Issue 11

McMaster’s Medical Research and Health Ethics Student Journal

Should doctors be allowed to refuse treatment?

Also in this issue: Debate on Canada’s health care Alzheimer’s drug may prevent breast cancer relapse Loneliness & cardiovascular disease Chaperones & protein folding

From Proteins to Patients Issue 11 | Nov 2007

www.meducator.org

Research Articles Presidential Address

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MedWire

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Tyler Law

MedBulletin

Healthcare in Canada: not private, but non-profit

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MedQuiz

Ran Ran

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About The McMaster Meducator The McMaster Meducator is an undergraduate medical journal that publishes articles on current topics in health research and medical ethics. We aim to provide an opportunity for undergraduate students to publish their work and share information with their peers. Our protocol strives to maintain the highest standard of academic integrity by having each article edited by a postgraduate in the relevant field. We invite you to offer us your feedback by visting our website: www.meducator.org.

Should doctors be allowed to refuse to treat their patients?

Simone Liang

Not chIC

Table of Contents

Issue 11 | November 2007

CSL

CoA

On

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Alzheimer’s drug may prevent breast cancer recurrence Manan Shah

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When your lonely heart breaks

The McMaster Meducator may be contacted via our e-mail address: meduemail @learnlink.mcmaster.ca or our mailing address: B.H.Sc. (Honours) Program Attention: The McMaster Meducator 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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Deborah Kahan

Ribosome

Chaperones and protein folding

Pi

Hsp 70-ATP Protein

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Partially folded protein

Kirandeep Bhullar

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Issue 11 | November 2007

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he world of medicine changes at a fast pace – new discoveries and advances are made every day, providing solutions to numerous health problems. Likewise, each advancement made seems to generate several new questions or challenges that need to be addressed. Keeping abreast of this capricious field is a daunting challenge – but one that the Meducator is prepared to face.

This issue, we bring the focus onto a number of matters that have developed out of our increasing knowledge of medicine and human health. Healthcare is a top priority for many Canadians, and the “public vs. private” debate continues, despite a serious misunderstanding of some of the core issues. Ran Ran has written an informative article to highlight and clarify these key issues. Finite healthcare resources are at the heart of Simone Liang’s article also, as she discusses the ethics of denying treatment to individuals with self-destructive habits, such as smoking. Healthcare of the elderly is a pressing concern, and Deborah Kahan’s article explains how the often unconsidered element of loneliness may exacerbate the risk of cardiovascular disease in this population. Kiran Bhuller explains the importance of chaperone proteins and the consequences of protein misfolding, such as Alzheimer’s disease. Finally, Manan Shah contributes an overview of a signalling pathway in breast cancer, and explains how a drug initially designed to treat Alzheimer’s disease may also be useful against breast cancer.

Aside from these informative articles, the Meducator provides other ways to access timely information about current developments in the world of medical research and health ethics. For example, you will find a number of items in the MedWire section – these MedWires are short, two to three sentence explanations designed to bring your attention to the health news that we found most interesting. MedWires are posted on our website every week. Also, you’ll find several MedBulletins, which are expositions on new research and ethics topics, and go into some depth to explain the relevance of these topics to health. These are posted in locations across campus (i.e. MDCL, BSB etc.) and are updated on our website each week. I encourage you to regularly visit our website, read what you find interesting, or subscribe to our RSS feeds for automatic updates. Our website has recently been relaunched, and we look forward to your comments.

The Meducator is the product of many dedicated individuals, without whom it wouldn’t be possible. I’d first like to thank Crystal Chung, for all her hard work, reliability, and support. Thanks to the VP Editors, for their impeccable editing work and consistent dedication: Harjot Atwal, Harman Chaudhry, Jacqueline Ho, Alexandra Perri, Jonathan Liu, Siddhi Mathur, Sarah Mullen, Navpreet Rana, and Jeannette So. Also thanks to Stephanie Low for putting the whole magazine together, and her team of layout staff, Ran Ran and Andrew Yuen, for preparing the images and making such a sharp cover. A sincere thanks to Avinash Ramsaroop for redesigning the website, and giving us the tools to reach more people. Lastly, I’d like to welcome our Junior Editors – Veronica Chan, Randall Lau, Simone Liang, and Fanyu Yang – and thank them for their enthusiasm and patience. The Meducator will be in your hands in years to come.

Meducator Staff President Tyler Law Vice-President Crystal Chung VP Medical Research and Health Ethics Harman Chaudhry Jacqueline Ho Jonathan Liu Siddhi Mathur Sarah Mullen Alexandra Perri Navpreet Rana Jeannette So VP Layout Stephanie Low VP Web Design Avinash Ramsaroop VP Public Relations Harjot Atwal Junior Executives Veronica Chan Randall Lau Simone Liang Ran Ran Fanyu Yang Andrew Yuen

Post Graduate Editors Dr. Robert Clarke, Ph.D., D.Sc.

Please enjoy this issue, and send us an email if you have any comments. Remember to visit www.meducator.org for an online version and to receive all the latest updates.

Dr. Gregory Curnew, M.D., C.M, FRCP(C)

Yours Truly,

Dr. Joaquin Ortega, Ph.D. Dr. Gregory Stoddart, B.A., Ph.D.

Tyler Law B.H.Sc. III

Dr. Mark Walker, Ph.D.

www.meducator.org

Presidential Address

Dear Reader,

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Issue 11 | November 2007

Reactive oxygen species represent some of the most degenerative mutagens created by normal biological mechanisms. The risk of cancer and the concentration of the metabolic byproduct are well documented, and its levels are kept within sustainable levels by manganese superoxide dismutase (SOD2). Examination of pancreatic carcinoma cells revealed that methylation of the sod2 locus results in a lowered concentration of SOD2, though the process is oddly necessary for proper genotypic expression.

Molecular consequences of high levels of SOD2 are numerous, first among which are the altered binding capacities of The risk of radiation induced various genes and transcription lung fibrosis (RILF), limits factors. the proper dosages of lung cancer radiation therapy that A recent clinical study from can be safely administered. New York University found New findings suggest that the that activity in the amygdala prevalence of RILF is highly and the front portion of the correlated with the presence anterior cingulate cortex of integrin α-v/β-6, a primary activator of transforming growth factor (TGF)-β1, which, in turn, triggers inflammatory and pro-fibrotic effects .

The American Society for Therapeutic Radiology and Oncology was recently presented with evidence of (ACC) increased when subjects dramatically reduced risk of imagined positive events in the RILF in patients administered future. These structures of the with monoclonal antibodies to brain are thus highly related to neutralize integrin α-v/β-6. optimistic thinking in humans.

The significantly less active ACC in depressed patients further affirms these conclusions; it is foreseen that the results will instigate further research on the fundamental mechanisms of depression.

experts are concerned that pain perception would be different in patients suffering from chronic diseases. It is expected that these findings will initiate large-scale studies on cannabis use in individuals with cancer and multiple sclerosis, among other diseases.

Researchers from the University of California concluded that smoking an excessive quantity of medicinal cannabis may aggravate symptoms of pain instead of relieving them. Since healthy subjects were used in the study,

Researchers at the University of Copenhagen have created models of neural networks to simulate the role of ‘PIN code-like’ mechanisms in the immune system defence against disease. This analogy is that every human has his

MedWire

Biologists from Indiana University now suggest that adaptation or natural selection is not as necessary a component to genetic development as previously believed. Nonadaptive processes that have no obvious form of internal regulation such as mutation, recombination and genetic drift, have resulted in the development of essential genetic frameworks, though the relationship remains to be elucidated. The development of successful regulatory mechanisms with no direct phenotypic expression lacks a formal explanation in the time honoured Darwinian adage.

Researchers at the Oregon Health & Science University have identified the gene mechanism by which a kidney protein complex regulates blood pressure in a rare form of hypertension. Similar to the rheostat that modulates the balance of salt and potassium

MED in the kidney, this proposed “switch” can raise or lower blood pressure. Researchers explain for the first time the key role that multiple WNK kinases play in this process and how they can be manipulated as a functional unit. This finding has significant implications for the elucidation of causes for other common forms of hypertension.

or her own unique immune system PIN code, making viral information useless in infecting the next individual.

This in turn makes it difficult to generalize the entire human immune system and to develop immunological treatments such as vaccines.

In future, these new neural networks may be able to more accurately predict the range of known and unknown immune system PIN codes for different individuals.

In Manchester University, scientists have found that a herpes simplex virus could be linked to Alzheimer’s. The virus, HSV-1, was found to be prevalent in 70 percent of Alzheimer’s patients. Those with HSV-1 had an increase in the levels of beta-amyloid protein, a key protein that forms the plaques found in the brains of Alzheimer’s patients.

The appearance of the virus was

more common in Alzheimer’s patients with a certain mutant gene known as ApoE4.

More studies are necessary before the association can be confirmed.

Compiled by the World Cancer Research, the largest inquiry on the relation of cancer and

Issue 11 | November 2007

A new type of stem cell isolated from menstrual blood of healthy females could be used in the treatment of damaged tissue. Cells found in the growth of new blood vessels as part of the uterine phase of the menstrual cycle can be cultured in the laboratory in a shorter time span. This replication rate is far faster than the umbilical cord blood and bone marrow cells currently used. Bone marrow stem cell therapy may be rejected or have limited

ability to generate new tissue.

Menstrual blood stem cells are a potential strategy to overcome such difficulties.

Researchers from the University of Sydney uncover a correlation between cannabis use and enhanced cognitive functioning in patients with schizophrenia.

Frequent and recent cannabis use showed significant enhancement of the attention, processing speed and executive functions of neuropsychological performances. These findings suggest that cannabinoid receptors in the brain may have a useful role in the treatment of high-order cognitive processes in schizophrenia.

A versatile infant vaccine for meningitis has shown considerable promise in clinical trials. Current vaccines against A, C, W-135 and Y strains of the disease do not work in children under two years. Developed

by Novartis, this conjugate vaccine is better at producing “immune memory” than the older polysaccharide vaccines.

The prospect of broader protection against meningitis and septicaemia is encouraging since the greatest burden of these deadly diseases fall upon young children.

The British Columbia Cancer Agency has furthered the possibility of tailoring cancer treatments, by using patients’ tumors cells and photodynamic therapy (PDT). PDT involves the use of light to trigger anticancer drugs in the body, and to stimulate the immune system into fighting cancer.

