Issue 6 by The Meducator

BIG PHARMA In whose best interest?

REMYELINATION

VIOXX: W H A T WENT W R O N G ?

LIVER CANCER

ALZHEIMER'S

PAIN INSENSITIVITY

Issue 6 | April 2005 www.meducator.org

April 2005 | Issue 6

McMASEER Inside Scoop Presidential Address Jennifer Clara Tang Med Bulletin Jonathan Liu Brent Mollon Med Update Jennifer Clara Tang/Jaron Chong

Research Article Remyelinating Damaged Nerves Waqas Kayani

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Big Pharma: In Whose Best Interest? Shama Sud

Vioxx: What Went Wrong? S a m m y H. Ali

Drugs, Tea and Curry: The Means to Finding a Cure for Alzheimer's Disease? 14 Danny Ricci Hepatocellular Carcinoma Andrew Heikkila

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FINDING A CURE FOR ALZHEIMER'S DISEASE Page 14

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VIOXX: WHAT WENT WRONG? Page 12

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r^...w^Jk j/? \. >«3g^ ww^m ^W&ZBdmu& HEPATOCELLULAR CARCINOMA Page 18

Congenital Insensitivity to Pain with Anhidrosis (CIPA) 20 Abdullah Alabousi CIPA Page 20

References References

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The McMaster Meducator may be contacted via our e-mail address: meduadmin@leamlink.mcmaster.ca The McMaster Meducator adopts an educational approach to our publication. Despite our or our mailing address: efforts to ensure correctness, w e recognize that the publication m a y be subject to errors B.H.Sc. (Honours) Programme and omissions. In light of these potential errors and new developments in the medical field, Attention:The McMaster Meducator w e invite you to partake in feedback and constructive discussion of the content herein Michael G. DeGroote Centre for Learning and for the purpose of furthering your understanding of the topic in the n a m e of education Discovery R o o m 3308 and discovery. An online discussion forum for each article is available on our website: Faculty of Health Sciences www.meducator.org. Students and professors alike are welcome. Please enjoy the 1200 Main Street West Meducator online experience! sllOO'S Hamilton, Ontario L8N 3Z5 Disclaimer: The views represented in the articles do not http://www.meducator.org necessarily reflect those of the McMaster Meducator and should not be substituted for medical advice.

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Issue 6 i 2005 April Dear Reader,

President & Chief Editor Jennifer Clara Tang

Recent pharmaceutical controversies have awakened the public from their "drug-induced" slumber. The dream of "miracle" drugs has been shattered Vice President/Deputy Chief Editor Jaron Chong with product recalls, warning labels and study results. In light of these events, the public has become more vigilant and cautious. But h o w long will it be before Vice President of society is lulled back into gentle complacency by the colourful advertisements of Medical Research & Health Ethics "big pharma"? Shama Sud examines the history of pharmaceutical tragedies from S a m m y H. Ali an ethical perspective in her article. To complement this discussion, S a m m y Ali Vice President of provides the science behind why Vioxx, a popular arthritis drug, was deemed un- Medical Research & Health Ethics safe. This issue of the McMaster Meducator also addresses a variety of other mediJeannette So cal research topics. Danny Ricci discusses traditional and alternative therapies for Junior Editor Alzheimer's disease. Waqas Kayani reviews the current research in the field of CNS Jonathan Liu • ••• repair through remyelination. Andrew Heikkila explains the pathology of hepatoJunior Editor cellular carcinoma (liver cancer). Finally, Abdullah Alabousi introduces readers to Brent Mollon a life without pain in his discussion of CIPA (Congenital Insensitivity to Pain with Vice President of Anhidrosis). Layout, Production & Distribution Anthony Collini This has been a fruitful year for the McMaster Meducator. We were recently Director of Graphics and Imaging honoured with an invitation to submit our publication to the permanent collection • ••• Katherine Saccucci of the McMaster Health Sciences Library. O n behalf of the Executive, I would like to extend m y gratitude to the people without which this publication would not be Vice President of Administration S h a m a Sud possible: the post-graduate editors for their unwavering support and patience, the Bachelor of Health Sciences Program (especially Del Harnish, Teresa Basilio, Penny Vice President of Public Relations A m a n d e e p Rai Losier and Andrea Phair-Renzi), and the writers for their dedication to quality. M y Vice President of personal thanks to the Executive for their Website Production & Design herculean efforts this year. You have all re helped to achieve the perfect blend of art and Edwin C.W. H o science that is necessary for the success of this Post-Graduate Editing publication. M y thanks goes to Jaron Chong, Dr. Larry W. Belbeck, D.V.M. Vice-President, for your support, patience Dr. Jonathon Bramson, Ph.D. and leadership, S a m m y Ali and Jeannette re Dr. Denys deCatanzaro, Ph.D. So, VP's Medical Research and Health Ethics, u Dr. Jack Diamond, Ph.D. for your skillful editing and resourcefulness, 3 Dr. Laurie Doering, Ph.D. Brent Mollon and Jonathan Liu, Jr. Editors, for Dr. Eleni Hapidou Ph.D. "D fascintating weekly MedBulletins, Anthony Dr. James L Henry, Ph.D. Collini, VP Layout and Distribution, for being 0) Dr. Mark Inman, Ph.D. the patient architect of a truly inspired layout, Dr. Shucui Jiang, M.D., Ph.D. Katherine Saccucci, VP Graphics, for your Dr. Jacek Kwiecien, Ph.D., D.V.M. aesthetically pleasing graphics, Shama Sud, VP Administration, for your well-organized Dr. Mark Loeb, M.D. minutes, Amandeep Rai, VP of Public Relations, for your innovative advertising Alison Miculan, M.A. strategies, and Edwin Ho, VP of W e b Design, for an up-to-date w e b page. I a m Dr. Parameswaran Nair, Ph.D. truly blessed to work with such exceptional and multi-talented individuals. Dr. Michel Rathbone, M.B., CH.B., Ph.D., F.R.C.P.(C) On behalf of all the staff and writers, I would like to extend our warmest wishes Meducator Founder to you, our readers. Watch for our next issue coming in October 2005! Jonathan M. Ng Meducator Header Design Jay Higgerty Sincerely yours, Meducator Logo Design Shawn McGrath Meducator Website Design Karen H o Staff Portrait Jennifer C. Tang AdrienneLi

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April 2005 | Issue 6

Sprinkles: AÂť N e w W a y of Managing Anemia

Graphic by Katherine Saccucci

In 2001, researchers at Toronto's Hospital for Sick Children received a large grant from the H.J. Heinz C o m p a n y for developing a n e w treatment for children suffering from anemia - particularly in developing countries. The World Health Organization currently estimates that around 5 0 % of children in Africa and Asia suffer from iron deficiency. Iron plays an integral role in oxygen delivery for our body. Red blood cells consist of m a n y protein and iron c o m p o u n d s - called hemoglobin - which have a high affinity for oxygen molecules. A low iron level, also known as anemia, often leads

to fatigue, impaired development (with respect to motor skills and intelligence) and increases the chance of maternal morbidity even from a small loss in blood volume. In the past, anemia has been treated using droplets of a solution containing high concentrations of iron. This method w a s typically avoided - especially for children - because it caused teeth stains and abdominal discomfort. "Sprinkles", a n e w form of vitamin C and iron supplementation, was developed by Sick Kids Hospital and is n o w being studied for its efficacy in developing countries such as Ghana, Sri Lanka and Nicaragua. Each sprinkle is composed of ferrous fumarate (an iron c o m p o u n d ) encapsulated by a lipid-derived coat which allows everything to be dissolved and absorbed only at low p H levels in the stomach. "Sprinkles" comes in small packets which readily

Stimulating Developments in Chronic Pain Treatments

This n e w system boasts a battery that patients can re-charge themselves. Moreover, the system comes with multiple program options, which is an improvement over previous systems which require physicians to Graphic by Katherine Saccucci manually program the devices. It is hoped that systems like this will allow patients to take a greater role P a t i e n t s suffering from chronic in the m a n a g e m e n t of their chronic pain m a y be looking forward pain - decreasing the strain chronic to the launch of a n e w high pain puts on the health care system. powered investigational neurostimThe current development of ulation system being developed by these medical systems m a y be good Medtronic, Inc. (MDT). Systems like news to the approximated 2 5 % of US this can be used to artificially stimu- citizens w h o suffer from chronic pain late neurons, which provides relief (which is defined as pain that perfor those suffering from chronic pain. sists/recurs for more than 6 months).

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mix with liquid-based foods without causing the undesirable "metallic taste". The average price per packet is around $0.025USD (a 60-day treatment would be $1.50 USD), thus, the researchers managed to fulfill their goal in developing a cost-effective way of treating anemia. Current follow-up studies on the effects of "Sprinkles" have shown positive results - it even works in conjunction with other nutritional supplements. With its high efficacy, low cost, ease of use, and neutral taste, "Sprinkles" is the ideal supplement for managing anemia in developing countries.

[SuppleFer. (n.d.). Micronutrient Sprinkles Program: Background. Retrieved January 27, 2005 from http://www. supplefer.com/background.html]

Brent Mollon

While chronic pain m a y result from any n u m b e r of disease or injuries, the detrimental impact it has on a person's life can be consistently seen. In order to best help these patients continue to live a normal, productive life, more research in the biomedical and psychological aspects of chronic pain should be conducted to allow for future breakthroughs in treatment. [Original summary by Biotech Week, Meducator Summary by Brent Mollon]

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Issue 6 | 2005 April

.Jr9PKIP.9 Deep for Answers...

c o m m o n form of depression with an overactive area in the brain responsible for mediating negative m o o d s - the subgenual cingulated (cg25). The cg25 region is also connected to the hypothalamus, which accounts Graphic by Katherine Saccucci for the circadian rhythm irregularities in patients with depression. A recent collaborative study conajor depression has remained the leading psy- ducted by experts from the Toronto chiatric disability a m o n g Western Hospital, University of Toadults under 50 in North America.To ronto, and Centre for Mental Health m a k e matters worse, 2 0 % of these and Addition has reported successpatients are often resistant to drugs ful m a n a g e m e n t of depressed paand psychotherapy - the most com- tients by using high frequency deep m o n methods of management. Al- brain stimulation (DBS). Deep brain though the cause of depression is stimulation involves the implantanot fully understood, researchers tion of a pacemaker in the affected hypothesize that it involves an inter- area. Through time, the constant action between genetic predisposi- stimulation s o m e h o w alters neural networks in a positive manner. tion and environmental situations. In the past D B S has been used sucOver the past few years, concessfully in treating patients with verging evidence (neuroimaging, Parkinson's disease, epilepsy, and biochemical, post mortem studies) tremors. The recent study involved have successfully linked the most

Driving with Cardiac Diseases: Should Physicians Have to Report?

