Issue 8

McMWER McMaster's Medical Research and Health Ethics Student Journal

Functional Electrical Stimulation

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Occupational HIV Exposure 'V

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Brain Development Historical & Current Trends in Neuroscience ssue8| March 2006

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Issue 8 I March 2006

7 : Inside Scoop Bariatric Basics Page 6

Presidential Address Jaron Chong

Med Bulletin Med QUIZ

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Research Articles

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Bariatric Basics

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Trends, Guidelines, Solutions, and Attitudes Navneet Singh

The Use of Postexposure Prophylaxis For Occupational HIV Exposure John Snelgrove

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Brain Development in Neuroscience A Brief Look at its Beginnings and the Current Trends Ronald Zahoruk

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Occupational HIV Exposure Page 10

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Brain Development Page 13

Functional Electical Stimulation Page 17

Functional Electrical Stimulation (FES) An Alternative Rehabilitative Option for Individuals with Spinal Cord Injuries Michelle W o n g

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G a m m a Knife Page 19

The Gamma KnifeÂŽ Stereotactic Radiosurgery as an Alternative Surgical Means Sarah Mullen

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The Face of Autism Sophie Kuziora

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About The McMaster Meducator The McMaster Meducator adopts an educational approach to our publication. Despite our efforts to ensure correctness, w e recognize that the publication m a y b e subject to errors and omissions. In light of these potential errors and n e w developments in the medical field, w e invite you to partake in feedback and constructive discussion of the content herein for the purpose of furthering your understanding of the topic - in the n a m e of education and discovery. For m o r e information and updates on the latest medical research and health ethics issues, visit www.meducator.org. Students and professors alike are welcome. Please enjoy the Meducator online experience!

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Issue 8 March 2006

M^EDUEMDli Meducator Staff

Dear Reader,

President Jaron Chong Diversity is the spice of life. This issue has it all from the smallest HIV virion to the largest Vice-President gamma-ray operated surgical tool. Navneet Singh presents an interesting look at Brent Mollon Bariatric surgery and startling n e w findings regarding the significance of Body Mass Index (BMI). John Snelgroveexaminestheimplicationsand possible treatments of occupational Creative Director exposure to HIV. Ronald Zahoruk gives us a general history of neuroscience from its earliest Anthony Collini beginning. Sarah Mullen covers the G a m m a Knife9, an exciting n e w tool in neurosurgery. Sophie Kuziora presents VP Medical Research an introduction to childhood autism covering its diagnosis and Health Ethics and treatment. Finally, Michelle W o n g discusses the Jonathan Liu Jeannette So promising technology of Functional Electrical Stimulation Shama Sud in the context of rehabilitation science. Whether you're interested in the latest technology or the earliest medical history, you'll be sure to find something that piques your VP Public Relations Amandeep Rai interest in Meducator Issue 8.

VP Web Design Diversity plays a role again in the organization necessary to Fify Soeyonggo put together an issue of the Meducator. The collaboration \ of post-graduate editors, sponsors, writers, and last but VP Adminstration 1| certainly not least, staff members is what makes every issue Sarah Mullen \:, possible. First and foremost, I would like to thank our postJunior Executives al graduate editors, w h o have taken time out of their busy Harjot Atwal schedules to provide our writers with valuable insight and Crystal Chung feedback. Over the years, the Meducator has had constant Tyler Law and exceedingly generous support from Dr. Del Harnish and the Bachelor of Health Sciences Joshua Ng Program. It is the writers that provide the founding material of any publication and all of their hard work and efforts are presented here today. Coming up on nearly three years, I have had the distinct honour of working with the finest Executive Staff assembled: Brent Mollon, VicePost Graduate President, for your leadership and sharp editorial eye. Jeannette So, Shama Sud, and Jonathan Editors Liu, VP's of Medical Research & Health Ethics, for all of your exemplary work with post-grad editors, writers, and articles alike. Anthony Collini, Creative Director, for your visual talent, Dr. Anita Berndt, PhD organizational skills, and keen sense of aesthetics. A m a n d e e p Rai, VP of Public Relations, for your witty ads and boundless knowledge of M U S C intricacies. Fify Soeyonggo, VP of W e b Dr. Dale Guenter, BSc, MD, M P H Design, for your site updates and w e b savvy. Sarah Mullen, VP Admin, for keeping the team well organized and running smoothly. Finally, and most importantly, to the future of the Dr. Anthony Kaufmann, Meducator: Harjot Atwal, Crystal Chung, Tyler Law, and Joshua Ng. I a m reassured in knowing MD, MSc, FRCSC that the Meducator has such incredibly multi-talented and promising young executives.

Dr. Kathryn Murphy, On behalf of all of the writers and staff, we hope you enjoy this issue of the McMaster PhD Meducator.

Dr. Kesava Reddy, MD, FRCPC Yours Truly, Dr. Arya Sharma, MD, PhD Dr. Adam Thrasher, PhD Jaron Chong Dr. Lonnie Zwaigenbaum, MD, MScTRCPC www.meducator.org

Issue 8 | March 2006

Education and Treatment Needed for More Progress Against the Med Bulletin by Joshua Ng HIV/AIDS Epidemic _ _ — — — UNAIDS and the WHO released their annual report on HIV/AIDS, entitled AIDS Epidemic Update 2005, early last week. The findings of this report show promising progress in selected countries afflicted by AIDS.The most welcomed findings include a general decline in adult AIDS prevalence in pregnant w o m e n in Zimbabwe and Burkina Faso.The study suggested that these declines were in large part due to increased availability of treatment for the virus, and ameliorated sexual behavioural patterns, including increased condom use, fewer sexual partners, and the occurrence of a first sexual experience later in life. Increased accessibility to antiretroviral treatments for the virus is said to have saved upwards of 350 000 lives within the past year.

However, despite the encouraging news, the AIDS epidemic continues to expand with 5 million new infections occurring within the last year. 3 million deaths, including about 500 000 deaths in children, occurred during 2005. A relatively n e w geographical area at high risk is Central Asia, which experienced a 2 5 % increase in cases over the calendar year. In order to strengthen the preventative measures being used by the W H O and UNAIDS, the report suggests the implementation of further educational programs, prevention of mother-to-child transmission during pregnancy, and programs fighting the spread of the virus through sex work and intravenous drug use.

Original Summary by http://www.who.int/mediacentre/news/releases/2005/unaids_who/en/index.html Photo by Joshua Ng

Viruses: A N e w Factor in Obesity M e d Bulletin by Crystal Chung Obesity has compelled people to blame fast food industries and junk food companies for the increasing weight of the population; but could obesity be caused by something uncontrollable and unavoidable?

According to physiologist Leah Whigham, certain strains of adenovirus (specifically Ad-2, Ad-31, and Ad-37) can increase the amount of fat the h u m a n body stores. In other words, those with the virus m a y be more prone to obesity than those without it! Whigham and her team of scientists tested the h u m a n adenoviruses on young male chickens. Each chicken consumed the same amount of food and lived in the exact same conditions. After just three and a half weeks, the chickens with virus strains gained three times the amount of fat in their gut and twice as m u c h body fat compared to chickens without the virus.

Photo by Joshua Ng

For a closer relationship to humans, Whigham's 2002 study, Human Adenovirus Ad-36 Promotes Weight Gain in Male Rhesus and Marmoset Monkeys, shows the same results: monkeys gained weight w h e n they started to produce antibodies to the virus (indicating that the virus was present). However, it is interesting to note that the cholesterol of the infected monkeys dropped at the same time.

Although this virus is not the root cause of obesity, many questions arise. For example, can we create a vaccine to preven obesity due to the virus?The answer is still unclear, but research is on its way to figuring out the mechanisms of the virus. S o m e m a y be concerned that it is contagious, but even that is yet to be determined.