The process involves culturing tumour cells to be sensitive to light, and then injecting the cells into the patient, before using light to provoke cells, the immune system, and anticancer drug. Researchers hope that by using the patient’s tumor cells, rather than lab cells, the PDT treatment will be more effective.

Researchers at Aberdeen University have found that mothers who smoke during pregnancy lower the prospective fertility in their unborn sons. After examining 22 fetuses, scientists found that the level of DHH gene, which is crucial to testicle development, was significantly affected if the fetuses’ mother smoked more than 10 cigarettes a day.

Though more research has to be conducted, this links the effects of smoking during pregnancy directly to future fertility of the unborn child.

Researchers from Stanford University have a new blood test that reveals the onset of Alzheimer’s two to six years in advance, by identifying 18 key proteins in the blood. The presence of these proteins signifies the higher likelihood of Alzhiemer’s onset. After testing the blood samples of 259 controls and early blood samples of 47 Alzheimer’s patients, the test showed an accuracy rate of 90 percent.

With this new test, patients more likely to develop Alzheimer’s can be diagnosed and treated earlier.

Two U.S. pediatricians have found a new strain of bacteria that causes ear infections in children and, unlike the other strains, is resistant to all prescribed treatments. After

failed treatments, the doctors punctured the eardrum and drained the fluid, resulting in discovery of the strain 19A. Currently, doctors are prescribing Levofloxin, an adult prescription not recommended for children, but effective against strain 19A.

MedWire

lifestyle reveals that people should aim to be thin to limit their risk of cancer. The research suggests that body fat is a key factor in cancer development, and that people should try to be within the lower portion of the “healthy” weight range. Though two-thirds of cancer situations are not linked to lifestyle, according to the inquiry, living a healthy lifestyle will limit the risks of developing cancer.

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A recent survey conducted by the British Medical Association (BMA) showed that approximately 1200 of 2,000 participants approved of a proposal for an opt-out system of organ donation. This system considers everyone as a potential donor unless an objection is registered before death. Adoption of a system of presumed consent would be an underlying strategy to improve the nation’s waining organ donor supply.

However, the BMA recognizes the considerable controversy behind this suggestion and welcomes opinions on the limitations it places on donor decision-making.

In the brain, insulin is integral to memory creation and learning. Neuroscientists at Northwestern University have uncovered the pathological mechanisms of insulin at the synapses.

Since the inability to form new memories is an early symptom of Alzheimer’s, understanding this insulininitiated process may be key to decoding possible causes of the disease. www.meducator.org

MedBulletin

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Issue 11 | November 2007

MedBulletin by Simone Liang

Bad Banked Blood?

One blood donation can save three lives, but are the transfusions as effective as they could be? Blood vessels constrict and dilate, but it is the nitric oxide in the blood that opens the vessels, allowing oxygen to be delivered to the tissues.

Regardless of the amount of oxygen available, the blood cells are not able to deliver oxygen to the tissues without the proper levels of nitric oxide. This could be the reason why people who undergo transfusions experienced higher incidents of strokes and heart attacks.

Recently, two separate research teams conducted independent studies concerning the levels of nitric oxide in the blood donations of clinics. One research team studied the nitric oxide levels in the blood, while the other investigated the effects of nitric levels. The blood donations are allowed to be kept for 42 days, but researchers saw “clear indications of nitric oxide depletion within the first three hours” said Dr. McMahon, leader of the second research team. In fact, the levels of nitric oxide continued to drop daily, and the gas itself dissipated once the blood had left the body.

However, once the nitric oxide levels were restored, the blood cells were able to continue delivering oxygen to the tissues.

There have only been initial studies conducted in the laboratory and on dogs, but there is intention to continue the studies with clinical trials, and to possibly find a way to maintain the levels of nitric oxide in blood donations.

References MSNBC. (2007) Banked blood may lack vital component. Retrieved October 8th, 2007, from http://www.msnbc.msn.com/id/21195326/ Scientific American. (2007). Donated blood quickly loses important gas: study. Retrieved October 12th, 2007, from http://www.sciam.com/article. cfm?alias=donated-blood-quickly-los

Could Psychological Disorders Impede Informed Consent?

MedBulletin by Fanyu Yang

The nature of Borderline Personality Disorder (BPD), characterized by intentional self-mutilation, raises growing debate over adequate consent for clinical research purposes. Patients with BPD display damaging and treatment resistant impulsivity, unstable self-image as well as overall inability to tolerate loneliness and intimacy. Despite fleeting episodes of severe psychotic stress, patients generally have normal cognitive function and can adequately assess the risks of their participation in any study. However, the issue of a BPD patient’s true informed consent is still necessary.

Patients with BPD may have poor rational decision-making abilities, which in turn, predispose them to place psychological needs before logical considerations. For example, a subject who consents to participation motivated by the devaluing tendencies of their interpersonal relationships or idealize feeling special, hurt and even suicidal. When BPD patients participate in a study with underlying psychological reasons, consent may not be valid because subjects are often motivated by factors other than self-interest.

On flip side, exclusively omitting patients with psychology disorders in studies is discriminatory on both ethical and statistical grounds. It could also detrimentally defy the purpose of research itself, especially in a chronic and debilitating condition such as BPD. Furthermore, it does not address the argument that BPD patients also do act in their self-interest, although the reasons may be slightly strange to others without the condition. Extreme caution should therefore be exercised in assessing both the subjects’ individual motives and their ability to consent based on comprehension of a study.

References: Dew, R. (2007). Informed consent for research in Borderline Personality Disorder. BMC Medical Ethics. 8:4 P.1186.

Issue 11 | November 2007

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The Immune System... Powerless Against

Hepatitis C?

MedBulletin by Veronica Chan

Researchers from the University of Birmingham recently confirmed the mechanism by which the Hepatitis C virus bypasses the body’s immune system, consequently inducing a rapid spread of the disease. Viruses typically attack by replicating themselves in large quantities within host cells, followed by their release to repeat this process in other cells. A study conducted using infected liver tumour cells demonstrated that Hepatitis C has the unique ability to undergo “cell-to-cell transmission.” In essence, this type of virus does not have to be released from the initial host cell before infecting another. It therefore evades the defense mechanisms of antibodies, which occur only outside of host cells. These latest findings consequently conflicts with many previous treatment methods to increase antibody activity, in attempt to reduce the disease’s potentially fatal effects.

Dr. Jennifer Timpe, one of study’s authors, noted that this distinctive transmission method accounts for the chronic and persistent nature of the illness. Currently, most Hepatitis C patients must resort to liver transplantation in the long run, as liver cancer and chronic liver failure are common consequences of such a viral infection. It is hoped that these ground-breaking results will provide new insight into the development of a plausible and much-needed treatment for Hepatitis C. References BBC News. (2007). How Hep C bypasses cell defences. Retrieved October 25th, 2007, from http://news.bbc.co.uk/2/hi/health/7075569.stm.

Worth Screening For?

MedBulletin by Simone Liang

In one year, nearly 1.7 million Americans contract various infections during their stay at the hospital. The “super bug”, methicillan-resistant Staphylococcus aureus (MRSA) is responsible for 10 percent of the 1.7 million ailments, and kills nearly 19,000 people a year. Found in hospitals, MRSA is transferred from physician to patient, when doctors fail to wash up properly after treating infected patients.

MRSA can also be found on the skin of healthy individuals. Recently, MRSA has been on the rise, spreading into schools and public areas, and estimated to infect more than 90,000 people a year.

Despite the serious situation, many doctors and infection control experts oppose the idea of screening for MRSA, which can limit the transfer of the bacteria and possibly eliminate MRSA altogether. Physicians argue that the costs of screening are too high, and that in some hospitals, it is unnecessary since the prevalence of MRSA cases is extremely low. At Chicago’s University Medical Centre, it will cost $80 000 for the testing supplies alone, and $28 million to install testing equipment in 155 hospitals in Pittsburgh, PA. Rather than trying to eliminate one strain of bacteria, experts argue that the efforts should be focused on controlling infection through proper sanitization.

In Illinois, Pennsylvania, and New Jersey, hospitals are now required to screen likely victims of MRSA. In one case, the infection rate of MRSA dropped 60 percent in three Chicago hospitals after screening began in 2005. Is the containment of a single strain of bacteria worth millions of dollars?

References: MSNBC. (2007) Few hospitals screen for ‘superbug’. Retrieved October 26th, 2007, from http://www.msnbc.msn.com/id/21456183/

www.meducator.org

MedBulletin

Exposition

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Issue 11 | November 2007

Healthcare in Canada: not private, but not-profit

Ran Ran

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Is it ethical to allow the private sector to provide services with public aims? Is public healthcare more cost- effective or socially responsible? Which sector will best meet the public’s ever- changing health requisites? This article reviews some of the key arguments on both sides of Canada’s public versus private healthcare debate, which is essential for a comprehensive understanding of this sensitive and proximal issue.

ne of the easiest ways to demonstrate the merits of Canada’s healthcare system is to compare it to that of our closest neighbour—the United States of America. According to the World Health Organization’s annual world health reports, Canada has consistently provided better healthcare than the United States at a relatively smaller cost to its citizens. Furthermore, the Canadian healthcare system’s quality and universality has been a point of pride at home and abroad (Steinbrook, 2006).

Unfortunately, the increasing costs of new technologies and prevalence of chronic diseases are overburdening the traditional system, thereby threatening its sustainability (Lewis et al., 2001). Despite structural reforms and promises of more effective practices, long wait times and decreased quality of care continue to plague the public health sector (Steinbrook, 2006). Public expectations of access are dissonant with what is publicly affordable. Some critics believe that adopting more marketdriven practices would improve system performance (Simpson, 2007). Others believe that privatization would only exacerbate the situation. These two opposing ideological standpoints form the foundation of the perennial publicversus-private healthcare debate. This article seeks to review and elucidate some of the key arguments on both sides of the debate.

First and foremost, several

oversimplifications must be addressed.

The terms “public” and “private” are misnomers. The erroneous implication is that Canada’s current healthcare system is exclusively “public”. In actuality, both public and private organizations fund medical services – 70% public and 30% private (Steinbrook, 2006).