Jonathan Liu six patients that were all resistant to the conventional methods of managing depression. The pacemaker devices were left in patients for a six month period and a PET follow up was conducted afterwards to check improvements in brain activity. Of the six patients, four reported significant improvements such as increased interest, better visual focus, and a general sense of calmness. Researchers hope to see DBS prescribed to patients that are treatment resistant. The final hurdle n o w involves finding the different affected brain regions as a result of various forms of depression. [Mayberb, H.a., Lozano, A.M., Voon, V., McNeely, H.E., Seminowicz, D., Hamani, C, Schwalb, J.M., & S.H. Kennedy. 2005. Deep Brain Stimulation for Treatment-Resistant Depression. Neuron 45: 651-660.)

Brent Mollon

nadian Cardiovascular Society has the social/ethical view of risk assesspublished a set of guidelines to iden- ment?" tify and report patients with cardiac While it is understood that indisease. However, researchers from dividuals should be restricted from Queens University have noted that operating a motor vehicle if they are there are unaddressed issues in the not well enough to do so, the assessGraphic by Katherine Saccucci mandatory reporting of patients. In ment of health is not always clearan article published in the Canadian cut. Even in the instances where a Legislation in many Canadian reJournal of Cardiology, Simpson et al. doctor is completely justified in regions requires that physicians (2004) note that the current legisla- porting their patient, it is feared that report the n a m e s of any pa- tion appear to neglect the harms legislation like this will degrade the tients with medical conditions that done to patients restricted from trust between physician and patient place them at increased risk while driving. As well, they have called - leading to reduced voluntary padriving. The idea behind this policy the efficacy of mandatory reporting tient reporting. is that the Ministry of Transport can into question. Lastly, and perhaps [Original Article: Simpson, C.S., Hoffmaster, Bâ&#x20AC;&#x17E; Mitchel, identify high risk drivers and remove most importantly, they questioned: LB. & Klein, GJ. (2004). Mandatory physician reporting their licenses if it is unsafe for them " H o w can the scientific/technical as- of drivers with cardiac disease: Ethical and practical considerations. Canadian Journal of Cardiology, 20, 1329to drive. To aid physicians, the Ca- sessment of risk be reconciled with 1334.)

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April 2005 | Issue 6 M e d Update by Jennifer Clara Tang

Vitamin E: Not a Panacea

McMaster study published in the March 16, 2005 issue of the Journal of the American Medical Association announced a surprising discovery: administering vitamin E supplements does not prevent cancer or major cardiovascular events in people with diabetes or cardiovascular conditions (HOPE, 2005). It is k n o w n that both cancer and atherosclerosis, KIRKLAND a condition that m a y cause cardiovascular events, are linked with oxidative stress (damage caused by free oxygen radicals). Based on this knowledge, researchers had previously hypothIMI |.t. U esized that vitamin E, an anti-oxidant, would counter the effect of the free radicals thus reducing the risk of these conditions ("No benefit...", 2005). The results of this study also indicate that long-term vitamin E supplementation m a y also contribSource: www.manekineko.us ute to heart failure (specifically, decreased function of the left ventricle). The study was a randomized, double-blind placebo controlled branch of the H O P E (Heart Outcomes Prevention Evaluation) trial and involved over 9,500 patients aged 55 years and older w h o had diabetes mellitus or vascular disease. O n e of the hallmarks of the study was its long duration. Stage one of the study was completed between 1993 and 1999. The investigators decided to extend the length of the study to 2003 in order to gather conclusive results.

The original journal article, entitled "Effects of Long-term Vitamin E Supplementation on Cardiovascular and Cancer" m a y be accessed at http://jama.ama-assn.Org/cgi/content/full/293/11/1338

M e d Update by Jennifer Clara Tang

i_ Peace Through Health Conference @ McMaster fr*e search

cMaster will be hosting the second annual Peace Through Health conference from M a y 6-8, 2005. c I The conference, "Peace Through Health: Learning o from Action" invites students, educators, media and health ro and peace professionals to engage in a weekend of speak\ ers, small group discussion, case-study focused learning Health Through Knowledge and a hike through Cootes'Paradise. Fostering communication and education about Peace Through Health initiatives will be the focus of this conference. Peace Through Health is the study of h o w "health interventions in actual and poSource: www.humanities.mcmaster.ca tential war zones m a y contribute to peace"(Peace..., 2005). Examples of Peace Through Health in action m a y be seen through humanitarian ceasefire, and through nurturing social and personal healing in war zones. Conference speakers include McMaster faculty Dr. Joanna Santa Barbara, Dr. Salim Yusuf, Dr. Vic Neufeld, Dr. Graeme M a c Q u e e n as well as representatives of the World Health Organization and the journal Lancet (McMaster..., 2005). -__ÂŤ___T____. '

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For more information visit www.humanities.mcmaster.ca/peace-health

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Issue 6 | 2005 April M e d Update by Jaron C h o n g

N e w Bioengineering Graduate Program Announced cMaster recently a n n o u n c e d a n e w interdisciplinary graduate program in bioengineering. As a collaborative effort b e t w e e n McMaster's Faculty of Health Sciences and the Faculty of Engineering, this c o m e s as the m o s t recent development in a long line of efforts by the university to bridge the t w o fields. In 2002, the university created a five-year undergraduate program in Chemical Engineering a n d Bioengineering a n d w a s quickly followed u p the Electrical and Biomedical Engineering degree. In 2004, M D A , makers of the C a n a d a r m , and Bell University Laboratories, each contributed $450,000 for the purposes of establishing a medical robotics and integrated systems lab. Pending approval by the Ontario Council o n Graduate Studies, McMaster will soon have bioengineering opportunities at all levels of post-secondary education. Both the Masters a n d Ph.D programs are accepting approximately 5 0 students from Health/Life Sciences a n d Engineering backgrounds for the 2005/2006 W''* 2 _j "Z- ^r __- -5 3 ~^^S"j~' academic year. To c o m p l e m e n t the program, a n e w building for the McMaster School of Biomedical Engineering (MSBE) is also being planned. With research foci including tissue engineering, medical robotics, and regenerative medicine, the c o m i n g years hold great promise for collaboration and discovery.

M o r e information is available o n the program's website at http://msbe.mcmaster.ca.

Artist's concept of proposed new School of Biomedical Engineering and School for Engineering Practice (msbe.mcmaster.ca)

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M e d Update by Jaron C h o n g

McMaster University Family Medicine Residency Program Expanded

Source: www.mayo.edu

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T w e n t y - t w o n e w family medicine residency positions, on top of a previous 41 positions, have been opened at the Michael G. DeGroote School of Medicine, McMaster University. Working in cooperation with the Ministry of Health and Long Term Care, this expansion represents a provincial investment of $10 million. $5 million will go directly into funding 141 n e w residency positions while the other $5 million is tagged to fund the construction of additional medical clinics at Queen's University and the University of Western Ontario. These two-year residency positions c o m m e n c e in 2006 and are expected to yield 337 family doctors by 2008, thereby increasing primary care accessibility for hundreds of thousands more Ontarians currently without a family physician. Traditionally, more McMaster medical graduates have gone into family medicine than the national average. Last year, 4 6 % of McMaster medical graduates went into family medicine as opposed to 3 3 % in other medical colleges throughout Canada. This expansion represents a solid investment in addressing both Ontario's health care needs for today and for years to come.

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April 2005 | Issue 6

Remyelinating Damaged Nerves

W a q a s Kayani Christopher Reeve (1952 - 2004) once said,"We live in a time w h e n the words impossible and unsolvable are no longer part of the scientific community's vocabulary. Each day w e m o v e closer to trials that will not just minimize the symptoms of disease and injury but eliminate them." Unfortunately Reeve passed away before the major breakthroughs in the field of central nervous system (CNS) nerve regeneration. Today, Reeve's words are a source of hope for millions of people around the world that suffer from illnesses that cause C N S nerve degeneration. Since the discovery that stem cells can serve as precursors for neuronal and glial cells researchers have been conducting m a n y animals trials to see whether transplanting stem cell-derived neuronal and glial cells can induce the remyelination of degenerated nerves. Also, researchers are searching for alternative cells with stem cell properties that can be used to produce neuronal and glial cells. Researchers found that they are also able to produce neuronal and glial cells from bone marrow cells, which have stem cell like properties. Once injected, the neuronal and glial cells migrate to the d a m a g e d area in the C N S and remyelinate previously demyelinated areas, restoring s o m e function to the damaged areas. The C N S is a very delicate system consisting of numerous neuronal cells and their processes and several supporting cells called glial cells. Given that stem cells can differentiate into various neuronal and glial cells, scientists have been experimenting with injection of stem cells into the C N S to determine if remyelination occurs. However, before delving into research involving the CNS, one needs to have an understanding of C N S anatomy and physiology. The C N S consists of the brain and the spinal cord, both of which are equipped with sensory and motor neurons and nerve fibers which allow for communication between the C N S and the rest of the body. Intact communication between the C N S and the body are essential for normal physiology (Carlson, 2004). There are nerve fibers termed axons which are very long, slender processes along which electric impulses (action potentials) are transmitted; these processes are typically surrounded by an insulation sheath

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or myelin. Myelinated axons conduct action potentials m u c h faster than unmyelinated axons. Recent research on ion channels indicates that myelin sheaths regulate proper distribution and therefore function of channels participating in proper (fast and strong) transmission of action potentials (Carlson, 2004). Although the C N S has an inherent capacity to remyelinate previously demyelinated nerve fibers, persistent demyelination can have a severe impact on the myelination process (Blakemore et al., 2000). Multiple sclerosis, trauma and leucodystrophies can cause such demyelination. Researchers believe there are two possible solutions to the problem of demyelination: to promote the production of cells with the capability to remyelinate, or to conduct research on animals with demyelination in the C N S by injecting differentiated neuronal and glial cells into the CNS. Once injected, the differentiated cells migrate to the lesion sites and remyelinate the demyelinated nerves to a certain extent (Blakemore et al., 2000). M a n y scientists believe the latter to be the next major breakthrough in the process of C N S regenerational recovery. Researchers have found that remyelination does occur and in s o m e experiments remyelination occurred in up to 6 7 % of demyelinating axons (Minodora et al., 2004). Researchers believe that the differentiated cells migrate to the region where the lesion has occurred and partially remyelinate the nerves, thus allowing for s o m e function to return. A reason w h y not all demyelinated nerves are remyelinated is because the injected cells are unable to migrate to all areas of the lesion (Minodora et al., 2004). Generally, researchers transplant stem cells either directly into the brain or to the area in the spinal cord that has the lesion (Wu et al., 2002). Such is the case with W u and others. (2004), w h o utilized a microsurgical operation to transplanted hippocampus-derived neurosphere cells into an injured spinal cord. However, W u and his colleagues found that injecting stem cells directly into the lesion would be clinically unrealistic if the lesion covers a large area (Wu et al., 2002). D u e to these discrepancies, W u and colleagues have devised a n e w method of injecting the cells into the CNS. They have conducted experiments where they inject the cells for transplantation into the cerebrospinal fluid (CSF) in the fourth ventricle. The researchers found that the distribution of cells injected through the CSF were superficial as compared to these injected directly into the CNS.The injected cells were also able to survive in different regions of the CNS, and were able to migrate to the lesion area; once they reached the lesion the transplanted cells www.meducator.org

