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Withrow D.,Queen's University | Alter D.A.,Li Ka Shing Knowledge Institute
Obesity Reviews | Year: 2011

In the last decade, the prevalence of obesity has increased significantly in populations worldwide. A less dramatic, but equally important increase has been seen in our knowledge of its effects on health and the burden it places on healthcare systems. This systematic review aims to assess the current published literature on the direct costs associated with obesity. A computerized search of English language articles published between 1990 and June 2009 yielded 32 articles suitable for review. Based on these articles, obesity was estimated to account for between 0.7% and 2.8% of a country's total healthcare expenditures. Furthermore, obese individuals were found to have medical costs that were approximately 30% greater than their normal weight peers. Although variations in inclusion/exclusion criteria, reporting methods and included costs varied widely between the studies, a lack of examination of how and why the excess costs were being accrued appeared to be a commonality between most studies. Accordingly, future studies must better explore how costs accrue among obese populations, in order to best facilitate health and social policy interventions. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.


Jaqaman K.,Harvard University | Grinstein S.,Li Ka Shing Knowledge Institute
Trends in Cell Biology | Year: 2012

There is mounting evidence that the plasma membrane is highly dynamic and organized in a complex manner. The cortical cytoskeleton is proving to be a particularly important regulator of plasmalemmal organization, modulating the mobility of proteins and lipids in the membrane, facilitating their segregation, and influencing their clustering. This organization plays a critical role in receptor-mediated signaling, especially in the case of immunoreceptors, which require lateral clustering for their activation. Based on recent developments, we discuss the structures and mechanisms whereby the cortical cytoskeleton regulates membrane dynamics and organization, and how the nonuniform distribution of immunoreceptors and their self-association may affect activation and signaling. © 2012 Elsevier Ltd.


Siddiqi F.S.,Li Ka Shing Knowledge Institute | Advani A.,Li Ka Shing Knowledge Institute
Diabetes | Year: 2013

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never develop ESRD but will instead die of cardiovascular (CV) disease (CVD). The first evidence of kidney injury in diabetes is often microalbuminuria, itself also an independent risk marker for CVD. Although the two processes are closely associated, the recent failure of antialbuminuric therapies to affect CV outcomes has encouraged a reconsideration of how albuminuria may occur in diabetes and how increased urinary albumin excretion may be indicative of CV risk. The relationship between CVD and urinary albumin content (even within the normal range) is widely considered to reflect the common underlying pathology of endothelial dysfunction. At the same time, recent years have witnessed a growing appreciation that diabetic albuminuria commonly arises from damage to glomerular podocytes, specialized epithelial cells acting as the final barrier to macromolecular flow into the urinary filtrate. These superficially discordant paradigms can be assimilated by the emerging concept of endothelial-podocyte crosstalk across the glomerular filtration barrier, whereby the actions of one type of cell may profoundly influence the function of the other. The bidirectional nature of this paracrine network is illustrated by the actions of the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor-2 and activated protein C systems, among others. Identification of novel mediators of endothelial-podocyte crosstalk may lead to the development of more effective treatments for diabetic nephropathy and its sequelae. © 2013 by the American Diabetes Association.


Kamel K.S.,Li Ka Shing Knowledge Institute | Halperin M.L.,Li Ka Shing Knowledge Institute
New England Journal of Medicine | Year: 2015

This review focuses on three issues facing clinicians who care for patients with diabetic ketoacidosis; all of the issues are related to acid-base disorders. The first issue is the use of the plasma anion gap and the calculation of the ratio of the change in this gap to the change in the concentration of plasma bicarbonate in these patients; the second concerns the administration of sodium bicarbonate; and the third is the possible contribution of intracellular acidosis to the development of cerebral edema, particularly in children with diabetic ketoacidosis. In this article, we examine the available data and attempt to integrate the data with principles of physiology and metabolic regulation and provide clinical guidance. Copyright © 2015 Massachusetts Medical Society.


