Issue 20 by The Meducator

november 2011 | Issue 20 | www.meducator.org

canada’s healthcare system TOWARDS PATIENT-CENTERED & PREVENTATIVE MEDICINE Hockey concussions THE CONSEQUENCES OF HEAD INJURY

platelet microparticles

BIOMARKERS FOR CARDIOVASCULAR HEALTH

antipsychotic drug development USING ALLOSTERIC MODULATORS TO TREAT SCHIZOPHRENIA interview: dr. richard heinzl

AT THE FOREFRONT OF GLOBAL HEALTHCARE

issue 20 | NOVEMBER 2011 LETTER FROM THE EDITOR MEDBULLETIN

FEATURE COLUMN FORUMSPACE

Healthcare Transformation

articles

Potential Treatment for Schizophrenia

by Ritesh Daya

Microparticles:

Reliable Biomarkers of Thrombosis Is it Time to Worry?

12 15

by Khizer Amin

INTERVIEW

Dr. Richard Heinzl

At the Forefront of Global Healthcare

Editorial Board Matthew Chong Khizer Amin Shelly Chopra Keith Lee Bhavik Mistry Vaibhav Mokashi Humna Amjad Ilia Ostrovski Kimia Sorouri Andrew Webster

Lebei Pi Jennifer Kwan Xena Li Ellen Liang Annie Cheung Yasmeen Mansoor

Communications Aashish Kalani Mohsin Ali John Han Ijlal Syed Paul Cheon Tahir Ali

Interviewed by Kimia Sorouri

MACWIRE

Deputy Editor-in-Chief Daniel Lee

Graphics & Design Brian Chin

by Shelly Chopra

Concussions in Ice Hockey:

Editor-in-Chief Hiten Naik

Strategic Advisor Ahmad Alkhatib

by Adrian Tsang

Allosteric Modulators:

MEDUCATOR STAFF

ADDRESS The Meducator BHSc (Honours) Program Michael G. DeGroote Centre for Learning and Discovery Room 3308 Faculty of Health Sciences 1200 Main Street West Hamilton, Ontario L8N 3Z5

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LETTER FROM THE EDITOR: Transforming our Healthcare

At McMaster and other universities around the country, there able to tackle the devastating illness in a safer, more effective is a continuous and concerted effort in the health sciences manner. to develop innovative policy and medical interventions that could change the way healthcare is structured and delivered. Ritesh’s article is followed by a piece by a Critical Review by Through research and other pursuits, scientists, health profes- Shelly Chopra. The article analyzes the possibility of using sionals and policy-makers are always working to transform microparticles as biomarkers for thrombosis. As technology healthcare, and as students, we can play an important role in advances, our understanding of these microscopic vesicles is improving, and it may soon be time to use them in a clinical this process—both now and in the future. context. Also in this issue is an article by Khizer Amin which We can begin to make a difference by engaging in active discus- examines concussions in the context of ice hockey. Khizer prosion. For example, events held by the McMaster Health Forum vides an important medical perspective to an issue that has Student Subcommittee promote focused dialogue on specific evolved from an afterthought to front page news. issues in the health sciences. To extend this dialogue further, The Meducator is introducing a new regular column called Fo- While university provides a great environment for us to enrumSpace. This column will be written by members of the Sub- courage change, it is important that we maintain our penchant committee and will provide a distinctly student perspective on for advocacy even after we leave. Soon after graduating from a particular topic of interest. In our inaugural column this McMaster’s MD program, Dr. Richard Heinzl co-founded issue, Adrian Tsang discusses the coming transformations in Doctors without Borders Canada in 1988, and has since dediCanadian health policy. As Adrian writes, the First Minister’s cated much of his life to promoting healthcare in developing Accord on health will be expiring in three years, providing an nations. The Meducator’s Kimia Sorouri took the time to interopportunity for substantial changes in our healthcare system. view Dr. Heinzl for this issue when he visited McMaster last As young people, we have an important stake in what changes month. unfold and it is important that our voices are heard. I would like to welcome all the new staff of The Meducator. But health policy is not the only way students can help to Energized with their new ideas, we continue to work towards transform our healthcare. For example, in a Research Insight ar- our vision of providing a platform for students to share their ticle, Ritesh Daya discusses his work on developing new treat- ideas and work in the health sciences. After twenty issues, The ments for schizophrenia. By focusing on drugs that target the Meducator has also seen its share of transformations - we hope allosteric sites of receptors, Ritesh describes how we may be you enjoy this edition.

HITEN NAIK

President & Editor-in-Chief Bachelor of Health Sciences (Honours) Program, Class of 2012

The Meducator | November 2011

MedBulletin

DRACO: A POTENTIAL CURE FOR ALL VIRAL INFECTIONS

EPIGENETIC CHANGES IN STEELWORKERS

Ilia Ostrovski

pon diagnosing a patient with a bacterial infection, a physician usually follows the standard protocol of prescribing an antibiotic. However, in the case of a viral infection, much less can be done to intervene. In fact, most modern viral treatments are highly specific, prone to viral resistance and can cause adverse effects.

Recently, a team of researchers at MIT Lincoln Laboratory led by Todd Rider described the development and effectiveness of a drug that is capable of treating any viral infection. Doublestranded RNA Activated Caspase Oligomerizer (DRACO) has already been proven effective against fifteen different viruses, including H1N1 influenza, West Nile virus, and rhinovirus (the culprit behind the common cold). In addition to treating these viruses post-infection, this broad-spectrum drug is prophylactic and thus has the potential to also revolutionize preventative medicine. DRACO selectively targets infected cells by detecting viral double stranded RNA (dsRNA), a marker of a virus’s attempt to replicate itself inside the infected cell. Upon detection, DRACO initiates a cascade that induces apoptosis (cell death), without harming healthy cells. Isolating infected cells as targets for intervention by recognizing dsRNA was an idea inspired by the natural defense mechanism that our body utilizes to combat viral infection. By coupling this identification process with the induction of apoptosis, Dr. Rider and his team have achieved unprecedented success in combating viral infections. Rider’s laboratory is now working on optimizing the efficiency of dsRNA detection and apoptosis-induction processes by DRACO, and they hope to begin human trials as soon as possible.

Andrew Webster

hroughout the world, steel mill workers are exposed to airborne particulate matter (APM) containing high concentrations of toxic metals such as nickel, chromium, and arsenic.1 While epidemiological studies have linked the APM of steel plants with an increased risk of lung cancer, the mechanism of action is unclear.2 Previous in vitro studies with lung epithelial cell lines have suggested that the metals in APM may bind to histones—the proteins around which DNA is coiled. By oxidative stress, they induce activating histone modifications, including H3K9 acetylation and H3K4 methylation. These modifications cause a slight uncoiling of the DNA strand, exposing specific gene sequences for transcription. It is thought that these modifications may contribute to carcinogenesis by enabling the expression of cancer-promoting genes.3 A recent study by the University of Milano investigated whether these carcinogenic histone modifications seen in the in vitro experiments are also produced in the peripheral blood leukocytes of steel plant workers exposed to a variety of airborne metal particulates.3 The three-year study employed enzyme-linked immunosorbent assays (ELISAs) to analyze the state of H3K9s and H3K4s in the blood of 63 healthy males working in the same steel plant. The results of the study confirmed that long-term exposure to inhalable nickel and arsenic (but not chromium) particulates is correlated with significant increases in the concentration of modified H3K9s and H3K4s in the blood. While further study is still required to confirm whether there is a definite link between diagnosed lung cancer and epigenetic changes caused by certain metals, this research highlights that even contemporary industrial environments may pose significant risks to worker health.3 Cantone L, Nordio F, Hou L, Apostoli P, Bonzini M, Tarantini L, et al. Inhalable Metal-Rich Air Particles and Histone H3K4 Dimethylation and H3K9 Acetylation in a Cross-sectional Study of Steel Workers. Environ Health Perspect 2011 Jul 2011;119(7):964-969. 2 Wild P, Bourgkard E, Paris C. Lung Cancer and Exposure to Metals: The Epidemiological Evidence. Methods in Molecular Biology 2009;472:139-167. 3 Alley DF, Langley-Turnbaugh S, Gordon NR, Wise JP, Van Epps G, Jalbert A. The effect of PM10 on human lung fibroblasts. Toxicol Ind Health 2009 Mar;25(2):111-120. Image adapted from: http://www.pbs.org/ 1

Rider TH, Zook CE, Boettcher TL, Wick ST, Pancoast JS, Zusman BD. Broad-Spectrum Antiviral Therapeutics. Plos One 2011 Jul 27;6(7):e22572. Image adapted from: http://web.mit.edu/

BIOMEDICAL RESEARCH AS A WEAPON

Khizer Amin

few nuts a day can go a long way in the control of diabetes. Low in carbohydrates but high in fibre, protein, and omega-3 fatty acids, the nutritional composition of nuts has garnered fascination and interest from the scientific community for years. Previous studies have shown that the consumption of nuts significantly reduces the chance of heart disease.1

Recently, researchers at the University of Toronto established the value of unsalted and unroasted mixed nuts—including almonds, pistachios, walnuts, pecans, hazelnuts, peanuts, cashews, and macadamias—in the management of Type II diabetes.2 In the study, 117 type II diabetics were randomly assigned to one of three treatment groups: a full portion of nuts, a whole muffin, or a half portion of nuts and half a muffin. This supplement to daily diet was maintained for three months. All treatments helped to significantly increase levels of good cholesterol. However, it was found that the nut-only treatment reduced baseline blood-glucose level significantly more than the other two treatments. Furthermore, individuals on the nut-only diet experienced significantly greater reductions in “bad” cholesterol levels than did those on the whole muffin treatment. This research has positive implications for people without diabetes as well. Nuts were found to be a suitable replacement for carbohydrate intake, and the daily diet was not associated with weight gain.2 In summary, an increase in the daily consumption of nuts could prove valuable in the maintenance of good health and a satisfactory body weight.

