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McGill University is a public research university in Montreal, Canada, officially founded by royal charter in 1821. The University bears the name of James McGill, a prominent Montreal merchant from Scotland and alumnus of Glasgow University, whose bequest in 1813 formed precursory McGill College.McGill's main campus is set at the foot of Mount Royal in Downtown Montreal with the second campus, situated near fields and forested lands in Sainte-Anne-de-Bellevue, 30 kilometres west of the downtown campus on the Montreal Island. All the academic units are organized into 11 main Faculties and Schools, and the institution is one of the two members of Association of American Universities located outside the United States. Valued at $33,421 per student, the University maintains one of the largest endowments among Canadian universities on a per-student basis.McGill offers degrees and diplomas in over 300 fields of study. Most students are enrolled in five larger Faculties, namely Arts, Science, Medicine, Engineering, and Management, with the highest entering grade of any Canadian university. Tuition fees vary significantly between in-province, out-of-province, and international students, and the scholarships are very generous yet highly competitive and relatively difficult to attain, compared to other Canadian universities.McGill counts among its alumni 12 Nobel laureates and 138 Rhodes Scholars, both the most in the country, as well as three astronauts, two Canadian prime ministers, 13 justices of the Canadian Supreme Court, four foreign leaders, 28 foreign ambassadors, nine Academy Award winners, three Pulitzer Prize winners, and 28 Olympic medalists. Throughout its long history, McGill alumni were also instrumental in inventing or initially organizing football, basketball, and ice hockey and founding several other universities, including the Universities of British Columbia, Victoria, and Alberta, and the Johns Hopkins School of Medicine. Wikipedia.

Miettinen O.S.,McGill University
Preventive Medicine | Year: 2014

Having thought much about medicine in my career-long effort to understand it and the research for its advancement, I have come to views rather different form the now-prevailing ones in respect to what preventive medicine is about; what epidemiology is in relation to preventive medicine; what distinguishes preventive medicine in preventive healthcare at large; the relation of preventive medicine to public health; the concept of health promotion; and also the core principles of preventive medicine. All of these views I set forth in this article, for the readers' critical reflection. © 2014 Elsevier Inc. All rights reserved.

Fellows L.K.,McGill University
Annals of the New York Academy of Sciences | Year: 2011

The work described here aims to isolate the component processes of decision making that rely critically on particular subregions of the human prefrontal cortex, with a particular focus on the orbitofrontal cortex. Here, experiments isolating specific aspects of decision making, using very simple preference judgment and reinforcement learning paradigms, were carried out in patients with focal frontal damage. The orbitofrontal cortex and the adjacent ventromedial prefrontal cortex play a critical role in decisions based on subjective value, across many categories of stimuli, and in learning to choose between stimuli based on value feedback. However, these regions are not required for learning to choose between actions based on feedback, which instead seems to rely critically on the dorsomedial prefrontal cortex. These results point to a potentially common role for the orbitofrontal cortex in representing the context-sensitive, subjective value of stimuli to allow consistent choices between them. They also argue for multiple, parallel, value-based processes that influence behavior through dissociable mechanisms. © 2011 New York Academy of Sciences.

Acute myocardial ischemia results in scar formation with ventricular dilatation and eventually heart failure. Placental growth factor (PlGF) is reported to stimulate angiogenesis and improve cardiac function. In this study, it was hypothesized that intramyocardial injection of PlGF contained in nanoparticles can be released at the site of action for an extended time period as a sustained slow-release protective mechanism that accelerates myocardial recovery in a rat model of ischemic cardiomyopathy. PlGF-loaded chitosan-alginate nanoparticles were injected into an acute myocardial infarction model in rats (n = 10 per group). Transthoracic echocardiography was performed at different time intervals. Enzyme-linked immunosorbent assay was used to measure the serum cytokines levels at 8 weeks. Hearts were stained with Masson's trichrome for scar area analysis. Immunofluorostaining was performed to evaluate the extent of myocardial angiogenesis at the infarction border. PlGF enzyme-linked immunosorbent assay was used to measure the in vitro release kinetics of PlGF-loaded nanoparticles. At 8 weeks after coronary ligation, hearts that were treated with PlGF-loaded chitosan-alginate nanoparticles had significant increases in left-ventricular function (P < 0.01), vascular density (P < 0.01), and in the serum level of the anti-inflammatory cytokine interleukin-10 (P < 0.05). There was significant decrease in scar area formation (P < 0.05) and in serum levels of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 (P < 0.01). In vitro PlGF-release kinetic studies showed a sustained release of PlGF from the particles over a 120-hour period. The use of nanoparticles as a vehicle for PlGF delivery, as opposed to the direct injection of the growth factor after acute myocardial infarction, can provide sustained slow-release PlGF therapy, enhancing the positive effects of the growth factor in the setting of acute myocardial ischemia.

Haji-Abolhassani A.,McGill University
Journal of vision | Year: 2013

We develop a probabilistic framework to infer the ongoing task in visual search by revealing what the subject is looking for during a search process. Based on the level of difficulty, two types of tasks, easy and difficult, are investigated in this work, and individual models are customized for them according to their specific dynamics. We use Hidden Markov Models (HMMs) to serve as a model for the human cognitive process that is responsible for directing the center of gaze (COG) according to the task at hand during visual search and generating task-dependent eye trajectories. This generative model, then, is used to estimate the likelihood term in a Bayesian inference formulation to infer the task given the eye trajectory. In the easy task, focus of attention (FOA) often lands on targets, whereas in the difficult one, in addition to the on-target foci of attention, deployment of attention on nontarget objects happens very often. Therefore, we suggest a single-state and a multi-state HMM to serve as the cognitive process model of attention for the easy and difficult tasks, respectively.

Kramer M.S.,McGill University
Cochrane database of systematic reviews (Online) | Year: 2012

Although the health benefits of breastfeeding are widely acknowledged, opinions and recommendations are strongly divided on the optimal duration of exclusive breastfeeding. Since 2001, the World Health Organization has recommended exclusive breastfeeding for six months. Much of the recent debate in developed countries has centred on the micronutrient adequacy, as well as the existence and magnitude of health benefits, of this practice. To assess the effects on child health, growth, and development, and on maternal health, of exclusive breastfeeding for six months versus exclusive breastfeeding for three to four months with mixed breastfeeding (introduction of complementary liquid or solid foods with continued breastfeeding) thereafter through six months. We searched The Cochrane Library (2011, Issue 6), MEDLINE (1 January 2007 to 14 June 2011), EMBASE (1 January 2007 to 14 June 2011), CINAHL (1 January 2007 to 14 June 2011), BIOSIS (1 January 2007 to 14 June 2011), African Index Medicus (searched 15 June 2011), Index Medicus for the WHO Eastern Mediterranean Region (IMEMR) (searched 15 June 2011), LILACS (Latin American and Caribbean Health Sciences) (searched 15 June 2011). We also contacted experts in the field.The search for the first version of the review in 2000 yielded a total of 2668 unique citations. Contacts with experts in the field yielded additional published and unpublished studies. The updated literature review in December 2006 yielded 835 additional unique citations. We selected all internally-controlled clinical trials and observational studies comparing child or maternal health outcomes with exclusive breastfeeding for six or more months versus exclusive breastfeeding for at least three to four months with continued mixed breastfeeding until at least six months. Studies were stratified according to study design (controlled trials versus observational studies), provenance (developing versus developed countries), and timing of compared feeding groups (three to seven months versus later). We independently assessed study quality and extracted data. We identified 23 independent studies meeting the selection criteria: 11 from developing countries (two of which were controlled trials in Honduras) and 12 from developed countries (all observational studies). Definitions of exclusive breastfeeding varied considerably across studies. Neither the trials nor the observational studies suggest that infants who continue to be exclusively breastfed for six months show deficits in weight or length gain, although larger sample sizes would be required to rule out modest differences in risk of undernutrition. In developing-country settings where newborn iron stores may be suboptimal, the evidence suggests that exclusive breastfeeding without iron supplementation through six months may compromise hematologic status. Based on the Belarusian study, six months of exclusive breastfeeding confers no benefit (versus three months of exclusive breastfeeding followed by continued partial breastfeeding through six months) on height, weight, body mass index, dental caries, cognitive ability, or behaviour at 6.5 years of age. Based on studies from Belarus, Iran, and Nigeria, however, infants who continue exclusive breastfeeding for six months or more appear to have a significantly reduced risk of gastrointestinal and (in the Iranian and Nigerian studies) respiratory infection. No significant reduction in risk of atopic eczema, asthma, or other atopic outcomes has been demonstrated in studies from Finland, Australia, and Belarus. Data from the two Honduran trials and from observational studies from Bangladesh and Senegal suggest that exclusive breastfeeding through six months is associated with delayed resumption of menses and, in the Honduran trials, more rapid postpartum weight loss in the mother. Infants who are exclusively breastfed for six months experience less morbidity from gastrointestinal infection than those who are partially breastfed as of three or four months, and no deficits have been demonstrated in growth among infants from either developing or developed countries who are exclusively breastfed for six months or longer. Moreover, the mothers of such infants have more prolonged lactational amenorrhea. Although infants should still be managed individually so that insufficient growth or other adverse outcomes are not ignored and appropriate interventions are provided, the available evidence demonstrates no apparent risks in recommending, as a general policy, exclusive breastfeeding for the first six months of life in both developing and developed-country settings.

Wing S.S.,McGill University
International Journal of Biochemistry and Cell Biology | Year: 2013

The ubiquitin proteasome system plays a critical role in skeletal muscle atrophy. A large body of research has revealed that many ubiquitin ligases are induced and play an important role in mediating the wasting. However, relatively little is known about the roles of deubiquitinases in this process. Although it might be expected that deubiquitinases would be downregulated in atrophying muscles to promote ubi-quitination and degradation of muscle proteins, this has not to date been demonstrated. Instead several deubiquitinases are induced in atrophying muscle, in particular USP19 and USP14. USP19, USP2 and A20 are also implicated in myogenesis. USP19 has been most studied to date. Its expression is increased in both systemic and disuse forms of atrophy and can be regulated through a p38 MAP kinase signaling pathway. In cultured muscle cells, it decreases the expression of myofibrillar proteins by apparently suppressing their transcription indicating that the ubiquitin proteasome system may be activated in skeletal muscle to not only increase protein degradation, but also to suppress protein synthesis. Deubiquitinases may be upregulated in atrophy in order to maintain the pool of free ubiquitin required for the increased overall conjugation and degradation of muscle proteins as well as to regulate the stability and function of proteins that are essential in mediating the wasting. Although deubiquitinases are not well studied, these early insights indicate that some of these enzymes play important roles and may be therapeutic targets for the prevention and treatment of muscle atrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Elsevier Ltd. All rights reserved.

Eluru N.,McGill University
Accident Analysis and Prevention | Year: 2013

There is considerable debate on the appropriate discrete choice framework for examining injury severity. Researchers in the safety field have employed ordered and unordered frameworks for examining the various factors influencing injury severity. The objective of the current study is to investigate the performance of the ordered and unordered response frameworks at a fundamental level. Towards this end, we undertake a comparison of the alternative frameworks by estimating ordered and unordered response models using data generated through ordered, unordered data and a combination of ordered and unordered data generation processes. We also examine the influence of aggregate sample shares on the appropriateness of the modeling framework. Rather than be limited by the aggregate sample shares in an empirical dataset, simulation allows us to explore the influence of a broad spectrum of sample shares on the performance of ordered and unordered frameworks. We also extend the data generation process based analysis to under reported data and compare the performance of the ordered and unordered response frameworks. Finally, based on these simulation exercises, we provide a discussion of the merits of the different approaches. The results clearly highlight the emergence of the generalized ordered logit model as a true equivalent ordered response model to the multinomial logit model for ordinal discrete variables. © 2013 Elsevier Ltd. All rights reserved.

The increasing importance of signal transducer and activator of transcription 3 (STAT3) expression in human cancers has led several laboratories to examine in detail the expression of one of its major negative regulators in oncogenesis - the T-cell protein tyrosine phosphatase, nonreceptor type32 (PTPN2). A recent paper by Shields and colleagues points to the associate depletion of PTPN2 in STAT3-positive breast cancers. We examine these findings and reflect on the mechanism of action of PTPN2 and the consequences of its modulation for STAT3 downstream signaling. © 2013 BioMed Central Ltd.

Blaschuk O.W.,McGill University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin isatransmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N-cadherin antagonists as anti-cancer drugs. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Brandenberger R.H.,McGill University
Classical and Quantum Gravity | Year: 2015

We review the status of string gas cosmology (SGC) after the 2015 Planck data release. SGC predicts an almost scale-invariant spectrum of cosmological perturbations with a slight red tilt, like the simplest inflationary models. It also predicts a scale-invariant spectrum of gravitational waves with a slight blue tilt, unlike inflationary models which predict a red tilt of the gravitational wave spectrum. SGC yields two consistency relations which determine the tensor to scalar ratio and the slope of the gravitational wave spectrum given the amplitude and tilt of the scalar spectrum. We show that these consistency relations are in good agreement with the Planck data. We discuss future observations which will be able to differentiate between the predictions of inflation and those of SGC. © 2015 IOP Publishing Ltd.

Bergthorson J.M.,McGill University | Thomson M.J.,University of Toronto
Renewable and Sustainable Energy Reviews | Year: 2015

The fundamental combustion and emissions properties of advanced biofuels are reviewed, and their impact on engine performance is discussed, in order to guide the selection of optimal conversion routes for obtaining desired fuel combustion properties. Advanced biofuels from second- and third-generation feedstocks can result in significantly reduced life-cycle greenhouse-gas emissions, compared to traditional fossil fuels or first-generation biofuels from food-based feedstocks. These advanced biofuels include alcohols, biodiesel, or synthetic hydrocarbons obtained either from hydrotreatment of oxygenated biofuels or from Fischer-Tropsch synthesis. The engine performance and exhaust pollutant emissions of advanced biofuels are linked to their fundamental combustion properties, which can be modeled using combustion chemical-kinetic mechanisms and surrogate fuel blends. In general, first-generation or advanced biofuels perform well in existing combustion engines, either as blend additives with petro-fuels or as pure "drop-in" replacements. Generally, oxygenated biofuels produce lower intrinsic nitric-oxide and soot emissions than hydrocarbon fuels in fundamental experiments, but engine-test results can be complicated by multiple factors. In order to reduce engine emissions and improve fuel efficiency, several novel technologies, including engines and fuel cells, are being developed. The future fuel requirements for a selection of such novel power-generation technologies, along with their potential performance improvements over existing technologies, are discussed. The trend in the biofuels and transportation industries appears to be moving towards drop-in fuels that require little changes in vehicle or fueling infrastructure, but this comes at a cost of reduced life-cycle efficiencies for the overall alternative-fuel production and utilization system. In the future, fuel-flexible, high-efficiency, and ultra-low-emissions heat-engine and fuel-cell technologies promise to enable consumers to switch to the lowest-cost and cleanest fuel available in their market at any given time. This would also enable society as a whole to maximize its global level of transportation activity, while maintaining urban air quality, within an energy- and carbon-constrained world. © 2014 Elsevier Ltd. All rights reserved.

Aboud F.E.,McGill University | Yousafzai A.K.,Aga Khan University
Annual Review of Psychology | Year: 2015

Health and nutritional risks co-occur in the lives of children under the age of 2 years who live in developing countries. We review evidence showing how these risks, in addition to inadequate psychosocial stimulation, prevent children from developing expected cognitive and language abilities. A systematic review and meta-analysis of 21 interventions aimed at enhancing stimulation and 18 interventions that provided better nutrition-all conducted since 2000-revealed that stimulation had a medium effect size of 0.42 and 0.47 on cognitive and language development, respectively, whereas nutrition by itself had a small effect size of 0.09. The implementation processes of these interventions are described and compared. A number of unresolved issues are outlined and discussed, including ways to maximize parental health behavior change, assess mediators that account for intervention effects, and expand the assessment of young children's brain functions that underlie language and cognition and are affected by nutrition and stimulation. © 2015 by Annual Reviews. All rights reserved.

Muramatsu W.,Nagasaki University | Nakano K.,Nagasaki University | Li C.-J.,McGill University
Organic Letters | Year: 2013

The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated sp3 C-H bond arylation of tetrahydroisoquinolines and isochromans is described. The corresponding products were facilely synthesized via a simple nucleophilic addition reaction between readily available aryl Grignard reagents and iminium (or oxonium) cations generated in situ by DDQ oxidation of tetrahydroisoquinolines (or isochromans) under mild conditions. © 2013 American Chemical Society.

Beauchemin N.,McGill University
Cancer Microenvironment | Year: 2011

Colorectal cancer cells establish a crosstalk with the tumor microenvironment, such that implantation and development of the tumor is generally favoured. CRC progression depends on mutations in the tumor's oncogenic pathways as well as metastasis suppressor genes, but is also influenced by the inflammatory components in the microenvironment. Inflammation results from the dietary intakes and is either compounded or counterbalanced by our lifestyles. Whether driven by intrinsic pathways or infection, inflammation produces a massive influx of cytokines and chemokines. Currently, in colorectal cancer, the best approach to counter this inflammatory wave in the microenvironment appears to be CCL2 cytokine targeting. A fairly new avenue of discovery has identified microRNAs regulating colorectal cancer-mediated inflammation, and in particular the IL-6 pro-inflammatory pathway that induces pro-apoptotic genes and HIF1a-elicited VEGF secretion. miRNAs also play a significant role in controlling metabolic genes such as the upregulation of the fatty acid synthase gene with the concomitant down-regulation of the carnitine palmitoyl transferase 1 gene. Within the metastatic environment, the Discoidin domain receptor-2 (DDR2) gene encodes a tyrosine kinase receptor for fibrillar collagen that contributes to colorectal cancer metastasis by increasing myofibroblasts, neoangiogenic vessels and proliferating cancer cells. Ongoing identification of gene signatures differentiating between primary tumor cells and their metastatic counterparts promises a wealth of new targets to be exploited for further therapeutic use within the next decade. © Springer Science+Business Media B.V. 2011.

Behavior change communications regarding child feeding have met with mixed success. The present study analyzes responses of 34 Bangladeshi caregivers seven months after they received a responsive feeding intervention. The intervention communicated and demonstrated five feeding interactions: hand-washing, self-feeding, verbal responsivity, managing refusals non-forcefully, and dietary diversity. Seventeen caregivers who adopted key behaviors addressed by the intervention and 17 who did not were compared in terms of socio-demographic variables, but more importantly in terms of their recall of the messages, their reported practice, and reported facilitators and barriers. Both those who changed and those who did not reported similar facilitators and barriers to practicing the new behaviors; there was also no difference in recall or in socio-demographic variables. Key themes identified through a constant comparative analysis helped to focus on common features of the lives of caregivers that made it easy or difficult to perform the practices. Some of these were household constraints such as poverty, shortage of time in which to complete chores, and avoiding waste and messiness; others related to the child's demands. Many caregivers misinterpreted instructions about talking to one's child in response to signals, as opposed to more common forms of supervision. Facilitators such as the child's evident pleasure and the caregiver's satisfaction did not always outweigh the barriers. Recommendations for improving interventions include helping caregivers solve problems tied to barriers and including more family members in the intervention. © 2012 Elsevier Ltd.

Indium phosphide (InP) quantum dots (QDs) have emerged as a presumably less hazardous alternative to cadmium-based particles, but their cytotoxicity has not been well examined. Although their constituent elements are of very low toxicity to cells in culture, they nonetheless exhibit phototoxicity related to generation of reactive oxygen species by excited electrons and/or holes interacting with water and molecular oxygen. Using spin-trap electron paramagnetic resonance (EPR) spectroscopy and reporter assays, we find a considerable amount of superoxide and a small amount of hydroxyl radical formed under visible illumination of biocompatible InP QDs with a single ZnS shell, comparable to what is seen with CdTe. A double thickness shell reduces the reactive oxygen species concentration approximately two-fold. Survival assays in five cell lines correspondingly indicate a distinct reduction in toxicity with the double-shell InP QDs. Toxicity varies significantly across cell lines according to the efficiency of uptake, being overall significantly less than what is seen with CdTe or CdSe/ZnS. This indicates that InP QDs are a useful alternative to cadmium-containing QDs, while remaining capable of electron-transfer processes that may be undesirable or which may be exploited for photosensitization applications.

Bennett G.J.,McGill University
Journal of Pain | Year: 2012

Spontaneous pain is often discussed in the context of both chronic inflammatory and neuropathic pain conditions, and it has been suggested that spontaneous pain, rather than stimulus-evoked pain, may be the more significant clinical problem. The following issues are discussed here. First, it is suggested that the concept of spontaneous pain makes no sense when the pain is the result of an ongoing inflammatory reaction. Evidence is reviewed that indicates that spontaneous pain is present in patients with neuropathic pain, but perhaps only in a subset of such patients. Second, it is suggested that in the presence of allodynia and hyperalgesia, stimulation from the activities of daily life occurs very many times a day and that these stimulus-evoked pains may summate to give a fluctuating level of daily pain that both patients and investigators mistake for spontaneous pain. Perspective: Which is more important - stimulus-evoked pain or spontaneous pain? This review suggests that to answer the question we will need to distinguish neuropathic spontaneous pain from inflammatory ongoing pain and to differentiate both from summated allodynic and hyperalgesic pains caused by the stimuli of daily life. © 2012 by the American Pain Society.

Varoni E.,McGill University
Minerva stomatologica | Year: 2012

Chlorhexidine (CHX) is one of the most commonly prescribed antiseptic agents in the dental field. It has a long-lasting antibacterial activity with a broad-spectrum of action and it has been shown to reduce plaque, gingival inflammation and bleeding. Its use is considered a powerful adjuvant to mechanical oral hygiene (brushing and flossing), especially in those cases in which it cannot be performed correctly. Available as mouthwash, gel, aerosol, spray and disks, CHX is considered a safe compound, with minimal and transitory local and systemic side effects. Data support its periodic use as an adjuvant to normal brushing and flossing in subjects unable to maintain proper oral hygiene due to physical and/or mental impairment, or lack of motivation, or decreased salivary rate. CHX is also a useful alternative to mechanical oral hygiene procedures in those cases in which they are contraindicated, e.g. after a surgical procedure, or as a preoperative rinse before procedures in which use of a dental dam is not possible. The aim of this article is to offer a complete review of literature regarding the characteristics, the applications and the problems associated with the use of chlorhexidine in the dental field.

Behrmann J.,McGill University
Allergy, Asthma and Clinical Immunology | Year: 2013

While a growing body of research is uncovering the aetiology and effective treatments for allergy, research that assess the broader ethical implications of this disease is lacking significantly. This article will demonstrate both the paucity of academic research concerning ethical implications in allergy and explain why ethical analysis is integral to formulating effective health strategies for allergic disease. An exhaustive literature search of publications in French and English identified less than 35 academic articles focussed on the topic of ethics and allergy; this is a miniscule number when compared to the amount of articles published on ethical issues related to other chronic illnesses, such as obesity. It is important to demonstrate to allergy specialists the need for, and utility of, further incorporating ethical analyses in allergology; the current success of Ethical, Legal, Social Implications (ELSI) research programmes in human genetics and nanotechnology will serve as notable examples. Indeed, future research and innovation in allergy will undoubtedly encounter ethical dilemmas and the allergology community should play a significant role in helping to address these issues. However, incorporating ethical analyses in allergology does not imply that the allergology community must acquire extensive knowledge in bioethics; instead, interdisciplinary research that incorporates expertise from allergology and bioethics would enable allergy specialists to advance critical knowledge development in this largely overlooked domain of study. © 2013 Behrmann; licensee BioMed Central Ltd.

Paris J.,McGill University
Journal of Personality Disorders | Year: 2011

It has been suggested that psychiatric diagnosis should come to depend on endophenotypes, in order to define more precisely the mechanisms behind mental disorders. This construct is associated with the assumption that mental processes can be reduced to activity at a neuronal level. The approach has had a strong influence on the conceptual basis of proposals for DSM-5, but could be consistent either with categorical or dimensional diagnosis. However, application of endophenotypes to personality disorders is unlikely for the foreseeable future, given an insufficient knowledge of etiology and pathogenesis. © 2011 The Guilford Press.

Prostaglandin E2 (PGE2) is a well known pain and proinflammatory mediator abundantly produced in inflamed tissue. It causes pain by directly exciting nociceptive primary sensory neurons (nociceptors) and indirectly stimulating the release of pain-related peptide substance P (SP) and calcitonin gene-related peptide (CGRP). In an ex vivo culture of sensory ganglion explants, we tested the hypothesis that PGE2 could induce the synthesis of SP and CGRP in nociceptors. A stabilized PGE2 analog, 16,16-dimethyl PGE2, in a concentration- and time-dependent manner, significantly increased mRNA and peptide levels of SP and CGRP. The agonists of EP1 and EP4 receptors also significantly increased SP and CGRP levels. Moreover, 16,16-dimethyl PGE2-induced SP and CGRP were blocked by EP1 and EP4 antagonists as well as the inhibitors of both protein kinase A and protein kinase C. Nerve growth factor was partially involved in PGE2-induced SP and CGRP synthesis. Taken together, these results indicate that PGE2 contributes to the synthesis of SP and CGRP in nociceptors, an event mediated by EP1 and EP4 receptors, nerve growth factor and protein kinase A and protein kinase C signalling pathways. We thus conclude that facilitating the synthesis of pain-related peptides in nociceptors is a novel mechanism underlying the role of PGE2 in nociception and chronic pain states. © 2010 International Society for Neurochemistry.

Ouhnana M.,McGill University
Journal of vision | Year: 2013

Regularity is a ubiquitous feature of the visual world. We demonstrate that regularity is an adaptable visual dimension: The perceived regularity of a pattern is reduced following adaptation to a pattern with a similar or greater degree of regularity. Stimuli consisted of 7×7 element arrays arranged on square grids presented in a circular aperture. The position of each element was randomly jittered from its baseline position by an amount that determined its degree of irregularity. The elements of the pattern consisted of dark Gaussian blobs (GBs), difference of Gaussians (DOGs), or random binary patterns (RBPs). Observers adapted for 60 s to either a single pattern or a pair of patterns with particular regularities, and the perceived regularities of subsequently presented test patterns were measured using a conventional staircase matching procedure. We found that the regularity aftereffect (RAE) was unidirectional: Adaptation only caused test patterns to appear less regular. We also found that RAEs transferred from GB adaptors to both DOG and RBP test patterns and from DOG and RBP adaptors to GB patterns. We suggest that regularity is coded by the peakedness in the distribution of spatial-frequency channel responses across scale, and that the RAE is a result of a flattening of this distribution by adaptation. Thus, the RAE may be a consequence of contrast normalization, and an example of norm-based coding where irregularity is the norm.

White C.W.,University of Colorado at Denver | Martin J.G.,McGill University
Proceedings of the American Thoracic Society | Year: 2010

Humans can come into contact with chlorine gas during short-term, high-level exposures due to traffic or rail accidents, spills, or other disasters. By contrast, workplace and public (swimming pools, etc.) exposures are more frequently long-term, low-level exposures, occasionally punctuated by unintentional transient increases. Acute exposures can result in symptoms of acute airway obstruction including wheezing, cough, chest tightness, and/or dyspnea. These findings are fairly nonspecific, and might be present after exposures to a number of inhaled chemical irritants. Clinical signs, including hypoxemia, wheezes, rales, and/or abnormal chest radiographsmay be present. More severely affected individuals may suffer acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). Up to 1% of exposed individuals die. Humidified oxygen and inhaled b-adrenergic agents are appropriate therapies for victims with respiratory symptoms while assessments are underway. Inhaled bicarbonate and systemic or inhaled glucocorticoids also have been reported anecdotally to be beneficial. Chronic sequelae may include increased airways reactivity, which tends to diminish over time. Airways hyperreactivity may be more of a problem among those survivors that are older, have smoked, and/or have pre-existing chronic lung disease. Individuals suffering from irritant-induced asthma (IIA) due to workplace exposures to chlorine also tend to have similar characteristics, such as airways hyperresponsiveness to methacholine, and to be older and to have smoked. Other workplace studies, however, have indicated that workers exposed to chlorine dioxide/sulfur dioxide have tended to have increased risk for chronic bronchitis and/or recurrent wheezing attacks (one or more episodes) but not asthma, while those exposed to ozone have a greater incidence of asthma. Specific biomarkers for acute and chronic exposures to chlorine gas are currently lacking. Animal models for chlorine gas inhalation have demonstrated evidence of oxidative injury and inflammation. Early epithelial injury, airways hyperresponsiveness, and airway remodeling, likely diminishing over time, have been shown. As in humans, ALI/ARDS can occur, becoming more likely when the upper airways are bypassed. Inhalation models of chlorine toxicity provide unique opportunities for testing potential pharmacologic rescue agents.

Characterizing the inherent spatial variability of soil water is intensive in terms of sampling effort and therefore costly. The objectives of this study were to examine time stability of the spatial pattern of soil water storage (SWS) at different seasons and depths, to identify representative monitoring locations (RMLs) that consistently reflect field average SWS, and to recommend efficient ways to identify these locations. Soil water was measured down to 1.4. m at 0.20-m vertical depth intervals using time domain reflectometry and neutron backscattering along a hummocky transect in semiarid central Canada. Strong Spearman rank correlation coefficients between SWS spatial series indicated similarity of spatial patterns, which showed strong seasonal dependence: intra-season time stability was stronger than inter-annual time stability, which was stronger than inter-season time stability. The observed time stability was used to identify an RML. The RML for the surface layer (0-0.20. m) was different from the root zone (0-0.60. m) and the total active soil profile (0-1.20. m), the latter two having adjacent RMLs. The bias (~. 3%-10% maximum) associated with using an RML to predict field-averaged SWS was examined using regression. However, the prediction of field-averaged SWS using an RML was better compared to the prediction using field extreme locations in terms of error associated with the prediction. Predictions using more than one RML yielded better results than when a single RML was used. Successful and rapid identification of RMLs greatly reduced the number of observations needed to characterize the average soil water behaviour of a field. The measurement of SWS through representative monitoring location(s) may be used for environmental monitoring and modelling, irrigation scheduling, nutrient recommendations, and predicting greenhouse gas emissions. © 2013 Elsevier B.V.

Piccirillo C.A.,McGill University
Current opinion in immunology | Year: 2013

Foxp3(+) regulatory T (Treg) cells represent a major mechanism for the maintenance of self-tolerance and immune homeostasis in various inflammatory responses. To achieve this, Foxp3(+) Treg cells must integrate a spectrum of environmental stimuli to orchestrate the required pathways for their coordinated action in vivo. Transcriptional and post-transcriptional mechanisms of gene regulation enable T cells to respond to inflammatory events, by altering the nature, amounts and activities of specific proteins produced for their controlled and coordinated modulation of immunity. Recent studies show that distinct translational programs orchestrate cellular processes in various immune cell types, including CD4(+) T cell subsets. Copyright © 2013. Published by Elsevier Ltd.

Breau S.,McGill University
Antipode | Year: 2014

The Occupy movement catalyzed public debate on the issue of growing income inequality. This paper examines recent patterns of inequality in Canada, paying particular attention to changes in the characteristics of the top 1% of income earners. At the national level, the gap between the top percentile and the other 99% has widened considerably: in 2006, 11% of the nation's income was concentrated in the hands of top earners (whose mean income of $344,000 is 11 times that of the average Canadian) compared with 7.7% just 15 years earlier. Beneath such national-level figures lie important geographical differences in the income hierarchy: the thresholds, average incomes and socio-economic characteristics of the top 1% vary widely across provinces and cities. Among the most important spatial shifts observed is the growing concentration of high-income groups in energy-rich Western Canada, where Calgary has become the most unequal city in the country. © 2013 The Author. Antipode © 2013 Antipode Foundation Ltd.

