143 research outputs found
Restructuring Canada's Refugee Determination Process: A Look at Bills C-55 and C-84
Bien que le Canada affiche depuis la Seconde Guerre mondiale une feuille de route généralement enviable en ce qui regarde l'accueil des réfugiés, l'existence d'une procédure formelle de revendication du statut de réfugié en sol canadien remonte seulement à la mise en oeuvre de la Loi sur l'immigration de 1976, en 1978. Le nombre de personnes qui se sont prévalues de ce système a toutefois excédé grandement ce qui avait été prévu par les fonctionnaires du Ministère de l'immigration. Ces derniers, en conséquence, insistent aujourd'hui pour que la Loi soit amendée de façon à réduire drastiquement l'accès à la revendication du statut de réfugié sur le territoire. Les amendements que proposent les projets de lois C-55 et C-84 ne sont pas sans rapport avec ce qui s'est fait récemment dans d'autres pays industrialisés, spécialement en Europe de l'ouest, où de nombreux obstacles à l'entrée des réfugiés ont été dressés. Mais quand on sait que les réfugiés sont au Canada protégés par la Charte canadienne des droits et libertés, il ne fait pas de doute que les nombreuses dispositions des projets de lois C-55 et C-84 qui semblent porter atteinte à des droits de la Charte vont faire l'objet de contestations judiciaires qui, il faut l'espérer, auront pour vertu de définir les obligations internationales du Canada à l'égard des réfugiés
Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes
Copyright © 2014 Kaloriti et al.Peer reviewedPublisher PD
Role of NADPH Oxidase versus Neutrophil Proteases in Antimicrobial Host Defense
NADPH oxidase is a crucial enzyme in mediating antimicrobial host defense and in regulating inflammation. Patients with chronic granulomatous disease, an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates (ROIs), suffer from life-threatening bacterial and fungal infections. The mechanisms by which NADPH oxidase mediate host defense are unclear. In addition to ROI generation, neutrophil NADPH oxidase activation is linked to the release of sequestered proteases that are posited to be critical effectors of host defense. To definitively determine the contribution of NADPH oxidase versus neutrophil serine proteases, we evaluated susceptibility to fungal and bacterial infection in mice with engineered disruptions of these pathways. NADPH oxidase-deficient mice (p47phox−/−) were highly susceptible to pulmonary infection with Aspergillus fumigatus. In contrast, double knockout neutrophil elastase (NE)−/−×cathepsin G (CG)−/− mice and lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI)-deficient mice that are defective in neutrophil serine protease activation demonstrated no impairment in antifungal host defense. In separate studies of systemic Burkholderia cepacia infection, uniform fatality occurred in p47phox−/− mice, whereas NE−/−×CG−/− mice cleared infection. Together, these results show a critical role for NADPH oxidase in antimicrobial host defense against A. fumigatus and B. cepacia, whereas the proteases we evaluated were dispensable. Our results indicate that NADPH oxidase dependent pathways separate from neutrophil serine protease activation are required for host defense against specific pathogens
NADPH Oxidase Limits Innate Immune Responses in the Lungs in Mice
Background: Chronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e.g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood. Methodology/Principal Findings: We found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47phox-/- mice and gp91phox-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-kB activation, and elevated downstream pro-inflammatory cytokines (TNF-α, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-kB activation. Conclusions/Significance: These studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD
Defining Responses to Therapy and Study Outcomes in Clinical Trials of Invasive Fungal Diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer Consensus Criteria
Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledg
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Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium
Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18–1.52) and without (HR=1.22, 95% CI: 1.12–1.33) further adjustment for residual disease, respectively. Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC
Immunotherapy for fungal infections with special emphasis on central nervous system infections
Opportunistic fungal infections are major causes of morbidity and
mortality in the immunocompromized. Fungi have evolved complex and
coordinated mechanisms to survive in the environment and the mammalian
host. Fungi must adapt to "stressors" in the host, including nutrient
scarcity, pH and reactive oxygen and nitrogen intermediates, in
addition to evading host immunity. Knowledge of the immunopathogenesis
of fungal infections has paved the way to promising strategies for
immunotherapy. These include strategies that increase phagocyte number,
activate innate host defense pathways in phagocytes and dendritic cells
and stimulate antigen-specific immunity (e.g., vaccines). Immunotherapy
must be tailored to specific immunocompromized states. Our review
focuses on cryptococcosis and coccidioidomycosis because of the
propensity of these diseases to involve the central nervous system
(CNS). The CNS has long been considered "immunologically privileged" in
the sense of being isolated from normal immune surveillance. This
notion is only partially accurate. Immune-based therapies for fungal
CNS disease are at an exploratory level and merit further evaluation in
clinical trials
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