Yasmeen Mansoor

MedBulletin

TREATING DIABETES WITH NUTS

cientific publications openly present revolutionary findings with an aim to share knowledge for the progress of human society. Publications involving healthcare and medicine hold an area of high interest in the scientific community due to the common goal of overcoming disease and improving human health. What is often overlooked, however, is the potential threat that such information can pose if placed in the hands of terrorists seeking to develop catastrophic bioweaponry.1 Many top tier journals have gained the attention of organizations such as the World Health Organization (WHO) and the US National Science Advisory Board for Biosecurity (NSABB) due to the potential misuse of the information that they present.1 This information is referred to as “dual use research” (DUR), and can facilitate terrorism depending on the detail of the information presented. Some examples of research topics that have been categorized as DUR are findings that show certain vaccines as ineffective, research about microbial virulence, and the need for biodefense (e.g. quarantine of infected patients) against antibiotic resistant bacteria.1 Bioterrorism is a relatively simple task to accomplish once the necessary information and the tools required are made available to a terrorist.2 The area of biotechnology itself has become so advanced that simple genetic engineering techniques can be used to synthesize deadly viruses and pathogens.2 Not only is bioterrorism geared as a threat to public health, but it can also harm agriculture, animals, or the environment. In terms of reducing the threat of future bioterrorism, journal editors are in the process of developing policies to communicate research in ways that “maximize public benefits and minimize risks of misuse.”1 Current strategies are targeted towards all members of the scientific community in an effort to raise awareness about the implications of their published research.1

Kendall C, Esfahani A, Truan J, Srichaikul K, Jenkins D. Health benefits of nuts in prevention and management of diabetes. Asia Pac J Clin Nutr 2010; 19(1):110-116 2 Jenkins D, Kendall C, Banach MS, Srichaikul K, Vidgen E, Mitchell S, et al. Nuts as a Replacement for Carbohydrates in the Diabetic Diet. Diabetes Care 2011; 34(8):1706-1711. Image adapted from: http://foodfortorte.blogspot.com/ 1

Nightingale SL. Scientific Publication and Global Security. JAMA-Journal of the American Medical Association Aug 3 2011;306(5):545-546. 2 Marietta, D. Terror in a vial. Sci Am 2010 2010-Jun;302(6):28. Image adapted from: http://www.vvallpaper.net/ 1

The Meducator | November 2011

MedBulletin

THE WORLD’S FIRST TRIAL IN VIRAL CANCER THERAPY Humna Amjad

esearchers at the Ottawa Hospital Research Institute (OHRI) and Pusan National University in Korea have recently reported the results of promising trial on intravenous virus therapy to combat cancer. This is the first trial of its kind to show expression of transgene in selective tumours after intravenous delivery using a specially engineered virus. The trial consisted of 23 patients, all of whom had cancers that spread (metastasized) to multiple organs and failed to respond to standard cancer treatment. The patients were given one of five doses of the engineered virus, and biopsies were obtained ten days later. Seven of eight (87%) patients that were given the two highest dosages presented increased viral replication in only their cancerous tissue, with normal tissue remaining unharmed.

This is the first time in medical history that an intravenouslydelivered viral therapy was able to selectively target cancerous tissue. Dr. John Bell, a Senior Scientist at OHRI, explains that intravenous delivery is vital for the treatment of metastatic cancer because it allows all tumours in the body to be targeted. Furthermore, in moderate doses, viral therapy has only mild side effects—somewhat similar to flu symptoms. Enthusiastic about the results, Dr. Bell states that, “[they] are promising, especially for an early-stage trial, with only one dosage of therapy. However, we are working to advance our understanding of these viruses and figure out how best to use them.” Indeed, in the future, engineered viruses may become the gold-standard treatment for combating cancer.

Breitbach CJ, Burke J, Jonker D, Stephenson J, Haas AR, Chow LQM, et al. Intravenous delivery of a multimechanistic cancer-targeted oncolytic poxvirus in humans. Nature 2011 Sep 1;477(7362):99-102. Image adapted from: http://www.health-healths.com

H1N1: BLOWN OUT OF PROPORTION Kimia Sorouri

uring the H1N1 (swine flu) outbreak, there was a clash between the global health system, the World Health Organization (WHO) and the pharmaceutical industry. It has been speculated that pharmaceutical companies encouraged WHO advisors to label the H1N1 outbreak a pandemic in order to boost vaccine sales. This notion of misinformation is echoed by external organizations that claim that the WHO exaggerated the dangers of H1N1 to the general public, resulting in a costly disruption to healthcare. The names of the members on committees involved in the WHO decision-making process have yet to be disclosed. Without this transparency, it is only natural to doubt the intentions and reliability of the decisions. Regardless of the level of authority, effective decisions arise from controlled communication among the decision-makers and timely disclosure of information to everyone else affected. This level of clarity among public health organizations was arguably not present during the H1N1 outbreak and may have contributed to the disease being amplified as a pandemic.

The WHO’s handling of the H1N1 pandemic prompted the American College of Chest Physicians to establish guidelines to avoid the undue influences of ‘big pharma’ in global health policy. Each guideline chapter was assigned initially to an individual free of such conflicts of interest. Furthermore, any information gathered from experts with conflicts of interest is vetted through a panel of members without such conflicts. The US National Academies and the European Medicines Agency have also followed in stride, all in an effort to regain public confidence.

Evans MR. The Swine Flu Scam? Journal of Public Health 2010 August 4; 32(3):296-297. Image adapted from: http://www.cdc.gov/

Keith Lee

espite the high prevalence of age-related cognitive decline and neurodegenerative diseases, little is known about the mechanisms by which these conditions progress. Some research suggests that accumulation of DNA damage is associated with neurodegeneration, but until recently little evidence has demonstrated direct causality in this association.

In order to elucidate the nature of this relationship, Dr. Nils Zuiderveen Borgesius and his team examined whether defects in DNA repair were sufficient to induce age-related neurodegeneration. For this purpose, the researchers mutated ERCC1, a gene in mice that is required for three different DNA-repair mechanisms. The mutant protein is not as effective at DNA repair, causing an accumulation of damaged DNA in the brain. By examining biological markers for neuronal injury, degeneration and cell death, it was established that defective DNA repair causes a brain phenotype that is representative of aging and neurodegeneration. Adult mice with the defective protein developed learning and memory problems and had impaired cognitive function compared to mice without the ERCC1 mutation. The results of this study demonstrate that an impaired DNA-repair system in mice is sufficient to reproduce the pathology and symptoms typical of neurodegenerative diseases. The discovery of this relationship provides insight into the development of new therapeutic and prevention strategies for age-related cognitive decline and neurodegenerative diseases.

Matthew Chong

MedBulletin

DEFICIENT DNA REPAIR “MOLECULAR CLOCK”: AND NEURODEGENERATION CLUES IN SKIN STEM CELLS

ircadian rhythms are defined as “a physiological timing mechanism that allows organisms to anticipate and adapt to the day-night cycle”.1 For instance, the rise and fall of the hormone melatonin is intricately tied to our sleep-wake cycle. The programmable nature of this cycle explains why one feels particularly groggy after oversleeping or so-called all-nighters.2 Circadian rhythms are not exclusive to the sleep-wake cycle and are found in a variety of organisms, large and small. Writing in Nature, Spanish scientists show that stem cells possess signaling proteins that regulate gene expression in a circadian-like manner. Differential, time-dependent gene expression within stem cells is important to maintain an active population of stem cells to respond to any alterations in homeostasis, while at the same time keeping some cells in reserve. Interestingly, when the main core protein of the clock was knocked out, there was an accumulation of dormant stem cells, which led to premature aging of the cell line and reduced tumorigenesis. Given the association of aging with cancer, the findings may be paradoxical, but nonetheless shed light on the molecular machinery that keeps our gene expression in sync with the world. Further research into the role of circadian rhythms within stem cells, which are important for tissue repair and regeneration, can give us a better understanding of the aging process and neoplasia.3

Cavallari N, Frigato E, Vallone D, Frohlich N, Lopez-Olmeda JF, Foa A, et al. A blind circadian clock in cavefish reveals that opsins mediate peripheral clock photoreception. PLoS biology. 2011;9(9):e1001142. Epub 2011/09/13. 2 Barion A. Circadian rhythm sleep disorders. Disease-a-month : DM. 2011;57(8):423-37. Epub 2011/09/21. 3 Janich P, Pascual G, Merlos-Suarez A, Batlle E, Ripperger J, Albrecht U, et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature. 2011. Epub 2011/11/15. Image adapted from: http://www.sciencedaily.com/ 1

Borgesius NZ, de Waard MC, van der Pluijm I, Omrani A, Zondag GC, van der Horst GT, et al. Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair. J Neurosci 2011 Aug 31;31(35):12543-12553. Image adapted from: http://www.e-nox.net/

The Meducator | November 2011

FORUMSPACE

Healthcare Transformation Adrian Tsang Bachelor of Health Sciences (Honours), Class of 2012 McMaster Health Forum Student Subcommittee In collaboration with the McMaster Health Forum Student Subcommittee, The Meducator is pleased to introduce ForumSpace, a column which aims to educate readers on current issues in health sciences, particularly health policy, as to engage students and promote active discussion. The Student Subcommittee oversees student-led activities designed to offer opportunities to explore issues of interest to McMaster students and the public, in line with a key mandate of the McMaster Health Forum—to nurture the leaders of tomorrow by exposing them to the leading thinkers and doers of today. This inaugural paper in the ForumSpace follows the event ‘Ill-Informed: The Future of Universal Healthcare in Canada’, held earlier this year, which inspired a small group of students to think further about these issues. Among them is the author of this article, Adrian Tsang, who is also a member of the Student Subcommittee. The aim of this article is to present some of those opinions and how they could contribute to the transformation of Canada’s healthcare system. The views expressed in this article are the views of the author and should not be taken to represent the views of the McMaster Health Forum.

