IMS Magazine Winter 2014

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Cardiovascular Disease Depression

Dr. Ravindran discusses the multifactorial etiology of this disorder


Personal genome sequencing in the limelight


with new Associate Director Mingyao Liu

Student-Led Initiative

Cover design by Brendan Polley; Photo of 3D heart model courtesy of Michael Corrin; Viewpoint Photo courtesy of; ID # 17061678.

IN THIS ISSUE... Commentary ................................... Letter from the Editor ...................... News and Views ............................ Director’s Message ........................ Feature ........................................... Spotlight: ........................................ Expert Opinion ................................ Book Reviews ................................. Close-up ......................................... Viewpoint ........................................ Behind the Scenes ......................... SURP Winners ................................ Future Directions ............................ Ask the Experts .............................. Past Events ..................................... Diversions .......................................

04 07 08 11 12 22 24 26 28 30 34 36 38 39 40 41


Cardiovascular Disease

MAGAZINE STAFF Editor-in-Chief Managing Editors Departmental Advisors Design Editors

Promotions & Advertising

Content Committee


Social Media

Adam Santoro Nancy Butcher Anna Podnos Marika Galadza Mary Seeman Catherine Au-Yeung YiChun Lin Brendan Polley Andrew Q Tran Andrew Tubelli Kimberly Blom Gray Moonen Leon Parasaud Anna Badner Brittany Campbell Jill Cates Danielle Cha Robert Civitarese Yekta Dowlati Sarah Gagliano Kasey Hemington Natasha Jawa Susy Lam Winny Li Joshua Lipszyc Chelsea Lowther Rebecca Ruddy Katherine Schwenger Annette Ye Chung Ho Leung Laura Feldcamp Matthew Wu Stephen Wu


Viewpoint: 23andme

Kasey Hemington explores the consequences of personal genetic information in the hands of consumers.


Copyright © 2014 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

Behind the Scenes with Michelle Rosen

A glimpse into the life of Michelle Rosen as she takes on her new role as IMS’ Curriculum Coordinator.


The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Cover design by Andrew Q Tran




Cardiovascular Disease Depression

Dr. Ravindran discusses the multifactorial etiology of this disorder


Personal genome sequencing in the limelight


with new Associate Director Mingyao Liu

Student-Led Initiative


y r a t n

e m

m o C

Mental health issues in academia Dear Editor, In the last issue of the IMS Magazine, the world-class research being undertaken by faculty and students in the Institute of Medical Science on mood disorders took center stage. Topics ranged from pathophysiology to treatment to the debilitating stigma that continues to surround mental illnesses. The article by Drs. Thomas Ungar and Rivian Weinerman was well-illustrative of the challenges still too often faced by people affected by a mental illness, including the significant barrier of stigma in seeking support and treatment. In our fast-paced academic culture, the barriers to treatment for mental illnesses– and their prevalence–also warrant careful consideration. Graduate students may be a particularly vulnerable group.1 Social isolation, financial hardship, and the expectation to rapidly produce high calibre research among other pressures seems an ideal breeding ground for significant mental health challenges. Research studies are too few and far between, but there is a growing awareness that this is a considerable but under-recognized problem facing graduate schools today. For example, a study of over 3 000 graduate students at the University of California found that 67% of respondents felt hopeless at least once in the last year,

Why we are failing our Aboriginal mothers

54% felt so depressed that they had a hard time functioning, and nearly 10% said they had seriously considered suicide.2 Increased awareness and discussion of these challenges to students is an important first step. It may be difficult for students (and their advisors) to recognize that help is needed, ranging from adjustments in lifestyle to therapy to antidepressant treatments. Stress is a normal part of training, but changes in behavior and personality such as an inability to attend class or do research, difficulty concentrating, decreased motivation, increased irritability, sleep disturbances, changes in appetite or energy levels, or increased social withdrawal can be important indicators.1 Addressing these issues head on, and without the stigma, may help us pave the way for happier and more productive students. - Nancy Butcher, M.Sc.

References 1. Gewin V. Mental health: Under a cloud. Nature. 2012;490(7419):299-301. 2. Berkeley Graduate Student Mental Health Survey. Berkeley graduate student mental health survey. University of California, Berkeley. 9 December 2004.


Dear Editor, In the last issue of the IMS Magazine we explored mood disorders and the stigma surrounding mental illness. One of the main mood disorders, major depression, occurs twice as frequently in women as it does in men and has a devastating effect on health, happiness, and productivity. Aboriginal mothers who are removed from their communities to give birth due to inadequate access to health care near their homes have high rates of post-partum depression, and this has a severe negative impact on infant health and development. Aboriginal women in Canada are suffering from a lack of equitable access to culturally appropriate midwifery, and this is resulting in higher risks of adverse pregnancy and poorer infant health outcomes when compared to the general Canadian population.1 Aboriginals are the fastest growing segment of the Canadian population, and almost half of them are under the age of 25. Not only are Aboriginal mothers younger than non-Aboriginal Canadian women, they are also having almost twice as many babies on average, and these babies tend to have high birth weight, which can be associated with infant birth trauma, asphyxia, and metabolic complications. Together with the major disparities in health status, housing, education, and food security and nutrition, it is clear that Aboriginal Canadians should be an important priority—not only for Canada, but also for the rest of the world, since infant mortality rate is the single most comprehensive indicator of the level of health development in a society and is recognized internationally in its inclusion in the World

COMMENTARY Call for Articles

Health Organization’s Millennium Development Goals.2 Regrettably, we cannot even accurately estimate infant mortality, pre-term birth, still births, and maternal deaths during childbirth in Aboriginal Canadian communities due to the lack of data collection. Some reports indicate that still birth, infant mortality, and perinatal death rates for Aboriginal children are about double the Canadian average. Aboriginal women are at nearly twice the risk for maternal mortality compared to the overall Canadian population. There is a consistent lack of funding allocated to providing accessible care to the Aboriginal Canadians, especially remote and poverty-stricken communities. For example, Health Canada has recently eliminated funding to the Women’s Health Contribution Program, which supported on-reserve Aboriginal programming for maternal and infant health, as well as treatment for pregnant women and mothers addicted to drugs or alcohol.3 A majority of pregnant Aboriginal women from rural, isolated regions spend at least the last four weeks of pregnancy outside their communities, often without the baby’s father and extended families for support.4 Given that in all Aboriginal cultures experienced midwives traditionally attend births, the removal of births from many Aboriginal communities has had profound spiritual and cultural consequences that have been linked to the loss of cultural identity. When women are separated from the support of their families and communities, there is an increase in small, premature infants, as well as maternal and newborn complications, including postpartum depression.5 Providing women with access to culturally appropriate midwifery in their own communities could help improve the health of mothers and infants in a holistic way. An Aboriginal midwife is not only a primary health care provider who cares for pregnant women, babies, and their families throughout pregnancy and for the first weeks in the postpartum, but she also a promotes breastfeeding, nutrition, and passes on important values about health to the next generation.

Having birthing centres and trained midwives in marginalized Aboriginal communities could focus on low-risk pregnancies, with healthy mothers delivering healthy babies. Recently, a step in this direction was taken by opening the Toronto Birthing Centre in Regent Park, where women deliver babies in the care of their own midwives. Aboriginal women living in urban areas, such as Toronto, may be disconnected from their historical roots, so having a birthing centre provides a space “that speaks to them, and to their needs, and their philosophies, and their world views.”6 Although this does not address the issue of access to culturally appropriate maternal and infant health care for people living in remote northern communities, it has the potential to inform us about practices that work best to solve indigenous health care issues. As an Ojibwa woman who gave birth at the Toronto Birthing Centre recalled in a Toronto Star interview, “Having midwives open to including First Nations’ traditions in the delivery made all the difference in feeling comfortable with giving birth.”6 The need for culturally appropriate midwifery in remote Canadian communities is clear—Aboriginal mothers are an especially vulnerable part of our population, and their needs should be addressed in a holistic and effective way—and it is time to speak up about this issue. - Anna Podnos, B.Sc., Ph.D. Candidate


The IMS Magazine is looking for scientific content to post on the IMS Magazine website. Whether you are a current blogger looking to cross-post your scientific musings, or are just looking to get your ideas out there on our platform, your submissions are welcome. Submissions are expected to be approximately 800 words in length (with considerable leeway) and priority will be given to individuals who comment and report on IMS specific issues (i.e. research in the department, conferences, general scientific issues that affect the IMS faculty and students, etc.) although viewpoints and commentaries are also welcome. Send an email to for more information.

Contact Us We encourage our readers to send their feedback, comments, questions, corrections, and letters to the editor to Please also visit us at Engage in dialogue with fellow IMS students and faculty, and even post your own article to our website. We are always looking for IMS student journalists to contribute to our content, whether they wish to discuss new research around the IMS, or wish to comment on a controversial topic in science and scientific training.

1. First Nations and Inuit Health. Health Canada. 2013. Available from: 2. The Millenium Development Goals. Women and Children First. 2014. Available from: 3. Health Canada’s Women’s contribution program cut. Winnipeg Free Press. 2012. Available from: 4. Healthier mothers and babies. Canadian Public Health Association. Available from: 5. Midwifery and Aboriginal Midwifery in Canada. National Aboriginal Health Organization. 2004. Available from: documents/naho/english/publications/DP_aboriginal_midwifery.pdf 6. Aboriginal health care: Toronto’s first stand-alone birth centre geared to cultural practices. The Toronto Star. August 28, 2013. Available from: gta/2013/08/28/aboriginal_health_care_torontos_first_standalone_birth_centre_geared_to_ cultural_practices.html

Disclaimer: The opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science of the University of Toronto. Comments are welcome at theimsmagazine@ @IMSMagazine



Letter from the Editor A

7 MINUTES FROM A STROKE OR HEART DISEASE. ACCORDING TO THE CONFERENCE BOARD OF Canada, $20.9 is spent covering the cost of these health events every year. These staggering numbers are a testament to the impact of cardiovascular disease (CVD) and illustrate how disease prevention and treatment are primary avenues of pursuit in our society. Wonderful organizations, such as the Heart and Stroke Foundation of Canada, put immense efforts into informing the public about CVD risks and prevention strategies, investing in CVD research, and advocating for better public health policies. Within the Institute of Medical Science (IMS) a number of world-class physicians and scientists are working to bring us one step closer to a healthier population. In this issue of the IMS Magazine we highlight some of the research going on in the department and are proud to feature Drs. Anne Bassett, Andrea Kassner, Joel Ray, Ravi Retnakaran, and Valerie Taylor, who focus on such topics as CVD and mental health, CVD in women, and best practices and rehabilitation. PERSON DIES EVERY

Continuing our fan-favorite viewpoint articles, Kasey Hemington writes about the controversial “Personal Genome Service” offered by 23andMe and highlights the ethical and psychological issues that necessarily attach themselves to these services. In a second viewpoint, I follow up on Amanda Ali’s opinions from a previous issue (see: “Publish or Perish”) and take another look at the problems facing scientific publishing, as recently highlighted by The Economist. Faculty and students will see more from behind the scenes in IMS with wonderful interviews with new Associate Director Mingyao Liu and water polo champion Michelle Rosen. Dr. Candice Silversides is featured in a spotlight article, and we get an update from some students who went to Honduras for a volunteerism trip.

Adam Santoro

Editor-In-Chief Adam Santoro is a fourth year graduate student in the IMS studying memory consolidation under the supervision of Dr. Paul Frankland at The Hospital for Sick Children.

It is with pride that I take over the reins of the IMS Magazine, and with sadness that I announce the departure of the magazine’s inaugural Editor-in-Chief Natalie Venier. The magazine grew from but a seed in Natalie’s mind to an absolutely wonderful publication that has captured the attention of so many within and outside IMS. Natalie and her “partner-in-crime”—outgoing managing editor Nina Bahl—set and met extremely high standards. With the infrastructure they established and their ongoing behind-the-scenes support, I am confident our team can bring the IMS Magazine to new heights. I would like to thank Dr. Allan Kaplan and the entire IMS department for their ongoing support and for their help and patience during our recent restructuring. Lastly, the magazine would not exist without the excellent contributions from our entire magazine committee, from the enriching content provided by our journalists, to the attentive editing of our editors, to the magnificent design by the design team. Like always, we strongly encourage feedback—whether by email, through our website, or in person. Enjoy! Adam Santoro Editor-In-Chief, IMS Magazine


News&Views at a glance... ANNOUNCEMENTS: The IMS is pleased to announce Michelle Rosen has accepted the full time appointed position of Curriculum and Communications Coordinator. Michelle has been with the IMS since June 2012 serving in various roles including interim Student and Faculty Affairs Coordinator and more recently as Curriculum Coordinator. Michelle’s long time experience at the University of Toronto as a student and staff member since 2006 prove to be a great asset. When Michelle is not coordinating course modules, verifying MSC1010/1011 Y requirements or re-jigging the website, she is at home with her two cats, Lily and Marsha, or playing waterpolo for Toronto Triggerfish. Last year Michelle’s waterpolo team won gold at the World Out Games competition in Antwerp, Belgium. We are very pleased to welcome Michelle as a permanent member of the IMS team. Please join us in celebrating this new addition to the IMS administration.

In Memoriam: James Sharpe Dr. James Sharpe (IMS member since 2002) died peacefully at age 72, on November 12th, 2013. Dr. Sharpe made significant contributions to the IMS community serving as a Laidlaw Manuscript Judge, awards committee member, and IMS course Director from 2008-2009 among other activities. Dr. Sharpe supervised many students during his years at IMS, including current IMS faculty member and Professor of Ophthalmology, Dr. Agnes Wong. He graduated a Doctor of Medicine from the University of Western Ontario in 1966. As a dedicated clinical neurologist, research scientist, and author he achieved world-renown and made scientific contributions in the areas of ocular motor disorders, vestibular disorders, and visual perception. He served as head of Neurology at the University of Toronto (1988-1998) and the University Health Network (1988-1996), as president of the North American Neuro-Ophthalmology Society, and as editor of the Canadian Journal of Neurological Sciences. Donations can be made to the “Dr. James A. Sharpe Endowment Fund” at the Toronto General and Western Hospital Foundation which will go towards Neural and Sensory research programs. To donate please contact: 416-340-4430 or 1-877-846-4483.



10 Last day to hold MSc or PhD defense for students wishing to convocate in June 2014


18 University closed for Good Friday


SCIENTIFIC DAY 2014 The Annual Scientific Day is the academic highlight of the year. It is designed to highlight student achievements, provide opportunities to work on presentation skills, and encourage student and faculty interaction. Scientific Day includes the Alan Wu Poster competition, Laidlaw Manuscript and Oral presentation competition, as well as an awards ceremony recognizing IMS faculty and students. Venue for this year’s Scientific Day will be announced shortly. All IMS students are required to present their research at Scientific Day once during their academic career at IMS (either an Alan Wu poster presentation or Laidlaw oral presentation). Students who presented at Scientific Day in their MSc and then transferred or pursued a PhD at IMS are not required to present again.