Original Summary from Dhurandhar, N., Whigham, L, Abbott, D., Schultz-Darken, N., Israel, B., Bradley S., Kemnitz, J., Allison,D., Atkinson, R. (20 Ad-36 Promotes Weight Gain in Male Rhesus and Marmoset Monkeys. American Society for Nutritional Sciences,~ I32(10),~3155-3160.

Article: Study Strengthens Link between Virus and Weight Gain, January 30,2006 summarized from Scientific American

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Issue 8 I March 2006

3-D Image of HIV Possible With Cryo-Electron Tomography

WEDUCLJOII

M e d Bulletin by Tyler Law

A team of scientists have produced a 3-D image of HIV's viral structure.

The team - consisting of m e m b e r s from the U K and Germany - produced the image by compositing a series of computer images of different viral specimens at different angles.They took images from 70 individual HIV viruses and used the similarities to create the 3-D structural image. This method, called cryo-electron tomography, produces an image of the virus core "with unprecedented clarity".

Previously, HIV had proved difficult to image partly because of its small size.

Providing a structural image of a virus can be instrumental in understanding h o w it causes illness. The images provided a clear look at both the viral m e m b r a n e and the conical core.They show that the core growth begins at the narrow end of the cone, and grows until it reaches the opposite membrane.

Photo by Harjot Atwal

The images helped answer questions regarding h o w the core develops within the membrane, since it allows the core to be viewed along with the m e m b r a n e three dimensionally. This was previously not possible because of conventional preparation techniques. However, this imaging process provided valuable insight into the viral maturation process. Full understanding of virus structure and processes can ultimately be used to develop treatments.

Original Summary by http://science.slashdot.org/science/06/01/24/2254227.shtml Briggs etal. "The Mechanism of HIV-1 Core Assembly: Insights from Three-Dimensional Reconstructions of Authentic Virions." Structure (2006). http://news.bbc.co.Uk/l/hi/health/4642940.stm

Sperm Cells Speed Up M e d Bulletin by Harjot Atwal According to research recently published in Nature, scientists believe they have found the reason for the rapid progress of sperm through the female reproductive system to the egg. The answer lies in a change in the motion of the sperm cell's tail.

Isolated samples of sperm taken directly from males show that the tail naturally moves in a fluid, steady wave. However, upon entering female genitalia, this oscillation shifts to a m u c h higher frequency allowing the sperm to penetrate more effectively towards the egg.

This process, known as hyperactivation, is said to be caused by the alkaline environment in the female reproductive tract. Scientists applied the technique of patch clamp recording, previously unused on sperm, to determine the electrical flow found in the cells.The results showed high electrical activity and have linked a protein called CatSperl, found in the tail, as having increased the flow of calcium ions through the cell. This reaction seems to give the energy needed to reach hyperactivation.

Photo by Tyler Law

In helping scientists to better understand how fertilization occurs, this new information could lead to the development of methods of contraception. It is very possible that pills could be ingested by either males or females that would inhibit CatSperl and stop hyperactivation. Alternatively, this knowledge could also help those couples that have greater problems conceiving children. The researchers believe, in m a n y cases, the difficulty lies with a deficiency of CatSperl in the male partner's sperm cells which could be solved with the right treatment. However, the scientists stress that although this is a great leap forward, there is still m u c h more to be learned before m a n y of the practical applications can be put to use.

Original Summary from http-//news.bbc.co.uk/2/hi/health/4696994.stm

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Issue 8 I March 2006

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Bariatric Basics Trends, Guidelines, Solutions, and Attitudes

Navneet Singh Bariatrics (from the Greek word baros, meaning weight) is an emerging term to describe the field of medicine that addresses medical problems associated with morbid obesity (Deitel & Melissas, 2005; Sharma, 2005). The term bariatrics applies to a morbidly-obese population in the same way geriatrics applies to an elderly population (Sharma, 2005).

Obesity (Body-Mass Index [BMI] >30kg/m 2 ) and morbid obesity (BMI >40kg/m 2 ) affect over 300 million persons worldwide (Padwal & Lewanczuk, 2005). Recent surveys conducted have indicated that the prevalence of obesity continues to rise in Canadian adults (Katzmarzyk, 2002).

BODY-WEIGHT CLASSIFICATION GUIDELINES

has a high or low BMI value is outside the healthy range.

First, elderly persons (aged 65 years or older) w h o are classified as overweight by their BMI m a y not be at an increased risk for health problems. Since fat loss is often associated with increased risk of death in the elderly, the normal BMI range for older patients is between 22 and 29 kg/m 2 . In contrast, normal BMI for younger adults is 18.5 to 24.9 kg/m 2 .

Second, the BMI cut-off points for overweight and obese individuals are based on health risks observed in Caucasian populations. Asian persons are at a higher risk for disease at a lower BMI and are considered to be overweight and obese at 23 kg/m 2 and 27 kg/m 2 , respectively. In contrast, Black persons are at lower risk than Caucasian persons with the same BMI. Lastly, athletes tend to have a higher BMI due to their muscular physique. Thus, BMI is not necessarily indicative for of health problems, and each case needs to be evaluated individually. The BMI cut off of 25 kg/m 2 can sensitively detect "most overweight people and does not erroneously detect overlean people" (Porth, 2005).

In 2003, Health Canada established the Canadian Guidelines Body Weight Classification in adults to classify levels of obesity (Health Canada, 2005). The guidelines are based on the BMI that can be calculated by an individual's weight in kilograms divided by the square of their height in meters. The BMI is used to indirectly estimate fat and predict health risks such as cardiovascular risks and diabetes. Individuals can be classified PREDICTING HEALTH RISKS USING BODY-MASS INDEX into one of six health risk categories based on BMI ( W H O Expert AND WAIST-CIRCUMFERENCE Consultation, 2004) (Table 1).

Dr. James Douketis, an associate professor at McMaster University, and his colleagues (2005) suggest that both Waist GUIDELINE CONSIDERATIONS Circumference (WC) and BMI are useful in determining health risks risk posed by adiposity. Based on a large population-based When using BMI to classify an individual into one of the health categories, it is important to note that several other factors need cohort study in the United States, findings suggest that a person to be considered (e.g. age, ethnicity, physical fitness) (Douketis, with a normal BMI and increased W C m a y have an abdominal Paradis, Keller & Martineau, 2005). In short, not everyone w h o body fat distribution and thus an increased risk of health

Health Risk Classification According to Body Mass Index (BMI) Risk of Developing Health Problems

Classification

B M I category (kg/m 2 )

Increased

Underweight

< 18.5

Least

Normal Weight

18.5-24.9

Increased

Overweight

25.0 - 29.9

High

Obese Class I

30.0 - 34.9

Very High

Obese Class II

35.0 - 39.9

Extremely High

Obese Class III

>40.0

Table 1: Health risks based on Canadian Guidelines for Body Weight Classification ( W H O Expert Consultation, 2004).

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Issue 8 | March 2006

Two H A M I L T O N INITIATIVES

BMI Category Normal 18.5-24.9 kg/m 2

Overweight 25-29.9 kg/m 2

Obese Class I 30-34.9 kg/m 2

Men:< 102 c m W o m e n : < 88 c m

Least Risk

Increased Risk

High Risk

Men:> 102 cm W o m e n : > 88 c m

Increased Risk

High Risk

Waist

Circumference

Figure 1: Using BMI and W C to predict health risks as opposed to BMI alone (Douketis etal., 2005).

Dr. Arya M. Sharma is a McMaster University Professor of Medicine and the Canada Research Chair in Cardiovascular Obesity Research and Management. H e recently played a major role in establishing Canada's first Obesity Network (CON-RCO).