ith three years left before the expiration of the First Minister’s times in their lives. With rising rates of patient dissatisfaction, it is Accord on health, the political stage is set for another chap- no longer “good enough” to simply direct patients but it is more ter to be written in Canada’s healthcare system. At the federal level, important to empower them as equally important participants in the Conservative party of Canada hold a majority, while the New their own care healthcare. The move towards a patient-centred apDemocratic Party, which originated from the political philosophy proach to care begins with adopting a charter for patient-centred of Tommy Douglas, take on the role of official opposition for the care and in the education of the future of Canada’s healthcare first time in Canadian history. All of this is happening against a providers.3 Shared decision-making, interdisciplinary care and self backdrop of what the CMA believes is a public healthcare system management strategies are vital components of a patient-centred that is in the decline.1 Five million Canadians do not have a fam- model. ily physician, unreasonable wait-times in emergency departments are a norm, mental health services lag behind demand and there 1. Shared Decision Making is a gap in social services for patients who cannot afford their pre- A person’s own health is often their greatest concern. Thus it is scription medication or find a long-term care bed.2 Spearheaded only reasonable that patients should work alongside physicians in by then president of the CMA, Dr. Jeffery Turnbull the National making informed decisions about their own care. The improveDialogue on Healthcare set out to gather the opinions of Canadi- ment in the rapport between patient and provider can increase ans on the looming need for healthcare transformation. rates of treatment adherence and increase likelihood of patients modifying lifestyle risk factors such as smoking and obesity which Under the Canada Health Act 1981, our single-payer universal greatly contribute to the chronic disease burden.3 healthcare system is charged with providing care that is universal, accessible, portable, comprehensive and publicly administered 2. Interdisciplinary Care which currently only apply to hospital and physician care. The Often care of patient can extend beyond the role of the physician. future of Canada’s healthcare system may very well extend beyond The implementation of interdisciplinary teams is a step forward in these and there is a need clarify a vision for the future towards a helping patients receive the specific care and complete care they Medicare system that is more effective and comprehensive. Un- require without logistical barriers.3 doubtedly, students and young Canadians also hold a large stake in Canada’s most cherished social program. It is this generation 3. Self-Management Strategies that will be providers and patients of the system in the coming When the CMA asked Canadians “What do you think Canadidecades, and will largely bare the cost of providing healthcare to ans’ responsibilities are, now and in the future, in regard to their the country’s aging population. The aim of this article is to present health?”, a vast majority acknowledged that citizens have a perthe opinions of young Canadians and how those values should sonal responsibility to look after the health of themselves and their contribute to the transformation of Canada’s healthcare system. families.4 Information needs to be disseminated to Canadians Patient-centered Care about their health and the risk of chronic disease. Patients should be empowered not told by providers how to improve their health. The patient should always be at the focus of any healthcare system. At the same time it is important for providers to identify barriers People do not become patients out of choice but often seek or patients may face to healthy lifestyle which may be socioeconomic, are even sometimes unable to seek care at the most vulnerable education, language and/or cultural related.

FORUMSPACE

HEALTH PROMOTION AND PREVENTION

physician expenses. As a result, Canadians pay the highest prices for drugs and have some of the worst drug coverage amongst OECD countries. A national pharmacare program not only improves the healthcare of the twenty-four percent of Canadians have no drug coverage, but its monopsony design also improves the cost-effectiveness of our health care system.

Follow the money. In Ontario, the 768 million dollar budget of the ministry of health promotion is minuscule in comparison to the 47 billion dollar budget of the Ministry of Health and Long Term Care5,6. Why is so much money being spent on curing and treating disease instead of finding ways to prevent it? Programs such as “Smoke-Free Ontario” and “EatRight Ontario” which aim By the year 2025, 23% of Canada’s population will be over the age to address the lifestyle risk factors that contribute to the grow- of 65. This subset of the population is projected to be the main ing burden of chronic disease are often put aside.5 Patients often consumer of healthcare resources in the years to come.1 In 2002, encounter the healthcare system when it is too late to prevent the the Romanow report recommended that homecare be considered a necessary part of an appropriate and integrated health care sysdisease and more expensive to treat it. tem.7 Home care is a cornerstone of a comprehensive, appropriate When Tommy Douglas first envisioned Canada’s healthcare sys- health care system for seniors and individuals requiring long term tem there were two parts to Medicare. The first focused on provid- care. With maintaining a high quality of life and appropriateness ing care but the second stage focused on prevention and health of care in mind, there is little dispute that individuals prefer to be promotion to ensure the systems sustainability. Cost-effectiveness in familiar surroundings during times of illness. aside, a system that focuses on treatment and neglects health promotion fails patients because it is unable to prevent disease and CONCLUSION the emotional or psychological stress associated with it. People have the responsibility to maintain their health, but it is the providers that have the responsibility to educate, facilitate and assist Looking forward “value for money” will be the maxim for patients, providers and policy-makers alike as the Canadian Healththeir patient’s goals. care system adapts to changing pressures and demand. Research has shown that certain initiatives result in improve outcomes and a reduction in wasted health resources. There is an ongoing need FILLING THE GAPS IN UNIVERSAL to increase evidence-based practice through not only increased reHEALTHCARE search but also swift and effective implementation of these proven Today a visit to a doctor’s office is covered by medicare, but the strategies. The healthcare relationship between patient and prodrugs they prescribe are not. Canada has very limited social provider is often multifaceted and can include numerous factors such grams in this respect and only Quebec has mandated that every as level of education, ability to understand and speak the primary citizen must have prescription drug insurance. Even then the ma- language of delivery, geographical residence and the ability to seek jority of citizens who are not senior or from low income fami- healthcare services and subsequent follow-up treatment and medilies must seek private insurance or coverage from their employer. cations. Many of these factors need to be taken into account when Across Canada, there is an assortment of public and private plans developing policy at the federal, provincial and professional level. and varying drug policies which are costly, inefficient and keep The responsibility to implement new policies and continue to enpotentially life-saving drugs inaccessible to patients merely be- sure that Canada’s healthcare system remains one of the best in the cause of the region in which they reside. In recent years, growth world falls not only on our political leaders and healthcare-providin spending on pharmaceuticals has surpassed that in hospital and ers but most importantly on patients and the citizens of Canada.

REFERENCES 1

Canadian Medical Association. Principles to Guide Health Care Transformation in Canada. July 2011; Available from: http:// www.cma.ca/multimedia/CMA/Content_Images/Inside_cma/ Advocacy/HCT/HCT-Principles_en.pdf

Canadian Medical Association. Voices in Action: Report on the National Dialogue on Health Care Transformation. 2011; Available from: http://www.cma.ca/multimedia/CMA/Content_Images/Inside_cma/Advocacy/HCT/HCT_townhalls_en.pdf

Canadian Medical Association. Health care transformation Change that Works. Care That Lasts. September 2010; Available from: http://www.cma.ca/multimedia/CMA/Content_Images/Inside_ cma/Advocacy/HCT/FastFacts/HCT-Overview2010_en.pdf

Ministry of Health Promotion. Results-based Plan Briefing Book 2010-11.October 2011; Available from: http://www.mhp.gov. on.ca/en/about/rbp/financial.asp

Canadian Medical Association. Building a Culture of Patient-Centered Care. September 2010; Available from: http://www.cma. ca/multimedia/CMA/Content_Images/Inside_cma/Advocacy/ HCT/FastFacts/HCT-Patient-Centred-Care-Charter2010_ en.pdf

Ontario Ministry of Finance. Ministry of Health and Long Term Care Estimates 2011-12. April 2011; Available from: http:// www.fin.gov.on.ca/en/budget/estimates/2011-12/volume1/ MOHLTC.html

Romanow, R. Building on Values: The Future of Health Care in Canada – Final Report. Commission on the Future of Health Care in Canada. November 2002; Available from: http://dsppsd.pwgsc.gc.ca/Collection/CP32-85-2002E.pdf

The Meducator | November 2011

Allosteric Modulators: Potential Treatment for Schizophrenia Ritesh Daya Honours Life Science Program, Class of 2011 Laboratory of Dr. Ram Mishra, McMaster University As an Honours Life Science student, Ritesh Daya worked in the department of Psychiatry and Behavioural Neuroscience. Following a presentation of his work at the Ontario Undergraduate NeuroXchange conference, Ritesh was given an award for best poster presentation by a group of delegates from The Meducator. Under the supervision of Dr. Ram Mishra, Ritesh has been investigating the pathophysiological mechanisms that underlie schizophrenia, a severe and debilitating mental illness. The focus of his research involves testing a novel allosteric modulator to potentially treat schizophrenia and other dopamine-related disorders.

chizophrenia is a debilitating mental illnesses, affecting ap- Dysregulation of the dopaminergic system in animals has been proximately seven in every 1000 Canadians.1 Symptoms in- shown to lead to various symptoms typical of schizophrenia.12,13 clude the inability to distinguish reality from illusion, as well as Thus, the dopamine receptor has become the focus of many studdeficiencies in social interaction, logical thinking, and emotional ies investigating schizophrenia and other related psychoses.8-11,14 response.2 While the etiology of schizophrenia remains unclear, it The dopamine receptor contains both an orthosteric site and an is thought to involve environmental, genetic, and developmental allosteric site. The former is the main active site of the receptor, factors.1 Schizophrenia affects not only the lives of the patients while the latter is an additional binding site on the receptor that themselves, but also that of their families and friends.1 Although it modulates activity of the active site. When the allosteric site is is relatively rare in the population, the disorder also puts an enor- occupied, the conformation of the orthosteric site is altered to mous burden on the health care system in Canada. In 2004 for either increase or decrease orthosteric binding. Conventional antiexample, the total economic cost associated with schizophrenia psychotic drugs bind the orthosteric site of the dopamine receptor, was 6.85 billion USD.4 usually with antagonistic effects.15

Much of the complexity surrounding schizophrenia results from the fact that it is not one simple illness, but rather a combination of multiple psychological conditions. Schizophrenia commonly manifests itself between the ages of 16 and 30 and is typically diagnosed through three categories of symptoms: positive, negative and cognitive.3 Positive symptoms include hallucinations, delusions, and disorganized speech and behaviour, while negative symptoms consist of social withdrawal, anhedonia and avolition.3 Cognitive symptoms involve deficits in thinking, memory, and learning.3 In many cases, various symptoms of schizophrenia can be alleviated by drug treatment. However, there is no single cure for this severe mental illness to date.3

However, recent developments have led to a new generation of anti-psychotic drugs—called allosteric modulators, which can be used in the treatment of various central nervous system (CNS) diseases and disorders.6 As their name suggests, these drugs bind to and modulate the allosteric site of specific receptors in the CNS. This provides these drugs with the unique ability to control the intensity of a response, which is in sharp contrast to the rudimentary “on/off” control of conventional antipsychotic drugs that bind to the active site of the receptor.16 Allosteric modulators also possess several other advantages over traditional antipsychotic drugs. Firstly, they are generally more specific for the target receptor. Secondly, they require the presence of an agonist to elicit an effect and thus cannot cause abnormal activation of the receptor. Lastly, they do not compete with endogenous ligands for the orthosteric site, which increases their potency.6 These novel characteristics open up the potential for a reduced side effect profile—a critical shortcoming of traditional antipsychotic drugs.