Furthermore, payment for and delivery of healthcare are two entirely different concepts. Canada, for the most part, provides public funds to private notfor-profit businesses, such as hospitals and independent practitioners (Ovretveit, 1996). Thus, the ostensible

“Public expectations of access are dissonant with what is publicly affordable” “public-versus-private” debate is more accurately a debate between notfor-profit and for-profit healthcare (Ovretveit, 1996). While it is important to keep this distinction in mind, the original terms will be preserved in this article for the sake of simplicity.

One of the key dilemmas in this debate revolves around the practicality of privately and publicly funded healthcare—in other words, which option is better able to meet the needs of the people (Ovretveit, 1996)?

Supporters of the current system reason that since the political infrastructure is

designed to respond to its constituents’ diverse demands, the government should continue to manage the lion’s share of healthcare funding. However, healthcare issues are not often a priority issue in the political agenda until they become pivotal debates during elections (Williams & McKeever, 2007). The versatility and effectiveness of private businesses allows their escape from the government’s alleged inefficiencies and monetary limitations. Conversely, the expedient nature of the private sector can also be their potential downfall when there is a conflict of interest, resulting in private interests overriding public ones. For example, Vioxx, a drug produced by the pharmaceutical giant Merck, was withdrawn from the market in the fall of 2004. Pressure from the private sector and subsequently from the FDA delayed the publication of a number of studies linking the drug to the increased incidence of heart attack after the studies were completed. Merck itself disassociated its staff researchers with the studies, subsequently criticizing these studies on a number of different fronts before yielding to the ensuing public outrage at the drug’s continued endorsement (CBC Health and Science News, 2005).

Cost-effectiveness is another debated issue—who can minimize the costs while achieving the same outcome?

Theoretically, privatization should result in greater cost-effectiveness as its practices are under greater pressure to be efficient and competitive (Williams & McKeever, 2007). Many studies in the

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Both public and private healthcare systems possess strengths and weaknesses. Some believe the “best of both worlds” could be encapsulated within a two-tiered system.

Employed by many developed countries but illegal in Canada, this system allows both systems to operate in parallel. Advocates are optimistic that alternate private avenues will alleviate pressures from the public health system and result in greater quality of care for all. Among other issues, opponents of the two-tier system believe that permitting a separate system of healthcare for the wealthy would only widen the socioeconomical gap and debase our original value of equality.

If there is any universal truth about humanity, then it is that people will become ill at some point in their lives. Given its relevance to our lives and proximity to our moral values, Canadians are very passionate about this debate. But passion must be supplemented by reason before decisions are cast. Canadians would benefit from a more comprehensive understanding of this complex issue as opposed to an oversimplified conceptualization of a prefatory dichotomy.

References Can for-profit healthcare be as efficient as not-profit healthcare?

literature show results that both support and refute this prediction (Devereaux et al., 2004; Sloan & Grabowski, 1997).

Proponents of not-profit healthcare argue that regardless of their cost-efficiency, for-profit healthcare often sacrifices quality of care. For instance, several studies indicate increased mortality rates in privately funded healthcare systems (Devereaux et al., 2002). The long-term costs of private healthcare has yet to be extensively studied.

Closely linked to this economic concern is an ethical one: should the private sector provide services with public aims? Critics of the private sector argue that it is unethical to profit off of another’s illnesses and that profit-driven incentives are highly unsuited for the conscientious practice of healing. In defence, opponents attest that since all primary care professionals profit from human malady, profitdriven medicine is not entirely foreign or unethical. On the other hand, Canada’s public single-payer system has also been accused of being immoral (Chaoulli, 2006). When the government prohibits individuals from seeking immediate treatment from private clinics, ill citizens are unnecessarily exposed to a greater risk of morbidity from long waiting times (Chaoulli, 2006). The case of Chaoulli v. Quebec (Attorney General) reflects this individualistic concern. After deliberation, Supreme Court Judges ruled that prohibiting private medical insurance violated the Québecois’ right to life, as guaranteed by Québec’s provincial charter (Chaoulli, 2006). Although the decision only applied to Québec, the morality of public healthcare was also brought into question nationwide—should the public good be placed before individual health?

Chaoulli J. (2006). A Seismic Shift: How Canada’s Supreme Court Sparked a Patients’ Rights Revolution. Policy Analysis, 568.

CBC Health and Science News. (2005). Study linking Vioxx to heart problems finally published. Retrieved Oct 21, 2007 from http://www.cbc. ca/health/story/2005/01/25/vioxx-050125.html.

Devereaux P. J., Ansdell D. H., Lacchetti C., Haines T., Burns K., Cook D. J., Ravindran N., Walter S. D., McDonald H., Stone S. B., Patel R., Bhandari M., Schünemann H. J., Choi P., Bayoumi A. M., Lavis J. N., Sullivan T., Stoddart G. & Guyatt G.H. (2004). Payments for care at private for-profit and private not-for-profit hospitals: a systematic review and meta-analysis. Canadian Medical Association Journal, 170(12), 1817-1824.

Devereaux P. J., Choi P., Lacchetti C., Weaver B., Schünemann H. J., Haines T., Lavis J. N., Grant B., Haslam D., Bhandari M., Sullivan T., Cook D.J., Walter S.D., Meade M., Khan H., Bhatnagar, N., & Guyatt, G. (2002). A systematic review and meta-analysis of studies comparing mortality rates of private for-profit and private not-for-profit hospitals. Canadian Medical Association Journal, 166(11), 1399-1406.

Lewis S., Donaldson C., Mitton C., & Currie G. (2001). The Future of Health Care in Canada. British Medical Journal, 323(20), 926-929.

Ovretveit J. (1996). Beyond the Public-Private Debate: the Mixed Economy of Health. Health Policy, 35, 75-93.

Simpson J. (2007, February 21). Canadians are warming to private health-care delivery. Globe and Mail.

Sloan F. A. & Grabowski H. G. (1997). The Impact of Cost-Effectiveness on Public and Private Policies in Health Care: an International Perspective. Introduction and Overview. Social Science Medicine, 45(4), 505-510.

Steinbrook R. (2006). Private Health care in Canada. The New England Journal of Medicine, 354(16), 1661-1664.

Williams C. (Presenter) & McKeever P. (Guest). (2007, February 1). On the line [Television broadcast]. Canada: Crossroads Television System. Retrieved Oct. 20, 2007, from http://www.freedomparty.org/ fpovideo/fpontv/2007.02.01.McKeever.On-the-Line.Pt-2.wmv

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Issue 11 | November 2007

Should doctors be allowed to refuse to treat their patients?

Simone Liang

With rising costs of healthcare and lack of doctors, are resources being wasted on self- destructive patients? Smokers tend to need repeated surgeries since the nicotine delays recuperation by weakening the bones. Obesity tends to increase the risk of complications, and individuals tend to gain weight while waiting for surgery. However, doctors cannot prioritize patients based on their treatment needs. If patients do not listen to their physicians, should doctors be allowed to postpone treatment?

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n the 21st century, healthcare has become a major field for employment and controversy. With the exponential growth in population and more aging baby boomers, the constant demand for doctors cannot be fulfilled and resources are strained. Healthcare costs are also rising and as treatments become more complex and costly, the public system could become a private one. With limited resources and costly procedures, physicians have the option to prioritize their patients depending on their case. Should doctors be allowed to refuse treatment for patients with severe self-destructive vices, such as smoking and obesity?

As more baby boomers reach retirement age, the need for doctors and treatments continues to intensify. As a result, doctors are required to use their medical expertise to

.

Obese individuals tend to gain weight as they wait for their surgery, increasing their risks of complications during surgery

determine which patients to treat first, while also considering the well-being of the patient. Patients with self-destructive habits need repeated treatments, which limits the number of patients the physician can examine and treat. Self-destructive habits encompass a range of poor lifestyle choices that endanger their health unnecessarily, though the definition may vary among members of the medical community. With an overwhelming number of patients, doctors are forced to decide upon the appropriate treatments for their patients, even if that includes not treating them until the resources are available.

After many years of post-secondary education and at least two years of residency, doctors are qualified to determine a patient’s necessary treatment. If they decide against treating the patient, then there should be a good reason. For example, if a treatment was going to do more harm than good, it would be reasonable for the doctors to refuse to proceed. With obese individuals and chronic smokers, doctors advise their patient to lose weight or to stop smoking at least six weeks before the surgery (Bitomsky, 2004). Smoking impairs post-operative bone healing and increases the risk of infection, while excess weight increases the possibility of complications in surgery. The failure rate in operations that involve the healing of bones is five times higher in smokers (Kohler & Righton, 2006). Smokers tend to be at a higher risk for poor surgical outcomes, and consequently, their surgeries are more likely to be repeated (Bitomsky, 2004).

Excess weight has similar effects in surgery, since the risks are higher, and the treatments tend to be less effective. In terms of hip and knee replacements, the patients’ joints wear out more rapidly, resulting in the need for frequent operations and adding further strain to the healthcare system (Kohler & Righton, 2006). Unfortunately, smokers often refuse to quit, while obese individuals tend to gain additional weight as they wait for surgery. With all the complications and consequences that may result if patients do not comply with the doctor’s recommendations, it is reasonable for the doctor to postpone the surgery.

However, many also argue that doctors do not have the right to choose their patients and that they are responsible for treating everyone regardless of their condition. If doctors are

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given the right to refuse patients with self-destructive habits, then there is no reason for them to treat complicated cases.

Situations like anorexia and bulimia are similar to smoking in the sense that repetitive treatments may be needed before progress is shown. The average patient is not required to improve their lifestyle choices prior to treatment, so smokers should not have to stop smoking and the obese should not have to lose weight (Kohler & Righton, 2006). With the option to refuse self-destructive patients, doctors should also be able to refuse treatment for people that similarly endanger themselves by participating in extreme sports. However, it can also be argued that this violates a doctor’s mandate to help the ill, and they should not be able to reject patients with difficult cases. Once doctors have the option to refuse treatment, it becomes difficult to analyze cases with consistency or without bias.

In fact, studies have shown that smokers and overweight individuals are often perceived negatively and

are more likely to face discrimination (Kohler & Righton, 2006).