The network is intended to connect everyone from the general public, industry, government, and researchers on issues of obesity. With 2 0 % of the population projected to have BMIs' exceeding 40 kg/m2 (morbidly-obese) by 2020, the initiative is a measure to address the obesity epidemic.

Dr. Sharma is also working to establish a centre to provide medical treatment for bariatric patients that is to be located at St. Joseph's Hospital. This is one of Canada's first initiatives to house a state-of-the art bariatric centre and staff. Considerable resources are being used to offer complete pre- and postoperative care for bariatric surgery.

Each year, approximately 100 000 bariatric surgeries are performed in the United States compared to Canada's 1100 (Padwal & Lewanczuk, 2005). Figure 3 shows the trendsof surgical

problems (Janssen, Katzmarzyk & Ross, 2002). For example, this study shows that a m o n g those with a BMI of 30-34.9 kg/m 2 , an increased W C confers a greater than 14-fold increased risk for certain diseases a m o n g w o m e n , but a lesser increase in risk a m o n g m e n . Figure 1 summarizes the conclusion of this study and is an additional resource for clinical care practitioners in deveoping a preliinary prognosis of heavy patients.

However, using both W C and BMI to estimate health risks Policy posed by adiposity is dependent on proper measurement of W C .

Unlike the proper method to measure W C shown in Figure 2, W C • Inform and trigger policy action • Facilitate prevention programs is usually incorrectly measured around the hip region (Douketis • Measure effect of interventions etal., 2005).

• Estimate burden of risk based on population attributable risks (Epidemiology)

PREDICTING HEALTH RISKS USING WAIST-TO-HIP RATIO

Epidemiological Dr. Salim Yusuf, a McMaster University of Professor of Medicine and INTERHEART Investigator, recently suggested that Waist- • Ascertain cause of disease by looking at: • Association with health outcomes within populations to-Hip Ratio (WHR) will likely b e c o m e the n e w gold standard • Association of health outcomes across populations due to its higher predictive power of cardiovascular risk between ethnicities in 27 098 participants in 52 countries (12 Clinical 461 cases and 14 637 controls) (Yusuf et al., 2005). Their study published in The Lancet found that the W H R shows a graded • Identify high-risk individuals for screening and highly significant association with myocardial infarction • Identify individuals for absolute risk assessment risk worldwide. The study also stated that the redefinition of • Determine the type and intensity of treatment obesity based on W H R instead of BMI increases the estimate of • Monitor individuals for effects of treatment over time myocardial infarctions attributable to obesity for most ethnic groups. However, an international debate has resulted as the Table 2: Uses of cut-off points ( W H O Expert Consultation, 2004). study w a s criticized for including haphazard controls and not being prospective according to Dr. Willet, a Harvard University bariatric procedures performed in Canada. Last year, OHIP paid Professor (Milne, 2005). for approximately 600 patients to travel to the United States for Ideally, BMI cut-off points adjusted for age and athleticism surgery, costing the province $13 to $14 million (Benady, 2005). for each ethnicity might be set - a concept c o m m o n l y referred Dr.Sharma has recommended thatthesefunds be redirected to as duality. However, dual cut-off points between ethnicities or to the establishment of facilities and skills a m o n g health care nations are controversial and m a y also be confusing. Opponents providers in Canada to ensure care for the increasing morbidly suggest that dual cut-off points m a y have poor effects on clinical obese population. This m o n e y could be used to perform twice practice, epidemiology and policy. The implications of accurate as m a n y bariatric surgeries in Ontario. Conservative estimates by cut-off points to define levels of obesity are stated in Table 2 the Ontario Health Technology Assessment Advisory Committee ( W H O Expert Consultation, 2004). suggest that 3800 surgeries are needed in Ontario per year (Medical Advisory Secretariat, 2005). Indeed, several of the 150 000 morbidly obese persons in Ontario might qualify for surgery.

(Benady, 2005).

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Issue 8 | March 2006

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Obese persons face systematic discrimination and bias in many aspects of their lives. In one study, parents treated their obese daughters differently than their non-obese daughters: obese daughters were less likely to receive financial support for their education (Crandall, 1995). In another study, a scripted interview was videotaped and made into two copies. One copy was modified to make the candidate seem obese. Fewer job offers were extended to the obese candidate when compared to the non-obese candidate. The study concluded that obese persons were more likely to be denied jobs and promotions (Pingitoire, Dugoni, Tindale & Spring, 1994). Other studies show the bias and discrimination faced by obese persons in settings including education, health care, as well as within existing policies.

Many health care providers fail to acknowledge obesity as a disease, and thus do not treat it. In two older clinical studies involving 318and 1200 patients, respectively, physician attitudes Figure 2: Proper technique to measure waist-circumference. A measuring tape towards obese persons were poor (Klein, Najman, Kohrman & is placed around the trunk between the lower costal margin and the iliac crest Munro, 1982; Price, Desmond, Krol, Snyder & O'Connell, 1987). while the patient is standing with feet about 25-30 c m (10-12 in) apart. The measuring tape is fit snugly around the abdomen but without compressing In the first study, 6 6 % of physicians said obese "patients lacked underlying soft tissue.The waist circumference is recorded to the nearest 0.5 c m self-control", 3 9 % said "obese patients were lazy", 2 3 % did not (1/4 in) at the end of a normal expiration. (Douketis et al., 2005). recommend treatment options and 4 7 % stated that counseling patients on weight loss was inconvenient. In the second study, TRENDS only 1 8 % of physicians discussed weight management with overweight patients and 4 2 % discussed weight management Prevalence of obesity (classes I, II and III) has steadily withrisen mildly obese patients. There are many similar studies with between 1985 to 2003 in Canada (Kamarzyk & Mason, 2006). In nurses, some of which report more adverse reactions to patients class III obesity alone, there has been a 2 2 5 % increase between (Hoppe & Ogden, 1997; Maroney & Golub, 1992; Bagley, Conklin, 1990 and 2003 (Figure 4).

Isherwood, Pechiulis & Watson, 1989).

Though obesity in Canada remains lower than in the United Currently, there is a division in attitudes towards obese States (Figure 5), similar trends have been reported for an patients. Some maintain the beliefs of Dr. Walker who, in his increase in prevalence of class III obesity. nationally syndicated newspaper column, suggested that "...for their own good and the good of the country, fat people should BIAS & DISCRIMINATION be locked up in prison camps" (Solovay, 2000). Others like Dr. Sharma believe in treatment and compassion towards obese Surgical procedures such as stomach stapling have been patients: "...Governments too easily sloughed off the problem criticized and are controversial among the general public. with advice to the public to'eat more fruit and vegetables'and Bariatric surgery is perceived as a cosmetic intervention rather 'walk more,'which are all right for prevention, but do nothing for than a medically necessary treatment. Many Canadians believe the morbidly obese.... W e don't send people w h o have colon that obese patients need to "stop being lazy" and simply go on cancer h o m e to eat more fibre" (Benady, 2005). |Qj a diet to lose weight instead of expending pharmacological, surgical and psychological resources to correct obesity (Puhl & Brownell, 2001). Contradictory to the beliefs of many physicians today, Hippocrates wrote, "Corpulence is not only a disease Annual number of bariatric surgical procedures itself, but the harbinger of others" recognizing that obesity is a in Canada, 1993-2003 disorder that increases the risk of various co-morbidities.

1200 -• V) The story of Gina Score, described by Puhl & Brownell a> m (2001), highlights the nature of discrimination and reality that _ 1000 • m obese persons face in our society. Gina was sent to a Juvenile- •a m detention camp for a minor theft. She was characterized as a u 800 • sensitive individual w h o was academically successful. Weighing £ 600 • B 224 pounds at a height of 5'4", she faced difficulties with everyday 0 a H physical exercises. At the camp, she was forced to run 2.7 miles S 400 3 200 • • H _ HI on a hot day and was "prodded and cajoled by instructors" the entire way. Unable to catch her breath, she collapsed on the z 1 H i • i [• H i ground. Despite her cyanotic lips and incoherent babbling, oJH—H—B—m—m—m—•—•—m—I instructors sat nearby drinking sodas, laughing and chatting 3 while accusing Gina of faking. Four hours after lying in the sun, an ambulance was called - her organs had failed. Gina died.

