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Leprohon P.,Faculte Of Medecine Of Luniversite Laval | Fernandez-Prada C.,Faculte Of Medecine Of Luniversite Laval | Gazanion T.,Faculte Of Medecine Of Luniversite Laval | Monte-Neto R.,Faculte Of Medecine Of Luniversite Laval | Ouellette M.,Faculte Of Medecine Of Luniversite Laval
International Journal for Parasitology: Drugs and Drug Resistance | Year: 2015

The use of next generation sequencing has the power to expedite the identification of drug resistance determinants and biomarkers and was applied successfully to drug resistance studies in Leishmania. This allowed the identification of modulation in gene expression, gene dosage alterations, changes in chromosome copy numbers and single nucleotide polymorphisms that correlated with resistance in Leishmania strains derived from the laboratory and from the field. An impressive heterogeneity at the population level was also observed, individual clones within populations often differing in both genotypes and phenotypes, hence complicating the elucidation of resistance mechanisms. This review summarizes the most recent highlights that whole genome sequencing brought to our understanding of Leishmania drug resistance and likely new directions. © 2014 The Authors.


Labelle Y.,Faculte Of Medecine Of Luniversite Laval
Tumor Biology | Year: 2012

Approximately 75 % of extraskeletal myxoid chondrosarcoma tumors (EMC) harbor a t(9;22) chromosome translocation generating an EWS/NR4A3 fusion protein that is thought to be instrumental in the tumoral process. Current evidence suggests that one function of the fusion protein is to overexpress target genes. We have generated an in vitro human cellular model in which the fusion protein is expressed in mesenchymal bone marrow stem cells. We have performed microarray analyses of these cells and identified several genes overexpressed in the presence of EWS/NR4A3 which are also overexpressed in EMC tumors. These genes and their products represent potential therapeutic targets for EMC tumors. © 2012 International Society of Oncology and BioMarkers (ISOBM).


PubMed | Memorial University of Newfoundland, Malden and UMC St Radboud Nijmegen, Womens College Hospital, FRCPC and 5 more.
Type: Journal Article | Journal: Journal of cutaneous medicine and surgery | Year: 2015

Onychomycosis is a difficult-to-treat infection whose current treatment paradigm relies primarily on oral antifungals. The emergence of new topical drugs broadens the therapeutic options and prompts a re-evaluation of the current Canadian treatment strategy.To define a patient-centred Canadian treatment strategy for onychomycosis.An expert panel of doctors who treat onychomycosis was convened. A systematic review of the literature on treatments for onychomycosis was conducted. Based on the results, a survey was designed to determine a consensus treatment system.First-line therapy should be selected based on nail plate involvement, with terbinafine for severe onychomycosis (>60% involvement), terbinafine or efinaconazole for moderate onychomycosis (20%-60% involvement), and efinaconazole for mild onychomycosis (<20% involvement). Comorbidities, patient preference and adherence, or nail thickness may result in the use of alternative oral or topical antifungals.These guidelines allow healthcare providers and patients to make informed choices about preventing and treating onychomycosis.


Leblanc M.-E.,University of Québec | Leblanc M.-E.,Faculte Of Pharmacie Of Luniversite Laval | Croteau S.,University of Québec | Ferland A.,University of Québec | And 13 more authors.
Obesity | Year: 2013

Objective Obesity is frequently associated with systemic hypertension. Blood pressure measure is inaccurate in severely obese patients because of poor cuff size fitting. The aim of the study is to assess the degree of agreement between the intra-arterial method as the gold standard vs. noninvasive methods, i.e., forearm blood pressure and upper-arm blood pressure measures. Design and Methods A total of 1285 measures of intra-arterial and forearm blood pressure were taken in 51 severely obese patients in a supine position in the operating and the recovery room. A subset of 352 upper-arm measures were taken in the recovery room and compared to the intra-arterial and the forearm methods. Results Correlation between the intra-arterial and the forearm measures was 0.90 (P < 0.001) for the 2570 data (systolic and diastolic). Compared to intra-arterial, the forearm method overestimated systolic (6 ± 16 mm Hg, P < 0.001) and underestimated diastolic blood pressure (2 ± 11 mm Hg, P = 0.03). Compared to intra-arterial, upper-arm underestimated systolic (8 ± 16 mm Hg, P < 0.01) and overestimated diastolic blood pressure (9 ± 7 mm Hg, P < 0.001). Conclusion The magnitude of differences between the intra-arterial and forearm method was less than differences between the intra-arterial and upper-arm method. Our results suggest that forearm method may be a more accurate alternative to upper-arm measurement to assess blood pressure in severely obese patients. Copyright © 2013 The Obesity Society.


Duquette A.,Faculte Of Medecine Et Center Hospitalier Of Luniversite Of Montreal | Brais B.,McGill University | Bouchard J.-P.,Faculte Of Medecine Of Luniversite Laval | Mathieu J.,Faculte Of Medecine Et Des Science Of La Sante Of Luniversite Of Sherbrooke
Movement Disorders | Year: 2013

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an increasingly recognized form of spastic ataxia worldwide, but early diagnosis remains a challenge. Methods: We reviewed the initial presentation (n=40) and early clinical evolution (n=50) of a large ARSACS cohort that was followed at the Saguenay Neuromuscular clinic. Results: The average age at presentation was 3.41±1.55 years. Increased deep tendon reflexes were more common than spasticity initially, and the neuropathy only became apparent clinically in the second decade. Despite a homogeneous genetic background, some patients showed no signs of neuropathy or spasticity by the age of 18 years. Conclusions: At presentation, ARSACS lacks certain features that are considered typical in adults after years of evolution. Considering that ARSACS is probably under-diagnosed, it should be included in the differential diagnosis of early onset ataxias with or without pyramidal features and is worthwhile to consider in older patients, even when some features are absent. © 2013 Movement Disorder Society.