Even among professionals who study obesity, stigmatization is still prevalent. In one study, obesity counselors and doctors were given words to categorize, and in the end, they ended up relating “fat people” to negative words such as “slow”, “lazy” and “sluggish” (Kohler & Righton, 2006). Obesity has also been proven to have a genetic component, suggesting that a change in lifestyle would not affect their situation (Kohler & Righton, 2006). The negative associations with smoking and obesity should not influence the medical treatment that patients receive. Cases such as anorexia nervosa are also selfdestructive habits yet doctors are not any less inclined to provide treatment. Physicians could also end up developing a bias for healthier patients since their incentive would be their fee-for-service payment schedule. Doctors are expected to provide equal treatment for everyone, and should not be able to refuse patients based on their own biased judgment and projected complications.

FOOD PYRAMID Eaten in moderation, sweet and fatty foods can form part of a heathy balanced diet Milk and dairy products contain calcium - vital for strong teeth and bones as well as proteins and vitamins

Meat, poultry, and fish are good sources of iron, zinc, and vitamin B

Fruits supply most of our dietry vitamin C

Vegetables are important to every diet

Breads, cereals, and potatoes, are the main sources of complex carbohydrates

Diet plays a significant role in health. Healthier patients are easier for doctors to treat, since they have fewer complications.

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Issue 11 | November 2007

Smoking impairs the healing of bones after surgery, so most smokers are encouraged to stop 6 weeks before their surgery date.

Over one-third of Canadians “believed that smokers should be given a lower priority in the public healthcare system”.

As treatments become more expensive, the cost of public healthcare will continue to rise. According to Statistics Canada, healthcare costs totaled $97.9 billion in 2000, and is predicted to reach $147 billion by 2020 (Kohler & Righton, 2006).

Those with self-destructive vices depend on the public system to finance their repeated treatments, consequently draining the healthcare system of its resources. Obesity is a growing epidemic that is straining our public healthcare system and problems associated with obesity, such as heart diseases and diabetes, are becoming more prevalent in society (Righton, 2006). With the growing strain on healthcare, the public is paying for additional treatments that may not be effective.

The results from Maclean’s Online Panel showed that over onethird of Canadians “believed that smokers should be given a lower priority in the public healthcare system” (Righton, 2006).

However, the public healthcare system in Canada is designed to allow everyone equal treatment, regardless of their condition.

It is human nature to pass judgment and as physicians become discouraged, choosing the easier treatment becomes a more viable option. Patients who choose to continue their self-destructive habits force doctors to repeat interventions with the same complications and results, leaving them worn out and frustrated. In one scenario, the same surgery was performed three times until the doctor refused to perform it.

The surgeries were failures because the patient was a chronic smoker which impeded post-operative bone healing (Kohler & Righton, 2006). By refusing to treat patients until they are willing to follow the doctor’s orders, physicians can attend to other patients to reduce added stress. When deciding upon which patients to treat, doctors must consider the well-being of their patients and the constraint of resources. Those with self-destructive habits limit the probability of an effective outcome, which further strains the healthcare system.

Doctors are required to treat everyone, but if patients are not compliant, there is little doctors can do. Most doctors

advise smokers to stop smoking before and after their surgery to increase the chance of success and limit the complications.

Overweight individuals are asked to lose weight for the same purpose. However, considering the association between lifestyle choices and illness, doctors should not blame patients for their choices in life. The stigma surrounding smoking and obesity as well as the possibility of genetic influence suggest that discrimination against them would be unethical. Should doctors be allowed to refuse to treat their patients?

References Bitomsky M. (2004, May 28). Doctors propose surgery discrimination against smokers.

Maclean’s, Retrieved January 21, 2007 from http://www.macleans. ca/topstories/health/article.jsp?content=20040520_201806_ 3320.

British Medical Journal debates whether smokers should be denied treatment. (January 2007). British Medical Journal.

Retrieved January 21, 2007, from http://prorev.com/health. htm.

Kohler N. & Righton B. (2006). Overeaters, smokers, and drinkers: the doctor won’t see you now. Maclean’s, Retrieved January 21, 2007 from http:// www.macleans.ca/topstories/health/article.jsp?content=200 60424_125702_125702 Righton B. (2006). The Lastest Health tip. Maclean’s, Retrieved January 21, 2007 from http://www.macleans.ca/topstories/health/article.jsp?content= 20060508_126329_126329.

Issue 11 | November 2007

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Alzheimer’s drug may prevent breast cancer recurrence

Manan Shah

Current research shows the unregulated growth in cancer cells in breast cancer is linked to the dysfunctional Notch Signaling Pathway. The intercellular domain (Notch-IC) of one of the proteins in this pathway is cleaved in response to binding of the extracellular ligand. In cancer cells, it is present in high levels, and activates a transcription factor responsible for regulating cell cycle genes.

DAPT, an Alzheimer’s drug has the potential to block extracellular ligand binding, but has some social and medical implications.

B

reast cancer is responsible for the deaths of 502,000 individuals a year worldwide, and is the leading cause of cancer deaths among women (Cancer Fact Sheet, 2006). There are many factors leading to the disease, including non-inherited, and inherited genetic mutations, and a variety of environmental elements. The different types of breast cancer begin with the growth of a tumour presenting with the possibility of metastasis. Due to the disease’s high incidence, it is important to have an understanding of the current and future therapies available for treatment (About Breast Cancer, 2006).

Treatment Methods There are several methods currently used to treat breast cancer and prevent relapse. The two major categories of treatments can be seperated into local and systemic; the former targets the immediate area where the treatment is administered, while the latter takes effect in the various systems of the body. Examples of local treatments are surgery and radiation therapy, while systemic treatments include HER-2 therapy, chemotherapy, and hormone therapy. Although these techniques are effective, each are associated with a set of limitations and side effects. For example, treatment via surgery may neglect cancerous cells that have metastasized to other parts of the body, while hormone therapy is a viable treatment only for patients that have cancer growth promoted by the presence of estrogen (About Breast Cancer, 2006). Hormone therapy can also result in side effects such as hot flashes, and if a patient’s treatment involves pharmaceutical aromatase inhibitors,

osteoporosis can be promoted (Hormone Therapy Side Effects, 2006). In chemotherapy, the development of side effects is specific to the class of drug administered; for instance, taxol induces disorder in the peripheral nervous system (Peilter & Russel, 2006).

Adding to the limited efficacy of the treatments is the risk of relapse confronting the patient once the therapy has concluded. It is for these reasons that funds and resources are diverted into developing novel and effective ways of treating breast cancer and preventing recurrence.

Experimentation with a drug commonly used to treat Alzheimer’s disease show promise in minimizing the risk of recurrance in breast cancer patients. The drug is classified as a γ-secretase inhibitor, and works by “attacking” the Notch gene (New Breast Cancer Drug, 2007).

The Notch G ene

The Notch gene was first discovered in Drosophila

by Thomas Hunt Morgan in 1917, and has since been identified in humans. The product of the Notch gene is a transmembrane protein that, in mammals, occurs in

``...a drug commonly used to treat Alzheimer`s disease shows promise in minimizing the risk of recurrence.`` www.meducator.org

Issue 11 | November 2007

No tch -IC

14

Cytoplasm Ligand/receptor interaction Jagged Notch-EC

Ligand endocytosis and degradation

ADAM protease cleavage

Nuclear Translocation Notch-IC

CSL

CoA

Not ch-I C

On

Transcription activation CSL CoR

Off

-secretase clevage

Notch-IC

Nucleus

Polyubiquitination and degradation

Figure 1 Notch ligand binding and γ-secretase cleavage, leading to the Notch-IC pathway (Shih & Wang, 2007).

four different forms (Notch 1, 2, 3, 4).

Each form consists of the same general three-part structure: an extracellular, a transmembrane, and an intracellular components (Figure 1). When expressed physiologically, the protein initiates a signaling pathway within the cell (Harris & Shi, 2006).

Notch Signalling Pathway The Notch signaling pathway begins with the extracellular domain of the protein, Notch-EC (extracellular), acting as a receptor site for incoming ligands.

When a Notch ligand binds onto the Notch-EC structure, γ-secretase cleaves the intracellular domain of the protein, Notch-IC (intracellular), sending it

towards the nucleus (Figure 1). A closer look at this mechanism is displayed in Figure 2. Once inside the nucleus, Notch-IC binds to a transcriptional factor called CBF-1. This event results in another protein, Lag-1/CSL, switching from a transcriptional repressor to an activator. The activated protein then transcribes certain genes that have several purposes (Figure 1) (Shih & Wang, 2007).

These products are responsible for the differentiation and maintenance of stem cells in both normal and cancerous development. In terms of the Notch pathway, cancerous cells exhibit high levels of Notch-IC. Recent studies that utilized mouse models and human cells have shown that high levels of

the intracellular protein results in the generation of mammary gland tumors (Shih & Wang, 2007).

G amma-S ecretase & G ammaS ecretase Inhibitors As previously mentioned, γ-secretase is a crucial mediator in the Notch signaling pathway; it allows the Notch-IC in cancerous cells to travel to the nucleus, leading to oncogenic development in the breast. Dr. Robert Clarke and his team of researchers from the University of Manchester showed that using an enzyme inhibitor may be a strategy to prevent the further development of cancer cells.

Issue 11 | November 2007

A

-secretase

15

Notch Receptor APP -secretase clevage

Extracellular

Cell Membrane

Cytoplasmic

-secretase clevage

Nucleus Modulation of target gene transcription

Notch-IC

Figure 2 A closer look at gamma secretase cleavage, freeing Notch-IC (Shih & Wang, 2007).

N - [ N - ( 3 , 5 - d i f l u o r o p h e n a c e t y l ) - Lalanyl]-Sphenylglycine t-butyl ester, also known as DAPT, in Alzheimer’s treatment was used by Clarke et al. in this study (Figure 3). This molecule may have been specifically chosen for its unique ability to inhibit each of the four Notch receptors in humans. The group found that the drug successfully inhibited the intracellular Notch pathway, and thus concluded that DAPT may prevent the recurrence of breast cancer (Clarke et al., 2007).

The remaining obstacles that DAPT must overcome in order to be used

in medical practice are its clinical trials.

Elucidating the interaction between the drug and normal cells is expected to pose issues for the experimental

pathway inhibits the differentiation of stem cells into these blood cells, which can result in organ dysfunction.

