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Hoffer L.J.,Lady Davis Institute for Medical Research | Bistrian B.R.,Beth Israel Deaconess Medical Center
American Journal of Clinical Nutrition | Year: 2012

Background: Widely varying recommendations have been published with regard to the appropriate amount of protein or amino acids to provide in critical illness. Objective: We carried out a systematic review of clinical trials that compared the metabolic or clinical effects of different protein intakes in adult critical illness and comprehensively reviewed all of the available evidence pertinent to the safe upper limit of protein provision in this setting. Design: MEDLINE was searched for clinical trials published in English between 1948 and 2012 that provided original data comparing the effects of different levels of protein intake on clinically relevant outcomes and evidence pertinent to the safe upper limit of protein provision to critically ill adults. Results: The limited amount and poor quality of the evidence preclude conclusions or clinical recommendations but strongly suggest that 2.0-2.5 g protein substrate · kg normal body weight -1 · d -1 is safe and could be optimum for most critically ill patients. At the present time, most critically ill adults receive less than half of the most common current recommendation, 1.5 g protein · kg -1 · d -1, for the first week or longer of their stay in an intensive care unit. Conclusion: There is an urgent need for well-designed clinical trials to identify the appropriate level of protein provision in critical illness. © 2012 American Society for Nutrition.


Fleming R.E.,Saint Louis University | Ponka P.,Lady Davis Institute for Medical Research | Ponka P.,McGill University
New England Journal of Medicine | Year: 2012

IRON-OVERLOAD DISORDERS ARE TYPICALLY INSIDIOUS, CAUSING PROGRESsive and sometimes irreversible end-organ injury before clinical symptoms develop. With a high index of suspicion, however, the consequences of iron toxicity can be attenuated or prevented. Some iron-overload disorders are quite common (e.g., HFE-associated hereditary hemochromatosis and β-thalassemia), whereas others are exceedingly rare. An understanding of the pathophysiology of these disorders is helpful in directing the workup and in identifying scenarios that merit consideration of the less common diagnoses. Since many of the molecular participants in iron metabolism have been characterized only in the past several years, we first review the current understanding of iron metabolism1 and then discuss specific iron-overload diseases. Copyright © 2012 Massachusetts Medical Society.


Shrier I.,Lady Davis Institute for Medical Research
British Journal of Sports Medicine | Year: 2015

The sport medicine clinician is faced with return-to-play (RTP) decisions for every patient who wants to return to activity. The complex interaction of factors related to history, physical examination, testing, activity and baseline characteristics can make RTP decision-making challenging. Further, when reasoning is not explicit, unnecessary conflict can arise among clinicians themselves, or among clinicians and patients. This conflict can have negative health consequences for the patient. In 2010, a transparent framework for RTP decisions was proposed. However, some have identified limitations to the framework and found difficulties in its implementation. This paper presents a revised framework that addresses the limitations, and provides concrete examples of how to apply it in simple and complex cases.


Schiffrin E.L.,Lady Davis Institute for Medical Research
Clinical Science | Year: 2014

Over the last 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling in hypertension, chronic kidney disease and heart disease. Effector T-cells include Th1 (interferon-γ -producing) and Th2 (interleukin-4 producing) lymphocytes, as well as Th17 (which produce interleukin-17) and T-suppressor lymphocytes such as Treg-cells (regulatory T-cells), which express the transcription factor Foxp3 (forkhead box P3) and participate respectively as pro- and anti-inflammatory cells. Pro-inflammatory T-lymphocytes participate in mechanisms of cardiovascular disease in part by mediating the effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neo-antigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. Once activated, Th1 cells may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via the effects of the cytokines produced or through their effects on perivascular fat. Treg-cells protect from blood pressure elevation by acting upon similar targets. Recent data suggests that participation of these mechanisms that have been demonstrated already in murine models also occurs in humans. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans. © 2014 Biochemical Society.


Schiffrin E.L.,Lady Davis Institute for Medical Research
Canadian Journal of Cardiology | Year: 2013