Are you an IMS faculty member looking to get more involved at IMS ? We have many faculty engagement opportunities available around Scientific Day. If you are a faculty member interested in serving as a judge for the Alan Wu Poster competition or adjudicator for the Laidlaw Manuscript competition, please contact Marika Galadza at pa.medscience@utoronto. ca or at 416-978-6696. We would like to thank all of our judges, adjudicators and discussants from last year’s Scientific Day. Your time and efforts make a big impact !

Mark your calendars, IMS Scientific Day will be held on Thursday, May 22nd, 2014, Venue TBA. This year’s keynote speaker is Dr. James Landers of the University of Virginia. Dr. Landers is a professor of Chemistry and Mechanical Engineering at the University of Virginia, as well as an associate professor of Pathology at the University of Virginia Health System. He has authored more than 180 papers and 25 book chapters on topics as diverse as receptor biochemistry, microchip fabrication, forensic DNA analysis and integrated microfluidic systems for application to both the clinical and forensic arenas. For more information on Scientific Day awards, presentations and submission deadlines for IMS students, please read the IMS Scientific Day 2014 memo on our website: llustration by Man-San Ma

*submissions for the Laidlaw and Alan Wu competitions are only open to current IMS students*

Scientific Day, venue TBA


11 Last day to enroll in summer courses

14 Winter session available



For more IMS departmental news check out the next issue of News and Views- the IMS departmental newsletter on the IMS website at: IMS MAGAZINE WINTER 2014 CARDIOVASCULAR DISEASE | 9


Director’s Message T


Association and of IMS. Congratulations and thanks to Adam Santoro, the new Editor-in-Chief, and his staff for all their hard work on this issue, and to Kamila Lear for her ongoing assistance in this project. This issue of the magazine focuses on important aspects of cardiovascular disease. The areas of research covered represent innovative work of our Faculty. Contributors include Drs. Andrea Kassner, Valerie Taylor, Ravi Retnakaran, Anne Bassett, and Joel Ray. Their research is very much in keeping with the new strategic initiative of IMS related to translational research. There have been a number of important recent additions to the IMS Leadership Team that I would like to tell you about. We welcomed Drs. Gary Levy and Charlotte Ringsted, who joined the IMS Executive Committee recently. Dr. Joseph Ferenbok has joined the Team as the Co-Director of the new MHSC degree program in Translational Research in Health Sciences. This program has received final approval from the Vice Dean, Graduate and Life Science Education and from the Dean of Medicine and will go through final governance at the University before being submitted to Government for approval. We hope to have students in place by September 2015. In addition, we just recently held our annual Open House on January 25, which attracted close to 100 students from across Ontario. Kudos to Cindi Morshead, Hazel Pollard, and the rest of the Recruitment Committee for their hard work in organizing this highly successful event. Finally, by the time this issue comes out, we will have had our first ever Alumni Event, The Symphony of Science, with the Toronto Symphony Orchestra playing Simon and Garfunkel on January 29. Hopefully, this will be the first of many events involving our alumni. Finally, please note that the 2014 IMS Scientific Day will take place on Friday May 23. The Bernard Langer Plenary Address will be given by Christopher Austin, who is the Director of the National Center for Advancing Translational Sciences at the National Institute of Health in the USA. The title of his address is: “Catalyzing Translational Innovation.” This topic is perfectly aligned with our strategic plan and our new translational degree program. Please be sure to attend!

Allan S Kaplan, MSc, MD, FRCP(C) Director, IMS

Allan S. Kaplan, MSc, MD, FRCP(C), became the IMS Director in July 2011. He is currently the Chief of Clinical Research at the Centre for Addiction and Mental Health (CAMH), Vice Chair for Research in the Department of Psychiatry, and Professor of Psychiatry in the Faculty of Medicine. He is also a Senior Scientist at both CAMH and the Toronto General Hospital Research Institute. He was the inaugural holder of the Loretta Anne Rogers Chair in Eating Disorders at the University Health Network from 2002 to 2010.

Allan S Kaplan MD FRCP(C) Director, Institute of Medical Science





Novel Visualization Methods of Microvasculature in Stroke Patients Improvements in the Clinical Assessment of Sickle Cell Disease to Reduce Stroke


troke is the third leading cause of death in Canada and the primary cause of serious, long-term disability. There are over 50 000 strokes in Canada each year and over 300 000 Canadians are living with the effects of stroke.1 My research focuses on novel imaging methods to quantify properties of the microvasculature in acute stroke patients and patients at high risk of stroke. We conduct studies using dynamic contrast-enhanced magnetic resonance imaging (MRI) in combination with sophisticated image analysis techniques to assess the integrity of the cerebral microvasculature in acute ischaemic stroke (AIS). In healthy blood vessels, a special lining of endothelial cells make up a protective layer known as the blood-brain barrier (BBB), which allows oxygen and nutrients to pass into the brain tissue while blocking other compounds.2 An ischaemic event can disrupt the integrity of the BBB, making it more permeable and susceptible to leakage. Dynamic contrast-enhanced MRI can quantify the concentration of a contrast agent over time as it is injected into the bloodstream, enters the cerebrovasculature, and accumulates around regions where the BBB is compromised.3 Using advanced pharmaco-kinetic modeling tools, maps indicating vascular permeability can be generated to identify regions where vessel integrity may be particularly weak. Quantitative permeability MRI has potential significance in the treatment of AIS as the risk of intracerebral haemorrhage (the rupturing of cerebral arteries) is a major concern for AIS patients. This is particularly important as clinical therapy using thrombolytic agents is known

to significantly increase the risk of haemorrhage. Our work so far has demonstrated the reliability of permeability measurements in predicting hemorrhage after initial AIS, comparing permeability imaging acquired using CT and MRI, and outlining the effect of reducing the total number of data samples used for permeability quantification. The aim is to select patients for clinical treatment based on precise physiological measurements to minimize the risk of subsequent complications. Stroke is also one of the top ten causes of death in childhood and is as prevalent as brain cancer in children.4 A recent investigation identified a number of chronic cerebrovascular diseases, such as moyamoya, transient cerebral arteriopathy and sickle cell disease (SCD) as major risk factors for childhood stroke.5 Being based at the Hospital for Sick Children has given me a unique opportunity to study stroke risk and prevention in pediatric SCD. Currently, baseline blood flow velocity measured in the major cerebral arteries using transcranial Doppler ultrasound is the clinical standard for stratifying stroke risk in children with SCD. Although the application of Doppler ultrasound has been a significant milestone in the prevention of stroke in SCD, arterial flow velocity remains an indirect measure and does not assess the actual physiological factors that lead to stroke. My lab is researching MRI measurements of cerebrovascular reactivity (CVR) as a novel screening tool for children with SCD. Cerebrovascular reactivity measurements can assess the capacity for cerebral blood vessels to dilate, which is critical for normal regulation of blood flow in the brain. Our study


uses a specialized computer-controlled gas delivery system that provides a vasoactive stimulus to the participant. Simultaneously, the resulting changes in cerebral blood flow are quantified using blood-oxygen level dependent (BOLD) MRI. BOLD imaging is a technique that is often associated with brain activation in functional MRI but can also be applied to CVR studies by detecting the blood flow response to a global stimulus in the brain. Importantly, BOLD imaging is completely non-invasive and, unlike other nuclear imaging modalities, does not expose subjects to ionizing radiation. For the first time, we have demonstrated that CVR can reliably measure developmental vascular changes in the brain in children with and without SCD. We observed that children with SCD have poor CVR and are, therefore, hemodynamically compromised compared to healthy controls. We expect that CVR abnormalities in children with SCD are strongly associated with stroke incidence. The inclusion of BOLD-CVR imaging to routine clinical assessment of SCD could eventually lead to improved selection of candidates for restorative interventions such as transfusion therapy or revascularization surgery. �

References 1. Heart and Stroke Foundation. Stroke Statistics. 2007. Ref Type: Online Source 2. Kassner A, Mandell DM, Mikulis DJ. Measuring permeability in acute ischemic stroke. Neuroimaging Clin N Am 2011 May;21(2):315xi. 3. Kassner A, Thornhill R. Measuring the integrity of the human blood-brain barrier using magnetic resonance imaging. Methods Mol Biol 2011;686:229-45. 4. Heart and Stroke Foundation. Stroke in children (Paediatric stroke). 2013. Ref Type: Online Source 5. Lanni G, Catalucci A, Conti L, Di SA, Paonessa A, Gallucci M. Pediatric stroke: clinical findings and radiological approach. Stroke Res Treat 2011;2011:172168.

Photo by Laura Feldcamp

Andrea Kassner, PhD Assistant Professor & Co-Director of Research, Department of Medical Imaging Senior Scientist, Physiology & Experimental Medicine, The Hospital for Sick Children


Dynamic contrast-enhanced MRI can quantify the concentration of a contrast agent over time as it is injected into the bloodstream, enters the cerebrovasculature, and accumulates around regions where the blood-brain barrier is compromised.




Valerie Taylor, MD, PhD Associate Professor, Department of Psychiatry, University of Toronto Associate Member, Institute of Medical Science Psychiatrist-in-Chief, Women’s College Hospital

The Association between Cardiovascular Disease and a Mood Disorder

A number of factors support a link between mood disorders and CVD. From a behavioral perspective, patients with MDD or BD are more likely to engage in unhealthy behaviors, such as smoking or having a sedentary lifestyle, that increase the risk of CVD.5 In general, 50% to 80% of patients with chronic mental illness are smokers6 and have rates of obesity, hypertension, dyslipidemia, and diabetes, in excess of those found in the general population.7,8 When diagnosed with heart disease, having a mood disorder is also associated with lack of medical adherence to pharmacolog-

ic treatments or interventions such as exercise.9,10 Patients with a mood disorder also have a lower frequency of hospitalization for heart disease and lesser exposure to cardiac treatment.11 Biologic factors may also be involved in this association, and several studies in depressed patients with coronary artery disease have reported reduced heart rate variability, suggesting increased sympathetic activity and/or reduced vagal activity,12 hypothalamic-pituitary-adrenal axis dysfunction,13 and an altered inflammatory response.14 Compounding all of the above is the fact that most medications used to treat mood disorders carry an inherent risk of weight gain.15,16 Work done by my research group supports the association between CVD and mood disorders and we found that risk of CVD, as indicated by a Framingham Score, increased much faster than would be expected in a young cohort (mean age 29.6 years) of individuals receiving treatment for MDD and BD for the first time. In only two years, the risk of CVD in this population increased appreciably, as did their rates of diabetes, obesity, and dyslipidemia.8 These data suggest that changes increasing risk for CVD begin early in this population and it highlights the need for proper screening and monitoring at the initial stages of treatment. There is still a lot of work to do, however, and studies are required to evaluate the efficacy of various interventions for managing metabolic dysregulation in patients with mood disorders. There also remains a need to elucidate the mechanism by which psychotropic medications negatively impact metabolic parameters. Given that MDD and BD will affect about 10% to 15% of the population,17 and that peo-


References 1. Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med. 2002;23:51-61. 2. Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J. 2006;27:2763-74. 3. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:E1-E211. 4. Anderson JL, Adams CD, Antman EM, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2007;116:e148-e304. 5. Carney RM, Freedland KE, Miller GE, et al. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res. 2002;53:897-902. 6. Compton MT, Daumit GL, Druss BG. Cigarette smoking and overweight/obesity among individuals with serious mental illnesses: a preventive perspective. Harv Rev Psychiatry. 2006;14:212-22. 7. Mclntyre RS, Konarski JZ, Wilkins K, et al. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being. Can J Psychiatry. 2006;51:274-80. 8. Taylor V, McKinnon MC, Macdonald K, et al. Adults with mood disorders have an increased risk profile for cardiovascular disease within the first two years of treatment Can J Psychiatry. 2010;55:362-8. 9. Thomas AJ, Kalaria RN, O’Brien JT. Depression and vascular disease: what is the relationship? J Affect Disord. 2004;79:81-95. 10. Everson-Rose SA, Lewis TT. Psychosocial factors and cardiovascular diseases. Annu Rev Public Health. 2005;26:469-500. 11. Laursen TM, Munk-Olsen T, Agerbo E, et al. Somatic hospital contacts, invasive cardiac procedures, and mortality from heart disease in patients with severe mental disorder. Arch Gen Psychiatry. 2009;66:713-20. 12. Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation. 2001;104:2024-8. 13. Taylor CB, Conrad A, Wilhelm FH, et al. Psychophysiological and cortisol responses to psychological stress in depressed and nondepressed older men and women with elevated cardiovascular disease risk. Psychosom Med. 2006;68:538-46. 14. Levi F, Lucchini F, Negri E, et al. Trends in mortality from cardiovascular and cerebrovascular diseases in Europe and other areas of the world. Heart. 2002;88:119-24. 15. Casey DE. Dyslipidemia and atypical antipsychotic drugs. J Clin Psychiatry. 2004;65(Suppl 18):27-35. 16. Heiskanen TH, Niskanen LK, Hintikka JJ, et al. Metabolic syndrome and depression: a cross-sectional analysis. J Clin Psychiatry. 2006;67:1422-7. 17. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19. 18. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3:A42.

Photo by Laura Feldcamp


broken heart can lead to sadness, but research now shows us that the reverse also happens–depression can harm your heart and is a serious health concern for individuals suffering from mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD). Mood disorders are overrepresented in patients with cardiovascular disease (CVD), and as a consequence, a significant amount of research has been focused on understanding this association. Since the late 1990s, there have been more than 100 published reviews on this topic, as well as numerous meta-analyses examining the role of mood disorders on cardiovascular morbidity and mortality.1,2 Despite differences in samples, duration of follow-up, and assessment of depressive symptoms, these studies have demonstrated relatively consistent results. As a result, several clinical guidelines recommend that screening for mood disorders be considered in patients with CVD, and conversely, that screening for CVD occur in patients experiencing mood changes, highlighting the bidirectional nature of this association.3,4

ple with this illness lose 25 years or more of life expectancy, with most of the excess premature death due to cardiovascular disease, it is important we focus on this association.18 ☐

Using Pregnancy for the Identification of Future Risk of Cardiovascular Disease in Young Women


Photo by Chung Ho Leung

regnancy has been described as a stress test for many systems in the body. This description is particularly appropriate for the pancreatic beta-cells that secrete insulin, as they must respond and compensate appropriately for the severe insulin resistance that characterizes late pregnancy. In this way, pregnancy is a natural stress test for the beta-cells.1 As beta-cell dysfunction has emerged as the key pathophysiologic determinant of an individual’s risk of ultimately developing type 2 diabetes mellitus (T2DM), a woman’s response to the metabolic challenge of pregnancy provides a means of stratifying her future diabetic risk. It is this concept that underlies a component of our research program at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital. Indeed, we have established a long-term prospective observational cohort study, in which women across the full range of glucose tolerance in pregnancy− from normal glucose tolerance to mildly abnormal glucose tolerance to gestational diabetes mellitus−are recruited in late second trimester and undergo cardio-metabolic characterization at that time and then serially in the years postpartum. Since each degree of gestational dysglycemia reflects a different level of underlying beta-cell dysfunction and hence a differential risk of ultimately progressing to T2DM,1-4 longitudinal characterization of the metabolic changes that occur over time in these patient subgroups can provide insight into the early pathophysiology of diabetes. Supported by funding from the Canadian Institutes of Health Research (CIHR), the Canadian Diabetes Association, the Heart and Stroke Foundation of Ontario, and

the Ontario Ministry of Research and Innovation, this program has yielded many important findings regarding the early natural history of pre-diabetes and diabetes in women, as per its initial objective. Along the way, however, unanticipated findings pertaining to cardiovascular disease have opened new avenues of investigation.