Issue 6 | 2005 April remyelinated degenerated nerves (Wu et al., 2002). Although bone marrow cell-induced myelination Although researchers have been able to stimulate looks promising, there are several major concerns. First, remyelination of injured spinal cord nerves in their the i m m u n e system of the rats m a y not accept the bone experimental rats, there were major complications that marrow cells, and may attack and destroy the injected arose in this process. W h e n considering remyelination of cells before they are able to migrate to the damaged nerves, most experiments fail rather than succeed due to area. For this reason, Akiyama and colleagues have been the pathological changes that affect the C N S (Minodora, using rats whose i m m u n e systems have been deactivated 2004). Another problem is that although the migration (Akiyama 2002). Another problem facing Akiyama's group process and myelination do occur in most animals, is that the bone marrow cells remyelinate the damaged very often it is incomplete. Age also seems to play a nerves at unpredictable levels, unlike stem-cell aggregate major role in the efficiency of myelination (Minodora, neuronal cells. This setback has brought into question the 2004). Minodora and colleagues have shown that older effectiveness of bone marrow aggregate neuronal cells in animals have a decreased chance of success and even if Area demyelinated White area is the remyelinated area myelination of older animals does succeed the yield as compared with younger animals is m u c h lower (Minodora, 2004). This observation is somewhat inconsistent with previous findings that the adult rat C N S has full potential of spontaneous remyelination after demyelinating injury, and indicates the need for more studies on spontaneous remyelination in animal models. The use of stem cells in research has been under tremendous scrutiny, so researchers have had little leeway in the experiments that they conduct. Despite these obstacles, research is rapidly moving forward. As research has advanced in neuronal migration and demyelination, so has research into finding alternative cells with stem cell-like properties. Due to the legal implications dealing with stem cell usage, such substitute cells can be used as precursors for the production of neuronal cells.The discovery of bone marrow cell properties is an important advancement within surrogate cell research. Researchers Area demyelinated Area remyelinated have found that bone marrow cells can be differentiated into a variety of different cell lineages, including nerve Figure 1: The two figures on the left are of a rat with a demyelinated cells (Akiyama, 2002). In various experiments conducted area. The same area after injection shows remyelination of the cells by Akiyama and colleagues, bone marrow cells were (Akiyama, 2002). extracted from rats, which thereafter differentiated into neuronal cells, glial cells, as well as other cell lineages.This remyelinating damaged areas (Akiyama, 2002). Although demonstrated that bone marrow cells have stem cell like these issues have raised some concerns, the research is still in its initial stages. properties (Akiyama et al., 2002). Even though Christopher Reeve died before his dream Researchers such as Akiyama are n o w injecting substitute cells into rats with lesions in their CNS, using of walking again was realized, there are millions of people the same transplantation procedures as used with stem whose lives could potentially be changed for the better cell aggregate neuronal cells. They have found that w h e n in due time. Researchers have shown that CNS d a m a g e in these cells are directly injected into a demyelinated nerve experimental rats can partially be repaired by the injection zone, they can cause partial remyelination (Akiyama , of neuronal and glial cells that originated from stem or 2002). Akiyama and colleagues have also shown that bone marrow cell aggregates. Although it seems that w e transplanting bonemarrowcellsintorats with dysfunctional are on the verge of a major breakthrough, there is still spinal cords restores function (Akiyama, 2002). Through s o m e time before h u m a n clinical trials can begin. E3 subsequent autopsies, the researchers found that the pattern of remyelination occurring in their bone marrow injected model rats was similar to that of normal rats that are myelinated with oligodendrocytes (Akiyama, 2002). www.meducator.org

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April 2005 | Issue 6

Big Pharma: In W h o s e Best Interest?

S h a m a Sud T h e recent recall of the anti-inflammatory drug Vioxx was a defining m o m e n t in the history of modern medicine. It has convincingly and dramatically driven h o m e the point that for pharmaceuticals, maximizing profits takes priority over public interest. Furthermore, it highlights the failure of the regulatory system to protect the public. Somewhere along the course of developments in medical treatments and technology, the priorities of the "big pharma" and their consumers they are marketing to seem to have diverged. From January 1st, 1994 to April 30, 2004, 2.3% of all n e w molecular entities approved by the FDA were recalled due to an intrinsic property of the drug that caused harmful side effects (FDA, 2004). While this figure m a y appear to be small, adverse side effects of over-the-counter and prescription drugs are responsible for the death of 100,000 Americans and severe injury of another 2.1 million every year, not including illness due to drug abuse or prescribing errors (CNN, 1998). Severe drug-induced reactions have been ranked sixth a m o n g the leading causes of death in the United States (CNN, 1998). A definite idea of w h o m a drug is suitable for, as well as its potential side effects, should be determined before consumers begin to use it. From a patient's perspective, this makes the most sense. However, it would appear as though the big pharma is not taking this as seriously as patients are. This article will consider three cases that demonstrate the need for greater accountability in the drug industry. The effect that a severe lack of information can have in terms of the safety and effectiveness of drugs first became evident with the Thalidomide tragedy. Thalidomide was a drugthatwasfirstputontothemarketin1957asatreatment for morning sickness in pregnant w o m e n (Thalidomide Victims Association of Canada, 2003). Unfortunately, its beneficial effects were outweighed by negative effects.The drug not only inhibited proper growth of the fetus leading to devastating birth defects such as blindness, deafness, cleft palate, disfigurement, and phocomelia in thousands of children around the world, but it was also responsible for the deaths of a staggering number of babies (Thalidomide Victims Association of Canada, 2003). O n e would assume

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that after such a tragedy, government drug regulations would be a m e n d e d to prevent the reoccurrence of such events. However, decades after the Thalidomide tragedy, people continue to be the victims of insufficient research and data on the part of the big pharma. T w o prime examples of this are the recall of the anti-inflammatory drug Vioxx and the relationship between antidepressants and suicide in adolescents and children. The FDA approved Vioxx (also k n o w n as rofecoxib) in 1999 (Beller, 2005). Vioxx is a non-steroidal antiinflammatory drug (NSAID) also k n o w n as a COX-2 inhibitor, prescribed as a painkiller primarily for arthritis. In the five years it was on the market, more than 80 million patients were prescribed Vioxx and its annual sales were over $2.5 billion (CBC N e w s Online, 2004; Beller, 2005). Vioxx's popularity soared because m a n y patients suffered from serious gastrointestinal bleeding from traditional NSAIDs such as aspirin (CBC N e w s Online, 2004). Researchers claimed that the drug reduced the likelihood of stomach ulcers and internal bleeding (CBC N e w s Online, 2004). Vioxx was recalled in September 2004 because of the findings in a study done by the FDA, which showed that it increased the risk of myocardial infarction (Beller, 2005). Researchers analyzed data from 1.4 million patients in California w h o had been taking Vioxx and other similar COX-2 inhibitors from 1999 to September 2004 (Olive, 2005). Of the 1.4 million, 8,143 patients were found to be suffering coronary heart disease, of w h o m 1,508 suffered sudden cardiac deaths (Olive, 2005). W h e n compared with other COX-2 inhibitors, researchers found that Vioxx posed a 3 4 % higher risk of heart disease of which m a n y cases would prove to be fatal (Olive, 2005). According to the lead researcher of the study, Dr. David Graham, "An estimated 88,000 - 140,000 excess cases of serious coronary heart disease probably occurred in the U.S.A. over the market life of rofecoxib (Vioxx)" (Olive, 2005). The most frightening part of this whole incident is that both the development of coronary heart disease, as well as the death of so m a n y people could have been prevented. Not only did Merck, the pharmaceutical company responsible for the production of Vioxx, spend adequate time testing the effects of the drug before having it approved by the FDA, but they also ignored the results of m a n y trials demonstrating Vioxx's devastating side-effects. A study published in the New England Journal of Medicine in 2000 showed that Vioxx appeared to increase the risk of heart disease w h e n compared with another painkiller, Naproxyn (CBC Health and Science News, 2004). Merck responded by saying that there was nothing wrong with Vioxx, but rather, it was Naproxyn www.meducator.org

Issue 6 | 2005 April that was having a cardioprotective effect. (CBC Health and Science News, 2004). Rather than looking further into the matter, Merck merely dismissed researchers'findings, thus endangering the lives of millions. Furthermore, another study was published in the Journal of the American Medical Association in August 2001 that showed a correlation between the use of Vioxx and heart attacks (CBC Health and Science News, 2004). W h a t was the response of the FDA and Health Canada? Merely to have the label on Vioxx bottles changed to indicate that the drug posed a risk for heart attacks (CBC Health and Science News, 2004). By November 2004, the University of Bern in Switzerland had compiled 29 different studies linking Vioxx to an increased risk of heart attacks, published during the five years Vioxx was on the market (CBC Health and Science News, 2004). Moreover, the negligence of limited research done by the big pharma on the effects of Selective Serotonin Reuptakelnhibitors(SSRIs)onpediatricdepression patients has also led to devastating results. Before the discovery of SSRIs, physicians relied on tricyclic antidepressants to treat depression (Garland, 2004). As tricyclic antidepressants were both ineffective and potentially toxic, physicians were open to research suggesting the effectiveness and better tolerance of SSRIs in patients being treated for depression, developed in the late 1990s (Garland, 2004). However, as several large randomized controlled trials of the eight most popular antidepressants c a m e to an end in 2003, both physicians and researchers received devastating news (Garland, 2004). First paroxetine (Paxil) was contraindicated in Canada, the United States and the United Kingdom as a treatment for Major M o o d Disorder ( M M D ) in patients under the age of 18 (Garland, 2004). Studies done with the drug had found it not only to be ineffective in the treatment of M M D , but that it was linked with twice the rate of aggression and suicide w h e n compared with the placebo (Garland, 2004). Furthermore, three trials involving venlafaxine, another SSRI, found this drug to be ineffective in treating M M D as well, and once again associated with double the rate of suicide and anger w h e n compared with the placebo (Garland, 2004).The startling results from these studies finally led the FDA to issue a public health advisory pertaining to all antidepressant medications being used to treat pediatric patients because of their ineffectiveness and relation to suicidal ideation and attempts (Garland, 2004). Another study testing the effects of sertraline on approximately 400 patients found that 6 9 % of patients showed an improvement w h e n on the medication versus 5 9 % in the placebo group (Garland, 2004). Only one in every ten patients experienced s o m e improvement in their condition yet this drug was being prescribed at the time to treat pediatric depression (Garland, 2004). These arejust three key instances where big pharma has neglected its utmost duty - providing effective treatments www.meducator.org

Canadian Broadcasting Corporation. (2005, January 25). Study linking Vioxx to heart problems finally published. Retrieved March 21, 2005 from the World Wide Web: www.cbc.ca

that improve the quality of life of patients. Public-health institutions will continue to experience an erosion of trust as long as devastating side effects keep arising from drugs that have not been thoroughly tested. In the longterm, a failure to act constructively w h e n signals of risk become evident will lead to significant public skepticism about what the priorities of the big pharma really are, and w h o m they are really interested in representing. More importantly, trusting patients will continue to suffer due to negligence on the part of the big pharma. At this point, the important thing to determine is what can be changed to improve this situation and to prevent future tragedies from occurring. First of all, Health Canada and the FDA must more effectively protect the public interest by developing and enforcing stricter policies with the health of the consumer as the primary focus for clinical trials of a drug. Serious side effects of drugs often remain unknow n until they have been widely prescribed. Therefore, clinical trials must be m u c h more extensive and thorough to ensure that the health of patients will not be put at risk. W h e n concerns about side effects arise, big pharma must immediately begin research to determine what is actually occurring, as it is their obligation to the public. Physicians also have an important role in protecting the public interest by ensuring thatthey lobby big pharma whenever they have any concerns about the effect a drug is having on a patient. Finally, and most importantly, the priorities of everyone involved in the health care system, including the pharmaceuticals, patients and physicians must be discussed and re-examined. The primary focus of healthcare must be on the people it serves.The health and well-being of patients must always c o m e first and every effort must be taken to prevent putting these principles into jeopardy. If everyone involved is working toward the same goal, achieving it becomes that m u c h easier. ___

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April 2005 | Issue 6

Vioxx: What Went Wrong?