Schizophrenic patients commonly exhibit an aberrant dopamine system. The first traditional drug treatments for schizophrenia involved targeting the dopaminergic system using antagonists (blockers) to the dopamine receptor family. Second generation antipsychotic drugs targeted the serotonergic and glutaminergic systems. However, these antipsychotic drug treatments often As an undergraduate student under the supervision of Dr. Ram prove to be inadequate, as they fail to manage all the symptoms Mishra, my efforts focused on developing new therapeutic comof schizophrenia while causing debilitating side effects.4,5 Of these, pounds that effectively regulate dopamine and other neurotransextrapyramidal (movement) and metabolic side effects are the mitter systems. It is hoped that this research will generate effective most common, critically limiting the therapeutic value of antipsy- therapies for the treatment of schizophrenia and other dopaminechotic treatment.5-7 Patients who respond positively to treatment related disorders. can often maintain functional lives. However, those who do not respond well often experience a lower quality of life and may be hospitalized as a result.5

RESEARCH INSIGHT

NOVEL COMPOUND FOR THE TREATMENT OF SCHIZOPHRENIA: VALIDATION IN RECEPTOR BINDING ASSAYS AND IN A PRECLINICAL ANIMAL MODEL OF SCHIZOPHRENIA Our laboratory, in collaboration with the University of Minnesota, has designed several allosteric modulators for the dopamine receptor. These novel compounds are structurally based on the endogenous brain peptide L-prolyl-L-leucyl-glycinamide, itself an allosteric modulator of the dopamine receptor. Radiolabeled ligand binding assays were performed to evaluate these species in bovine striatal tissues. Our primary interest was to assess one of such allosteric modulators that had previously been shown to positively modulate the dopamine D2 receptor. This receptor, a subtype of the dopamine family of receptors, is specifically implicated in schizophrenia.17 Our compound of interest was capable of significantly increasing binding of [3H]N-propylnorapomorphine, a dopamine D2/D3 radiolabeled agonist, in bovine striatal samples. The increase in [3H]N-propylnorapomorphine binding under specific conditions represents significant positive modulatory activity of the compound. The success of this compound in receptor binding assays provided a basis for its assessment in a pre-clinical animal model of schizophrenia. The observation that chronic amphetamine users often exhibit psychotic-like symptoms that closely resemble paranoid schizophrenia led to the development of a pre-clinical animal model of schizophrenia.21 In this model, rats are challenged with repeated doses of amphetamine, which results in the development of schizophrenia-like behaviors such as defects in movement and social interaction.18-20,22,23 Interestingly, low doses of our drug reversed schizophrenic defects in this animal model. Biochemical changes were subsequently measured in postmortem brain tissue with high performance liquid chromatography. In the striatum—an area of the brain highly implicated in schizophrenia—we observed an increase in striatal dopamine in amphetamine-sensitized rats.5 This change was also prevented in rats concurrently treated with amphetamine and our allosteric compound. These results have significant implications for treating schizophrenia during early diagnosis and once symptoms have fully developed.

A DA

Orthosteric Site A Allosteric Site

DOPAMINE RECEPTOR

Cell Membrane

Orthosteric Site

DOPAMINE RECEPTOR

Cell Membrane

DA DA DOPAMINE RECEPTOR

Cell Membrane FIGURE 1: Simplified diagram showing allosteric modulation of the dopamine D2 receptor.

Endogenous dopamine (DA) activates the dopamine receptor by binding to its orthosteric (active) site. The affinity of the receptor for DA can be altered by binding of an allosteric modulator (A) to the allosteric site. This may decrease the ability of DA to bind, as shown in panel B, or increase its affinity, as shown in panel C.6

CONCLUSION

Further validation of our findings is required prior to offering this Allosteric modulators hold significant potential for the treatment compound as a treatment for schizophrenia. Our future goals in- of neurological disorders. Unlike drugs that bind to the orthoclude evaluating this compound in other well-established models steric site, allosteric modulators have the advantage of increased of schizophrenia, developing the drug further and testing in hu- selectivity, modulatory control, and non-competitive binding man clinical trials. To date, our laboratory has completed assessing in the presence of endogenous ligands. Specifically, our lab’s althe drug’s toxicological profile and verified its safety at various losteric compound was successful in preventing and treating the concentrations. Gross examination of organs showed no toxic ef- development of schizophrenic-like symptoms in an animal model fects on the liver, kidney, and brain at five times the effective dose. of schizophrenia. Of particular importance is its ability to do so We have recently filed for an international patent after obtaining a with few extrapyramidal or metabolic side effects, a significant shortcoming of current antipsychotic medications. Our findings provisional patent for this novel compound. warrant further research in the development of compounds that may successfully treat schizophrenia and potentially other mental illnesses.

The Meducator | November 2011

Reviewed by Dipa Basu, PhD Candidate Dipa Basu is a PhD candidate under the supervision of Dr. Ram Mishra at McMaster University in the Department of Medical Sciences. She is currently studying drug receptor interactions and their implications in neurological disorders such as schizophrenia and Parkinsonâ&#x20AC;&#x2122;s disease.

REFERENCES 1

Goeree,R. et al. The economic burden of schizophrenia in Canada in 2004. Curr. Med. Res. Opin. 21, 2017-2028 (2005).

Andreasen,N.C. & Carpenter,W.T. Diagnosis and Classification of Schizophrenia. Schizophrenia Bulletin 19, 199-214 (1993).

Seeman,P. All Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2 Receptors. CNS. Neurosci. Ther. (2010).

Peleg-Raibstein,D., Yee,B.K., Feldon,J. & Hauser,J. The amphetamine sensitization model of schizophrenia: relevance beyond psychotic symptoms? Psychopharmacology (Berl) 206, 603-621 (2009).

van Os,J. & Kapur,S. Schizophrenia. Lancet 374, 635-645 (2009).

Meyer,J.M. et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr. Res. 101, 273-286 (2008).

Citrome,L., Jaffe,A., Levine,J., Allingham,B. & Robinson,J. Relationship between antipsychotic medication treatment and new cases of diabetes among psychiatric inpatients. Psychiatr. Serv. 55, 1006-1013 (2004).

Tenn,C.C., Kapur,S. & Fletcher,P.J. Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition. Psychopharmacology (Berl) 180, 366-376 (2005).

Paulson,P.E. & Robinson,T.E. Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum. Analysis of circadian patterns using automated on-line microdialysis. Neuropsychopharmacology 14, 325-337 (1996).

Seeman,P. & Kapur,S. Schizophrenia: more dopamine, more D2 receptors. Proc. Natl. Acad. Sci. U. S. A 97, 7673-7675 (2000).

Tenn,C.C., Fletcher,P.J. & Kapur,S. Amphetamine-sensitized animals show a sensorimotor gating and neurochemical abnormality similar to that of schizophrenia. Schizophr. Res. 64, 103-114 (2003).

Peleg-Raibstein,D., Yee,B.K., Feldon,J. & Hauser,J. The amphetamine sensitization model of schizophrenia: relevance beyond psychotic symptoms? Psychopharmacology (Berl) 206, 603-621 (2009).

Conn,P.J., Christopoulos,A. & Lindsley,C.W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41-54 (2009). Parsons,B. et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr. Res. 110, 103-110 (2009). Howes,O.D. & Kapur,S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr. Bull. 35, 549-562 (2009). Lodge,D.J. & Grace,A.A. The hippocampus modulates dopamine neuron responsivity by regulating the intensity of Phasic neuron activation. Neuropsychopharmacology 31, 1356-1361 (2006).

Kapur,S. Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia. American Journal of Psychiatry 160, 13-23 (2003).

Roiser,J.P. et al. Do patients with schizophrenia exhibit aberrant salience? Psychological Medicine 39, 199-209 (2009).

Neill,J.C. et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism. Pharmacology & Therapeutics 128, 419-432 (2010).

Lazar,N.L., Neufeld,R.W.J. & Cain,D.P. Contribution of nonprimate animal models in understanding the etiology of schizophrenia. Journal of Psychiatry & Neuroscience 36, E5-E29 (2011).

Beaulieu,J.M. & Gainetdinov,R.R. The Physiology, Signaling, and Pharmacology of Dopamine Receptors. Pharmacological Reviews 63, 182-217 (2011).

Mukherjee,J., Christian,B.T., Narayanan,T.K., Shi,B. & Mantil,J. Evaluation of dopamine D-2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride. Neuropsychopharmacology 25, 476-488 (2001).

Wang,L., Martin,B., Brenneman,R., Luttrell,L.M. & Maudsley,S. Allosteric modulators of g protein-coupled receptors: future therapeutics for complex physiological disorders. J. Pharmacol. Exp. Ther. 331, 340-348 (2009).