Ravi Retnakaran, MD, MSc, FRCPC Endocrinologist and Clinician-Scientist Leadership Sinai Centre for Diabetes Associate Professor, Department of Medicine, University of Toronto

While the absolute levels of such risk factors would not be at the level to attract clinical attention in practice, particularly since they are in young women of childbearing age who have a very low likelihood of having cardiovascular disease at the time, the clear gradients that emerged after stratifying women by their gestational glucose tolerance status were of interest. Indeed, these gradients raised the possibility that these women may be at different degrees of risk for ultimately developing cardiovascular disease in the future, in the same way as they are known to be at different levels of risk for T2DM.

It has been suggested that atherosclerosis and T2DM may arise from a “common soil,” since many individuals appear to be susceptible to both conditions.5 Accordingly, we have been characterizing the cardiovascular risk factor profiles of the maternal cohort described above. This profile consists of both traditional cardiovascular To test this hypothesis, we looked at rates risk factors (such as blood pressure and of clinical cardiovascular disease as tracked lipids) and emerging non-traditional risk by administrative data for the province of factors (such as fat-derived hormones like Ontario in women with varying degrees adipokines and inflammatory proteins). of glucose intolerance in pregnancy.10 As Interestingly, in evaluating these profiles, we found that relationships existed between a wom...within 12 years of their index an’s glucose tolerance pregnancy, women with a history of status in pregnancy and her cardiovascular risk gestational diabetes mellitus had an factors as early as three increased incidence of cardiovascular months after delivery.6-9 Indeed, these risk facdisease. tors followed gradients that tracked with her glucose tolerance status in the recent preg- predicted, these data revealed, within 12 nancy. In other words, at three months years of their index pregnancy, women postpartum, women with gestational dia- with a history of gestational diabetes melbetes mellitus (the most severe dysglycemia litus had an increased incidence of cardioin pregnancy) had higher levels of vascular vascular disease. Similarly, and akin to the risk factors than women with milder ges- analogous gradients of risk seen for T2DM, tational impaired glucose tolerance, who women with milder glucose intolerance in in turn had higher levels than women with pregnancy also had an increased risk after normal glucose tolerance in pregnancy. 12 years, one that was lesser than that of


FEATURE women with gestational diabetes mellitus but higher than their peers.10 The model emerging from these data is that long-term exposure to the cardiovascular risk factor gradients that we have documented in women with varying degrees of gestational dysglycemia ultimately contributes to the development of clinical cardiovascular disease. We are thus studying the changes over time in vascular risk factors and function in the maternal cohort described earlier in order to gain insight into the early natural history of cardiovascular disease. The presence of gradients of vascular risk factors in the early postpartum raises the question of whether these differences were present prior to the pregnancy. To address this question, in collaboration with colleagues in Ottawa, Canada and Changsha, China, we are conducting a CIHR-funded study in China, where we have established a so-called “pre-conception cohort.” In this unique study, we are recruiting a cohort of women prior to pregnancy and performing cardio-metabolic characterization at that time, which is then repeated longitudinally during and after pregnancy.11 This approach will provide insight into the pre-pregnancy status and determinants of the risk gradients that we have previously noted in pregnancy and in the postpartum. Finally, in both of the maternal cohorts described so far (Toronto and China), the earliest underpinnings of cardio-metabolic disease may be in the offspring. Indeed, with current interest in the long-term programming implications of the first 2 000 days of life, the children of the women participating in these cohorts provide the unique opportunity to characterize early changes in cardio-metabolic risk factors

in the setting of well-defined maternal exposures.12-15 Taken together with maternal characterization before, during, and after pregnancy, these birth cohorts are enabling the application of a life-course approach towards elucidation of the early natural history and pathophysiologic determinants of T2DM and cardiovascular disease. ☐

References 1. Retnakaran R. Glucose tolerance status in pregnancy: A window to the future risk of diabetes and cardiovascular disease in young women. Curr Diabetes Rev. 2009; 5(4):239-44. 2. Retnakaran R, Qi Y, Sermer M, et al. Glucose intolerance in pregnancy and future risk of pre-diabetes or diabetes. Diabetes Care. 2008; 31(10):2026-31. 3. Retnakaran R, Qi Y, Sermer M, et al. Beta-cell function declines within the first year postpartum in women with recent glucose intolerance in pregnancy. Diabetes Care. 2010; 33(8):1798-1804. 4. Retnakaran R, Qi Y, Connelly PW, et al. Risk of early progression to pre-diabetes or diabetes in women with recent gestational dysglycemia but normal glucose tolerance at 3-months postpartum. Clin Endocrinol. 2010; 73(4):476-83. 5. Stern MP. Diabetes and cardiovascular disease. The "common soil" hypothesis. Diabetes. 1995; 44(4):369-74. 6. Retnakaran R, Qi Y, Connelly PW, et al. The graded relationship between glucose tolerance status in pregnancy and postpartum levels of LDL cholesterol and apolipoprotein B in young women: Implications for future cardiovascular risk. J Clin Endocrinol Metab. 2010; 95(9):4345-53. 7. Retnakaran R, Qi Y, Sermer M, et al. Glucose intolerance in pregnancy and postpartum risk of metabolic syndrome in young women. J Clin Endocrinol Metab. 2010; 95(2):670-7. 8. Retnakaran R, Qi Y, Connelly PW, et al. Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta-cell dysfunction and fasting glycaemia. Diabetologia. 2010; 53(2):268-76. 9. Retnakaran R, Qi Y, Sermer M, et al. The postpartum cardiovascular risk factor profile of women with isolated hyperglycemia at 1-hour on the oral glucose tolerance test in pregnancy. Nutr Metab Cardiovasc Dis. 2011; 21(9):706-12. 10. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease in young women: population-based cohort study. CMAJ. 2009; 181(6-7):371-76. 11. Wen SW, Xie RH, Tan H, Walker MC, et al. Preeclampsia and gestational diabetes mellitus: pre-conception origins? Med Hypotheses. 2012; 79(1): 120-25. 12. Retnakaran R, Ye C, Hanley AJ, et al. Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birthweight in women without gestational diabetes mellitus. CMAJ. 2012; 184(12):1353-60. 13. Borgono C, Hamilton JK, Ye C, et al. Determinants of insulin resistance in infants at 1 year of age: impact of gestational diabetes mellitus. Diabetes Care. 2012; 35(8):1795-97. 14. Kew S, Hamilton JK, Ye C, et al. Vitamin D status and cardio-metabolic assessment in infancy. Pediatric Res. 2013; 74(2):217-22. 15. Retnakaran R, Ye C, Hanley AJ, et al. Effect of maternal gestational diabetes on the cardiovascular risk factor profile of infants at 1 year of age. Nutr Metab Cardiovasc Dis. 2013; 23(12):1175-81.

Substituting shellfish and red meats with fish, poultry and vegetables can reduce cholesterol levels and arteriosclerosis.



he’s been hearing the voices a little lately—the ones that aren’t really there. She sounds a bit different than other people when she speaks, and struggled in school until dropping out in grade 10. She’s been in and out of hospitals her whole life, starting with the surgery to fix the heart defect she was born with. And now, at 38 years old, she finally knows why. She has 22q11.2 deletion syndrome (22q11.2DS), a common but underdiagnosed multisystem condition caused by the deletion of approximately 50 genes on one of the pair of chromosomes 22. It can affect nearly every system of the body. Although the usual estimate is that this deletion occurs in about 1 in every 2 000–4 000 live births, recent prenatal testing studies show a higher rate of about 1 in 350.1, 2 Before the genetic deletion was identified as the cause, patients with 22q11.2DS used to be diagnosed with multiple different syndromes because of the variable clinical presentation. These included DiGeorge syndrome, velo-cardio-facial syndrome, and conotruncal anomaly face syndrome. The major features of 22q11.2DS include birth defects, neurodevelopmental abnormalities, and later-onset neuropsychiatric conditions. For example, about 1 in 3 babies with 22q11.2DS have a serious congenital heart defect, such as tetralogy of Fallot, which requires surgical repair. During childhood, developmental delay and palatal anomalies that cause nasal speech often become apparent. As patients enter adolescence and adulthood, about 1 in 4 develop schizophrenia, making the 22q11.2 deletion the highest known molecular genetic risk factor for schizophrenia. Schizophrenia associated with the 22q11.2 deletion is clinically indistinguishable from idiopathic forms of schizophrenia and is responsive to standard antipsychotic treatments. Our growing knowledge of the syndrome, including its changing face over the lifespan, is the fruit of a close collaboration between clinical practice and research over the past two decades. Advances in pediatric care now mean that more patients are living to adulthood. This knowledge has greatly improved clinical care and genetic counselling for patients and their families.3 And new discoveries important for clinical care are still being made—a new association was identified between 22q11.2DS and early-onset Parkinson’s disease just last

The Heart-Mind Connection Learning from and giving back to patients Nancy Butcher, MSc, PhD candidate Institute of Medical Science, University of Toronto Clinical Genetics Research Program, Centre for Addiction and Mental Health

Anne S. Bassett, MD, FRCPC Canada Research Chair in Schizophrenia Genetics and Genomic Disorders Dalglish Chair in 22q11.2 Deletion Syndrome Professor of Psychiatry, University of Toronto Full Member, Institute of Medical Science, University of Toronto Associate Staff, Division of Cardiology, University Health Network Associate Member, Canadian College of Medical Geneticists Director, Clinical Genetics Research Program

Photo courtesy of Matthew Wu

fall.4 The increasing population of adults with 22q11.2DS has created a new need for advanced, multidisciplinary care informed by evidence-based medicine. Because 22q11.2DS can affect nearly every part of the body, patients and their families often need to visit multiple hospitals to see several specialists. Through a generous $4 million donation by The W. Garfield Weston Foundation, this need is now being met. The Dalglish Family Hearts and Minds Clinic for Adults with 22q11.2 Deletion Syndrome officially opened its doors last year at the Toronto General Hospital, University Health Network (UHN), with the first patient seen in February 2013. This is the world’s first multidisciplinary clinic devoted to adults with 22q11.2DS and their families. The Dalglish Family Hearts and Minds Clinic provides a one-stop-shop for patients with 22q11.2DS and their families. The clinic is directed by Dr. Anne Bassett, Professor of Psychiatry and Full Member of the Institute of Medical Science at the University of Toronto (U of T) and The Dalglish Family Chair in 22q11.2 Deletion Syndrome together with the co-director, Dr. Alan Fung, Assistant Professor of Psychiatry at U of T. The ultimate goal for the clinic is to serve as a model of integrated and personalized care not only for 22q11.2DS, but also other complex conditions. The clinic team includes a nurse, a dietician, and a social worker, as well as doctors from multiple specialties, including cardiology, psychiatry, endocri-

nology, genetics, and neurology. Through close collaboration with the established 22q Deletion Syndrome Clinic at The Hospital for Sick Children, the plan is to develop an integrated transition clinic for teens and youths. The focus will be on preventative health care–especially preventing serious psychiatric illnesses like schizophrenia and/or ameliorating their effects. Along with the focus on clinical care, research and education are major components of the mandate of The Dalglish Family Hearts and Minds Clinic. Trainees, researchers, and clinicians will gain expertise in 22q11.2DS and thus in managing complex multisystem disorders in adults. This is a major aspect of the vision for UHN. Researchers and their collaborators are examining the clinical challenges that patients with 22q11.2DS and their families face, especially in the areas of cardiology, psychiatry, and neurology. These include both basic and clinical research studies that are immediately translatable into patient care. An exciting new project to sequence the entire genome in hundreds of patients with 22q11.2DS using the latest technology, whole genome sequencing, may provide new insights into the genetic underpinnings of diseases and conditions associated with 22q11.2DS. This could help explain and predict, for example, why some people are born with heart defects, and others develop schizophrenia. There are implications not only for those with 22q11.2DS, but also for the millions of people worldwide with

these common disorders. The Dalglish Clinic shares a strong clinical and research relationship with the Toronto Congenital Cardiac Centre for Adults (TCCCA), where many adults with 22q11.2DS in the province receive worldclass care for the associated cardiac defects. As 22q11.2DS is often undetected, patients sometimes receive their first diagnosis as adults at TCCCA. Working together with The Dalglish Clinic, patients receive the collaborative, multidisciplinary care necessary to manage their unique needs. The clinic is contributing to the Peter Munk Cardiac Centre Biobank and database and enabling new research studies in 22q11.2DS. Biobanking of these tissue specimens may permit the development of molecular therapies for patients with 22q11.2DS and its component disorders. By facilitating both clinical and basic research in 22q11.2DS, it is hoped that The Dalglish Clinic will help answer the questions that are most important to the patients and their families. ☐

References 1. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175-84. 2. Costain G, McDonald-McGinn DM, Bassett AS. Prenatal genetic testing with chromosomal microarray analysis identifies major risk variants for schizophrenia and other later-onset disorders. Am J Psychiatry. 2013;170(12):1498. 3. Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332-9. 4. Butcher NJ, Kiehl T-R, Hazrati L-N, et al. Individuals with 22q11.2 deletion syndrome are at increased risk of early-onset Parkinson disease: Identification of a novel genetic form of Parkinson disease and its clinical implications. JAMA Neurology. 2013(70):1359-66.


FEATURE When a placenta goes bad … About 60% of the human placenta consists of blood vessels that are critical for transport of nutrients and oxygen to the fetus, while removing waste and carbon dioxide byproducts. Abnormal placental development can disrupt pregnancy and profoundly endanger maternal and infant health. Placental dysfunction may result in adverse maternal clinical outcomes that we broadly call the “maternal placental syndromes” (MPS), the prevalence of which is about 7% of delivered pregnancies.1 While MPS—preeclampsia, placental abruption, and placental infarction1,2—pertains to the mother, the ensuing negative effects on the fetus include growth restriction, small for gestational age birthweight, preterm birth, and stillbirth.