S a m m y H. Ali Arthritis is one of the most common medical problems in the world. Nearly four million Canadians are affected with arthritis and other rheumatic conditions; these numbers are expected to escalate as the population continues to age (PHAC, 2003). At present there exists only treatments for arthritis, but no cure. Osteoarthritis is a degenerative form of arthritis which occurs w h e n the cartilaginous lining that cushions the ends of bones in joints deteriorates, leaving bones to rub against one another (Hunder, 1999). Rheumatoid Arthritis (RA), on the other hand, is not associated with wear and tear. It is thought to be an autoimmune disease in which an unidentified agent stimulates an i m m u n e response in the joint capsule (Hunder, 1999). The ensuing inflammatory response results in the thickening of the joint capsule synovium. If untreated, inflammatory mediators digest cartilage, bone, tendons and ligaments. Given the aforementioned etiology of RA, treatment regimens have focused primarily upon reducing the autoInflammatory response associated with the disease.This has led to the utilization and development of various families of anti-Inflammatory drugs - one of which are the Nonsteroidal Anti-inflammatory Drugs (NSAIDs). This class of drugs, of which aspirin is a member, inhibits inflammation by interfering with an inflammatory mediator known as cyclo-oxygenase (COX). Clinical trials demonstrate that although NSAIDs are effective in alleviating symptoms associated with RA, they present a marked increase in gastrointestinal ulceration (Kremer, 2000). These findings led to the development of NSAIDs that specifically inhibit

Figure 1: Inflammation of the joint capsule results in destruction of the articular cartilage and meniscus separating the two bones. If untreated, inflammatory mediators will continue to digest synovium, bones, ligaments and tendons.

the one isozyme of C O X which is involved in inflammation, COX-2, but leftthe other isozyme (COX-1) untouched.These COX-2 specific NSAIDs exhibit the same anti-inflammatory potential as their traditional counterparts without the adverse gastrointestinal complications (Bombardier et al., 2000). Perhaps the most prominent of the COX-2 specific inhibitors is Vioxx. Despite these advantages, Vioxx was verified to increase risk of heart attack, stroke, and serious cardiovascular events by greater than 5 0 % (Bombardier et al., 2000); these findings resulted in a nationwide recall of the pharmaceutical drug.

PHYSIOLOGICAL FUNCTION OF CYCLO-OXYGENASE (COX) Cyclo-oxygenase (COX) plays an important role in the production of prostaglandins. Prostaglandins are a family of chemical messengers which allow for local signaling within tissues.The effects of the signal are highly dependent upon both the specific type of prostaglandin as well as the

Prostaglandin

Physiological Function(s)

Thromboxane A 2 (TXA 2 )

Platelet Aggregation (blood clot formation) & Vasoconstriction

Prostacyclin (PGI.,)

Anti-aggregation (blood thinning) & Vasodilation

PGE 2

Induce i m m u n e response, Vasodilation, Protect gastric mucosa

Table 1: Prostaglandin Functions

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Issue 6 | 2005 April properties of the target tissue cells. For instance, the same prostaglandin may have different effects when acting upon the endothelial cells of the gastrointestinal tract than on the vasculature of inflamed tissue. Prostaglandins participate in a variety of physiological mechanisms, including:

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Cox 1/2

Activation of an inflammatory response Haemostatic mechanisms: formation or destruction of blood clots depending on the type of prostaglandin Dilation or constriction of blood vessels Production of the protective mucosal layer which lines the inside of the gut and inhibition of gastric acid secretion Regulation of blood supply to the kidneys

PGHi

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PGD

All members of the prostaglandin family (Table 1) are Figure 2: Cyclo-oxygenase (COX) enzymes convert the membrane lipid enzymatically produced products of arachidonic acid. Arachidonic Acid (AA) into a prostaglandin intermediate, PGH . Tissue 2 Arachidonic acid is a dietary unsaturated fat which is specific synthases then proceed to convert this intermediate into the metabolized from phospholipid membrane of cells. The various prostaglandins. first stage of prostaglandin synthesis is the transformation of arachidonic acid into cyclic endoperoxide intermediates; this pathway is catalyzed by the COX enzymes (Pairet & the production of prostaglandins which mediate normal physiological processes. This includes the prostaglandin van Ryn, 2004). thromboxane A 2 involved platelet aggregation, and prostaglandin PGE 2 which protects the gastric mucosa PROSTAGLANDIN SYNTHESIS PATHWAY from ulceration.The inducible COX-2, on the other hand, is believed to be primarily responsible for the production of Protaglandin synthesis proceeds via two primary stages: prostaglandins in inflamed tissues.

1) COX catalyzes the breakdown of Arachidonic Acid into a cyclic endoperoxide intermediate in a two step process ADVERSE GASTROINTESINAL EFFECTS OF NSAIDS that ultimately produces Prostaglandin H 2 (PGH2). Traditional NSAIDs function by non-selectively inhibiti both isozymes of COX. Therefore, while the inhibition of 2) Downstream of COX action, a range of tissuespecific synthases transform PGH 2 into the different COX-2 results in a reduced inflammatory response, the inhibition of COX-1 interferes with essential physiological prostaglandins. processes. One such compromised process is the protection of the gastric mucosa from ulceration. Therefore treatment SUBTYPES OF COX of arthritis with non-selective NSAIDs, such as aspirin, There are two isozymes, or forms, of the COX enzyme,contributes to gastrointestinal morbidity. designated COX-1 and COX-2. The first, COX-1, has been demonstrated to be constitutive in most cells; in other words, it is present at a fairly constant level regardless of physiological demand (Pairet & van Ryn, 2004). Conversely, very little COX-2 is found in resting cells. However, it is powerfully induced in fibroblasts, endothelial cells and vascular smooth muscle by cytokines and in macrophages by lipopolysacharide (Pairet & van Ryn, 2004). These observations have led to the hypothesis that the constitutively expressed COX-1 is involved in

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COX-2

SPECIFIC INHIBITORS

Although the active sites of COX-1 and COX-2 are simila there are structural differences.The NSAID binding pocket on COX-2 is larger than that of COX-1. The important consequence of this difference is that COX-2 binds more readily to bulkier inhibitors (Smith et al., 2000). This has served as the framework for the development of COX-2 selective NSAIDs.

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April 2005 | Issue 6 a balance between liquid and solid (clotting) blood. In particular, it is thromboxane A 2 (TXA2) which initiates platelet aggregation and clot formation, and prostacyclin Nonspecific (PGI2) which serves as an anti-aggregatory blood thinner NSAIPs/ASA (Clark, 2004). TXA 2 production in platelets is mediated by COX-1, while PGI2 production in vascular endothelial COX-2 inhibitors cells is mediated by COX-2. Traditional non-selective NSAIDs inhibit both COX-1 and COX-2 and therefore the Prostacyclin (PGI2) Thromboxane (TxA, effects on haemostasis are counterbalanced. However, COX-2 specific NSAIDs inhibit PGI2 production only; this Vasodilator Vasoconstrictor Inhibitor of platelet aggregation shifts the haemostatic balance towards increased platelet Promotes platelet aggregation aggregation and vasoconstriction of blood vessels (Clark, 2004). These two conditions lead to the increased / \ Thrombosis Haemostasis cardiovascular complications found in patients using Figure 3: Traditional Non-specific NSAIDs and aspirin inhibit both COXVioxx. 1 and COX-2 activity, preventing the production of both Thromboxane The results of the VIGOR (VIOXX Gastrointestinal A 2 and Prostacyclin (PGI2); therefore, the effects on haemostasis (blood clotting) are balanced. COX-2 specific inhibitors inhibit only Prostacyclin Outcomes Research) in 2000 revealed that while Vioxx (PGI2) production causing a shift towards increase vasoconstriction and demonstrated less gastrointestinal toxicity than the blood clotting. (Clark, 2004) comparative non-selective NSAID, it also led to a marked increase in adverse cardiovascular events (Bombardier et al. 2000). However, it was not until four years later w h e n ADVERSE CARDIOVASCULAR EFFECTS OF COX-2 the APPROVe (Adenomatous Polyp Prevention on VIOXX) INHIBITORS trial confirmed these cardiotoxicity findings that Vioxx was recalled. E3 Aside from inflammation, one fundamental physiological Endothelial ce

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function of prostaglandins is haemostasis, maintaining

Drugs, Tea and Curry: The Means to Finding a Cure for Alzheimer's Disease? disease become forgetful, confused, disoriented and may experience paranoia and delirium. As the brain deteriorates, they lose the ability to read, speak, eat, walk and write. Alzheimer's disease leads to dementia, the permanent or progressive loss of intellectual abilities, including the impairment of judgment, abstract thinking and memory. The causes of Alzheimer's disease are still D a n n y Ricci unknown, though evidence suggests that the disease results from a combination of genetic and environmental There is no known cure for Alzheimer's disease, but certain factors, as well as the aging process (Tortora & Grabowski, substances and drugs have shown promising results in 2003). Researchers have been studying the neuronal treating this neural degenerative disorder. abnormalities that occur during Alzheimer's disease and also n e w methods to treat the disease. Alzheimer's disease is a neural degenerative disorder that affects 1 1 % of the population over the age of 65 (Tortora & Grabowski, 2003). A German physicist, PLAQUE DEPOSITS IN THE CEREBRAL CORTEX Alois Alzheimer, discovered Alzheimer's disease in 1906, after his study of a 51-year old w o m a n w h o had various One of the changes that occurs in the brain during abnormalities in the brain, particularly the cerebral cortex Alzheimer's disease is the development of plaques in the (Kolb & Whishaw, 2001). Individuals with Alzheimer's cerebral cortex (Kolb & Whishaw, 2001). The plaques are