Microparticles: Reliable Biomarkers of Thrombosis? Shelly Chopra Bachelor of Health Sciences (Honours) Program, Class of 2014 Microparticles are vesicles that bud off cells in response to extracellular stimulation or apoptosis. They play an important role in the regulation of physiological and pathological pathways such as clot formation and the progression of thrombotic disease by influencing the expression of critical proteins and cofactors. The following critical review evaluates research findings on the potential significance of microparticles as indicators of thrombotic risk.

rom “platelet dust” to “trigger[s] of vascular repair,” the description of microparticles (MPs) has evolved over the past four decades.1,2 These submicron (0.1-1 µm diameter) vesicles shed off cellular plasma membrane in response to cell activation, stress, or apoptosis (Figure 1). MPs have been observed to bind and fuse with endothelial and blood cells, enabling the delivery of protein and RNA contained within them.3 In platelets and monocytes, this fusion promotes haemostasis, suggesting the procoagulant nature of certain MPs. This homeostatic role of MPs seems to depend on the quantity and type of MPs. As demonstrated in many studies, MPs that bear elevated levels of tissue factor (TF), a potent initiator of platelet activation, play a role in the pathogenesis of thrombotic and hypertensive conditions.4 This review will discuss the potential of MPs as biomarkers of thrombosis and the clinical implications of current MP research.

MICROPARTICLE PHYSIOLOGY A. Procoagulant Properties of Microparticles MPs are a key component of haemostasis because they directly activate protein factors and enzymes responsible for initiating the coagulation cascade. The membranes of platelet-derived MPs

are known to contain receptor sites for procoagulant factors IIa, Va, VII, and IXa. In addition, certain MPs also express the phospholipid phosphatidylserine (PS) on their cell membrane, which catalyzes clotting by providing a surface for the reaction to occur.5 Interestingly, the surface provided by PS on MPs was found to have up to 100 times greater procoagulant activity than an equal area on an activated platelet.6 The significance of microparticle formation in directing haemostasis is highlighted in Scott syndrome, a condition characterized by a deficiency in platelet coagulant activity. This deficiency is directly linked to a defective scramblase, an enzyme in the plasma membrane responsible for the externalization of PS. As a result, PS expression on MP membranes is reduced, inhibiting the binding and enzymatic activity of procoagulant factors.7 B. Microparticles are Mediators of Apoptosis Both inhibition of MP clearance and excessive MP in circulation have been linked to a number of immunosuppressive and thrombotic diseases. Normally, the presence of PS on MPs is an immune-system recognition marker as it is externalized on apoptotic cells to trigger macrophage-mediated removal of cellular debris. However, elevated levels of MPs can stimulate unnecessary

Microparticles

Cell Activation OR Apoptic stimulus Loss of membrane asymmetry Membrane phospholipid redistribution

PS exposure

MP formation & release Cell contraction Cytoskeleton reorganization Blebbs formation

FIGURE 1: Basic mechanism of MP formation and release.4 Microparticle formation is initiated in response to extracellular activation of apoptotic stimulus. A series of membrane phospholipid reorganization events follow, destabilizing the physiological asymmetry of the membrane. This step in the budding of microparticles with external PS exposure.

CRITICAL REVIEW

The Meducator | November 2011

development. Statins function by inhibiting the enzyme responsible for cholesterol synthesis. This decreases the supply of cholesterol available for lipid-raft formation, and as a result, disrupts lipid-raft structure and stability.10 In turn, the destabilization of lipid rafts inhibits appropriate externalization of PS and TF, both of which are necessary to generate viable prothrombotic MPs.10 The essential role of lipid rafts in formation of TF-bearing MPs may explain the correlation between high cholesterol levels and incidence of thrombotic diseases.12

FIGURE 2: Electron micrograph of MPs shedding from parent monocyte. Taken by Hilary Christensen, Department of Pathology, University of Toronto.

apoptosis, an outcome that demonstrates the pathological role of MPs in immunosuppressive and thrombotic diseases.8

MICROPARTICLES AND THROMBOTIC DISEASE A. Thrombosis Many disorders associated with elevated levels of MPs involve abnormal thrombosis.4 Thrombosis refers to the process of forming a clot inside a blood vessel, thereby restricting blood flow (occlusion). In addition to PS expression, the presence of tissue factor (TF) on MPs promotes thrombosis. TF is a protein cofactor required to initiate coagulation. Under normal conditions, circulating blood contains very low levels (10-9 M) of active TF as it is expressed mainly in tissues outside the vascular system. During inflammation and elevated immune response, however, monocytes and endothelial cells express TF and release it into circulation via microparticles.9 Some TF-bearing MPs also contain adhesion molecules, such as PSGL-1, that allow them to bind to platelets and further stimulate the clotting cascade.3

B. Microparticle Tissue Factor Activity Although elevated levels of TF-bearing MPs in cardiovascular disease are a consistent finding in many research studies, the specific characteristics of TF are debated. TF-bearing MPs are found in healthy individuals, but their measurable activity is generally very low.9 This may be attributed to a latent, inactive form of TF present on the MPs. TF-bearing MPs may only be activated upon assembly at the site of vascular damageâ&#x20AC;&#x201D;a theory that explains why MPs do not initiate coagulation on their own.9 However, MPs detected in cardiovascular disease may bear an active, pathologic form of TF that contributes directly to thrombus formation. Adding to the complexity of TF-bearing MPs, recent research suggests certain MPs carrying TF pathway inhibitor are also present in blood circulation.13 As the name suggests, these MPs function to reduce thrombus formation. Although this finding may explain the specific physiological and pathological functions of MPs, the interaction between MPs bearing TF pathway inhibitors and active/inactive TF-carrying MPs remains to be clarified. C. Cancer-associated Thrombosis The role of MPs in cancer-associated thrombosis has been clearly established. As the second leading cause of death in cancer patients, thrombosis has been researched for the past 150 years.14 In 1865, Armand Trousseau discovered abnormal, migratory thrombi in patients to be associated with visceral malignancyâ&#x20AC;&#x201D;a condition now fittingly referred to as Trousseau syndrome.15 Tumour microparticle formation has been observed in many animal studies and more recently in the blood of patients with leukemia.16 Tumour-induced MPs are characterized typically by PS and mucins, proteins that promote a prothrombotic state. The presence of TF on these MPs furthers the progression of systemic thrombosis and enhances tumour angiogenesis (blood vessel growth within the tumour). Increased levels of TF- or mucin-bearing MPs have been associated with tumour size and survival.17 A recent clinical study found that patients with metastatic pancreatic cancer have high levels of MP-linked TF activity, confirming the link betweeen tumours and thrombosis.18

FUTURE DIRECTIONS

TF-bearing MPs bud from lipid raft domains on parent monocytic cell membranes. Lipid rafts are regions of the plasma membrane The measurable impact of MPs has contributed to the developwith a proportionally higher concentration of glycolipids (such as ment of a clearer understanding of the pathogenesis of cardiovascholesterol) and glycoproteins that associate with PSGL-1 and TF. cular and haematological disorders. The normal physiologic role The role of lipid raft proteins in generating prothrombotic MPs of MPs to promote haemostasis and mediate clearance of apoptotis best characterized by the effect of statins, a class of drugs com- ic bodies has been shown to transform into pathologic outcomes monly used to lower blood cholesterol and inhibit artherosclerosis when MP levels rise in circulation. This duality in MP function

remains unresolved but MP structure specificity and origin may Prothrombotic MPs promote haemostasis in models of thrombe responsible. For example, a high concentration of active TF- bocytopenia, a condition characterized by low platelet count. In bearing MPs are a risk factor for thrombotic disease.3 a clinical trial, administration of old, frozen platelets displayed similar haemostatic effects.19 Platelet MP shedding is known to Despite their association with various thrombotic diseases, the increase during storage, a finding that may explain the results of measurement of MP levels has not yet been used as a diagnostic the trial and lead to more MP-based therapies.12 tool. In addition to the need for better characterization of MPs, standardization of detection and quantification methods is need- Circulating MPs are important for maintaining haemostatic ed to further the clinical potential of MPs. Currently, researchers balance and are biomarkers of cardiovascular disease. This positend to use different parameters of MP detection, which can be tions them as promising candidates for use in a diagnostic tool or problematic when comparing data across studies.3,12 treatment of blood disorders. However, further research on MP physiology, pathology, and quantification techniques is necessary The therapeutic role of MPs in diseases characterized by excessive before the full potential of MPs can be realized. bleeding or low MP concentration has been recently investigated.

Reviewed by Peter Gross, MD, MSc, FRCPC and Nima Vaezzadeh, BSc Dr. Peter Gross is an Associate Professor in the Division of Hematology and Thromboembolism of the Department of Medicine at McMaster University. His research interests include thrombosis prevention, thrombus stability, and the role of statins on haemostasis. His lab employs a variety of methodological techniques ranging from intravital microscopy to flow cytometry. Nima Vaezzadeh is a PhD Candidate under the supervision of Dr. Peter Gross. He is currently studying the therapeutic potential of monocyte-derived microparticles as inhibitors of bleeding.

REFERENCES 1

Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967 May;13(3):269-288.

Boulanger CM. Microparticles, vascular function and hypertension. Curr Opin Nephrol Hypertens 2010 Mar;19(2):177-180.

Davizon P, Lopez JA. Microparticles and thrombotic disease. Curr Opin Hematol 2009 Sep;16(5):334-341.

Boulanger CM, Amabile N, Tedgui A. Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension 2006 Aug;48(2):180-186.

Bernimoulin M, Waters EK, Foy M, Steele BM, Sullivan M, Falet H, et al. Differential stimulation of monocytic cells results in distinct populations of microparticles. J Thromb Haemost 2009 Jun;7(6):1019-1028. Sinauridze EI, Kireev DA, Popenko NY, Pichugin AV, Panteleev MA, Krymskaya OV, et al. Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007 Mar;97(3):425-434. Toti F, Satta N, Fressinaud E, Meyer D, Freyssinet JM. Scott syndrome, characterized by impaired transmembrane migration of procoagulant phosphatidylserine and hemorrhagic complications, is an inherited disorder. Blood 1996 Feb 15;87(4):1409-1415. Rak J. Microparticles in cancer. Semin Thromb Hemost 2010 Nov;36(8):888-906.

Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA. Tissuefactor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005 Sep 1;106(5):1604-1611.