Burns K.E.,Li Ka Shing Knowledge Institute
The Cochrane database of systematic reviews | Year: 2013

Noninvasive positive-pressure ventilation (NPPV) provides ventilatory support without the need for an invasive airway. Interest has emerged in using NPPV to facilitate earlier removal of an endotracheal tube and to decrease complications associated with prolonged intubation. We evaluated studies in which invasively ventilated adults with respiratory failure of any cause (chronic obstructive pulmonary disease (COPD), non-COPD, postoperative, nonoperative) were weaned by means of early extubation followed by immediate application of NPPV or continued IPPV weaning. The primary objective was to determine whether the noninvasive positive-pressure ventilation (NPPV) strategy reduced all-cause mortality compared with invasive positive-pressure ventilation (IPPV) weaning. Secondary objectives were to ascertain differences between strategies in proportions of weaning failure and ventilator-associated pneumonia (VAP), intensive care unit (ICU) and hospital length of stay (LOS), total duration of mechanical ventilation, duration of mechanical support related to weaning, duration of endotracheal mechanical ventilation (ETMV), frequency of adverse events (related to weaning) and overall quality of life. We planned sensitivity and subgroup analyses to assess (1) the influence on mortality and VAP of excluding quasi-randomized trials, and (2) effects on mortality and weaning failure associated with different causes of respiratory failure (COPD vs. mixed populations). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 5, 2013), MEDLINE (January 1966 to May 2013), EMBASE (January 1980 to May 2013), proceedings from four conferences, trial registration websites and personal files; we contacted authors to identify trials comparing NPPV versus conventional IPPV weaning. Randomized and quasi-randomized trials comparing early extubation with immediate application of NPPV versus IPPV weaning in intubated adults with respiratory failure. Two review authors independently assessed trial quality and abstracted data according to prespecified criteria. Sensitivity and subgroup analyses assessed (1) the impact of excluding quasi-randomized trials, and (2) the effects on selected outcomes noted with different causes of respiratory failure. We identified 16 trials, predominantly of moderate to good quality, involving 994 participants, most with chronic obstructive pulmonary disease (COPD). Compared with IPPV weaning, NPPV weaning significantly decreased mortality. The benefits for mortality were significantly greater in trials enrolling exclusively participants with COPD (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.56) versus mixed populations (RR 0.81, 95% CI 0.47 to 1.40). NPPV significantly reduced weaning failure (RR 0.63, 95% CI 0.42 to 0.96) and ventilator-associated pneumonia (RR 0.25, 95% CI 0.15 to 0.43); shortened length of stay in an intensive care unit (mean difference (MD) -5.59 days, 95% CI -7.90 to -3.28) and in hospital (MD -6.04 days, 95% CI -9.22 to -2.87); and decreased the total duration of ventilation (MD -5.64 days, 95% CI -9.50 to -1.77) and the duration of endotracheal mechanical ventilation (MD - 7.44 days, 95% CI -10.34 to -4.55) amidst significant heterogeneity. Noninvasive weaning also significantly reduced tracheostomy (RR 0.19, 95% CI 0.08 to 0.47) and reintubation (RR 0.65, 95% CI 0.44 to 0.97) rates. Noninvasive weaning had no effect on the duration of ventilation related to weaning. Exclusion of a single quasi-randomized trial did not alter these results. Subgroup analyses suggest that the benefits for mortality were significantly greater in trials enrolling exclusively participants with COPD versus mixed populations. Summary estimates from 16 trials of moderate to good quality that included predominantly participants with COPD suggest that a weaning strategy that includes NPPV may reduce rates of mortality and ventilator-associated pneumonia without increasing the risk of weaning failure or reintubation.


Gilbert R.E.,Li Ka Shing Knowledge Institute
Current Atherosclerosis Reports | Year: 2014

Diabetes is characterised by widespread endothelial cell dysfunction that underlies the development of both the micro- and macrovascular complications of the disease, including nephropathy, cardiomyopathy, and non-proliferative retinopathy. In the kidney, major changes are noted in glomerular endothelial cell structure in their fenestrations and glycocalyx. These changes, along with endothelial cell loss and capillary rarefaction in both the glomerulus and tubulointerstitium, lead to the progressive loss of glomerular filtration that render diabetes the most common cause of end-stage renal disease in much of the developed world. New treatments in diabetes that directly address the abnormal structure and function of the endothelial cell are desperately needed. © Springer Science+Business Media New York 2014.