Lovejoy S.,McGill University
Climate Dynamics | Year: 2014

Although current global warming may have a large anthropogenic component, its quantification relies primarily on complex General Circulation Models (GCM's) assumptions and codes; it is desirable to complement this with empirically based methodologies. Previous attempts to use the recent climate record have concentrated on "fingerprinting" or otherwise comparing the record with GCM outputs. By using CO2 radiative forcings as a linear surrogate for all anthropogenic effects we estimate the total anthropogenic warming and (effective) climate sensitivity finding: ΔT anth = 0.87 ± 0.11 K, λ2xCO2,eff= 3.08 ± 0.58 K. These are close the IPPC AR5 values ΔT anth = 0.85 ± 0.20 K and λ2xCO2= 1.5 - 4.5 K (equilibrium) climate sensitivity and are independent of GCM models, radiative transfer calculations and emission histories. We statistically formulate the hypothesis of warming through natural variability by using centennial scale probabilities of natural fluctuations estimated using scaling, fluctuation analysis on multiproxy data. We take into account two nonclassical statistical features-long range statistical dependencies and "fat tailed" probability distributions (both of which greatly amplify the probability of extremes). Even in the most unfavourable cases, we may reject the natural variability hypothesis at confidence levels >99 %. © 2014 Springer-Verlag Berlin Heidelberg.

Hynes A.,McGill University
Canadian Journal of Earth Sciences | Year: 2014

As the asthenospheric mantle rises at oceanic spreading centres, it undergoes partial melting, producing oceanic crust and depleted mantle, both of which have lower intrinsic density than the asthenospheric mantle from which they were derived. With a warmer asthenosphere in the Archean, these effects are enhanced, leading to the possibility that subduction was no longer feasible. I investigate the density of the oceanic crust and underlying mantle for a mantle with temperatures 200 °C higher than today, using models of the chemistry of melting and the mineralogy of the ensuing rocks. For the melting model used, crustal thicknesses are 21 km and the depth to which the mantle is partially melted is 114 km, compared with 7 and 54 km for a comparable model of modern Earth. Two thermal-evolution models for Archean oceanic lithosphere are examined. One assumes twice the heat flow into the base of the plates, which severely restricts the depths to which the plates can cool with age. A second assumes the plates can cool to the depth to which the asthenosphere undergoes partial melting, resulting in heat flow into the base of the plates only 1.3 times as large as today. With the first model, oceanic plates do not become denser than an equivalent column of asthenosphere. With the second, they do after -50 Ma of cooling. In both cases, however, the cooling is sufficient to provide a significant driving force for the initiation of subduction because the sole requirement for a subduction-initiation drive is that the cooled lithosphere be denser than the column of differentiated asthenosphere that would replace it. This, combined with the low flexural rigidity of Archean plates, makes the initiation of subduction probably slightly easier than it is today. The relatively low density of oceanic plates results in lower slab pull, but this effect is counterbalanced both by the likelihood that some of the low-density crust may have been delaminated, and by the effect of passage of the thicker crust through the eclogite transition. Given our present knowledge of Archean thermal conditions, there does not appear to be a compelling theoretical argument against efficient subduction processes at that time.

Cole M.G.,McGill University
Current Opinion in Psychiatry | Year: 2010

Purpose of review There are two contradictory views on the prognosis of delirium in older hospital patients. On one hand, the Diagnostic and Statistical Manual, 4th Text Revision (DSM-IV-TR), describes delirium as a transient cognitive disorder, the majority of affected individuals having a full recovery. On the other hand, longitudinal studies of delirium in this population report that the outcomes are poor. This review proposes to reconcile these two contradictory views. Recent findings In older hospital patients, delirium appears to persist in 44.7% of patients at discharge and in 32.8, 25.6 and 21% of patients at 1, 3 and 6 months, respectively. The outcomes (cognition, function, nursing home placement, mortality) of patients with persistent delirium are consistently worse than the outcomes of patients who recover from delirium. Summary The majority of older hospital patients with delirium may recover but the persistence of delirium in a substantial minority of patients may account, in large part, for the poor outcomes of delirium in this population. This proposal has potentially important implications for clinical practice and research. © 2010 Wolters Kluwer Health π Lippincott Williams & Wilkins 0951-7367.

Liu Y.,McGill University
Journal of Geophysical Research B: Solid Earth | Year: 2014

Scaling between slip event duration and equivalent moment is diagnostic of the underlying physics of rupture process. For episodic slow slip events (SSEs) in subduction zones, their moment-duration relation is not clearly defined and shows considerable variation among individual margins where multiple episodes of SSEs are geodetically detected. Here I set up a 3-D planar thrust fault model within the framework of rate-state friction to study the spatiotemporal evolution of slip and stress during SSEs. SSE source properties, including along-strike length, duration, equivalent moment, and stress drop, are quantified, and their scaling relations are compared to observations. Modeled SSEs have nearly constant stress drops of 0.001 to 0.01 MPa, due to near-lithostatic pore pressure at the SSE depths. The modeled moment-duration scaling is between 1 (linear) and 2 (squared). When multiple SSEs appear simultaneously along the strike, the stress interaction between approaching slip fronts results in higher average propagation speeds for longer lengths, which leads to a scaling close to 2. When SSEs are well offset in space and time, stress interaction is negligible and the scaling is close to 1. Two types of SSE along-strike segmentation gaps are identified from model results. The "primary" gaps are persistent segmentation boundaries due to along-strike variation of effective normal stress, while the "secondary" gaps evolve through SSE cycles and reflect the stress condition within a primary segment. This implies that some geodetically inferred SSE segmentation boundaries may result from slower slip velocities below the resolution limits of geodetic inversion models. © 2014. American Geophysical Union.

Cristescu M.E.,McGill University
Molecular Ecology | Year: 2015

A diverse array of molecular markers and constantly evolving analytical approaches have been employed to reconstruct the invasion histories of the most notorious invasions. Detailed information on the source(s) of introduction, invasion route, type of vectors, number of independent introductions and pathways of secondary spread has been corroborated for a large number of biological invasions. In this review, I present the promises and limitations of current techniques while discussing future directions. Broad phylogeographic surveys of native and introduced populations have traced back invasion routes with surprising precision. These approaches often further clarify species boundaries and reveal complex patterns of genetic relationships with noninvasive relatives. Moreover, fine-scale analyses of population genetics or genomics allow deep inferences on the colonization dynamics across invaded ranges and can reveal the extent of gene flow among populations across various geographical scales, major demographic events such as genetic bottlenecks as well as other important evolutionary events such as hybridization with native taxa, inbreeding and selective sweeps. Genetic data have been often corroborated successfully with historical, geographical and ecological data to enable a comprehensive reconstruction of the invasion process. The advent of next-generation sequencing, along with the availability of extensive databases of repository sequences generated by barcoding projects opens the opportunity to broadly monitor biodiversity, to identify early invasions and to quantify failed invasions that would otherwise remain inconspicuous to the human eye. © 2015 John Wiley & Sons Ltd.

Magder S.,McGill University
Current Opinion in Critical Care | Year: 2014

Purpose of Review: Many devices are currently available for measuring cardiac output and function. Understanding the utility of these devices requires an understanding of the determinants of cardiac output and cardiac function, and the use of these parameters in the management of critically ill patients. This review stresses the meaning of the physiological measures that are obtained with these devices and how these values can be used. Recent Findings: Evaluation of devices for haemodynamic monitoring can include just measurement of cardiac output, the potential to track spontaneous changes in cardiac output or changes produced by volume infusions or vasoactive drugs, or the ability to assess cardiac function. Each of these puts different demands on the need for accuracy, precision, and reliability of the devices, and thus devices must be evaluated based on the clinical need. Summary: Evaluation of cardiac function is useful when first dealing with an unstable patient, but for ongoing management measurement of cardiac output itself is key and even more so the trend in relationship to the patient's overall condition. This evaluation would be greatly benefited by the addition of objective measures of tissue perfusion. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Aboud F.E.,McGill University | Akhter S.,International Center for Diarrhoeal Disease Research
Pediatrics | Year: 2011

OBJECTIVES: The goal of this study was to determine if a responsive stimulation and feeding intervention improved developmental and nutritional outcomes compared with a regular information-based parenting program. The hypothesis was that mothers in the intervention would exhibit better parenting skills and children would exhibit better developmental and nutritional outcomes than controls. METHODS: A cluster-randomized field trial was conducted with 302 children aged 8 to 20 months and their mothers in rural Bangladesh who were randomly assigned according to village to 1 of 3 groups. The control mothers received 12 informational sessions on health and nutrition. The intervention groups received an additional 6 sessions delivered by peer educators who included modeling and coached practice in self-feeding and verbal responsiveness with the child during play. A second intervention group received, along with the sessions, 6 months of a food powder fortified with minerals and vitamins. Developmental outcomes included the Home Observation for Measurement of the Environment (HOME) Inventory, mother-child responsive talk, and language development. Nutritional outcomes included weight, height, self-feeding, and mouthfuls eaten. We used analysis of covariance to compare the 3 groups at the posttest and at follow-up, covarying the pretest levels and confounders. RESULTS: At follow-up, responsive stimulation-feeding groups had better HOME inventory scores, responsive talking, language, mouthfuls eaten, and hand-washing. Micronutrient fortification resulted in more weight gain. CONCLUSIONS: A brief behavior-change program that focused on modeling and practice in stimulation and feeding was found to benefit children's nutrition and language development. Micronutrients benefited children's weight but not length. Copyright © 2011 by the American Academy of Pediatrics.

Wagner J.R.,McGill University
PLoS computational biology | Year: 2010

Allelic imbalance (AI) is a phenomenon where the two alleles of a given gene are expressed at different levels in a given cell, either because of epigenetic inactivation of one of the two alleles, or because of genetic variation in regulatory regions. Recently, Bing et al. have described the use of genotyping arrays to assay AI at a high resolution (approximately 750,000 SNPs across the autosomes). In this paper, we investigate computational approaches to analyze this data and identify genomic regions with AI in an unbiased and robust statistical manner. We propose two families of approaches: (i) a statistical approach based on z-score computations, and (ii) a family of machine learning approaches based on Hidden Markov Models. Each method is evaluated using previously published experimental data sets as well as with permutation testing. When applied to whole genome data from 53 HapMap samples, our approaches reveal that allelic imbalance is widespread (most expressed genes show evidence of AI in at least one of our 53 samples) and that most AI regions in a given individual are also found in at least a few other individuals. While many AI regions identified in the genome correspond to known protein-coding transcripts, others overlap with recently discovered long non-coding RNAs. We also observe that genomic regions with AI not only include complete transcripts with consistent differential expression levels, but also more complex patterns of allelic expression such as alternative promoters and alternative 3' end. The approaches developed not only shed light on the incidence and mechanisms of allelic expression, but will also help towards mapping the genetic causes of allelic expression and identify cases where this variation may be linked to diseases.

Lasko P.,McGill University
Current Biology | Year: 2013

Three recent studies revise the prevailing view of regulation of the mid-blastula transition in Drosophila, indicating particular requirements for the Cdc25 phosphatase Twine and for zygotic transcription of a specific set of genes. © 2013 Elsevier Ltd All rights reserved.

Pollak M.,McGill University
Journal of Clinical Investigation | Year: 2013

Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.

Park C.B.,McGill University
Biology of reproduction | Year: 2012

Preterm birth is the single leading cause of perinatal mortality in developed countries, affecting approximately 12% of pregnancies and accounting for 75% of neonatal loss in the United States. Despite the prevalence and severity of premature delivery, the causes and mechanisms that underlie spontaneous and idiopathic preterm birth remain unknown. Our inability to elucidate these fundamental causes has been attributed to a poor understanding of the signaling pathways associated with the premature induction of parturition and a lack of suitable animal models available for preterm birth research. In this study, we describe the generation and analysis of a novel conditional knockout of the transforming growth factor beta (TGFB) superfamily member, Nodal, from the maternal reproductive tract of mice. Strikingly, uterine Nodal knockout females exhibited a severe malformation of the maternal decidua basalis during placentation, leading to significant intrauterine growth restriction, and ultimately preterm birth and fetal loss on Day 17.5 of gestation. Using several approaches, we characterized aberrant placental development and demonstrated that reduced proliferation combined with increased apoptosis resulted in a diminished decidua basalis and compromised maternal-fetal interface. Last, we evaluated various components of the established parturition cascade and determined that preterm birth derived from the maternal Nodal knockout occurs prior to PTGS2 (COX-2) upregulation at the placental interface. Taken together, the results presented in this study highlight an in vivo role for maternal NODAL during placentation, present an interesting link between disrupted decidua basalis formation and premature parturition, and describe a potentially valuable model toward elucidating the complex processes that underlie preterm birth.

Holder G.P.,McGill University
Astrophysical Journal | Year: 2014

If the radio background is coming from cosmological sources, there should be some amount of clustering due to the large scale structure in the universe. Simple models for the expected clustering combined with the recent measurement by ARCADE-2 of the mean extragalactic temperature lead to predicted clustering levels that are substantially above upper limits from searches for anisotropy on arcminute scales using the Australia Telescope Compact Array and the Very Large Array. The rms temperature variations in the cosmic radio background appear to be more than a factor of 10 smaller (in temperature) than the fluctuations in the cosmic infrared background. It is therefore extremely unlikely that this background comes from galaxies, galaxy clusters, or any sources that trace dark matter halos at z ≲ 5, unless typical sources are smooth on arcminute scales, requiring typical sizes of several Mpc. © 2014. The American Astronomical Society. All rights reserved..

Tsang D.,McGill University
Astrophysical Journal | Year: 2014

A fully analytic expression for the linear corotation torque to first order in eccentricity for planets in non-barotropic protoplanetary disks is derived, taking into account the effect of disk entropy gradients. This torque formula is applicable to both the co-orbital, corotation torques and the non-co-orbital, corotation torques - for planets in orbits with non-zero eccentricity - in disks where the thermal diffusivity and viscosity are sufficient to maintain the linearity of these interactions. While the co-orbital, corotation torque is important for migration of planets in Type I migration, the non-co-orbital, corotation torque plays an important role in the eccentricity evolution of giant planets that have opened gaps in the disk. The presence of an entropy gradient in the disk can significantly modify the corotation torque in both these cases. © 2014. The American Astronomical Society. All rights reserved..

Rey A.D.,McGill University
Soft Matter | Year: 2010

This paper presents an overview of liquid crystal (LC) models of phase diagrams, phase transitions, self-assembly, interfaces, defects, and rheology and their integrated applications to biological mesophase materials and processes. Biological liquid crystals, classified into analogues (helicoidal plywoods), biopolymer solutions (in vitro DNA, polypeptides, collagen solutions) and in vivo LCs (membranes, silk, DNA), are discussed in terms of molecular characteristics and the symmetry of the thermodynamic phases. The thermodynamics and self-assembly of biological liquid crystals (BLCs) are discussed in terms of the Doi-Maier-Saupe lyotropic model and its extensions to chiral phases, showing the role of excluded volume and chirality. The defect physics of BLCs is described using the Landau-de Gennes model of chiral and achiral nematostatics to identify (i) thermodynamic phases, and (ii) observed textures and defect lattices under confinement and flow. The rheology and flow properties of BLCs are described using the Leslie-Ericksen and the Landau-de Gennes models of nematodynamics. The applications of integrated thermodynamic/defect/rheology modeling to the experimental characterization of several BLCs, including collagen and DNA solutions, are shown to provide organizing principles and quantitative tools to establish the properties of these natural materials. The phase transitions, tactoidal spherulites, flow-birefringence in dilute solutions, and banded textures in sheared concentrated solutions of collagen show how the principles of LC physics operate in BLC materials. Drying and spreading drops of DNA solutions leading to the formation of nematic monodomain aligned along the contact line are shown to follow self-assembly structuring under the action of interfacial, bulk, and contact line torques. Finally modeling of spider and silkworm LC spinning is presented as an example of biological polymer processing, where a high performance fiber material is produced through a lyotropic LC protein solution. The concerted structuring action of capillary confinement, strong anchoring, and nematic flow leads to predictions in agreement with the reported textural transitions in the duct of spiders and silkworms. The quantitative description of BLC materials and processes using mesoscopic models provides another tool to develop the science and future biomimetic applications of these ubiquitous natural anisotropic soft materials. © 2010 The Royal Society of Chemistry.

Malhotra M.,McGill University
International journal of nanomedicine | Year: 2011

Preparation of poly (ethylene glycol) (PEG)-grafted chitosan is essential for improving the biocompatibility and water solubility of chitosan. Presently available methods for this have limitations. This article describes a new method for preparing PEGylated chitosan nanoparticles. For this chitosan was chemoselectively modified using a novel scheme at the C6 position of its repeating units by PEG. The amine groups at the C2 position of the chitosan were protected using phthalic anhydride. Sodium hydride was used to catalyze the etherification reaction between chlorinated chitosan and methyl-PEG, and PEG-grafted chitosan was successfully synthesized. Each step was characterized using 13C nuclear magnetic resonance and Fourier transform infrared. After PEGylation the phthaloylated chitosan was successfully deprotected using hydrazine monohydrate. The synthetic scheme proposed demonstrates a new method for grafting PEG onto chitosan with a moderate degree of substitution. The potential of this polymer in nanoparticle preparation using an ionic gelation method and its gene delivery potentials were investigated by complexing a fluorescently labeled control siRNA. The result showed that suitable nanoparticles can be synthesized using this polymer and that they have capacity to carry genes and provide adequate transfection efficacy with no toxicity when tested in neuronal cells.

Gurvitz M.,Boston Adult Congenital Heart Service | Marelli A.,McGill University | Mangione-Smith R.,University of Washington | Jenkins K.,Boston Adult Congenital Heart Service
Journal of the American College of Cardiology | Year: 2013

Objectives This study sought to develop quality indicators (QIs) for outpatient management of adult congenital heart disease (ACHD) patients. Background There are no published QIs to promote quality measurement and improvement for ACHD patients. Methods Working groups of ACHD experts reviewed published data and United States, Canadian, and European guidelines to identify candidate QIs. For each QI, we specified a numerator, denominator, period of assessment, and data source. We submitted the QIs to a 9-member panel of international ACHD experts. The panel rated the QIs for validity and feasibility in 2 rounds on a scale of 1 to 9 using the RAND/University of California-Los Angeles modified-Delphi method, and final QI selection was on the basis of median scores. Results A total of 62 QIs were identified regarding appropriateness and timing of clinical management, testing, and test interpretation. Each QI was ascertainable from health records. After the first round of rating, 29 QIs were accepted, none were rejected, and 33 were equivocal; on the second round, 55 QIs were accepted. Final QIs included: 8 for atrial septal defects; 9 for aortic coarctation; 12 for Eisenmenger; 9 for Fontan; 9 for D-transposition of the great arteries; and 8 for tetralogy of Fallot. Conclusions This project resulted in development of the first set of QIs for ACHD care based on published data, guidelines, and a modified Delphi process. These QIs provide a quality of care assessment tool for 6 ACHD conditions. This rigorously designed set of QIs should facilitate measuring and improving the quality of care for this growing group of patients. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.

Menzies D.,McGill University | Nahid P.,San Francisco General Hospital
American Journal of Respiratory and Critical Care Medicine | Year: 2013

In 2012, new publications in the Journal described both the predictive value of the new IFN-γ release assays for diagnosis of latent tuberculosis (TB), but also provided evidence that these new tests cannot be interpreted simply as positive or negative, as initially hoped. Surgical masks can reduce transmission of TB infection, but other measures such as state-wide implementation of targeted testing and treatment of latent TB or active case finding require substantial and sustained effort to successfully reduce TB morbidity and mortality. A quasiexperimental study revealed that a package of social interventions could substantially reduce risk of TB disease in heavily exposed (and infected) children in the preantibiotic era. Astudy in a high-TB burden setting suggested that anewrapid drugsusceptibility test for TB may be more practical for implementation than traditional culture-based phenotypic tests. And two studies of TB vaccines revealed that currently used bacillus Calmette-Guérin strains vary in their ability to affect correlates of immunogenicity, whereas a new candidate vaccine, MVA85A, was safe and immunogenic in adults. Studies of nontuberculous mycobacteria (NTM) described a rapid rise in the prevalence and spatial clustering ofNTMin the United States over the past decade. Although risk factors for pulmonary NTM such as advanced age and low BMI are known, the mechanisms underlying infection and disease remain mysterious. Four studies of therapy of NTM disease highlighted the pressing need for well-designed international randomized controlled trials to improve our management of NTM disease. Copyright © 2013 by the American Thoracic Society.

Amabili M.,McGill University
Nonlinear Dynamics | Year: 2012

Internal resonances in geometrically nonlinear forced vibrations of laminated circular cylindrical shells are investigated by using the Amabili- Reddy higher-order shear deformation theory. A harmonic force excitation is applied in radial direction and simply supported boundary conditions are assumed. The equations of motion are obtained by using an energy approach based on Lagrange equations that retain dissipation. Numerical results are obtained by using the pseudo-arc length continuation method and bifurcation analysis. A one-to-one-to-two internal resonance is identified, giving rise to pitchfork and Neimark-Sacher bifurcations of the non-linear response. A threshold level in the excitation has been observed in order to activate the internal resonance. © Springer Science+Business Media B.V. 2011.

Ghayesh M.H.,McGill University
Archive of Applied Mechanics | Year: 2012

Geometrically nonlinear dynamics of an axially accelerating beam is investigated numerically in this paper. Employing the Galerkin scheme, the equation of motion is reduced to a set of nonlinear ordinary differential equations with coupled terms. The linear part of this set of equations is then solved to determine the linear natural frequencies. The frequency of the axial acceleration is set to twice the first or second linear natural frequency (subharmonic resonance), and bifurcation diagrams of Poincaré maps are obtained via direct time integration and choosing the amplitude of the speed variations as a bifurcation parameter. The results are presented for four different values of the mean value of the axial speed, specifically in the form of time traces, phase-plane portraits, fast Fourier transforms (FFTs), and Poincaré maps. © Springer-Verlag 2012.

Devroye L.,McGill University
Statistics and Computing | Year: 2014

We provide a uniformly efficient and simple random variate generator for the entire parameter range of the generalized inverse Gaussian distribution. A general algorithm is provided as well that works for all densities that are proportional to a log-concave function φ, even if the normalization constant is not known. It requires only black box access to φ and its derivative. © 2012 Springer Science+Business Media New York.

Bell G.,McGill University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2013

Populations subject to severe stress may be rescued by natural selection, but its operation is restricted by ecological and genetic constraints. The cost of natural selection expresses the limited capacity of a population to sustain the load of mortality or sterility required for effective selection. Genostasis expresses the lack of variation that prevents many populations from adapting to stress. While the role of relative fitness in adaptation is well understood, evolutionary rescue emphasizes the need to recognize explicitly the importance of absolute fitness. Permanent adaptation requires a range of genetic variation in absolute fitness that is broad enough to provide a few extreme types capable of sustained growth under a stress that would cause extinction if they were not present. This principle implies that population size is an important determinant of rescue. The overall number of individuals exposed to selection will be greater when the population declines gradually under a constant stress, or is progressively challenged by gradually increasing stress. In gradually deteriorating environments, survival at lethal stress may be procured by prior adaptation to sublethal stress through genetic correlation. Neither the standing genetic variation of small populations nor the mutation supply of large populations, however, may be sufficient to provide evolutionary rescue for most populations. © 2012 The Author(s) Published by the Royal Society. All rights reserved.

Methylated DNA binding protein 2 (MBD2) binds methylated promoters and suppresses transcription in cis through recruitment of a chromatin modification repressor complex. We show here a new mechanism of action for MBD2: suppression of gene expression indirectly through activation of microRNA hsa-mir-496. Overexpression of MBD2 in breast epithelial cell line MCF-10A results in induced expression and demethylation of hsa-mir-496 while depletion of MBD2 in a human breast cancer cell lines MCF-7 and MDA-MB231 results in suppression of hsa-mir-496. Activation of hsa-mir-496 by MBD2 is associated with silencing of several of its target genes while depletion of MBD2 leads to induction of hsa-mir-496 target genes. Depletion of hsa-mir-496 by locked nucleic acid (LNA) antisense oligonucleotide leads to activation of these target genes in MBD2 overexpressing cells supporting that hsa-mir-496 is mediating in part the effects of MBD2 on gene expression. We demonstrate that MBD2 binds the promoter of hsa-mir-496 in MCF-10A, MCF-7 and MDA-MB-231 cells and that it activates an in vitro methylated hsa-mir-496 promoter driving a CG-less luciferase reporter in a transient transfection assay. The activation of hsa-mir-496 is associated with reduced methylation of the promoter. Taken together these results describe a novel cascade for gene regulation by DNA methylation whereby activation of a methylated microRNA by MBD2 that is associated with loss of methylation triggers repression of downstream targets.

Young S.N.,McGill University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2013

Acute tryptophan depletion (ATD) studies indicate that low serotonin can lower mood and also increase aggression, although results vary somewhat between studies with similar participants. Lowering of mood after ATD is related to the susceptibility of the study participants to clinical depression, and some participants show no effect on mood. This indicates that low serotonin can contribute to lowered mood, but cannot-by itself-cause lowered mood, unless other unknown systems interact with serotonin to lower mood. Studies using tryptophan supplementation demonstrate that increased serotonin can decrease quarrelsomeness and increase agreeableness in everyday life. Social interactions that are more agreeable and less quarrelsome are associated with better mood. Thus, serotonin may have direct effects on mood, but may also be able to influence mood through changes in social behaviour. The increased agreeableness and decreased quarrelsomeness resulting from increases in serotonin will help foster congenial relations with others and should help to increase social support. As social support and social isolation have an important relationship with both physical and mental health, more research is needed on the implications of the ability of serotonin to modulate social behaviour for the regulation of mood, and for future physical and mental health. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Purpose: Enhanced Recovery After Surgery (ERAS) programs have increasingly attracted the attention of clinicians who are intent on minimizing postoperative morbidity, decreasing variability in surgical care, and containing hospital costs. The purpose of this review is to discuss the relevant pathophysiology of the surgical stress response and its associated mechanisms that regulate important metabolic changes.Principal findings: The combination of hormonal release and various inflammatory responses inherent in the stress response to surgery contributes to a state of insulin resistance that represents one of the main pathogenic factors modulating perioperative outcome. The consequence of a decrease in insulin sensitivity is a significant change in protein and glucose metabolism characterized by an increase in the production of endogenous hepatic glucose, a decrease in the uptake of peripheral glucose, and an increase in the breakdown of protein. Muscle is the main tissue for uptake of insulin-mediated glucose, and consequent with the reduced activation of a specific glucose transporter protein (GLUT 4), glucose cannot be transported into the muscle cells. Consequently, breakdown of muscle protein, also related to insulin resistance, occurs to supply amino acids for gluconeogenesis, thus leading to the overall loss of lean muscle tissue. Besides the metabolic changes associated with the surgical insult, pain, relative perioperative starvation, and poor mobilization further contribute to a loss of insulin sensitivity and an increased catabolic state. Many of the ERAS elements that are implemented, including perioperative feeding, epidural analgesia, and minimally invasive surgery, modulate the stress response, promote insulin sensitivity, and attenuate the breakdown of protein.Conclusions: The implementation of a targeted ERAS program has been shown to modulate perioperative insulin sensitivity, thus improving postoperative outcomes and accelerating the return of baseline function. © 2014, Canadian Anesthesiologists' Society.

Ghayesh M.H.,McGill University
Journal of Sound and Vibration | Year: 2012

The coupled longitudinal-transverse nonlinear dynamics of an axially accelerating beam is numerically investigated; this problem is classified as a parametrically excited gyroscopic system. The axial speed is assumed to be comprised of a constant mean value along with harmonic fluctuations. Hamilton's principle is employed to derive the equations of motion of the system which are in the form of two coupled partial differential equations. The equations are discretized using the Galerkin method, which yields a set of coupled second-order nonlinear ordinary differential equations with time-dependent coefficients. The sub-critical dynamics of the system is examined via the pseudo-arclength continuation technique, while the global dynamics is investigated using direct time integration. The mean axial speed and the amplitude of the speed variations are varied so as to construct the bifurcation diagrams of Poincaré maps. The vibration specifications of the system are investigated more detailed via plotting time histories, phase-plane portraits, and fast Fourier transforms (FFTs). © 2012 Elsevier Ltd.

Huang Y.,McGill University
Journal of Climate | Year: 2013

A simulation experiment is conducted to inquire into the mean climate state and likely trends in atmospheric infrared radiation spectra. Upwelling and downwelling spectra at five vertical levels from the surface to the top of the atmosphere (TOA) are rigorously calculated from a climate-model-simulated atmosphere for a 25-yr period. Tracing the longwave radiation flux vertically and spectrally renders a dissection of the greenhouse effect of the earth atmosphere and its change due to climate forcings and feedbacks. The results show that the total outgoing longwave radiation (OLR) at theTOAmay be conserved due to 1) compensating temperature and opacity effects and 2) contrasting temperature changes in troposphere and stratosphere. The tightly coupled tropospheric temperature and opacity effects reduce the overall tropospheric contribution to OLR change to be comparable to the overall stratospheric contribution, which suggests that transient OLR change is constrained by the relative strengths of stratospheric and tropospheric temperature changes. The total OLR energy, however, is redistributed across its spectrum. The earliest detectable global climate change signal lies in the CO2 absorption bands, which results from stratospheric cooling and the CO2 opacity effect. This signal can be detected much sooner than surface temperature change and is little affected by achievable instrument accuracy. In contrast, both tropospheric temperature and opacity effects increase downwelling longwave radiation (DLR), which makes DLR a verifiable aspect of global warming. The time it takes to detect surface DLR change roughly equals that of surface temperature change. Measuring downwelling radiances at strong water vapor lines at the tropopause can particularly help monitor stratospheric water vapor. © 2013 American Meteorological Society.

Nahid P.,San Francisco General Hospital | Menzies D.,McGill University
American Journal of Respiratory and Critical Care Medicine | Year: 2012

The number of tuberculosis (TB) cases and global TB incidence rates is decreasing according to the latest World Health Organization Global Tuberculosis Report (1). This is very welcome news. However, the 8.8 million incident cases of TB, 1.1 million deaths from TB among HIV-negative people, the 350,000 deaths from HIV-associated TB, and the millions of children orphaned as a result of parental deaths caused by TB provide a stark reminder of the magnitude of devastation caused by TB each year. Advances in understanding TB epidemiology diagnosis and treatment in 2011, many ofwhichwere reported in the Journal, provide hope that the annual decline in TB cases will accelerate. Copyright © 2012 by the American Thoracic Society.