The cardiometabolic profile is often the culprit …

A diseased placenta can predict premature cardiovascular disease Joel Ray, MD, MSc, FRCPC Departments of Medicine and Obstetrics and Gynaecology Institute of Health Policy, Management and Evaluation Institute of Medical Science Institute for Clinical Evaluative Sciences Li Ka Shing Knowledge Institute St. Michael’s Hospital and the University of Toronto

And premature cardiovascular disease is more likely to follow after pregnancy … Some common risk factors for placental vascular disease so happen to be common risk factors for the premature-onset cardiovascular disease—coronary artery


Photo courtesy of

Canary out of the Coal Mine

We and others have identified a likely association between a woman’s cardiometabolic profile (i.e., number of markers of the metabolic syndrome) before pregnancy, and her risk of MPS, especially preeclampsia.3,4 After pregnancy the risk of postpartum metabolic syndrome also appears to be higher among those with early-onset MPS. For example, among 849 women with a history of MPS, metabolic syndrome was present in 24.5% of women with early-onset MPS and 11.7% of women with late-onset MPS (adjusted odds ratio [OR] 2.51, 95% confidence interval [CI] 1.66 to 3.80).5 Women with early-onset MPS exhibited a higher risk of hyperinsulinemia and other individual metabolic syndrome features. Hence, we think that that the cardiometabolic profile of a woman before pregnancy, and which persists after pregnancy, may be the common link between MPS and premature cardiovascular disease in the years that follow.

disease, left ventricular impairment, cerebrovascular disease, and peripheral arterial disease—in the affected woman.6,7 Thus, the systematic evaluation of a woman’s pregnancy outcome (including that of her fetus/ newborn), and the pathological integrity of her delivered placenta, may offer an unrealized and efficient means of identifying a subset of women at high risk of cardiovascular disease (and its risk factors) in their post-pregnancy years.2

without MPS (adjusted RR 1.8, 95% CI 1.42.3).10 The mean age at the onset of a heart failure event was 38 years; the maximum age was 60.5 years.

In 2008, McDonald et al. examined 5 case-control and 10 cohort studies, totaling 116 175 women with preeclampsia, and 2 259 576 women without preeclampsia.8 In the cohort studies, women with a history of preeclampsia were at increased future risk of coronary artery disease (relative risk [RR] 2.33, 95% CI 1.95-2.78). Coronary artery disease risk rose with preeclampsia severity: mild (RR 2.00, 95% CI 1.83-2.19, moderate (RR 2.99, 95% CI 2.51-3.58, and severe (RR 5.36, 95% CI 3.96-7.27).8

There is consistent evidence that MPS—especially preeclampsia—may be a risk factor for premature cardiovascular disease and, perhaps, heart failure. The common link may be partly related to cardiometabolic dysfunction that both predates and persists after pregnancy.1,11 There is an impetus to develop specific recommendations about the long-term management of women, whose pregnancy was affected by preeclampsia, fetal growth restriction, and/ or an intrauterine fetal death attributed to placental vascular disease.12-14 In 2011 the American Heart Association (AHA) Effectiveness-based guidelines for the prevention of cardiovascular disease in women14 introduced a new and bold statement:

Using population-based administrative data, we previously studied the risk of cardiovascular disease among more than 1 million Ontarian women, who were free of cardiovascular disease prior to their first obstetrical delivery.1 The adjusted RR for cardiovascular disease was 2.0 (95% CI 1.72.2) in the presence of MPS, and was more pronounced when MPS was accompanied by intrauterine growth restriction (RR 3.1, 95% CI 2.2-4.5) or stillbirth (RR 4.4, 95% CI 2.4-7.9). Moreover, the risk of cardiovascular disease was highest in women with MPS and one to two (RR 4.5, 95% CI 3.7-5.4) or three to four features (RR 11.7, 4.9-28.3) of metabolic syndrome before pregnancy, relative to none. Thus, there may be an additive effect of having MPS in conjunction with worse fetal outcomes, as well as more metabolic syndrome features prior to and following pregnancy.9 This is important, in that it may enable one to better identify high-risk groups for cardiovascular disease, based on MPS and other common features before and after pregnancy. We also recently completed the “Heart Failure and Dysrhythmias after Maternal Placental Syndromes: HAD MPS Study.”10 Therein, among 1.13 million individual deliveries, after a median follow-up of 7.8 years, hospitalization for heart failure occurred at an incidence rate of 1.37 per 10,000 person-years in women with MPS and 0.59 per 10 000 person-years in women

the overt onset of cardiovascular disease or diabetes, might be shown to be a novel and cost-effective form of primary prevention of these conditions. It is at this point that the “canary may be freed from the coal mine.” ☐

And we may be able to do something about it—release the References canary from the coal mine 1. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular

“Future research should evaluate the potential for exposures, events, or interaction with the medical system during periods of potential vulnerability across a woman’s lifespan such as… pregnancy… to identify women at risk and to determine the effectiveness of diagnostic and preventive interventions during these critical times.” The work that we and others are generating have and will enhance these recent AHA recommendations, by better elucidating which cardiometabolic risk factors persist after delivery, as well as the degree to which the placenta—a highly vascular and transient organ of pregnancy, and the dysfunction of which often underlies MPS—may offer the most objective assessment (vis-àvis blood vessel disease) of the impact of pregnancy on future cardiovascular disease risk.

health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005; 366:1797-803. 2. Newstead J, von Dadelszen P, Magee LA. Preeclampsia and future cardiovascular risk. Expert Rev Cardiovasc Ther 2007; 5:283-94. 3. Wolf M, Sandler L, Muñoz K, Hsu K, Ecker JL, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab 2002; 87:1563-8. 4. Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV, Sukhatme VP, Levine RJ, Karumanchi SA. Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia. Hypertension 2004; 43:988-92. 5. Stekkinger E, Zandstra M, Peeters LL, Spaanderman ME. Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome. Obstet Gynecol 2009; 114:1076-84. 6. Ray JG, Vermeulen MJ, Schull MJ, McDonald S, Redelmeier DA. Metabolic syndrome and the risk of placental dysfunction. J Obstet Gynaecol Can 2005; 27:1095-101. 7. 7. Ray JG. Metabolic syndrome and higher risk of maternal placental syndromes and cardiovascular disease. Drug Dev Res 2006; 67: 607-1. 8. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008; 156:918-30. 9. Forest JC, Girouard J, Massé J, Moutquin JM, Kharfi A, Ness RB, Roberts JM, Giguère Y. Early occurrence of metabolic syndrome after hypertension in pregnancy. Obstet Gynecol 2005;105:1373-80. 10. Ray JG, Schull MJ, Kingdom JC, Vermeulen MJ. Heart failure and dysrhythmias after maternal placental syndromes: HAD MPS Study. Heart 2012; 98:1136-41. 11. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation 2010; 122:579-84. 12. Piña IL. Cardiovascular disease in women: challenge of the middle years. Cardiol Rev 2011;19:71-5. 13. Hermes W, Franx A, van Pampus MG, Bloemenkamp KW, van der Post JA, Porath M, Ponjee G, Tamsma JT, Mol BW, de Groot CJ. 10-Year cardiovascular event risks for women who experienced hypertensive disorders in late pregnancy: the HyRAS study. BMC Pregnancy Childbirth 2010; 10:28. 14. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, Newby LK, Piña IL, Roger VL, Shaw LJ, Zhao D, Beckie TM, Bushnell C, D'Armiento J, Kris-Etherton PM, Fang J, Ganiats TG, Gomes AS, Gracia CR, Haan CK, Jackson EA, Judelson DR, Kelepouris E, Lavie CJ, Moore A, Nussmeier NA, Ofili E, Oparil S, Ouyang P, Pinn VW, Sherif K, Smith SC Jr, Sopko G, Chandra-Strobos N, Urbina EM, Vaccarino V, Wenger NK; American Heart Association. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association. J Am Coll Cardiol 2011; 57:1404-23.

While the focus of our work has been the identification of women at higher risk of cardiometabolic dysfunction, we remain optimistic that pending research by others will show the benefits of a healthy lifestyle in women of reproductive age. Specifically, the identification of the subset of women at highest risk of long-term complications, at a relatively early point in her life, before IMS MAGAZINE WINTER 2014 CARDIOVASCULAR DISEASE | 21

SPOTLIGHT scopic losses and gains of genetic material) in a congenital cardiac disorder called “tetralogy of Fallot” (TOF). TOF is the most common cyanotic heart defect and children born with this heart defect are often called “blue babies.” Silversides discovered that patients with TOF were more likely to have these rare genetic changes when compared to controls. Strikingly, many of the genetic changes are also found in patients with neurodevelopmental disorders, including intellectual disability, autism, and schizophrenia, highlighting the potential links that exist between the heart and the mind.

Candice Silversides, MD, FRCPC



TORONTO CONGENITAL CARDIAC Centre for Adults (TCCCA) at the Toronto General Hospital, I was acutely aware of how fortunate I was to be meeting with one of Toronto’s leading cardiologists, Dr. Candice Silversides. Dr. Silversides is a successful clinician scientist within the Institute of Medical Science (IMS), Head of the Obstetric Medicine Program at Mount Sinai Hospital, as well as staff cardiologist and Research Director of the TCCCA. She has built her multi-faceted research career around studying adults with congenital cardiac disease, a relatively new field in cardiology, thanks to advances in pediatric cardiac surgery. TEPPING INTO THE

When asked to name her biggest research accomplishment, Dr. Silversides was hesitant to choose just one, which is not surprising, considering her impressive publication record. With over 100 peer-reviewed publications, Silversides has contributed to multiple areas within the field of adult congenital cardiac disease including genetics, clinical outcomes, and management guidelines. Of noteworthy mention is Silversides’ recent publication in PLOS Genetics that aimed to describe the burden of copy number variations (CNVs; micro-


My interview with Dr. Silversides ended with one of those instances where you find yourself wishing you had just five more minutes to chat. Silversides is as kind and personable as she is smart—certainly a physician I would want standing by my bedside. When asked what advice she would give to someone starting off in her field she replies, “To do medicine and research is very hard work, but it is very rewarding when you get to do a job where you learn something new every day. None of my days are the same, and I guess that is what makes it so much fun.” ☐

Photo by Laura Feldcamp

Dr. Silversides explains that “60 years ago, in your grandparents’ generation, many of the children born with congenital cardiac defects would not have survived…nowadays, children with congenital heart defects are living in adulthood. However, there is still a lot we do not know about these adults, including one of my specific interests, the impact of pregnancy on the con-

genitally abnormal heart. This emerging field of cardiology is very exciting for clinicians and researchers who continue to define this new adult cardiac phenotype.” We can thank researchers and clinicians at U of T, who have broadened our understanding of congenital heart disease in the adult population, and who have helped to define standards of care for this group of patients. Dr. Silversides says U of T has been a world leader in this area for over 20 years and continues to be so.

In true IMS fashion, the vast majority of Dr. Silversides’ research is translational in nature. When developing a new research question, she often asks herself, “If I had the patient right in front of me, what would I need to know?” It’s not hard to see the influence her clinical training has had on her research trajectory—after receiving her MD degree from the University of Manitoba, she went on to complete a residency in internal medicine and a Master’s degree through the Harvard School of Public Health. It wasn’t until she sub-specialized in cardiology and completed two fellowships in adult congenital cardiac disease and echocardiography that her research interests ignited. When asked if she ever envisioned herself ending up in this field she admits, “No, I lucked out by meeting a few key people who got me interested in different aspects of congenital cardiology, and that has taken me in a lot of different directions.”


ENRICH YOUR WORLD: VOLUNTEER Negar Karimian MSc (MD from Iran) Supervisors: Herbert Gaisano, Mladen Vranic Stream: Completed MSc at IMS Saber Ghadakzadeh (MD from Iran) Supervisor: Benjamin Alman Stream: MSc student at IMS By Katherine Schwenger



Photo by Negar Karimian and Saber Ghadakzadeh

medical research with practical experience; it provides an opportunity to become involved in health care and conduct research on a global scale. Recently, I had a chance to meet with two students in the Institute of Medical Science (IMS), with a strong passion for international volunteerism. Both Negar Karimian and Saber Ghadakzadeh are originally from Iran, where they were trained as medical doctors. Negar recently completed her MSc and Saber is currently a Master’s student in IMS. They feel an urge to help others across the world and say that “as physicians, we feel responsible to deliver health care to underserved areas on a global scale.” The pair decided to devote their time to volunteer efforts in Honduras—a region with one of the greatest health care needs worldwide. Through the Honduras consulate in Montreal and an active non-government organization in the region, a ten-day trip to two rural communities, with six days of mobile clinics, was organized (August 2013). Both Negar and Saber were excited about the potential to return to a clinical setting. “We really missed practice,” they revealed. While in rural Honduras, they performed two emergency outpatient surgeries. Without these procedures, patients would have faced serious complications. During the six clinic days they worked with local staff, including two physicians and a dentist, visit-

ing a total of approximately 1 800 patients. “Working with local physicians who were more experienced with the region-specific health conditions was great,” Negar and Saber recalled. Reflecting on their trip, they felt that collaborative efforts between local universities and one like University of Toronto are extremely important. Negar and Saber described collaboration as “the most efficient and sustainable approach” towards overcoming obstacles and difficulties in health care. When asked about the role of such trips in solidifying the importance of translational research, they stated that collaboration would help with knowledge transfer, so that local medical professionals could better treat their patients, as well as facilitate research in different areas, including epidemiological studies. It is important to understand that in order to better facilitate collaborations with these countries, their local and international resources must be better connected. As the students described, “gaining a better understanding of disease by studying different populations is a crucial step in translational research.” In order to promote sustainability, Saber and Negar felt that local and international health care professionals must establish programs through universities to educate regional and local healthcare workers and patients. These various levels of health care professionals (nurses, community workers,

etc.) would help detect and treat diseases early on and would also contribute to data collection for epidemiological studies. For Negar and Saber, this ten-day volunteer trip to Honduras was an amazing experience. Although several MDs are involved in research programs at IMS, such an undertaking is not limited to students in their situation. “It can be a life changing experience for students from any background,” they stated. Without question, they would recommend volunteering to their colleagues from any educational background. They also support the idea of initiating collaborative research and training programs between IMS faculty and faculty from local universities. When asked if they had any trips planned for the future, Negar and Saber responded, “We have yet to confirm our next destination, but we are certainly going to continue our contribution to these underserved communities.” Negar and Saber would like to thank all their friends and family members who sponsored their last trip. “Our financial supporters brought smiles to many faces that deserved them,” they said in appreciation of their sponsors. ☐


EXPERT OPINION Tricia L. da Silva, MA Graduate Student Institute of Medical Sciences Faculty of Medicine, University of Toronto Arun V. Ravindran, MB, PhD, FRCPC, FRCPsych Professor of Psychiatry, University of Toronto Chief, Division of Mood and Anxiety Disorders, Centre for Addiction and Mental Health




ing cause of disability worldwide and is projected to be the second highest contribution to the global burden of disease by the year 2020, second only to heart disease.1 It has an estimated lifetime prevalence worldwide of 7-19%, and tends to occur more frequently in women than in men.2 This highly common mental illness causes significant personal, social and occupational/academic impairment, and there is also substantial cost to society in terms of lost worker productivity and health care resource utilization, which have been estimated at $80-100 billion USD annually.1

A wide range of pharmacological and psychological treatments have been developed to treat depression.4 But in spite of appro-

However, clinicians and researchers also concur that, in order to identify potential new treatments, a better understanding of the etiology of depression is urgently needed. No single cause has been identified for depression, and it is generally agreed that the multiple factors are contributary; these may be biological, psychosocial, or environmental in nature, and likely interact in triggering and maintaining depression. A brief review of some of the key factors is presented below.