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Issue 6 | 2005 April composed of protein material called amyloid, which is produced through the division of a large molecule, k n o w n as the amyloid precursor protein. Three types of enzymes, known as alpha, beta and g a m m a secretases, divide the amyloid precursor protein into smaller fragments (Pedrini et al., 2005). The division of the amyloid precursor protein can produce soluble, harmless fragments (such as amyloidbeta38) if alpha-secretase divides the protein. However, if the division of the amyloid precursor protein involves the beta-secretase, then insoluble fragments called amyloidbeta42 are formed (Pedrini et al., 2005). The amyloidbeta42 fragments combine together to produce plaques deposited outside of neural cells (Tortora & Grabowski, 2003). Although amyloid-beta42 plaques are one of the c o m m o n signs of Alzheimer's disease, researchers are studying w h y the amount of insoluble amyloid-beta42 plaques deposited in the brains of Alzheimer's patients m a y not be related to the severity of their symptoms. Studies performed at the National Institutes of Health suggest that there are two types of amyloid-beta fibrils (the main fibrils in the plaque deposits located in the cerebral cortex). These two different types of fibrils have different molecular structures and are not equally hazardous (Petkova et al., 2005). The researchers also found that the basic building blocks of amyloid-beta fibrils, the protofilaments, possess two different three-dimensional structures. During an in vitro study, the researchers concluded that the structure of the protofilaments is determined by variations in the growth conditions under which amyloid-beta is allowed to accumulate (Petkova et al., 2005). In addition, the structure of the protofilaments determines whether the fibrils are twisted or parallel to each other. Furthermore, it was found that the two types of fibrils express different toxicities in neuronal cell cultures. The researchers believe that the difference is due to the nature of the amino acids exposed on the fibril surfaces (Petkova et al., 2005).

Oasis Herbs and Spices, www.oasisherbsandspices.com

amyloid precursor protein (Lleo et al., 2004). Researchers at the Massachusetts General Hospital studied the effect of NSAIDs on the interaction between one of the enzymes that divides amyloid precursor protein, gamma-secretase, and the actual amyloid precursor protein in vitro. The researchers concluded that NSAIDs reduce the production of amyloid-beta42 relative to nontoxic amyloid-beta molecules but do not reduce the total quantity of amyloid-beta molecules (Lleo et al., 2004). Presenilin 1, which is a section of the g a m m a secretase enzyme, is believed to be the division site for amyloid precursor protein. As a result, the researchers at the Massachusetts General Hospital also conducted a study using a technique k n o w n as fluorescence resonance energy transfer (Lleo et al., 2004). Using this technique, the researchers demonstrated that NSAIDs open the presenilin 1 site and alter the relative positions of amyloid precursor protein and presenilin 1. Even though ibuprofen affects amyloid precursor protein and presenilin, other NSAIDs, such as naproxen and aspirin, have no effect on the amount of amyloid-beta42 in the brain as they do not change the positions of amyloid precursor protein or presenilin 1 (Lleo etal.,2004). Researchers studying the effects of NSAIDs on NON-STEROIDAL ANTI-INFLAMMATORY DRUGS Alzheimer's disease are trying to scientifically explain w h y (NSAIDs) certain NSAIDs increase the probability that the amyloid precursor protein is divided to produce the soluble The amyloid-beta fibrils that make up the plaque deposits amyloid-beta38 instead of the insoluble amyloid-beta42. m a y have different forms, but w h e n using non-steroidal O n e explanation is that these drugs reshape the site of the anti-inflammatory drugs (NSAIDs) to treat Alzheimer's amyloid precursor protein where division occurs (Lleo et disease, the different forms of fibrils m a k e no difference. al., 2004). NSAIDs, including the drugs ibuprofen (such as Advil NSAIDs are not the only types of drugs that influence and Motrin), naproxen, flurbiprofen, and aspirin, treat the division of the amyloid precursor protein. Statin drugs, various inflammatory disorders, such as tennis elbow such as Lipitor (atorvastatin) and Zocor (simvastatin), are and rheumatoid arthritis (Tortora & Grabowski, 2003). used to lower cholesterol, but researchers are suggesting Researchers speculate that NSAIDs produce a beneficial that they can also be used to treat Alzheimer's disease. effect against Alzheimer's by influencing the division of These types of drugs can treat Alzheimer's disease by www.meducator.org

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April 2005 | Issue 6 ACAT, an enzyme that converts cholesterol in cell membranes into droplet form to be stored in cells for later use (Hutter-Paier et al., 2004). Therefore, w h e n the active site of A C A T is blocked, cholesterol cannot be stored. STATINS Researchers at Harvard Medical School demonstrated that inhibiting A C A T with an inhibitor, CP-113,818, Statins and the amyloid precursor protein are potentially eliminated nearly all of the amyloid-beta42 deposits in a related due to a type of protein known as Rho, which is a m o u s e model of Alzheimer's disease. After analyzing the part of a family of molecules called small G-proteins. These brain tissue from the mice used in the study, the researchers proteins are involved in various cellular functions, such as believed that the A C A T inhibitor lowers production of cytoskeletal reorganization and gene expression (Pedrini amyloid-beta42 instead of reducing its deposition (Hutteret al., 2005). Researchers at Thomas Jefferson University in Paier etal., 2004). Philadelphia have explored the effect of statins on amyloid The apparent connection between cholesterol and precursor processing and the Rho pathway in neural Alzheimer's disease is supported by findings related to cultured cells.The researchers were particularly interested apolipoprotein E,a moleculethataidsinthetransportation in a protein called ROCK1, which is activated by Rho. Once and metabolism of cholesterol and triglycerides.The genes ROCK1 is activated, it phosphorylates a number of other that code for apolipoprotein E influence the risk of people proteins (Pedrini et al., 2005). getting Alzheimer's disease (Dodart et al., 2005). Most The researchers at Thomas Jefferson University individuals carry the E3 version of the apolipoprotein E concluded that the activation of ROCK1 promoted the type gene (Rovner, 2005). However, there are s o m e individuals of amyloid precursor protein division that formed amyloidw h o possess the E2 version and are less likely than the E3 beta42.The researchers determined that the statin drugs carriers to develop Alzheimer's disease. The individuals Lipitor and Zocor inhibited ROCK1 activity and promoted having the E4 version are more likely than the individuals the formation of the soluble amyloid-beta38 (Pedrini et al., with the E3 version to develop Alzheimer's since the E4 2005). version facilitates the accumulation of amyloid-beta42 in The researchers believe that ROCK1 affects the division the brain (Dodart et al., 2005). of the amyloid precursor protein through alpha-secretase. Researchers at the Salk Institute in La Jolla, California This interaction m a y be indirect, with an accessory molecule suggested that inserting copies of the E2 version of the being phosphorylated by ROCK1. This accessory molecule apolipoprotein E gene into an organism's D N A would then interacts with the alpha-secretase enzyme (Pedrini enhance the production of the protective form of et al., 2005). However, Cordle and Landreth (2005) at Case Western Reserve University prefer to explain the effects apolipoprotein E. To test their hypothesis, the researchers of statins on Alzheimer's disease in a different way. They injected viruses carrying several apolipoprotein E versions into the brains of numerous mice (Dodart etal., 2005). Once suggest that amyloid-beta42 produces an inflammatory the D N A of the mice took up the n e w genes, the mice began response in the brain and promote white blood cells, such as microglia and monocytes, to release molecules (for producing the apolipoprotein E version programmed by example, interleukin-1-beta and tumor necrosis factor the particular version they had received. The researchers alpha) to encourage inflammation (Cordle & Landreth, found that expression of the E4 version promoted fibril 2005). Later, neurons die due to the exposure to these formation and deposition of amyloid-beta42. However, inflammatory molecules. However, w h e n monocytes and the expression of the E2 version resulted in a reduction of microglial cells are exposed to statins, the expression of amyloid-beta42 in the brain (Dodart et al., 2005). performing the samefunction as NSAIDs:affect the division of the amyloid precursor protein (Pedrini et al., 2005).

the monocytes and microglia was inhibited due to the presence of amyloid-beta42. Therefore, in addition to its cholesterol-lowering effects, statins m a y also have antiinflammatory properties, according to the studies done by Cordle and Landreth (Cordle & Landreth, 2005). H o w is cholesterol involved with decreasing amyloidbeta42 deposition in the brain? Researchers are trying to better understand the relationship between cholesterol and amyloid-beta42 deposits by studying another type of drug that affects cholesterol levels: Acyl-coenzyme A/ cholesterol acyltransferase (ACAT) inhibitors. This type of drug blocks acyl-coenzyme A/cholesterol acyltransferase

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TEAANDCURRY One research team found that green and black tea inhibit the activity of acetylcholinesterase in vitro (Okello et al., 2004). Alzheimer's disease is characterized by the decrease in the neurotransmitter acetylcholine, involved in memory. Tea also inhibits the e n z y me butyrylcholinesterase, which also breaks d o w n acetylcholine. Furthermore, green tea inhibits the activity of beta-secretase, one of the enzymes that divide the amyloid precursor protein into amyloid-

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Issue 6 | 2005 April

O- Na

0 OCH

CH2O

Curcumin Figure 1: The chemical structures of Congo red and curcumin, the yellow pigment found in curry. Both Congo red and curcumin have two polar groups separated by a hydrophobic bridge (Rovner, S.L., 2005).

beta fragments. The researchers have yet to isolate the mouse's brain appeared to break apart. These properties active ingredients in tea, but they have already ruled out would be invaluable because the outward symptoms of the possibilities of theophylline, theobromine and caffeine Alzheimer's disease do not b e c o m e apparent until decades after amyloid begins to accumulate in the brain (Yang et (Okello etal., 2004). In addition to tea, the yellow pigment in curry, al., 2005). curcumin, has been shown to aid in fighting Alzheimer's disease. Research conducted at the University of California WHAT'S NEXT? focused on h o w curcumin functions in the body (Yang et al., 2005). The researchers state that the structure of Alzheimer's disease continues to take millions of lives curcumin is similar to the structure of Congo red, a dye every year. Thereto re, it is imperative that researchers from known to bind to amyloid-beta42 fibrils in cultured cells. all parts of the world d o as m u c h as possible to uncover a Congo red, however, is both toxic and unable to cross the treatment that will dramatically reduce the effects of this blood-brain barrier (because it is negatively-charged) to disease. Based on the studies being done at the present reach amyloid-beta42 plaques (Yang et al., 2005). time, a beneficial treatment for Alzheimer's disease is not The researchers at the University of California think going to be a "magic" potion or an outrageously ingenious that because curcumin has a hydrophobic nature, instead therapy. Instead, c o m m o n medications, such as Advil and of being negatively charged like Congo red, curcumin can Lipitor, or a simple cup of tea could be the "miracle cure" be allowed to enter the brain. Also, curcumin has been which scientists and researchers dealing with Alzheimer's used as an antioxidant food preservative and as an anti- disease have been searching for. The medication you take inflammatory extract in traditional Indian medicine. As a to reduce inflammation and lower your cholesterol, the result, the researchers believe that curcumin m a y combat cup of tea you drink at the local coffee shop, and even both the oxidative d a m a g e and inflammation associated the chicken curry that you eat for supper could be the with Alzheimer's disease (Yang et al., 2005). answer to the prayers of so m a n y individuals affected by Through in vitro tests, the researchers at the UniversityAlzheimer's disease around the world. EJ of California have shown that curcumin inhibits the formation of amyloid-beta fibrils. In addition, researchers have found that w h e n curcumin is injected into the bloodstream or fed to a mouse, the curcumin crosses over into the mouse's brain and binds to amyloid-beta42 (Yang et al., 2005). Moreover, w h e n curcumin was added to the diet of an aged mouse, the amyloid-beta42 plaques in the