Fairn G.D.,Li Ka Shing Knowledge Institute | Grinstein S.,Li Ka Shing Knowledge Institute
Trends in Immunology | Year: 2012

Phagocytosis mediates the clearance of apoptotic bodies and also the elimination of microbial pathogens. The nascent phagocytic vacuole formed upon particle engulfment lacks microbicidal and degradative activity. These capabilities are acquired as the phagosome undergoes maturation; a progressive remodeling of its membrane and contents that culminates in the formation of phagolysosomes. Maturation entails orderly sequential fusion of the phagosomal vacuole with specialized endocytic and secretory compartments. Concomitantly, the phagosomal membrane undergoes both inward and outward vesiculation and tubulation followed by fission, thereby recycling components and maintaining its overall size. Here, we summarize what is known about the molecular machinery that governs this complex metamorphosis of phagosome maturation. © 2012 Elsevier Ltd.


Gilbert R.E.,Li Ka Shing Knowledge Institute
Circulation Journal | Year: 2013

Although seemingly diverse, the tissue injury at sites of diabetic complications, whether in the heart, kidneys or eyes, shares the common histopathological feature of endothelial cell loss, a consequence of both increased cell death and deficient regeneration. In medium-sized and larger arteries the loss of the protective lining contributes to the atherosclerotic process, while at sites of microvascular disease endothelial cell loss leads to capillary rarefaction and ischemia. The pathophysiology of these changes and their consequences on organ structure and function in diabetes are reviewed, and the potential for endothelial regenerative strategies to enhance repair and ameliorate the long-term complications of diabetes is explored.


Slutsky A.S.,Li Ka Shing Knowledge Institute
American journal of respiratory and critical care medicine | Year: 2015

Mechanical ventilation is a life-saving therapy that catalyzed the development of modern intensive care units. The origins of modern mechanical ventilation can be traced back about five centuries to the seminal work of Andreas Vesalius. This article is a short history of mechanical ventilation, tracing its origins over the centuries to the present day. One of the great advances in ventilatory support over the past few decades has been the development of lung-protective ventilatory strategies, based on our understanding of the iatrogenic consequences of mechanical ventilation such as ventilator-induced lung injury. These strategies have markedly improved clinical outcomes in patients with respiratory failure.


Schweizer T.A.,Li Ka Shing Knowledge Institute
Current Alzheimer research | Year: 2015

OBJECTIVES: Grey matter atrophy in the right hemisphere has been shown to be more severe in dementia patients with delusions, suggesting a neuroanatomical localization that may be pertinent to impending neurodegeneration. Delusional symptoms may arise when atrophy in these areas reduces the regulatory functions of the right hemisphere, in tandem with asymmetric neuropathology in the left hemisphere. We hypothesized that delusional patients with either amnestic mild cognitive impairment (MCI) or early Alzheimer Disease (AD) would experience more pronounced grey matter atrophy in the right frontal lobe compared with matched patients without delusions.METHODS: We used neuroimaging and clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative. A comparison group of twenty-nine nondelusional MCI/early AD participants were compared with twenty-nine delusional participants using voxel-based morphometry, matched at baseline by age, sex, education, and Mini-Mental State Exam score. All included participants were diagnosed with amnestic MCI at study baseline.RESULTS: Fifteen voxel clusters of decreased grey matter in participants with delusions were detected. Prominent grey matter decrease was observed in the right precentral gyrus, right inferior frontal gyrus, right insula, and left middle occipital gyrus, areas that may be involved in control of thought and emotions.CONCLUSION: Greater right fronto-temporal grey matter atrophy was observed in MCI or early AD participants with delusions compared to matched patients without delusions. Consistent with our predictions, asymmetric grey matter atrophy in the right hemisphere may contribute to development of delusions through loss of executive inhibition.

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