Piccin A, Murphy WG, Smith OP. Circulating microparticles: pathophysiology and clinical implications. Blood Rev 2007 May;21(3):157-171.

Steppich B, Mattisek C, Sobczyk D, Kastrati A, Schomig A, Ott I. Tissue factor pathway inhibitor on circulating microparticles in acute myocardial infarction. Thromb Haemost 2005 Jan;93(1):35-39.

Pruemer J. Prevalence, causes, and impact of cancer-associated thrombosis. Am J Health Syst Pharm 2005 Nov 15;62(22 Suppl 5):S4-6.

Varki A. Trousseauâ&#x20AC;&#x2122;s syndrome: multiple definitions and multiple mechanisms. Blood 2007 Sep 15;110(6):1723-1729.

Carr JM, Dvorak AM, Dvorak HF. Circulating membrane vesicles in leukemic blood. Cancer Res 1985 Nov;45(11 Pt 2):59445951.

Toth B, Nieuwland R, Liebhardt S, Ditsch N, Steinig K, Stieber P, et al. Circulating microparticles in breast cancer patients: a comparative analysis with established biomarkers. Anticancer Res 2008 Mar-Apr;28(2A):1107-1112.

Khorana AA, Francis CW, Menzies KE, Wang JG, Hyrien O, Hathcock J, et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008 Nov;6(11):1983-1985.

George JN, Pickett EB, Heinz R. Platelet membrane microparticles in blood bank fresh frozen plasma and cryoprecipitate. Blood 1986 Jul;68(1):307-309.

Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359:938-949.

Ponce J, de la Ossa NP, Hurtado O, Millan M, Arenillas JF, Davalos A, et al. Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection. Stroke 2008 Apr;39(4):1269-1275.

CRITICAL REVIEW

The Meducator | November 2011

Concussions in Ice Hockey Is it Time to Worry? Khizer Amin Bachelor of Health Sciences (Honours) Program, Class of 2014 Recent events have highlighted the issue of concussions in sports, particularly in ice hockey. A concussion is an injury to the brain caused by acceleration forces imparted on the brain. Symptoms vary in severity from confusion and minor headaches to loss of consciousness and amnesia. Concussions are a common sports injury that have been associated with neurological and psychiatric impairment, and second-impact syndrome may even lead to death. The serious nature of these injuries has evoked calls from the scientific community to make hockey a safer game by modifying current rules and regulations. This Critical Review summarizes recent research on concussions and discusses the implications in the context of sports.

fter receiving two hits to the head in the span of two games, tools, since the onset of symptoms may only present themselves at Sidney Crosby was sidelined from hockey in February.1 The a later time.7 The injured individual is able to report any changes long and arduous recovery process that ensued garnered continu- in mood, appetite, tiredness and sleep patterns. Computerized ous questions about when Crosby would return, and upon his neuropsychological testing is a recent development that allows return, whether he would be able to regain his high calibre of athletes, trainers, and parents to monitor cognitive functioning.8 play.1 A concussion with consequences of this magnitude is by After a concussion, results from this test can be compared to baseno means a rare occurrence in sport; in fact, head injuries are the line scores (from a test done prior to any injury) to monitor an most common cause of death amongst athletes.2 However, Sidney individual’s recovery process. Crosby’s reputation as one of the best in the game has pointed the public spotlight on the severity and consequences of concussions and head injury. Since the incident, researchers have seized the opportunity eager to engage the general public in dialogue regarding the issues of aggression and unnecessary physicality in sport.

DEFINITION OF CONCUSSION A concussion is defined by the American Association of Neurological Surgeons (AANS) as, “a clinical syndrome characterized by immediate and transient alteration in brain function, including alteration of mental status and level of consciousness, resulting from mechanical force or trauma.”3 Immediate symptoms vary from case to case, ranging from a temporary loss of consciousness to amnesia, dizziness, and prolonged confusion.4 The generally accepted guidelines for what constitutes a concussion have evolved greatly over recent years as the scientific community has furthered its understanding and knowledge of traumatic brain injuries. In the past, researchers and clinicians characterized loss of consciousness as a necessary and defining symptom of concussions. Furthermore, concussions were not believed to result in long-term debilitations.5 In contrast to these old beliefs, recent research has found that concussions are a serious risk factor for neurological disorders that may only become apparent years after the original incident.5,6 The development of modern diagnostic techniques has decreased the number of concussions that go undetected and thus untreated. Neurological testing and on-field evaluations for potentially concussed athletes are now more robust and comprehensive. In particular, ‘day-after-concussion’ examinations are valuable diagnostic

CRITICAL REVIEW

FIGURE 1: Rotational force on the brain due to impact of collision.4 Biomechanical research suggests that concussions results primarily from rotational motion of the cerebral hemispheres in the anterior-posterior plane in response to acceleration forces. The brain rotates around the fulcrum of the midbrain, which is fixed in place. This can lead to extensive shearing and damage of brain tissue, as well as an increase in intracranial pressure.

THE MECHANISM OF CONCUSSION Concussions are generally a functional injury and can often occur without any externally visible impression or contusion to the body.9 They occur when the brain is accelerated into the skull due to some sort of impact or external force. Concussions are caused by a combination of two major types of forces: translational and rotational.5 Translational forces cause linear accelerations, resulting in stretching and compression of the brain.10 The collision of the brain against the inner walls of the cranium causes brain tissue damage and elevated intracranial pressure. Conversely, rotational forces cause the brain to accelerate angularly along its mid-vertical axis. This force often results in the shearing of brain tissue and temporary loss of consciousness due to the impact from rotation at the midbrain (Figure 1).4 Current evidence suggests that rotational accelerations imparted on the brain are the more severe and important force implicated in the onset of concussions.5

Rehabilitation Stage

Functional Exercise at each stage

Objective of each stage

1. No Activity

Complete physical and cognitive rest

Recovery

2. Light aerobic exercise

Walking, swimming or stationary cycling keeping intensity <70% MPHR No resistance training

Increase HR

3. Sport-specific exercise

Skating drills in ice hockey, running drills in soccer. No head impact activities.

Add movement

4. Non-contact training drills

Progression to more complex training drills e.g. passing drills May start load progressive resistance training

Exercise, coordination, and cognitive

5. Full contact practice

Following medical clearance participate in normal training activities

Restore confidence & assess functional skills by coashing staff

6. Return to play

Normal game play

CONCUSSIONS IN SPORT Concussions are most commonly a result of falling or striking an object or another person.11 Athletes are prone to such injuries due to the physicality and aggressive behaviour often associated with sport. Amongst individuals 16—34 years of age, a Canadian National Population Health Survey found that 85% of concussions are sport-related.12 A study in Alberta monitoring the number of emergency department visits due to sport and recreational head injuries reported that ice hockey players accounted for the largest proportion of head injuries, at about 21%.13 This may be due to the excessively physical nature of the game, or simply because of the sheer number of participants in the sport, which is after all ‘Canada’s game’. Other major causes of head injuries were – in order from least to most frequent—cycling, playground activities, soccer, football, and rugby.13 It is clear, therefore, that concussions and head injuries are of concern across a variety of sports and activities, and an exploration of both general and activity-specific intervention methods is warranted.

TABLE 1: Guidelines for appropriate Return to Play.9 An athlete should follow this stepwise progression in the rehabilitation and return to play process, advancing to the next level only if asymptomatic at the current one. Each step should take about 24 hours; if symptoms are present, athletes should return to the previous level, get sufficient rest, and seek medical attention.

Second-impact syndrome is a condition that has gained scientific and media recognition in recent years. Essentially, this refers to incurring a second concussion while an individual is still suffering from the adverse effects of an earlier one.17,18 It is possible that the two concussions have a compounding effect in terms of the Recent studies have associated concussions in sports with a decline damage caused to the brain. Even a very minor blow to the head in long-term brain function.14,15 Athletes incurring a concussion after an initial concussion has been associated with sharp increases in early adulthood were found to score lower on neuropsychologi- in intracranial pressure, haemorrhaging, and subsequent death.18 cal testing and suffer from bradykinesia (slowed movement) de- Due to the severity of concussions and the danger of secondcades after diagnosis.15 A link between concussions and the onset impact syndrome, it is important for players, coaches, trainers, of clinical depression in later life has also been made; athletes who and team doctors to follow appropriate return-to-play guidelines have incurred one or two concussions are 1.5 times more likely to (Table 1). suffer from depression in later years.16 Increased awareness of the consequences of concussions in sport Youth athletes are prone to the most negative sequelae of con- has prompted many athletes to donate their brains towards concussions. Concussions can inhibit proper development of the cussion research.19 These donations have fuelled much research brain resulting in developmental disabilities, severe motor dys- towards discerning important details about the mechanisms and functions and psychiatric conditions that will burden the child long-term impacts of concussions. For example, researchers at for the entirety of their life.17 This is of great concern when con- Boston University recently studied the brain of Rick Martin, a sidering that 10-12% of Canadian minor league hockey players former NHL star. Analysis of Martin’s brain revealed that he had aged 9-17 report being victims of head injuries each season.17 chronic traumatic encephalopathy, a disease which leads to cognitive decline and ultimately dementia.20

The Meducator | November 2011

The minimum age at which hockey associations should allow participants to body check has become a highly controversial and debated topic in the hockey community. Proponents for lowering Concussions in hockey are most often caused by body checking,21 the minimum age argue that it allows youth to properly learn and a form of physical contact between players, which is legal in the adjust to the techniques behind giving and taking a hit. HowNHL and many minor leagues. However, the newfound dangers ever, a systematic review exploring the relationship between body of concussions in recent findings has called into question the cur- checking and injuries found that leagues which permit checking rent culture that exists around aggression and fighting in hockey in younger players are associated with higher rates of injuries and fractures.21 Based on their findings, the authors recommended and other sports.17 that body checking be removed from leagues for younger athletes, Athletes, officials, fans, and the general public often become de- with the minimum age for introduction of physical contact being sensitized to aggression in sport and begin to accept it as part of at least 13 years. In line with this, the Ontario Hockey Federation the game.22 In fact, many individuals display elevated levels of recently introduced new regulations that effectively banned body aggression while engaged in sports,23 which begs the question of checking in all house leagues and some select leagues.25 why physical aggression is accepted and legal in athletics but not in other facets of everyday life.

