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Pineault N.,He Ma Quebec | Pineault N.,UniversiteLaval | Cortin V.,He Ma Quebec | Boyer L.,He Ma Quebec | And 4 more authors.

Background aims. Expansion of hematopoietic progenitors ex vivo is currently investigated as a means of reducing cytopenia following stem cell transplantation. The principal objective of this study was to develop a new cytokine cocktail that would maximize the expansion of megakaryocyte (Mk) progenitors that could be used to reduce periods of thrombocytopenia. Methods. We measured the individual and synergistic effects of six cytokines [stem cell factor (SCF), FLT-3 ligand (FL), interleukin (IL)-3, IL-6, IL-9 and IL-11] commonly used to expand cord blood (CB) CD34+ cells on the expansion of CB Mk progenitors and major myeloid populations by factorial design. Results. These results revealed an elaborate array of cytokine individual effects complemented by a large number of synergistic and antagonistic interaction effects. Notably, strong interactions with SCF were observed with most cytokines and its concentration level was the most influential factor for the expansion and differentiation kinetics of CB CD34+ cells. A response surface methodology was then applied to optimize the concentrations of the selected cytokines. The newly developed cocktail composed of SCF, thrombopoietin (TPO) and FL increased the expansion of Mk progenitors and maintained efficient expansion of clonogenic progenitors and CD34+ cells. CB cells expanded with the new cocktail were shown to provide good short- and long-term human platelet recovery and lymphomyeloid reconstitution in NOD/SCID mice. Conclusions. Collectively, these results define a complex cytokine network that regulates the growth and differentiation of immature and committed hematopoietic cells in culture, and confirm that cytokine interactions have major influences on the fate of hematopoietic cells. © 2011 Informa Healthcare. Source

Kilpatrick K.,Canadian Center for Advanced Practice Nursing Research | Kilpatrick K.,University of Montreal | Kilpatrick K.,Hopital Maisonneuve Rosemont Research Center | Kaasalainen S.,McMaster University | And 17 more authors.
Journal of Evaluation in Clinical Practice

Rationale, aims and objectives Increasing numbers of clinical nurse specialists (CNSs) are working in outpatient settings. The objective of this paper is to describe a systematic review of randomized controlled trials (RCTs) evaluating the cost-effectiveness of CNSs delivering outpatient care in alternative or complementary provider roles. Methods We searched CINAHL, MEDLINE, EMBASE and seven other electronic databases, 1980 to July 2012 and hand-searched bibliographies and key journals. RCTs that evaluated formally trained CNSs and health system outcomes were included. Study quality was assessed using the Cochrane risk of bias tool and the Quality of Health Economic Studies instrument. We used the Grading of Recommendations Assessment, Development and Evaluation to assess quality of evidence for individual outcomes. Results Eleven RCTs, four evaluating alternative provider (n = 683 participants) and seven evaluating complementary provider roles (n = 1464 participants), were identified. Results of the alternative provider RCTs (low-to-moderate quality evidence) were fairly consistent across study populations with similar patient outcomes to usual care, some evidence of reduced resource use and costs, and two economic analyses (one fair and one high quality) favouring CNS care. Results of the complementary provider RCTs (low-to-moderate quality evidence) were also fairly consistent across study populations with similar or improved patient outcomes and mostly similar health system outcomes when compared with usual care; however, the economic analyses were weak. Conclusions Low-to-moderate quality evidence supports the effectiveness and two fair-to-high quality economic analyses support the cost-effectiveness of outpatient alternative provider CNSs. Low-to-moderate quality evidence supports the effectiveness of outpatient complementary provider CNSs; however, robust economic evaluations are needed to address cost-effectiveness. © 2014 John Wiley & Sons, Ltd. Source

Joyal J.-S.,University of Montreal | Joyal J.-S.,McGill University | Omri S.,Hopital Maisonneuve Rosemont Research Center | Sitaras N.,Hopital Maisonneuve Rosemont Research Center | And 5 more authors.
Acta Paediatrica, International Journal of Paediatrics