Another potential drawback of DAPT is that the inhibitor may interact with γ-secretase as well as other molecules not involved with Notch signaling, thus harming regular cell activities. Essentially, the core issue that needs to be addressed is developing target specificity for the drug. However, its trial processes may proceed relatively fast, as its use as an Alzheimer’s drug can accelerate the clinical trial process (Shih & Wang, 2007).

``...the core issue that needs to be addressed is developing target specificity for the drug.`` trials; regular Notch activity is required for normal organ function in certain parts of the body. For example, the Notch pathway contributes to the development of cellular components in the blood. Inhibition of the Notch

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Issue 11 | November 2007

H N

F O

O

Ph Figure 3

CH3

N H

Structure of the DAPT molecule (New Product Highlights, 2004).

COO tBu

F Conclusion Understanding the pathway of the Notch gene in breast cancer, along with the discovery of DAPT’s anti-tumour role, has presented scientists with a new therapeutic strategy that can be used to fight cancer. Furthermore, irregular Notch activity has not only been found in breast cancer; research suggests it may be linked to cancer in the lungs, skin, prostate, brain and among other locations.

As a result, research involving the Notch pathway and γ-secretase inhibitors such as DAPT is currently at the forefront of oncology (Shih & Wang, 2007).

References About Breast Cancer. (2006). Canadian Breast Cancer Foundation. Retrieved October 17, 2007, from http:// www.cbcf.org/breastcancer/bc_whatbc.html.

Cancer Fact Sheet. (2006). World Health Organization.

Retrieved October 20, 2007, from http://www.who. int/mediacentre/factsheets/fs297/en/index.html.

Harris A. & Shi W. (2006). Notch Signaling in Breast Cancer and Tumor Angiogenesis: Cross-Talk and Therapeutic Potentials. Journal of Mammary Gland Biology Neoplasia, 11. 41–52.

Hormone Therapy Side Effects. (2006). Cancer Help UK. Retrieved November 14, 2007, from http://www.cancerhelp.org.uk/help/default.asp?page=22866#flushes.

New Breast Cancer Drug Unveiled. (2007). BBC News.

Retrieved October 3, 2007, from http://news.bbc. co.uk/2/hi/uk_news/england/manchester/7021504. stm.

Peltier, A. & Russell, J. (2006). Advances in Understanding Drug-Induced Neuropathies. Drug Safety, 29(1), 23-30.

Clarke, R. & Farnie, G. (2007). Mammary Stem Cells and Breast Cancer - Role of Notch Signaling. Stem Cell Reviews, 3(2),169-75.

Shih, I., & Wang, T. (2007). Notch Signaling, Gamma Secretase Inhibitors, and Cancer Therapy. Cancer Research, 67(5), 1879-1882.

New Product Highlights. (2004).Cell Transmissions. Retrieved October 16, 2007, from http://www.sigmaaldrich.com/img/assets/18420/page_11.pdf.

Issue 11 | November 2007

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MedBulletin by Simone Liang

Cervical cancer tends to appear when women are in their 30’s, which is also when many women are potentially on the pill. A longitudinal study conducted at the University of Oxford found a slightly increased risk of cervical cancer in women who were regularly taking oral contraceptives. Nevertheless, the increased risk of cervical cancer returned to the norm after ten years, when the women stopped taking the pill.

Led by Dr. Green, 24 international studies found that, compared to women who have never taken oral contraceptives, the risk of cervical cancer was doubled in women who had been on the pill for a minimum of five years. In developing countries, the risk of cervical cancer in women who had taken the pill, rose from 7.3 in 1000 to 8.3 in 1000 after five years. Within developed countries, women who had never taken the pill had a 3.8 in 1000 chances of developing cervical cancer. Women who were on the pill for at least five years had a 4 in 1000 chance of cervical cancer, and after ten years, the risk increased to 4.5 in 1000.

Researchers are not sure why oral contraceptives increase the risk of cancer, but some suggest that it is due to an imbalance of hormones levels caused by the pill. However, the boost in hormones also protects against ovarian, womb, and other cancers that are currently undetectable. Experts are confident that the increased risk of cervical cancer is minor, and that with routine screening, there should be little reason to worry.

References MSNBC. (2007). Pill linked to Cervical cancer. Retrieved November 9, 2007 from http://www.msnbc.msn.com/id/21706750/

A Merciful Hand? - A Doctor’s Decision to Deny Resuscitation

MedBulletin by Randall Lau

In the absence of a “Do Not Resuscitate” (DNR) order, doctors are legally bound to attempt resuscitation even in the terminally ill. The process of resuscitation is invasive and undignified, often capable of prolonging suffering and the onset of death. In some instances, the physician attempts only a token resuscitation, termed a “slow code”. It constitutes resuscitating terminally ill patients too slowly to constitute a reasonable attempt at saving the life.

In the case of the terminally ill, dignity and unnecessary suffering become the physicians’ primary concerns, and the code is used if the patient is in such a compromised mental state that the decision cannot be reasonably accepted, and the judgment of the families is deemed unrealistically hopeful.

Ten years ago, the existence of the slow code was revealed to the public, though hospitals continue its use amidst the ignorance of patients. The code’s use has not been addressed by the profession or any level of legislature, and its use is often inspired by a fear of legal action. But as the public asserts, the practice is deceptive.

Physicians, however, are raised in a culture which is in constant denial that death is a necessary end of natural life; and they are trained never to extinguish hope where a last protocol remains. Aside from religious convictions, society often refuses to accept medical realism. In response, physicians feel that the definitions of hope for the terminally ill require reevaluation to adopt an increasingly deterministic view of life.

References: Medical News Today. (2007). Token Resuscitation Attempts On Hopelessly Ill Patients Prolongs Suffering. Retrieved November 8, 2007 from http://www. medicalnewstoday.com/articles/87559.php National Public Radio. (2007). End of Life: Slow Code. Retrieved November 8, 2007 from http://www.npr.org/programs/death/980211.death.html

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Cervical Cancer associated with Birth Control

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Issue 11 | November 2007

When your lonely heart breaks: The association between loneliness and cardiovascular death in the elderly Loneliness, while not currently recognized as a clinical syndrome, has recently become the focus of much attention due to its correlation with an increased risk for cardiovascular disease and other degenerative conditions in the elderly.

Despite its influence on health and longevity, few studies have identified effective interventions for managing loneliness, and research has revealed that physicians are not informed or comfortable in treating loneliness.

This article reviews the mechanisms by which loneliness impacts on cardiovascular health, and explores medical management of this health determinant.

Deborah Kahan

Case #1: Mrs. G. and the Walk-in Doctor

M

rs.G.isa71-year-oldwomanwhohasrecentlybeeninhospital foramyocardialinfarction. Herpreviousfamilydoctorisnow retired, and she is being looked after by a young doctor in a walk-inclinic. Sheseesthedoctortwoweeksafterleavingthehospital.

He finds that Mrs. G. is taking all of her prescribed medications, is no longer having any symptoms of heart disease and that her blood pressureisnormal.Thedoctorbooksafollow-upappointmentforone month later but the patient cancels the appointment because she is unable to arrange transportation. Two months later, she dies in her sleep from sudden cardiac death.

In this case, this patient received optimal medical management. Could loneliness have contributed to this woman’s heart attack? This has been the focus of considerable research

1

and speculation in recent years. This article reviews the impact of loneliness on cardiovascular health, and the role of physicians in identifying and managing loneliness.

Epidemiology Loneliness is very common amongst the elderly. In a Finnish survey of 4000 elderly subjects, 39 percent reported feelings of loneliness (Routasalo, 2006). In recent years, it has been found that an increasing number of elderly people are living alone and fewer have close friends or family. In 1987, 8.5 million American senior citizens lived alone, and it is projected that 13.3 million elderly people will live alone by 2020 (Diehm, 2000). A study published by Duke University reported that in 1985, the average American had three close confidants, whereas in 2004, the

Hypothalamus

1

Hypothalamus

2 2

2 3

2 3

Pituitary Pituitary gland

gland

Adrenal Adrenal gland

gland

Figure 1 1. Stress hormones cause the release of corticotropin-releasing factor by the hypothalamus.

2. This stimulates the release of ACTH from the pituitary gland.

3. ACTH then travels to the blood stream.

4. ACTH in the blood stream causes adrenal glands to release catecholamines that prepare the body for a ‘fight or flight’ response (Advameg, 2007).

Issue 11 | November 2007 average American only had two confidants with one quarter of study participants having no close confidants (McPherson, 2006).

A number of social and health factors influence the risk of loneliness. Women are more likely to report loneliness than men (Beal, 2006). Loss of a spouse, lack of new contacts, poverty, lack of religious beliefs, loss of mobility and physical disability are all significant risk factors (Cohen-Mansfield, 2005; Lauder, 2006). Mental illness and alcohol abuse are also risk factors for loneliness (Akerlind, 1992; Elisa, 2006).

Loneliness and Longevity Loneliness may be a risk factor for life-threatening cardiovascular conditions. Studies have found a strong association between longevity and social support. In a study on male health professionals, participants who were unmarried, had fewer than six relatives or friends or were inactive in the community had a higher risk of death from stroke, heart disease, accidents and suicide (Kawachi, 1996). In a nine-year study, subjects with the greatest number of close friends or relatives had a 60 percent reduction in the risk of death (Berkowitz, 2002). A nationwide study of 280,000 Americans reported that widowed men and women had a 25 and 50 percent greater risk of cardiovascular death, respectively (Johnson, 2000). Lonely individuals are not only at a greater risk for being diagnosed with heart disease, but are also less likely to recover. In a Swedish study of 1290 patients undergoing coronary bypass surgery, those reporting loneliness had a 2.6 times greater risk of death after thirty days, and a 1.8 times greater risk at five years, after adjusting for other risk factors (Herlitz, 1999).

Since these are observational studies, it is difficult to establish a causal relationship between loneliness and health.

For example, a cross-sectional survey of 1300 adults found that smoking and obesity are more prevalent amongst lonely

Elderly people may often be lonely and are therefore at greater risk for the health complications that loneliness could cause. Physicians should be aware of the role that loneliness plays in the health of this population and address the issue accordingly.

