Rheumatology.


Pausova Z.,University of Nottingham | Pausova Z.,Hospitalier Of Luniversite Of Montreal | Abrahamowicz M.,Montreal Neurological Institute | Mahboubi A.,Montreal Neurological Institute | And 7 more authors.
Hypertension | Year: 2010

Intra-abdominal accumulation of fat is a hallmark of male body-fat distribution and a major risk factor for hypertension. Sympathoactivation may be one of the mechanisms linking intra-abdominal obesity to hypertension. The aim of the present study was to investigate whether a functional variation in the androgen-receptor gene (AR, a variable number of CAG repeats in exon 1) is associated with intra-abdominal adiposity, sympathetic modulation of vasomotor tone, and blood pressure in adolescent boys but not girls. We studied 223 boys and 259 girls (age 12 to 18 years) from a French-Canadian founder population. Intra-abdominal fat and subcutaneous-abdominal fat were quantified with an MRI. Blood pressure was recorded beat-to-beat during an hour-long protocol including physical and mental challenges, and these blood pressure time series were used to assess sympathetic modulation of vasomotor tone by power spectral analysis. The results showed that boys with a "low" versus " intermediate" or "high" CAG-repeat number in AR demonstrated higher intra-abdominal fat (by 28% and 48%, respectively) but not subcutaneous-abdominal fat. These intra-abdominal fat differences remained significant after adjusting for serum levels of sex hormones and subcutaneous-abdominal fat. Furthermore, boys with low versus intermediate or high CAG-repeat numbers also showed higher blood pressure, with the differences being most pronounced during mental stress (8.0 and 8.5 mm Hg, respectively) and higher sympathetic modulation of vasomotor tone. As expected, no such differences were seen among girls. In adolescent boys, low CAG-repeat numbers in AR may be a genetic risk factor for intra-abdominal obesity and hypertension; sympathoactivation may be an underlying link between the 2 conditions. Copyright © 2010 American Heart Association. All rights reserved.


Vela C.,Hopital Maisonneuve Rosemont Recherche Ophtalmologie | Samson E.,Hopital Maisonneuve Rosemont Recherche Ophtalmologie | Zunzunegui M.V.,Hospitalier Of Luniversite Of Montreal | Haddad S.,Hospitalier Of Luniversite Of Montreal | And 3 more authors.
BMC Ophthalmology | Year: 2012

Background: The risk of visual impairment increases dramatically with age and therefore older adults should have their eyes examined at least every 1 to 2 years. Using a world-wide, population-based dataset, we sought to determine the frequency that older people had their eyes examined. We also examined factors associated with having a recent eye exam. Methods. The World Health Surveys were conducted in 70 countries throughout the world in 2002-2003 using a random, multi-stage, stratified, cluster sampling design. Participants 60 years and older from 52 countries (n = 35,839) were asked "When was the last time you had your eyes examined by a medical professional?". The income status of countries was estimated using gross national income per capita data from 2003 from the World Bank website. Prevalence estimates were adjusted to account for the complex sample design. Results: Overall, only 18% (95% CI 17, 19) of older adults had an eye exam in the last year. The rate of an eye exam in the last year in low, lower middle, upper middle, and high income countries was 10%, 24%, 22%, and 37% respectively. Factors associated with having an eye exam in the last year included older age, female gender, more education, urban residence, greater wealth, worse self-reported health, having diabetes, and wearing glasses or contact lenses (p < 0.05). Conclusions: Given that older adults often suffer from age-related but treatable conditions, they should be seen on a regular basis to prevent visual impairment and its disabling consequences. © 2012 Vela et al; licensee BioMed Central Ltd.


Lands L.C.,McGill University | Iskandar M.,McGill University | Beaudoin N.,Hospitalier Of Luniversite Of Montreal | Meehan B.,McGill University | And 2 more authors.
Journal of Medicinal Food | Year: 2010

Cystic fibrosis (CF) is characterized by malnutrition, chronic pulmonary inflammation, and oxidative stress. Whey protein is rich in sulfhydryl groups and is recognized for its ability to increase glutathione and reduce oxidative stress. Previously, we have shown that supplementation with whey increased intracellular glutathione levels in patients with CF. We have subsequently shown that hyperbaric pressure treatment of whey protein promotes the release of novel peptides for absorption, increases intracellular glutathione in healthy subjects, and reduces in vitro production of interleukin (IL)-8. We hypothesized that pressurized whey supplementation in children and adults with CF could have significant nutritional and anti-inflammatory benefits. A pilot open-label study of 1-month dietary supplementation with pressurized whey in CF patients was undertaken to assess the effects. Twenty-seven patients with CF (nine children, 18 adults) were enrolled. The dose of pressurized whey was 20g/day in patients less than 18 years of age and 40g/day in older patients. Anthropometric measures, pulmonary function, serum C-reactive protein (CRP), whole blood glutathione, and whole blood IL-8 and IL-6 responses to phytohemagglutinin (PHA) stimulation were measured at baseline and at 1 month. Three adults withdrew (one with gastrointestinal side effects, two with acute infection). Both children and adults showed enhancements in nutritional status, as assessed by body mass index. Children showed improvement in lung function (forced expiratory volume in 1 second). The majority of patients with an initially elevated CRP showed a decrease. PHA-stimulated IL-8 responses tended to decrease in the adults. Whole blood glutathione levels did not change. Thus, oral supplementation with pressurized whey improves nutritional status and can have additional beneficial effects on inflammation in patients with CF. © Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition 2010.