Figure 3: Annual number of bariatric surgical procedures in Canada, 1993-

<& $ J* $ J J" & \& \& &

2003 (Padwal & Lewanczuk, 2005).

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Issue 8 | March 2006 40 35

REDEEM EE]

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daughters? Pers Soc Psych Bull, 21, 724-735.

Deitel, M. & Melissas, J. (2005).The origin of the word"bari". Obes Surg, 15(7), 1005-1008.

30 Douketis, J.D., Paradis, G., Keller, H. & Martineau, C. (2005). Canadian 25 guidelines for body weight classification in adults: application in 20 clinical practice to screen for overweight and obesity and to assess Obesity disease risk. CMAJ, 12, 172(8), 995-998.

15 Class I Obesi Health Canada. (2005). Canadian Guidelines for Body Weight J y 10 Classification in Adults [Electronic Version]. Retrieved October 5, Class II and III Obesity 5 2005 from www.hc-sc.gc.ca/hpfb-dgpsa/onpp-bppn/cg_bwc_ —• a introduction_e.html Hoppe, R. & Ogden, J. (1997). Practice nurses'beliefs about obesity and 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 weight related interventions in primary care. Int J Obes Relat Metab Disord,21(2), 141-146.

450 Janssen, I., Katzmarzyk, P.T. & Ross R. (2002). Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med, 162, 2074-2079.

Katzmarzyk, P.T. (2002). The Canadian obesity epidemic: an historical perspective. Obes Res, 10(7), 666-674.

Katzmarzyk, P.T., Mason, C, (2006). Prevalence of class I, II and III obesity Class 1 Obesity in Canada. CMAJ, 17, 174(2), 156-7.

Klein, D., Najman, J, Kohrman, A.F., Munro, C. (1982). Patient Overweight characteristics that elicit negative responses from family physicians.

JFamPract, 14(5), 881-888.

50 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Maroney, D. &Golub, S. (1992). Nurses'attitudes toward obese persons and certain ethnic groups. Percept Mot Skills, 75(2), 387-391.

Figure 4: Prevalence of overweight and obesity (classes l-lll) in Canada, Medical Adivsory Secretariat. (2005). Bariatric Surgery [Electronic 1985-2003. Top: Changes in absolute prevalence. Bottom: Changes relative to Version]. Retrieved October 4, 2005 from http://www.health.gov. baseline (1985 = 100%) (Kamarzyk & Mason, 2006). on.ca/english/providers/program/mas/reviews/review_baria_0105. html Milne, C. (2005). Does BMI still measure up [Electronic Version]?

Retrieved February 21, 2006 from http://http://www.medicalpost. com/mpcontent/article.jsp?content=20051212_200648_4920 Padwal, R.S. & Lewanczuk, R.Z. (2005).Trends in bariatric surgery in Canadian adult obesity rates lower than United States Canada, 1993-2003. CMAJ, 15, 172(6), 735. % Pingitoire, R., Dugoni, R.,Tindale, S. & Spring, B. (1994)Bias against 35 33 • Canada overweight job applicants in a stimulated employment interview. J Appl Psychol, 79, 909-917.

• U.S. 30 27 Porth, C. (2005). Pathophysiology: Concepts of altered health states, 7th 23 23 Ed. Lippincott Williams and Wilkins. Philadelphia, PA. 25 Price, J.H., Desmond, S.M., Krol, R A , Snyder, F.F. & O'Connell, J.K. 20 (1987). Family practice physicians' beliefs, attitudes, and practices regarding obesity. A m J Prev Med, 3(6), 339-345.

15 Puhl, R. & Brownell, K.D. (2001). Bias, discrimination, and obesity. Obes 10 • Res, 9(12), 788-805.

Sharma, A.M. (2005). Managing weighty issues on lean evidence: the 5 challenges of bariatric medicine. CMAJ. 4, 172(1), 30-31.

Solovay, S. (2000). Tipping the Scales of Injustice: Fighting Weight-Based Discrimination Prometheus Books Amherst, NY. Women Men Statistics Canada. (2005). Canadian Community Health Survey: Obesity Figure 5: Canadian adult obesity rates lower than United States (Statistics a m o n g children and adults [Electronic Version]. Retrieved October Canada, 2005).

4, 2005 fromhttp://www.statcan.ca/Daily/English/050706/ d050706a.htm W H O Consultation Report. (2000). Obesity: preventing and managing the global epidemic. World Health Organ Tech Rep Ser, 894, i-xii, REFERENCES 1-253.

W H O Expert Consultation. (2004). Appropriate body-mass index for Bagley, C.R., Conklin, D.N., Isherwood, R.T., Pechiulis, D.R. & Watson, LA. Asian populations and its implications for policy and intervention (1989). Attitudes of nurses toward obesity and obese patients. strategies. Lancet, 10, 363(9403), 157-163.

Percept Mot Skills, 68(3 Pt 1), 954.

World Health Organization. (2000). Obesity: Preventing and Managing Belanger-Ducharme, F. &Tremblay, A. (2005). Prevalence of obesity in the Global Epidemic: Report of a W H O Consultation on Obesity.

Canada. Obes Rev, 6(3), 183-186.

Yusuf, S., Hawken ,S., Ounpuu, S„ Bautista, L, Franzosi, M.G., Benady, S. (2005). McMaster to target obesity with proposed centre Commerford, P., Lang, C.C., Rumboldt, Z., Onen, C.L, Lisheng, L, [Electronic Version]. Retrieved September 1, 2005 from http://www.

Tanomsup, S., Wangai Jr, P., Razak, R, Sharma, AM., Anand, S.S. & medicalpost.com/mpcontent/article.jsp?content=20050822_ INTERHEART Study Investigators. (2005). Obesity and the risk of 201542_5104 myocardial infarction in 27,000 participants from 52 countries: a Crandall, C.S. (1995). D o parents discriminate against their heavy-weight case-control study. Lancet, 5, 366(9497), 1640-1649.

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Issue 8 | March 2006

"MEEIEJJ-U

The Use of Postexposure Prophylaxis For Occupational HIV Exposure

John Snelgrove

to be caused by occupational exposure (CDC, 2001a). Health Care Workers (HCW) w h o are exposed to HIV m a y avoid infection with the use of immediate chemoprophylaxis treatment. This is called Post-Exposure Prophylaxis (PEP) and although little epidemiological evidence exists for its efficacy, many physicians agree that it could potentially prevent HIV infection if used appropriately.

"Will I lose my dignity Will someone care Will I wake tomorrow From this nightmare?"