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April 2005 | Issue 6

Hepatocellular Carcinoma

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A n d r e w Heikkila Hepatocellular carcinoma (HCC), is one of the world's most c o m m o n and deadly cancers, and is the most frequently observed solid tumour of the liver (Franca et al., 2004). Its aggressive nature and ability to metastasize leads to a poor patient prognosis. H C C accounts for nearly one million annual deaths globally, and has shown an increased incidence in North America over the past decade. The five-year survival rate for untreated patients is less than five percent (Bosch et al., 1999). A brief exploration of the etiology, structural and functional alterations of the liver, and treatment options currently in trial will permit an improved understanding of this ubiquitous illness. ETIOLOGY

presence of cirrhosis, H C C develops a m o n g young patients because hepatitis B virus infection usually occurs early in life. The prolonged time frame provided for the infection to disseminate eventually provides an environment conducive to the establishment of liver tumours. In the Western World, infection with the hepatitis C virus acts as a major causative agent for H C C development (Gross, 1998).

A BRIEF INTERLUDE Cancer results when genes that control the cell cycle mutate. This alteration in D N A m a y cause the entire cell to lose control of its reproduction cycle, and a substantial increase in the ability to grow and reproduce ensues (Arcturus, 2004). A cell with one mutation has a greater probability of undergoing a further mutation, and so a cycle is initiated which culminates in a complete loss of mitotic control (Arcturus, 2004). Angiogenesis is a characteristic of m a n y tumours, permitting a sustained supply of nutrients and oxygen (Fuchs & Pritchard, 2002). Angiogenic growth factors are similar to those present in embryonic development, w o u n d healing, and normal tissue growth (Vascular Endothelial in Growth Factor, 2000). This process of blood vessel development and proliferation aids in the metastasizing of the primary tumour. In HCC, the main sites of metastases include the lungs, bones, and adrenal glands (Franca et al., 2004).

Cirrhosis is considered the most central risk factor predicting this cancer. Found in approximately 8 0 % of all cases, cirrhosis involves the replacement of hepatocytes (functional cells of the liver cells) with fibrous tissue and disruption of normal blood flow throughout the liver (Ulmer, 2000). Identification and subsequent follow up of cirrhosis is often required to diagnose the presence of a tumour. Alcohol consumption is a well-known causative CHANGES TO THE ORGAN AND ORGANISM factor of cirrhosis. Although a direct carcinogenic link between alcohol and the liver has yet to be elucidated, there Patients with HCC typically display symptoms of right is increasing evidence to support the correlation (Franca quadrant pain, weight loss, and general weakness (Franca et al., 2004). Males, w h o are heavier consumers of alcohol et al., 2004). However, H C C is often tested for in any patient than w o m e n , are eight times more likely to develop H C C with chronic liver disease, permitting the early initiation of than females in regions of the world where there is a high treatment if a tumour is located. Other patients are not prevalence of the cancer (MD Consult, 2004). In addition diagnosed until the tumour is well advanced and exceeds to alcohol, certain plants, synthetic pharmaceutical agents, a diameter of 10 c m (Ulmer, 2000). Acute abdominal pain and industrial pollutants have demonstrated causative and intra-abdominal bleeding resulting from rupture of the capacities for H C C in animal models and h u m a n studies. liver tumour are scenarios which also favor the diagnosis Aflatoxin B and vinyl chloride have received attention as of H C C (Befeler & Di Biscelgie, 2002). two of the most prevalent industrial carcinogens (Akriviadis The liver consists of two large lobes. Each lobe is etal., 1998). composed of m a ny lobules, considered the functional In African and South Asian nations, hepatitis B is the units of the liver (Tortora & Grabowski, 2003). Each lobule primary cause of H C C (Franca et al., 2004). Regardless of the consists of numerous hepatocytes which branch in an

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Issue 6 | 2005 April irregular and interconnected fashion around a large central vein.The liver receives blood from two sources.The Hepatic portal vein first, the hepatic artery, presents the liver with oxygenated blood, while the second, the hepatic portal vein, brings nutrient-rich deoxygenated blood. This blood drains into the liver sinusoids, then the central vein, hepatic vein, and finally into the right atrium of the heart via the inferior vena cava. A m o n g the many functions of the liver, the production of bile is fundamental.This yellow-green liquid Left hepatic duct is required for lipid emulsification and absorption in the C o m m o n hepatic duct small intestine (Tortora & Grabowski, 2003). HCC affects the structural appearance and functional Falcifoi capabilities of the liver. The growing tumour takes on ligament Ligamentum teres a histology characterized by alterations to trabecular structures. The trabeculae become encased in an endothelial lining and are separated from other trabeculae Figure 1: Anatomical illustration of the posterior aspect of the liver. by sinusoid-like channels (Mitros, 2004). Bile, carbohydrate, lipid, and protein metabolism are all affected by the presence of a tumour. The ability to adequately process Helicoidal computed tomography (HCT) is a sensitive and detoxify drugs may be jeopardized, depending on diagnostic tool often used following the detection of the size and location of the tumour (Tortora & Grabowski, HCC by ultrasound (Franca et al., 2004). Combining H C T 2003). A deficiency in the coagulation factors produced in images with intravenous contrast provides a greater the liver suggests a generally limited synthetic capacity of level of sensitivity w h e n identifying individuals with the organ, and may limit the ability of the blood to clot HCC. The accuracy of computed tomography permits following injury (Hepatocellular Carcinoma Diagnosis and the identification of metastasized tumour in both lymph Management, 2004). Patients with HCC typically have nodes and the vascular system, providing a more holistic elevated levels of alkaline phosphatase, indicative of picture of the illness (Franca et al., 2004). biliary obstruction (Hepatocellular Carcinoma Diagnosis Histopathological measurements are presently the and Management, 2004). Massive lesions or enlargements most accurate means of diagnosing H C C (Ebara et al., 1989). in the liver, as well as the circulation of free fluid around the Fine needle aspirative biopsy is a c o m m o n procedure used organ, are further H C C characteristics that impact normal tocollectliversamplesforhistolopathology.Thistechnique functioning. alone has demonstrated specificity between 90 and 100%, and through combinations with the aforementioned diagnostic tools, the accuracy of H C C diagnosis will be STAGING AND DIAGNOSIS undoubtedly enhanced (Ebara et al., 1989). The diagnosis, staging, and treatment of HCC are three The staging of H C C is a complex procedure. Numerous factors which are intimately linked. Treatment is effective classification systems are in place to stage the disease and to subsequently determine the prognosis. These only if it is received at a specific developmental stage. Ultrasound is the superior technique for diagnosing classification systems, including those of the Barcelona focal hepatic lesions; it allows physicians to identify Clinic Liver Cancer (BCLC) Group (Llovet et al., 1999) and the tumours in early stages (Ebara et al., 1989). Nodule Cancer of the Liver Italian Program, consider the degree of size is the primary H C C characteristic which accounts hepatocellular dysfunction, often considered the primary for differential ultrasonographic images. Ultrasound prognostic variable (Franca et al., 2004). sensitivity is approximately 4 0 % for tumours less than one centimeter in diameter. Tumours of greater size have values which exceed 9 5 % (Bizollon et al., 1998). These sensitivity values increase w h e n ultrasound is used in conjunction with Doppler, which measures the flow rate of blood. This combination permits the identification of tumour thrombosis and the presence of hepatofugal pulsatile flow and intratumoural necrosis (Tanaka et al., 1993).

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TREATMENT AND PREVENTION Many cancer treatments are invasive and lengthy, and thus significantly impact the quality of life of patients. Chemoembolization and complete liver transplantation are two c o m m o n treatment options for patients with HCC.

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April 2005 | Issue 6 Chemoembolization relies on the knowledge that most H C C tumours receive nutrients from the liver's arterial system (Franca et al., 2004). Thus, blocking the hepatic artery is a definitive m o d e of treatment which has demonstrated great promise. As a non-surgical technique, chemoembolization utilizes interventional radiology to occlude the hepatic artery following identification with fluoroscopy (Befeler & Di Biscelgie, 2002). This technique effectively causes ischemic necrosis of approximately 8 0 % of tumours, while leaving viable the unaffected hepatocytes and cells of the portal vein (Franca et al., 2004). Because of the specificity of this procedure, there is a realistic potential that high doses of chemotherapeutic agents m a y be delivered to the tumour with the result of high extraction rates following only one round of administration (Befeler & Di Biscelgie, 2002). The only clear limitation of this approach is that the blocking and chemotherapeutic agents must be re-administered every few months to maintain adequate functional levels in the liver. W h e n the affected liver has lost function and can no longer be treated by surgical resection, total liver transplantation is the recommended treatment for patients with H C C (Befeler & Di Biscelgie, 2002). Cases in which there is a small, single tumour, free of distant metastases and vascular invasion often have very encouraging prognoses following liver transplantation. Since the entire liver is replaced, any primary liver diseases are effectively removed along with the neoplasia. The limitation of this

method lies in the extremely low number of liver donors (Bruix & Llovet, 2002). This creates a cascade effect which increases both the time on waiting lists and the monetary cost of the procedure to patients (Franca et al., 2004).

CONCLUSION Preventing or modifying the risk factors associated with H C C is a critically important, yet often overlooked, means of decreasing the incidence of this cancer. The dissemination of information concerning lifestyle choices enables individuals to m a k e healthier decisions in their daily lives (MD Consult, 2004). Tobacco and alcohol use have demonstrated a correlation with the presence of cirrhosis, and cirrhosis itself is the primary risk factor for the development of H C C ( M D Consult, 2004). Drug abuse, an activity which substantially increases the risk of hepatitis B and C exposure, is a further lifestyle choice which can influence the presence of HCC. Furthermore, environmental carcinogenic agents should be avoided, participation in vaccination programs for hepatitis should be practiced, and screening programs should be attended by individuals w h o are aware of a family history of liver disease ( M D Consult, 2004). M

Congenital Insensitivity to Pain with Anhidrosis (CIPA) of an individual. However, pain is a complex perception that differs enormously amongst individuals (Tortora and Grabowski, 2003).