Rudiak-Gould P.,McGill University
Bulletin of the American Meteorological Society | Year: 2013

Climate communicators should target specific ideological obstacles to belief rather than panhuman psychological biases or scientific ignorance. The first would be to attempt to convince skeptics that the social system is not actually good, the world not truly just, progress not so assured. This would be an unforgivingly difficult task, considering how steadfastly people hold onto core ideological commitments. The second, less ambitious way to proceed would be to mold climate change to the audience's worldview rather than vice versa; to recast climate change belief as an ideological windfall and victory. The 'deficit model' of science education would assume that people reject man-made climate change because they are not sufficiently scientifically literate. A more enlightened perspective, advocated by researchers in Science and Technology Studies (STS), assumes that scientific misconceptions arise not from publics' ignorance but from their knowledge, the cultural frameworks, intuitive concepts, and moral visions with which people take up and interpret scientific issues.

The influence of developmental nicotine exposure on the brain represents an important health topic in light of the popularity of nicotine replacement therapy (NRT) as a smoking cessation method during pregnancy. In this study, we used a model of NRT during pregnancy and breastfeeding to explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring. We focused on two dynamic lifelong phenomena in the dentate gyrus (DG) of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP). Pregnant rats were implanted with osmotic mini-pumps delivering either nicotine or saline solutions. Plasma nicotine and metabolite levels were measured in dams and offspring. Corticosterone levels, DG neurogenesis (cell proliferation, survival and differentiation) and glutamatergic electrophysiological activity were measured in pups. Juvenile (P15) and adolescent (P41) offspring exposed to nicotine throughout prenatal and postnatal development displayed no significant alteration in DG neurogenesis compared to control offspring. However, NRT-like nicotine exposure significantly increased LTP in the DG of juvenile offspring as measured in vitro from hippocampal slices, suggesting that the mechanisms underlying nicotine-induced LTP enhancement previously described in adult rats are already functional in pups. These results indicate that synaptic plasticity is disrupted in offspring breastfed by dams passively exposed to nicotine in an NRT-like fashion.

Huang Y.,McGill University
Journal of Climate | Year: 2013

This paper mainly addresses two issues that concern the longwave climate feedbacks. First, it is recognized that the radiative forcing of greenhouse gases, as measured by their impact on the outgoing longwave radiation (OLR), may vary across different climate models even when the concentrations of these gases are identically prescribed. This forcing variation contributes to the discrepancy in these models' projections of surface warming.Amethod is proposed to account for this effect in diagnosing the sensitivity and feedbacks in the models. Second, it is shown that the stratosphere is an important factor that affects the OLR in transient climate change. Stratospheric water vapor and temperature changes may both act as a positive feedback mechanism during global warming and cannot be fully accounted as a "stratospheric adjustment" of radiative forcing. Neglecting these two issues may cause a bias in the longwave cloud feedback diagnosed as a residual term in the decomposition of OLR variations. There is no consensus among the climate models on the sign of the longwave cloud feedback after accounting for both issues. © 2013 American Meteorological Society.

Turro E.,University of Cambridge | Astle W.J.,McGill University | Tavare S.,University of Cambridge
Bioinformatics | Year: 2014

Motivation: Most methods for estimating differential expression from RNA-seq are based on statistics that compare normalized read counts between treatment classes. Unfortunately, reads are in general too short to be mapped unambiguously to features of interest, such as genes, isoforms or haplotype-specific isoforms. There are methods for estimating expression levels that account for this source of ambiguity. However, the uncertainty is not generally accounted for in downstream analysis of gene expression experiments. Moreover, at the individual transcript level, it can sometimes be too large to allow useful comparisons between treatment groups.Results: In this article we make two proposals that improve the power, specificity and versatility of expression analysis using RNA-seq data. First, we present a Bayesian method for model selection that accounts for read mapping ambiguities using random effects. This polytomous model selection approach can be used to identify many interesting patterns of gene expression and is not confined to detecting differential expression between two groups. For illustration, we use our method to detect imprinting, different types of regulatory divergence in cis and in trans and differential isoform usage, but many other applications are possible. Second, we present a novel collapsing algorithm for grouping transcripts into inferential units that exploits the posterior correlation between transcript expression levels. The aggregate expression levels of these units can be estimated with useful levels of uncertainty. Our algorithm can improve the precision of expression estimates when uncertainty is large with only a small reduction in biological resolution.Availability and implementation: We have implemented our software in the mmdiff and mmcollapse multithreaded C++ programs as part of the open-source MMSEQ package, available on https://github.com/ eturro/mmseq.Contact: Supplementary information: Supplementary data are available at Bioinformatics online. © 2013 The Author.

Wu D.-J.,University of Chinese Academy of Sciences | Piao Y.-S.,University of Chinese Academy of Sciences | Cai Y.,McGill University
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

We study cosmological evolutions of the generalized model of nonlinear massive gravity in which the graviton mass is given by a rolling scalar field and is varying along time. By performing dynamical analysis, we derive the critical points of this system and study their stabilities. These critical points can be classified into two categories depending on whether they are identical with the traditional ones obtained in General Relativity. We discuss the cosmological implication of relevant critical points. © 2013 Elsevier B.V.

Whitley R.,McGill University
Transcultural Psychiatry | Year: 2012

Definitions of cultural competence often refer to the need to be aware and attentive to the religious and spiritual needs and orientations of patients. However, the institution of psychiatry maintains an ambivalent attitude to the incorporation of religion and spirituality into psychiatric practice. This is despite the fact that many patients, especially those from underserved and underprivileged minority backgrounds, are devotedly religious and find much solace and support in their religiosity. I use the case of mental health of African Americans as an extended example to support the argument that psychiatric services must become more closely attuned to religious matters. I suggest ways in which this can be achieved. Attention to religion can aid in the development of culturally competent and accessible services, which in turn, may increase engagement and service satisfaction among religious populations. © The Author(s) 2012.

Dauphinee W.D.,McGill University
Medical Education | Year: 2012

Context The concept of outcomes has been used in health care for over 140years. The use of outcomes in assessing quality of care regained prominence in the 1960s based on Donabedian's framework of structures, processes and outcomes. In the 1990s, the use of outcomes in medical education gained great favour, although the outcomes used were not carefully defined. Recently, a debate has ensued about the costs and, thus, sustainability of current health care programmes, focusing on the (non-)necessity of services, missed prevention opportunities and the efficiency of treatment programmes. Measurements using education outcomes and health care outcomes must take these issues into account, preferably from a common framework. As health care becomes increasingly costly and even inefficient, issues of effectiveness are often neglected in policy making. Methods This paper uses peer-reviewed evidence and an outcomes framework to explore the implications of current realities for the makers of education policy in the health professions and for the staff who train health professionals. Discussion If the ultimate impacts of practices and policies in health professions education are not considered, how will we know if our education structures, processes and outcomes are optimal? This essay examines this question from the perspectives of three related issues. The first refers to the need for a common framework if the outcomes of patient and community care are to be evaluated properly. The second perspective refers to whether it is feasible to consider both patient-based outcomes and patient-reported outcomes in assessing the impact of education programmes, especially at more advanced levels of training. The third perspective concerns the challenges and limitations that may be encountered in focusing on patient outcomes as a measure of the impact of education. The concluding discussion suggests how the results of such longer-term impact studies should be interpreted as key validity checks on the quality and effectiveness of medical education and clinical education if we are to address the validity and efficiency of outcomes used in education and training. © Blackwell Publishing Ltd 2012.

Habibovic P.,University of Twente | Barralet J.E.,McGill University
Acta Biomaterialia | Year: 2011

The field of bioinorganics is well established in the development of a variety of therapies. However, their application to bone regeneration, specifically by way of localized delivery from functional implants, is in its infancy and is the topic of this review. The toxicity of inorganics is species, dose and duration specific. Little is known about how inorganic ions are effective therapeutically since their use is often the result of serendipity, observations from nutritional deficiency or excess and genetic disorders. Many researchers point to early work demonstrating a role for their element of interest as a micronutrient critical to or able to alter bone growth, often during skeletal development, as a basis for localized delivery. While one can appreciate how a deficiency can cause disruption of healing, it is difficult to explain how a locally delivered excess in a preclinical model or patient, which is presumably of normal nutritional status, can evoke more bone or faster healing. The review illustrates that inorganics can positively affect bone healing but various factors make literature comparisons difficult. Bioinorganics have the potential to have just as big an impact on bone regeneration as recombinant proteins without some of the safety concerns and high costs. © 2011 Acta Materialia Inc.

Meaney M.J.,McGill University
Child Development | Year: 2010

Variations in phenotype reflect the influence of environmental conditions during development on cellular functions, including that of the genome. The recent integration of epigenetics into developmental psychobiology illustrates the processes by which environmental conditions in early life structurally alter DNA, providing a physical basis for the influence of the perinatal environmental signals on phenotype over the life of the individual. This review focuses on the enduring effects of naturally occurring variations in maternal care on gene expression and phenotype to provide an example of environmentally driven plasticity at the level of the DNA, revealing the interdependence of gene and environmental in the regulation of phenotype. © 2010, Copyright the Author(s). Journal Compilation © 2010, Society for Research in Child Development, Inc.

Anaby D.,McGill University
Developmental medicine and child neurology | Year: 2012

The purpose of this study was (1) to examine the changes in participation rates over 1 year among children and adolescents after acquired brain injury and (2) to explore the effect of child and family factors on these changes. The participation levels of 136 children and young people (88 males; 48 females; age range 4y 11mo-17y 6mo; mean age 11y 6mo) after acquired brain injury (3≤ Glasgow Coma Scale score ≤15; mean 12.8) were assessed three times: at their return to school, and at 8 and 12 months after returning to school. The Children's Assessment of Participation and Enjoyment measured the participants' diversity and intensity of participation in out-of-school activities. At baseline, information on general family functioning and medical and demographic information was collected as possible predictors. Mixed-effect model analyses of participation scores were performed while controlling for child's age at injury. The severity of the injury explained rates of change across time for participation intensity in recreational, physical, and social activities. Household income influenced changes in the intensity of recreational activities, whereas family functioning predicted changes in the diversity of skill-based activities. Participation is a relevant outcome of recovery that needs to be assessed and monitored post brain injury. Special attention can be directed to severity of injury and family functioning when developing intervention plans. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Lawler P.R.,McGill University | Lawler J.,Beth Israel Deaconess Medical Center
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Thrombospondins TSP-1 and TSP-2 are potent endogenous inhibitors of angiogenesis. They inhibit angiogenesis through direct effects on endothelial cell migration, proliferation, survival, and apoptosis and by antagonizing the activity of VEGF. Several of the membrane receptor systems and signal transduction molecules that mediate the effects of TSP-1 and TSP-2 have been elucidated. TSP-1 and TSP-2 exert their direct effects through CD36, CD47, and integrins. Recent data indicate that CD36 and β1 integrins collaborate to transmit the signals that are initiated by TSP-1 and TSP-2. Furthermore, these receptors appear to associate with VEGFR2 to form a platform for the integration of positive and negative signals for angiogenesis. Cross talk between pro- and antiangiogenic signal transduction pathways may enable TSP-1 and TSP-2 to inhibit angiogenesis by antagonizing survival pathways while also activating apoptotic pathways. CD36 and CD47 are both involved in the suppression of nitric oxide (NO). Advances in understanding of the molecular regulation of angiogenesis by TSP have paved the way for innovations in experimental treatment of cancers and will likely continue to offer vast avenues for discovery in other disease processes as well. © 2012 Cold Spring Harbor Laboratory Press.all rights reserved.

Sakai T.,University of Electro - Communications | Belyakov A.,Belgorod State University | Kaibyshev R.,Belgorod State University | Miura H.,University of Electro - Communications | Jonas J.J.,McGill University
Progress in Materials Science | Year: 2014

The evolution of the new microstructures produced by two types of dynamic recrystallization is reviewed, including those brought about by severe plastic deformation (SPD). The microstructural changes taking place under these conditions and the associated mechanical behaviors are described. During the conventional discontinuous dynamic recrystallization (dDRX) that takes place at elevated temperatures, the new grains evolve by nucleation and growth in materials with low to medium stacking fault energies (SFE). On the other hand, new ultrafine grains can be produced in any material irrespective of the SFE by means of SPD at relatively low temperatures. These result from the gradual transformation of the dislocation sub-boundaries produced at low strains into ultrafine grains with high angle boundaries at large strains. This process, termed in situ or continuous dynamic recrystallization (cDRX), is still not perfectly understood. This is because many SPD methods provide data concerning the microstructural changes that take place but little information regarding the flow stress behavior. By contrast, multi-directional forging (MDF) provides both types of data concurrently. Recent studies of the deformation behavior of metals and alloys under SPD conditions, carried out using MDF as well as other SPD methods, are synthesized and the links between the microstructural and mechanical observations are examined carefully. Some models for grain formation under SPD conditions are discussed. Next, the post-dynamic recrystallization behavior, i.e. that of annealing after both dDRX and cDRX, is described. The differing annealing behaviors result from the differences in the natures of the deformed microstructures. Finally, an integrated recrystallization model for these phenomena, i.e. dynamic and static recrystallization of both the continuous and discontinuous types, is presented and discussed. © 2013 Elsevier Ltd. All rights reserved.

Medin Z.,Los Alamos National Laboratory | Cumming A.,McGill University
Astrophysical Journal Letters | Year: 2014

We show that convection driven by chemical separation can significantly affect the cooling light curves of accreting neutron stars after they go into quiescence. We calculate the thermal relaxation of the neutron star ocean and crust including the thermal and compositional fluxes due to convection. After the inward propagating cooling wave reaches the base of the neutron star ocean, the ocean begins to freeze, driving chemical separation. The resulting convection transports heat inward, giving much faster cooling of the surface layers than found assuming the ocean cools passively. The light curves including convection show a rapid drop in temperature weeks after outburst. Identifying this signature in observed cooling curves would constrain the temperature and composition of the ocean as well as offer a real time probe of the freezing of a classical multicomponent plasma. © 2014. The American Astronomical Society. All rights reserved.

This review synthesizes recent research evidence regarding the parenting characteristics associated with families with children with Attention-Deficit/ Hyperactivity Disorder (ADHD). ADHD is a complex, heterogeneous disorder with a range of genetic and environmental factors that contribute to its behavioral expression and different developmental trajectories. The current review adopts a developmental psychopathology perspective to conceptualize the risk and protective factors that might shape the developmental pathways of the disorder across different domains. Following from Johnston and Mash's review (Johnston and Mash, Clin Child Fam Psychol Rev 4:183-207, 2001), the present review systematically examines empirical studies from 2000-2008 that investigate parenting variables in relation to the development of children with ADHD, with a particular focus on the development of externalizing and internalizing comorbidities, as well as functional impairments in academic and social contexts. The most recent research evidence uses correlational designs to show that ADHD is associated with problematic family functioning, including greater stress within the family, higher rates of parental psychopathology and conflicted parent-child relationships, which appears to be exacerbated in children with comorbid oppositional and conduct problems. However, there is an absence of literature that considers the role that parents play in contributing to children's development in areas such as academic achievement and peer competence, as well as the development of internalizing difficulties. Future research should examine family factors that are associated with resilience in children with ADHD, using longitudinal designs that reflect the dynamic changes associated with a developmental psychopathology framework. © Springer Science+Business Media, LLC 2009.

Cadotte M.,University of Toronto | Albert C.H.,CNRS Alpine Ecology Laboratory | Albert C.H.,McGill University | Walker S.C.,University of Montreal
Ecology Letters | Year: 2013

Species enter and persist in local communities because of their ecological fit to local conditions, and recently, ecologists have moved from measuring diversity as species richness and evenness, to using measures that reflect species ecological differences. There are two principal approaches for quantifying species ecological differences: functional (trait-based) and phylogenetic pairwise distances between species. Both approaches have produced new ecological insights, yet at the same time methodological issues and assumptions limit them. Traits and phylogeny may provide different, and perhaps complementary, information about species' differences. To adequately test assembly hypotheses, a framework integrating the information provided by traits and phylogenies is required. We propose an intuitive measure for combining functional and phylogenetic pairwise distances, which provides a useful way to assess how functional and phylogenetic distances contribute to understanding patterns of community assembly. Here, we show that both traits and phylogeny inform community assembly patterns in alpine plant communities across an elevation gradient, because they represent complementary information. Differences in historical selection pressures have produced variation in the strength of the trait-phylogeny correlation, and as such, integrating traits and phylogeny can enhance the ability to detect assembly patterns across habitats or environmental gradients. © 2013 John Wiley & Sons Ltd/CNRS.

Jonas J.J.,McGill University
Materials Science Forum | Year: 2013

The factors affecting pipeline fractures are reviewed briefly, with particular emphasis on the influence of the {100}<011> texture component. The deformation texture components introduced by rolling in the austenite temperature range are introduced, together with the component changes associated with recrystallization. The effect of the γ-to-α phase transformation on the austenite deformation and recrystallization texture components is described. The changes to the texture brought about by rolling in the ferrite (or in the intercritical) phase field are also outlined. The controlled rolling parameters that promote minimization of the texture intensity of the deleterious {100}<011> component are summarized. © (2013) Trans Tech Publications, Switzerland.

Ferguson G.,University of Saskatchewan | Gleeson T.,McGill University
Nature Climate Change | Year: 2012

Climate change and human population growth are expected to have substantial impacts on global water resources throughout the twenty-first century. Coastal aquifers are a nexus of the world's oceanic and hydrologic ecosystems and provide a water source for the more than one billion people living in coastal regions. Saltwater intrusion caused by excessive groundwater extraction is already impacting diverse regions of the globe. Synthesis studies and detailed simulations have predicted that rising sea levels could negatively impact coastal aquifers through saltwater intrusion and/or inundation of coastal regions. However, the relative vulnerability of coastal aquifers to groundwater extraction and sea-level rise has not been systematically examined. Here we show that coastal aquifers are more vulnerable to groundwater extraction than to predicted sea-level rise under a wide range of hydrogeologic conditions and population densities. Only aquifers with very low hydraulic gradients are more vulnerable to sea-level rise and these regions will be impacted by saltwater inundation before saltwater intrusion. Human water use is a key driver in the hydrology of coastal aquifers, and efforts to adapt to sea-level rise at the expense of better water management are misguided. © 2012 Macmillan Publishers Limited. All rights reserved.

Mortola J.P.,McGill University
Respiratory Physiology and Neurobiology | Year: 2011

This study examined the static and dynamic properties of the respiratory system in avian hatchlings, and the effects of incubation in hypoxia (15% O 2) on these variables. In 1-day old chicken (Gallus gallus) hatchlings killed by an anesthetic overdose the static compliance of the respiratory system (C rs) was measured from the pressure-volume curve, constructed by step changes in lung volume. The dynamic compliance, C rs(dyn), resistance, R rs, and time constant, τ rs, were measured during mechanical ventilation at rates up to 90cpm. The results indicated that (1) static C rs in hatchlings is several folds higher than in neonatal mammals of similar size, (2) during mechanical ventilation the respiratory system becomes hyperinflated and much stiffer; at 65cpm (which is the respiratory frequency of hatchlings spontaneously breathing at rest) C rs(dyn) was about one tenth of the static value, (3) after prenatal hypoxia static C rs, C rs(dyn), R rs and τ rs were similar to controls; only the magnitude of the hyperinflation was slightly decreased. It is concluded that in avian hatchlings (a) despite the large respiratory volume of the air sacs, expiration can occur passively because the hyperinflation greatly decreases C rs(dyn) and shortens τ rs, and (b) prenatal hypoxia of the level tested has no major effects on the mechanical properties of the respiratory system. © 2010 Elsevier B.V.

Hepple R.T.,McGill University
Frontiers in Aging Neuroscience | Year: 2014

Atrophy is a defining feature of aging skeletal muscle that contributes to progressive weakness and an increased risk of mobility impairment, falls, and physical frailty in very advanced age. Amongst the most frequently implicated mechanisms of aging muscle atrophy is mitochondrial dysfunction. Recent studies employing methods that are well-suited to interrogating intrinsic mitochondrial function find that mitochondrial respiration and reactive oxygen species emission changes are inconsistent between aging rat muscles undergoing atrophy and appear normal in human skeletal muscle from septuagenarian physically active subjects. On the other hand, a sensitization to permeability transition seems to be a general property of atrophying muscle with aging and this effect is even seen in atrophying muscle from physically active septuagenarian subjects. In addition to this intrinsic alteration in mitochondrial function, factors extrinsic to the mitochondria may also modulate mitochondrial function in aging muscle. In particular, recent evidence implicates oxidative stress in the aging milieu as a factor that depresses respiratory function in vivo (an effect that is not present ex vivo). Furthermore, in very advanced age, not only does muscle atrophy become more severe and clinically relevant in terms of its impact, but also there is evidence that this is driven by an accumulation of severely atrophied denervated myofibers. As denervation can itself modulate mitochondrial function and recruit mitochondrial-mediated atrophy pathways, future investigations need to address the degree to which skeletal muscle mitochondrial alterations in very advanced age are a consequence of denervation, rather than a primary organelle defect, to refine our understanding of the relevance of mitochondria as a therapeutic target at this more advanced age. © 2014 Hepple.

Hirsh V.,McGill University
Frontiers in Oncology | Year: 2014

Until now ̃30-40% of patients with advanced lung cancer develop bone metastases, but as the newer therapies are extending survival, the chance of developing bone metastases increases. Bone metastases cause skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia, which can have debilitating consequences affecting patients' health-related quality of life (HR-QOL) and performance status (PS). Poor PS then prevents the patients to receive further lines of treatments, which are available today. SREs are associated with increased economic costs. In one clinical trial, the median time to first SRE was only 5 months. Early detection of bone metastases can prevent SREs and avoid inappropriate implementation of major surgery or chemoradiation therapy. With the new generation bisphosphonate zoledronic acid (ZA) or denosumab (anti-RANKL activity), one can reduce the number of patients who experience SREs, decrease the annual incidence of SREs and delay the median time to first SRE. These agents are effective even after the onset of SREs. They are well tolerated, with manageable side effects. The biochemical markers of bone metabolism especially N-telopeptide of type I collagen and bone specific alkaline phosphatase (BALP) can be both prognostic and predictive markers for the patients with bone metastases from non-small cell lung cancer (NSCLC). Anticancer activity of ZA and denosumab further supports their use as soon as bone metastases are diagnosed in patients with NSCLC. Further trials will inform us about the efficacy of these agents for prevention of bone metastases and even about possible effects on visceral metastases. © 2014 Hirsh.

Piper R.C.,University of Iowa | Dikic I.,Goethe University Frankfurt | Lukacs G.L.,McGill University
Cold Spring Harbor Perspectives in Biology | Year: 2014

When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Fagotto F.,McGill University
Development (Cambridge) | Year: 2014

The subdivision of the embryo into physically distinct regions is one of the most fundamental processes in development. General hypotheses for tissue separation based on differential adhesion or tension have been proposed in the past, but with little experimental support. During the last decade, the field has experienced a strong revival, largely driven by renewed interest in biophysical modeling of development. Here, I will discuss the various models of boundary formation and summarize recent studies that have shifted our understanding of the process from the simple juxtaposition of global tissue properties to the characterization of local cellular reactions. Current evidence favors a model whereby separation is controlled by cell surface cues, which, upon cell-cell contact, generate acute changes in cytoskeletal and adhesive properties to inhibit cell mixing, and whereby the integration of multiple local cues may dictate both the global morphogenetic properties of a tissue and its separation from adjacent cell populations. © 2014. Published by The Company of Biologists Ltd.

Wintermark P.,McGill University
Seminars in Perinatology | Year: 2015

Injury to the developing brain remains an important complication in critically ill newborns, placing them at risk for future neurodevelopment impairments. Abnormal brain perfusion is often a key mechanism underlying neonatal brain injury. A better understanding of how alternations in brain perfusion can affect normal brain development will permit the development of therapeutic strategies that prevent and/or minimize brain injury and improve the neurodevelopmental outcome of these high-risk newborns. Recently, non-invasive MR perfusion imaging of the brain has been successfully applied to the neonatal brain, which is known to be smaller and have lower brain perfusion compared to older children and adults. This article will present an overview of the potential role of non-invasive perfusion imaging by MRI to study maturation, injury, and repair in perinatal brain injury and demonstrate why this perfusion sequence is an important addition to current neonatal imaging protocols, which already include different sequences to assess the anatomy and metabolism of the neonatal brain. © 2015 Elsevier Inc.

Ruths J.,Singapore University of Technology and Design | Ruths D.,McGill University
Science | Year: 2014

Campbell, Shea, and Albert propose an adaptation of the Barabási-Albert model of network formation that permits a level of tuning of the control profiles of these networks. We point out some limitations and generalizations of this method as well as highlight opportunities for future work to refine formation mechanisms to provide control profile tuning in synthetic networks.

Ricciardi A.,McGill University | Hoopes M.F.,Mount Holyoke College | Marchetti M.P.,St. Marys College | Lockwood J.L.,Rutgers University
Ecological Monographs | Year: 2013

A predictive understanding of the ecological impacts of nonnative species has been slow to develop, owing largely to an apparent dearth of clearly defined hypotheses and the lack of a broad theoretical framework. The context dependency of impact has fueled the perception that meaningful generalizations are nonexistent. Here, we identified and reviewed 19 testable hypotheses that explain temporal and spatial variation in impact. Despite poor validation of most hypotheses to date, evidence suggests that each can explain at least some impacts in some situations. Several hypotheses are broad in scope (applying to plants and animals in virtually all contexts) and some of them, intriguingly, link processes of colonization and impact. Collectively, these hypotheses highlight the importance of the functional ecology of the nonnative species and the structure, diversity, and evolutionary experience of the recipient community as general determinants of impact; thus, they could provide the foundation for a theoretical framework for understanding and predicting impact. Further substantive progress toward this goal requires explicit consideration of within-taxon and across-taxa variation in the per capita effect of invaders, and analyses of complex interactions between invaders and their biotic and abiotic environments. © 2013 by the Ecological Society of America.

Jung H.,Yonsei University | Gkogkas C.G.,University of Edinburgh | Sonenberg N.,McGill University | Holt C.E.,University of Cambridge
Cell | Year: 2014

The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function. © 2014 The Authors.

Dewan S.,University of California at Irvine | Ramaprasad J.,McGill University
MIS Quarterly: Management Information Systems | Year: 2014

Motivated by the growing importance of social media, this paper examines the relationship between new media, old media, and sales in the context of the music industry. In particular, we study the interplay between blog buzz, radio play, and music sales at both the album and song levels of analysis. We employ the panel vector autoregression (PVAR) methodology, an extension of vector autoregression to panel data. We find that radio play is consistently and positively related to future sales at both the song and album levels. Blog buzz, however, is not related to album sales and negatively related to song sales, suggesting that sales displacement due to free online sampling dominates any positive word-of-mouth effects of song buzz on sales. Further, the negative relationship between song buzz and sales is stronger for niche music relative to mainstream music, and for less popular songs within albums. We discuss the implications of these results for both research and practice regarding the role of new media in the music industry.

Al Deeb M.,McGill University
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine | Year: 2014

Acute dyspnea is a common presenting complaint to the emergency department (ED), and point-of-care (POC) lung ultrasound (US) has shown promise as a diagnostic tool in this setting. The primary objective of this systematic review was to determine the sensitivity and specificity of US using B-lines in diagnosing acute cardiogenic pulmonary edema (ACPE) in patients presenting to the ED with acute dyspnea. A systematic review protocol adhering to Cochrane Handbook guidelines was created to guide the search and analysis, and we searched the following databases: PubMed, EMBASE, Ovid MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, and the Cochrane Database of Systematic Reviews. References of reviewed articles were hand-searched, and electronic searches of conference abstracts from major emergency medicine, cardiology, and critical care conferences were conducted. The authors included prospective cohort and prospective case-control studies that recruited patients presenting to hospital with symptomatic, acute dyspnea, or where there was a clinical suspicion of congestive heart failure, and reported the sensitivity and specificity of B-lines in diagnosing ACPE. Studies of asymptomatic individuals or in patients where there was no suspicion of ACPE were excluded. The outcome of interest was a diagnosis of ACPE using US B-lines. A final diagnosis from clinical follow-up was accepted as the reference standard. Two reviewers independently reviewed all citations to assess for inclusion, abstracted data, and assessed included studies for methodologic quality using the QUADAS-2 tool. Contingency tables were used to calculate sensitivity and specificity. Three subgroup analyses were planned a priori to examine the effects of the type of study, patient population, and lung US protocol employed. Seven articles (n = 1,075) were identified that met inclusion criteria (two studies completed in the ED, two in the intensive care unit [ICU], two on inpatient wards, and one in the prehospital setting). The seven studies were rated as average to excellent methodologic quality. The sensitivity of US using B-lines to diagnosis ACPE is 94.1% (95% confidence interval [CI] = 81.3% to 98.3%) and the specificity is 92.4% (95% CI = 84.2% to 96.4%). Preplanned subgroup analyses did not reveal statistically significant changes in the overall summary estimates, nor did exclusion of three potential outlier studies. This study suggests that in patients with a moderate to high pretest probability for ACPE, an US study showing B-lines can be used to strengthen an emergency physician's working diagnosis of ACPE. In patients with a low pretest probability for ACPE, a negative US study can almost exclude the possibility of ACPE. Further studies including large numbers of ED patients presenting with undifferentiated dyspnea are required to gain more valid and reliable estimates of test accuracy in ED patients. © 2014 by the Society for Academic Emergency Medicine.

Sauve V.,McGill University
Cell Research | Year: 2014

The Parkinson's disease (PD)-associated proteins, Parkin and PINK1, together comprise a mitochondrial quality control pathway that promotes neuronal survival through autophagy of damaged mitochondria. Three recent studies have found that Parkin recruitment to mitochondria and ubiquitin ligase activity is controlled by the phosphorylation of ubiquitin by PINK1.

Ghayesh M.H.,McGill University
International Journal of Non-Linear Mechanics | Year: 2010

Parametric vibrations and stability of an axially accelerating string guided by a non-linear elastic foundation are studied analytically. The axial speed, as the source of parametric vibrations, is assumed to involve a mean speed, along with small harmonic variations. The method of multiple scales is applied to the governing non-linear equation of motion and then the natural frequencies and mode shape equations of the system are derived using the equation of order one, and satisfying the compatibility conditions. Using the equation of order epsilon, the solvability conditions are obtained for three distinct cases of axial acceleration frequency. For all cases, the stability areas of system are constructed analytically. Finally, some numerical simulations are presented to highlight the effects of system parameters on vibration, natural frequencies, frequency-response curves, stability, and bifurcation points of the system. © 2009 Elsevier Ltd. All rights reserved.

Protein-folding diseases are an ongoing medical challenge. Many diseases within this group are genetically determined, and have no known cure. Among the examples in which the underlying cellular and molecular mechanisms are well understood are diseases driven by misfolding of transmembrane proteins that normally function as cell-surface ion channels. Wild-type forms are synthesized and integrated into the endoplasmic reticulum (ER) membrane system and, upon correct folding, are trafficked by the secretory pathway to the cell surface. Misfolded mutant forms traffic poorly, if at all, and are instead degraded by the ER-associated proteasomal degradation (ERAD) system. Molecular chaperones can assist the folding of the cytosolic domains of these transmembrane proteins; however, these chaperones are also involved in selecting misfolded forms for ERAD. Given this dual role of chaperones, diseases caused by the misfolding and aberrant trafficking of ion channels (referred to here as ion-channel-misfolding diseases) can be regarded as a consequence of insufficiency of the pro-folding chaperone activity and/or overefficiency of the chaperone ERAD role. An attractive idea is that manipulation of the chaperones might allow increased folding and trafficking of the mutant proteins, and thereby partial restoration of function. This Review outlines the roles of the cytosolic HSP70 chaperone system in the best-studied paradigms of ion-channel-misfolding disease - the CFTR chloride channel in cystic fibrosis and the hERG potassium channel in cardiac long QT syndrome type 2. In addition, other ion channels implicated in ion-channel-misfolding diseases are discussed.