IMPLICATIONS ON THE CULTURE OF ICE HOCKEY

CONCLUSION

In the past, proponents of physical contact in sports have argued that safety equipment such as helmets and mouthguards provide Concussions are serious injuries with potential serious long-term ample protection from injuries. While there is evidence of a re- neurological and psychiatric consequences. Based on current sciduced number of general injuries, there is little scientific evidence entific evidence, it is apparent that modifications to the rules surdemonstrating that current equipment is capable of preventing rounding hockey are warranted and could potentially reduce rates concussions.9,24 Furthermore, while helmets do indeed reduce the of concussion. Imposing greater sanctions on actions such as head force of impact to the head, there is no evidence that wearing hits and checks from behind may help to make Canada’s game helmets corresponds to a reduced rate of concussions in athletes.9 safer for all participants. Only 1 in every 4000 minor hockey As such, there has been a gradual paradigm shift in the scientific league players will ever fulfill the ultimate dream of playing in the community regarding the best means of reducing concussions. NHL.17 In this light, is it reasonable for our youth to have to–or Rather than advocating for increased use of safety equipment, be allowed to–put their future livelihoods on the line every time there is now an increased focus on changing rules, regulations, they step onto the ice? and the culture of sport to reduce the number of falls and hits to the head in the first place.9,21

Reviewed by Kelly Russell, PhD Kelly Russell holds a PhD in sport injury epidemiology. She is currently completing a post-doctorate fellowship in the area of paediatric head injuries. Her research interests include skiing and snowboarding, extreme sports and risk-taking behaviours, and the use of protective equipment.

CRITICAL REVIEW

REFERENCES Joyce G. Will he ever be the same? [Internet]. Sportsnet magazine. 2011 Sep 29; Available from: http://www.sportsnet.ca/magazine/2011/09/29/joyce_crosby/ 2 Cantu RC. Head injuries in sport. British journal of sports medicine [Internet]. 1996 Dec 30(4):289–96. Available from: http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1332409 &tool=pmcentrez&rendertype=abstract 3 Concussion [Internet]. 2005 [cited 2011 Oct 10]; Available from: http://aans.org/en/Patient Information/Conditions and Treatments/Concussion.aspx 4 Ropper A, Gorson K. Concussion. The New England Journal of Medicine. 2007;356(2):166–72. 5 Webbe FM. Definition, Physiology, and Severity of Cereberal Concussion. New York: Guilford Press; 2006. 6 Tator CH. Brain injury is a major problem in Canada and annual incidence is not declining. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques [Internet]. 2010 Nov; 37(6):714–5. Available from: http://www. ncbi.nlm.nih.gov/pubmed/21059528 7 Casson IR, Pellman EJ, Viano DC. Concussion in Athletes: Information for Team Physicians on the Neurologic Evaluation. Seminars in Spine Surgery [Internet]. 2010 Dec [cited 2011 Aug 23];22(4):234–44. Available from: http://linkinghub.elsevier. com/retrieve/pii/S104073831000064X 8 Lovell M. The management of sports-related concussion: current status and future trends. Clinics in sports medicine [Internet]. 2009 Jan [cited 2011 Sep 12];28(1):95–111. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19064168 9 McCrory P, Meeuwisse W, Johnston K, Dvorak J, Aubry M, Molloy M, et al. Consensus statement on concussion in sport - the Third International Conference on Concussion in Sport held in Zurich, November 2008. The Physician and sportsmedicine [Internet]. 2009 Jun;37(2):141–59. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20048521 10 Meaney DF, Smith DH. Biomechanics of concussion. Clinics in sports medicine [Internet]. 2011 Jan [cited 2011 Jul 29];30(1):19–31, vii. Available from: http://www.ncbi.nlm.nih. gov/pubmed/21074079 11 Colantonio A, Saverino C, Zagorski B, Swaine B, Lewko J, Jaglal S, et al. Hospitalizations and emergency department visits for TBI in Ontario. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques [Internet]. 2010 Nov;37(6):783–90. Available from: http://www.ncbi.nlm.nih. gov/pubmed/21059539 12 Gordon KE, Dooley JM, Wood EP. Descriptive epidemiology of concussion. Pediatric neurology [Internet]. 2006 May [cited 2011 Sep 12];34(5):376–8. Available from: http://www.ncbi. nlm.nih.gov/pubmed/16647998 13 Kelly KD, Lissel HL, Rowe BH, Vincenten J a, Voaklander DC. Sport and recreation-related head injuries treated in the emergency department. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine [Internet]. 2001 Apr;11(2):77–81. Available from: http://www.ncbi.nlm. nih.gov/pubmed/11403118 14 De Beaumont L, Lassonde M, Leclerc S, Théoret H. Long-term and cumulative effects of sports concussion on motor cortex inhibition. Neurosurgery [Internet]. 2007 Aug [cited 2011 Aug 16];61(2):329–36; discussion 336–7. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/17762745 15 De Beaumont L, Théoret H, Mongeon D, Messier J, Leclerc S, Tremblay S, et al. Brain function decline in healthy retired athletes who sustained their last sports concussion in early adulthood. Brain : a journal of neurology [Internet]. 2009 Mar [cited 2011 Aug 3];132(Pt 3):695–708. Available from: http://www. 1

ncbi.nlm.nih.gov/pubmed/19176544 Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Harding HP, Matthews A, et al. Recurrent concussion and risk of depression in retired professional football players. Medicine and science in sports and exercise [Internet]. 2007 Jun;39(6):903–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17545878 17 Marchie A, Cusimano MD. Bodychecking and concussions in ice hockey: Should our youth pay the price? CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne [Internet]. 2003 Jul 22;169(2):124–8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?art id=164979&tool=pmcentrez&rendertype=abstract 18 Trauma C-sports H, Saunders RL, Robert E. The Second Impact in Catastrophic Contact-Sports Head Trauma. October [Internet]. 1984;252(4):538–9. Available from: http://jama.ama-assn. org/content/252/4/538.short 19 Athlete Brain Donations for Concussion Study Reach 300 [Internet]. 2010 [cited 2011 Oct 16]; Available from: http://sports. espn.go.com/espn/news/story?id=5677532 20 Christie J. Former Sabres Rick Martin had brain disease [Internet]. 2011 [cited 2011 Oct 16]; Available from: http://www. theglobeandmail.com/sports/hockey/former-sabres-star-rickmartin-had-brain-disease/article2192489/ 21 Warsh JM, Constantin S a, Howard A, Macpherson A. A systematic review of the association between body checking and injury in youth ice hockey. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine [Internet]. 2009 Mar;19(2):134–44. Available from: http://www.ncbi.nlm. nih.gov/pubmed/19451769 22 Fields SK, Collins CL, Comstock RD. Violence in youth sports: hazing, brawling and foul play. British journal of sports medicine [Internet]. 2010 Jan [cited 2011 Oct 10];44(1):32–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19858113 23 Boardley ID, Kavussanu M. Effects of goal orientation and perceived value of toughness on antisocial behavior in soccer: the mediating role of moral disengagement. Journal of sport & exercise psychology [Internet]. 2010 Apr;32(2):176–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20479477 24 Daneshvar DH, Baugh CM, Nowinski CJ, McKee AC, Stern R a, Cantu RC. Helmets and mouth guards: the role of personal equipment in preventing sport-related concussions. Clinics in sports medicine [Internet]. 2011 Jan [cited 2011 Jul 9];30(1):145–63, x. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2987604&tool=pmcentrez &rendertype=abstract 25 Lee E. Ontario Hockey Federation bans bodychecking in house leagues [Internet]. 2011; Available from: http://www.thestar. com/sports/hockey/article/986873--ontario-hockey-federationbans-bodychecking-in-house-leagues 16

The Meducator | November 2011

INTERVIEW: Dr. Richard Heinzl At the Forefront of Global Healthcare Interview with Dr. Richard Heinzl MD, MPH, MSc, FACPM, LLD Conducted by Kimia Sorouri Bachelor of Health Sciences (Honours) Program Class of 2015 Dr. Richard Heinzl is a McMaster Medical School alumni. He also studied at Harvard and Oxford University, where he received Master degrees in Public Health and Science, respectively. Dr. Heinzl was connected to McMaster University prior to becoming a student himself as his father, Rudy Heinzl, was the Dean of Student Affairs for 11 years. Dr. Heinzl founded the Canadian chapter of Médicins Sans Frontières only a year after graduating from Medical School. When he is not abroad practicing medicine or performing research, Dr. Heinzl often returns to McMaster to share his immense knowledge and life experiences. His most recent presentation at McMaster on October 19th was organized by the Medical School community. During this presentation, Dr. Heinzl shared key aspects of a health plan he is constructing for the Kalinago people of Dominica.

Dr. Heinzl, during your presentation at McMaster University on October 19th, you mentioned the importance of the people of Dominica, the Kalinagos or Caribs, in having ownership over the research you and your team are conducting to improve their healthcare. Could you tell us more about the importance of ownership of the research by the locals?

It might seem obvious that research about the health of a certain population should naturally be owned or at least co-owned by them. After all, the research is conducted with them, about them and ultimately for them. Unfortunately, many times research is conducted on a population with promises to bring the results back to them, only to find that the results never return. They remain in a university or organization or journal and are never shared. This happened in the past with the Kalinago people, so they were naturally wary of outsiders coming in with research plans and good intentions.

What are some of the unexpected results you are finding from your research in Dominica?

We were able to gain an overall sense of the health of the Kalinago people. Even though this is a very poor society, (Chief Joseph calls it “the Third World of the Third World”), certain indicators point to what is actually a very positive health status both physically and emotionally. Generally Dominicans eat fresh fruits and vegetables and fish, and they are quite active (having to walk steep hills), so they are fit. We saw very little obesity and almost no smoking. It has been reported that there are more centenarians in Dominica per capita than anywhere else. I don’t know if it’s true but that would be a positive and unexpected finding.