Over the past 20 years it has become recognized that low-grade inflammation plays a role in cardiovascular disease. More recently, participation of the innate and the adaptive immune response in mechanisms that contribute to inflammation in cardiovascular disease has been reported in atherosclerosis and hypertension. Different subsets of lymphocytes and their cytokines are involved in vascular remodelling and hypertensive renal disease as well as heart disease. Effector T cells including T-helper (Th) 1 (interferon-γ-producing) and Th2 lymphocytes (interleukin-4 producing), as well as Th17 (which produce interleukin-17), and T suppressor lymphocytes such as T regulatory cells, which express the transcription factor forkhead box P3, participate respectively as pro- and anti-inflammatory cells, and mediate effects of angiotensin II and mineralocorticoids. Involvement of immune mechanisms in cardiac, vascular, and renal changes in hypertension has been demonstrated in many experimental models, an example being the Dahl-salt sensitive rat and the spontaneously hypertensive rat. How activation of immunity is triggered remains unknown, but neoantigens could be generated by elevated blood pressure through damage-associated molecular pattern receptors or other mechanisms. When activated, Th1 may contribute to blood pressure elevation by affecting the kidney, vascular remodelling of blood vessels directly via effects of the cytokines produced, or through their effects on perivascular fat. T regulatory cells protect from blood pressure elevation acting on similar targets. These novel findings may open the way for new therapeutic approaches to improve outcomes in hypertension and cardiovascular disease in humans. © 2013 Canadian Cardiovascular Society.


Pollak M.N.,Lady Davis Institute for Medical Research
Cancer Discovery | Year: 2012

Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress. Significance: There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design ©2012 American Association for Cancer Research.


Schipper H.M.,Lady Davis Institute for Medical Research
Neurobiology of Aging | Year: 2011

Alzheimer disease (AD) is a common and devastating dementing illness for which there is no effective neuroprotective therapy or cure. The presence of the apolipoprotein E (apoE) ε4 allele is a well-established genetic modifier (risk factor) of sporadic AD. In this review, we provide an update on the implications of apoE for the neurobiology and epidemiology of AD. Moreover, recent evidence is adduced indicating that (i) many AD risk factors are potentially modifiable by adaptive lifestyle changes and pharmacotherapy and (ii) the potency of these modifiable AD determinants and responsiveness to intervention are often significantly impacted by the presence or absence of the ε4 allele. Delineation of the influences of the APOE genotype on modifiable AD risk factors and prevention may spur consideration of APOE testing for presymptomatic individuals seeking to define their personal risk. © 2009 Elsevier Inc.


Thandapani P.,Lady Davis Institute for Medical Research | O'Connor T.R.,University of Queensland | Bailey T.L.,University of Queensland | Richard S.,Lady Davis Institute for Medical Research
Molecular Cell | Year: 2013

Motifs rich in arginines and glycines were recognized several decades ago to play functional roles and were termed glycine-arginine-rich (GAR) domains and/or RGG boxes. We review here the evolving functions of the RGG box along with several sequence variations that we collectively term the RGG/RG motif. Greater than 1,000 human proteins harbor the RGG/RG motif, and these proteins influence numerous physiological processes such as transcription, pre-mRNA splicing, DNA damage signaling, mRNA translation, and the regulation of apoptosis. In particular, we discuss the role of the RGG/RG motif in mediating nucleic acid and protein interactions, a function that is often regulated by arginine methylation and partner-binding proteins. The physiological relevance of the RGG/RG motif is highlighted by its association with several diseases including neurological and neuromuscular diseases and cancer. Herein, we discuss the evidence for the emerging diverse functionality of this important motif. © 2013 Elsevier Inc.


Wilkinson N.,Lady Davis Institute for Medical Research | Pantopoulos K.,Lady Davis Institute for Medical Research
Blood | Year: 2013

Hypoxia inducible factor 2α (HIF2α) transcriptionally activates several genes in response to hypoxia. Under normoxic conditions, it undergoes oxygen-dependent degradation by the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) system. The presence of an iron-responsive element (IRE) within the 5′ untranslated region of HIF2α mRNA suggests a further iron- and oxygen-dependent mechanism for translational regulation of its expression via iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively). We show here that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2α-dependent abnormalities in erythropoiesis and systemic iron metabolism. Thus, 4- to 6-week-old IRP1-/- mice exhibit splenomegaly and extramedullary hematopoiesis, which is corrected in older animals. These erythropoietic abnormalities are caused by translational de-repression of HIF2α mRNA and subsequent accumulation of HIF2α, which induces expression of erythropoietin (Epo). Increased levels of circulating Epo lead to reticulocytosis, polycythemia, and suppression of hepatic hepcidin mRNA. This in turn promotes hyperferremia and iron depletion in splenic macrophages due to unrestricted expression of ferroportin. Our data demonstrate that IRP1 is the principal regulator of HIF2α mRNA translation in vivo and provide evidence that translational control of HIF2α expression dominates over PHD/VHL-mediated regulation of HIF2α stability in juvenile IRP1 -/- mice. © 2013 by The American Society of Hematology.


Eggermont A.M.M.,French Institute of Health and Medical Research | Eggermont A.M.M.,Erasmus Medical Center | Spatz A.,Lady Davis Institute for Medical Research | Robert C.,French Institute of Health and Medical Research
The Lancet | Year: 2014

In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to aff ect survival. The eff ect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns diff er substantially anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefi t of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.

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