Biological factors Family and twin studies confirm the significant contribution of genetic factors to onset of depression, with heritability estimated at 30-40%.6 As it is a genetically complex disorder, a wide range of genes are thought to be involved in the pathophysiology of depression, and among them, the serotonin transporter gene and the tryptophan hydroxylase genes (involved in the synthesis of serotonin) are thought to be particularly relevant.6


Altered activity of neurotransmitter systems and the hypothalamic-pituitary-adrenal (HPA) axis have also been implicated in depression. Neurotransmitters (e.g. serotonin, norepinephrine, and dopamine) moderate mood, as well as the physiological and cognitive symptoms of depression, while the hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the stress response and regulation of mood/emotion.6,7 Altered monoaminergic and HPA axis activity have been shown to be associated with depression, but the type of association may vary in different subtypes of depression.6,7 Monoaminergic activity may also play a role in depression in another way. Patients with other medical illnesses, e.g. heart disease, stroke, Parkinson’s Disease, and Alzheimer’s Disease, often present with clinical depression, as well.8 Similarly, a number of me dications used to treat physical and mental illnesses have been noted to induce depression.8 It has been proposed that the emergence of depression in these contexts is likely mediated by the monoaminergic neurotransmitter systems.8 Hormonal abnormalities have also been linked to depression. Adrenocorticotropic hormone (ACTH), thyroid hormones, and estrogen all modulate neurotransmitter activity.6,8 Cushing’s Disease (characterized by ACTH overproduction) and thyroid hormone deficiency are known to present with depression-like symptoms.6 Further, fluctuation in estrogen levels over the lifespan

Photo by Matthew Wu

Depression can manifest in several different forms: unipolar, bipolar, atypical, melancholic, persistent (chronic), postpartum, psychotic, and seasonal.3 Common symptoms include affective symptoms (such as low mood, irritability, anxiety, and suicidality), cognitive symptoms (i.e. difficulties with concentration, decision making and motivation) and neurovegetative symptoms (changes in appetite, sleep, energy and sexual functioning, and psychomotor changes). However, differences in some phenomenology, such as circumstances of onset, presence of concurrent psychosis, direction of neurovegetative changes, and chronicity, do distinguish between forms of depression.

priate treatment, about 20-40% of patients are resistant to treatment or experience subsyndromal symptoms, with resulting impact on their functioning and well-being.5 This is a clinical concern as unremitted depression is associated with higher rates of relapse, poorer quality of life, and increased mortality rates.5 As a result, there is increasing drive to find more effective treatments and to enhance long-term outcomes for both patients and society.

EXPERT OPINION has been proposed as a possible risk factor for depression in women.6,8 Alterations in estrogen levels (e.g. at the start of the menstrual cycle, in the postnatal period or during (peri)menopause) is said to result in monoamine changes and to increase their vulnerability to depression.8

Psychological factors The cognitive theory of depression suggests that maladaptive cognitive processes, reflected in a self-perpetuating cycle of negative thoughts/interpretations (about the self, life, and the future), emotions and behaviors, may play a key role in depression.9 Indeed, those with a negative outlook have been found to report lower mood following a negative event than others, and a negative mind-set has also been noted in depressed individuals.9 Whether a negative cognitive bias is a cause or result of the illness is still a matter of debate, but its association with depression is the basis for cognitive therapy, a proven effective treatment for depression. Related to this, certain personality traits are also seen as increasing vulnerability to depression. Individuals who display high levels of neuroticism (i.e. a tendency toward negative mood states such as anxiety, envy, jealousy, moodiness), have been found to be more prone to developing depression.6 In contrast, those high in extroversion or openness to experience appear less likely to do so. Learned helplessness is another proposed causative model for depression. It is thought that repeated exposure to stress reduces personal sense of control over such events in vulnerable individuals, inducing to a sense of helplessness and perceived lack of self-efficacy, and in turn, inability or lack of motivation to avoid stress.10 Learned helplessness has been found to correlate with depression and impaired performance and also to predict changes in depression over time.10 The ability to cope with stress also plays a role in depression. Maladaptive (emotion-focused) coping style predicts depression and stress, while adaptive (problem-focused) coping is associated with lower incidence of these symptoms, as well as better resilience and functioning.11

Social/Environmental factors Stressful life events are a widely accepted social/environmental contributor to de-

pression, and depressed individuals report an increase in both major and minor life events and ‘daily hassles’.6 Childhood abuse (particularly sexual abuse) or neglect, experience of trauma (to self or others), bereavement, or major life transitions (e.g. going to university, losing a job, ending a romantic relationship) have all been correlated with depressive onset.6 Poverty, as well as other adverse social determinants, such as physical illness, poor working conditions or lack of social support, are also associated with increased risk of depression.8 Among other social factors, marital status may be a protective influence for men, as higher rates of depression have been reported in single men than married men.8 For women, having children at a young age, being at home with several children, and lack of adequate social support, all appear to increase risk of depression.

Multifactorial Interaction in Contribution to Depression The biological, psychosocial, and environmental factors described above do not act in isolation. They interact to increase the overall vulnerability to depression, which may also contribute to subtype, severity and chronicity. Some such interactions are described below. For example, neurotic individuals may be more likely to experience negative life events, either because they perceive events more negatively, or act/react in a way that worsens situational impacts on them, which increases their risk of depression.6 Neuroticism also appears to predict the type and incidence of negative life events experienced. Similarly, childhood abuse has been correlated with higher neuroticism, more negative events experienced in adulthood, and higher rates of depression.6 These phenomena demonstrate a “nature-nurture” contribution to depression, as temperament is heritable to a large degree. In a similar vein, emotional neglect and abuse has been noted to produce a permanent sensitization of the HPA axis in very young children.6 By extension, such neglect/abuse also has a permanent (deleterious) effect on the activity of neurotransmitter systems involved in mood regulation. Together, these neurobiological changes negatively influence stress reactivity and emotional response, thereby intensifying experiences of stressors and risk of depres-

sion. However, it is also of note that the base reactivity of the HPA axis at birth is genetically determined, and post-birth experiences serve to heighten or reduce its sensitivity.6 As a result, some individuals may have a predisposition to stress sensitivity and depression that is exacerbated (not triggered) by negative childhood experiences. This overlapping gene-environment interaction can have profound lifelong consequences for vulnerable individuals. In addition, children of depressed parents have been found to exhibit more negative self-perceptions, hopelessness and pessimism in response to interpersonal conflicts than other children, perhaps reflecting a learned response to stressors.6 Since maladaptive coping styles and cognitive outlooks are both strongly linked to depression,9-11 the interaction between genetic vulnerability (based on family history) and learned negativity (via modeling) may further heighten risk of depression.

Conclusion Multiple factors (biological, psychological, social/environmental) contribute to increased vulnerability to depression,6-8 which often results in significant functional impairment in both the short-and longterm outcomes, and also higher risk of early mortality.1 Further exploration of these factors will help greatly to improve patient management and treatment (both pharmacological and psychological), as well as in prevention strategies. ☐

References 1. Eaton WW, Martins SS, Nestadt G, et al. The burden of mental disorders. Epidemiol Rev. 2008;30:1-14. 2. WHO Consortium in Psychiatric Epidemiology. Cross-national comparisons of the prevalences and correlates of mental disorders. Bull World Health Organ. 2000;78(4):413-26. 3. Patten SB, Kennedy SH, Lam RW, O’Donovan C, Filteau MJ, Parikh SV, Ravindran AV; Canadian Network for Mood and Anxiety Treatments (CANMAT). CANMAT clinical guidelines for the management of major depressive disorder in adults. I. Classification, burden and principles of management. J Affect Disord. 2009;117 Suppl 1:S5-14. 4. Davidson JR. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry. 2010;71 Suppl E1:e04. 5. Paykel ES. Partial remission, residual symptoms, and relapse in depression. Dialogues Clin Neurosci. 2008;10(4):431-7. 6. Goldberg D. The aetiology of depression. Psychol Med. 2006;36:1341-7.Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. 7. Langlieb AM, DePaulo Jr. JR. Etiology of depression and implications on work environment. JOEM. 2008;50(4):391-5. 8. Clark DA, Beck AT. Cognitive theory and therapy of anxiety and depression: convergence with neurobiological findings. Trends Cogn Sci. 2010;14(9):418-24. 9. Nolen-Hoeksema S, Girgus JS, Seligman ME. Learned helplessness in children: a longitudinal study of depression, achievement, and explanatory style. J Pers Soc Psychol. 1986;51(2):435-42. 10. Mahmoud JS, Staten R, Hall LA, et al. The relationship among young adult college students’ depression, anxiety, stress, demographics, life satisfaction, and coping styles. Issues Ment Health Nurs. 2012;33(3):149-56.


Book Reviews Stiff

The Curious Lives of Human Cadavers by Mary Roach, W.W. Norton & Company, Inc. 2004. 303 pages


and assess the damage to the cadaver along with the location of the person on the plane to piece together the exact cause of the crash. These surprising uses of human cadavers are fascinating to read because, although it is more well known that testing is done to ensure safety of cars and to improve military tactics, it is not generally known that cadavers unravel the mysteries of plane crashes.

n Stiff: The Curious Lives of Human Cadavers, Mary Roach explores the many ways human cadavers have are used, and have been used in the past for medical and scientific research purposes. Roach ventures from the use of cadavers in medical school anatomy classes, to techniques used in the 1800s to determine cause of death, and to alternatives to burial and cremation. While the subject matter is quite morbid and could have been sad or morose, Roach approaches the material with a light-hearted candor and humor that makes it an enjoyable read while still maintaining the respect for which this subject calls. In the first chapter, Roach writes of her visit to an anatomy laboratory where she observed students learning about facial anatomy and face-lifts on human heads. She discusses the practice of objectification wherein people working with cadavers think of them as objects to limit any emotionality and make it easier to dissect them. However, there are memorial services held by the school at the end of the year for the cadavers, attended voluntarily by the students to honor the individuals who donated their bodies to science. It was interesting and comforting to know that the cadavers are treated with such respect.

Review by Rebecca M. Ruddy

This book is filled with intriguing stories describing the author’s journey to various laboratories and research sites to provide a look into what it means to “donate your body to science.”

In the chapters that follow, Roach provides an interesting look into the use of human cadavers for determining the cause(s) of plane crashes, developing or improving weapons for the Army, and for crash tests as dummies. It was fascinating to discover all of the uses of human cadavers and the advances in safety that have occurred as a result of their use in research. An interesting and surprising chapter centers on the use of human cadavers when a black box is unrecoverable or damaged following a plane crash. Scientists are able to recover the cadavers from a plane wreck, specifically one that occurred over the ocean, 26 | IMS MAGAZINE WINTER 2014 CARDIOVASCULAR DISEASE

The history of human cadavers in science is explored toward the end of the book. Although it is essential to learn about the history of cadavers and how their use first began in research to appreciate how far studies on human cadavers have come, it is a bit lengthy. A particular chapter about cannibalism seemed to be more anecdotal about the author’s journey to discover the truth about what she had read about cannibalism, as opposed to hard facts and research. However, the chapter regarding studies performed on human heads (“Just a Head”) following decapitation and head transplants is particularly interesting.

Overall, the purpose of Stiff: The Curious Lives of Human Cadavers is to provide the reader with a broad understanding of the uses of human cadavers today and in certain parts of history. This book is filled with intriguing stories describing the author’s journey to various laboratories and research sites to provide a look into what it means to “donate your body to science.” In the end, Roach also sheds light on what she would choose to have done to her body once the time comes. She offers an interesting perspective given the amount of research she has done for this book. It also allows the reader to take an introspective journey and determine the fate of their body after death. This book was an intriguing and fascinating read and offered the reader an exciting look into the world of human cadavers in a surprisingly humorous and enjoyable way. ☐

Brain on Fire My Month of Madness

by Susannah Cahalan, Free Press, 2012. 264 pages

Review by Chelsea Lowther


her spinal fluid and blood sample to a research laboratory headed by neuro-oncologist Dr. Joseph Dalmau at the University of Pennsylvania. As we wait for the results on Susannah’s 25th day in her locked down epilepsy unit, a final round of neuropsychological tests reveal she is cognitively regressed to the point that she could no longer identify a pen. This current picture of Susannah is contrasted with images of her earlier self: a smart, tenacious 24-year-old on the brink of her dream career.

e first meet Susannah Cahalan, a bright aspiring journalist at a prominent New York newspaper, facing the mundane problem of bed bugs in her new downtown apartment. However, not all is as it seems—Brain on Fire is Susannah’s gripping real life account of her “descent into madness.” What begins as a slight obsession over bed bugs quickly turns into a downward spiral of recurring psychotic episodes, seizures, and day long memory lapses. Susannah carefully chronicles her month long stay at the New York University Langone Medical Centre and the slew of tests and physicians that follow, leaving readers eager to know: what exactly is wrong with her and will she ever return to her normal self? Brain on Fire is a poignant reminder to seasoned veterans and future physicians not to lose track of the patient in the middle of a medical mystery. We are introduced to Susannah’s first neurologist, Dr. Bailey, who quickly dismisses her illness as alcohol withdrawal. We later learn that Susannah confronts Dr. Bailey with her final diagnosis and he tries to explain that he saw over 35 patients that day. The exchange is cringeworthy to say the least and a haunting indication that second opinions are sometimes worthwhile.

Amidst the medical jargon and eerie video surveillance descriptions is a deeply personal tale of one woman’s experience into madness.

Susannah is on a roller coaster of diagnoses (bipolar disorder, schizophrenia, and epilepsy) and assessments (spinal taps, blood work, and psychological testing) that ring with such detail you are left wondering why textbooks cannot be written with the same creative prose. We cannot help but feel for Susannah’s family and boyfriend who receive one negative test after another. Infectious disease? No. Autoimmune disorder? No. Encephalitis? No. Is she crazy? To be determined. When all seems lost we are reminded that science usually has the last word. A single publication from 2005 in Annals of Neurology has prompted Susannah’s second neurologist, Dr. Najjar, to send

Amidst the medical jargon and eerie video surveillance descriptions is a deeply personal tale of one woman’s experience into madness. All the details of which were gathered from her foggy memory, medical records, psychological test results, family members, friends, nurses, physicians, and even her unit security guards. We learn how Susannah’s illness affects her commonly feuding parents, new boyfriend, as well as new and old friends. We empathize with her parents as they struggle to deal with the “new” Susannah, balancing between her current disability and the desire to grant her independence.