-Jonathan Larson, Rent

Occupational health is usually conceptualized in terms of safe work practices and educating workers about potential hazards. However, in the field of healthcare, OCCUPATIONAL EXPOSURE TO HIV there are additional occupational risks associated with exposure to disease-causing agents. O n e such risk is exposure to the Unlike most cases of sexually-transmitted HIV, contact with h u m a n immunodeficiency virus, HIV. mucosal surfaces during occupational exposure has been As of 2001, the U.S. Centre for Disease Control (CDC) has identified as the transmission route in only a minority of cases reported 56 cases of HIV known to be transmitted through (CDC, 2001b). Usually, exposure is by percutaneous injury, occupational exposure, with an additional 138 cases suspected which has a calculated risk of infection of 0.3% per episode

Infection Status of Source Patient

Exposure Risk

Less-Severe • Superficial injury • Injury with solid device • No visible blood on device

HIV+class2 HIV+ class 1 • Symptomatic or high known • Asymptomatic or low known viral load, or viral load • Patient has AIDS, or • Acute seroconversion

Basic 2-drug PEP regimen recommended

More-Severe • Injury with large hollow-bore instrument • Deep puncture Extended 3-drug PEP regimen • Visible blood on device recommended • Device previously in source patient's artery or vein

HIV Status Unknown • N o sample available for HIV testing • Ex. Deceased source patient

Extended 3+ drug regimen recommended

Generally no PEP warranted; consider basic 2-drug regimen for source or setting with HIV risk factors

Extended 3+ drug PEP regim e n recommenced

Generally no PEP warranted; consider basic 2-drug regimen for source or setting with HIV risk factors

Table 1: Recommended PEP regimens based on occupational exposure risk and infection status of source patient. Modified from CDC. Updated U.S. public health service guidelines for the management of occupational exposures to HBV, HCV and HIV and recommendations for postexposure prophylaxis (CDC, 2001 a)

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(95% CI=0.2%-0.5%) (Henderson, Saah, Zak et al., 1986; Bell, 1997). Hollow-bore needlestick injuries have been responsible for most HIV infections a m o n g H C W s , likely the result of the larger inoculum of source-patient blood compared with that found on solid surgical instruments (Henderson & Gerberding, 2003). The C D C formulates occupational PEP guidelines based on the likelihood that the source-patient is infected with HIV and whether a sufficient amount of blood or bodily fluid was transmitted to result in infection, given the specific transmission route.

of viral R N A into complementary D N A (cDNA). NRTI and NtRTIs work by substituting faulty nucleotides into the elongating c D N A during reverse transcription. This results in dysfunctional c D N A or c D N A chain termination. The first antiretroviral agent approved for HIV treatment was the NRTI zidovudine (AZT) (Fischl, 2003). In both basic and extended regimens of PEP, zidovudine is one of the drugs preferentially recommended.

The basic PEP regimen uses zidovudine with another NRTI called lamivudine (CDC, 2001a).

Almost all expanded PEP regimens include one Protease Inhibitor (PI) in combination with two NRTI/NtRTIs. After m R N A translation, viral protease is required to cleave primary structure BASIC VERSUS EXPANDED PEP polypeptides for subsequent folding and assembly into viral An important consideration with occupational HIV exposure is proteins. Pis inhibit viral proteases, resulting in dysfunctional that PEP is prescribed based not on clinical measures, but on the HIV proteins that assemble into immature, non-infectious HIV risk profile associated with the exposure. This is to avoid delay virons. Ritonavir (RTV) and lopinavir (LPV) are two Pis suggested in onset of treatment, which has a theoretically preventative for use in combination with zidovudine and lamivudine in the effect that limits the proliferation of HIV during the short time preferred expanded PEP regimen (CDC, 2001a). Ritonavir has the virus is localized to dendritic cells and regional lymph nodes low affinity for h u m a n aspartic proteases such as renin and (Henderson & Gerberding, 2003). The C D C has issued guidelines pepsin, meaning cytotoxicity is low in concentrations used for indicating which exposure events are considered "less-severe" ARV therapy and PEP (Danner, 2003). In addition to protease and "more-severe." Based on the risk associated with exposure inhibition, ritonavir is used to boost the efficacy of other Pis by and any other relevant risk factors, the guidelines recommend inhibiting enzymes that metabolize them. For this reason, it is no PEP, a basic two-drug regimen of PEP, or an expanded multi- often combined with other Pis in a single capsule, such as the drug regimen of PEP (CDC, 2001a). Table 1 shows a simplified ritonavir/lopinavir combination recommended in expanded version of the CDC's guidelines. The duration of PEP has been PEP. Lopinavir is a potent, highly-specific "second generation" PI set by the C D C at 28 days, with the understanding that it is more that is active against ritonavir-resistant HIV-1 isolates (Johnson & beneficial to adjust the number or type of drugs to accommodate Kuritzkes, 2003).

Although the only known epidemiological study on PEP side effects rather than stop PEP prematurely (CDC, 2001 a). had a small sample size and was retrospective in nature, its findings infer that the prognosis does look good for most ANTIRETROVIRALS (ARVS) USED FOR PEP occupational exposures. Zidovudine alone appears to provide an 8 0 % protective effect (Henderson & Gerberding, 2003), and The main drugs used in PEP target either reverse transcriptase the combination of other ARVs administered within hours of function or protease activity. Nucleoside/tide Reverse exposure and maintained for the full course of the PEP regimen Transcription Inhibitors (NRTI/NtRTI) block reverse transcription suggest that seroconversion can be avoided in m a n y cases.

TOXICITY, DRUG INTERACTIONS AND SIDE EFFECTS OF PEP

A substantial number of HCWs are unable to complete the fourweek regimen of PEP due to ARV side effects (Wang, Panlilio, Doi et al., 2003). Side effects range from non-life-threatening adverse events to more severe cases of hyperglycemia, hepatic steatosis and hyperlipidemia (CDC, 2001a). In a study of 449 H C W s w h o took PEP, 7 6 % identified at least one adverse event, in addition to c o m m o n side effects that include nausea (57%), malaise (38%), headache (18%), vomiting (16%), diarrhea (14%) and myalgia (6%) (Wang, Panlilio, Doi et al., 2003). Serious or lifethreatening drug interactions are also of concern, particularly with PI usage. Ritonavir/lopinavir has been associated with accelerated clearance of certain drugs, increased serum cholesterol and triglycerides and severe events such as cardiac arrhythmia, respiratory depression and ischemia of tissues (Johnson & Kuritzkes, 2003). For this reason, several over-thecounter and prescription drugs are contraindicated w h e n Pis are included in the PEP regimen.

Patient monitoring is essential during PEP for early drug Figure 1: Thymidine nucleoside with 3' hydroxyl group. The arrow points to the toxicity detection. W h e n drug toxicity is detected, a modified 3'carbon.

PEP regimen is suggested along with expert consultation.

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2nd Ed., Churchill Livingston, N e w York.

Danner, S.A. (2003). Ritonavir. In R. Dolin, H. Masur, & M. Saag (Eds.), Part of the discourse surrounding HIV legal and ethical issues is AIDS Therapy (2nd Ed.). N e w York: Churchill Livingston. framed as a balancing act between protecting the rights of the Johnson, S.C., Kuritzkes D.R. (2003). Lopinavir. In R. Dolin, H. Masur, M. Saag (Eds.), AIDS Therapy (2nd Ed.). N e w York: Churchill individual and the rights of society (OLRC, 1992). S o m e H C W s Livingston. are fortunate enough to k n o w their source-patient's HIV status, Fischl, M. (2003). Zidovudine. In R. Dolin, H. Masur, & M. Saag (Eds.), however, it is not unreasonable that an exposure could occur AIDS Therapy (2nd Ed.). N e w York: Churchill Livingston. withoutthisknowledge. Attaining HIVstatusinformation isoften Henderson, D.K., Saah, A.J., Zak, B.J., et al. (1986). Risk of nosocomial seen as a privacy issue, whereas not attaining this information infection with human T-cell lymphotrophic virus type III/ m a y have deleterious consequences for the exposed H C W . lymphadenopathy-associated virus in a large cohort of intensively People with HIV infection remain stigmatized in society, making exposed health care workers. Annals of Internal Medicine, 104, the acquisition of HIV status information without consent a 644,1986. difficult prospect.