Alam A.,McGill University
Current Opinion in Nephrology and Hypertension | Year: 2015

Purpose of review Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. This article will describe the factors associated with both functional and structural evidence of disease progression. It will also review the results of recent clinical trials that have shown an impact on markers of disease progression. Recent findings A variety of prognostic factors have been described that relate to a decline in glomerular filtration rate or an increase in total cyst or kidney volumes. We now have clinical trials that show that glomerular filtration rate decline and kidney volume growth can be slowed in those with ADPKD. Summary With the emergence of potential disease-modifying therapies, factors that can accurately identify those who are most at risk for renal progression or ADPKD-related complications need to be identified and validated. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

There is mounting evidence to suggest aberrant astrocytic function in depression and suicide. Independent studies have reported astrocytic abnormalities in certain brain regions, but it remains unclear whether this is a brain-wide phenomenon. The present study examined this question by measuring glial fibrillary acidic protein (GFAP) expression in postmortem brain samples from suicide completers and matched non-psychiatric controls. Suicide completers were selected based on their recent characterization as low GFAP expressors in the prefrontal cortex, (Brodmann areas 8/9 and 10). Real-time PCR and immunoblotting were used to measure GFAP gene expression and protein levels in BA4 (primary motor cortex), BA17 (primary visual cortex), cerebellar cortex, mediodorsal thalamus and caudate nucleus. We found downregulation of GFAP mRNA and protein in the mediodorsal thalamus and caudate nucleus of depressed suicides compared with controls, whereas GFAP expression in other brain regions was similar between groups. Furthermore, a regional comparison including all samples revealed that GFAP expression in both subcortical regions was, on average, between 11- and 15-fold greater than in cerebellum and neocortex. Examining astrocyte morphology by immunohistochemistry showed that astrocytes in both thalamus and caudate displayed larger cell bodies and extended more ramified processes across larger domains than the previously described cortical astrocytes. This study reveals that astrocytic abnormalities are not brain wide and suggests that they are restricted to cortical and subcortical networks known to be affected in mood disorders. Additionally, our results show a greater diversity in human astrocytic phenotypes than previously thought.Molecular Psychiatry advance online publication, 2 June 2015; doi:10.1038/mp.2015.65. © 2015 Macmillan Publishers Limited

Radiation Therapy Oncology Group 85-31 was a randomized trial comparing radiotherapy (RT) alone vs. RT plus adjuvant androgen suppression for life in unfavorable-prognosis carcinoma of the prostate. We examined the impact of early initiation of salvage hormonal therapy (HT) in relapsing patients randomized to RT alone arm. Patients were divided into two groups: early salvage HT and late salvage HT. The early salvage group was defined as receiving HT with a prostate-specific antigen (PSA) level of less than 10 ng/mL, and the late salvage HT group had a PSA level of 10 ng/mL or greater. The outcomes were overall survival (OS), cause-specific mortality (CSM), and local failure (LF). The Kaplan-Meier estimation and log-rank test were used for OS, and the cumulative incidence estimation and Gray's test were used for CSM and LF. Proportional hazards regression models were used to compare the outcomes adjusted for other covariates. The median follow-up times of surviving patients in the early and late salvage HT groups were about 11 and 13 years, respectively. The late salvage HT group had significantly more post-prostatectomy patients and patients with high Gleason scores. After adjustment for all covariates, OS was significantly longer in the early salvage HT group (hazard ratio, 1.5; p = 0.01). However, there were no statistically significant differences in LF or CSM between the groups. The early introduction of salvage HT resulted in improved OS but not improved CSM and LF. A randomized trial to define the optimal salvage hormonal timing is warranted in this group of patients with PSA recurrence after RT. Copyright © 2010 Elsevier Inc. All rights reserved.

Steingart K.R.,University of Washington | Pai M.,McGill University
PLoS Medicine | Year: 2011

Background: Undiagnosed and misdiagnosed tuberculosis (TB) drives the epidemic in India. Serological (antibody detection) TB tests are not recommended by any agency, but widely used in many countries, including the Indian private sector. The cost and impact of using serology compared with other diagnostic techniques is unknown. Methods and Findings: Taking a patient cohort conservatively equal to the annual number of serological tests done in India (1.5 million adults suspected of having active TB), we used decision analysis to estimate costs and effectiveness of sputum smear microscopy (US$3.62 for two smears), microscopy plus automated liquid culture (mycobacterium growth indicator tube [MGIT], US$20/test), and serological testing (anda-tb ELISA, US$20/test). Data on test accuracy and costs were obtained from published literature. We adopted the perspective of the Indian TB control sector and an analysis frame of 1 year. Our primary outcome was the incremental cost per disability-adjusted life year (DALY) averted. We performed one-way sensitivity analysis on all model parameters, with multiway sensitivity analysis on variables to which the model was most sensitive. If used instead of sputum microscopy, serology generated an estimated 14,000 more TB diagnoses, but also 121,000 more false-positive diagnoses, 102,000 fewer DALYs averted, and 32,000 more secondary TB cases than microscopy, at approximately four times the incremental cost (US$47.5 million versus US$11.9 million). When added to high-quality sputum smears, MGIT culture was estimated to avert 130,000 incremental DALYs at an incremental cost of US$213 per DALY averted. Serology was dominated by (i.e., more costly and less effective than) MGIT culture and remained less economically favorable than sputum smear or TB culture in one-way and multiway sensitivity analyses. Conclusions: In India, sputum smear microscopy remains the most cost-effective diagnostic test available for active TB; efforts to increase access to quality-assured microscopy should take priority. In areas where high-quality microscopy exists and resources are sufficient, MGIT culture is more cost-effective than serology as an additional diagnostic test for TB. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors' Summary. © 2011 World Health Organization.

In this study, we investigate how the responses of the human visual pathway to temporal frequency are modified as information transfers between the lateral geniculate nucleus (LGN) and primary visual cortex (V1) and to the extrastriate areas of the dorsal and ventral streams (V2, V3, VP, V3A, V4, and MT). We use high-field fMRI (4 T) to record simultaneously the responses of these areas across temporal frequency for chromatic stimuli (L/M-cone opponent and S-cone opponent) and stimuli of high and low achromatic contrasts. We find that: (1) the LGN has relatively low-pass responses for temporal frequency at both high and low achromatic contrasts, indicating that LGN cell spiking activity is not well reflected in the BOLD response. In addition, M cell-like temporal responses were not found, even at low contrasts. (2) Responses in V1 and extrastriate areas V2, V3, VP, and V3A display a progressively low-pass dependence on temporal frequency for achromatic stimuli (2-16 Hz) and are flat for chromatic stimuli (2-8 Hz), showing little overall difference between chromatic and achromatic cortical temporal filtering. (3) Strongly differential effects are found between dorsal and ventral stream processing by the level of MT and V4. V4 shows a significant low-pass temporal dependence for all achromatic and chromatic stimuli, whereas MT has temporally high-pass or flat responses for achromatic and chromatic stimuli. MT was the only visual area that showed M cell-like responses. We conclude that the dorsal and ventral pathways of human vision progressively develop characteristic differences in temporal processing that affect both chromatic and achromatic stimuli.

Childress L.,McGill University | Hanson R.,Technical University of Delft
MRS Bulletin | Year: 2013

The exotic features of quantum mechanics have the potential to revolutionize information technologies. Using superposition and entanglement, a quantum processor could efficiently tackle problems inaccessible to current-day computers. Nonlocal correlations may be exploited for intrinsically secure communication across the globe. Finding and controlling a physical system suitable for fulfilling these promises is one of the greatest challenges of our time. The nitrogen-vacancy (NV) center in diamond has recently emerged as one of the leading candidates for such quantum information technologies thanks to its combination of atom-like properties and solid-state host environment. We review the remarkable progress made in the past years in controlling electrons, atomic nuclei, and light at the single-quantum level in diamond. We also discuss prospects and challenges for the use of NV centers in future quantum technologies. Copyright © Materials Research Society 2013.

Schwabe L.,Ruhr University Bochum | Pruessner J.C.,McGill University
Biological Psychiatry | Year: 2014

The processes of memory formation and storage are complex and highly dynamic. Once memories are consolidated, they are not necessarily fixed but can be changed long after storage. In particular, seemingly stable memories may re-enter an unstable state when they are retrieved, from which they must be re-stabilized during a process known as reconsolidation. During reconsolidation, memories are susceptible to modifications again, thus providing an opportunity to update seemingly stable memories. While initial demonstrations of memory reconsolidation came mainly from animal studies, evidence for reconsolidation in humans is now accumulating as well. Here, we review recent advances in our understanding of human memory reconsolidation. After a summary of findings on the reconsolidation of human fear and episodic memory, we focus particularly on recent neuroimaging data that provide first insights into how reconsolidation processes are implemented in the human brain. Finally, we discuss the implications of memory modifications during reconsolidation for the treatment of mental disorders such as posttraumatic stress disorder and drug addiction. © 2014 Society of Biological Psychiatry.

Bradler K.,McGill University
IEEE Transactions on Information Theory | Year: 2011

We introduce an infinite sequence of quantum channels for which the Holevo capacity is additive. The channel series is closely related to the quantum channels arising from universal quantum cloning machines. The additivity proof is motivated by a special property the studied channels enjoy: the property of conjugate degradability. As a consequence of the announced proof, we also provide an easy way of proving the additivity of the Holevo capacity for the original Unruh channel for which the quantum capacity is already known. Consequently, we present not only an infinite series of finite-dimensional channels but also a nontrivial example of an infinite-dimensional channel for which the classical and quantum channel capacities are easily calculable. © 2011 IEEE.

Lefebvre L.,McGill University
Biology Letters | Year: 2011

In 1985, Kummer & Goodall pleaded for an ecology of intelligence and proposed that innovations might be a good way to measure cognition in the wild. Counts of innovation per taxonomic group are now available in hundreds of avian and primate species, as are counts of tactical deception, tool use and social learning. Robust evidence suggests that innovation rate and its neural correlates allow birds andmammals to cope betterwith environmental change. The positive correlations between taxonomic counts, and the increasing number of cognitive and neural measures found to be associated with ecological variables, suggest that domain general processesmight bemore pervasive than previously thought in the evolution of intelligence. © 2011 The Royal Society.

Paris J.,McGill University
Journal of Nervous and Mental Disease | Year: 2012

Dissociative identity disorder (DID), once considered rare, was frequently diagnosed during the 1980s and 1990s, after which interest declined. This is the trajectory of a medical fad. DID was based on poorly conceived theories and used potentially damaging treatment methods. The problem continues, given that the DSM-5 includes DID and accords dissociative disorders a separate chapter in its manual. Copyright © 2012 by Lippincott Williams & Wilkins.

Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence. We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression. We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.

Szyf M.,McGill University
Trends in Molecular Medicine | Year: 2015

The idea that inherited genotypes define phenotypes has been paramount in modern biology. The question remains, however, whether stable phenotypes could be also inherited from parents independently of the genetic sequence per se. Recent data suggest that parental experiences can be transmitted behaviorally, through in utero exposure of the developing fetus to the maternal environment, or through either the male or female germline. The challenge is to delineate a plausible mechanism. In the past decade it has been proposed that epigenetic mechanisms are involved in multigenerational transmission of phenotypes and transgenerational inheritance. The prospect that ancestral experiences are written in our epigenome has immense implications for our understanding of human behavior, health, and disease. © 2015 Elsevier Ltd.

Echavarria R.,McGill University
Journal of the American Heart Association | Year: 2013

Angiopoietin-1 (Ang-1) promotes survival and migration of endothelial cells, in part through the activation of mitogen-activated protein kinase (MAPK) pathways downstream of Tie-2 receptors. Dual-specificity phosphatases (DUSPs) dephosphorylate phosphotyrosine and phosphoserine/phosphothreonine residues on target MAPKs. The mechanisms by which DUSPs modulate MAPK activation in Ang-1/Tie-2 receptor signaling are unknown in endothelial cells. Expression of various DUSPs in human umbilical vein endothelial cells exposed to Ang-1 was measured. The functional roles of DUSPs in Ang-1-induced regulation of MAPK activation, endothelial cell survival, migration, differentiation, and permeability were measured using selective siRNA oligos. Ang-1 differentially induces DUSP1, DUSP4, and DUSP5 in human umbilical vein endothelial cells through activation of the PI-3 kinase, ERK1/2, p38, and SAPK/JNK pathways. Lack-of-function siRNA screening revealed that DUSP1 preferentially dephosphorylates p38 protein and is involved in Ang-1-induced cell migration and differentiation. DUSP4 preferentially dephosphorylates ERK1/2, p38, and SAPK/JNK proteins and, under conditions of serum deprivation, is involved in Ang-1-induced cell migration, several antiapoptotic effects, and differentiation. DUSP5 preferentially dephosphorylates ERK1/2 proteins and is involved in cell survival and inhibition of permeability. DUSP1, DUSP4, and DUSP5 differentially modulate MAPK signaling pathways downstream of Tie-2 receptors, thus highlighting the importance of these phosphatases to Ang-1-induced angiogenesis.

Ford J.D.,McGill University
American Journal of Public Health | Year: 2012

Indigenous populations have been identified as vulnerable to climate change. This framing, however, is detached from the diverse geographies of how people experience, understand, and respond to climate-related health outcomes, and overlooks nonclimatic determinants. I reviewed research on indigenous health and climate change to capture place-based dimensions of vulnerability and broader determining factors. Studies focused primarily on Australia and the Arctic, and indicated significant adaptive capacity, with active responses to climate-related health risks. However, nonclimatic stresses including poverty, land dispossession, globalization, and associated sociocultural transitions challenge this adaptability. Addressing geographic gaps in existing studies alongside greater focus on indigenous conceptualizations on and approaches to health, examination of global-local interactions shaping local vulnerability, enhanced surveillance, and an evaluation of policy support opportunities are key foci for future research.

Hendry A.,McGill University
Current Biology | Year: 2013

Contemporary evolution can shape ecological dynamics at population, community and ecosystem levels. Innovative new experiments with walking sticks confirm this expectation by showing that adaptation to predatory birds has large effects on walking stick population sizes, arthropod communities and herbivory. © 2013 Elsevier Ltd.

Lee T.,McGill University
Experiments in Fluids | Year: 2011

The impact of Gurney flaps, of different heights and perforations, on the growth and development of a tip vortex, both along the tip and in the near field of a finite NACA 0012 wing, at Re = 1.05 × 105 was investigated by using particle image velocimetry (PIV). Wind-tunnel force balance measurements were also made to supplement the PIV results. This study is a continuation of the work of Lee and Ko (Exp Fluids 46(6):1005-1019, 2009) on the near-wake measurements behind perforated Gurney flaps. The present results show that along the tip, the overall behavior of the secondary vortices and their interaction with the primary, or tip, vortex remained basically unchanged, regardless of flap height and perforation. The peak vorticity of the tip vortex, however, increased with flap height and always exhibited a local maximum at x/c = 0.8 (from the leading edge). In the near field, the strength and structure of the near-field tip vortex were found to vary greatly with the flap height and perforation. The small flaps produced a more concentrated tip vortex with an increased circulation, while the large Gurney flaps caused a disruption of the tip vortex. The disrupted vortex can, however, be re-established by the addition of flap perforation. The larger the flap perforation the more organized the tip vortex. The Gurney flaps have the potential to serve as an alternative off-design wake vortex control device. © 2010 Springer-Verlag.

Cooke D.G.,McGill University | Krebs F.C.,Technical University of Denmark | Jepsen P.U.,Technical University of Denmark
Physical Review Letters | Year: 2012

The formation of mobile charges in a roll-to-roll processed poly-3-hexylthiophene-fullerene bulk heterojunction film is observed directly by using transient terahertz spectroscopy with sub-100 fs temporal resolution. The transient terahertz ac conductivity reveals that 20% of the incident pump photons are converted into highly delocalized charges within the 40 fs, 3.1 eV pump pulse duration, which then rapidly becomes localized within 120 fs. Approximately 2/3 of these carriers subsequently decay, possibly into an exciton, on a 1 ps time scale. © 2012 American Physical Society.

Pain and body image distress are common among women with SSc, but their relative associations with reduced sexual function have not been assessed. The objective of this study was to assess the independent associations of pain and body image distress with reduced sexual function in women with SSc. Female SSc patients completed measures of sexual function (sexual relationships subscale of the Psychosocial Adjustment to Illness Scale-Self-Report), body image dissatisfaction (Satisfaction with Appearance Scale) and pain (visual analogue scale). Multiple regression analysis was used to assess the associations of body image dissatisfaction and pain with reduced sexual function, controlling for sociodemographic and disease variables. The sample included 117 female SSc patients [33 (28.2%) diffuse; mean age 51.4 (11.9) years; mean time since diagnosis 9.1 (8.5) years]. Unadjusted analyses found that reduced sexual function was associated with pain (r = 0.44, P < 0.001), body image dissatisfaction (r = 0.35, P < 0.001) and being married (r = 0.34, P < 0.001). In multivariate linear regression, disease duration (β = 0.17, P = 0.046), pain (β = 0.29, P = 0.001) and unmarried status (β = -0.23, P = 0.006) were independently associated with reduced sexual function. Dissatisfaction with appearance was not significantly associated with reduced sexual function (β = 0.16, P = 0.067). Pain is an important indicator of sexual function among women with SSc. Body image dissatisfaction was not independently associated with sexual impairment and appears to be less important factor than pain in determining sexual function. Future research should focus on isolating specific sources of pain that may be amenable to intervention in order to improve sexual function.

Brandenberger R.H.,McGill University | Martin J.,Paris Institute of Astrophysics
Classical and Quantum Gravity | Year: 2013

The accelerated expansion of space during the cosmological inflation period leads to trans-Planckian issues which need to be addressed. Most importantly, the physical wavelength of fluctuations which are studied at the present time by means of cosmological observations may well originate with a wavelength smaller than the Planck length at the beginning of the inflationary phase. Thus, questions arise as to whether the usual predictions of inflationary cosmology are robust considering our ignorance of physics on trans-Planckian scales, and whether the imprints of Planck-scale physics are at the present time observable. These and other related questions are reviewed in this paper. © 2013 IOP Publishing Ltd.

Afilalo J.,McGill University
Journal of the American Geriatrics Society | Year: 2014

The role of androgen deficiency as a biological determinant of frailty has received considerable attention. Cross-sectional studies have shown that low bioavailable testosterone (BT) is associated with prevalent frailty. High levels of luteinizing hormone and sex hormone binding globulin are also associated with prevalent frailty. Longitudinal studies have had mixed results, suggesting, for the most part, that a decline in BT over time is associated with progression of frailty. A number of potential biases were found in the current body of evidence, including misclassification bias (due to testosterone assays that were insensitive in lower ranges), selection bias (due to preferential inclusion of healthier individuals), and residual confounding (due to correlation of low testosterone with several disease states and adverse health characteristics). Consideration of these biases is vital to ensure that future epidemiological studies and interventional trials generate valid conclusions. © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.

Renoux C.,McGill University
BMJ (Clinical research ed.) | Year: 2010

OBJECTIVES: To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy. DESIGN: Population based nested case-control study. Setting About 400 general practices in the United Kingdom contributing to the General Practice Research Database. Participants Cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. Oestrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). Main outcome measures Rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date. RESULTS: There were 15,710 cases of stroke matched to 59 958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 (95% CI 0.75 to 1.20) relative to no use. The risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose. CONCLUSIONS: The use of transdermal HRT containing low doses of oestrogen does not seem to increase the risk of stroke. The presence of residual confounding, however, cannot be entirely excluded in the interpretation of this finding.

Sasseville D.,McGill University
Dermatitis | Year: 2012

Acrylates are plastic materials that are formed by the polymerization of monomers derived from acrylic or methacrylic acid. They have found numerous applications in paints, varnishes and adhesives, in the printing industry, in the medical and dental professions, and in artificial nails. Beginning in the 1950s, many reports of occupational and nonoccupational allergic contact dermatitis to (meth)acrylate monomers have been published. These molecules are strong irritants, and patch testing can induce active sensitization. When patch tested, acrylate-allergic patients often display multiple positive tests. These reactions may represent cross-reactions, or concomitant reactions due to the presence, in the products responsible for sensitization, of impurities not disclosed in material safety data sheets. (Meth)acrylates are volatile and unstable chemicals, as demonstrated by their rapid disappearance from commercially available patch test allergens when exposed to air for more than a few hours. © 2012 American Contact Dermatitis Society. All Rights Reserved.

Dostie J.,McGill University | Bickmore W.A.,University of Edinburgh
Current Opinion in Genetics and Development | Year: 2012

For more than a century, developments in light microscopy drove forward our understanding of how chromosomes are organized in the cell nucleus. Now, derivatives of the chromosome conformation capture (3C) technique have harnessed the power of molecular biology to provide more genome-wide perspectives on the spatial relationships of DNA sequences, both within and between chromosomes. Here we consider what new insights into chromosome territory organization and mechanisms of gene regulation these innovative tools are providing, and the extent to which the visual and the molecular approaches give consistent or differing views of chromosome territory organization. © 2012 Elsevier Ltd.

Krnjevic K.,McGill University
Journal of Physiology | Year: 2010

This article reviews especially the early history of glutamate and GABA as neurotransmitters in vertebrates. The proposal that some amino acids could mediate synaptic transmission in the CNS initially met with much resistance. Both GABA and its parent glutamate are abundant in the brain; but, unlike glutamate, GABA had no obvious metabolic function. By the late 1950s, the switch of interest from electrical to chemical transmission invigorated the search for central transmitters. Its identification with Factor I, a brain extract that inhibited crustacean muscle, focused interest on GABA as a possible inhibitory transmitter. In the first microiontophoretic tests, though GABA strongly inhibited spinal neurons, these effects were considered 'non-specific'. Strong excitation by glutamate (and other acidic amino acids) led to the same conclusion. However, their great potency and rapid actions on cortical neurons convinced other authors that these endogenous amino acids are probably synaptic transmitters. This was partly confirmed by showing that both IPSPs and GABA greatly increased Cl- conductance, their effects having similar reversal potentials. Many anticonvulsants proving to be GABA antagonists, by the 1970s GABA became widely accepted as a mediator of IPSPs. Progress was much slower for glutamate. Being generated on distant dendrites, EPSPs could not be easily compared with glutamate-induced excitation, and the search for specific antagonists was long hampered by the lack of blockers and the variety of glutamate receptors. These difficulties were gradually overcome by the application of powerful techniques, such as single channel recording, cloning receptors, as well as new pharmacological tools. © 2010 The Author. Journal compilation © 2010 The Physiological Society.

Bowie D.,McGill University
Journal of Physiology | Year: 2010

Ligand-gated ion channels are an important class of signalling protein that depend on small chemical neurotransmitters such as acetylcholine, l-glutamate, glycine and γ-aminobutyrate for activation. Although numerous in number, neurotransmitter substances have always been thought to drive the receptor complex into the open state in much the same way and not rely substantially on other factors. However, recent work on kainate-type (KAR) ionotropic glutamate receptors (iGluRs) has identified an exception to this rule. Here, the activation process fails to occur unless external monovalent anions and cations are present. This absolute requirement of ions singles out KARs from all other ligand-gated ion channels, including closely related AMPA- and NMDA-type iGluR family members. The uniqueness of ion-dependent gating has earmarked this feature of KARs as a putative target for the development of selective ligands; a prospect all the more compelling with the recent elucidation of distinct anion and cation binding pockets. Despite these advances, much remains to be resolved. For example, it is still not clear how ion effects on KARs impacts glutamatergic transmission. I conclude by speculating that further analysis of ion-dependent gating may provide clues into how functionally diverse iGluRs families emerged by evolution. Consequently, ion-dependent gating of KARs looks set to continue to be a subject of topical inquiry well into the future. © 2010 The Author. Journal compilation © 2010 The Physiological Society.

Tiwari M.K.,Anand Agricultural University | Adamowski J.,McGill University
Water Resources Research | Year: 2013

A new hybrid wavelet-bootstrap-neural network (WBNN) model is proposed in this study for short term (1, 3, and 5 day; 1 and 2 week; and 1 and 2 month) urban water demand forecasting. The new method was tested using data from the city of Montreal in Canada. The performance of the WBNN method was compared with the autoregressive integrated moving average (ARIMA) and autoregressive integrated moving average model with exogenous input variables (ARIMAX), traditional NNs, wavelet analysis-based NNs (WNN), bootstrap-based NNs (BNN), and a simple naïve persistence index model. The WBNN model was developed as an ensemble of several NNs built using bootstrap resamples of wavelet subtime series instead of raw data sets. The results demonstrated that the hybrid WBNN and WNN models produced significantly more accurate forecasting results than the traditional NN, BNN, ARIMA, and ARIMAX models. It was also found that the WBNN model reduces the uncertainty associated with the forecasts, and the performance of WBNN forecasted confidence bands was found to be more accurate and reliable than BNN forecasted confidence bands. It was found in this study that maximum temperature and total precipitation improved the accuracy of water demand forecasts using wavelet analysis. The performance of WBNN models was also compared for different numbers of bootstrap resamples (i.e., 25, 50, 100, 200, and 500) and it was found that WBNN models produced optimum results with different numbers of bootstrap resamples for different lead time forecasts with considerable variability. Key Points Comparison of different methods for urban water demand forecasting Wavelet-bootstrap-neural network method is found accurate and reliable. Significance of input variables on forecasting performance. ©2013. American Geophysical Union. All Rights Reserved.

Szyf M.,McGill University
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2010

DNA methylation is a covalent modification of DNA that plays an important role in setting gene expression programs during development. Recent evidence suggests that changes in DNA methylation patterns are involved in human disease through altering normal gene expression programming. In contrast to genetic changes aberrant DNA methylation patterns are potentially reversible raising the hope for DNA methylation based therapeutics. It was previously believed that the only relevant DNA methylation reaction in mature cells is DNA methyltransferase (DNMT), which accurately copies the DNA methylation pattern during cell division. The major effort in the field has therefore focused on developing DNMT inhibitors for cancer a disease of mitotic cells. However, recent evidence suggests that the DNA methylation state in both mitotic and postmitotic cells is a balance of DNA methylating and demethylating activities. This expands the scope of DNMT inhibitors to postmitotic tissues such as the brain. Since the identity of the DNA demethylating activity is still a mystery, the development of DNA demethylation inhibitors has been lagging. This review will discuss DNA methylation and demethylation machineries, and their therapeutic potentials as targets for small molecule inhibitors. © 2010.

Pastinen T.,McGill University
Nature Reviews Genetics | Year: 2010

Functional genomics is rapidly progressing towards the elucidation of elements that are crucial for the cis-regulatory control of gene expression, and population-based studies of disease and gene expression traits are yielding widespread evidence of the influence of non-coding variants on trait variance. Recently, genome-wide allele-specific approaches that harness high-throughput sequencing technology have started to allow direct evaluation of how these cis-regulatory polymorphisms control gene expression and affect chromatin states. The emerging data is providing exciting opportunities for comprehensive characterization of the allele-specific events that govern human gene regulation. © 2010 Macmillan Publishers Limited. All rights reserved.

Schiffrin E.L.,McGill University
Molecular Interventions | Year: 2010

Cardiovascular disease is characterized by enhanced oxidative stress in the vascular wall, heart, kidney, and brain. Epidemiological evidence suggests that antioxidants, including vitamins C and E, α-carotene, and β-carotene, may be therapeutic; however, interventional trials of antioxidants have provided mixed results, with some showing deleterious consequences. It is thus crucial that we consider the implications of trial design and execution, and further investigation of cellular pro-and antioxidant mechanisms is critical. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor blockers reduce the generation of reactive oxygen species, in experimental models as well as in humans, and have demonstrated beneficial cardiovascular effects. Polyphenols and antioxidants contained in foods and beverages may also be cardioprotective. Recent studies suggest that the judicious development of antioxidant agents may provide an effective approach to quench oxidative stress in tissues and improve cardiovascular health.

Glass L.,McGill University | Siegelmann H.T.,University of Massachusetts Amherst
Current Opinion in Genetics and Development | Year: 2010

Logical models provide insight about key control elements of biological networks. Based solely on the logical structure, we can determine state transition diagrams that give the allowed possible transitions in a coarse grained phase space. Attracting pathways and stable nodes in the state transition diagram correspond to robust attractors that would be found in several different types of dynamical systems that have the same logical structure. Attracting nodes in the state transition diagram correspond to stable steady states. Furthermore, the sequence of logical states appearing in biological networks with robust attracting pathways would be expected to appear also in Boolean networks, asynchronous switching networks, and differential equations having the same underlying structure. This provides a basis for investigating naturally occurring and synthetic systems, both to predict the dynamics if the structure is known, and to determine the structure if the transitions are known. © 2010 Elsevier Ltd.

Pollak M.,McGill University
Nature Reviews Cancer | Year: 2012

Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors. © 2012 Macmillan Publishers Limited. All rights reserved.

Oocyte cryopreservation is important for assisted reproductive technologies (ART). Although cryopreservation of metaphase II (MII) oocytes has been successfully used, MII oocytes are vulnerable to the damage inflicted by the freezing procedure. Cryopreservation of germinal vesicle stage oocytes (GV-oocytes) is an alternative choice; however, blastocyst development from GV-oocytes is limited largely due to the need for in vitro maturation (IVM). Herein, we evaluated the effects of l-carnitine (LC) supplementation during vitrification and thawing of mouse GV-oocytes, IVM, and embryo culture on preimplantation development after in vitro fertilization (IVF). We first compared the rate of embryonic development from the oocytes that had been collected at the GV stage from three mouse strains, (B6.DBA)F1, (B6.C3H)F1, and B6, and processed for IVM and IVF, as well as that from the oocytes matured in vivo, i.e. ovulated (IVO). Our results demonstrated that the rate of blastocyst development was the highest in the (B6.DBA)F1 strain and the lowest in the B6 strain. We then supplemented the IVM medium with 0.6 mg/ml LC. The rate of blastocyst development improved in the B6 but not in the (B6.DBA)F1 strain. Vitrification of GV-oocytes in the basic medium alone reduced the rate of blastocyst development in both of those mouse strains. LC supplementation to the IVM medium alone did not change the percentage of blastocyst development. However, LC supplementation to both vitrification and IVM media significantly improved blastocyst development to the levels comparable with those obtained from vitrified/thawed IVO oocytes in both of the (B6.DBA)F1 and B6 strains. We conclude that LC supplementation during vitrification is particularly efficient in improving the preimplantation development from the GV-oocytes that otherwise have lower developmental competence in culture.

Nezhad A.S.,McGill University
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2014

The demand for rapid and accurate diagnosis of plant diseases has risen in the last decade. On-site diagnosis of single or multiple pathogens using portable devices is the first step in this endeavour. Despite extensive attempts to develop portable devices for pathogen detection, current technologies are still restricted to detecting known pathogens with limited detection accuracy. Developing new detection techniques for rapid and accurate detection of multiple plant pathogens and their associated variants is essential. Recent single DNA sequencing technologies are a promising new avenue for developing future portable devices for plant pathogen detection. In this review, we detail the current progress in portable devices and technologies used for detecting plant pathogens, the current position of emerging sequencing technologies for analysis of plant genomics, and the future of portable devices for rapid pathogen diagnosis. © 2014 the Partner Organisations.

