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Montréal, Canada

Sivan S.S.,ORT Braude College | Wachtel E.,Weizmann Institute of Science | Roughley P.,Genetics Unit
Biochimica et Biophysica Acta - General Subjects | Year: 2014

Background Aggrecan is the major non-collagenous component of the intervertebral disc. It is a large proteoglycan possessing numerous glycosaminoglycan chains and the ability to form aggregates in association with hyaluronan. Its abundance and unique molecular features provide the disc with its osmotic properties and ability to withstand compressive loads. Degradation and loss of aggrecan result in impairment of disc function and the onset of degeneration. Scope of review This review summarizes current knowledge concerning the structure and function of aggrecan in the normal intervertebral disc and how and why these change in aging and degenerative disc disease. It also outlines how supplementation with aggrecan or a biomimetic may be of therapeutic value in treating the degenerate disc. Major conclusions Aggrecan abundance reaches a plateau in the early twenties, declining thereafter due to proteolysis, mainly by matrix metalloproteinases and aggrecanases, though degradation of hyaluronan and non-enzymic glycation may also participate. Aggrecan loss is an early event in disc degeneration, although it is a lengthy process as degradation products may accumulate in the disc for decades. The low turnover rate of the remaining aggrecan is an additional contributing factor, preventing protein renewal. It may be possible to retard the degenerative process by restoring the aggrecan content of the disc, or by supplementing with a bioimimetic possessing similar osmotic properties. General significance This review provides a basis for scientists and clinicians to understand and appreciate the central role of aggrecan in the function, degeneration and repair of the intervertebral disc. © 2014 Elsevier B.V. Source


Kupcsik L.,Genetics Unit
Methods in molecular biology (Clifton, N.J.) | Year: 2011

The MTT reduction assay is used to determine the level of metabolic activity in eukaryotic cells, -including animal, plant, and fungal cells. If the metabolic rate is constant, the technique can be employed to count living cells in a sample. Once it is set up, the method is very robust, and can be automatized to be applied on a large number of samples. Source


Holmes L.B.,North American AED Antiepileptic Drug Pregnancy Registry | Holmes L.B.,Genetics Unit | Mittendorf R.,North American AED Antiepileptic Drug Pregnancy Registry | Mittendorf R.,Loyola University | And 4 more authors.
Archives of Neurology | Year: 2011

Objective: To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy. Design: A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry between February 1, 1997, and June 1, 2010. Information on AED use and demographic characteristics was collected in 3 telephone interviews. Setting: United States and Canada. Patients: A total of 6857 pregnant women taking an AED for any reason. Main Outcome Measures: Major congenital malformations were identified at birth and through the first 12 weeks after delivery. Diagnoses were based on the mother's report and confirmed by medical records. The risks of malformations were compared between polytherapy and monotherapy groups, using exact odds ratios (ORs) and 95% confidence intervals (CIs). Results: The risk of malformations was 1.9% among infants exposed to lamotrigine as monotherapy (n = 1441). Among the infants exposed to lamotrigine as polytherapy (n = 505), the risks were 9.1% for lamotrigine plus valproate sodium (OR, 5.0; 95% CI, 1.5-14.0) and 2.9% for lamotrigine plus any other AEDs (1.5; 0.7-3.0). The risk of malformations was 2.9% for the infants exposed to carbamazepine monotherapy (n = 1012). For the infants exposed to carbamazepine as polytherapy (n = 365), the risks were 15.4% for carbamazepine plus valproate (OR, 6.2; 95% CI, 2.0-16.5) and 2.5% for carbamazepine plus any other AEDs (0.8; 0.3-1.9). Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use, and chronic maternal diseases did not explain the results. Conclusions: The risk of malformations among infants exposed to lamotrigine and carbamazepine as polytherapy was higher than the corresponding monotherapies only when the polytherapy includes valproate. These findings suggest that counseling for fetal risks from AED polytherapy should be based on the specific drugs included. ©2011 American Medical Association. All rights reserved. Source


St-Arnaud R.,Genetics Unit | St-Arnaud R.,McGill University
Journal of Steroid Biochemistry and Molecular Biology | Year: 2010

The CYP24A1 enzyme (25-hydroxyvitamin D-24-hydroxylase) not only is involved in the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)2D] but also generates the 24,25-dihydroxyvitamin D [24,25(OH)2D] metabolite. The biological activity of 24,25(OH)2D remains controversial. While in vitro studies suggest that primary cultures of rat rib chondrocytes respond to 24,25(OH)2D in a maturation-specific manner and that the metabolite is necessary for the cells to progress from a proliferating, immature status to a differentiated, 1,25(OH)2D-responsive stage, in vivo evidence to support this putative role remains lacking. Studies in chicken showed increases in serum levels of 24,25(OH)2D and of the renal mRNA levels of Cyp24a1 following fracture, suggesting a role for 24,25(OH)2D in fracture repair. The Cyp24a1-deficient mouse strain represents an invaluable tool to examine the putative role of 24,25(OH)2D in mammalian fracture repair. We have compared fracture repair between Cyp24a1-/- mice and wild-type controls. We have observed a delay in the mineralization of the cartilaginous matrix of the soft callus in Cyp24a1-/- mutant animals, accompanied by reduced expression of chondrocyte marker genes. These results show that Cyp24a1 deficiency delays fracture repair and strongly suggest that vitamin D metabolites hydroxylated at position 24, such as 24,25(OH)2D3, play an important role in the mechanisms leading to normal fracture healing. © 2010 Elsevier Ltd. Source


Anacker C.,Kings College London | Anacker C.,National Health Research Institute | Zunszain P.A.,Kings College London | Cattaneo A.,Kings College London | And 7 more authors.
Molecular Psychiatry | Year: 2011

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (16%) and mature, microtubulin- associated protein-2 (MAP2)-positive neurons (26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27 Kip1 and p57 Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans. © 2011 Macmillan Publishers Limited All rights reserved. Source

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