Henderson, D.K., Gerberding, J.L (2003). Occupational and Economic constraints are another important consideration nonoccupational exposure management. In R. Dolin, H. Masur, & M. Saag (Eds.), AIDS Therapy (2nd Ed.). Churchill Livingston, N e w with respect to any form of A R V therapy, including PEP. For York. people living in Ontario w h o are infected with HIV, A R V drugs are Ontario Health Coalition. (2002). Accessibility handbook. Retrieved on partially covered under the Ontario Drugs Benefit Plan. However, November 2, 2005 from http://www.web.net/~ohc/docs/access. individuals w h o are not yet diagnosed as HIV-positive but have htm. been prescribed PEP generally must cover the costs associated Ontario Law Reform Commission. (1992). Report on Testing for AIDS. with the drug regimen or apply for occupational compensation p76.

(Ontario Health Coalition, 2002).

Wang, S.A., Panlilio, A.L., Doi, P.A., et al. (2000). Experience of health Another consideration worth mentioning is the impact PEP care workers taking postexposure prophylaxis after occupational could have on a person's life. It is possible that family life, job HIV exposures: Findings of the HIV Postexposure Prophylaxis productivity and self-efficacy could be negatively affected if side Registry. Infection Control and Hospital Epidemiology, 21(12), 780-785. effects persist, which is often the case. This highlights the need for proper counselling and monitoring of side effects and regimen adherence. Indeed, the high rate of PEP discontinuation a m o n g occupational exposure cases has been attributed to lack of H C W counselling regarding potential side effects and the importance of regimen completion (Wang, Panlilio, Doi et al., 2003).

CONCLUSION

Occupational exposure among healthcare workers has not been identified as a substantial transmission route for HIV. However potential exposure justifies careful consideration of the postexposure treatment options available. The use of postexposure prophylaxis can prevent the onset of HIV infection if A R V drugs are administered correctly and within a short timeframe. The drug regimen prescribed must take into consideration the severity of the exposure, the HIV status of the source patientâ&#x20AC;&#x201D;whether k n o w n or u n k n o w n â&#x20AC;&#x201D; a n d potential drug interactions or debilitating side effects. Non-medical consequences of PEP must also be addressed and sufficient counselling is necessary to accompany medical treatment, fjf REFERENCES Bell, D.M. (1997). Occupational risk of human immunodeficiency virus infection in health-care workers: an overview. A m J Med, 102(5B), 9-15.

Center for Disease Control. (2001 a). Updated U.S. public health service guidelines for the management of occupational exposures to HBV, HCV and HIV and recommendations for postexposure prophylaxis. Morbidity and Mortality Weekly Report, 50.

Retrieved on November 2, 2005 from http://www.cdc.gov/mmwr/ PDF/rr/rr5011.pdf.

Center for Disease Control. (2001 b). Surveillance of health care workers with HIV/AIDS. Atlanta. In Henderson D.K. & Gerberding J.L. (2003). Occupational and nonoccupational exposure management. In Dolin R., Masur H., Saag M. eds. AIDS Therapy. www.meducator.org

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Brain Development in Neur A Brief Look at its Beginnings and th Current Trends

Ronald Zahoruk

"The immature brain is not simply a small adult brain, and contributions to what would become modern-day neuroscience, normal development of the brain depends on a complex series including the introduction of "plasticity" (Eichenlaum, 2002). of interactions between nature and nurture during the criticalPlasticity refers to, in a very basic sense, changes that occur in the period. Studies of the developing visual system have provided organization of the brain as a result of experience (Eichenlaum, many insights into the roles of experience and neural plasticity 2002). More specifically, plasticity involves changes that occur to mechanisms in cortical development" (Murphy, 2005). the location of specific neural information processing functions and structures as a consequence of experience (Kandel et al., One of the most exciting frontiers in neuroscience today 2001). Though the precise definition of this term continues to is the study of brain development. A global empirical be widely debated, plasticity is a theme that has permeated all initiative has been underway to understand h o w areas of neural development research. the brain develops. Volumes of books would be required to Another major contribution to the field of brain development encompass the breadth of this research. The aims of this article, came in the form of Hebbian learning, coined after the influential however, are to briefly touch upon s o m e of the important Canadian psychologist Donald Hebb in 1949. This theory historical findings, and to highlight a few of the contemporary describes how, at the level of the synapse, a basic mechanism lines of inquiry to illustrate the field's continued advances. exists for plasticity, whereby an increase in synaptic efficacy arises Classically speaking, one of the most fiercely debated topics from the presynaptic cell's repeated and persistent stimulation of within this area and in all areas of developmental biology the postsynaptic cell (Hebb, 1949). This led to what has become is whether neural development is a consequence of one's a very c o m m o n theme in neuroscience research: cells that "fire genetic make-up or the environment in which they are reared. together, wire together." In other words, the connection between Researchers today willingly acknowledge that the development cells that are stimulated simultaneously are strengthened. In of one's brain is the product of a complicated sequence of events 1966, Hebbian learning saw true empirical validation through a that is determined by both genetic and environmental factors. phenomenon known as "long-term potentiation" (Bliss & Lomo, Neuroscientists around the world are continuing to elucidate 1973). Long-term potentiation, or LTP, is a neurophysiological the relationship between these factors and brain development. term used to describe high-frequency stimulation trains that S o m e of this research takes place here at McMaster University. produce larger, prolonged excitatory post-synaptic potentials (EPSPs) compared to the responses evoked by a single stimulus train (Bliss & Lomo, 1973). In effect, the connection between two HISTORY neurons was observed to be stronger. With this observation, a The development of the brain has long been at the forefront ofwhole n e w way to view brain development, as well as learning neuroscience research. In 1906, Santiago R a m o n Y Cajal and and memory, c a m e to fruition.

Around the same time, other landmark work in brain Camillo Golgi w o n the Nobel Prize in Physiology and Medicine development was explored by David Hubel and Torsten Wiesel. for their research on the anatomical organization of the brain.

Hubel and Wiesel showed that competition exists between In the process, Cajal became one of the founders of modern both eyes in the visual cortex of cats during early development, neuroscience. ultimately affecting the adult visual system (Hubel and Using Golgi's staining procedure involving silver chromate, Wiesel, 1965).

During this critical period, neural connections Cajal successfully learned h o w to darkly stain the neuronal are particularly susceptible to being changed based on cell membrane, and thus isolated individual neurons. He was environmental input and are governed by the rules of Hebbian able to see h o w neurons were interconnected through axonal synaptic plasticity (Hubel and Wiesel, 1965). Through these "arborizations"- treelike branchings that connect one neuronal experiments, the scientific community was able to see directly cell to multiple parts of another single neuronal cell or multiple that experience does in fact affect cortical organization, and the cells (Eichenlaum, 2002). This discovery led physiologists and idea that nature and nurture acted as two discrete forces was no anatomists to believe that, although each neuron is a separate longer intellectually feasible. entity, each one is in contact with other cells. This ultimately From the 1970's to the present, many genetic techniques led to the idea that the nervous system is m a d e up of billions employed in all areas of biological science (which include the of individual neuron units. Cajal continued to m a k e m a n y www.meducator.org

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advent of cloning and gene knock-out strategies, sophisticated biochemical and molecular tools) have seen a steady integration into the study of h o w the brain develops. Today, these tools, such as the Polymerase Chain Reaction (PCR) are commonplace and often part of the large ensemble of laboratory methods inextricably linked to h o w many researchers conduct their studies.

PRESENT RESEARCH

As mentioned earlier, neuroscientists all over the world are constantly breaking n e w ground in learning h o w the brain develops. McMaster neuroscientist Dr. Kathryn Murphy, for example, is affiliated with both the Departments of Psychology and the Department of Medical Physics and Applied Radiation Sciences, and investigates brain development from the perspective of the visual system. Using a wide variety of neurobiological, computational and psychophysical techniques, Dr. Murphy explores the effect of visual experience on the shape of the brain over time. Her career has seen many unique and important contributions to the world of neuroscience, including the discovery of "colour blobs" in the primary visual cortex of the cat (the area of the visual cortex where colour is processed) (Murphy et al., 1995). However, the last number of years has seen a particular emphasis on the role of plasticity in critical periods at the neuronal level, focusing on synaptic excitation and inhibition.