Masucci G.L.,Hospitalier Of Luniversite Of Montreal | Donath D.,Hospitalier Of Luniversite Of Montreal | Tetreault-Laflamme A.,Hospitalier Of Luniversite Of Montreal | Carrier J.-F.,Hospitalier Of Luniversite Of Montreal | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: To compare low (mean 0.44, SD ± 0.0163 mCi) with high source activity (0.61 ± 0.0178 mCi) in I125 permanent seed brachytherapy regarding seed loss, dosimetric outcome, and toxicity. Methods and Materials: The study included 199 patients with prostate cancer treated by permanent seed brachytherapy alone: the first 105 with seeds of lower activity (first cohort), the following 94 with higher seed activity (second cohort). The V100, V150, V200, and D90 were analyzed on the CT scan 30 days after implantation (CTD30). The V100, V150, and D2 of the rectum were also calculated on CTD30. Seed loss was determined 30 days after implantation. Urinary toxicity was measured with the International Prostate Symptom Score (IPSS) questionnaire. Results: Lower seed activity was associated with lower V150 and V200 (p = 0.01 and p ≤ 0.001, respectively) on CTD30. More patients had a V100 <90% and D90 <140 Gy in the lower activity cohort (p = 0.098 for D90 and p = 0.029 for V100) on CTD30. There was no difference between cohorts in dose to the rectum (p = 0.325-0.516) or difference in patients' IPSS score from baseline (p = 0.0.117-0.618), although there was a trend toward more urinary toxicity at 4 and 8 months for high activity seeds. Seed loss as a percentage of implanted seeds was not different (p = 0.324). Conclusions: Higher seed activity (I 125 ≥ 0.6 mCi) results in at least equal V100 and D90 on CTD30. However, dose inhomogeneity and a trend toward more urinary toxicity at 4 and 8 months after treatment may lead to a higher long-term urinary complications. © 2010 Elsevier Inc. All rights reserved.


Weghofer A.,Medical University of Vienna | Weghofer A.,The Center for Human Reproduction | Himaya E.,Hospitalier Of Luniversite Of Montreal | Kushnir V.A.,The Center for Human Reproduction | And 4 more authors.
Reproductive Biology and Endocrinology | Year: 2015

Background: Women with hyper-and hypothyroidism are at increased risk for infertility and adverse pregnancy outcomes. Whether in women considered euthyroid thyroid function (TSH values) and thyroid autoimmunity (thyroid antibodies) influence in vitro fertilization (IVF) cycle outcome has, however, remained controversial. Any such effect should be easily visible in women with low functional ovarian reserve (LFOR) and thus small oocyte and embryo numbers. Methods: We evaluated the relationship between TSH levels and embryo quality in euthyroid women with LFOR undergoing IVF. Mean age for the study population was 39.9 ± 4.6 years. Embryo quality was assessed in 431 embryos from 98 first IVF cycles according to TSH levels (with cut-off 2.5μIU/mL), and to presence versus absence of thyroid autoantibodies. Results: Mean Anti Mullerian hormone (AMH) was 0.8 ± 0.8 ng/mL and mean TSH was 1.8 ± 0.9 μIU/mL. Comparable embryo quality was observed in women with TSH ≤ and >2.5μIU/mL. TPO antibodies significantly affected embryo quality in women with low-normal TSH levels (P = 0.045). In women with high-normal TSH levels, increasing TSH had a negative impact on embryo quality (P = 0.027). A trend towards impaired embryo quality with TPO antibodies was also observed in these patients (p = 0.057). Conclusions: TPO antibodies affect embryo quality in euthyroid women with low-normal TSH ≤2.5 μIU/mL. In women with high-normal TSH levels, increasing TSH levels, and possibly TPO antibodies, appear to impair embryo quality. These results suggest that the negative impact of thyroid autoimmunity becomes apparent, once thyroid hormone function is optimized. © 2015 Weghofer et al.; licensee BioMed Central.