Hidden undertones in her memoir is the sneaking belief that anything— even the locked down epilepsy unit—is better than a psychiatric ward. Hospital staff even goes as far as to threaten to send her to the psychiatric unit if she does not start behaving better. While I find this book to be well-written, captivating, and chock-full of interesting medical information I cannot help but put it into the category of popular media that continues to perpetuate the stigmatization of individuals with mental illness. For if you do not have a clearly defined biological explanation for your abnormal behavior, well, then we would rather not say too much. Having said that, I believe anyone with an interest in medical mysteries will enjoy this book and I promise the ending will be sweetly satisfying and scientifically intriguing! ☐



Close-up: Dr. Mingyao Liu Professor of Surgery, Medicine and Physiology Associate Director, Institute of Medical Science Faculty of Medicine, University of Toronto Senior Scientist Head, Respiratory and Critical Care Research Group Toronto General Research Institute, University Health Network

By Brittany Campbell

“So, what can I do for you today?� he asks, folding his hands on his desk across from me. I informed Dr. Liu that I wanted to learn more about his position, his responsibilities, and his background that prepared him for his new position as the Associate Director of the Institute of Medical Science (IMS). Dr. Liu not only gave me biographical information, but also a peek into the

science-fiction-like research he oversees, plans for the future of the IMS, and attributes he hopes to see in future leaders of research and medicine. Dr. Liu has had various academic administrative roles over the years at the University of Toronto and is a full Professor of Surgery in the Department of Physiology and Medicine. He has been the newly appointed Associate Director for just under a year now, but Dr. Liu has been involved with the IMS since 2000, starting out as the sole graduate coordinator. His work included admissions, curriculum, and degree facilitation for five years until he took on the position of Associate Dean for the School of Graduate Studies for the next two years. Dr. Liu then


moved to the Faculty of Medicine to serve as the Director for International Research Relations, and finally returned to the IMS to assume his current position. Leading up to his current coordinative and academic roles, Dr. Liu obtained his M.D. in 1983 and a M.Sc. in 1986. As students, we report to our supervisors and graduate coordinators. Our supervisors, however, report to Dr. Liu. He is in charge of over 600 faculty, each with a fiveyear appointment. This means that every year, over 120 faculty contracts need to be reviewed for renewal. Dr. Liu and the Appointment Committee reviews applications and evaluates faculty in terms of research productivity, funding, and graduate super-

Photo by Chung Ho Leung


I ARRIVED AT HIS OFFICE ON THE SECOND floor of the MaRS building, I did not expect Dr. Mingyao Liu to rise from his desk and offer to hang my coat for me upon greeting. It was the first of many signs I noticed, throughout the interview, of a director who cares deeply for the students he oversees. HEN

CLOSE-UP vision. The IMS has two primary types of memberships that faculty can have: Regular Member (Full or Associate) and Restricted Member. The former has many more members than the latter and is composed of supervisors that are independent researchers who are qualified to train and guide students in their career development. Restricted members are primarily teachers, offering expertise in Program Advisory Committee meetings and teaching courses in the Professional Masters Programs, without necessarily having independent research funding. Restricted memberships are often used as a training ground for a Regular Associate membership.

biotics, cleared of blood clots, or given oth- remarks. He notes that just under half of er aggressive treatments to raise the lung to the province’s money goes to hospitals and successful transplantation standards with the health care industry, and that the UHN no risk of side effects to the recipient. “The and The Hospital for Sick Children are goal is to maximize the number of success- among the top 15 biggest businesses in the ful transplantations without expanding the province. His message to students is that donor pool,” he says. These new transplant techniques have been successfully applied to over 100 patients Instead of encouraging everyone to beto date. Moreover, they come a future professor, we need to help have been able to use appeople to realize that there are numerous proximately 45% of docareers in health care. We need to move nated lungs for transplant away from the doctor-professor binary. compared with the 15% of donated lungs that are typically usable. Dr. Liu admits that one challenge in his there is room for everyone in health care role is orienting new faculty members into The breakthroughs do not stop there. Long and that it is simply a matter of better career such a large research community. The IMS term goals include assessing and using eveducation and mentoring. Dr. Liu himself spans different hospital sites with what Dr. ery lung in a hierarchal fashion: lungs in has undertaken this challenge, along with Liu calls different “research cultures.” For good condition can be transplanted right the other senior academic administrators example, The Hospital for Sick Children is away, lungs that need improvement will at the University of Toronto, to introduce strongly rooted in cellular and molecular be put through ex-vivo treatments, and the new Professional Master’s program in biology research, Toronto Western Hos- lungs that are beyond repair can hopefully Translational Science to the IMS. He bepital is well-known for neuroimaging and be de-cellularized and rebuilt using tissue lieves experts in translation are the future autoimmune research, and Toronto Gener- engineering technology. Eventually this research leaders and has pointed the faculty al Hospital (TGH) is at the cutting-edge of team plans to expand and use modified in the direction of training them. transplantation and translational research. versions of the ex-vivo technique on other Dr. Liu’s own research is based out of TGH, organs like the liver, heart and kidneys. He We ended with a light-hearted discussion where he is developing state-of-the-art lung describes his research as “very translation- about his desired qualities in our future transplantation models. al” and explains that this type of research leaders. He held both hands out in front success is only possible with a large team of of him and shook them. “Good hands,” he “The organ donation rate is very low, alpeople that span several areas of expertise. says, “a great researcher has to have good most flat over the decades,” Dr. Liu informs From clinician-scientists and researchers, hands and a smart head. A big heart too, me. “In addition, the majority of the lungs to engineers and biotechnologists, to ven- but usually those three things do not come are injured, infected with pneumonia, carry ture capitalists and fundraising managers, to the same person.” I nod in response. blood clots, or are otherwise unsuitable for medical research today “For those who do clinical care, perhaps is an ever-expanding good hands and a big heart are enough….” team of people and Dr. he muses. “For those who are very ambiLiu feels that our educa- tious, there is the clinician-scientist route.” ... a great researcher has to have good tion system struggles to Regardless of their career choice, Dr. Liu meet the demand. promises to help his students in their career hands and a smart head. A big heart too ... development, through open discussions “Instead of encouragand good direction, and recommends othing everyone to become er principal investigators to do the same. a future professor, we “Don’t be afraid to discuss your goals,” he need to help people to advises, “we want to know and we want to transplantation.” He goes on to tell me that realize that there are numerous careers in help. You are the future leaders.” in the past, the only thing separating a bad health care. We need to move away from lung from a good lung was a solid clinical the doctor-professor binary,” he cautions. inspection. Now—as one half of a fruitful 20 Although Dr. Liu predicts a significant year partnership with the Surgeon-in-Chief opening in faculty positions as the older of the University Health Network (UHN), generation retires, he believes that we still Dr. Shaf Keshavjee—Dr. Liu and their team need to train students for a wider range of have developed a technique called “ex-vivo positions. “We can’t continue to be proud of lung perfusion.” Donated lungs deemed research-heavy, course-light programs. We subpar for transplant initially are kept alive need to offer more professional-based gradoutside the body while being assessed, and uate programs to train students to occupy be treated as necessary with high dose anti- different niches in the healthcare field,” he




The Consequences of Personal Genetic Information in the Hands of Consumers By Kasey Hemington


The company, 23andMe, is selling a Personal Genome Service (PGS): customers send in personal information, saliva samples, and 99 USD in return for a slice of their raw genetic data—a set of single-nucleotide polymorphisms selected by researchers—and accompanying ancestral and health interpretations. Ethically, legally—it’s a nightmare. The Silicon Valley startup’s privacy statement is a rosy promise to protect personal information except where ‘required by law’, but that doesn’t mean customers are getting the whole picture. For example, most customers probably aren’t aware that while the recent United States Genetic Information Nondiscrimation Act (GINA) protects Americans against genetic discrimination by health care providers and employers, there is no protection against discrimination from long-term care insurance providers. Here in Canada, there is no act like the GINA at all, meaning employers and health insurance providers of Canadians purchasing the kit could request results and use them as basis for discrimination.1 A failure to provide them may be treated as any other failure to provide health information. The Parkinson Society Canada even lists a warning for the 23andMe Parkinson Community Research project, stating that “for Canadians, there is potential risk to their privacy as well as insurance or

employment implications.”2 What’s more, while accounts can be deactivated, it isn’t clear if all clients’ personal information can be permanently erased. One can’t help but be wary that endless Facebook-esque privacy battles will follow, except with consequences bigger than photo and wall post regrets. Ultimately, the goal of the project itself is information exploitation—not just selling trendy saliva kits with potential health implications for individuals. With founder Anne Wojcicki’s love of big data and her former marriage to Google co-founder and now 23andMe investor Sergey Brin,


her long-term plan certainly includes the mining of your data. Ms. Wojcicki herself recently interviewed with Fast Company, saying “I want 25 million people. Once you get 25 million people, there’s just a huge power of what types of discoveries you can make. Big data is going to make us all healthier.”3 The discoveries she refers to also imply company profits. Pharmaceutical companies will pay to access genetic or behavioural data that predict risk of developing cancer, diabetes, and Parkinson’s disease. Hospitals will pay for personalized drug metabolism profiles to optimize patient dosage. Academic institutions will

Illustration by Andrew Tubelli

he stories on the company blog are sensational and alluring—a PR dream come true. Long searching adoptees learn of their true ethnic roots and visit native countries that they never imagined they belonged to. Upon discovering a relative’s cancer diagnosis, a woman demands further screening at her own check-up when the doctor finds something but wants to wait. An older gentleman is alerted that given his genetic profile, his medications are likely the cause of his newly developed muscle weakness, and he fiercely petitions his doctor for alternatives.

VIEWPOINT want to access the massive data sets they could only dream of collecting with traditional methods. At this point, if you’re thinking of buying one of these fascinating spit-collecting contraptions despite the aforementioned complications, you might be out of luck. Technically, the kits are still for sale, but due to a recent warning letter from the United States Food and Drug Administration (FDA) on November 22nd, 2013, 23andMe has suspended the provision of its neatly packaged interpretations. Customers now only receive raw data—useless unless they are genetics experts or are willing to spend months reading scientific articles and trusting their personal interpretations.4 The FDA’s communication was two-fold: The main issue is that, as the PGS is marketed as a tool in diagnosis, treatment, and prevention of disease, it is classified as a medical device, and 23andMe has failed to provide the data necessary to demonstrate device accuracy. Highlighted concerns include persons taking drastic and potentially harmful prevention measures against disease or failing to adequately protect themselves when PGS reports do not accurately reflect true risk. 23andMe has informed the public that it is complying with the warning by including only genetic results without interpretation for the time being, and is working to complete the necessary studies. A second issue, for which the FDA did not request any specific actions, pertained to self-management of medications. 23andMe isn’t just about the risk of disease—the health report portion of the PGS is divided into disease risks, carrier status for conditions, specific traits, and drug responses. The fear of customers taking it upon themselves to manage medications without a complete understanding of the drugs—even if the results are 100% accurate—is real. From the letter, though, it appears the FDA will consider offering full approval even if this issue is not addressed. FDA territory may only include accuracy of the PGS as a medical device, but other risks such as the self-management of prescriptions as mentioned by the FDA, also need to be considered in the provision of genetic services. Failure to closely monitor how people will interpret the information is just as important as the scientific accuracy of the tests. 23andMe’s blog directs readers to a series of studies that appear to answer a related ques-

tion: Will newfound knowledge of high genetic risk for disease cause long-term stress and anxiety?5 According to these studies, the answer is no, though some reviews and blogs by individuals do express the opposite. But even if we move past this burning question and assume that the decision to get tested is that of the individual, there are other fundamental flaws in the information as 23andMe presents it. Let’s get one thing straight: Humans don’t intuitively understand numbers, and we’re incredibly vulnerable to interpreting them differently based on their presentation. This is why the PGS costs $99 instead of $100 and why companies decide to split stocks—making the company appear more affordable although the underlying value has not changed. This is why people buy lottery tickets and why casinos stay in business. Here’s what it means to impressionable humans interpreting the information in a PGS: In the health risks section (according to online reviews), red and green ink are used to indicate a higher or lower than average risk for developing a disease, respectively. This puts unnecessary emphasis on positively or negatively comparing oneself to an arbitrary average comprised of different ethnicities, ages, and lifestyles. For example, Jimmy finds out he has a 3.4% chance of developing restless leg syndrome (in red) compared to a hypothetical average of 2% and only an 18% chance of getting cancer, compared to 23% on average (green). Jimmy might run to the doctor the minute he has a poor night’s sleep. If he does have restless leg syndrome, he might be diagnosed more quickly, but no one has taken Jimmy’s environment into account when considering his risks; he is 68, a smoker, and morbidly obese. With his true risk of developing cancer likely higher than 18%, will Jimmy take positive steps toward cancer prevention and discuss cancer screening with his doctor as a result of his 23andMe report? Will a genetics company communicate to him that environmental factors are far more important than genetics in this case, or that 18% is still a risky die to roll? University of Toronto Professor of Biochemistry Dr. Laurence Moran recently described a viable solution (at least for Canadians) to this potential public health crisis waiting to be ignited by the fiscal motives or ignorance of private industry. He suggests that the Canadian government should

provide free genetic counselling. His theory is that since government counsellors, unlike private providers, would be trusted to provide unbiased advice, the private competition would simply die out.6 This is reasonable in theory, but the Canadian government has no plans to revolutionize healthcare through genetic testing in the immediate future, and so we can at least commend 23andMe for moving things forward at lightning speed, despite the road bumps. A feasible, more immediate addition to Prof. Moran’s long term suggestion might be the requirement of a closer working relationship between government bodies like the FDA, and genetics firms. Fully disclosing the methods used in determining disease risks to medical personnel would ensure the information is useful amongst the medical community and promote doctor-patient discussion. Meanwhile, the provision of direct web links to local health authority disease screening recommendations would strengthen an individual’s sense of responsibility for their own health outcomes. Newfound genetics knowledge does have the potential to revolutionize healthcare, as long as there is a plan in place to ensure accurate genetic information is presented without bias, and that it empowers the public to take constructive steps towards improved personal health.

References 1. Office of the Privacy Commissioner of Canada. (2012). Genetic Information, the Life and Health Insurance Industry and the Protection of Personal Information: Framing the Debate. Retrieved December 28th from gi_intro_e.asp 2. Parkinson Society Canada (2013). 23andMe Parkinson Community Research. Retrieved December 28th from site/c.kgLNIWODKpF/b.5743161/k.1E3F/23andMe_Parkinson_Community_Research.htm 3. Murphy, E. (2013). Inside 23andMe Founder Anne Wokcicki’s $99 DNA Revolution. Retrieved December 28th from 4. Food and Drug Administration (2013). 23andMe Inc. Retrieved on December 28th from WarningLetters/2013/ucm376296.htm. 5. 23andMe (2013). Few Worries about Genetic Testing. Retrieved on December 22nd from few-worry-about-genetic-testing/. 6. Moran, L. (2013). Michael Eisen defends 23andMe against the FDA. Retrieved on December 28th from http://sandwalk.blogspot. ca/2013/12/michael-eisen-defends-23andMe-against.html.