Sharma P.,University of Tennessee Health Science Center | Levesque T.,Faculte Of Medecine Of Luniversite Laval | Boilard E.,Faculte Of Medecine Of Luniversite Laval | Park E.A.,University of Tennessee Health Science Center
Biochemical and Biophysical Research Communications | Year: 2014

Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia. © 2014 Elsevier Inc. All rights reserved.


PubMed | Faculte Of Medecine Of Luniversite Laval, Université de Sherbrooke, University of Ottawa, Montreal Neurological Institute and Complexe Hospitalier Of La Sagamie Et Faculte Of Medecine Et Des Science Of La Sante Of Luniversite Of Sherbrooke
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients.


Gagnon-Audet A.-A.,University of Québec | Poirier P.,University of Québec | Turcotte H.,University of Québec | Martin J.,University of Québec | And 4 more authors.
Clinical and Investigative Medicine | Year: 2013

Purpose: Obesity is associated with left ventricular diastolic dysfunction and altered heart rate variability, as well as pulmonary dysfunction. The relationship between asthma and cardiac dysfunction in severely obese subjects is unknown, although it has been hypothesized that cardiac dysfunction may contribute to increase airway hyper-responsiveness (AHR). This study aimed to determine if AHR is associated with le- ventricular diastolic dysfunction and heart rate variability in severely obese subjects. Methods: Sixty-one subjects with severe obesity (BMI ≥35 kg/m2 with comorbidities) completed this study. All subjects completed respiratory questionnaires, spirometry, lung volume measurements, methacholine inhalation test, 24hour Holter monitoring and a complete echocardiography evaluation. Blood samples were obtained for measurement of metabolic markers. Subjects with AHR, defined by a provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) <8 mg/ml, were compared with those with no AHR (PC20 <8 mg/ml). Results: According to these criteria, 32 subjects had AHR and 29 had no AHR(mean PC201.70 mg/ml and 15.3 mg/ml respectively, p<0.001). The groups were similar for anthropometric data and comorbidities. Fasting glucose, Hb1Ac, total cholesterol, LDL, triglycerides, Apo-B, C-reactive protein (CRP) and pro-BNP levels were also comparable between groups (p>0.05). CRP level correlated with PC20 (AHR, r=0.38, p=0.03). Indices of heart rate variability and overall cardiac function were similar in subjects with or without AHR but grade 2 le- ventricular diastolic dysfunction was more prevalent in subjects with AHR (p=0.037). Conclusions: Altered cardiac function, dysglycemia and dyslipidemia do not seem to be significantly associated with AHR in severely obese subjects in contrast to systemic in-flammation. © 2013 CIM.


PubMed | Faculte Of Medecine Of Luniversite Laval
Type: Journal Article | Journal: Clinical and experimental rheumatology | Year: 2013

Beyond their role in haemostasis, platelets can actively contribute to immunity. The activation of the platelet collagen receptor glycoprotein VI (GPVI) promotes the release of small extracellular vesicles called microparticles. These microparticles are found in the joint bathing fluid of patients with rheumatoid arthritis (RA) and are thought to amplify inflammation. The gene coding for GPVI is localised on chromosome 19q13.4 and contains different single nucleotide polymorphisms (SNPs). Five non-synonymous SNPs define the major and minor haplotypes of GPVI. The minor haplotype is associated with higher risk of cardiovascular incidents. In this study, we examined whether this minor haplotype is also associated with RA.Allelic discrimination of the SNPs reported to define these haplotypes encoding SKTQH and PEALN protein isoforms, ie rs1613662, rs1654416, rs2304167, rs1654413 and rs1671152, was performed in 399 RA patients and their two parents, all of Western European ethnicity. Statistical analysis relied on the transmission disequilibrium test by the use of the FBAT programme. Haplotypes were also estimated by the FBAT programme.We observed no statistically significant transmission disequilibrium for the SNPs tested. The major haplotype TAAC, which encodes the SKTQH isoform, was identified in 78% of our cohort individuals, and the CGGA haplotype which encodes the PEALN isoform was identified in 8% of our individuals. We observed no association of these haplotypes of the GPVI gene with RA.This demonstrates that the SNPs tested within the GPVI gene are not associated with RA susceptibility and/or severity, suggesting that platelet GPVI may contribute to arthritis independently of its gene polymorphism.


PubMed | Faculte Of Medecine Of Luniversite Laval and University of Québec
Type: Journal Article | Journal: PloS one | Year: 2014

Pelvic inflammation is a hallmark of endometriosis pathogenesis and a major cause of the diseases symptoms. Abnormal immune and inflammatory changes may not only contribute to endometriosis-major symptoms, but also contribute to ectopic endometrial tissue growth and endometriosis development. A major pro-inflammatory factors found elevated in peritoneal fluid of women with endometriosis and to be overexpressed in peritoneal fluid macrophages and active, highly vascularized and early stage endometriotic lesions, macrophage migration inhibitory factor (MIF) appeared to induce angiogenic and inflammatory and estrogen producing phenotypes in endometriotic cells in vitro and to be a possible therapeutic target in vivo. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngeneic wild type (WT) mice and vice versa, our current study revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant down regulation of the expression of major inflammatory (cyclooxygenease-2), cell adhesion (v and 3 integrins), survival (B-cell lymphoma-2) and angiogenic (vascular endothelial cell growth) factors relevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. Interestingly, cross-experiments revealed that MIF presence in both endometrial and peritoneal host tissues is required for ectopic endometrial tissue growth and pointed to its involvement in endometrial-peritoneal interactions. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis.

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