PAIN, NOCICEPTION AND

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The perception of pain, referred to as nociception, depends on receptors and pathways that are specific to this sensation. Pain sensation begins in response to the stimulation of relatively unspecialized nerve cell endings t is very easy to recognize. It is known all over the world called nociceptors (Tortora and Grabowski, 2003). Once and it breaks all language barriers. It is referred to as nociceptors are stimulated, they convert a variety of stimuli pain. This unpleasant experience notifies an individual into action potentials. They are then carried by nerve fibres that something is wrong in the body and needs to be to the spinal cord and the brain, where the nerve impulse is corrected. It also serves a protective function by signalling interpreted as pain (Tortora and Grabowski, 2003 & Purves the presence of harmful agents that m a y d a m a g e the body etal., 2001). Abdullah Alabousi

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Issue 6 | 2005 April Unfortunately, there are only a few individuals in the world w h o are born with a disease that renders them S P unable to feel pain. This disease is known as Congenital CC-1 LRMs Insensitivity to Pain with Anhidrosis, or CIPA (Theodorou CC-2 et al., 2000). CIPA is extremely rare and there is currently no data available as to the prevalence and incidence of this disease. lg-2 CIPA is an autosomal-recessive disorder characterized ffiWjTO, by recurrent episodic fevers, anhidrosis (inability to sweat), and absence of reaction to noxious or painful stimuli (Indo, 2002 & G u o et al., 2004). People with congenital insensitivity to pain go through life in danger of destroying their bodies because they do not realize the harm they are doing to themselves. The main features of the disorder include lack of pain Figure 1: The binding of N G F to the TRKA protein, leads to its autophosphorylation, which is essential for intracellular signal sensation, painless injuries of oral structures, fever during transduction (Indo, 2002). hot weather due to anhidrosis, mental retardation, as well as infection and scarring of the tongue, lips and g u m s (Theodorou et al., 2000). The lack of pain sensations in mutation that causes CIPA (Melamed et al., 2004, Indo, CIPA is due to the absence of unmyelinated fibres and 2002, Rozentsveig et al., 2004, Sato et al., 2004, Mardy et reduced numbers of small myelinated afferent fibres al., 1999 & G u o et al., 2004).The mutation of theTRKA gene that carry impulses to the spinal cord once they are leads to the production of defective TRKA proteins. This, in activated by tissue-damaging stimuli (Rosemberg et al., turn, causes abnormalities in the N G F signal transduction 1994). Anhidrosis, on the other hand, is due to a loss of pathway and various N G F dependent neurons are not innervation of eccrine sweat glands, which are distributed maintained, mainly due to apoptosis during development throughout the skin and are responsible for the regulation (Indo, 2002 and Melamed et al., 2004). 37 different TRKA of body temperature through sweat production (Indo, mutations have so far been identified in CIPA patients. These mutations include nine frameshift, seven nonsense, 2002;Tortora & Grabowski, 2003). seven splice, and 14 missense mutations (Indo, 2001).

NGF AND TRKA MUTATIONS: WHAT'S NEXT? In normal individuals, Nerve Growth Factor (NGF) stimulates the growth and supports the survival of autonomic sympathetic neurons as well as nociceptive sensory neurons, which transmit pain sensations to the spinal cord and the brain (Alberts et al., 2002). N G F consists of three types of polypeptide chains; alpha, beta and g a m m a , which interact to form the protein. The N G F beta chain is the one responsible for the nerve growth stimulating activity of N G F (Petruska and Mendell, 2004). NGF functions as a survival signal and acts by suppressing programmed cell death, apoptosis (Yuan and Yankner, 2000). The TRKA protein is a receptor tyrosine kinase (RTK), which has high affinity for N G F and phosphorylates itself in response to it (Figure 1). The autophosphorylation of TRKA activates various pathways of intracellular signal transduction that bring about support for the survival of nociceptive neurons (Indo, 2001). Not being able to transduce N G F into developing sympathetic and sensory neurons leads to the death of this class of neurons. Recent studies point to the TRKA gene as the site of the www.meducator.org

At this point in time there is no treatment available for CIPA patients but there is supportive therapy. Supportive therapy could include organizations that are dedicated to educating people about CIPA, as well as support groups for individuals w h o have to deal with the disease. From a clinical standpoint, CIPA is a serious illness that is very difficultto diagnose due to variable presentation in different patients and the lack of simple diagnostic tests to detect it (Rosemberg et al., 1994). However, a recent strategy has been developed that enables healthcare professionals to screen forTRKA mutations.This development should aid in the diagnosis and genetic counselling of this painless but severe genetic disorder with devastating complications (Indo, 2002). Also, understanding the molecular pathology of CIPA would provide unique opportunities to explore the critical role of the peripheral sensory nervous system, which transmits information about noxious stimuli for pain in h u m a n s (Indo, 2002). EQ

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April 2005 | Issue 6

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S a m m y H. Ali - Vioxx: What Went Wrong?

Conference to explore lessons learned from peace through health (2005, March 24). Bombardier C, Laine F, Reicin A, et al. Comparison of upper gastrointestinal t Retrieved March 24, 2005 from http://dailynews.mcmaster.ca/story. coxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; cfm?id=3241# 343:1520 8. HOPE and HOPE-TOO Trial Investigators (2005). Effects of Long-term Vitamin E Supple Clark, D. Layton, L. & Shakir, SA. (2004) Do Some Inhibitors of COX-2 Increase mentation on Cardiovascular Events and Cancer: A Randomized Controlled the Risk ofThromboembolic Events? Linking Pharmacology with Pharmaco Trial. JAMA 2005 293: 1 338-1 347 epidemiology. Drug Safety; 27(7): 427-456 McMaster-Lancet Challenge Conference (2005). Retrieved March 25, 2005 from Hunder, GG. (1999). Mayo Clinic on arthritis. Rochester, Minn: Mayo Clinic. http://www.humanities.mcmaster.ca/peace-health/Conf2005/Conf-2005. Kremer J. From prostaglandin replacement to specific COX-2 inhibition. A critical ap htm praisal. J Rheumatol 2000; 27 (Suppl. 60): 9 12 No benefit with vitamin E in preventing cancer, heart attacks, stroke or death: Pairet, M. & van Ryn, J. COX-2 Inhibitors. Birkhauser: Switzerland 2004 McMaster study (2005, March 15). Retrieved March 24, 2005, from http:// Public Health Agency of Canada (PHAC). (2003). Arthritis in Canada: an ongo dailynews.mcmaster.ca/story.cfm?id-3215 ing challenge, http://www.phac-aspc.gc.ca Peace Through Health (2005). Retrieved March 24, 2005 from http://www.humanities. Smith, W L DeWitt, D L & Garavito RM. (2000) Cyclooxygenases: Structural, Cellular, and mcmaster.ca/peace-health/ Molecular Biology Annu. Rev. Biochem.; 69:145-82

Danny Ricci - Drugs, Tea and Curry: The Means to Finding a Cure for Alzheimer's

Disease? McGuinty Government Increasing Number of Family Physicians (2005, March 11). Retrieved March 25, 2005, from http://www.health.gov.on.ca/english/me Cordle, A. & Landreth, G. (2005). 3-Hydroxy-3-Methylglutaryi-Coenzyme A Reducta dia/news_releases/archives/nr_05/nr_031105.htm Inhibitors Attenuate Amyloid-Induced Microglial Inflammatory Responses. McMaster School of Biomedical Engineering (2005). Retrieved March 25, 2005, from Journal of Neuroscience, 25(2), 299-307. http://msbe.mcmaster.ca/school/index.html Dodart, J.C, Marr, R.A., Koistinaho, M., Gregersen, B.M., Malkani, S„ Verma, I.M., & Paul, S.M. McMaster University to produce more family physicians (2005, March 11). Retrieved (2005). Gene delivery of human apolipoprotein E alters brain amyloid-beta March 25, 2005, from http://www.fhs.mcmaster.ca/pubrel/famphysicians. burden in a mouse model of Alzheimer's disease. Proceedings of the Na htm