Recent research indicates that suicide rates are elevated in those living at higher altitudes in both the United States and South Korea. A possible mechanism that was proposed is metabolic stress associated with hypoxia. This commentary discusses these results, and also the association between elevated suicide rates and other conditions associated with hypoxia (smoking, chronic obstructive pulmonary disease and asthma). Tryptophan hydroxylase may not normally be saturated with oxygen, so mild hypoxia would decrease serotonin synthesis. Low brain serotonin is known to be associated with suicide. Thus, the commentary proposes and discusses the hypothesis that decreased brain serotonin synthesis associated with hypoxia is a mechanism that may contribute to suicide in conditions causing hypoxia. Finally the commentary proposes various studies that could test aspects of this hypothesis. © 2013 Canadian Medical Association.

Rassier D.E.,McGill University
Journal of Muscle Research and Cell Motility | Year: 2012

The force-length relation is one of the most prominent features of striated muscles, and predicts that the force produced by a fully activated muscle is proportional to the overlap between myosin and actin filaments within sarcomeres. However, there are situations in which the force-length relation deviates from predictions based purely on filament overlap. Notably, stretch of activated skeletal muscles induces a long-lasting increase in force, which is larger than the force produced during isometric contractions at a similar length. The mechanism behind this residual force enhancement and deviations from the original force-length relation are unknown, generating heated debate in the literature. We performed a series of experiments with short segments of myofibrils and isolated sarcomeres to investigating the mechanisms of the residual force enhancement and the force length-relation. In this paper, evidence will be presented showing that force enhancement is caused by: (i) half-sarcomere non-uniformities, and (ii) a sarcomeric component, which may be associated with Ca2+-induced stiffness of titin molecules. These mechanisms have large implications for understanding the basic mechanisms of muscle contraction. © Springer Science+Business Media B.V. 2012.

Briet M.,University of Paris Descartes | Schiffrin E.L.,McGill University
Current Hypertension Reports | Year: 2013

Essential hypertension is associated with large and small vascular remodeling that impacts cardiovascular prognosis. Longitudinal follow-up of hypertensive patients has shown that large arterial stiffness decreases partly independently of blood pressure reduction, suggesting specific pharmacological effects of antihypertensive therapy. Inhibitors of the renin-angiotensin- aldosterone system are among the agents that have been shown to affect vascular remodeling to a greater degree. Lifestyle modifications, including exercise and weight reduction, also improve large and small vascular remodeling. New antihypertensive drugs, including neprilysin inhibitors associated with an angiotensin receptor blocker, aldosterone synthase inhibitors and new devices such as renal denervation and baroreceptor stimulation, may exert beneficial effects on vascular remodeling and are currently under evaluation. © 2012 Springer Science+Business Media New York.

Szyf M.,McGill University
Clinical Genetics | Year: 2012

DNA methylation is a chemical modification of DNA that confers, upon identical sequences, different identities that are reflected in different gene expression programming. DNA methylation has a well-established role in cellular differentiation by providing a mechanism for one genome to express multiple phenotypes in a multicellular organism. Recent data point however to the possibility that in addition to the innate process of cellular differentiation, DNA methylation can serve as a genome adaptation mechanism, adapting genome function to changing environmental contexts including social environments. A critical time point for this process is early life when cues from the social and physical environments define lifelong trajectories of physical and mental health. DNA methylation and additional epigenetic modifications could therefore serve as molecular links between 'nurture' and 'nature'. Data that are consistent with this new role for DNA methylation as a mechanism for conferring an 'environment' specific identity to DNA will be discussed. © 2012 John Wiley & Sons A/S.

Braverman N.E.,McGill University | Moser A.B.,Johns Hopkins Hospital
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

Plasmalogens are a unique class of membrane glycerophospholipids containing a fatty alcohol with a vinyl-ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone. These two features provide novel properties to these compounds. Although plasmalogens represent up to 20% of the total phospholipid mass in humans their physiological roles have been challenging to identify, and are likely to be particular to different tissues, metabolic processes and developmental stages. Their biosynthesis starts in peroxisomes, and defects at these steps cause the malformation syndrome, Rhizomelic Chondrodysplasia Punctata (RCDP). The RCDP phenotype predicts developmental roles for plasmalogens in bone, brain, lens, lung, kidney and heart. Recent studies have revealed secondary plasmalogen deficiencies associated with more common disorders and allow us to tease out additional pathways dependent on plasmalogen functions. In this review, we present current knowledge of plasmalogen biology in health and disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease. © 2012 Elsevier B.V..

Niezen R.,McGill University
Transcultural Psychiatry | Year: 2013

As a tool of instant information dissemination and social networking, the Internet has made possible the formation and affirmation of public identities based on personality traits that are usually characterized by clinicians as pathological. The wide variety of online communities of affirmation reveals new conditions for permissiveness and inclusiveness in expressions of these socially marginal and clinically pathologized identities. Much the same kind of discourse common to these online communities is evident in some suicide forums. Web sites with suicide as their central raison d'être, taken together, encompass a wide range of ideas and commitments, including many that provide collective affirmation outside of (and often with hostility toward) professional intervention. The paradox of a potentially life-affirming effect of such forums runs counter to a stark dualism between online therapy versus "prochoice" forums and, by extension, to simple models of the influence of ideas on the lethality of suicide. Different forums either intensify or mitigate self-destructive tendencies in ways that are significant for understanding the place of communication in the occurrence of suicide and for therapeutic practice. © The Author(s) 2013.

Francois P.,McGill University | Siggia E.D.,Rockefeller University
Current Opinion in Genetics and Development | Year: 2012

Quantitative models of development that consider all relevant genes typically are difficult to fit to embryonic data alone and have many redundant parameters. Computational evolution supplies models of phenotype with relatively few variables and parameters that allows the patterning dynamics to be reduced to a geometrical picture for how the state of a cell moves. The clock and wavefront model, that defines the phenotype of somitogenesis, can be represented as a sequence of two discrete dynamical transitions (bifurcations). The expression-time to space map for Hox genes and the posterior dominance rule are phenotypes that naturally follow from computational evolution without considering the genetics of Hox regulation. © 2012 Elsevier Ltd.

This review examined evidence supporting stepped care for borderline personality disorder as an alternative to routine extended treatment. Empirical studies have shown that patients with borderline personality disorder have a heterogeneous course, but symptomatic improvement can sometimes be relatively rapid. Currently, there is no evidence that any long-term treatment is superior to briefer interventions for borderline personality disorder. Long-term therapy may not be necessary for all patients, and its routine use leads to access problems. A stepped-care model, similar to models applied to other severe mental disorders, might provide a better use of resources. Stepped care can be used to limit the use of expensive programs and reduce waiting lists. Not all patients with borderline personality disorder can be treated briefly, but a steppedcare model allows those with less severe symptoms to be managed with fewer resources, freeing up more time and personnel for the treatment of those who need treatment the most.

A geometrically non-linear theory is developed for shells of generic shape allowing for third-order thickness and shear deformation and rotary inertia by using eight parameters; geometric imperfections are also taken into account. The geometrically non-linear strain-displacement relationships are derived retaining full non-linear terms in all the 8 parameters, i.e. in-plane and transverse displacements, rotations of the normal and thickness deformation parameters; these relationships are presented in curvilinear coordinates, ready to be implemented in computer codes. Higher order terms in the transverse coordinate are retained in the derivation so that the theory is suitable also for thick laminated shells. Three-dimensional constitutive equations are used for linear elasticity. The theory is applied to circular cylindrical shells complete around the circumference and simply supported at both ends to study initially static finite deformation. Both radially distributed forces and displacement-dependent pressure are used as load and results for different shell theories are compared. Results show that a 6 parameter non-linear shell theory is quite accurate for isotropic shells. Finally, large-amplitude forced vibrations under harmonic excitation are investigated by using the new theory and results are compared to other available theories. The new theory with non-linearity in all the 8 parameters is the only one to predict correctly the thickness deformation; it works accurately for both static and dynamics loads. © 2014 Elsevier Ltd.

Pollak M.,McGill University
Cancer Prevention Research | Year: 2010

Retrospective studies that may be impractical to confirm prospectively suggest that diabetics treated with metformin have a substantially reduced cancer burden compared with other diabetics. It is unclear if this reflects a chemopreventive effect, an effect on transformed cells, or both. It also remains to be established if these data have relevance to people without diabetes. Laboratory models, however, provide independent impressive evidence for the activity of metformin and other biguanides in both cancer treatment and chemoprevention. Investigations of mechanisms of action of biguanides have revealed considerable complexity and have identified important gaps in knowledge that should be addressed to ensure the optimal design of clinical trials of these agents. Such trials may define important new indications for biguanides in the prevention and/or treatment of many common cancers. ©2010 AACR.

Lukacs G.L.,McGill University | Verkman A.S.,University of California at San Francisco
Trends in Molecular Medicine | Year: 2012

Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is caused by loss-of-function mutations of the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated plasma membrane chloride channel. The most common mutation, deletion of phenylalanine 508 (ΔF508), impairs CFTR folding and, consequently, its biosynthetic and endocytic processing as well as chloride channel function. Pharmacological treatments may target the ΔF508 CFTR structural defect directly by binding to the mutant protein and/or indirectly by altering cellular protein homeostasis (proteostasis) to promote ΔF508 CFTR plasma membrane targeting and stability. This review discusses recent basic research aimed at elucidating the structural and trafficking defects of ΔF508 CFTR, a prerequisite for the rational design of CF therapy to correct the loss-of-function phenotype. © 2011.

Szyf M.,McGill University
Genome Medicine | Year: 2012

Changes in gene expression that reset a cell program from a normal to a diseased state involve multiple genetic circuitries, creating a characteristic signature of gene expression that defines the cell's unique identity. Such signatures have been demonstrated to classify subtypes of breast cancers. Because DNA methylation is critical in programming gene expression, a change in methylation from a normal to diseased state should be similarly reflected in a signature of DNA methylation that involves multiple gene pathways. Whole-genome approaches have recently been used with different levels of success to delineate breast-cancer-specific DNA methylation signatures, and to test whether they can classify breast cancer and whether they could be associated with specific clinical outcomes. Recent work suggests that DNA methylation signatures will extend our ability to classify breast cancer and predict outcome beyond what is currently possible. DNA methylation is a robust biomarker, vastly more stable than RNA or proteins, and is therefore a promising target for the development of new approaches for diagnosis and prognosis of breast cancer and other diseases. Here, I review the scientific basis for using DNA methylation signatures in breast cancer classification and prognosis. I discuss the role of DNA methylation in normal gene regulation, the aberrations in DNA methylation in cancer, and candidate-gene and whole-genome approaches to classify breast cancer subtypes using DNA methylation markers. © 2012 BioMed Central Ltd.

Afilalo M.,McGill University | Morlion B.,University Hospitals Leuven
Pain Physician | Year: 2013

Background: Chronic non-cancer-related pain affects a large proportion of the adult population and is often difficult to manage effectively. Although opioid analgesics have been used to relieve chronic pain of different etiologies, opioids are associated with a range of side effects that may reduce patient quality of life and lead to reduced compliance with treatment.Tapentadol is a centrally acting analgesic with 2 mechanisms of action, μ-opioid receptor agonism and norepinephrine reuptake inhibition, that is available in an extended-release formulation for the management of chronic pain. Objective: To review the efficacy of tapentadol extended release (ER) for the management of moderate to severe chronic nociceptive and neuropathic pain. Methods: Efficacy results are summarized for four 15-week phase 3 studies of tapentadol ER in patients with moderate to severe chronic osteoarthritis knee pain (2 studies; ClinicalTrials.gov Identifiers: NCT00421928 and NCT00486811), low back pain (NCT00449176), and pain related to diabetic peripheral neuropathy (DPN; NCT00455520); a one-year phase 3 study of tapentadol ER in patients with moderate to severe chronic osteoarthritis pain or low back pain (NCT00361504); and a pooled analysis of data from the 15-week studies in patients with osteoarthritis knee pain or low back pain. A summary of the comparative tolerability for tapentadol ER and the active comparator used in these studies, oxycodone controlled release (CR), is provided. Results: Results of these studies showed that tapentadol ER (100 - 250 mg bid) was effective for the management of moderate to severe chronic osteoarthritis knee pain, low back pain, and pain related to DPN. Tapentadol ER (100 - 250 mg bid) has been shown to provide comparable pain relief to oxycodone HCl CR (20 - 50 mg bid) for chronic osteoarthritis knee pain and low back pain over up to one year of treatment. Tapentadol ER (100 - 250 mg bid) was associated with an improved tolerability profile, particularly gastrointestinal tolerability profile, and with lower rates of treatment discontinuations and adverse event-related discontinuations compared with oxycodone HCl CR (50 - 250 mg bid) over up to one year of treatment in patients with osteoarthritis knee pain and low back pain. Limitations: Differences in the design and duration of these phase 3 studies may limit comparisons of the efficacy results; nevertheless, this summary of efficacy results demonstrates the broad efficacy of tapentadol ER for different types of nociceptive and neuropathic pain. Conclusions: Tapentadol ER (100 - 250 mg bid) is effective for moderate to severe osteoarthritis pain, low back pain, and pain related to DPN and provides efficacy similar to that of oxycodone HCl CR (20 - 50 mg bid) for patients with osteoarthritis and low back pain. Tapentadol ER treatment has been associated with better gastrointestinal tolerability and compliance with therapy than oxycodone CR, which suggests that tapentadol ER may be a better option for the long-term management of chronic pain.

Bowie D.,McGill University
Journal of Physiology | Year: 2012

AMPA-type ionotropic glutamate receptors (iGluRs) represent the major excitatory neurotransmitter receptor in the developing and adult vertebrate CNS. They are crucial for the normal hardwiring of glutamatergic circuits but also fine tune synaptic strength by cycling into and out of synapses during periods of sustained patterned activity or altered homeostasis. AMPARs are grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 receptor subunit. GluA2-containing receptors are thought to be the most abundant AMPAR in the CNS, typified by their small unitary events, Ca 2+ impermeability and insensitivity to polyamine block. In contrast, GluA2-lacking AMPARs exhibit large unitary conductance, marked divalent permeability and nano- to micromolar polyamine affinity. Here, I review evidence for the existence of a third class of AMPAR which, though similarly Ca 2+ permeable, is characterized by its near-insensitivity to internal and external channel block by polyamines. This novel class of AMPAR is most notably found at multivesicular release synapses found in the avian auditory brainstem and mammalian retina. Curiously, these synapses lack NMDA-type iGluRs, which are conventionally associated with controlling AMPAR insertion. The lack of NMDARs suggests that a different set of rules may govern AMPAR cycling at these synapses. AMPARs with similar functional profiles are also found on some glial cells suggesting they may have a more widespread distribution in the mammalian CNS. I conclude by noting that modest changes to the ion-permeation pathway might be sufficient to retain divalent permeability whilst eliminating polyamine sensitivity. Consequently, this emerging AMPAR subclass need not be assembled from novel subunits, yet to be cloned, but could simply occur by varying the stoichiometry of existing proteins. © 2012 The Author. The Journal of Physiology © 2012 The Physiological Society.

Selvadurai A.P.S.,McGill University
Composite Structures | Year: 2010

This paper presents a theoretical analysis of an external matrix crack located in a unidirectional fibre-reinforced elastic solid modelled as a transversely isotropic material. The presence of matrix cracking with fibre continuity introduces bridging action that has an influence on the stress intensity factors at the crack tip of the external crack. This paper presents a model for the bridged crack, where the fibre ligaments induce a constant displacement-dependent traction constraint over the external crack. This gives rise to a Fredholm integral equation of the second kind, which can be solved in an approximate fashion. We examine the specific problem where the bridged external circular crack is loaded by a doublet of concentrated forces. Numerical results are presented to illustrate the influence of the fibre-matrix modular ratio and the location of the loading on the bridged-crack opening mode stress intensity factor. © 2009 Elsevier Ltd. All rights reserved.

Fisher W.D.,McGill University
The American journal of managed care | Year: 2011

In total hip or total knee arthroplasty, hypercoagulability typically begins on the operating table and a hypercoagulable state persists for up to 3 months after surgery. For that reason, it is critical to begin anticoagulation as soon as possible after wound closure and to continue it beyond the standard time of hospital discharge: current guidelines recommend up to 35 days following total hip arthroplasty and at least 10 days following total knee arthroplasty. Currently, low molecular weight heparin is commonly used for in-hospital prophylaxis, while for post-discharge use, warfarin is the drug most frequently prescribed in the United States. While both are efficacious, both have challenges associated with administration and, in the case of warfarin, a narrow therapeutic window, both food and drug interactions, routine blood monitoring, and an unpredictable dose response. New oral anticoagulants are being developed that will be easier to administer, have minimal or no drug interactions, and do not require coagulation monitoring. These drugs, which include dabigatran, apixaban, and rivaroxaban, should encourage improved compliance with guideline recommendations for optimal duration of thromboprophylaxis and lead to a reduced incidence of venous thrombolic events.

Ghayesh M.H.,University of Wollongong | Farokhi H.,McGill University
International Journal of Engineering Science | Year: 2015

In this paper, the nonlinear dynamics of a microplate is investigated based on the modified couple stress theory. The von Kármán plate theory is employed to model the system by retaining in-plane displacements and inertia. The equations of motion are derived via an energy method based on the Lagrange equations, yielding a set of second-order nonlinear ordinary differential equations with coupled terms. These equations are recast into a set of first-order nonlinear ordinary differential equations and the resulting equations are solved by means of the pseudo-arclength continuation technique. The nonlinear dynamics is examined through plotting the frequency-response and force-response curves of the system. The influence of system parameters on the resonant responses is highlighted. The differences in the response amplitude of the system modelled based on the modified couple stress theory and the classical one are discussed. © 2014 Elsevier Ltd. All rights reserved.

Yanagisawa H.,University of Texas Southwestern Medical Center | Davis E.C.,McGill University
International Journal of Biochemistry and Cell Biology | Year: 2010

Evolution of elastic fibers is associated with establishment of the closed circulation system. Primary roles of elastic fibers are to provide elasticity and recoiling to tissues and organs and to maintain the structural integrity against mechanical strain over a lifetime. Elastic fibers are comprised of an insoluble elastin core and surrounding mantle of microfibrils. Elastic fibers are formed in a regulated, stepwise manner, which includes the formation of a microfibrillar scaffold, deposition and integration of tropoelastin monomers into the scaffold, and cross-linking of the monomers to form an insoluble, functional polymer. In recent years, an increasing number of glycoproteins have been identified and shown to be located on or surrounding elastic fibers. Among them, the short fibulins-3, -4 and -5 particularly drew attention because of their potent elastogenic activity. Fibulins-3, -4 and -5 are characterized by tandem repeats of calcium binding EGF-like motifs and a C-terminal fibulin module, which is conserved throughout fibulin family members. Initial biochemical characterization and gene expression studies predicted that fibulins might be involved in structural support and/or matrix-cell interactions. Recent analyses of short fibulin knockout mice have revealed their critical roles in elastic fiber development in vivo. We review recent findings on the elastogenic functions of short fibulins and discuss the molecular mechanism underlying their activity in vitro and in vivo. © 2010 Elsevier Ltd.

McKinney R.A.,McGill University
Journal of Physiology | Year: 2010

In the central nervous system, most excitatory synapses occur on dendritic spines, which are small protrusions from the dendritic tree. In the mature cortex and hippocampus, dendritic spines are heterogeneous in shape. It has been shown that the shapes of the spine can affect synapse stability and synaptic function. Dendritic spines are highly motile structures that can undergo actin-dependent shape changes, which occur over a time scale ranging from seconds to tens of minutes or even days. The formation, remodelling and elimination of excitatory synapses on dendritic spines represent ways of refining the microcircuitry in the brain. Here I review the current knowledge on the effects of modulation of AMPA and NMDA ionotropic glutamate receptors on dendritic spine formation, motility and remodelling. © 2010 The Author. Journal compilation © 2010 The Physiological Society.

Boyaci T.,McGill University | Ozer O.,University of Texas at Dallas
Operations Research | Year: 2010

This paper investigates a capacity planning strategy that collects commitments to purchase before the capacity decision and uses the acquired advance sales information to decide on the capacity. In particular, we study a profit-maximization model in which a manufacturer collects advance sales information periodically prior to the regular sales season for a capacity decision. Customer demand is stochastic and price sensitive. Once the capacity is set, the manufacturer produces and satisfies customer demand (to the extent possible) from the installed capacity during the regular sales period. We study scenarios in which the advance sales and regular sales season prices are set exogenously and optimally. For both scenarios, we establish the optimality of a control band or a threshold policy that determines when to stop acquiring advance sales information and how much capacity to build. We show that advance selling can improve the manufacturer's profit significantly. We generate insights into how operating conditions (such as the capacity building cost) and market characteristics (such as demand variability) affect the value of information acquired through advance selling. From this analysis, we identify the conditions under which advance selling for capacity planning is most valuable. Finally, we study the joint benefits of acquiring information for capacity planning through advance selling and revenue management of installed capacity through dynamic pricing. ©2010 INFORMS.

Clarke H.J.,McGill University
Results and Problems in Cell Differentiation | Year: 2012

Post-transcriptional mechanisms play a central role in regulating gene expression during oogenesis and early embryogenesis. Growing oocytes accumulate an enormous quantity of messenger RNAs (mRNAs), but transcription decreases dramatically near the end of growth and is undetectable during meiotic maturation. Following fertilization, the embryo is initially transcriptionally inactive and then becomes active at a species-specific stage of early cleavage. Meanwhile, beginning during maturation and continuing after fertilization, the oocyte mRNAs are eliminated, allowing the embryonic genome to assume control of development. How the mammalian oocyte manages the storage, translation, and degradation of the huge quantity and diversity of mRNAs that it harbours has been the focus of enormous research effort and is the subject of this review. We discuss the roles of sequences within the 3′-untranslated region of certain mRNAs and the proteins that bind to them, sequence-non-specific RNA-binding proteins, and recent studies implicating ribonucleoprotein processing (P-) bodies and cytoplasmic lattices. We also discuss mechanisms that may control the temporally regulated translational activation of different mRNAs during meiotic maturation, as well as the signals that trigger silencing and degradation of the oocyte mRNAs. We close by highlighting areas for future research including the potential key role of small RNAs in regulating gene expression in oocytes. © 2012 Springer-Verlag Berlin Heidelberg.

Lasko P.,McGill University
Cold Spring Harbor Perspectives in Biology | Year: 2012

Localization of an mRNA species to a particular subcellular region can complement translational control mechanisms to produce a restricted spatial distribution of the protein it encodes. mRNA localization has been studied most in asymmetric cells such as budding yeast, early embryos, and neurons, but the process is likely to be more widespread. This article reviews the current state of knowledge about the mechanisms of mRNA localization and its functions in early embryonic development, focusing on Drosophila where the relevant knowledge is most advanced. Links between mRNA localization and translational control mechanisms also are examined. © 2012 Cold Spring Harbor Laboratory Press.

Szyf M.,McGill University | Bick J.,Yale University
Child Development | Year: 2013

Although epidemiological data provide evidence that early life experience plays a critical role in human development, the mechanism of how this works remains in question. Recent data from human and animal literature suggest that epigenetic changes, such as DNA methylation, are involved not only in cellular differentiation but also in the modulation of genome function in response to early life experience affecting gene function and the phenotype. Such modulations may serve as a mechanism for life-long genome adaptation. These changes seem to be widely distributed across the genome and to involve central and peripheral systems. Examining the environmental circumstances associated with the onset and reversal of DNA methylation will be critical for understanding risk and resiliency. © 2012 Society for Research in Child Development, Inc.

Sandri M.,University of Padua | Sandri M.,Venetian Institute of Molecular Medicine | Sandri M.,National Research Council Italy | Sandri M.,McGill University
Nature Cell Biology | Year: 2012

Nutrient deprivation and other stress stimuli elicit metabolic changes (such as the induction of autophagy and activation of FOXO transcription factors) that help an organism adapt to stressful conditions. A link between these stress response pathways is revealed by the finding that FOXO3 upregulates the expression of glutamine synthetase to promote glutamine accumulation, inhibit mTOR signalling and promote autophagy. © 2012 Macmillan Publishers Limited. All rights reserved.

Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-β (Aβ) as an important contributor to Alzheimer's disease (AD) pathology, capable of triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, the occurrence and pathological relevance of intracellular Aβ remain a matter of controversial debate. In this study, we have used a multidimensional approach including high-magnification and super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry analysis and ELISA to investigate the Aβ pathology and its associated cognitive impairments, in a novel transgenic rat model overexpressing human APP. Our microscopy studies with quantitative co-localization analysis revealed the presence of intraneuronal Aβ in transgenic rats, with an immunological signal that was clearly distinguished from that of the amyloid precursor protein (APP) and its C-terminal fragments (CTFs). The early intraneuronal pathology was accompanied by a significant elevation of soluble Aβ42 peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. Aβ38, Aβ39, Aβ40 and Aβ42 peptides were detected in the rat CSF by MALDI-MS analysis even at the plaque-free stages; suggesting that a combination of intracellular and soluble extracellular Aβ may be responsible for impairing cognition at early time points. Taken together, our results demonstrate that the intraneuronal development of AD-like amyloid pathology includes a mixture of molecular species (Aβ, APP and CTFs) of which a considerable component is Aβ; and that the early presence of these species within neurons has deleterious effects in the CNS, even before the development of full-blown AD-like pathology.

Weinstock D.,McGill University
Bioethics | Year: 2014

Freedom of Conscience and Freedom of Religion should be taken to protect two distinct sets of moral considerations. The former protects the ability of the agent to reflect critically upon the moral and political issues that arise in her society generally, and in her professional life more specifically. The latter protects the individual's ability to achieve secure membership in a set of practices and rituals that have as a moral function to inscribe her life in a temporally extended narrative. Once these grounds are distinguished, it becomes more difficult to grant healthcare professionals' claims to religious exemptions on the basis of the latter than it is on the basis of the former. While both sets of considerations generate 'internal reasons' for rights to accommodation, the relevant 'external' reasons present in the case of claims of moral conscience do not possess analogues in the case of claims of religious conscience. However, the argument applies only to 'irreducibly religious' claims, that is to claims that cannot be translated into moral vocabulary. What's more, there may be reasons to grant the claims of religious persons to exemptions that have to do not with the nature of the claims, but with the beneficial effects that the presence of religious persons may have in the context of the healthcare institutions of multi-faith societies. copy; 2013 John Wiley & Sons Ltd.

Nezhad A.S.,McGill University | Geitmann A.,University of Montreal
Journal of Experimental Botany | Year: 2013

Invasive behaviour is the hallmark of a variety of cell types of animal, plant, and fungal origin. Here we review the purpose and mechanism of invasive growth and migration. The focus is on the physical principles governing the process, the source of invasive force, and the cellular mechanism by which the cell penetrates the substrate. The current experimental methods for measuring invasive force and the modelling approaches for studying invasive behaviour are explained, and future experimental strategies are proposed. © The Author 2013.

Goltzman D.,McGill University
Trends in Endocrinology and Metabolism | Year: 2010

Parathyroid hormone (PTH), the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH) 2D], and PTH-related peptide (PTHrP), the mediator of hypercalcemia of malignancy, are all osteolytic hormones. Recent studies have demonstrated that endogenous PTH and PTHrP also exert bone anabolic activity and that PTHrP is a crucial modulator of growth plate development. At least part of these PTHrP functions can be mediated by intracrine effects, involving a unique interplay of cell surface membrane and intracellular signaling. 1,25(OH) 2D also exerts bone anabolic effects and, as with PTHrP, acts on multiple extraskeletal tissues. The skeletal functions of these hormones now extend beyond modulating bone resorption, and important extraskeletal activities have been discovered which involve unique local modes of action. © 2010 Elsevier Ltd.

We investigated the identity and quantitative variations of proteins extracted from human sperm heads using a label-free Gel-MS approach. Sperm samples were obtained from three men with high sperm counts at three different time points. This design allowed us to analyse intra-individual and inter-individual variations of the human sperm head proteome. Each time point was analyzed in triplicate to minimize any background artifactual effects of the methodology on the variation analyses. Intra-individual analysis using the spectral counting method revealed that the expression levels of 90% of the common proteins identified in three samples collected at various time-points, separated by several months, had a coefficient of variation of less than 0.5 for each man. Across individuals, the expression level of more than 80% of the proteins had a CV under 0.7. Interestingly, 83 common proteins were found within the core proteome as defined by the intra- and inter-variation analyses set criteria (CV<0.7). Some of these uniformly expressed proteins were chaperones, peroxiredoxins, isomerases, and cytoskeletal proteins. Although there is a significant level of inter-individual variation in the protein profiles of human sperm heads even in a well-defined group of men with high sperm counts, the consistent expression levels of a wide range of proteins points to their essential role during spermatogenesis.

Goebl W.,University of Music and Performing Arts Vienna | Palmer C.,McGill University
PLoS ONE | Year: 2013

Skilled piano performance requires considerable movement control to accomplish the high levels of timing and force precision common among professional musicians, who acquire piano technique over decades of practice. Finger movement efficiency in particular is an important factor when pianists perform at very fast tempi. We document the finger movement kinematics of highly skilled pianists as they performed a five-finger melody at very fast tempi. A three-dimensional motion-capture system tracked the movements of finger joints, the hand, and the forearm of twelve pianists who performed on a digital piano at successively faster tempi (7-16 tones/s) until they decided to stop. Joint angle trajectories computed for all adjacent finger phalanges, the hand, and the forearm (wrist angle) indicated that the metacarpophalangeal joint contributed most to the vertical fingertip motion while the proximal and distal interphalangeal joints moved slightly opposite to the movement goal (finger extension). An efficiency measure of the combined finger joint angles corresponded to the temporal accuracy and precision of the pianists' performances: Pianists with more efficient keystroke movements showed higher precision in timing and force measures. Keystroke efficiency and individual joint contributions remained stable across tempo conditions. Individual differences among pianists supported the view that keystroke efficiency is required for successful fast performance. © 2012 Goebl, Palmer.

Pollak M.,McGill University
Clinical Cancer Research | Year: 2012

Over the past decade, encouraging preclinical and early clinical data concerning the relevance of the insulin receptor/insulin-like growth factor (IGF) receptor family to neoplasia led to ambitious clinical trial programs of more than a dozen drug candidates that target these receptors. These candidates include antireceptor antibodies, antiligand antibodies, receptor-specific tyrosine kinase inhibitors, and agents such as picropodophyllin and metformin that have novel mechanisms of action. Several recently reported phase III clinical trials of anti-IGF-I receptor antibodies have been disappointing and are sufficient to disprove the hypothesis that the antibodies tested have large favorable impacts on unselected patients with cancer. However, many of these trials were designed prior to recent insights concerning pathophysiology and predictive biomarkers. Future studies are required, but it will be important to optimize their design rather than simply repeat the approaches taken to date. ©2012 AACR.