Science: The Long Game A

ctive readers of scientific journalism no doubt smell the stench of rot on the scientific publication system. The Economist put out two outstanding articles, “How Science Goes Wrong” and “Trouble at the Lab,” discussing the problems scientists face with data replication;1,2 Nobel winner Randy Schekman is boycotting top scientific journals Nature, Science, and Cell because of their focus on sexy results instead of “good science”;3 and countless blog posts from well-known and anonymous scientists alike express similar distress about this broken system. The Economist articles outlined some scary truths about the current state of science.1,2 Researchers at Amgen, a multinational

biopharmaceutical company, could only replicate 6 out of 53 major cancer research studies. Approximately 80 000 patients were involved in retracted clinical trials. Negative results account for an increasingly lower proportion of reported findings (now at 14%). The list goes on. There are a number of theories as to why the publication system is so flawed, with careerism being near the top (see our previous article “Publish or Perish” by Amanda Ali); with so much pressure to produce high impact research, scientists shoot for the moon with fantastical studies that promise “paradigm-shifting” results, or even worse, they may outright fabricate data. Of course, if one does enough fantastical experiments,


statistics dictates that one is bound to produce a false positive. With such an emphasis on high impact data the foundations of the scientific method start to shake. Who is going to, or even wants to perform simple, yet necessary replication studies? Who can publish negative results in any sort of meaningful fashion these days? Blame can goes the other way too, with the peer-review system being put in the spotlight. As reported in The Economist, a biologist at Harvard submitted a fabricated article to over 300 journals; 157 journals fell into his trap and accepted it.1 A former editor of the British Medical Journal (BMJ) submitted an article with deliberate mistakes to over 200 regular editors at BMJ.

Photo courtesy of; ID # 18796768

By Adam Santoro

VIEWPOINT None of them could pick out all the mistakes, with most editors just spotting out a small fraction of them. The problems of the publication system also extend beyond the scientific enterprise and into the general public. Associated news releases promote a non-scientific way of knowing. Unique and “ground-breaking” experiments are published constantly in top tier journals and are reported in newspapers and websites worldwide as norm-shattering results. “What we thought we knew about X but were wrong!” Should we really be telling the public that the scientific community is making overreaching conclusions from single papers? What happened to independent replication, and placement of hypotheses into an already established framework of knowledge? It is difficult to come up with solutions to these problems, and many of the best solutions would be essentially impossible to implement. A simple improvement could be a double blind submission process whereby reviewers do not see the names of the authors, and vice versa. This can potentially alleviate any biases that exist; big labs should not always publish in top-tier journals because of the name of the principal investigator, the data should instead speak for itself (which, admittedly, it more often does). A study that is not blind and is submitted to a journal is harshly critiqued by reviewers. It baffles me as to why we accept a lack of blindness in the review system.

sist of mini-analyses of the data (and not Science, as a way of knowing, should, and necessarily the data originating from your does, demand respect. Science as an epislab). For example, I can access the database, temology is not broken, and is still the see a few experiments that were deposited best (and only way) in which we acquire by different labs, and write a paper assess- truths about the natural world. We must ing the validity of a hypothesis based on the remember that science is a long game, and data. With this approach it would be unwise given enough time, bad hypotheses and to accept a hypothesis and write about it if poorly collected data will be filtered out. there is only one experiment addressing it, and so papers would be fewer in number and more Science, as a way of knowing, should, impactful in nature. By and does, demand respect. Science as an separating the data from the origin we take a more epistemology is not broken, and is still the objective stance on the best (and only way) in which we acquire process and we let the truths about the natural world. data itself, not the intents and biases of the experimenter, to do the hard work in pushing scientific progress. To take things a step further, Likewise, we should embrace the scientific a necessary component of completing a process and incorporate its strengths into Ph.D. could be the replication of data in the our publication system. Data should be acsystem and a deposit of the confirmed re- cumulated–over time, and repeated many sults (or negative results). This would pro- times–before we accept hypotheses and mote replication of data and the publish- publish grand proclamations. We may have ing of negative results, all while instilling to come up with new ways of assessing inthe importance of these processes into the dividual scientific prowess and we may deal young minds of future scientists. I don’t see with huge difficulties in organization, but I any reason as to why a Ph.D. student today take these as challenges to produce a better would want to perform a replication study, system, not simply problems that we have and all of us are unfortunately left without to overcome. an outlet to publish negative data and simply have to shrug our shoulders and move References on when they are produced.

This idea is by no means flawless, and the problems with it are numerous. For example, we ... with so much pressure to produce high lose our measuring stick impact research, scientists shoot for the for evaluating scientists, moon with fantastical studies that promise there are disincentives to “paradigm-shifting” results, or even worse, actually produce the data they may outright fabricate data. since there is a lack of ownership over it, there would be extremely difficulty organization issues, and we would lose the In a completely ideal world (read: impos- ability to pursue a beautiful scientific stosible to implement), I would like to see the ry (perhaps the best part of doing science following system in place: a centralized is having an idea-your own idea−and living data repository, including both positive and it through). However, I think we would be negative results. I am unsure as to whether better off dealing with these technical and data should be presented void of origina- egoistic problems than with the problems tion, because let’s face it, we can be more of our current situation, which challenge confident in data produced by some labs the very foundations of the scientific promore than others. Papers would then con- cess.

1. Anonymous. Problems with scientific research: How science goes wrong. (accessed January 10, 2014). 2. Anonymous. Unreliable research: Trouble at the lab. http://www. (accessed January 10, 2014). 3. Ian Sample. Nobel winner declares boycott of top science journals. (accessed January 10, 2014).


Behind the Scenes with



I bring a creative, flexible and friendly approach to my work, and enjoy the engagement and resulting successes.


riginally from Burlington, Michelle Rosen grew up mostly in Toronto. She completed her honours bachelor’s in sociology with a double minor in women’s studies and history at the University of Toronto (UofT). She had initially contemplated about working in academia, but after travelling around the world during some time off, she started administrative work at UofT in 1996. She worked for the government, but yet again she came to UofT in the field of administration emphasizes how she really “really enjoy(s) organizing and coordinating projects.” Rosen was initially hired as a temporary worker at the Institute of Medical Science (IMS) to replace a colleague on maternity leave as Student and Faculty Affairs Coordinator in June 2012. During that time she managed IMS awards, faculty appointments, and curriculum administration. Rosen worked closely with the graduate coordinators, faculty, students, and staff to ensure that they were nearing achievable goals that promoted IMS’ translational approach to education. Towards the end of her temporary arrangement, she applied for her current position in IMS and became a term employee in November 2013. Rosen’s new position is very intriguing; she currently works as the Curriculum Coordinator, where she focuses on the development of the new Translational Masters program. She coordinates all curriculum related committees and manages all administrative processes related to courses and course evaluation. Rosen works closely with the director of the Translational Masters program and the IMS course director to develop new course content for the program.

Photo by Chung Ho Leung

For Rosen, social communication is paramount in her present position, “I really enjoy talking to students and enjoy being an advocate for them.” She specifies that her job requires multitasking, customer-service skills, and organization. Although challenging, Rosen finds her current position very gratifying, “I bring a creative, flexible and friendly approach to my work, and enjoy the engagement and resulting successes.” It is fascinating to know Rosen cherished her interest in website design by enrolling in a web development program at Humber College in the fall of 2011. This background has made her even more valuable to IMS, as she is one of the co-leads on the design team for developing the new IMS website ( Rosen has a special love for travelling, “All the places I go and people I meet inspire me in life.” She is encouraged by the difference and by the unknown, and in this way travelling impacts her vision about the world. Among the locations she has travelled so far, her favourite is India. One will be amazed of Rosen’s many hobbies outside of work, with perhaps the most fascinating being water polo. Rosen is a professional water polo player. Being a swimmer since childhood, she started playing water polo about four years ago and recently her team won a gold medal at a European water polo tournament. She also recently ran her first 10K in December 2013 after a few months of training. Moreover, Rosen has a profound interest in cooking, declaring her love of cooking shows.

Insider Information: Favourite dessert? Apple pie and ice cream Favourite vacation spot? India Favourite store? IKEA Favourite TV show? Big Bang Theory Favourite pet? Cats Favourite colour? Blue Favourite sport to watch? Figure skating Last read? A dance with dragons

All the places I go and people I meet inspire me in life.


Summer Undergraduate Research Program (SURP) Essay Winners

By Justin Wang Supervisor: Dr. Michael Fehlings Sylvia Plath once decried the frailty of the human heart in describing it as “a trembling thing, a fragile, shining instrument of crystal, which can either weep or sing.”1 When healthy, the heart robustly supplies and sustains every organ in the human body, beating dutifully to continuously circulate essentially life itself. But as Plath stated so insightfully, the heart can be temperamental, and it can weep as well as sing. In 2008, cardiovascular disease was responsible for 29% of all deaths in Canada.2 Upwards of 22 million people live with heart failure worldwide. Annually, only 3 800 heart transplants are documented.3 Even excluding those ineligible for transplantation, with increasing rates of heart disease, the supply of available donor hearts cannot meet the demand. Thus came idea of biosynthesizing artificial hearts. The bioengineering of organs is not a novel idea. In 2006, scientists engineered artificial bladders in vitro and successfully transplanted them into human patients.4 Recently, a synthetic trachea was produced via a 3-D printer and safely transplanted into a 6-week old infant with tracheobronchomalacia.5 However, the heart produces more challenges for biosynthesis because of its more complex structure and unique physiological characteristics. Anatomically, all four compartments of the heart and the great vessels must be produced. Even more difficult is fully vascularizing the heart with the coronary arteries and fine capillaries.6 In 2008, Dr. Doris Taylor and her team devised a method of utilizing the extracellular matrix from a human heart as the scaffold on which to introduce new cardiac cells. This strategy bypasses the difficulties of producing the heart’s struc-

ture from scratch and gives future transplanted cardiac stem cells a native environment to grow. It involves placing a donor heart in a bioreactor, where it is continuously perfused with SDS and other compounds until only the extracellular matrix, consisting of collagen and other structural proteins remains.3 Importantly, the heart utilized can be cadaveric or does not need to be from a human donor at all. Stephen Badylak, from the University of Pittsburgh, touts the merits of using pig hearts as they are safer, more resilient to illness, and are available in greater supply.6

to a fully functional heart while maintaining rhythm and contractile strength presents challenges.9,10 The Ott group utilized a bioreactor to electrically and mechanically facilitate synchronized contractions of the bioengineered heart. The heart remained ill-adapted to react to common physiological changes, such as blood pressure fluctuations or hormonal influences.6 However, after 8-10 days in the bioreactor, the heart gained the ability to contract on its own at approximately 2% of the pumping capacity of an adult heart or 25% that of a 16-week fetal heart.3

Other complexities arise from recellularizing the heart. The effects of heart disease or infarction are devastating in part because mature cardiomyocytes have lost their ability to proliferate and recover. Therefore, stem cells at some earlier stage of differentiation must be utilized. Induced pluripotent stem cells can differentiate from multipotent progenitor cells to vascular, ventricular, and endothelial progenitors to cardiomyocyte intermediates and lastly to mature cardiomyocytes, endothelial cells, and vascular smooth muscle cells.7 A decision has to be made regarding at what point, where in the scaffold, which cells, and how many cells need to be transplanted. Previous studies have looked at the potential of bone marrow-derived mesenchymal stem cells, hematopoietic stem cells, adipose-derived stem cells, embryonic stem cells, and induced pluripotent stem cells as potential cell populations ideal for implantation.8 There must be a difference between cells differentiating into cardiac muscle and cells differentiating into the vasculature. Harald Ott and his group successfully utilized neonatal cardiac cells and aortic endothelial cells to recellularize their heart scaffold.3

Thus, although a biosynthesized, fully implantable, and functional heart remains momentarily just out of reach, the sense of potential and innovation remains high. Massive strides are being taken from creating implantable patches of cardiomyocytes to biosynthesizing heart valves to isolating new cardiac stem cell lines.7,8,11 These advances have the potential to improve the standard of care and the quality of life for patients in incredibly innovative ways. Furthermore, these studies offer hope—hope of a day when we are no longer limited by simply being able to fix what is broken, but to also create what is missing.

In order for the heart to work, all cardiomyocytes must contract as a functional syncytium—simultaneously and rhythmically. Spontaneous and synchronized contraction of cardiomyocytes in vitro has been well established but to extrapolate that


References 1. Plath S. I Thought I Could Not Be Hurt. Letters Home Correspondence.1975; 1950-63. 2. Heart and Stroke Assoc. Heart and Stroke Foundation of Canada Statistics. Ottawa, ON. 2011. 3. Ott H, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nature Medicine. 2008; 14: 213-21. 4. Atala A, et al. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006; 367: 1241-46. 5. Zopf Da, Nelson ME, Ohye RG. Bioresorbable airway splint created with a three-dimensional printer. N Engl J Med. 2013; 368: 2043-45. 6. Maher B. Tissue engineering: how to build a heart. Nature News. 2013. 7. Vunjak-Novakovic G, et al. Bioengineering heart muscle: a paradigm for regenerative medicine. Annu. Rev. Biomed. Eng. 2011; 13: 245-6. 8. Kuraitis D, et al. The future of regenerating the myocardium. Curr. Opin. Cardiol. 2010; 25: 575-82. 9. Grunow B, et al. In vitro developed spontaneously contracting cardiomyocytes from rainbow trout as a model system for human heart research. Cell Physiol. Biochem. 2011; 27: 1-12. 10. Vidarsson H, Hyliner J, Sartipy P. Differentiation of human embryonic stem cells to cardiomyocytes for in vitro and in vivo applications. Stem Cell Rev. 2010; 6: 108-120. 11. Sacks MS, et al. Bioengineering challenges for heart valve tissue engineering. Annu. Rev. Biomed. Eng. 2009; 11: 289-313.