tional Academy of Sciences of the United States of America, 102(4), 1211-1216. Retrieved March 2, 2005, from www.pnas.org_cgi_doi_1 0.1073_ pnas.0409072102. Gong, B., Vitolo, O.V.,Trinchese, F, Liu, S., Shelanski, M., & Arancio, O. (2004). Persistent Waqas Kayani - Remyelinating Damaged Nerves improvement in synaptic and cognitive functions in an Alzheimer mouse Akiyama, Y., Radtke, C, & Kocsis, J. (2002a). Remyelination of the rat spinal cord by model trans after rolipram treatment. Journal of Clinical Investigation, 114(11), 1624-1634. plantation of identified bone marrow stromal cells. Journal of Lleo, A., Berezovska, O., Herl, L., Raju, S., Deng, A., Bacskai, B.J., Frosch, M.P., Irizarry, M., & Neuroscience, 22 (15), 6623-6630 Hyman, B.T. (2004). Nonsteroidal anti-inflammatory drugs lower A-Beta42 Akiyama, Y., Radtke, C, Honmou, O., & Kocsis, J. (2002b). Remyelination of the spinal and change presenilin 1 conformation. Nature Medicine, 10(10), 1065-1066. cord following intravenous delivery of bone marrow cells. GLIA, 39 (3), 229Okello, E.J., Savelev, S.U., & Perry, E.K. (2004). In vitro Anti- beta-secretase and Dual Anti 236 cholinesterase Activities of Camellia sinensis L. (tea) Relevant to Treatment of Blakemore, W., Smith, P., & Franklin, R. (2000). Remyelinating the demyelinated CNS. Dementia. Phytotherapy Research, 18,624-627. Neural Transplantation in Neurodegenerative Disease: Curre-nt Status and Hutter-Paier.B., Huttunen H.J., Puglielli, L, Eckman, C.8., Kim, D.Y., Hofmeister, A., Moir, R.D., New Directions Novartis Foundation Symposium, 231, 289-298 Domnitz, S.B., Frosch, M.P., Windisch.M., & Kovacs, D.M. (2004). The ACAT In Carlson, N. (2004). Physiology of Behavior. Boston: Pearson. hibitor CP-113,818 Markedly Reduces Amyloid Pathology in a Mouse Model Minodora, T, Nistor, G., Lane.T., Keirstead, H.(2004). Remyelination, axonal of Alzheimer's Disease. Neuron, 44, 3227-238. sparing, and locomotor recovery following transplantation of glial-com Kolb, B., & Whishaw, I.Q. (2001). An Introduction to Brain and Behavior. N e w York: Worth. mitted progenitor cells into the M H V model of multiple sclerosis. Experi Pedrini, S., Carter, T.L., Prendergast, G., Petanceska, S., & Ehrlich, M.E. (2005). H o w Statins mental Neurology, 187, 254-265 Wu, 5., Suzuki, Y„ Kitada, H., Kataoka, H., Kitaura, M., Chou, H., Nishimura, Y., & Ide, C May Protect against Alzheimer Disease. Public Library of Science Medicine, (2002). N e w method for transplantation of neurosphere cells into injured 2(1), 0004. spinal cord through cerebrospinal fluid in rat. Neuroscience Letters, 318, Petkova, AT., Leapman, R.D., Guo, Z, Yau, W.M., Mattson, M.P., & Tycko, R. (2005). Self81-84 Propagating, Molecular-Level Polymorphism in Alzheimer's Beta-Amyloid Fibrils. Science, 307, 262-265. Shama Sud - Big Pharma: In Whose Best Interest? Rovner, S.L (2005). UNTANGLING ALZHEIMER'S: From tea to statins, familiar products re veal the mechanisms behind this complex disease and inspire new ways to Beller, G. A. (2005). Lessons to be learned from the Vioxx debacle [Electronic Version]. treat it. Chemistry and Engineering News, 83(8), 38-45. Retrieved Journal of Nuclear Cardiology, 12,1-2. February 23, 2005 from: http://pubs.acs.org/cen/coverstory/83/308alzheimer. CBC Health and Science News. (2005). Study linking Vioxx to heart problems finally html. published. Retrieved February 24, 2005 from http://www.cbc.ca/story/sci Tortora, G.J., & Grabowski, S.R. (2003). Principles of Anatomy and Physiology (10th ed.). ence/national/2005/01/25/vioxx-050125.html Hoboken: John Wiley & Sons, Incorporated. CBC Health and Science News. (2004). Vioxx case shows need for tougher drug testing: Yang, F., Lim, G.P., Begum, A.N., Ubeda, O.J., Simmons, M.R., Ambegaokar, S.S., Chen, P., analysts. Retrieved February 25, 2005 from http://www.cbc.ca/story/sci Kayed, R., Glabe, C.G., Frautschy, S.A., & Cole, G.M. (2005). Curcumin Inhibits ence/national/2004/10/01/drug_testing041001 .html Formation of Amyloid-Beta Oligomers and Fibrils, Binds Plaques, and Reduces CBC News Online. (2004). Vioxx, Celebrex: concerns over popular arthritis drugs [Elec Amyloid in Vivo. Journal of Biological Chemistry, 280(7), 5892-5901. tronic Version]. Retrieved February 24, 2005 from http://www.cbc.ca/ news/background/drugs/COX-2.html Andrew Heikkila - Hepatocellular Carcinoma CNN Interactive. (1998). Study: drug reactions kill an estimated 100,000 a year. Re trieved March 20, 2005 from http://edition.cnn.com/HEALTH/9804/14/ Akriviadis, E.A., Llovet, J.M., & Efremidis, S.C. (1998). Hepatocellular carcino drug.reaction/ 85,1319-31. Garland, J. E. (2004). Facing the evidence: antidepressant treatment in children and Arcturus. (2004). Cancer progression and how normal cells develop into cancer. Retrieved adolescents [Electronic Version]. Canadian Medical Association Journal, November 22, 2004 from http://www.arctur.com/consumer_portal/cancer/ 170.489-491. cancer_progression.htm. McCoy, K. (2005). Drug complaints reach record high. Retrieved March 20, 2005 from Bagnato, A., & Natali, P.G. (2004). Endothelin receptors as novel targets in tumour therapy. http://www.usatoday.com/money/industries/health/drugs/2005-03-13JTranslMed, 2,16. fda-usat_x.htm Befeler, A.S., & Di Biscelgie, A.M. (2002). Hepatocellular carcinoma: diagnosis and treat Olive, D. (2005). Drug companies manufacture risk [Electronic Version). Retrieved ment. Gastroenterology, 122,1609-1619. February 24, 2005 from www.thestar.com/NASApp/cs/ Bizollon.T., Rode, A., Bancel, B., Gueripel, v., Ducerf, C, Bauliex, J., &Trepo, C. (1998) Diaq N e w biomedical engineering graduate program announced via webcast (2005, March 8). Retrieved March 25, 2005, from http://dailynews.mcmaster.ca/story. cfm?id=3194

ContentServer?pagename=thestar/Render&c=Page&cid=968867505381 Thalidomide Victims Association of Canada. (2003). What is Thalidomide? [Electronic Version] Retrieved February 24, 2005 from http://www.thalidomide.ca/en/ information/what is thalidomide.html

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nostic value and tolerance of lipiodol-computed tomography for the detection of small hepatocellular carcinoma: correlation with pathologic examination of explanted livers. Journal of Hepatology, 28, 491-496 Bosch, F.X., Ribes, J., & Borras, J. (1999). Epidemiology of primary liver cancer. Seminars in

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Issue 6 | 2005 April </)

Liver Disease, 19,271-285. Indo, Y. (2002). Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or heredi Bruix, J., & Llovet, J.M. (2002). Prognostic prediction and treatment strategy in hepatocel tary sensory and autonomic neuropathy type IV. Clin Auton Res., 12(s01). 120lular carcinoma. Hepatology, 35, 519-524. 132. Ebara, M., Ohto, M., & Kondo, F. (1989). Strategy for early diagnosis of hepatocellular card Mardy, S., Miura, Y., Endo, F, Matsuda, I., Sztriha, L, Frossard, P., Moosa, A., Ismail, E.A., noma (HCC). Annals of the Academy of Medicine, 18, 83-89. Macaya, A, Andria, G.r Toscano, E., Gibson, W., Graham, G.E., & Indo, Y. (1999). Franca, A.V.C., Elias, J., Lima, B.L.G., Martinelli, A.L.C., & Carrilho, FJ. (2004). Diagnosis, stag Congenital insensitivity to pain with anhidrosis: novel mutations in theTRKA ing and treatment of hepatocellular carcinoma. Braz J Med Biol Res, 37, 1689(NTRK1) gene encoding a high-affinity receptor for nerve growth factor. A m J 1705. H u m Genet., 64,1570-1579. Fuchs, B., & Pritchard, D. (2002). Etiology of Osteosarcoma. Clinical Orthopaedics and Melamed, I., Levy, J., Parvari, R., & Gelfand, E.W. (2004). A novel lymphocyte singnaling Related Research, 397, 40-52. defect: TRKA mutation in the syndrome of congenital insensitivity to pain and Gross, J.B. Jr. (1998). Clinician's guide to hepatitis C. Mayo Clin Proc, 73(4), 355-360. anhidrosis (CIPA). Journal of Clinical Immunology, 24, 441-448. M D Consult. (2004). Hepatocellular carcinoma diagnosis and management. Nolano, M., Crisci, C, Santoro, L„ Barbieri, F., Casale, R., Kennedy, W.R., Wendelschafer-rabb, Retrieved November 26, 2004 from http://home.mdconsult.com. G., Provitera, V., Di Lorenzo, N„ & Caruso, G. (2000). Absent innervation of skin Kaya, M., Wada, T, Akatsuka, T, et al. (2000). Vascular endothelial growth factor expression and sweat glands in congenital insensitivity to pain with anhidrosis. Clin in untreated osteosarcoma is predictive of pulmonary metastasis and poor Neurophysiol., 111, 1596-1601. prognosis. Clinical Cancer Research, 6, 572-577, Petruska, J.C., & Mendell, L.M. (2004). The many functions of nerve growth factor: multiple Llovet, J.M., Fuster, J., & Bruix, J. (1999). Intention-to-treat analysis of surgical treatment for actions on nociceptors. Neurosci Lett., 361,168-171. early hepatocellular carcinoma: resection versus transplantation. Hepatology, Purves, D., Fitzpatrick, D., Williams, S.M., McNamara, J.O., Augustine, G.J., Katz, L.C., & Le 30, 1434-1440. Mantia, A.S. (2001). Neuroscience. (2nd Ed.). United States: Sinauer Associates, Mitros, F.A. (2004). Benign tumours and tumour-like conditions of liver. Retrieved Novem Inc. ber 22, 2004 from http://www.med.uottawa.ca/patho/gastro/giweek4notes. Rosemberg, S., Nagahashi, M.S.K., & Kliemann, S. (1994). Congenital insensitivity to pain htm. with anhidrosis (hereditary sensory and autonomic neuropathy type IV). Ortega, N„ Hutchings, H., & Plouet, J. (1999). Signal relays in the VEGF system. Frontiers in Pediatr. Neurol., 11,50-56. Bioscience, 4, 141-152. Rozentsveig, V., Katz, A., Weksler, N., Schwartz, A., Schilly, M„ Klein, M., & Gurman, G.M. Tanaka, K„ Numata, K„ Okazaki, H„ Nakamura, S., Inoue, S., &Takamura, Y. (1993). (2004). The anaesthetic management of patients with congenital insensitivity Diagnosis of portal vein thrombosis in patients with hepatocellular to pain with anhidrosis. Paediatr. Anaesth., 14, 344-348. carcinoma: efficacy of color Doppler sonography compared with Sato, Y., Tsuboi, Y., Kurosawa, H., Sugita, K„ & Eguchi, M. (2004). Anti-apoptotic effect of angiography. American Journal of Roentgenology, 160, 1279-1283. nerve growth factor is lost in congenital insensitivity to pain with anhidrosis ^^ Tortora, G. J. & Grabowski, S. R. (2003). Principles of anatomy and physiology. (10th ed.) (CIPA) B lymphocytes. J Clin Immunol., 24, 302-308. N e w York: John Wiley & Sons Inc. Theodorou, S.D., Klimentopoulou, A.E., & Papalouka, E. (2000). Congenital insensitivity to Ulmer, S.C. (2000). Hepatocellular carcinoma: a concise guide to its status and manage pain with anhidrosis. Report of a case and review of the literature. Actarthop ment. Postgraduate medicine, 107, 117-124. Belg.,66, 137-145. R&D Systems 2000 Catalogue. (2000). Vascular endothelial growth factor (VEGF). Re Tortora, G„ & Grabowski, S.J. (2003). Principles of Anatomy and Physiology. (10th Ed.). N e w C trieved November 28 from http://www.sghms.ac.uk/depts/histopathology/ Jersey: John Wiley and Sons Ltd. lnvasion-Metastasis.html. Yuan, J., & Yankner, B.A. (2000). Apoptosis in the nervous system. Nature, 407, 802-809

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Abdullah Alabousi - Congenital Insensitivity to Pain with Anhidrosis (CIPA) Guo.Y.C, Liao, K.K., Soong, B.W,Tsai, C.P., Niu, D.M., Lee, H.Y., & Lin, K.P. (2004). Congenital insensitivity to pain with anhidrosis in Taiwan: a morphometric and genetic study. Eur Neurol., 51,206-214. Indo, Y. (2001). Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. H u m Mutat., 18, 462-471.

The McMaster Meducator Executive 2005

Top R o w (Left to Right): Jonathan Liu, Brent Mollon, Anthony Collini, Amandeep Rai, S a m m y H. Ali, Edwin C.W. Ho Bottom Row: Jeannette So, Shama Sud, Jennifer Clara Tang, Jaron Chong, Katherine Saccucci

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