Cortical plasticity is widely believed to be mediated in the cortex through activation of glutamatergic N-methyl-Daspartate (NMDA) receptors (LoTurcco et al., 1991; Watanabe et al., 1992; Hicks and Conti, 1996; Popescu, 2005). These pentameric membrane proteins, with a central ion channel pore permeable to Na + , K+ and Ca 2+ ions, are composed of a primary NR1 subunit and different NR2-type subunits, the latter of which have been shown to alter receptor kinetics (McBain and Mayer, 1994). It has been demonstrated that during early development in h u m a n and animal models, repeated stimulus activation causes N M D A receptor-mediated synaptic current to become more phasic in nature through a structural shift from NR2B-type to NR2A-type subunits (Yamakazi et al., 1992; Williams et al., 1993;Takahashi, 2005; Murphy et al., 2005). O n the other hand, cortical inhibition during plasticity and neuronal circuitry formation is attributed to the neurotransmitter gamma-aminobutyric acid (GABA), which binds to ionotropic G A B A A receptors and allows CI" ion entry through a central channel pore (Murphy et al., 2005; Bosman, Rosahl, & Brussaard, 2002; Gibbs et al., 1996). G A B A A receptors, the most numerous inhibitory receptors in the mammalian nervous system, are pentameric m e m b r a n e proteins composed of different types of alpha, beta and g a m m a subunits - most commonly, 2 alpha, 2 beta and a g a m m a (Farrant & Nuser, 2005).

Similar to N M D A receptors, a shift in subunit composition occurs during development which leads to an increase in overall receptors kinetics, with GABAAalphal subunits replacing the GABAAalpha3-type (Murphy et al., 2005; Bosman et al., 2005).

This confers a more phasic quality to Inhibitory Post-Synaptic Current (IPSC) (Hensch et al., 1998, Bosman et al., 2002). In contrast to N M D A receptors, this shift in subunit structure, specifically the upregulation GABAAalphal, has been shown to be independent of stimulus perception (Bosman et al., 2002).

In both cases, this switch from tonic to more transient synaptic

currents is viewed as a progression toward "mature" synapse formation.

Through developmental expression profiles acquired from performing western blots on tissue samples taken at various stages throughout development, Dr. Murphy and her students were able to quantify the amount of specific N M D A and G A B A receptorsubunit protein presentat each stage. The benefit of this technique is that one can take as m a n y samples as necessary for an unlimited duration, with whatever experimental parameters required, in order to test whether there is a change in subunit expression and by h o w m u c h in relative terms (See Figure 1). For instance, one of the most widely studied developmental profiles are monocularly deprived animals - one eye is deprived of sight during some time in early development, typically the critical period. In 2004, Murphy and her colleagues demonstrated that N M D A R 1 receptor subunit expression is decreased in the case of

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monocular deprivation (Murphy et al., 2004). O n e interpretation of this result is that diminished N M D A R 1 expression would ultimately lead to lower excitatory input in the deprived eye's projections to the visual cortex. Consequently, this lower level of excitation would not be adequate to activate the existing N M D A receptors, and the connections would become weakened. This would ultimately cause loss of acuity in the visual field, as seen in children with unilateral cataracts (as cited by Murphy et al., 2004).

Dr. Murphy's research, along with others w h o do similar work, have given great insight into disorders of the visual system such as congenital amblyopia and cataracts, and have also served as a paradigm for generalized brain development, including cases of genetic abnormality.

Age (Years)

Age (Years)

Figure 1: Western blots of tissue samples taken at various stages of development (Murphy etal., 2004).

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Farrant, M., & Nusser, Z. (2005). Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci,6,215-229.

Gibbs, J.W., Zhang, Y.F., Kao, C.Q., Holloway, K.L., Oh, K.S., & Coulter, D. (1996). Characterization of G A B A A receptor function in human temporal cortical neurons. J Neurophysiol, 75(4), 1458-71.

Hebb, D. O. (1949). The organization of behavior: A neuropsychological theory. N e w York: Wiley.

Hensch,T. K., & Fagiolini, M. (2005). Excitatory-inhibitory balance and critical period plasticity in developing visual cortex. Progress in Brain Research, 147,115-125.

Hicks, T.P., & Conti, F. (1996). Amino acids as the source of considerable excitation in cerebral cortex. Can J Physiol Pharmacol., 74(4), 34161.

Figure 2: GABAA receptor. A pentameric membrane protein commonly Hubel, D. H., & Wiesel, T. N. (1965). Binocular interaction in striate composed of 2 alpha, 2 beta and a g a m m a subunit (Farrant& Nuser, 2005). cortex of kittens reared with artificial squint. Journal of Neurophysiology, 28,1029-1040.

Kandel, E.R., Schwartz, J.H., & Jessell, T.M. (2001). Principles of Neural FUTURE DIRECTIONS Science (4th ed.). N e w York: McGraw-Hill.

LoTurco, J.J., Blanton, M.G., & Kriegstein, A.R. (1991). Initial expression and endogenous activation of N M D A channels in early With the continued advancement of brain development neocortical development. J Neurosci, 11 (3), 792-9. research through strides m a d e in other areas of molecular science, the field is constantly being enhanced with the latest McBain, C.J., & Mayer, M l . (1994). N-methyl-D-aspartic acid receptor structure and function. Physiol Rev, 74(3), 723-60. and most advanced laboratory tools. For example, o n e of most Murphy, K.M., Jones, D.G. & Van Sluyters, R.C. (1995). Cytochromeinteresting areas of research in genetics today involves making oxidase blobs in cat primary visual cortex. Journal of use of gene chip technology: a device that allows one to quantify Neuroscience, 15, 4196-4208. the relative expression of thousands of genes simultaneously Murphy K.M., Duffy, K.R., & Jones, D.G. (2004). Experience-dependent through a microarray. Recently, U e n o and colleagues (2006) Changes in N M D A R 1 Expression in the Visual Cortex of an Animal used microarray analysis to study h o w neuronal progenitor Model for Amblyopia. Visual Neuroscience, 21, 653-670 cells in early neural development regulate D N A replication in Murphy, K.M., Beston, B.R., Boley, P.M., Jones, D.G. (2005). Development of H u m a n Visual Cortex: A Balance between Excitatory and the face of extrinsic stress (i.e. factors that cause D N A damage).

Inhibitory Plasticity Mechanisms. Dev Psychobiol, 46(3), 209-21.

They found a correlation between gene product expression and the checkpoints that neurons g o through during early Popescu, G. (2005). Principles of N-Methyl-D-aspartate Receptor Allosteric Modulation. Mol Pharmacol, 68,1148-1155. development. Based o n the local environment, these cells Takahashi, T. (2005). Postsynaptic receptor mechanisms underlying can decide to undergo apoptosis (programmed cell death) or developmental speeding of synaptic transmission. Neurosci Res, continue proliferation (Ueno et al., 2006).

53(3), 229-40.

The study of h o w the brain develops has always been at the Ueno, M., Katayama, K.I., Yamauchi, H., Nakayama, H., Doi, K. (2006). forefront of neuroscience research; it remains a very exciting Cell cycle and cell death regulation of neural progenitor cells and constantly growing field. It has helped explain the complex in the 5-azacytidine (5AzC)-treated developing fetal brain. Exp relationship between environment and genetic constitution.

Neurol. Jan 18; [Epub ahead of print] It has also elucidated m a n y of the molecular causes behind Watanabe, M., Inoie, Y, Sakimura, K., & Mishina, M. (1992).