Illustration courtesy of; ID #17770872

Building an Unbroken Heart

Cognitive Impairment and Medication Nonadherence in Heart Failure Patients By Abra Shen Supervisor: Dr. Jennifer Jones

Medication nonadherence is common in patients with cardiovascular diseases and is a growing concern to patients, caregivers, clinicians, and healthcare systems. A study published in 2006 found that by day 7 of being discharged from hospital for acute myocardial infarction, 27% of patients had not filled their prescriptions for their cardiac medications.1 Not taking prescribed medications has been found to negatively affect overall prognosis and increase risk of mortality.2 For example, in patients with hypertension, medication nonadherence contributes to the development of further vascular disorders such as coronary heart disease and stroke.3 Here, we explore cognitive impairment (CogI) as an important but often overlooked factor that impacts medication adherence in patients with heart failure (HF). A healthy brain necessitates good cardiovascular health; the brain relies on blood to supply oxygen, nutrients, and other components to nerve cells. Patients with HF may have reduced cerebral blood flow and low cardiac output, which is associated with lower brain volume and other neuroanatomic changes.4 They are at a four times higher risk of CogI compared to healthy individuals, which may greatly impact how medical professionals plan and deliver treatment.5 A meta-analysis of 22 studies that included 2937 HF patients and 14,848 healthy controls showed a 62% increase in CogI in the HF group compared to the control group.6 The potential consequences of this elevated risk cannot be dismissed. CogI is associated with poorer medication adherence and may significantly impact an individual’s daily activities, lead to poor health-related self-care,7 and can worsen HF prognosis.8 Patients with HF are expected to follow treatment regimens that are often highly complex and require significant cognitive ability to comply. Not only is it difficult for cognitively impaired patients to remember which pills to take and when, but it is also more challenging for them to understand

the importance of taking their medication. Without a true understanding of the benefits of adherence, patients will be less motivated to develop compliance; typical patient education may not be sufficient for this population. In a comparison of HF patients with and without CogI, medication adherence significantly worsened by eight percentage points in the CogI group—8% of prescribed pills were either undertaken or overtaken.9 This raises significant challenges for these patients as poor adherence to HF drugs is associated with an increased number of cardiovascular-related emergency department visits10 in addition to an increased risk of morbidity and mortality.11 Despite these challenges faced by individuals with CogI, poor cognition is too often overlooked when caring for patients of heart failure.12 Physicians and nurses should screen for cognitive decline with written or verbal assessments. Some patients are embarrassed of their declining memory and other cognitive deficits and may not share these details with their health care providers. Thus, health care providers should also educate caregivers about the symptoms of CogI to encourage them to pay greater attention to patients’ behaviors. To help patients with CogI, small adjustments may help – verbal care instructions and medication schedules should be written down so that those with poor attention, learning and memory may develop better self-care management. For the technology-savvy, mobile applications that send alerts to remind patients to take their medications may be beneficial. For physical reminders, a pill box with compartments for every day of the week could help. Possible larger-scale interventions to improve adherence also include better patient education, patient motivation and support,13 and discharge medication counseling.1 There are currently clinical trials that are attempting to investigate the effects of exercise and a diet intervention to enhance cognitive and cardiovascular health,14 understand how CogI impacts self-management,15 and evaluate the use of an internet-based disease management platform.16 Further research should investigate the effectiveness of neuropsychiatric rehabilitation for CogI patients in improving heart function and reducing rates of hospitalization and mortality from HF.8 Overall, the quality of care for HF patients should be-

gin to shift from a cardiovascular-focused approach to a broadened approach that includes comprehensive care and places importance on cognition. By understanding how to better care for these patients’ well-being and developing strategies to improve medication adherence, we may be able to improve prognosis and quality of life.

References 1. Jackevicius CA, Li P, Tu JV. Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction. Circulation. 2008; 117: 1028–1036. 2. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005; 353: 487–497. 3. Munger, MA, Van Tassell BW, LaFleur J. Medication Nonadherence: An Unrecognized Cardiovascular Risk Factor. MedGenMed. 2007; 9(3): 58. 4. Dardiotis E, Giamouzis G, Mastrogiannis D, et al. Cognitive Impairment in Heart Failure. Cardiol Res Pract. 2012; 2012: 595821. 5. Elsevier. (2009). Heart Failure Linked to Cognitive Impairment [Press release]. Retrieved from press-releases/research-and-journals/heart-failure-linked-to-cognitive-impairment 6. Vogels RL, Scheltens P, Schroeder-Tanka JM et al. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail. 2007 May;9(5):440-9. 7. J Cameron J, Worrall-Carter L, Page K et al. Does cognitive impairment predict poor self-care in patients with heart failure? Eur J Heart Fail. 2010 May;12(5):508-15. 8. Sohani ZN, Samaan Z. Does depression impact cognitive impairment in patients with heart failure? Cardiol Res Pract. 2012;2012:524325. 9. Hawkins LA, Kilian S, Firek A et al. Cognitive impairment and medication adherence in outpatients with heart failure. Heart Lung. 2012 Nov-Dec;41(6):572-82. 10. Hope CJ, Wu J, Tu W et al. Association of medication adherence, knowledge, and skills with emergency department visits by adults 50 years or older with congestive heart failure. Am J Health Syst Pharm. 2004; 61: 2043–2049. 11. Ho PM, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. Circulation. 2009 Jun 16;119(23):3028-35. 12. Burke, M. Cognitive dysfunction underdiagnosed in heart failure patients. Retrieved from,0,w 13. Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med. 2004;164:722–732. 14. Duke University. ENLIGHTEN: Exercise and NutritionaL Interventions for coGnitive and Cardiovascular HealThENhancement. In: [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited2013 Jul]. Available from: show/NCT01573546NLM Identifier: NCT01573546. 15. Kent State University. Self-management and Cognitive Function in Adults With Heart Failure (Heart ABC). In: [Internet]. Bethesda (MD): National Library of Medicine (US). 2000[cited2013 Jul]. Available from: NCT01461629 NLM Identifier: NCT01461629 16. Simon Fraser University. Trial of an Internet-based Platform for Managing Chronic Diseases at a Distance (iCDM). In: ClinicalTrials. gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited2013 Jul]. Available from: NCT01342263 NLM Identifier: NCT01342263.



Future Directions with Karrie Wong, PhD


WONG HAS ALWAYS WANTED TO CONTRIBUTE to the fight against cancer because of her own personal battle with it in the past. After graduating high school in Bellingham, a small town in Washington, Karrie was forced to take a year off due to spinal chondrosarcoma, as she underwent a major surgery and spent two months in a hospital. “Physical pains aside, it was a time that I could now look back on fondly—I met many interesting people during my two months in the hospital, read many interesting books, and ultimately became a stronger person, at least mentally,“ Karrie told me. After that year, Karrie began her undergraduate studies at the University of Toronto in the Laboratory Medicine and Pathobiology (LMP) program, and went on to complete her PhD with the the Institute of Medical Science (IMS). Karrie is now a post-doctoral fellow in Dr. Glenn Dranoff ’s lab at Dana-Farber Cancer Institute at Harvard Medical School. ARRIE

During Karrie’s fourth year of undergraduate studies, she received the CIHR Regenerative Medicine Summer Studentship, which gave her an opportunity to delve into the field of immunology research. “Because the program was in regenerative medicine, I was actually not expecting to be assigned a cancer-related project. I guess we could call it fate, then, that Reg Gorczynski was assigned to me as my supervisor. In our first meeting he asked me what my research interest was, and I told him that I was really interested in the role of the immune system in driving and controlling cancer. He then told me about an ongoing project in the lab, investigating the role of CD200, an immunomodulatory molecule, in tumour immunity. It was a project that suited my interest perfectly, and so after a summer and one year of working in Reg’s lab as a technician, I decided to pursue my PhD with him.” In the early days of her career, Karrie’s passion for research was evident, as she had completed her fourth-year project with LMP and had accumulated more than two summers worth of research experience. For Karrie, her decision to pursue graduate studies with the IMS was an easy one.

“From my experience with research up to that point I had somehow given myself the impression that I was good at it (well, I was naïve then). I also became very interested in the role of the immune system in cancer and the potentials of cancer immunotherapy, and hence my choice to focus my PhD project on the novel immunotherapeutic target CD200 molecule for treatment of chronic lymphocytic leukemia. In terms of a career path, I’m definitely working towards becoming an independent investigator with my own research laboratory— although I will not rule out a career in the industry either. Whether in an academic or industrial setting, I’m aiming to continue to work on developing cancer immunotherapies.” Since the beginning of her graduate studies, Karrie saw the value of postdoctoral training for the development of a successful career in research. As such, she was careful when choosing her first postdoctoral project. “Dr. Dranoff is considered a leader in the field of cancer immunotherapy, and so it was really a no-brainer for me to apply to his lab. Luckily, because of his role as an external appraiser for my doctoral thesis, he was well-aware of my work and everything just went from there.” Karrie says that “the most important features of an enjoyable work environment are trust, passion, and fun—an environment in which colleagues would trust each other, have stimulating discussions about science, and could make jokes out of our experimental failures. Science is hard, and so an amiable, stimulating lab environment goes a long way to compensate for the daily frustrations of bench work.”

getting my abstracts selected for oral presentations (and hence travel awards) was one of my major motivations in the lab. I also travel to a new country almost every year. Because I’m a nerd, I also joined a book club—although it was more like a chatting and drinking club, as we tended to spend more time in our meetings chatting about everything but the books that we were supposed to be discussing. I also really took advantage of being an IMS student, which offered me a great selection of courses outside of my research focus of cancer and immunology—the two global health courses that I completed during my PhD studies were amongst the most enjoyable courses I had ever done. In the last year of my PhD, I decided to go out of my comfort zone—I took a painting class and a French class. I wasn’t any good at either, but being able to divert my brain to something beyond the different signalling pathways really helped me through that difficult year. Now, in Boston, I have taken up street photography, and I intend to continue to pursue these interests as my career evolves.”

Outside of science, Karrie holds many interests, and has gone on many adventures throughout her PhD. She says, “Traveling, in particular, is very close to my heart, and I feel that it’s really important for me to explore the world. As scientists, we tend to focus on very specific things—one protein, one disease model, etc. Sometimes it’s easy to get lost amidst, say, months of a Western blot not working. One of the benefits of being a graduate student is the chance to attend international meetings—

Karrie’s passion for research, determination, and love of adventure have helped her achieve an academic dream, and she now has a PhD in Medical Science under her belt to rely on while she is looking for new cancer immunotherapies at the Dana-Farber Cancer Institute. Her personal story will remain an inspiration to many people, showing that overcoming great difficulties can be empowering and give special meaning to the work that some of us will dedicate our lives to.


Photo by Karrie Wong

By Anna Podnos

ASK THE EXPERTS Dear Experts, I am going to be beginning my Master’s degree at the IMS shortly and wondering which courses I should enroll in? -Curious Student Dear C.S., The IMS offers a wide array of courses from diverse fields, including neuroscience, physiology, epidemiology, and ethics to name a few. It is often recommended you enroll in courses related to the field of research you are studying. You can discuss course options with your supervisor and PAC committee as they often have good insights into which courses may best help you thrive in your program. IMS students are also permitted to take graduate courses from other graduate departments, and this may be something to consider. IMS students are not bound by the one-course limit and if courses from other fields appeal to you, discuss the possibility of enrolling in additional courses with your supervisor and PAC committee.

All of this research and coursework is making me want to par-tay! I recently moved to Toronto and I am curious if there are events that I could attend to socialize with fellow IMS students? -Seeking Friends

Illustration by Jean YiChun Lin

Dear S.F., Research and coursework could be stressful and time consuming. It is important to avoid school burnout and allocate some time to activities you enjoy doing. Although I would personally recommend online gaming, socializing with fellow graduate students is also an appropriate option. The IMS office often sends out emails of upcoming official events. In addition, it is recommended you join the IMS Facebook group, as it is very active and there are students planning social events in attractions across Toronto.

I have an imminent presentation for a research conference and I do not feel confident with my public speaking skills. Are there any resources at University of Toronto that you could suggest would help hone my presentation skills? -Nervous Wreck Dear N.W., Do not fret! There are a number of resources available to you at University of Toronto without a fee and delivered to you by knowledgeable instructors. For instance, the School of Graduate Studies has an English Language and Writing Support unit which offers multiple courses for both native and non-native speakers of English. These courses typically run for 4-6 weeks on a weekly basis and are offered multiples times throughout the year. In addition to public speaking courses, this service also provides courses to improve writing and comprehension.

I understand that there is a minimum course requirement and mandatory course modules for the Masters program. I am trying to best strategize my schedule and wondering which year of the program would be most efficient to fulfill these requirements? -Timely Diva Dear T.D., I appreciate your early interest in organizing your schedule. It may be advisable to fulfill the requirements in your first year of the program and to direct your full attention to the completion of your thesis in your second year. New graduate students often have to obtain ethics approval for their study prior to collecting their data, and this may be a lengthy process. During this time, you could focus on completing coursework. However, it is always advisable that you discuss these issues with your supervisor and PAC committee.


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Ask the Experts


Dear Experts,

Dear Experts,

Dear Experts,




By Joshua Lipszyc

Dear Experts, My cousin is getting married in Honolulu during the December break. I want to know if it is permitted for me to take a week off to attend his wedding. -Excited Best Man


Dear E.B.M., The IMS allows several weeks of vacation time per year. However, it is important that you are not missing important program deadlines, including coursework, supervisory, and PAC meetings. If you are enrolled in a course or course module during this period, you may need to discuss accommodations with the course instructor regarding your absence. It is also advisable to discuss this matter with your supervisor to ensure that the vacation does not interrupt your research progress.

Get to know the IMS administration staff throughout your graduate degree. We are here to help! Do you have a question for the experts? Please send it to (ATTN: Experts).


PAST EVENTS IMS does Ripley’s Aquarium

PAST EVENTS IMS takes part in My Virtual Dream

IMS holiday party IMS gets dance lessons!

IMS holiday party silent auction for Workman Arts! 40 | IMS MAGAZINE WINTER 2014 CARDIOVASCULAR DISEASE



pick-up lines

The light you give me has brought me to a higher energy level. Things usually do not exist in an excited state for long, but I will always be hot for you. I suggest that we model neural metastability and oscillate in a cooperative manner.

I don’t need neurons to stimulate your sensory system. Let my ligand bind your G protein. I swear you’ll experience a cascade of reactions. We fit together like the sticky ends of recombinant DNA. You’re so hot, you denature my proteins. Baby, you make me vasodilate!

by Anna Badner

Honey, you’re so sweet that even my liver GLUT2 transporters would be at Vmax. I miss you like an ischaemic heart misses its blood supply. Nice antibody. Wanna conjugate? Baby, you can fill my caudate nucleus with dopamine anytime of day. I’d love to manipulate your variables in a controlled environment. I’m like an antigen and you’re IgG, so why don’t you act like an opsonin to facilitate some serious phagocytosis?

You’re my own topoisomerase, you relieve the stress off me. You’re like the ligase that fills in the Okazaki fragments in my heart. My love for you is like the universe, never ending and always expanding! When stem cell research gets there, I will give you a part of my heart! Blood is red, Cyanosis is blue I get tachycardia Whenever I think of you.

Call me Avogadro cause I got your number... Follow my current, because, baby we got potential.

#overlyhonestmethods It’s Friday, the whole lab is waiting for the boss to go home so we can go home #overlyhonestmethods

I can’t send you the original data file because I don’t remember what the excel file names mean anymore #overlyhonestmethods

We asked the undergrad to make coffee. He made decaf and now our experiment is guaranteed to fail #overlyhonestmethods

Brains were removed and dissected in, on average, 58 seconds. We know precisely due to a long running lab competition #overlyhonestmethods

Samples were spun for 13 minutes instead of the intended 3 because the hand written protocol was hard to read #overlyhonestmethods Experiment 2 was done as an excuse to use a bizarre piece of equipment we ‘inherited’ from a closed lab #overlyhonestmethods We did not make the corrections suggested by Reviewer 1 because we think Reviewer 1 is **** (uninformed) #overlyhonestmethods Blood samples were spun at 1500rpm because the centrifuge made a scary noise at higher speeds #overlyhonestmethods

Samples were left at 4°C for 48 hours because.... we forgot that they were in the fridge. #overlyhonestmethods Treatment 2 consisted of n=24 instead of n=25 b/c one of the tubes rolled under the freezer & we couldn’t find it. #overlyhonestmethods We actually did Exp 2 before Exp 1. The elegant reasoning written here is completely posthoc. #overlyhonestmethods The eppendorf tubes were “shaken like a polaroid picture” until that part of the song ended #overlyhonestmethods





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