19 individuals, elevating their risk for heart disease (Lauder, 2006). However, other studies attempt to statistically adjust for causative factors of heart disease, such as smoking and obesity.

While the connection between cardiovascular disease and loneliness has been the focus of much attention, loneliness may also contribute to other serious health problems in the elderly, such as depression and dementia. A Swedish study found that socially isolated elderly patients were significantly more susceptible to developing dementia than their peers with a social support network (Fratiglioni, 2000). Studies have also determined that loneliness is a major risk factor for depression which is independent of demographic variables, social support, or perceived stress (Barb, 2006; Cacioppo, 2006). A survey of 1000 elderly patients found that loneliness and a lack of relationship with their neighbours were the most important predictors of psychological distress and depression (Paul, 2006). In one study of patients over the age of 85, neither loneliness nor depression alone contributed to a significant morbidity; when both factors were present, a significant difference was detected (Arehart-Treichel, 2005).

Mechanisms Research concerning the cardiovascular effects of loneliness has focused primarily on hypertension. One study of adults over 50 showed that loneliness can increase a blood pressure reading by 30 points in patients (Cacioppo, 2006). In another study of 230 older patients, a strong relationship was found between loneliness and systolic blood pressure (Hawkley, 2006). Other stress-related mechanisms may also damage the cardiovascular system. For example, the stress hormone cortisol is associated with elevated levels of several clotting factors, such as fibrinogen and von Willebrand factor (von Kanel, 2007). These clotting factors increase the risk of blood clots in the arteries of the heart or brain. Stress also alters heart rhythm, and may cause the release of fat in the bloodstream, temporarily increasing cholesterol (Encyclopedia of Mental Disorders, 2006).

The effects of loneliness on the cardiovascular system may be mediated through hormones and neurotransmitters.

Loneliness is linked with the elevated stress response which activates the hypothalamic-pituitary-adrenal system (HPA) (Encyclopedia of Mental Disorders, 2006). One study showed that daily cortisol levels are influenced by loneliness and other emotional states (Adams, 2006). Moreover, researchers at McGill University have discovered that a lack of social support is associated with higher levels of cortisol (McGill Reporter, 2002).

Cortisol is synthesized in the adrenal gland, located just above the kidneys. Its release is controlled by a pituitary hormone called adrenocorticotropic hormone (ACTH), which also releases epinephrine and norepinephrine from the adrenal glands in response to stress (Figure 1).

Epinephrine and norepinephrine are catecholamines that prepare the body for a ‘fight or flight’ reaction; a combination of increased heart rate and arterial constriction www.meducator.org

20 elevates blood pressure. Persistently high blood pressure damages the inner wall of the blood vessels. Plaques, such as fatty deposits, settle in the roughened sections of the vessel wall and may trigger clot formation. The plaques and clots block the flow of blood through vessels in the heart and the brain, leading to heart attacks and strokes (Encyclopedia of Mental Disorders, 2006).

Can Loneliness Be Treated?

Despite the impact of loneliness on health, there has been a lack of research into practical interventions for its management.

A systematic review identified 21 studies on interventions for loneliness (Cattan, 2005). Nine out of ten studies that used group programs were effective, whereas only two of eleven individual counselling interventions were successful. Group programs gave patients the opportunity to meet new people and engage in group activities, while teaching them loneliness-management strategies (Aday, 2006; Collins, 2006). While these studies demonstrated improvements in self-reports of loneliness and social engagement, they generally had small sample sizes and were conducted over a short time period. The improvements were not always sustained and the studies failed to demonstrate increased longevity or decreased mortality from heart disease (Kremers, 2006).

Despite its link to depression, the review did not identify any interventions to manage loneliness and it is not recognized as a clinical syndrome. While not all lonely patients are clinically depressed, loneliness can be both a risk factor and a result of depression. Furthermore, clinically depressed patients are less likely to seek professional help due to fear or lack of motivation for basic social interaction.

Antidepressants might help such patients by balancing the moods that contribute to the patient’s isolating behaviour (Psychology Information Online, 2003). Counseling for depression can be effective; for example, one review found that ‘activity scheduling’ improved the quality of life in depressed patients (Cuijpers, 2006). More research into loneliness and its response to counselling

Issue 11 | November 2007 is needed to maximize the benefits of this intervention.

What Can Doctors Do? Lonely patients are more likely to access health care services such as the emergency department than non-lonely patients with similar illnesses (Geller, 1999). Yet surveys have found that physicians feel less comfortable dealing with loneliness than with other psychosocial problems in the elderly (Gray, 1983). In a qualitative study, physicians reported that older people are often reluctant to admit that they are lonely or depressed (Murray, 2006). Another qualitative study found

``Older people are often reluctant to admit that they are lonely or depressed.`` that both physicians and patients view loneliness and depression as an inevitable part of aging, for which little can be done (Burroughs, 2006).

Given its importance to health, researchers have advised clinicians to pay greater attention to loneliness. “…

Loneliness should command clinicians’ attention in its own right--not just as an adjunct to the treatment of other problems such as depression.” (Heinrich, 2006). This suggests that physicians should inquire about loneliness in elderly patients who exhibit symptoms for heart disease, depression, grief, dementia, or alcohol abuse. It should be the physician’s responsibility to arrange referrals to community services and provide advice, support and sufficient follow-up. The physician-patient relationship should be maintained in periods of increasing disability and social isolation (Quill, 1995). As one author commented, “there is a world of difference between facing an uncertain future alone and facing it with a committed, caring knowledgeable partner [the physician]…” (Quill, 1995).

Doctors should encourage the patient to become involved in community

activities such as religious organizations, social clubs, health centers, adult education classes or volunteering.

Housebound patients can volunteer through telephone support services or letter-writing for charity organizations.

They should also be encouraged to join support groups with those who have similar illnesses (Tidy, 2005). Small lifestyle changes such as owning a pet may also be beneficial in helping to manage loneliness (Banks, 2002).

Case #2:, Mrs.G and her Lifelong Family Doctor Mrs.Gvisitsherfamilydoctorwhomshehas known for 25 years. The doctor determines she has normal blood pressure and no symptoms of angina. He asks Mrs. G how she is feeling; she says that she’s frightened that she will die of a heart attack and she’s lonelybecauseherchildrenarenotgoingto be able to visit her at Christmas. She won’t visit neighbours because she fears that walkingupanddownherstairsmighttrigger another heart attack. The doctor suggests attending cardiovascular rehabilitation program offered at the local hospital, but Mrs. G is hesitant due to the traveling involved. Consequently, he suggests that she spend a small amount of time each day walking around her neighbourhood. The doctor advises the patient to take the train to visit her children and grandchildren.

The doctor calls the occupational therapistwhoworkswiththepatienttouse community resources for information and support. After following the advice of her physician and therapist, Mrs. G. has had no signs of recurrence of heart disease and continues to see her doctor regularly

Conclusion Loneliness is a major risk factor for cardiovascular disease, as well as for other health problems such as depression and dementia. Its effects may be mediated through elevations in the stress hormones. This leads to an increase in blood pressure, which can cause heart attacks and strokes. There are many causes of loneliness, including lack of mobility, poverty, loss of loved ones, physical disability and mental

Issue 11 | November 2007 illness. Interventions that involve community support and group activities appear to be effective in alleviating loneliness. There is currently no evidence indicating that formal interventions to treat loneliness will decrease the likelihood of death from cardiovascular diseases. However, patients with heart disease and social support have a lower mortality rate compared to similar patients without social support. Physicians who have a close relationship with their patients are in a position to help them overcome loneliness through support, advice, referral to organizations in the community, and treatment of depression if necessary.

References Adams, E.K., Hawkley, L., Kudielka, B., & Cacioppo, J. (2006). Dayto-day dynamics of experience--cortisol associations in a population-based sample of older adults. Proceedings of the National Academy of Sciences of the United States of America, 103(45), 17058-63.

Aday, R., Kehoe, G., & Farney, L.A. (2006). Impact of senior center friendships on aging women who live alone. Journal of Women & Aging, 18(1), 57-73.

Akerlind, I., & Hornquist, J. (1992). Loneliness and alcohol abuse: a review of evidences of an interplay. Social Sciences & Medicine, 34(4), 405-14.

Arehart-Treichel, J. (2005). Depression Plus Loneliness May Hasten Death in Elderly. Psychiatric News, 40(2).

Banks, M.R., WA (2002). The effects of animal assisted therapy on loneliness in an elderly population in long term care facilities. J Gerontol A Biol Sci Med Sci, 57(7), M428-32.

Barg, F.K., Huss-Ashmore, R., Wittink, M.N., Murray, G.F., Bogner, H.R., & Gallo, J.J. (2006). A Mixed-Methods Approach to Understanding Loneliness and Depression in Older Adults. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 61,S329-S339 Beal, C. (2006). Loneliness in older women: a review of the literature.

Issues Ment Health Nurs, 27(7), 795-813.

Berkowitz, G. (2002) “UCLA Study On Friendship Among Women: An alternative to fight or flight.” Retrieved December 28, 2006 from http://www.moorecg.com/UCLA_study.pdf.

Burroughs, H., Lovell, K., Morley, M., Baldwin, R., Burns, A., & ChewGraham, C. (2006). “‘Justifiable depression’: how primary care professionals and patients view late-life depression? A qualitative study.” Family Practice, 23(3), 369-77.

Cacioppo, J., Hawkley, L., & Masi, C. (2006). Loneliness Is a Unique Predictor of Age-Related Differences in Systolic Blood Pressure Psychology and Aging. The American Psychological Association, 21(1), 152–164.

Cacioppo, J., Hughes, M.E., Waite, L., Hawkley, L., & Thisted, R.(2006).

Loneliness as a specific risk factor for depressive symptoms: cross-sectional and longitudinal analyses. Psychology and Aging, 21(1), 140-51.

Claesson, M., Birgander, L., Lindahl, B., Nasic, S., Astrom, M., Asplund, K., & Burell, G. (2005). Women’s hearts--stress management for women with ischemic heart disease: explanatory analyses of a randomized controlled trial. Journal of Cardiopulmonary Rehabilitation, 25(2), 93-102.

Cattan, M., White, M., Bond, J., & Learmouth, A. (2005). Preventing social isolation and loneliness among older people: a systematic review of health promotion interventions. Ageing & Society, 25, 41-67.