Retinopathy of prematurity (ROP) is a major cause of severe visual deficits in children. This review focuses on the role of newly identified factors from retinal neurons, which through their opposing actions on vascular development contribute to ROP. These hypoxia-generated mediators include the Krebs cycle intermediate, succinate acting via GPR91, and the neuronal guidance molecule Semaphorin 3A.Conclusion:Neuron-derived factors guide retinal vascularization and are major contributors to the pathogenesis of ROP. © 2012 The Author(s)/Acta Pædiatrica © 2012 Foundation Acta Pædiatrica. Source

Manuguerra-Gagne R.,Hopital Maisonneuve Rosemont Research Center | Manuguerra-Gagne R.,University of Montreal | Boulos P.R.,HOpital Maisonneuve Rosemont | Boulos P.R.,University of Montreal | And 10 more authors.
Stem Cells

Among bone marrow cells, hematopoietic and mesenchymal components can contribute to repair damaged organs. Such cells are usually used in acute diseases but few options are available for the treatment of chronic disorders. In this study, we have used a laser-induced model of open angle glaucoma (OAG) to evaluate the potential of bone marrow cell populations and the mechanisms involved in tissue repair. In addition, we investigated laser-induced tissue remodeling as a method of targeting effector cells into damaged tissues. We demonstrate that among bone marrow cells, mesenchymal stem cells (MSC) induce trabecular meshwork regeneration. MSC injection into the ocular anterior chamber leads to far more efficient decrease in intraocular pressure (IOP) (p < .001) and healing than hematopoietic cells. This robust effect was attributable to paracrine factors from stressed MSC, as injection of conditioned medium from MSC exposed to low but not to normal oxygen levels resulted in an immediate decrease in IOP. Moreover, MSC and their secreted factors induced reactivation of a progenitor cell pool found in the ciliary body and increased cellular proliferation. Proliferating cells were observed within the chamber angle for at least 1 month. Laser-induced remodeling was able to target MSC to damaged areas with ensuing specific increases in ocular progenitor cells. Thus, our results identify MSC and their secretum as crucial mediators of tissue repair in OAG through reactivation of local neural progenitors. In addition, laser treatment could represent an appealing strategy to promote MSC-mediated progenitor cell recruitment and tissue repair in chronic diseases. © AlphaMed Press. Source

Tahiri H.,University of Montreal | Duhamel F.,University of Montreal | Omri S.,Hopital Maisonneuve Rosemont Research Center | Picard E.,University Pierre and Marie Curie | And 3 more authors.
Investigative Ophthalmology and Visual Science

Purpose. Choroidal neovascularization (CNV) is a major cause of vision loss in which choroidal vessels penetrate the RPE-an important source of growth factors, including nerve growth factor (NGF), whose activation via the p75NTR receptor promotes apoptosis and inhibits angiogenesis. We demonstrated previously that human T-lymphocyte-derived microparticles (LMPs) significantly inhibit angiogenesis in several models of ocular neovascularization. We investigated how LMPs modulate pro- and antiangiogenic microenvironments during choroidal angiogenesis. Methods. Antiangiogenic effects of LMPs were investigated using a rat model of choroidal angiogenesis. The impact of LMPs on expression of major angiogenic factors was assessed by real-time quantitative PCR (qPCR). To determine whether p75NTR signalling was implicated in LMPs-induced activities, we used a specific antibody and short hairpin RNA (shRNA) targeting p75NTR. Cellular apoptosis was determined via evaluation of activated caspase-3 and annexin V binding. Results. The LMPs time-dependently inhibited choroidal angiogenesis by more than 64% after 48 hours of treatment. Removal of the RPE from choroidal explants abolished the antiangiogenic effects of LMPs. The mRNA levels of pigment epithelium-derived factor (PEDF) and NGF were increased significantly following LMPs treatment of intact, but not RPE-removed choroids. Downregulation of PEDF and p75NTR significantly blocked the antiangiogenic effects of LMPs. Finally, induction of choroidal endothelial cell apoptosis by LMPs was dependent on p75NTR. Conclusions. We demonstrate for the first time to our knowledge that LMPs markedly inhibit choroidal angiogenesis via mechanisms that are dependent on the integrity of the RPE, and that are mediated largely by the PEDF and proapoptotic activities of p75NTR. © 2013 The Association for Research in Vision and Ophthalmology, Inc. Source

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