Papadopoulos V.,McGill University | Miller W.L.,University of California at San Francisco
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2012

Adrenal gonadal, placental and brain mitochondria contain several steroidogenic enzymes, notably the cholesterol side chain cleavage enzyme, P450scc, which is the enzymatic rate-limiting step in steroidogenesis which determines cellular steroidogenic capacity. Even before this step, the access of cholesterol to this enzyme system is both rate-limiting and the site of acute regulation via the steroidogenic acute regulatory protein (StAR) which interacts with a complex multi-component 'transduceosome' on the outer mitochondrial membrane (OMM). The components of the transduceosome include the 18 kDa translocator protein (TSPO), the voltage-dependent anion channel (VDAC-1), TSPO-associated protein 7 (PAP7, ACBD3 for acyl-CoA-binding-domain 3), and protein kinase A regulatory subunit 1α (PKAR1A). The precise fashion in which these proteins interact and move cholesterol from the OMM to P450scc, and the means by which cholesterol is loaded into the OMM, remain unclear. Human deficiency diseases have been described for StAR and for P450scc. Mitochondria also contain several 'downstream' steroidogenic enzymes. © 2012 Elsevier Ltd. All rights reserved.

Geary T.G.,McGill University
Current Opinion in Infectious Diseases | Year: 2012

PURPOSE OF REVIEW: Anthelmintic mass drug administration (MDA) has limited pathology and transmission of filariases, schistosomiasis and gastrointestinal nematodiases in many areas of the world. This record has led to the adoption of ambitious goals for eliminating these infections on a global scale within the next decade or two by expansion of MDA with available drugs. This review considers the attributes of anthelmintics that favor or limit attainment of the scaled-up plans for elimination, and highlights situations for which new or reformulated drugs may be needed. RECENT FINDINGS: Many challenges face elimination campaigns. Anthelmintic needs include, first, a macrofilaricidal regimen that speeds up elimination, is safe to use in regions of Onchocerca volvulus and Loa loa coendemicity, and provides a rapid method to resolve infections introduced into previously controlled areas; second, a replacement of praziquantel for schistosomiasis should a resistance arise; third, formulations of praziquantel to enhance compliance, and pediatric formulations for preschool children; fourth, a regimen that provides high efficacy against Trichuris trichiura (new anthelmintic, prolonged dosing strategy or anthelmintic combinations); fifth, pediatric formulations of albendazole and mebendazole compatible with elimination operations; and sixth, an alternative to benzimidazoles in the anticipation of the development of drug resistance. SUMMARY: Expansion of MDA programs to attain elimination of human helminthiases is a noble and worthwhile endeavor. Increased drug pressure should be expected to select resistance alleles. Alternative anthelmintics and regimens should be developed for deployment to ensure that the ambitious goals for elimination are not endangered due to an inadequate pharmacopeia. © 2012 Wolters Kluwer Health|Lippincott Williams & Wilkins.

Saleh M.,McGill University
Immunological Reviews | Year: 2011

One of the fundamental aspects of the innate immune system is its capacity to discriminate between self and non-self or altered self, and to quickly respond by eliciting effector mechanisms that act in concert to restore normalcy. This capacity is determined by a set of evolutionarily conserved pattern recognition receptors (PRRs) that sense the presence of microbial motifs or endogenous danger signals, including tissue damage, cellular transformation or metabolic perturbation, and orchestrate the nature, duration and intensity of the innate immune response. Nod-like receptors (NLRs), a group of intracellular PRRs, are particularly essential as evident by the high incidence of genetic variations in their genes in various diseases of homeostasis. Here, I overview the signaling mechanisms of NLRs and discuss the mounting evidence of evolutionary conservation between their pathways and the cell death machinery. I also describe their effector functions that link the sensing of danger to the induction of inflammation, autophagy or cell death. © 2011 John Wiley & Sons A/S.

Several studies have reported limited or no reduction in serum cholesterol in response to probiotic formulations. Recently, probiotics have shown promise in treating metabolic disease due to improved strain selection and delivery technologies. The aim of the present study was to evaluate the cholesterol-lowering efficacy of a yoghurt formulation containing microencapsulated bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, taken twice per d over 6 weeks, in hypercholesterolaemic adults. A total of 114 subjects completed this double-blind, placebo-controlled, randomised, parallel-arm, multi-centre study. This interventional study included a 2-week washout, 2-week run-in and 6-week treatment period. Subjects were randomised to consume either yoghurts containing microencapsulated L. reuteri NCIMB 30242 or placebo yoghurts. Over the intervention period, subjects consuming yoghurts containing microencapsulated L. reuteri NCIMB 30242 attained significant reductions in LDL-cholesterol (LDL-C) of 8·92 % (P = 0·016), total cholesterol (TC) of 4·81 % (P = 0·031) and non-HDL-cholesterol (HDL-C) of 6·01 % (P = 0·029) over placebo, and a significant absolute change in apoB-100 of - 0·19 mmol/l (P = 0·049). Serum concentrations of TAG and HDL-C were unchanged over the course of the study. Present results show that consumption of microencapsulated BSH-active L. reuteri NCIMB 30242 yoghurt is efficacious and safe for lowering LDL-C, TC, apoB-100 and non-HDL-C in hypercholesterolaemic subjects. The efficacy of microencapsulated BSH-active L. reuteri NCIMB 30242 yoghurts appears to be superior to traditional probiotic therapy and akin to that of other cholesterol-lowering ingredients.

Malla A.,McGill University
Canadian journal of psychiatry. Revue canadienne de psychiatrie | Year: 2013

A major source of limitation to the real effectiveness of antipsychotics is the high rate of patient nonadherence or, more frequently, partial adherence. Using long-acting injectable (LAI) formulations is likely to reduce the impact of such adherence problems. Conversely, the use of LAIs in Canada remains low relative to many other jurisdictions. Based on effectiveness data from randomized control trials and other, less rigorous, studies, as well as our 2 qualitative studies exploring numerous issues around the use of LAIs, including their low use, we put forward 10 different recommendations for consideration by clinicians. These are also based on the experience of many clinicians and clinician scientists. These recommendations address mostly clinical challenges associated with the use of LAIs. Their application in clinical settings is illustrated in our report through several case examples highlighting the large variation across patients and different phases of illness. It is recommended that LAIs should be considered as a treatment option for psychotic disorders across all phases, including the first 2 to 5 critical years.

Palter J.B.,McGill University
Annual Review of Marine Science | Year: 2015

The Gulf Stream carries the warm, poleward return flow of the wind-driven North Atlantic subtropical gyre and the Atlantic Meridional Overturning Circulation. This northward flow drives a significant meridional heat transport. Various lines of evidence suggest that Gulf Stream heat transport profoundly influences the climate of the entire Northern Hemisphere and, thus, Europe's climate on timescales of decades and longer. The Gulf Stream's influence is mediated through feedback processes between the ocean, atmosphere, and cryosphere. This review synthesizes paleoclimate archives, model simulations, and the instrumental record, which collectively suggest that decadal and longer-scale variability of the Gulf Stream's heat transport manifests in changes in European temperature, precipitation, and storminess. Given that anthropogenic climate change is projected to weaken the Atlantic Meridional Overturning Circulation, associated changes in European climate are expected. However, large uncertainty in the magnitude of the anticipated weakening undermines the predictability of the future climate in Europe. Copyright © 2015 by Annual Reviews. All rights reserved.

Tasse A.M.,McGill University
Human Genetics | Year: 2011

Early biomedical research focused primarily on the study of specific diseases or sets of diseases within small groups of living research participants. Accordingly, the first ethical frameworks governing biomedical research addressed short-term, limited-scope research involving living research participants. Due to recent interest in longitudinal population studies and biobanking, research is increasingly long term. This shift raises several ethical and legal issues concerning the impact of a participant's death on research. This paper offers an overview of these issues in the context of longitudinal biobanking genetic research. Our first part outlines the legal and ethical frameworks that govern the effect of the participants' death on consent. This will be followed by an analysis of the legal and ethical frameworks that govern the secondary use of deceased participants' data and samples and the return of deceased participants' individual research results to biological family members. In our second part, we will review the current literature and discuss the above mentioned issues using the bioethics "principlism" theory before concluding. © Springer-Verlag 2011.

Thiel A.,McGill University | Heiss W.-D.,Max Planck Institute for Neurological Research
Stroke | Year: 2011

Activated microglia is one of the most important cellular components of poststroke neuroinflammation, which occurs early in the area of the infarct but also in remote regions with fiber tract connections to the site of the primary lesion. The development of different radioligands for the translocator protein, a mitochondrial membrane protein expressed in microglial cells when they transform from the resting to the activated state, allows to study the temporal dynamics of this cellular neuroinflammatory component in vivo in animal models and human stroke using positron emission tomography. In this article, we review the advantage and limitations of current and future methods for microglia imaging as well as new results of multimodal imaging approaches in clinical stroke, which try to combine microglia imaging with diffusion tensor imaging to investigate the clinical relevance of remote microglia activation along fiber tracts for poststroke recovery. © 2011 American Heart Association, Inc.

Ambalavanan A.,McGill University
European Journal of Human Genetics | Year: 2015

Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.European Journal of Human Genetics advance online publication, 28 October 2015; doi:10.1038/ejhg.2015.218. © 2015 Macmillan Publishers Limited

The authors conducted a survey to characterize the strategies used by general dentists to manage pain related to temporomandibular muscle and joint disorders (TMJDs) and to assess the feasibility of conducting a randomized controlled trial (RCT) to determine the effectiveness of these strategies. Dentists from three dental practice-based research networks (PBRNs) (The Dental Practice-Based Research Network, Practitioners Engaged in Applied Research and Learning Network and Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry) agreed to participate in this survey. Of 862 dentists surveyed, 654 were general dentists who treated TMJDs; among these, 80.3 percent stated they would participate in a future RCT. Dentists treated an average of three patients with TMJD-related pain per month. Splints or mouthguards (97.6 percent), self-care (85.9 percent) and over-the-counter or prescribed medications (84.6 percent) were the treatments most frequently used. The treatments dentists preferred to compare in an RCT were splint or mouthguard therapy (35.8 percent), self-care (27.4 percent) and medication (17.0 percent). Most general dentists treat TMJD-related pain, and initial reversible care typically is provided. It is feasible to conduct an RCT in a dental PBRN to assess the effectiveness of splint or mouthguard therapy, self-care or medication for the initial management of painful TMJD. There is an opportunity to do an RCT in a dental PBRN, which could lead to the development of evidence-based treatment guidelines for the initial treatment of TMJD-related pain by primary care dentists.

Amabili M.,McGill University
Journal of Sound and Vibration | Year: 2010

Nonlinear forced vibrations of rectangular plates carrying a central concentrated mass are studied. The plate is assumed to have immovable edges and rotational springs; numerical results are presented for clamped plates. The Von Kármán nonlinear plate theory is used, but in-plane inertia in both the plate and the mass is retrained. The problem is discretized into a multi-degree-of-freedom (dof) system by using an energy approach and Lagrange equations taking damping into account. A pseudo-arclength continuation method is used in order to obtain numerical solutions. Results are presented as both (i) frequency-amplitude curves and (ii) time domain responses. The effect of gravity and the effect of the consequent initial plate deflection are also investigated. © 2010 Elsevier Ltd. All rights reserved.

Although epidemiological data provides evidence that there is an interaction between genetics (nature) and the social and physical environments (nurture) in human development; the main open question remains the mechanism. The pattern of distribution of methyl groups in DNA is different from celltype to cell type and is conferring cell specific identity on DNA during cellular differentiation and organogenesis. This is an innate and highly programmed process. However, recent data suggests that DNA methylation is not only involved in cellular differentiation but that it is also involved in modulation of genome function in response to signals from the physical, biological and social environments. We propose that modulation of DNA methylation in response to environmental cues early in life serves as a mechanism of life-long genome "adaptation" that molecularly embeds the early experiences of a child ("nurture") in the genome ("nature"). There is an emerging line of data supporting this hypothesis in rodents, non-human primates and humans that will be reviewed here. However, several critical questions remain including the identification of mechanisms that transmit the signals from the social environment to the DNA methylation/demethylation enzymes. © 2011 Landes Bioscience.

Mortola J.P.,McGill University
Respiratory Physiology and Neurobiology | Year: 2011

The article discusses the establishment of pulmonary ventilation (V̇E) in the avian embryo, the metabolic and V̇E sensitivity to hypoxia and the effects of sustained embryonic hypoxia on the hatchling's V̇E chemosensitivity. Throughout embryogenesis, hypometabolism is the common response to hypoxia, with no compensation by anaerobic energy supply. It originates primarily from the depression in body growth and, later in development, from the depression of thermogenesis. The V̇E responses to acute hypoxia or hypercapnia are clearly detectable during the internal pipping phase; their magnitude rapidly increases in the first postnatal day. Sustained prenatal hypoxia diminishes the V̇E chemosensitivity of the hatchling and reduces the hypometabolic response to an acute hypoxic episode. The former most likely originates from a disturbance in the normal development of the carotid bodies, the latter from the central action of hypoxia on thermogenesis. The avian embryo is a model suitable for the studies of the development of respiratory control and offers an alternative to mammalian models for investigations on the short- and long-term effects of prenatal hypoxia. © 2011 Elsevier B.V.

Jones E.A.V.,McGill University
Respiratory Physiology and Neurobiology | Year: 2011

During embryonic development, blood flow is needed not only to nourish the developing embryo but is also important for shaping the vascular network such that it becomes hemodynamically efficient. The first blood vessels form a network called the capillary plexus. After the onset of blood flow, the capillary plexus remodel into a more hierarchical tree-shaped network. Mechanical forces created by blood flow are required for remodelling to occur and these forces are believed to induce a maturation of the blood vessels that stabilizes the growing vascular network. The role of mechanical force has been extensively studied in the mature cardiovascular system. Though the events induced by blood flow during development are thought to be similar to what occurs in the adult, there are several important differences between the embryo and the adult. We therefore discuss what is known about the role of mechanical forces in vascular remodelling from the adult cardiovascular system and highlight how embryonic development differs from the adult. We consider the role of blood flow in altering branching morphology, arterial-venous identity and the formation of the blood vessel wall during early vascular development. © 2011 Elsevier B.V.

McCaffrey L.M.,McGill University | Macara I.G.,University of Virginia
Trends in Cell Biology | Year: 2011

Epithelial cells comprise the foundation for the majority of organs in the mammalian body, and are the source of approximately 90% of all human cancers. Characteristically, epithelial cells form intercellular adhesions, exhibit apical/basal polarity, and orient their mitotic spindles in the plane of the epithelial sheet. Defects in these attributes result in the tissue disorganization associated with cancer. Epithelia undergo self-renewal from stem cells, which might in some cases be the cell of origin for cancers. The PAR polarity proteins are master regulators of epithelial organization, and are closely linked to signaling pathways such as Hippo, which orchestrate proliferation and apoptosis to control organ size. 3D ex vivo culture systems can now faithfully recapitulate epithelial organ morphogenesis, providing a powerful approach to study both normal development and the initiating events in carcinogenesis. © 2011 Elsevier Ltd.

Heijman J.,University of Duisburg - Essen | Voigt N.,University of Duisburg - Essen | Nattel S.,Montreal Heart Institute | Nattel S.,McGill University | Dobrev D.,University of Duisburg - Essen
Circulation Research | Year: 2014

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca-handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management. © 2014 American Heart Association, Inc.

Kramer M.S.,McGill University
Annals of Nutrition and Metabolism | Year: 2011

Whether breastfeeding protects against the development of allergic disease has been a frequent subject of study and debate for 75 years. This paper summarizes the published evidence concerning the risks of atopic dermatitis, asthma, allergic rhinitis, positive allergen skin tests, and food allergy associated with infant feeding. The summary is based largely on systematic reviews and meta-analyses carried out by other authors. In addition, I also incorporate the evidence from our long-term follow-up of Belarusian children participating in a cluster-randomized trial of a breastfeeding promotion intervention. Copyright © 2011 S. Karger AG, Basel.

Jones E.A.V.,McGill University
Seminars in Cell and Developmental Biology | Year: 2011

Within a day of gastrulation, the embryonic heart begins to beat and creates blood flow in the developing cardiovascular system. The onset of blood flow completely changes the environment in which the cardiovascular system is forming. Flow provides physiological feedback such that the developing network adapts to cue provided by the flow. Targeted inactivation of genes that alter early blood fluid dynamics induce secondary defects in the heart and vasculature and therefore proper blood flow is known to be essential for vascular development. Though hemodynamics, or blood fluid dynamics, are known to activate signaling pathways in the mature cardiovascular system in pathologies ranging from artherosclerosis to angiogenesis, the role in development has not been as intensively studied. The question arises how blood vessels in the embryos, which initially lack cells types such as smooth muscle cells, differ in their response to mechanical signals from blood flow as compared to the more mature cardiovascular system. Many genes known to be regulated by hemodynamics in the adult are important for developmental angiogenesis. Therefore the onset of blood flow is of primary importance to vascular development. This review will focus on how blood flow initiates and the effects of the mechanical signals created by blood flow on cardiovascular development. © 2011 Elsevier Ltd.

Polychronakos C.,McGill University
Nature Genetics | Year: 2011

An efficient way to design genotyping arrays for fine mapping is to group phenotypes with common biology. The first application of the Immunochip to celiac disease provides an insightful view of what this strategy can achieve. © 2011 Nature America, Inc. All rights reserved.

Thanassoulis G.,McGill University
Canadian Journal of Cardiology | Year: 2013

The past 10 years have seen a remarkable revolution in the genetics of cardiovascular (CV) disease. Although much work remains to bring these discoveries to the bedside, genetics has opened up remarkable possibilities in understanding the causes of CV disease through a relatively novel study design known as "Mendelian randomization." Akin to a randomized trial, Mendelian randomization is a genetic study design that takes advantage of the "randomization" of genetic information at birth to evaluate a potential causal relationship between a genetically determined biomarker and an outcome. By providing evidence for causal relationships, Mendelian randomization can improve our understanding of fundamental mechanisms in human disease, potentially accelerate the identification of bona fide drug targets, and ultimately improve the care of patients with CV disease. This review describes the concept and design of Mendelian randomization genetic studies, discusses their strengths and weaknesses, and presents recent examples of Mendelian randomization studies in the CV literature that have helped clarify the causal role of selected biomarkers in CV medicine. © 2013 Canadian Cardiovascular Society.

Haller B.C.,McGill University
BioScience | Year: 2014

Scientific research is often conceptually divided into empirical and theoretical approaches, and researchers often specialize as empiricists or theorists. Both approaches are essential to scientific progress, but interactions between the two groups have at times seemed problematic. I present results from a recent survey of 614 scientists (predominantly ecologists and evolutionary biologists) regarding interactions between theoretical and empirical work. Some overall themes emerged from these results. One theme is a widespread and mutual lack of trust, understanding, and interaction between empiricists and theorists. Another is a general desire, among almost all of the respondents, for greater understanding, more collaboration, and closer interactions between empirical and theoretical work. The final theme is that institutions, such as journals, funding agencies, and universities, are often seen as hindering such interactions. These results provide a clear mandate for institutional changes to improve interactions between theorists and empiricists in ecology and evolutionary biology. © The Author(s) 2014.

Cancer cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids. MVs are generated via diverse biological mechanisms triggered by pathways involved in oncogenic transformation, microenvironmental stimulation, cellular activation, stress, or death. Vesiculation events occur either at the plasma membrane (ectosomes, shed vesicles) or within endosomal structures (exosomes). MVs are increasingly recognized as mediators of intercellular communication due to their capacity to merge with and transfer a repertoire of bioactive molecular content (cargo) to recipient cells. Such processes may occur both locally and systemically, contributing to the formation of microenvironmental fields and niches. The bioactive cargo of MVs may include growth factors and their receptors, proteases, adhesion molecules, signalling molecules, as well as DNA, mRNA, and microRNA (miRs) sequences. Tumour cells emit large quantities of MVs containing procoagulant, growth regulatory and oncogenic cargo (oncosomes), which can be transferred throughout the cancer cell population and to non-transformed stromal cells, endothelial cells and possibly to the inflammatory infiltrates (oncogenic field effect). These events likely impact tumour invasion, angiogenesis, metastasis, drug resistance, and cancer stem cell hierarchy. Ongoing studies explore the molecular mechanisms and mediators of MV-based intercellular communication (cancer vesiculome) with the hope of using this information as a possible source of therapeutic targets and disease biomarkers in cancer.

This exploratory study investigated the relationships between students' perceptions of their classroom experiences and instructional and contextual factors involved with the use of Classroom Communication Systems (CCS) technology. A mixed methods approach was employed to examine these relationships using data collected from 931 students enrolled in one public university. Thematic analysis explored students' perceptions of the use of CCS. Three logit models with a sound predictability and model fit were established using logistic sequential regression. These models identified crucial instructional and contextual factors and examined the degree to which each of these factors was associated with student perceptions of classroom experiences with CCS. This study found that positive student perceptions of classroom experience with CCS were closely associated with the use of specific types of questions, formative feedback and assessment approaches, and the pedagogical training of the classroom instructors. These findings elucidate specific aspects of CCS use that are related to how students perceive the effectiveness of this technology, and may ultimately assist instructional designers and faculty developers in designing and implementing CCS to enhance students' classroom experiences. © 2014 Elsevier Ltd. All rights reserved.

DNA-based species identification, known as barcoding, transformed the traditional approach to the study of biodiversity science. The field is transitioning from barcoding individuals to metabarcoding communities. This revolution involves new sequencing technologies, bioinformatics pipelines, computational infrastructure, and experimental designs. In this dynamic genomics landscape, metabarcoding studies remain insular and biodiversity estimates depend on the particular methods used. In this opinion article, I discuss the need for a coordinated advancement of DNA-based species identification that integrates taxonomic and barcoding information. Such an approach would facilitate access to almost 3 centuries of taxonomic knowledge and 1 decade of building repository barcodes. Conservation projects are time sensitive, research funding is becoming restricted, and informed decisions depend on our ability to embrace integrative approaches to biodiversity science. © 2014 Elsevier Ltd.

Coomes O.T.,McGill University
Professional Geographer | Year: 2010

Studies of indigenous agricultural systems in Amazonia often devote only limited attention to the accessibility and exchange of crop plant germplasm among Amerindian and folk peoples. I argue that scarcity of crop planting material-geographically, seasonally, and socially-in rural Amazonia has given rise to socioeconomic relations that profoundly influence indigenous agriculture and rural life. Access to seeds, cuttings, and other plant propagules is shown to be critical in the building and maintenance of crop and varietal diversity, in subsistence security for lowland farmers, and in market product specialization among traditional farmers. Further study of seed supply systems in Amazonia is needed to inform discussions of in situ crop conservation as well as intellectual property rights over plants and seed. Moreover, a focus on seed systems provides a new lens through which to study Amazonian peoples, their relations with one another, the market, and society. © Association of American Geographers.

Neonatal ventral hippocampus (nVH) lesion in rats is a useful model to study developmental origins of adult cognitive deficits and certain features of schizophrenia. nVH lesion-induced reorganization of excitatory and inhibitory neurotransmissions within prefrontal cortical (PFC) circuits is widely believed to be responsible for many of the behavioral abnormalities in these animals. Here we provide evidence that development of an aberrant medial PFC (mPFC) α-1 adrenergic receptor (α-1AR) function following neonatal lesion markedly affects glutamatergic synaptic plasticity within PFC microcircuits and contributes to PFC-related behavior abnormalities. Using whole-cell patch-clamp recording, we report that norepinephrine-induced α-1AR-dependent long-term depression (LTD) in a subset of cortico-cortical glutamatergic inputs is strikingly diminished in mPFC slices from nVH-lesioned rats. The LTD impairment occurs in conjunction with completely blunted α-1AR signaling through extracellular signal-regulated kinase 1/2. These α-1AR abnormalities have functional significance in a mPFC-related function, that is, extinction of conditioned fear memory. Post-pubertal animals with nVH lesion show significant resistance to extinction of fear by repeated presentations of the conditioned tone stimulus. mPFC infusion of an α-1AR antagonist (benoxathian) or LTD blocking peptide (Tat-GluR23Y) impaired fear extinction in sham controls, but had no significant effect in the lesioned animals. The data suggest that impaired α-1 adrenergic regulation of cortical glutamatergic synaptic plasticity may be an important mechanism in cognitive dysfunctions reported in neurodevelopmental psychiatric disorders.Neuropsychopharmacology advance online publication, 9 July 2014; doi:10.1038/npp.2014.142.

Feldman L.S.,McGill University
World Journal of Surgery | Year: 2011

Laparoscopic splenectomy was first reported in 1991-1992 by several groups. The impact and role of laparoscopy for splenectomy can be considered as significant as that for gallbladder disease, achalasia, esophageal reflux, and adrenal disease. In many centers, the laparoscopic approach is now routine for most cases of elective splenectomy. The laparoscopic approach is associated with reduced morbidity, especially pulmonary, wound, and infectious complications. This article reviews a standardized approach to laparoscopic and hand-assisted splenectomy and covers indications, operative strategy, and complications. Several special considerations, including massive splenomegaly, postsplenectomy thrombosis of the portosplenic venous system, and accessory spleens are also discussed. © 2011 Société Internationale de Chirurgie.

Davies T.J.,McGill University | Buckley L.B.,University of North Carolina at Chapel Hill
Global Ecology and Biogeography | Year: 2012

Aim At broad geographical scales, species richness is a product of three basic processes: speciation, extinction and migration. However, determining which of these processes predominates is a major challenge. Whilst palaeontological studies can provide information on speciation and extinction rates, data are frequently lacking. Here we use a recent dated phylogenetic tree of mammals to explore the relative importance of these three processes in structuring present-day richness gradients. Location The global terrestrial biosphere. Methods We combine macroecological data with phylogenetic methods more typically used in community ecology to describe the phylogenetic history of regional faunas. Using simulations, we explore two simple phylogenetic metrics, the mean and variance in the pairwise distances between taxa, and describe their relationship to phylogenetic tree topology. We then use these two metrics to characterize the evolutionary relationships among mammal species assemblages across the terrestrial biome. Results We show that the mean and variance in the pairwise distances describe phylogenetic tree topology well, but are less sensitive to phylogenetic uncertainty than more direct measures of tree shape. We find the phylogeny for South American mammals is imbalanced and 'stemmy' (long branches towards the root), consistent with recent diversification within evolutionarily disparate lineages. In contrast, the phylogeny for African mammals is balanced and 'tippy' (long branches towards the tips), more consistent with the slow accumulation of diversity over long times, reflecting the Old World origin of many mammal clades. Main conclusions We show that phylogeny can accurately capture biogeographical processes operating at broad spatial scales and over long time periods. Our results support inferences from the fossil record - that the New World tropics are a diversity cradle whereas the Old World tropics are a museum of old diversity. © 2012 Blackwell Publishing Ltd.

Gutzler R.,Max Planck Institute for Solid State Research | Perepichka D.F.,McGill University
Journal of the American Chemical Society | Year: 2013

Organic oligomers and polymers with extended π-conjugation are the fundamental building blocks of organic electronic devices. Novel routes are being explored to create tailor-made organic materials, and recent progress in organic chemistry and surface chemistry has led to the synthesis of planar 2D polymers. Here we show how extending π-conjugation in the second dimension leads to novel materials with HOMO-LUMO gaps smaller than in 1D polymers built from the same parent molecular repeat unit. Density functional theory calculations on experimentally realized 2D polymers grant insight into HOMO-LUMO gap contraction with increasing oligomer size and show fundamental differences between 1D and 2D "band gap engineering". We discuss how the effects of cross-conjugation and dihedral twists affect the electronic gaps. © 2013 American Chemical Society.

Faria S.L.,McGill University
Frontiers in Oncology | Year: 2014

Radiotherapy has had important role in the palliation of NSCLC. Randomized trials tend to suggest that, in general, short regimens give similar palliation and toxicity compared to longer regimens. The benefit of combining chemotherapy to radiosensitize the palliative radiation treatment is an open question, but so far it has not been proved to be very useful in NSCLC. The addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case and probably should not be used as a routine management. Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) are modern techniques being used each time more frequently in the treatment of single or oligometastases. In general, they offer good tumour control with little toxicity (with a more expensive cost) compared to the traditionally fractionated radiotherapy regimens. © 2014 Faria.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. Numerous randomized controlled trials (RCTs) show that using thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective and cost-effective. Despite this, prophylactic therapies for VTE are underutilized. System-wide using the I(2)statistic and subgroup analyses. Before analysis, we decided that results would be pooled if three or more studies were available for a particular intervention. We assessed publication bias using funnel plots and cumulative meta-analysis. We included a total of 55 studies. One of these reported data in patient-days and could not be quantitatively analyzed with the others. The 54 remaining studies (8 RCTs and 46 NRS) eligible for inclusion in our quantitative synthesis enrolled a total of 78,343 participants. Among RCTs, there were sufficient data to pool results for one primary outcome (received prophylaxis) for the 'alert' intervention. Alerts, such as computerized reminders or stickers on patients' charts, were associated with a risk difference (RD) of 13%, signifying an increase in the proportion of patients who received prophylaxis (95% confidence interval (CI) 1% to 25%). Among NRS, there were sufficient data to pool both primary outcomes for each intervention type. Pooled risk differences for received prophylaxis ranged from 8% to 17%, and for received appropriate prophylaxis ranged from 11% to 19%. Education and alerts were associated with statistically significant increases in prescription of appropriate prophylaxis, and multifaceted interventions were associated with statistically significant increases in prescription of any prophylaxis and appropriate prophylaxis. Multifaceted interventions had the largest pooled effects. I(2) results showed substantial statistical heterogeneity which was in part explained by patient types and type of hospital. A subgroup analysis showed that multifaceted interventions which included an alert may be more effective at improving rates of prophylaxis and appropriate prophylaxis than those without an alert. Results for VTE and safety outcomes did not show substantial benefits or harms, although most studies were underpowered to assess these outcomes. We reviewed a large number of studies which implemented a variety of system-wide strategies aimed to improve thromboprophylaxis rates in many settings and patient populations. We found statistically significant improvements in prescription of prophylaxis associated with alerts (RCTs) and multifaceted interventions (RCTs and NRS), and improvements in prescription of appropriate prophylaxis in NRS with the use of education, alerts and multifaceted interventions. Multifaceted interventions with an alert component may be the most effective. Demonstrated sources of heterogeneity included patient types and type of hospital. The results of our review will help physicians, nurses, pharmacists, hospital administrators and policy makers make practical decisions about local adoption of specific system-wide measures to improve prevention of VTE, an important public health issue. We did not find a significant benefit for VTE outcomes; however, earlier RCTs assessing the efficacy of thromboprophylaxis which were powered to address these outcomes have demonstrated the benefit of prophylactic therapies and a favourable balance of benefits versus the increased risk of bleeding events.

Isnard A.,McGill University
Frontiers in cellular and infection microbiology | Year: 2012

The intramacrophage protozoan parasites of Leishmania genus have developed sophisticated ways to subvert the innate immune response permitting their infection and propagation within the macrophages of the mammalian host. Several Leishmania virulence factors have been identified and found to be of importance for the development of leishmaniasis. However, recent findings are now further reinforcing the critical role played by the zinc-metalloprotease GP63 as a virulence factor that greatly influence host cell signaling mechanisms and related functions. GP63 has been found to be involved not only in the cleavage and degradation of various kinases and transcription factors, but also to be the major molecule modulating host negative regulatory mechanisms involving for instance protein tyrosine phosphatases (PTPs). Those latter being well recognized for their pivotal role in the regulation of a great number of signaling pathways. In this review article, we are providing a complete overview about the role of Leishmania GP63 in the mechanisms underlying the subversion of macrophage signaling and functions.