Ferguson R.,McGill University | Ramanakumar A.V.,McGill University | Richardson H.,Queen's University | Tellier P.-P.,McGill University | And 4 more authors.
Human Immunology | Year: 2011

Human leukocyte antigen (HLA)-E and HLA-G molecules act as powerful modulators of innate and adaptive immune responses. The study examined whether HLA-E and/or HLA-G polymorphisms are associated with human papillomavirus (HPV) infection susceptibility and persistence in 636 female university students in Montreal. HLA-G*01:01:02 and HLA-G*01:01:08 alleles were associated with increased risk of HPV-16 (odds ratio (OR) = 2.10, 95% confidence interval (CI), 1.11-3.96) and any infections with HPV types from α species 1, 8, 10, and 13 (OR = 2.72, 95% CI, 1.11-6.68). HLA-G*01:01:02 and HLA-G*01:03 alleles were associated with persistent HPV-16 (OR = 2.07, 95% CI, 1.16-3.68) and persistent infections with HPV types from α species 2, 3, 4, and 15 (OR = 2.99, 95% CI, 1.12-8.00). HLA-E polymorphism was not associated with risk of acquisition or persistence of HPV infection. These results suggest that HLA-G molecules may play a role in mediating HPV infection risk. © 2011 American Society for Histocompatibility and Immunogenetics.


Haddad P.,Hospitalier Of Luniversite Of Montreal | Dussault S.,Hospitalier Of Luniversite Of Montreal | Groleau J.,Hospitalier Of Luniversite Of Montreal | Turgeon J.,Hospitalier Of Luniversite Of Montreal | And 2 more authors.
Atherosclerosis | Year: 2011

Background: Hypercholesterolemia has been associated with impaired angiogenesis and reduced blood flow recuperation after ischemia. However, the precise mechanisms involved are unknown. Here we investigated the role of Nox2-derived reactive oxygen species (ROS) in the modulation of neovascularization by hypercholesterolemia. Methods and results: Mice deficient for the Nox2-containing NADPH oxidase (Nox2 -/-) and control mice (Nox2 +/+) were put on a high cholesterol diet (HCD) for a total of 15 weeks. After three months, hindlimb ischemia was surgically induced by femoral artery removal. Nox2 expression and oxidative stress levels in ischemic tissues were significantly increased by HCD in control mice, but not in Nox2 -/- mice. Nox2 -/- mice were also protected against hypercholesterolemia-induced impairment of neovascularization, as demonstrated by faster blood flow recovery after ischemia and increased capillary density in ischemic muscles. Nox2 deficiency was associated with preserved activity of eNOS in ischemic tissues, and improved activity of endothelial progenitor cells (EPCs). In vitro, HUVECs treated with the NADPH oxidase inhibitor apocynin or endothelial cells isolated from the aorta of Nox2 -/- mice exhibited reduced ROS formation following exposure to oxLDL. This was associated with improved nitric oxide (NO) bioavailability and protection against oxLDL-induced inhibition of angiogenic activities. Conclusions: Nox2-containing NADPH oxidase deficiency protects against hypercholesterolemia-induced impairment of neovascularization. The potential mechanisms involved include reduced ROS formation, preserved activation of angiogenic signals, and improved functional activities of EPCs and mature endothelial cells. © 2011 Elsevier Ireland Ltd.


Raghu G.,University of Washington | Million-Rousseau R.,Actelion Pharmaceuticals | Morganti A.,Actelion Pharmaceuticals | Perchenet L.,Actelion Pharmaceuticals | And 52 more authors.
European Respiratory Journal | Year: 2013

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Copyright © ERS 2013.


Sternberg C.N.,San Camillo and Forlanini Hospitals | Skoneczna I.A.,Center of Oncology of Poland | Castellano D.,University Hospital 12 Of Octubre | Theodore C.,Hopital Foch | And 8 more authors.
Oncology (Switzerland) | Year: 2013

Background: This open-label, randomized phase III trial evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as first-line treatment for locally advanced (T4b) or metastatic urothelial tract or bladder cancer. Methods: Patients were randomized to larotaxel 50 mg/m2 with cisplatin 75 mg/m2 every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 with cisplatin 70 mg/m2 on day 1 every 4 weeks (gemcitabine/cisplatin). The primary endpoint was overall survival (OS). Results: The trial was prematurely closed following the sponsor's decision to stop clinical development of larotaxel (n = 337 randomized). The larotaxel dose was reduced to 40 mg/m2 and cisplatin to 60 mg/m2 following a data monitoring committee safety review of the first 97 patients. At the time of analysis, the median OS was 13.7 months [95% confidence interval (CI) 11.2-17.1] with larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21; 95% CI 0.83-1.76; p = 0.33]. The median progression-free survival (PFS) was 5.6 months (95% CI 4.1-6.2) with larotaxel/cisplatin and 7.6 months (95% CI 6.6-9.1) with gemcitabine/cisplatin (HR 1.67; 95% CI 1.24-2.25). More myelosuppression was observed with gemcitabine/cisplatin. Conclusion: There was no difference in OS. Although the trial was closed prematurely, PFS appeared worse with larotaxel/cisplatin, suggesting that larotaxel/cisplatin does not improve outcomes versus cisplatin/gemcitabine. © 2013 S. Karger AG, Basel.

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