In your presentation, you also spoke about the importance of cell phones as a form of liberation technology. How have you witnessed health care change as a result of the advent of such communication technologies and resources such as the internet?

Once the ownership of the Kalinagos was established, what kind of relationship did that create between your I like that phrase “liberation technology.” When I was in the field team and the locals? with Médecins Sans Frontières in the 80s and 90s, we could only carry with us a couple of very heavy textbooks, such as Harrison’s They became very enthusiastic and fully endorsed the research. In Principles of Internal Medicine, which didn’t have all the answers. fact, they took the lead on the project and this made all the differ- Sometimes there were patients in front of us and we didn’t know ence. The Chief and other leaders went on the radio and television what was wrong or what to do and there was no way to ask for and explained to the people why such basic health research is im- help. In those moments we dreamed up the Internet and cell portant. This allowed the teams of surveyors (who were Kalinago phones. We saw them as godsends. We know that if people have citizens) and us to be welcomed by respondents. It made the data access to information they will be empowered and in so doing, gathering much more thorough and robust, and therefore more new ways of understanding and improving their health will be valuable. What’s more, once trust was established, we all could unleashed. Kofi Annan, the former secretary General of the UN relax and we had fun. used to say the Internet is the great hope for the world’s poor. And C. Everett Koop, the former Surgeon General of the US, used to say Information is the best medicine. I would agree.

INTERVIEW

Coming back to Dominica. Even though it is a poor society, 70% of the people have cell phones. That’s striking. That fact alone tells you something about their inherent value. In rural Africa cell phones show up in places previously disconnected from the world. When I was in Cambodia in the early 90s it used to take a two day drive in a Toyota Land Cruiser to obtain clinical information from a tertiary healthcare centre. It now takes seconds. Cell phones can be used to email a photo of a rash, give crucial updates to patients taking HIV medicines and allow pregnant mothers to join a forum about birth complications.

One of your many projects, MediSpecialist.com, aims to allow doctors to consult online, furthering the concept of a borderless world of healthcare. Could you please give our readers some further insight into this project?

MediSpecialist was a dot com era start up. The four principals of Cambodia Calling: the company were myself, Dr. Stuart Smith, a former McMaster A Memoir from the Frontlines of psychiatry professor and leader of the Liberal party in Ontario, Dr. Phil Gold, the co-discoverer of the carcinoembryonic antiHumanitarian Aid gen, and Ron Cape, widely regarded as one of the fathers of the biotechnology industry. So it was mind-blowing company. While everyone was figuring out how to use the Web to download music In your novel, Cambodia Calling, you recount an and do their banking, I had an idea to collect hundreds of outextraordinary year you spent as an MSF field staff in standing medical specialists online, give them a capability to do Cambodia. If your readers were to take away one message medical opinions digitally and put that in the hands of patients from the novel, what would you like it to be? and their physicians. It meant someone with a rare leukemia in rural Saskatchewan could obtain advice from a world leader in, Thank you for calling it a novel. It was written as such, although say, Oxford, UK. While MediSpecialist is no longer operational it’s all true. Others have called it a creative narrative, or coming in its original form, the discoveries we made have been emulated of age story, or even a journey of discovery. The message might be by others and are in use by several corporations I work with today. that travel is a gift. That we owe it to ourselves to travel—to immerse ourselves in something completely different (not necessarily Your work has taken you to many different coun- a war zone, but something unknown, perhaps uncomfortable and tries around the world where humanitarian crisis is yet remarkable). By doing so we will be challenged to understand prevalent. What were some of the dominant barriers you other peoples and we will come to know the world and ourselves encountered while working in such countries? in a new light.

Violence. Underdevelopment. Ignorance. Politics. Corruption. In what direction do you think the future of global Unwelcoming geography. Military intimidation. Prejudice of all health care is headed? types. Inequality. Lack of freedoms. All of which are the ingredients of poverty. I gave a talk at McMaster once about 15 years ago entitled, “Electrons are Faster than 4x4s.” This was back in the days when people Is returning after a mission abroad as challenging as still thought cell phones were only for CEOs and diplomats so the it is to leave? talk was met with some mild deprecation and perplexion. There is a brilliant MIT futurist named Ray Kurzweil. When you apply It was in the beginning. I remember coming home the first time his thinking to humanitarian work overseas in remote, ultra-poor and realizing I hadn’t read a newspaper in six months because the communities, astonishing new possibilities emerge. For example stories they were covering were so different from what I thought it’s been suggested one day we will be able to download a cure for was important. Someone would say “Tell me all about your trip” AIDS. And some believe that artificial intelligence will soon outand after a minute they would be looking out the window and strip the existing diagnostic capabilities of my medical colleagues. before long they would change the subject and we’d be on about (I believe both). Kurzweil’s concept of double exponential change hockey or the stock market. The far away world is hard for people means that not only will technology drive tremendous innovation, to grasp. For myself now, I’ve been away so many times, it’s more but also it will do so at such a mind-boggling rate that it will be like I hold both world’s in my head simultaneously. That makes almost impossible to see it happening before us and very difficult coming and going easier. to predict what will be. Liberation technology indeed.

The Meducator | November 2011

Research Highlights AT MCMASTER

MACWIRE

Compiled by Bhavik Mistry and Ilia Ostrovski

Prostate cancer is the most common type of cancer afflicting males in the United States. The question of what treatment regiment will optimally balance efficacy with minimal adverse effects is thus one that physicians are faced with particularly often. Dr. Damu Tang, Associate Professor of Medicine, concluded that elevated levels of the protein MAN2C1 predispose patients to more aggressive forms of the disease. In studying the mechanism of PTEN, a tumor suppressor protein, Tang discovered that its protective effects are impaired by MAN2C1. This finding provides physicians with a potential diagnostic marker for recognizing more severe cases for the purpose of determining when more aggressive therapy is warranted.

Dr. Daniel Goldreich, Associate Professor of Psychology, Neuroscience and Behaviour, discovered that individuals with congenital blindness are able to detect tactile information much faster than sighted people. Goldreich’s methodological approach involved analyzing the ability of participants to perceive the movement of a small probe at the tip of their index finger. From this promising study, Dr. Goldreich hopes to develop software that can track the perceptual ability of blind individuals as they learn Braille.

Recent research by Dr. Ray Truant, Professor in the Department of Biochemistry and Biomedical Sciences, has demonstrated an effective approach in delaying the onset of Huntington’s Disease (HD). This condition is associated with aberrant modifications to the huntingtin protein, which Dr. Traunt and his team were able to stop using drugs known as kinase inhibitors. Dr. Traunt’s team is now investigating the ability of these kinase inhibitors to cross the bloodbrain barrier. If successful, stage 1 clinical trials could begin in five years.

Bhattacharjee A, Ye AJ, Lisak JA, Vargas MG, Goldreich D. Vibrotactile masking experiments reveal accelerated somatosensory processing in congenitally blind braille readers. J Neurosci. 2010 Oct;30(43):14288-14298. Image adapted from: http://www.ltscotland.org.uk

Atwal RS, Desmond CR, Caron N, Maiuri T, Xia J, Sipione S, et al. Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat Chem Biol. 2011 May;7(7):453-46.

The advent of antibiotics has engaged researchers in a tireless race against what was believed to be the rapid microbial adaptation of drug-resistant properties. In a paper published in Nature, the research teams of Dr. Gerry Wright and Dr. Henrik Poinar subvert the idea that resistance arises spontaneously by demonstrating that the genes coding for these traits are ancient. Through studying bacterial DNA from soil frozen in 30000-year-old permafrost, the authors show that microbes have been adapting to obstacles in nature for millenia. As a result of this finding, the notion of creating a drug that is not susceptible to resistance may one day become obsolete in the scientific community.

Infectious organisms have been known to develop resistance to antibiotic treatment. Recently, researchers Dr. Gerry Wright, Dr. Eric Brown, and Dr. Brian Coombes from the Department of Biochemistry and Biomedical Sciences discovered a new therapeutic approach for cystic fibrosis patients suffering from persistent bacterial infections. In particular, the joint initiative uncovered how a combination of an over-thecounter anti-diarrhea drug and the antibiotic, minocylcin, could be used to effectively inhibit bacterial growth. This novel discovery sheds light on a potential means to combat antibioticresistant bacteria and may lead to a safer method for treating lung infections in patients with cystic fibrosis.

Dr. Mick Bhatia, Director of McMaster Stem Cell and Cancer Research Institute, recently discovered new mechanisms behind the selective ability of human pluripotent stem cells to make important lineage decisions. A pluripotent stem cell can differentiate into 1 of 266 cell types in the human body. Previously, it was believed that all stem cells were alike and had an equal chance of differentiating into specialized cells. However, Dr. Bhatia suggests that this is not really the case. His study shows how a pluripotent stem cell can be ‘forced’ into a different cell type based on specific cell surface markers and histone modification marks on gene loci associated with pluripotent stem cells. Future investigations will involve understanding how these processes apply to induced pluripotent stem cells, which are stem cells generated from adult skin cells.

D’costa VM, King CE, Kalan L, Mariya Morar, Wilson W. L. Sung, Carsten Schwarz, et al. Resistance to antibiotics is ancient. Nature. 2011 August 31; 477(7365):457-461. Image adapted from: http://www.immunitytherapy.com

Ejim L, Farha MA, Falconer SB, Wildenhain J, Coombes BK, Tyers M, et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011 Jun;7(6):348-350. Image adapted from: http://www.labspaces.net

Hong SH, Rampalli S, Lee JB, McNicol J, Collins T, Draper JS, et al. Cell fate potential of human pluripotent stem cells is encoded by histone modifications. Cell Stem Cell. 2011 Jul;9(1):24-36. Image adapted from: http://newsroom.stemcells.wisc.edu

He L, Fan C, Kapoor A, Ingram AJ, Rybak AP, Austin RA, et al. a-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells. Nature Communications. 2011 May;2:307. Image adapted from: http://wikimedia.org

Image adapted from: http://brain.oxfordjournals.org

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