Lovejoy S.,McGill University
Climate Dynamics | Year: 2015

Using modern climate data and paleodata, we voyage through 17 orders of magnitude in scale explicitly displaying the astounding temporal variability of the atmosphere from fractions of a second to hundreds of millions of years. By combining real space (Haar fluctuation) and Fourier space analysis, we produce composites quantifying the variability. These show that the classical “mental picture” in which quasi periodic processes are taken as the fundamental signals embedded in a spectral continuum of background “noise” is an iconic relic of a nearly 40 year old “educated guess” in which the flatness of the continuum was exaggerated by a factor of ≈1015. Using modern data we show that a more realistic picture is the exact opposite: the quasiperiodic processes are small background perturbations to spectrally continuous wide range scaling foreground processes. We identify five of these: weather, macroweather, climate, macroclimate and megaclimate, with rough transition scales of 10 days, 50 years, 80 kyrs, 0.5 Myr, and we quantify each with scaling exponents. We show that as we move from one regime to the next, that the fluctuation exponent (H) alternates in sign so that fluctuations change sign between growing (H > 0) and diminishing (H < 0) with scale. For example, mean temperature fluctuations increase up to about 5 K at 10 days (the lifetime of planetary structures), then decrease to about 0.2 K at 50 years, and then increase again to about 5 K at glacial-interglacial scales. The pattern then repeats with a minimum RMS fluctuation of 1–2 K at ≈0.5 Myr increasing to ≈20 K at 500 Myrs. We show how this can be understood with the help of the new, pedagogical “H model”. Both deterministic General Circulation Models (GCM’s) with fixed forcings (“control runs”) and stochastic turbulence-based models reproduce weather and macroweather, but not the climate; for this we require “climate forcings” and/or new slow climate processes. Averaging macroweather over periods increasing to ≈30–50 yrs yields apparently converging values: macroweather is “what you expect”. Macroweather averages over ≈30–50 yrs have the lowest variability, they yield well defined climate states and justify the otherwise ad hoc “climate normal” period. However, moving to longer periods, these states increasingly fluctuate: just as with the weather, the climate changes in an apparently unstable manner; the climate is not what you expect. Moving to time scales beyond 100 kyrs, to the macroclimate regime, we find that averaging the varying climate increasingly converges, but ultimately—at scales beyond ≈0.5 Myr in the megaclimate, we discover that the apparent point of convergence itself starts to “wander”, presumably representing shifts from one climate to another. © 2014, Springer-Verlag Berlin Heidelberg.

Grodzinsky Y.,McGill University | Grodzinsky Y.,Hebrew University of Jerusalem | Nelken I.,Hebrew University of Jerusalem
Science | Year: 2014

How does a certain pattern of vibration in the air reliably represent a meaningful speech sound?

Selvadurai A.P.S.,McGill University
Geofluids | Year: 2015

The paper examines the influence of axial stress-induced closure of a fracture on its permeability. The experiments were conducted on a cylinder of Barre Granite measuring 457 mm in diameter and 510 mm in height, containing a central cylindrical cavity of diameter 75 mm. Radial flow hydraulic pulse tests were conducted in a previous research investigation (Selvadurai et al., PAGEOPH, 2005) to determine the permeability characteristics of the intact granite. In the continuation of the research, a fracture was introduced in the cylinder with its nominal plane normal to the axis of the cylinder. Axial compressive stress was applied normal to the plane of the fracture. An increase in the compressive normal stress acting on the fracture caused a reduction in the aperture of the fracture, which resulted in the reduction in its permeability. Steady state radial flow tests were conducted on the fractured axially stressed sample to determine the variation of fracture permeability with axial normal stress. The analytical developments also take into account flow through the matrix region as the normal stress increases. The results of the experimental investigations indicate that the complete stress relief of a fracture previously subjected to a normal stress of 7.5 MPa can result in a permeability increase of approximately three orders of magnitude. These findings are relevant to shallow depth geotechnical construction activities where enhanced fluid flow can be activated by stress relief. As the fracture aperture closes with high normal stress, the flow through the matrix can be appreciable and if this factor is not taken into consideration the interpretation of fracture permeability can be open to error. This factor can be of interest to the interpretation of permeability of fractures in deep crustal settings where the stresses acting normal to the fracture surface can inhibit flow in the fracture. Fluid flow in fractures can be significantly influenced by the stresses that are acting both normal to and in the plane of the fracture. This experimental research illustrates the influence of normal stress-induced hydraulic closure of the fracture on the evolution of fracture permeability. Experiments conducted on a 457 mm diameter cylinder containing a planar fracture show that the permeability can exhibit a three orders of magnitude decrease as the normal stresses are increased from zero to 7.5 MPa. This change can occur without the development of gouge during the application of axial stresses. © 2015 John Wiley & Sons Ltd151-2 February 2015 10.1111/gfl.12107 Special Issue: Crustal Permeability THE PHYSICS OF PERMEABILITY © 2014 John Wiley & Sons Ltd.

Oswin N.,McGill University
Transactions of the Institute of British Geographers | Year: 2010

The two meanings of 'domestic', as both residential dwelling and national territory, collide unusually forcefully in Singapore since its Housing Development Board (HDB) provides most housing in this city-state. While many scholars have interrogated the boundaries between homely/unhomely and foreign/domestic in Singapore by examining gender, ethnic/racial and class politics of HDB, in this paper I argue for the analytical usefulness of considering Singapore housing and citizenship as heteronormative; and, more broadly, for the value of a queer theoretical approach in advancing critical geographies of home. Combining archival research with contemporary observation, I examine discourses of respectable domesticity and proper family across Singapore's colonial and postcolonial periods in order to understand not just the exclusion of gays and lesbians, but also the 'queering' of a range of figures such as the single mother, the migrant worker, the unfilial child, and many others. Since the production of this range of non-heteronormative others is produced by a much more complex set of cultural logics than a focus on the deployment of a sexual binary can capture, the queer theoretical approach I argue for understands heteronormativity not as a universal policing of a heterosexual-homosexual binary, but as the geographically and historically specific coincidence of race, class, gender, nationality and sexual norms. © 2010 The Author. Journal compilation © Royal Geographical Society (with The Institute of British Geographers) 2010.

Voigt K.,McGill University
American Journal of Public Health | Year: 2015

Electronic nicotine delivery systems (ENDS)-commonly called e-cigarettes-are at the center of a polarized debate. How should they be regulated? Central to this debate is the concern that e-cigarettes could lead to the renormalization of smoking and that the regulation of ENDS should therefore be modeled on the regulation of conventional cigarettes. I argue that arguments based on the renormalization of smoking can lend support to restrictions on marketing of ENDS, but that such arguments are problematic when used to justify restrictions on where ENDS can be used. The debate has been insufficiently sensitive to the ethical complexities of attempts to manipulate social norms to change health behaviors; these complexities must also inform the debate about ENDS and their regulation.

Suissa S.,McGill University | Suissa S.,McGill Pharmacoepidemiology Research Unit
Epidemiology | Year: 2015

Observational studies of drug effects conducted using health care mega-databases often involve large cohorts with multiple time-varying exposures and covariates. These present formidable technical challenges in data analysis, necessitating sampling approaches such as nested case-control designs. The nested case-control approach is, however, baffling to medical journal readers, particularly the comparisons involving "cases" versus "controls" and the convoluted way in which forward-looking relations from exposure to outcome are extracted from backward-looking data. I propose a "quasi-cohort" approach involving alternative ways of data presentation and analysis that are more in line with the underlying cohort design, including the computation of quasi-rates, rate ratios, and quasi-rate differences. I illustrate the quasi-cohort approach using data from a study of pneumonia risk associated with inhaled corticosteroid use in a cohort of 163,514 patients with chronic obstructive pulmonary disease, including 20,344 who had the outcome event of pneumonia hospitalization during more than 304 million person-days of follow-up. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Paraoxonase 1 (PON1) protects against oxidative modification of low density lipoproteins. The PON1 gene has 3 polymorphisms considered strong determinants of PON1 levels: Q192R and L55M in the coding region and C-108T in the promoter region. PON1 levels are also influenced by smoking. The authors hypothesized that PON1 variants could increase the risk of vascular thrombosis, leading in turn to placental insufficiency and small-for-gestational-age (SGA) birth. The author compared PON1 variants and haplotypes between 448 newborn SGA cases and 431 newborn controls from Montréal, Québec, Canada (1998-2000) and studied the effects of interaction with maternal smoking. Transmission of the variants in case-parent trios was used as validation of the case-control results; the authors combined case-control and family data to analyze the associations of variants with SGA birth. In the case-control analysis, the T allele from C-108T increased the risk of SGA birth (additive odds ratio = 1.30, 95% confidence interval (CI): 1.06, 1.59), and the TRL haplotype (T from C-108T, R from Q192R, and L from L55M) was associated with an odds ratio of 1.51 (95% CI: 1.07, 2.15). Among smokers, the CRL haplotype was protective (odds ratio = 0.48, 95% CI: 0.28, 0.82). Case-parent trio results were compatible with case-control results. © The Author 2010.

Turecki G.,McGill University | Brent D.A.,Western Psychiatric Institute and Clinic
The Lancet | Year: 2016

Summary Suicide is a complex public health problem of global importance. Suicidal behaviour differs between sexes, age groups, geographic regions, and sociopolitical settings, and variably associates with different risk factors, suggesting aetiological heterogeneity. Although there is no effective algorithm to predict suicide in clinical practice, improved recognition and understanding of clinical, psychological, sociological, and biological factors might help the detection of high-risk individuals and assist in treatment selection. Psychotherapeutic, pharmacological, or neuromodulatory treatments of mental disorders can often prevent suicidal behaviour; additionally, regular follow-up of people who attempt suicide by mental health services is key to prevent future suicidal behaviour. © 2016 Elsevier Ltd.

Talwar V.,McGill University | Lee K.,University of Toronto
Child Development | Year: 2011

The present study compared the lie-telling behavior of 3- and 4-year-old West African children (N=84) from either a punitive or a nonpunitive school. Children were told not to peek at a toy when left alone in a room. Most children could not resist the temptation and peeked at the toy. When the experimenter asked them if they had peeked, the majority of the punitive school peekers lied about peeking at the toy while significantly fewer nonpunitive school children did so. The punitive school children were better able to maintain their deception than nonpunitive school children when answering follow-up questions. Thus, a punitive environment not only fosters increased dishonesty but also children's abilities to lie to conceal their transgressions. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

Drake R.E.,Dartmouth Psychiatric Research Center | Latimer E.,McGill University
World Psychiatry | Year: 2012

This paper summarizes the findings for North America of the WPA Task Force on Steps, Obstacles and Mistakes to Avoid in the Implementation of Community Mental Health Care. Community mental health has evolved over five decades in the United States and Canada. The United States has led the world in innovation and spending, but provide variable quality of care; Canada has steadily developed a more uniform public health system for less cost. Lessons learned from North America include: team-based approaches and other evidence-based practices, when implemented with high fidelity, can improve outcomes in routine mental health care settings; recovery ideology and peer support enhance care, though they have not been studied rigorously; effective community-based care for people with serious mental disorders is expensive.

Hudson M.,McGill University
Arthritis care & research | Year: 2011

To determine the effect of different methods of modeling smoking on vascular outcomes in rheumatic diseases. Data from the Canadian Scleroderma Research Group Registry were used. Patients self-reported their smoking history. Vascular outcomes were severity of Raynaud's phenomenon, presence of finger ulcers, and severity of finger ulcers. Several models were developed to capture the experience of smoking: 1) ever compared to never smoking; 2) current and past smoking compared to never smoking; 3) never, past, and current smoking compared using polynomial contrasts; 4) smoking intensity, duration, and time since cessation assessed separately; and 5) smoking modeled using the Comprehensive Smoking Index (CSI), which integrates intensity, duration, and time since cessation into a single covariate. This study included 606 patients, of which 16% were current, 42% were past, and 42% were never smokers. Current and past smokers smoked a mean±SD of 25±17 and 17±18 pack-years, respectively. Smoking duration was shorter in past compared to current smokers (18.3 versus 31.7 years). Past smokers reported having stopped smoking approximately mean±SD 16±12 years prior, although this ranged from 1 to 50 years. Smoking had no effect on vascular outcomes in the simplest model comparing ever to never smokers. Models that isolated past smokers revealed the presence of a healthy smoker bias in that group. The model using the CSI demonstrated a strong negative effect of smoking on vascular outcomes. Proper modeling of the effect of smoking is essential in studies of vascular outcomes of rheumatic diseases. Copyright © 2011 by the American College of Rheumatology.

The first three cell lineages formed in the implanting mouse embryo are the epiblast (EPI), primitive endoderm (PE) and trophectoderm. The EPI and PE are the two lineages derived from the inner cell mass (ICM) of the blastocyst, which give rise to the fetus and extraembryonic yolk sac, respectively. Previous studies suggest that embryonic day 3.5 ICM cells begin as a mixture of PE or EPI progenitors randomly distributed in the ICM which then sort out during blastocyst expansion to form two morphologically distinct layers. How are these two progenitors first specified? A proposed model is that the divisional history of ICM cells affects EPI/PE lineage specification. Two independent research groups addressed this issue using completely different approaches and reached different conclusions (Morris et al.; 2010; Yamanaka et al.; 2010). What causes the apparent discrepancy between the two studies? This commentary highlights two important differences in the design of the two studies: the timing of EPI/PE lineage evaluation and the strategy for scoring the results. It is proposed that these studies are not in conflict, but rather are complementary. © 2011 ALPHA Scientists in Reproductive Medicine and the European Society of Human Reproduction and Embryology. Published by Elsevier Ltd. All rights reserved.

Gallo S.,McGill University
Applied physiology, nutrition, and metabolism = Physiologie appliquée, nutrition et métabolisme | Year: 2010

Health policy in North America advocates that all breastfed infants receive a vitamin D supplement of 400 IU per day for the primary prevention of rickets. Despite this recommendation, rickets still occurs in Canada. It is not known whether vitamin D deficiency in the Canadian population is solely attributable to inadequacies in vitamin supplementation. Thus, the evaluation of current practices, including awareness and compliance with recommendations, is clearly needed. The objective of this study was to describe the vitamin D supplementation practices of mothers of newborns living in the Montreal area. This was a cross-sectional telephone survey of 343 mothers delivering a healthy term infant from December 2007 to May 2008 at the Royal Victoria Hospital (Montreal, Que.). Ninety percent of all mothers breastfed their infants during the first 6 months; 53% did so exclusively. Of mothers exclusively breastfeeding, 74% reported meeting the Health Canada recommendation. The main reason for not adhering to the recommendation was the assumption by mothers who began to feed fortified formula (400 IU.L-1) that supplementation was no longer necessary. Fifty percent of infants receiving mixed feedings without supplementation prior to 6 months did not achieve the recommended intake. Receiving advice about supplementation and the higher education of mothers were significant positive determinants of supplementation practices. This work identified infants consuming mixed feedings and those consuming only formula in the first 6 months as groups at high risk for not meeting the recommended 400 IU.day-1 of vitamin D. Therefore there may still be gaps in knowledge regarding vitamin D supplementation.

Whitley R.,McGill University
Culture, Medicine, and Psychiatry | Year: 2014

The current supremacy of the 'bio-bio-bio' model within the discipline of psychiatry has progressively marginalized social science approaches to mental health. This situation begs the question, what role is there for the anthropology of mental health? In this essay, I contend that there are three essential roles for the anthropology of mental health in an era of biological psychiatry. These roles are to (i) provide a meaningful critique of practices, beliefs, and movements within current psychiatry; (ii) illuminate the socio-cultural, clinical, and familial context of suffering and healing regarding emotional distress/mental illness; and (iii) act as a catalyst for positive change regarding healing, services and provisions for people with emotional distress/mental illness. My argument is unified by my contention that a credible anthropology of mental health intending to make a societal contribution should offer no opposition without proposition. In other words, any critique must be counter-balanced by the detailing of solutions and proposals for change. This will ensure that the anthropology of mental health continues to contribute critical knowledge to the understanding of mental suffering, distress, and healing. Such social and cultural approaches are becoming especially important given the widespread disenchantment with an increasingly dominant biological psychiatry. © 2014 Springer Science+Business Media New York.

Magder S.,McGill University
Current Opinion in Critical Care | Year: 2010

Purpose of review: Fluid boluses are a key element of hemodynamic resuscitation, but overuse of fluids also can be harmful. It is thus important to understand how fluids actually improve clinical problems and how one can predict fluid responsiveness. It is also important to understand potential limitations of fluid therapy. Recent findings: Currently there is a lot of attention being paid to the assessment of fluid responsiveness, but there is a lack of studies evaluating indications for fluid treatment and the potential harm from excess fluid use. This review emphasizes the physiological factors that determine the response to fluids, the limitations of these responses, and the predictors of fluid responsiveness. A key principle is that fluid resuscitation improves clinical indicators by increasing cardiac output, and if the volume infusion does not increase cardiac output there will be no benefit. Summary: Assessment of changes in cardiac output, either directly or indirectly, is a key component of managing fluid therapy. Avoiding harm with the use of fluids requires understanding what is physiologically possible. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Shore G.C.,McGill University | Papa F.R.,University of California at San Francisco | Oakes S.A.,University of California at San Francisco
Current Opinion in Cell Biology | Year: 2011

Inability to meet protein folding demands within the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), a signaling pathway with both adaptive and apoptotic outputs. While some secretory cell types have a remarkable ability to increase protein folding capacity, their upper limits can be reached when pathological conditions overwhelm the fidelity and/or output of the secretory pathway. Irremediable 'ER stress' induces apoptosis and contributes to cell loss in several common human diseases, including type 2 diabetes and neurodegeneration. Researchers have begun to elucidate the molecular switches that determine when ER stress is too great to repair and the signals that are then sent from the UPR to execute the cell. © 2010 Elsevier Ltd.

Basu N.,McGill University
Environmental Toxicology and Chemistry | Year: 2015

Thousands of environmental contaminants have neurotoxic properties, but their ecological risk is poorly characterized. Contaminant-associated disruptions to animal behavior and reproduction, both of which are regulated by the nervous system, provide decision makers with compelling evidence of harm, but such apical endpoints are of limited predictive or harm-preventative value. Neurochemical biomarkers, which may be used to indicate subtle changes at the subcellular level, may help overcome these limitations. Neurochemical biomarkers have been used for decades in the human health sciences and are now gaining increased attention in the environmental realm. In the present review, the applications and implications of neurochemical biomarkers to the field of ecotoxicology are discussed. The review provides a brief introduction to neurochemistry, covers neurochemical-based adverse outcome pathways, discusses pertinent strengths and limitations of neurochemical biomarkers, and provides selected examples across invertebrate and vertebrate taxa (worms, bivalves, fish, terrestrial and marine mammals, and birds) to document contaminant-associated neurochemical disruption. With continued research and development, neurochemical biomarkers may increase understanding of the mechanisms that underlie injury to ecological organisms, complement other measures of neurological health, and be integrated into risk assessment practices. © 2014 SETAC.

Research towards the application of nanoparticles as carrier vehicles for the delivery of therapeutic agents is increasingly gaining importance. The angiogenic growth factors, human vascular endothelial growth factor (VEGF) and human angiopoietin-1 are known to prevent vascular endothelial cell apoptosis and in fact to stimulate human vascular endothelial cell (HUVEC) proliferation. This paper aims to study the combined effect of these bioactive proteins coencapsulated in human serum albumin nanoparticles on HUVECs and to evaluate the potential application of this delivery system towards therapeutic angiogenesis. The angiogenic proteins, human VEGF and human angiopoietin-1, were coencapsulated in albumin nanoparticles for better controlled delivery of the proteins. The application of a nanoparticle system enabled efficient and extended-release kinetics of the proteins. The size of the nanoparticles crosslinked with glutaraldehyde was 101.0 ± 0.9 nm and the zeta potential was found to be -18 ± 2.9 mV. An optimal concentration of glutaraldehyde for the nanoparticle coating process was determined, and this provided stable and less toxic nanoparticles as protein carriers. The results of the study indicate that nanoparticles crosslinked with glutaraldehyde produced nanoparticles with tolerable toxicity which provided efficient and controlled release of the coencapsulated proteins. The nanoparticles were incubated for two weeks to determine the release profiles of the proteins. At the end of the two-week incubation period, it was observed that 49% ± 1.3% of human angiopoietin-1 and 59% ± 2.1% of human VEGF had been released from the nanoparticles. The proliferation and percent apoptosis of the HUVECs in response to released proteins was observed. The results indicate that the released proteins were biologically active and the combined application of both the proteins demonstrated a significant highly proliferative and antiapoptotic effect on HUVECs as compared with the effect demonstrated by the individual proteins released. These studies could serve as a basis to encourage further research into the potential in vivo application of these protein-loaded nanoparticles in the field of therapeutic angiogenesis.

Lam C.S.,McGill University | Lam C.S.,University of British Columbia
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We search for possible symmetries present in the leptonic mixing data from SU(3) subgroups of order up to 511. Theoretical results based on symmetry are compared with global fits of experimental data in a chi-squared analysis, yielding the following results. There is no longer a group that can produce all the mixing data without a free parameter, but a number of them can accommodate the first or the second column of the mixing matrix. The only group that fits the third column is Δ(150). It predicts sin ¡22θ13=0.11 and sin ¡22θ23=0.94, in good agreement with experimental results. © 2013 American Physical Society.

Lovejoy S.,McGill University
Geophysical Research Letters | Year: 2015

The ScaLIng Macroweather model (SLIMM) is a new class of stochastic atmospheric model. It exploits the large system memory to overcome the biases of conventional numerical climate models, it makes hindcasts and forecasts over macroweather forecast horizons (≈10 days to decades). Using the simplest (scalar), SLIMM model with only two parameters, we present various twentieth century hindcasts including several of the slowdown ("pause") in the warming since 1998. The 1999-2013 hindcast is accurate to within ±0.11 K, with all the 2002-2013 anomalies hindcast to within ±0.02 K. In comparison, the Climate Model Intercomparison Project Phase 3 hindcasts were on average about 0.2 K too warm. ©2015. American Geophysical Union. All Rights Reserved.

Loreau M.,McGill University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Community ecology and ecosystem ecology provide two perspectives on complex ecological systems that have largely complementary strengths and weaknesses. Merging the two perspectives is necessary both to ensure continued scientific progress and to provide society with the scientific means to face growing environmental challenges. Recent research on biodiversity and ecosystem functioning has contributed to this goal in several ways. By addressing a new question of high relevance for both science and society, by challenging existing paradigms, by tightly linking theory and experiments, by building scientific consensus beyond differences in opinion, by integrating fragmented disciplines and research fields, by connecting itself to other disciplines and management issues, it has helped transform ecology not only in content, but also in form. Creating a genuine evolutionary ecosystem ecology that links the evolution of species traits at the individual level, the dynamics of species interactions, and the overall functioning of ecosystems would give new impetus to this much-needed process of unification across ecological disciplines. Recent community evolution models are a promising step in that direction. © 2010 The Royal Society.

Fussmann G.F.,McGill University
Hydrobiologia | Year: 2011

Rotifers, both as individuals and as a phylogenetic group, are particularly worthwhile subjects for the study of evolution. Over the past decade molecular and experimental work on rotifers has facilitated major progress in three lines of evolutionary research. First, we continue to reveal the phylogentic relationships within the taxon Rotifera and its placement within the tree of life. Second, we have gained a better understanding of how macroevolutionary transitions occur and how evolutionary strategies can be maintained over millions of years. In the case of rotifers, we are challenged to explain the evolution of obligate asexuality (in the bdelloids) as mode of reproduction and how speciation occurs in the absence of sex. Recent research with bdelloid rotifers has identified novel mechanisms such as horizontal gene transfer and resistance to radiation as factors potentially affecting macroevolutionary change. Third, we are finding that microevolutionary change can be sufficiently rapid to interact with ecological dynamics. Rotifers can be easily cultured, reproduce quickly, and occur at high levels of clonal, genetic diversity in nature. These features make them excellent eukaryotic model systems for the study of eco-evolutionary dynamics. © Springer Science+Business Media B.V. 2010.

Vaezi M.,McGill University
IEEE Transactions on Information Theory | Year: 2013

In a recent paper [1], Rini et al. proved a capacity result for the discrete memoryless cognitive interference channel, under the condition named 'better cognitive decoding.' We show that this capacity region is the same as the capacity region characterized by Wu et al. in [2]. © 1963-2012 IEEE.

This study was designed to test the interaction between amyloid-β and tau proteins as a determinant of metabolic decline in preclinical Alzheimer’s disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-β1–42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-β and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-β plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-β PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.Molecular Psychiatry advance online publication, 29 March 2016; doi:10.1038/mp.2016.37. © 2016 Macmillan Publishers Limited

Kaya A.,McGill University | Kaya A.,Bogazici University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We obtain the exact renormalization group flow equation for a self-interacting real scalar field in an expanding cosmological background. The beta functional for the potential in the local potential approximation is determined in terms of the mode functions defining the vacuum of the theory. For a scalar in an inflating Universe, which is released in the Bunch-Davies vacuum, the flow equation is analyzed in detail using the optimized cutoff function for the quartically truncated potential. In that case, the constant term in the potential, which can in fact be viewed as the cosmological constant, decreases as the IR cutoff is removed, supporting the existence of a quantum mechanical screening mechanism. On the other hand, the running of the quartic coupling constant at IR is altered by the expansion, which seems to affect the quantum triviality of the theory. © 2013 American Physical Society.

Dairy foods contain complex nutrients which interact with the host. Yet, evolution of lactase persistence has divided the human species into those that can or cannot digest lactose in adulthood. Such a ubiquitous trait has differential effects on humanity. The literature is reviewed to explore how the divide affects lactose handling by lactase non persistent persons. There are two basic differences in digesters. Firstly, maldigesters consume less dairy foods, and secondly, excess lactose is digested by colonic microflora. Lactose intolerance in maldigesters may occur with random lactose ingestion. However, lactose intolerance without maldigestion tends to detract from gaining a clear understanding of the mechanisms of symptoms formation and leads to confusion with regards to dairy food consumption. The main consequence of intolerance is withholding dairy foods. However, regular dairy food consumption by lactase non persistent people could lead to colonic adaptation by the microbiome. This process may mimic a prebiotic effect and allows lactase non persistent people to consume more dairy foods enhancing a favorable microbiome. This process then could lead to alterations in outcome of diseases in response to dairy foods in lactose maldigesters. The evidence that lactose is a selective human prebiotic is reviewed and current links between dairy foods and some diseases are discussed within this context. Colonic adaptation has not been adequately studied, especially with modern microbiological techniques. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Scuccimarri R.,McGill University
Pediatric Clinics of North America | Year: 2012

Kawasaki disease is a systemic vasculitis and the leading cause of acquired heart disease in North American and Japanese children. The epidemiology, cause, and clinical characteristics of this disease are reviewed. The diagnostic challenge of Kawasaki disease and its implications for coronary artery outcomes are discussed, as are the recommended treatment, ongoing treatment controversies, concerns associated with treatment resistance, and the importance of ongoing follow up. © 2012 Elsevier Inc.

Black M.M.,University of Maryland Baltimore County | Aboud F.E.,McGill University
Journal of Nutrition | Year: 2011

Children throughout the world are confronted with growth problems ranging from underweight and stunting to overweight and obesity. The development of healthy eating behaviors depends on both healthy food and responsive parenting behaviors. With origins from anthropology, psychology, and nutrition, responsive parenting reflects reciprocity between child and caregiver, conceptualized as a 4-step mutually responsive process: 1) the caregiver creates a routine, structure, expectations, and emotional context that promote interaction; 2) the child responds and signals to the caregiver; 3) the caregiver responds promptly in a manner that is emotionally supportive, contingent, and developmentally appropriate; and 4) the child experiences predictable responses. This paper examines evidence for the practice and developmental benefits of responsive parenting with a view to providing a theoretical basis for responsive feeding. Recommendations are made that future efforts to promote healthy growth and to prevent underweight and overweight among young children incorporate and evaluate responsive feeding. © 2011 American Society for Nutrition.

Lam C.S.,McGill University | Lam C.S.,University of British Columbia
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

Using the group theory of mixing to examine all finite subgroups of SU(3) with an order less than 512, we found recently that only the group Δ(150) can give rise to a correct reactor angle θ13 of neutrino mixing without any free parameters. It predicts sin â¡22θ13=0.11 and a submaximal atmospheric angle with sinâ¡22θ 23=0.94, in good agreement with experiment. The solar angle θ12, the charge conjugation-parity phase δ, and the neutrino masses mi are left as free parameters. In this article we provide more details of this case and discuss possible gains and losses by introducing right-handed symmetries and/or valons to construct dynamical models. A simple model is discussed where the solar angle agrees with experiment and all its mixing parameters can be obtained from the group Δ(600) by symmetry alone. The promotion of Δ(150) to Δ(600) is, on one hand, analogous to the promotion of S3 to S4 in the presence of tribimaximal mixing, and on the other hand, it is similar to the extension from A4 to S4 in that case. © 2013 American Physical Society.

Cuello A.C.,McGill University
Neurochemical Research | Year: 2012

In this mini-review I summarize our research efforts in ascertaining the possible neuro-reparative properties of the GM1 ganglioside and its cooperative effects with NGF in stroke-lesion models. We also review aspects of our NGF investigations which have recently led to the discovery that NGF is released in an activity-dependent manner in the form of its precursor molecule, proNGF. These studies support the notion that in the CNS NGF metabolism conversion and degradation occur in the extracellular milieu. We have also validated this pathway in vivo demonstrating that the pharmacological inhibition of the pro-to mature NGF conversion results in the brain accumulation of proNGF and loss and atrophy of cortical cholinergic synapses. Furthermore, we have gathered neurochemical evidence for a compromise of this newly discovered NGF metabolic pathway in Alzheimer's disease, explaining the vulnerability of NGF-dependent forebrain cholinergic neurons in this disease despite normal NGF synthesis and abundance of NGF precursor. © Springer Science+Business Media, LLC 2012.

Lasko P.,McGill University
Wiley Interdisciplinary Reviews: RNA | Year: 2011

Molecular asymmetries underlying embryonic axis patterning and germ cell specification are established in Drosophila largely by position-dependent translational regulation of maternally expressed messenger RNAs. Here, I review several mechanisms of posttranscriptional regulation in the Drosophila oocyte and syncytial embryo, and how they relate to embryonic patterning, with a strong emphasis on the most recent advances in the area. The review is not exhaustive, but focuses on examples that illustrate the interplay between specific regulatory events and the general metabolic machinery that governs translation and mRNA stability. Biophysical investigations into how the Bicoid gradient is formed are discussed, as are the elaborate mechanisms controlling how the Oskar and Nanos proteins become restricted to the posterior pole of the embryo. Work on Vasa, a translational activator of some germ line mRNAs and on 4EHP, a negative regulator that unproductively binds the 5′ cap structure of target mRNAs, is also briefly reviewed. Finally, the emerging understanding of the role of microRNAs in regulating translation of germ line mRNAs is also discussed. © 2011 John Wiley & Sons, Ltd.