Cohen-Mansfield J. & Parpura-Gill A. (2006). Loneliness in older

21 persons: a theoretical model and empirical findings. Int Psychogeriatrics, 55(5), 1-16.

Collins C.C. & Benedict J. (2006). Evaluation of a community-based health promotion program for the elderly: lessons from Seniors CAN. American Journal of Health Promotion, 21(1), 45-8.

Cuijpers P., van Straten A..& Warmerdam L. (2006). Behavioural activation treatments of depression: A meta-analysis. Clinical Psychology Review, 27(3), 318-326.

Diehm W. J. (2000). Dealing with Loneliness. Retrieved December 29, 2006, from http://seniors-site.com/widowm/lonely.html Elisha D., Castle D. & Hocking B. (2006). Reducing social isolation in people with mental illness: the role of the psychiatrist.

Australasian Psychiatry, 14(3), 281-4.

Fratiglioni L. (2000). Influence of social network on occurrence of dementia: a community-based longitudinal study. Lancet, 355, 1315-9.

Geller J., Janson P., McGovern E. & Valdini A.(1999). Loneliness as a Predictor of Hospital Emergency Department Use. Journal of Family Practice, 48(10), 801-804.

Grace Living Centres (2002). Retrieved December 28, 2006, from http://www.gracelivingcenters.com/why_were_unique.htm Gray N. & Caudall H. (1983). Physician attitudes towards the elderly.

Thesis, University of Nebraska. Retrieved December 28, 2006, from http://digitalcommons.unl.edu/dissertations/AAI8412297/ Hawkley L., Masi C., Berry J. & Cacioppo J. (2006). Loneliness is a unique predictor of age-related differences in systolic blood pressure. Psychology and Aging, 21(1), 152-64.

Heinrich L. M. & Gullone E. (2006). The clinical significance of loneliness: a literature review. Clinical Psychology Review, 26(6), 695-718.

Herlitz J., Wiklund I., Caidahl K., Hartford M., Haglid M., Karlsson B., Sjoland H. & Karlsson T. (1998). The feeling of loneliness prior to coronary artery bypass grafting might be a predictor of shortand long-term postoperative mortality. European Journal of Vascular and Endovascular Surgery, 16(2), 120-5.

House J. (2001). Social Isolation Kills, But How and Why? Psychosomatic Medicine, 63, 273-274.

Jakobsson U. & Hallberg I.R. (2005). Loneliness, fear, and quality of life among elderly in Sweden: a gender perspective. Aging Clinical and Experimental Research, 17(6), 494-501.

Johnson, N., Backlund, E., Sorlie, P. & Loveless, C. (2000). Marital status and mortality: the national longitudinal mortality study.

Annals of Epidemiology, 10(4)L, 224-38.

Kawachi I., Colditz G.A., Ascherio A.., Rimm E.B., Giovannucci E., Stampfer M. J. & Willett W. C. (1996). A prospective study of social networks in relation to total mortality and cardiovascular disease in men in the USA. Journal of Epidemiology and Community Health, 50(3), 245-51.

Kremers J. P., Steverink N., Albersnagel F.A. & Slaets J. P. (2006).

Improved self-management ability and well-being in older women after a short group intervention. Aging and Mental Health, 10(5), 476-84.

Lauder, W., Mummery, K. & Sharkey, S. (2006). Social capital, age and religiosity in people who are lonely. Journal of Clinical Nursing, 15(3), 334-40.

Lauder W., Mummery K., Jones M. & Caperchione C.(2006). A comparison of health behaviours in lonely and non-lonely populations. Psychology, Health & Medicine, 11(2), 233-45.

Lawhorne, L. (2005). Depression in the older adult. Primary Care, 32(3), 777-92.

McGill Reporter, Comeau, S. (2002). Stress, Memory, and Social Status. Retrieved December 29, 2006, from, http://www.mcgill. ca/reporter/35/02/lupien/ *** For a complete list of references, please visit www.meducator.org

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Issue 11 | November 2007

Chaperones and protein folding

Kirandeep Bhullar

Although the human body has many different coordinated mechanisms designed to ensure proper protein synthesis, mistakes sometimes occur that can lead to serious health problems. The misfolding of proteins, for example, can cause a number of disorders including Mad Cow Disease, Cystic Fibrosis, and Alzheimer ’s Disease. Molecular chaperone systems are sometimes able to rectify some of these partial unfolding mistakes that occur in protein synthesis. Researchers in this field claim that increased knowledge about chaperone mechanisms may lead to new targets for anti- cancer therapies.

P

roteins are the most important macromolecules and play a pivotal role in performing and regulating the functions of the cell. For a protein to be fully functional, it should have a three dimensional structure with proper folding. Chaperones, also known as heat shock proteins, are a class of protein found in all the organisms starting from bacteria to humans and are located in every cellular compartment. Chaperones have a very important role as they are largely responsible for efficient folding of proteins in most cells. Chaperones have non-specific binding, which means that they can bind to a wide range of proteins (Lodish et al., 2004).

Types of Chaperones There are various chaperone systems that differentiate between targets based on the conformation or the sequence

of the protein substrate (Houry, 2001). The four main chaperone systems found in Eschericia coli cytoplasm are ribosome-associated trigger factor, the Hsp70 system, the Hsp60 system and the Clp ATPases. Each of these systems carry out a unique function to ensure the proper folding of target proteins (Houry, 2001).

Trigger factors assist in the folding of newly synthesized nascent proteins by binding next to the exit site on the larger subunit of the ribosome. This ensures the effective association between the trigger factor and nascent polypeptide chain and is important for cell survival. It has been found that trigger factors have peptidyl-prolyl isomerase (PPIase) activity. PPIase mediate rotation about peptide bonds and directs protein folding (Figure 1) (Houry, 2001).

Molecular chaperones are another chaperone system involved with protein maturation (Georgopoulos,

TF Ribosome-binding site 1

118 144

PPIase

unknown 251

432

Figure 1 Trigger factor domain organization. The figure shows the ribosome-binding site of trigger factor and the peptidyl-prolyl isomerase (PPIase) activity region. These components of trigger factor domains assist in the correct folding of the nascent polypeptide as it is being released from the ribosome (Houry, 2001).

Issue 11 | November 2007

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Hsp70 Family (Heat-shock protein) Ribosome

Pi

Hsp 70-ATP Protein

ADP

Partially folded protein

ATP

Properly folded protein

Figure 2 Molecular chaperone-mediated protein folding. The Hsp70-ATP complex binds to the polypeptide as it emerges from a ribosome. ATP hydrolysis results in conformational change, causing the target protein to fold partially. When ATP rebinds to Hsp70, the protein is release and is properly folded (Lodish et al., 2004).

1993). These chaperones consist of the Hsp70 family and its homologues which are all conserved ATPases (Lodish et al., 2004). Members of the Hsp70 family play an important role in protein translocation and in high order protein assembly (Georgopoulos, 1993). Hsp70 bound to ATP assumes an open conformation and the exposed hydrophobic pocket of Hsp70 binds to the exposed hydrophobic regions of the unfolded target protein. The hydrolysis of ATP to ADP causes a conformational change of Hsp70 that allows it to encapsulate the protein.

In this position, the target protein can now begin to undergo folding, which continues until an exchange of ATP for ADP occurs, releasing the target protein. The target protein is now properly folded and is functional (Figure 2) (Lodish et al., 2004). Thus, molecular chaperone proteins bind to the polypeptide chain as it emerges from the ribosome (site of protein synthesis), stabilize it and allow it to fold properly.

Another chaperone system which assists in the protein folding is the GroES/GroEL system, also known as chaperonins. GroEL and its cofactor GroES represent the

Hsp60 families and the Hsp 10 families, respectively (Houry, 2001). These heat shock proteins are large oligomeric proteins that fold proteins by forming an isolation chamber and consist of macromolecular assemblies, which have

a cylinder-like appearance (Lodish et al., 2004). GroEL’s mechanism includes forming a barrel-shaped complex using its hydrophobic rim and together with its co-protein GroES, facilitates protein refolding in an ATP-dependent manner (Figure 3) (Ranson, White & Saibil, 1998). The hydrophobic portion of the misfolded target protein binds with the GroEL rim, resulting in the capture of the misfolded protein. Once the protein has been trapped, the GroES cap and ATP bind to the GroEL subunit.

The binding of the GroES cap and ATP produces conformational changes in GroEL which stretches, encloses, and partly folds the protein. The last step is the hydrolysis of ATP to ADP which shifts GroEL to the open, relaxed state and releases the folded protein (Figure 4) (Lodish et al., 2004).

The last major chaperone

Figure 3 Various conformations of GroEL subunit.

The structures shown are: (a) the tight conformation where the GroEL subunit is not bound to anything; (b) the GroEL-ADP complex; (c) the GroEL-ATP complex; (d) the GroEL-GroES-ADP complex; (e) the GroELGroES-ATP complex. Note that ATP from (c) is the most asymmetric. The GroEL-GroES-ATP complex results in the partial folding of a protein. The complexes in (d) and (e) are similar to each other but the overall orientation of the rings is different between the two complexes. In the presence of ADP, GroES binding is asymmetrical (d) whereas in the presence of ATP, the structure appears to be more symmetrical (e) (Ranson, White & Saibil, 1998).

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24 system are the Clp ATPases. These are the ATPase-dependent chaperones responsible for the assembly and disassembly of protein complexes.

Clp ATPases act like specificity factors which help to present the various protein substrates to catalytic proteases for degradation by unfolding or disaggregating them. There are different classes of Clp ATPases found in Eschericia coli cytoplasm, each of which can function as a molecular chaperone as well as ATP-dependent regulatory components for various proteases.

However, there are still many questions surrounding Clp ATPases that remain unanswered (Houry, 2001).

Significance of Proper Protein Folding Proteins are synthesized as a linear array of amino acids and they become functional when folded into their native state. Chaperones help other proteins in their initial folding and rescue them during partial misfolding due to aging or environmental cues. It is important for the cell to have a collection of chaperones in order to recover or eliminate misfolded proteins, as they tend to accumulate as large aggregates that compromise cell survival.

Accumulation of protein aggregates is the fingerprint for amyloid misfolding disorders such as Alzheimer’s Disease, as well as prion diseases that include bovine spongiform encephalopathy and scrapie.