Naimi A.I.,McGill University
American Journal of Epidemiology | Year: 2015

Epidemiologists are increasingly using natural effects for applied mediation analyses, yet 1 key identifying assumption is unintuitive and subject to some controversy. In this issue of the Journal, Jiang and VanderWeele (Am J Epidemiol. 2015;182(2):105-108) formalize the conditions under which the difference method can be used to estimate natural indirect effects. In this commentary, I discuss implications of the controversial "cross-worlds" independence assumption needed to identify natural effects. I argue that with a binary mediator, a simple modification of the authors' approach will provide bounds for natural direct and indirect effect estimates that better reflect the capacity of the available data to support empirical statements on the presence of mediated effects. I discuss complications encountered when odds ratios are used to decompose effects, as well as the implications of incorrectly assuming the absence of exposure-induced mediator-outcome confounders. I note that the former problem can be entirely resolved using collapsible measures of effect, such as risk ratios. In the Appendix, I use previous derivations for natural direct effect bounds on the risk difference scale to provide bounds on the odds ratio scale that accommodate 1) uncertainty due to the cross-world independence assumption and 2) uncertainty due to the cross-world independence assumption and the presence of exposure-induced mediator-outcome confounders. © 2015 The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

Whitley R.,McGill University
Epidemiology and Psychiatric Sciences | Year: 2015

This paper introduces, describes and analyses the emerging concept of Global Mental Health (GMH). The birth of GMH can be traced to London, 2007, with the publication of a series of high-profile papers in The Lancet. Since then, GMH has developed into a movement with proponents, adherents, opponents, an ideology and core activities. The stated aims of the Movement for GMH are 'to improve services for people living with mental health problems and psychosocial disabilities worldwide, especially in low-and middle-income countries where effective services are often scarce'. GMH could be considered an attempt to right a historic wrong. During the colonial and post-colonial eras, the mental health of subject populations was accorded a very low priority. This was fuelled by scientific racism, which alleged that mental illness was uncommon in places such as Africa. As developing nations have made the epidemiological transition, the burden of mental illness has proportionately increased, with research suggesting a massive 'treatment gap' between those in need and those actually receiving formal mental health care. As such, much GMH research and action has been devoted to: (i) the identification and scale-up of cost-effective evidence-supported interventions that could be made more widely available; (ii) task-shifting of such intervention delivery to mental-health trained non-specialist Lay Health Workers. GMH has come under sustained critique. Critics suggest that GMH is colonial medicine come full circle, involving the top-down imposition of Western psychiatric models and solutions by Western-educated elites. These critiques suggest that GMH ignores the various indigenous modalities of healing present in non-Western cultures, which may be psychologically adaptive and curative. Relatedly, critics argue that GMH could be an unwitting Trojan horse for the mass medicalisation of people in developing countries, paving the way for exploitation by Big Pharma, while ignoring social determinants of health. © 2015 Cambridge University Press.

Candida glabrata is the second most important human fungal pathogen. Despite its formal name, C. glabrata is in fact more closely related to the nonpathogenic budding yeast Saccharomyces cerevisiae. However, less is known about the biology of this pathogen. Zinc cluster proteins form a large family of transcriptional regulators involved in the regulation of numerous processes such as the control of the metabolism of sugars, amino acids, fatty acids, as well as drug resistance. The C. glabrata genome encodes 41 known or putative zinc cluster proteins, and the majority of them are uncharacterized. We have generated a panel of strains carrying individual deletions of zinc cluster genes. Using a novel approach relying on tetracycline for conditional expression in C. glabrata at the translational level, we show that only two zinc cluster genes are essential. We have performed phenotypic analysis of nonessential zinc cluster genes. Our results show that two deletion strains are thermosensitive whereas two strains are sensitive to caffeine, an inhibitor of the target of rapamycin pathway. Increased salt tolerance has been observed for eight deletion strains, whereas one strain showed reduced tolerance to salt. We have also identified a number of strains with increased susceptibility to the antifungal drugs fluconazole and ketoconazole. Interestingly, one deletion strain showed decreased susceptibility to the antifungal micafungin. In summary, we have assigned phenotypes to more than half of the zinc cluster genes in C. glabrata. Our study provides a resource that will be useful to better understand the biological role of these transcription factors. Copyright © 2014 Klimova et al.

Hudson R.,McGill University
Synlett | Year: 2013

(A) AzideAlkyne Click Reaction Under homogeneous copper(I) conditions, this reaction can occur at room temperature in water. 4 Under heterogeneous conditions, the reaction requires either 70 °C temperature5 or the addition of a ligand such as 2,2-bipyridine. 6 (B) CC Cross-Coupling Panda and co-workers7 demonstrated a synergistic effect between copper and iron within the CuFe2O 4 lattice to catalyze the coupling of terminal alkynes with aryl halides. Neither CuO NPs, nor Fe3O4 NPs alone, could catalyze the transformation as effectively. (C) CN Cross-Coupling Panda and co-workers8 again demonstrated a synergistic effect between copper and iron, this time in the CuFe2O4 NP-catalyzed coupling of N-heterocycles with aryl halides. (D) CO Cross-Coupling The Sun group9 effectively coupled aryl halides with phenols to generate the corresponding biaryl ethers by catalysis with CuFe2O4nanoparticles. (E) CS Cross-Coupling The coupling under basic conditions and elevated temperatures of aryl halides with either aromatic thiols or diaryl suphides afforded the corresponding diaryl sulphide in excellent yields. The catalytic efficiency of various [M]Fe2O 4 nanoparticles were compared and M = copper was found to be the most reactive for this transformation.10 (F) CSe Cross-Coupling Various diaryl selenides were synthesized by the coupling of aryl halides with diaryl diselenides. The reaction required the use of a base and temperatures of 120°C. 11 (G) Sugar Deacylation Various protected sugars were deacylated with copper ferrite nanoparticles under mild conditions. By altering the solvent and reducing the reaction time, selective deacylation at the anomeric position could be achieved. 12 (H) A3 Coupling The three-component, one-pot coupling of aldehyde, alkyne, and amine was reported. Although A3 coupling has already been achieved for Fe 3O4 nanoparticles, substituting copper within the lattice enabled the use of milder conditions. 13 (I) Biginelli Condensation In another demonstration of a three-component one-pot reaction, the Biginelli condensation between an aldehyde, urea or thiourea, and ?- ketoesters was achieved with CuFe2O4 NPs to afford the corresponding dihydropyrimidinones or dihydropyrimidinthiones. 14 (J) Asymmetric Hydrosilylation With the aid of a chiral BINAP ligand, CuFe2O 4 NPs have catalyzed the asymmetric hydrosilylation of prochiral ketones, which afforded the corresponding alcohols upon TBAF workup. 15 © Georg Thieme Verlag Stuttgart. New York.

The surface of semiconductor nanocrystals is one of their defining features by virtue of their nanometer size. Yet the surface is presently among the most poorly understood aspects of nanocrystal science. This perspective provides an overview of spectroscopic work that has revealed the first insights into the nature of the surface, focusing upon CdSe nanocrystals. We focus on two aspects of surface processes in nanocrystals: the kinetics of surface trapping and the thermodynamics of core/surface equilibria. We describe femtosecond pump/probe spectroscopic experiments which reveal the signatures of carrier trapping at the surface. We also describe temperature dependent steady-state photoluminescence experiments which reveal new aspects of the surface. This work suggest that the surface emission is largely driven by homogeneous broadening via phonon progressions. The implications are that the surface electronic state bears similarity to the quantized excitonic core of the nanocrystal. © 2014 Elsevier B.V. All rights reserved.

Dewan S.,University of California at Irvine | Ramaprasad J.,McGill University
Information Systems Research | Year: 2012

Online social media such as blogs are transforming how consumers make consumption decisions, and the music industry is at the forefront of this revolution. Based on data from a leading music blog aggregator, we analyze the relationship between music blogging and full-track sampling, drawing on theories of online social interaction. Our results suggest that intensity of music sampling is positively associated with the popularity of a blog among previous consumers and that this association is stronger in the tail than in the body of music sales distribution. At the same time, the incremental effect of music popularity on sampling is also stronger in the tail relative to the body. In the last part of the paper, we discuss the implications of our results for music sales and potential long-tailing of music sampling and sales. Put together, our analysis sheds new light on how social media are reshaping music sharing and consumption. © 2012 INFORMS.

Brown K.A.,McGill University
Paediatric Anaesthesia | Year: 2011

Adenotonsillectomy is the mainstay of treatment for pediatric obstructive sleep apnea syndrome (OSAS). However, there is evidence that the child with severe OSAS is at increased risk of respiratory compromise. The most difficult risk factor to assess is the severity of OSAS, and these difficulties are reviewed. © 2011 Blackwell Publishing Ltd.

Giguere P.,Laval University | Dudek G.,McGill University
IEEE Transactions on Robotics | Year: 2011

This paper describes a tactile probe designed for surface identification in a context of all-terrain low-velocity mobile robotics. The proposed tactile probe is made of a small metallic rod with a single-axis accelerometer attached near its tip. Surface identification is based on analyzing acceleration patterns induced at the tip of this mechanically robust tactile probe, while it is passively dragged along a surface. A training dataset was collected over ten different indoor and outdoor surfaces. Classification results for an artificial neural network were positive, with an 89.9% and 94.6% success rate for 1- and 4-s time windows of data, respectively. We also demonstrated that the same tactile probe can be used for unsupervised learning of terrains. For 1-s time windows of data, the classification success rate was only reduced to 74.1%. Finally, a blind mobile robot, performing real-time classification of surfaces, demonstrated the feasibility of this tactile probe as a guidance mechanism. © 2011 IEEE.

Zappitelli M.,McGill University
Pediatric Nephrology | Year: 2013

Early acute kidney injury (AKI) diagnosis in critically ill children has been an important recent research focus because of the known association of AKI with poor outcomes and the requirement of early intervention to mitigate negative effects of AKI. In children having surgery, the preoperative period offers a unique opportunity to predict postoperative acute kidney injury (AKI), well before AKI occurs. Pediatric AKI epidemiologic studies have begun to identify which preoperative factors may predict development of postoperative cardiac surgery. Using these clinical risk factors, it may be possible to derive preoperative clinical risk scores and improve upon our ability to risk-stratify children into AKI treatment trials, pre-emptively provide conservative renal injury prevention strategies, and ultimately improve patient outcomes. Developing risk scores requires rigorous methodology and validation before widespread use. There is little information currently on the use of preoperative biological or physiological biomarkers to predict postoperative AKI, representing an important area of future research. This review will provide an overview of methodology of preoperative risk score development, discuss pediatric-specific issues around deriving such risk scores, including the combination of preoperative clinical and biologic biomarkers for AKI prediction, and suggest future research avenues. © 2012 IPNA.

Nijnik A.,McGill University
Current Opinion in Microbiology | Year: 2013

With increasing pathogen resistance to antibiotics, population ageing, and threat of pandemics there is a strong interest in the development of new approaches for the treatment of infectious diseases. Immunomodulatory therapies are defined as interventions that target the host rather than the pathogen, modulating the immune response with the aim of disease prevention or treatment. Our growing understanding of the immune system continues to offer novel drug targets and approaches for immunomodulatory interventions. In this review we will cover prominent examples of immunomodulatory therapies already in clinical use, as well as the recent advances in the development of new immunomodulators in ongoing clinical trials. © 2013 Elsevier Ltd.

In providing palliative and end-of-life care, professional and lay hospice workers alike attend to patient and family needs to encourage a dignified death. However, there are few comparative inquiries documenting how differential workplace preparation affects the processes and outcomes related to being confronted to death and dying. This qualitative study explores and compares these experiences among a diverse sample of health workers (N=25) in a grassroots cancer care hospice in Bangalore, India. Our findings underscore how personal views, socio-economic status, beliefs and values, occupational experience, and workplace interventions interact to shape 'worldviews' about death and dying. Whereas health workers report conflicting feelings of relief and sadness when confronted with the death of their patients, these mixed emotions are often lessened through open dialogue among newly trained and more experienced health workers. Moreover, experienced hospice workers wished to ensure that less experienced ones are provided with the necessary workplace support to lessen psychological 'hardening' that may occur with repeated exposure to death. In dealing with the diverse needs of hospice workers, both individual and collective needs must be considered to ensure an optimal workplace climate. Future work should study how hospice workers' views on death and dying evolve with time and experience. © The Author(s) 2011.

Foulkes W.D.,McGill University | Smith I.E.,Institute of Cancer Research | Reis-Filho J.S.,Institute of Cancer Research
New England Journal of Medicine | Year: 2010

A PUBMED SEARCH OF THE MEDICAL LITERATURE SHOWS THAT THE FIRST mention of "triple-negative" breast cancer was in October 2006; since then, the term has appeared in more than 600 publications.1 This increase reflects the growing recognition of the importance of triple-negative breast cancer (see the Glossary for this and other key terms) by oncologists, pathologists, and geneticists, as well as by the approximately 12 to 17% of women with breast cancer who have triple-negative breast cancer. As a group, patients with triple-negative tumors have a relatively poor outcome and cannot be treated with endocrine therapy or therapies targeted to human epidermal growth factor receptor type 2 (HER2). A close cousin of triple-negative breast cancer is basal-like breast cancer (synonymous terms include "basal-type," "basal-epithelial phenotype," "basal breast cancer," and "basaloid breast cancer"). This molecular subtype of breast cancer is characterized by a gene-expression profile that is similar to that of the basal-myoepithelial layer of the normal breast. 2 Immunohistochemical markers have been used as a surrogate for this profile. The multiplicity of names reflects an underlying uncertainty as to the true nature of this entity. Copyright © 2010 Massachusetts Medical Society.

Tallon P.P.,Charles University | Pinsonneault A.,McGill University
MIS Quarterly: Management Information Systems | Year: 2011

Strategic information technology alignment remains a top priority for business and IT executives. Yet with a recent rise in environmental volatility, firms are asking how to be more agile in identifying and responding to market-based threats and opportunities. Whether alignment helps or hurts agility is an unresolved issue. This paper presents a variety of arguments from the literature that alternately predict a positive or negative relationship between alignment and agility. This relationship is then tested using a model in which agility mediates the link between alignment and firm performance under varying conditions of IT infrastructure flexibility and environmental volatility. Using data from a matched survey of IT and business executives in 241 firms, we uncover a positive and significant link between alignment and agility and between agility and firm performance. We also show that the effect of alignment on performance is fully mediated by agility, that environmental volatility positively moderates the link between agility and firm performance, and that agility has a greater impact on firm performance in more volatile markets. While IT infrastructure flexibility does not moderate the link between alignment and agility, except in a volatile environment, we reveal that IT infrastructure flexibility has a positive and significant main effect on agility. In fact, the effect of IT infrastructure flexibility on agility is as strong as the effect of alignment on agility. This research extends and integrates the literature on strategic IT alignment and organizational agility at a time when both alignment and agility are recognized as critical and concurrent organizational goals.

Oswin N.,McGill University
Environment and Planning D: Society and Space | Year: 2010

During a 2007 reform of Singapore's Penal Code, Prime Minister Lee Hsien Loong rejected calls by gay and lesbian activists for the removal of a colonial-era statute that prohibits 'gross indecency' between two men. This paper critically responds to the perpetuation of this illiberal sexual politics by exploring heteronormativity in the city-state as a colonial trace. It takes a postcolonial queer approach that combines insights from work on the globalization of sexuality, histories of colonialism, and postcolonial development geographies to interrogate the sedimentation of heteronormativity in Singapore over its late-colonial and early-postcolonial periods. Emphasis is placed on the role of colonized elites in transforming an entrepot of single male migrant workers into a nation of nuclear families. By attending to the contingent materialities of colonial governance through an examination of the intimate politics advanced by local colonial actors, the legacy of heteronormativity in Singapore is revealed to be about much more than heterosexuality and homosexuality. As such, it is argued that an approach that goes beyond sexuality per se to disrupt the progress narrative on which heteronormativity in Singapore relies might therefore be a useful way to challenge the narrow imagination of intimate possibilities. © 2010 Pion Ltd and its Licensors.

Davies Jonathan T.,McGill University | Buckley L.B.,University of North Carolina at Chapel Hill
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Phylogenetic diversity (PD) captures the shared ancestry of species, and is increasingly being recognized as a valuable conservation currency. Regionally, PD frequently covaries closely with species richness; however, variation in speciation and extinction rates and/or the biogeographic history of lineages can result in significant deviation. Locally, these differences may be pronounced. Rapid recent speciation or high temporal turnover of lineages can result in low PD but high richness. In contrast, rare dispersal events, for example, between biomes, can elevate PD but have only small impact on richness. To date, environmental predictors of species richness have been well studied but global models explaining variation in PD are lacking. Here, we contrast the global distribution of PD versus species richness for terrestrial mammals. We show that an environmental model of lineage diversification can predict well the discrepancy in the distribution of these two variables in some places, for example, South America and Africa but not others, such as Southeast Asia. When we have information on multiple diversity indices, conservation efforts directed towards maximizing one currency or another (e.g. species richness versus PD) should also consider the underlying processes that have shaped their distributions. © 2011 The Royal Society.

Modi S.B.,University of Toledo | Mishra S.,McGill University
Journal of Operations Management | Year: 2011

Extant research in operations management has revealed divergent insights into the value potential of resource efficiency. While one view relates efficiency with good operations management and asserts that slack resources are a form of waste that should be minimized, the other view suggests that limited resource slack can impose heavy costs on firms by making them brittle. In this research, the authors build on these views to investigate the relationship of inventory, production, and marketing resource efficiency of firms with three metrics of financial performance (i.e., Stock-Returns, Tobin's Q, and Returns-on-Assets). The authors evaluate the theoretical framework using secondary information on all U.S. based publicly-owned manufacturing firms across the 16-year time period of 1991-2006. Analysis utilizing a mixed-model approach reveals that a focus on resource efficiency is positively associated with firm financial performance. However, findings also support the arguments favoring slack, indicating that the financial gains from resource efficiency exhibit diminishing returns. © 2011 Elsevier B.V. All rights reserved.

MacKenzie C.A.,McGill University
Journal for Nature Conservation | Year: 2012

Revenue sharing aims to balance the disadvantages people encounter living next to protected areas while fostering improved conservation behaviours. In Uganda, 20% of protected area entrance fees are shared with local governments to benefit communities adjacent to national parks. The process to distribute funds and implement projects was investigated by interviewing Uganda Wildlife Authority wardens, local government and village residents around Kibale National Park, Uganda. The perceived benefit of revenue sharing by officials and local communities was collected through interviews and a household survey, while the influence of the program on conservation objectives was assessed by measuring illegal resource extraction from the national park adjacent to study villages. It was found that the program is evolving into an effective mechanism for sharing benefits, but that better project management and increased accounting transparency could further improve the program. If the projects specifically dealt with the problem of crop raiding by park-protected animals, then villagers did benefit and lower levels of illegal activity were found inside the park. Generally household perceived benefit was low, however reduced in-park illegal activity was recorded where the village chairperson perceived higher benefit from the program, implying that the village leadership may be influencing the conservation behaviours within the community. Compared with other incentive options such as loss compensation, direct payment, and collaborative management, revenue sharing appears to be an effective and practical choice, given the limited funding available to the wildlife authority to benefit local communities while trying to improve conservation behaviours. © 2011 Elsevier GmbH.

Cooperstock J.,McGill University
IEEE Signal Processing Magazine | Year: 2011

Significant uses of immersive communication systems include support for group design activities in a -distributed context, combining human-human communication and interactivity with synthetic computer-generated content, such as threedimensional (3-D) models or visualizations. As the demands of distributed human communication and simultaneous interaction with synthetic media continue to expand into new collaborative applications, including surgical planning, simulation training, and entertainment, we see a growing need to improve upon the state of the art of the associated technologies. To this end, we consider the demands on next-generation telepresence systems to support some of the most demanding collaborative human activities. Specifically, we explore the communications requirements for tightly coupled activities in a shared reality environment, where distributed users are free to move about their physical spaces, and interact with one another as if physically copresent. © 2010 IEEE.

Lock M.,McGill University
Science Technology and Human Values | Year: 2011

As genetic tests become cheaper and more readily available, pressure is increasing to routinely test individuals for susceptibility genes for complex common disorders. Using Alzheimer's disease (AD) as an illustrative example, it is shown how population databases of AD cases on which individual risk estimates are based are faulty due to confusion about the AD phenotype. Furthermore, the APOEe4 genotype associated with increased risk of AD is neither necessary nor sufficient to cause AD. The article concludes with ethnographic findings that result from interviews with individuals who have been tested for their APOE status. © The Author(s) 2011.

Sagan S.M.,McGill University | Sarnow P.,Stanford University
Science | Year: 2013

No longer elusive, mammalian antiviral RNA interference is now confirmed.

A recent addition to the anti-human immunodeficiency virus armamentarium of drugs is rilpivirine, which is a potent non-nucleoside reverse transcriptase inhibitor. This review focuses on the clinical utility of rilpivirine in terms of efficacy and virologic suppression, drug resistance, drug-drug interactions, and safety. The rilpivirine-tenofovir-emtricitabine combination is a safe and effective regimen for use in most patients who are ready to start first-line anti-human immunodeficiency virus therapy. Although drug resistance can be a problem in patients who initiate therapy on rilpivirine-based regimens with viral loads > 100,000 copies of viral RNA/mL, this problem can be alleviated by first starting therapy with efavirenz-tenofovir-emtricitabine for several months to suppress viral load to<50 copies/mL before switching to rilpivirine-based therapy. E138K is the most important mutation associated with resistance against rilpivirine and its development must be avoided whenever possible, because this mutation confers broad cross-resistance against all approved members of the non-nucleoside reverse transcriptase inhibitor family of drugs. © 2013 Wainberg.

Wang Q.S.,McGill University
Smart Materials and Structures | Year: 2010

In this paper, a finite element model incorporating active control techniques has been developed to stabilize the first two buckling modes of both a simply supported and a cantilevered beam. The goal is to increase the corresponding beam buckling loads by using piezoelectric actuators along with optimal feedback control. The uniform beams are bonded with two pairs of segmented piezoelectric actuators at the top and bottom. Resistive strain gauges are attached to the centres of the actuators as sensors. Measurements are taken using these, to estimate the system states. The beams are simply supported or cantilevered and subjected to a slowly increasing axial compressive load. Finite element formulations based on the classical Euler-Bernoulli beam theory and linear piezoelectric constitutive equations for the actuators are presented. The associated reduced-order modal equations and the state-space equations are derived for the design of a standard linear quadratic regulator (LQR). The finite element analysis and the active control simulation results are consistent with both theoretical analysis results and experimental data. The designed full state feedback LQR controller is shown to be successful in stabilizing the first two buckling modes of the beams. Also the control simulation shows that the present optimally located segmented actuator pairs along the beam are more effective for buckling control. © 2010 IOP Publishing Ltd.

Mahajan A.,McGill University
IEEE Transactions on Automatic Control | Year: 2013

Subsystems that are coupled due to dynamics and costs arise naturally in various communication applications. In many such applications the control actions are shared between different control stations giving rise to a control sharing information structure. Previous studies of control-sharing have concentrated on the linear quadratic Gaussian setup and a solution approach tailored to continuous valued control actions. In this paper a three step solution approach for finite valued control actions is presented. In the first step, a person-by-person approach is used to identify redundant data or a sufficient statistic for local information at each control station. In the second step, the common-information based approach of Nayyar (2013) is used to find a sufficient statistic for the common information shared between all control stations and to obtain a dynamic programming decomposition. In the third step, the specifics of the model are used to simplify the sufficient statistic and the dynamic program. © 1963-2012 IEEE.

Woolley M.J.,University of New South Wales | Clerk A.A.,McGill University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2014

We study theoretically a three-mode optomechanical system where two mechanical oscillators are independently coupled to a single cavity mode. By optimized two-tone or four-tone driving of the cavity, one can prepare the mechanical oscillators in an entangled two-mode squeezed state, even if they start in a thermal state. The highly pure, symmetric steady state achieved allows the optimal fidelity of standard continuous-variable teleportation protocols to be achieved. In contrast to other reservoir engineering approaches to generating mechanical entanglement, only a single reservoir is required to prepare the highly pure entangled steady state, greatly simplifying experimental implementation. The entanglement may be verified via a bound on the Duan inequality obtained from the cavity output spectrum. A similar technique may be used for the preparation of a highly pure two-mode squeezed state of two cavity modes, coupled to a common mechanical oscillator. © 2014 American Physical Society.

Lock M.,McGill University
BioSocieties | Year: 2013

The assumption of a rapidly spreading 'epidemic' of Alzheimer's disease (AD), the result of aging populations worldwide, coupled with no effective medication for this condition, has incited a move to bring about the prevention of AD before the appearance of clinical symptoms. The following discussion details the establishment of a research conglomerate designed to prevent AD by means of the systematic detection of biomarker changes in healthy middle-aged or younger people. Among the biomarkers currently being standardized are changes in amyloid-β in cerebrospinal fluid (CSF), and deposition of amyloid-β plaques in the living brain detectable by means of brain scans. Possession of one specific allele of the APOE gene is an additional biomarker. However, these molecular features are merely indicators of increased risk, and pre-symptomatic dementia cannot be definitively diagnosed on the basis of the presence of one or more of them. The composition, distribution, and function of the key molecule being tracked, amyloid-β, remains poorly understood and, highly significant, a large number of individuals with a heavy amyloid load in their brains live to old age with no behavioral signs of dementia. The concluding section considers preparations for a randomized controlled trial designed to detect and eliminate amyloid-β deposition very early in its formation. © 2013 Macmillan Publishers Ltd.

Stoljar N.,McGill University
Journal of Medicine and Philosophy | Year: 2011

The received view in medical contexts is that informed consent is both necessary and sufficient for patient autonomy. This paper argues that informed consent is not sufficient for patient autonomy, at least when autonomy is understood as a "relational" concept. Relational conceptions of autonomy, which have become prominent in the contemporary literature, draw on themes in the thought of Charles Taylor. I first identify four themes in Taylor's work that together constitute a picture of human agency corresponding to the notion of agency implicit in relational accounts of autonomy. Drawing on these themes, I sketch two arguments against the position that informed consent secures autonomy. The first is that informed consent is an " opportunity" concept whereas autonomy is an "exercise" concept; the second is that informed consent requires merely weak evaluation and not strong evaluation. On Taylor's analysis of agency, strong evaluation is required for agency and for autonomy. © 2011 The Author.

Rak J.,McGill University
Frontiers in Pharmacology | Year: 2013

In multicellular organisms both health and disease are defined by patterns of communication between the constituent cells. In addition to networks of soluble mediators, cells are also programed to exchange complex messages pre-assembled as multimolecular cargo of membraneous structures known extracellular vesicles (EV). Several biogenetic pathways produce EVs with different properties, and known as exosomes, ectosomes, and apoptotic bodies. In cancer, EVs carry molecular signatures and effectors of the disease, such as mutant oncoproteins, oncogenic transcripts, microRNA, and DNA sequences. Intercellular trafficking of such EVs (oncosomes) may contribute to horizontal cellular transformation, phenotypic reprograming, and functional re-education of recipient cells, both locally and systemically. The EV-mediated, reciprocal molecular exchange also includes tumor suppressors, phosphoproteins, proteases, growth factors, and bioactive lipids, all of which participate in the functional integration of multiple cells and their collective involvement in tumor angiogenesis, inflammation, immunity, coagulopathy, mobilization of bone marrow-derived effectors, metastasis, drug resistance, or cellular stemness. In cases where the EV role is rate limiting their production and uptake may represent and unexplored anticancer therapy target. Moreover, oncosomes circulating in biofluids of cancer patients offer an unprecedented, remote, and non-invasive access to crucial molecular information about cancer cells, including their driver mutations, classifiers, molecular subtypes, therapeutic targets, and biomarkers of drug resistance. New nanotechnologies are being developed to exploit this unique biomarker platform. Indeed, embracing the notion that human cancers are defined not only by processes occurring within cancer cells, but also between them, and amidst the altered tumor and systemic microenvironment may open new diagnostic and therapeutic opportunities. © 2013 Rak.

Identifying the best markers to judge the adequacy of lipid-lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid-lowering therapies are in development. Reductions in LDL-C, non-HDL-C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. We performed a random-effects frequentist and Bayesian meta-analysis of 7 placebo-controlled statin trials in which LDL-C, non-HDL-C, and apoB values were available at baseline and at 1-year follow-up. Summary level data for change in LDL-C, non-HDL-C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta-analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL-C; 20.0% (15.2%, 24.7%) for non-HDL-C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL-C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non-HDL-C (P<0.001). Similarly, in Bayesian meta-analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL-C or non-HDL-C (BFs ranging from 484 to 2380). Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo-controlled statin trials was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C.

Stephens D.A.,McGill University
International Journal of Public Health | Year: 2011

Introduction: In this article, we introduce Marginal Structural Models, which yield unbiased estimates of causal effects of exposures in the presence of time-varying confounding variables that also act as mediators. Objectives: We describe estimation via inverse probability weighting; estimation may also be accomplished by g-computation (Robins in Latent Variable Modeling and Applications to Causality, Springer, New York, pp 69-117, 1997; van der Wal et al. in Stat Med 28:2325-2337, 2009) or targeted maximum likelihood (Rosenblum and van der Laan in Int J Biostat 6, 2010). Conclusions: When both time-varying confounding and mediation are present in a longitudinal setting data, Marginal Structural Models are a useful tool that provides unbiased estimates. © 2010 Swiss School of Public Health.

Cybulsky A.V.,McGill University
Contributions to Nephrology | Year: 2011

The understanding of cellular and molecular mechanisms involved in the pathogenesis of membranous nephropathy (MN) has come from studies carried out in the Heymann nephritis model of MN in the rat, which closely resembles the clinical and pathologic features of the human disease. MN involves the in situ formation of subepithelial immune deposits as a result of circulating antibodies binding to podocyte antigens. Complement activation leads to assembly of C5b-9 on podocyte plasma membranes, and results in sublethal podocyte injury and proteinuria. The podocyte responds to sublethal C5b-9 attack by activating protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress pathways, proteinases, etc. These signals impact on cell metabolic pathways, the structure/function of lipids and key proteins in the cytoskeleton and slit diaphragm, and on the turnover of extracellular matrix components. Some effects of C5b-9, including dissolution of the actin cytoskeleton, loss of nephrin expression, reduction in F-actin-bound nephrin and loss of slit diaphragm integrity, affect podocytes adversely. Other effects of complement, such as endoplasmic reticulum stress, may limit injury or promote recovery. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of human MN, including the presence of autoantibodies directed to podocyte antigens in human MN. Increased understanding of nephritogenic antigens, complement activation, and the cellular signaling pathways and targets of C5b-9 will facilitate the design of new approaches to therapy of this important glomerular disease. Copyright © 2011 S. Karger AG, Basel.

Magder S.,McGill University
Current Opinion in Critical Care | Year: 2011

Purpose of Review: Interactions between the heart and lungs are magnified in patients undergoing mechanical ventilation and the consequences of these interactions always need to be considered when managing ventilated patients. In patients with normal lungs and normal cardiovascular function monitoring needs are minimal, but when oxygenation and cardiac function are compromised careful assessment of the consequences of changes in ventilator settings needs to be considered to ensure that adequate oxygen delivery is maintained. Recent Findings: Primary determinants of heart-lung interactions are first reviewed and then approaches to the use of simple hemodynamic measurements such as respiratory variations in central venous and pulmonary artery occlusion, or arterial pressure are described for assessing oxygen delivery, volume responsiveness as well as indicators of ventilatory mechanics. Summary: Use of simple measurements available during routine monitoring can be very helpful to the informed clinician for optimizing hemodynamic performance as well as patient ventilator interactions. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.