Cystic Fibrosis is caused by a defective chloride channel (CFTR) in epithelial cells which leads to excessive mucous production in the lungs. The most common mutation associated with this disorder is the deletion of phenylalanine at residue position 508.

CFTR genes containing this mutation cannot fold properly and fail to mature

Issue 11 | November 2007 to a fully glycosylated form. The nascent protein folds incorrectly, is recognized as abnormal by cellular mechanisms, and is degraded rather than transported to the plasma membrane. Other causes of this disorder include mutations in the nucleotide-binding domain and membrane-spanning domain. The

``It is important for the cell to have a collection of chaperones in order to recover or eliminate misfolded proteins.`` symptoms of Cystic Fibrosis include difficulty in breathing and it often results in various lung infections (Weish & Smith, 1993).

Bovine spongiform encephalopathy (BSE), also known as Mad Cow Disease, is one of the most commonly known prion-misfolding disorders. When these prions become associated with a normal protein, they convert the appropriately folded protein into an abnormal conformation.

This proves to be fatal for the host organism and results in the formation

of further aggregates of the misfolded protein. BSE is marked by the formation of tangled filamentous plaques. There are other neurodegenerative disorders which are also caused by the aggregation of proteins that are stably folded in a pathological conformation (Lodish et al., 2004). Although the etiology of various neurodegenerative disorders may be different, the common factor is that during the aggregate formation, the alpha-helical domains start disappearing and there is an increase in the betadominated secondary structures (Figure 5) (Chaudari & Paul, 2006). It has also been found that during the protein aggregation, amyloid fibrils polymerize to cross beta sheet structures in such a way that the beta strands are arranged perpendicular to the long axis of the fiber (Figure 6) (Chaudari & Paul, 2006).

Concluding Remarks From the above discussion, it is clear that a normally folded protein is essential for proper function. The misfolding of proteins can be caused by mutations, inappropriate post-translational mechanisms and other environmental

Chaperonins ADP + Pi

Protein

Properly folded protein

ATP GroEL

GroES

Figure 4 The GroES/GroEL functional cycle. In the absence of ATP or in the presence of ADP, GroEL is in its tight state which is capable of binding to the misfolded protein. When ATP binds to GroEL, it assumes the open, relaxed state which results in the release of folded protein. (Lodish et al., 2004).

Issue 11 | November 2007

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Figure 5 During amyloid formation in various neurodegenerative disorders, the alpha-helical structures are replaced by beta-pleated sheets, resulting in a change in the overall secondary structure of a native protein. (A) Native protein contains alpha-helical secondary structure. (B) The alphahelical structure is converted in a beta-pleated sheet due to misfolding. (C) Misfolded protein which contains mainly beta-pleated secondary structure (Chaudari & Paul, 2006).

Figure 6 A diagrammatic representation of how aggregate formation takes place. Misfolded monomers, which consist of mainly beta-pleated secondary structure, interact with each other through hydrogen bonding resulting in the formation of long beta sheets (Chaudari & Paul, 2006).

cues which are still being researched. Misfolding also marks the protein for proteolytic degradation, and the accumulation of protein fragments during this process contributes to the development of certain diseases.

Therefore, chaperones are extremely important for effective protein folding and prevention of deleterious disorders. Recent advancements in understanding how chaperones control protein folding, and how cells regulate the chaperone’s activities, has provided insight into the signal pathway alterations involved in cancer development. Hopefully, this new information will help identify new targets for anti-cancer therapies (Chaudari & Paul, 2006). Chaperones are currently the subject of a great deal of research, and the scientific community is exploring the importance of chaperones in other cellular processes.

References Chaudari T. K. & Paul S. (2006). Protein-Misfolding Disease and Chaperone-Based Therapeutic Approaches. Federation of European Biochemical Societies, 273, 331-1349.

Georgopoulos C. (1993). Role of the Major Heat Shock Proteins as Molecular Chaperones. Annual Review Cell Biology, 9, 601-634.

Houry W. A.. (2001). Chaperone-Assisted Protein Folding in the Cell Cytoplasm. Current Protein and Peptide Science, 2, 227-244.

Lodish H. et al. (2004). Molecular Cell Biology (5th ed.). United States of America: W.H. Freeman and Company.

Martin J. & Hartl F. U. (1997). Chaperone-Assisted Protein Folding.

Current Opinion in Structural Biology, 7, 41-52.

Ranson N. A., White H.E., & Saibil H. R. (1998). Chaperonins.

Biochemical Journal, 333, 233-242.

Weish M. J, & Smith A. E. (1993). Molecular Mechanism of CFTR Chloride Channel Dysfunction in Cystic Fibrosis. Cell, 73, 12511254.

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Issue 11 | November 2007

Twinkle Twinkle, Little Spot

MedBulletin by Fanyu Yang

Recent research from the Schepens Eye Research Institute offers a bright prospect for the early detection of retinal degeneration. The induced twinkle after-effect (TAE) is an inexpensive and effective technique that can accurately identify the location and breadth of specific blind spots caused by loss of photoreceptors in the eye.

While detecting blind spots may appear to be no extraordinary feat, it is often difficult due to the brain’s automatic compensation for any missing information in its visual receptive field. This adapted “fill in” process also takes place in individuals with normal vision at a specific location in the intersection between the optic nerve and retina. Thus many people fail to seek medical attention because they perceive no early symptoms until the detrimental onset of diseases such as diabetic retinopathy and glaucoma.

TAE is a visual illusion in the blind spot when individuals look into a blank space after staring at a noisy visual target such as a detuned television screen. The areas can then be easily mapped using a blank touch screen for patients to outline the twinkling areas with their finger. In comparison to the traditional retinal specific microperimetry, the induced twinkle aftereffect technique is simple and self-directed tool that allows patients to detect their own vision changes on a daily basis.

Researchers are optimistic for its eventual mass-distribution as an online public health entity.

References ScienceDaily. (2007). Retinal Patients Detect Vision Loss Quickly And Cheaply. Retrieved October 26, 2007, from http://www.sciencedaily.com- / releases/2007/10/071023213308.htm

Contraceptives for Children?

MedBulletin by Veronica Chan

Following a period of heated controversy, the King Middle School in Portland, Maine, is now one of the first schools in the United States to offer contraceptives for its students, from 11 to 13 years of age. This decision was largely in response to reports of worrisome statistics; five students admitted to being sexually active, and seventeen pregnancies were reported among the three Portland middle schools within the last four years.

The lack of parental consent required for the prescription of birth control pills, due to patient privacy laws, is particularly appalling to critics of this new policy. Moreover, this new endeavour may indirectly promote sexual activity in young adolescents.

The potential increase in the spread of sexually transmitted infections as well as this legislation’s conflict with many religious beliefs are causing widespread concern among members of the school community.

Despite these arguments, the school’s nurse coordinator Amanda Rowe insists that it is important to protect students who are already sexually active by making birth control options readily available. Furthermore, she asserts that students requesting contraceptives are required to undergo extensive counseling about the negative implications of such choices.

Unquestionably, both parties are striving to advocate for what is believed to be in the best interest of these students. The appropriateness of contraceptive availability to young adolescents will continue to be debated as there are no definite answers.

Does it potentially protect them or challenge moral values by encouraging early sexual activity? Whichever perspective one holds, careful observations of this initiative’s outcomes will shed light onto the controversies raised by this question.

References: Time. (2007). Birth Control for Kids? Retrieved October 18th, 2007 from http://www.time.com/time/nation/article/0,8599,1673227,00.html.

Associated Press. (2007). Maine School to Offer Contraceptives. Retrieved October 18th, 2007 from http://ap.google.com/article/ALeqM5iVGnJMjw7hzjRGVQ_ yviGL9GR2CwD8SBTGB80

Issue 11 | November 2007

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Have you read all the articles? Test yourself and see how well you understood the articles by answering the questions below.

1. DAPT, a potential drug for curing breast cancer acts on the Notch signaling pathway involved in breast cancer by: a) directly inactivating the transcription factor b) dephosphorylating the extracellular domain c) inhibits each of the four notch receptors d) cleaves the intercellular domain of Notch protein 2. Which of the following is a risk factor for loneliness? a) life-threatening cardiovascular conditions b) high levels of cortisol in the bloodstream c) smoking and obesity d) loss of mobility 3. One of the reasons, as presented in the article, that critics of one-tier, not-for-profit healthcare put forth to argue Canada’s current healthcare system is in need of change is: a) Dental health is not covered under the current system b) Increasing costs are threatening sustainability c) For-profit healthcare has earned universal praise d) Politicians do not understand healthcare e) To put an end to the politics associated with the “public-versusprivate” debate

4. What do doctors view as “self-destructive” behaviour? a) Smoking b) Anorexia c) Bulimia d) All of the above

MedQuiz

MedQuiz

5. The Chaoulli case established that: a) Healthcare must be provided on the basis of need, not ability to pay b) For-profit motives are inherently against the public’s interest c) The private sector must be removed from the Canadian healthcare system completely d) Vioxx, developed by a for-profit pharmaceutical company, was responsible for adverse cardiovascular events e) For-profit healthcare may be warranted if the current healthcare system cannot ensure a Quebec citizen’s Right to Life 6.

Which of the following diseases is not caused by protein misfolding? a) bovine spongiform encephalopathy b) Alzheimer’s disease c) Cystic Fibrosis d) Patau Syndrome

Answers: c, d, b, d, e, d

Meducator Staff

McMaster’s Medical Research and Health Ethics Student Journal

Should doctors be allowed to refuse treatment?

Also in this issue: Debate on Canada’s health care Alzheimer’s drug may prevent breast cancer relapse Loneliness & cardiovascular disease Chaperones & protein folding

From Proteins to Patients Issue 11 | Nov 2007

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Back Row (Left to Right): Simone Liang, Alexandra Perri, Fanyu Yang, Avinash Ramsaroop, Jonathan Liu, Ran Ran, Stephanie Low Middle Row: Harman Chaudhry, Jeanette So, Veronica Chan, Jaqueline Ho, Siddhi Mathur, Navpreet Rana, Sarah Mullen, Randall Lau, Andrew Yuen Front Row (Left to Right): Crystal Chung, Tyler Law Absent: Harjot Atwal

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