Developmental changes in distribution of N M D A receptor neuropathology, developmental disorders and general brain channel subunit mRNAs. Neurweport, 3,113-114. functioning. This is impressive and very important research. In Williams, K., Russell, S.L., Shen, Y.M., & Molin-Off, P.B. (1993). order to better understand the world around us, it is imperative Developmental switch in the expression of N M D A receptors that w e also obtain a better understanding of ourselves. With occurs in vivo and in vitro. Neuron 10, 267-278. contributions from McMaster's Dr. Murphy, and others like her, Yamazaki, M., Mori, H., Araki, K., Mori, K.J., & Mishina, M. (1992). our understanding of h o w the brain functions and supports the Cloning, expression and modulation of a mouse N M D A receptor incredible processes of the h u m a n mind will not only benefit the subunit. IWBS Lett, 300, 39-45. scientific community, but society at large, fjfj Benzodiazepines T

Cl-

REFERENCES

Bliss, TV, & Lomo,T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol, 232 (2), 331-56.

Bosman, L W . J., Heinen, K, Spijker, S., & Brussaard, A. B. (2005). Mice Lacking the Major Adult G A B A A Receptor Subtype Have Normal Number of Synapses, But Retain Juvenile IPSC Kinetics Until Adulthood. J Neurophysiol, 94, 338-346.

Eichenbaum, H. (2002).The Cognitive Neuroscience of Memory, "Four Themes in Research on Neurobiology and Memory" (pp. 7-9).

Boston, MA: Oxford University Press.

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Functional Electrical Stimulation (FES) An Alternative Rehabilitative Option for Individuals with Spinal Cord Injuries Michelle W o n g

Rehabilitation science is continually exploring n e w interventions to improve the quality of life for individuals after a spinal cord injury. The current rehabilitative options include conventional physiotherapy, occupational therapy and experimental interventions such as Functional Electrical Stimulation (FES) and Body Weight Support (BWS) treadmill training (Thrasher et al., 2005; Hicks et al., 2005).

Spinal cord injuries are usually defined as either complete or incomplete, depending on the location of the spinal cord lesion.

The American Spinal Injury Association (ASIA) Impairment Scale ranks the severity of spinal cord d a m a g e on a scale from A to E. An individual in category A is considered to have a complete injury with no voluntary motor or sensory function. Individuals in categories B, C, or D have incomplete injuries where sensory function alone, partial sensory and motor preservation or useful motor functions are preserved, respectively. Patients in category E are considered normal with both sensory and motor functions intact. The ASIA Impairment Scale is currently the most widely used system for classifying spinal cord injuries (ASIA, 2001).

WHAT IS FUNCTIONAL ELECTRICAL STIMULATION (FES)?

ASIA IMPAIRMENT SCALE |~| /\â&#x20AC;&#x201D;Complete: No motor or sensory function is preserved in the sacral segments S4-S5. i~l B = Incomplete: Sensory, but not motor function is preserved below the neurological level and includes the sacral segments S4-S5. [~| C =

Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3.

One of the most innovative approaches to improve the motor function in patients with spinal cord injuries is FES. This procedure involves sending electrical pulses to induce muscle contraction in a paralyzed limb after a spinal cord injury. W h e n f~1 ÂŁ)= Incomplete: Motor function is these pulses are applied to motor nerves, action potentials are preserved below the neurological generated which travel along the axon to the target muscle.The motor nerves of the targeted muscle must be intact in order for level, and at least half of key the action potentials to be propagated (Popovic et al., 2001). muscles below the neurological The motor nerves can be activated by surface or implanted level have a muscle grade of 3 or electrodes. Surface or transcutaneous electrodes are applied more. directly to the skin with adhesive gel above the nerve bundles of a particular muscle. These electrodes allow for the option to P I E = Normal: Motor and sensory implement FES into a rehabilitation program during the early function are normal. stages of recovery. However, the surface electrodes require technical assistance and are most practical on a short-term basis.

Conversely, implanted or percutaneous stimulation involves surgical intervention to place electrodes on the nerves or on the Figure 1: The American Spinal Injury Association (ASIA) Impairment Scale muscles close to nerves. These can be used for a longer period ranking the severity of spinal cord damage (ASIA, 2001). of time, but should be implanted 18-24 months after injury.

Infections from the implanted electrodes are a liability and the behaviour of the activated muscles m a y change over time, resulting in undesired contractions (Popovic et al., 2001).

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IviEDlJUlOfi THE FUTURE OF FES

Many FES systems have proven to be effective in controlled clinical environments. However, other confounding variables such as the recovery of voluntary muscle control m a y obscure the overall benefits of FES (CIGNA Health Care Coverage Position, 2005). The t w o possible applications of FES are either shortterm therapeutic treatment in a clinical setting or the long-term orthotic use of a FES system (Bajd et al., 1999). However, early intervention is important in maximizing recovery after spinal cord injury and the combination of current FES treatment with standard physical therapy is the most promising approach to date (Popovic et al., 2001). ยงQj Figure 2: The Odstock Dropped Foot Stimulator, an example of Functional Electrical Stimulation used to increase foot clearance during walking (Taylor, 1999).

REFERENCES

American Spinal Injury Association (2001). Classification Workshe Retrieved August 4, 2005 from http://www.asia-spinalinjury.org/ publications/2001 _Classif_worksheet.pdf CIGNA Health Care Coverage Position (2005). Functional Electrical W H A T IS FES U S E D FOR? W H A T IS FES-ASSISTED WALKING? Stimulation. Retrieved August 4, 2005 from http://www.cigna.com/ health/provider/medical/procedural/coverage_positions/medical/ Most FES systems today are pre-programmed to perform mm_0349_coveragepositioncriteria_functional_electrical_stimulatasks specific to the needs of the individual. FES is currently tion.pdf used in various neuroprostheses such as cochlear implants, Graupe, D., & Kohn, K. H. (1998). Functional Neuromuscular Stimulator cardiac pacemakers, bladder voiding systems, grasping and for Short-distance Ambulation by Certain Thoracic-level Spinalreaching neuroprostheses, and FES-assisted sitting and walking cord-injured Paraplegics. Surg Neurol, 50, 202-207.

Guest, R. S., Klose, K. J., Needham-Shropshire, B. M., & Jacobs, P. L. prostheses (Popovic & Thrasher, 2004).

(1997). Evaluation of a Training Program for Persons with SCI FES-assisted walking involves stimulating the relevant Paraplegia Using the Parastep 1 Ambulation System; Part 4 - Effect leg muscles in a coordinated fashion to perform the walking on Physical Self-Concept and Depression. Arch Phys M e d Rehabil, motion. The main nerve stimulated is the peroneal nerve and 78(8), 804-807. the lower-limb muscle groups activated include the hip flexors Hesse, S., Werner, C, & Bardeleben, A. (2004). Electromechanical Gait and extensors, knee flexors and extensors, and the ankle plantar Training with Functional Electrical Stimulation: Case Studies in flexors and dorsiflexors (Bajd et al., 1999). Walking is then Spinal Cord Injury. Spinal Cord, 42, 346-352. performed with or without assistive devices or o n a treadmill. Hicks, A. L., Adams, M. M., Martin Ginis, K., Giangregorio, L., Latimer, A., Individuals must have a significant a m o u n t of upper body control Phillips, S. M., McCartney, N. (2005). Long-term body-weight-supto maintain stability and balance while walking.The schedule of ported treadmill training and subsequent follow-up in persons with chronic SCI: effects on functional walking ability and measures of application and the intensity and frequency of FES stimulation subjective well-being. Spinal Cord, 43(5), 291-298. is patient-specific and needs to be monitored to prevent muscle Popovic, M. R., Curt, A., Keller, T., & Dietz, V (2001). Functional Electrical fatigue (Popovic et al., 2001).

Stimulation for Grasping and Walking: Indications and Limitations.

Spinal Cord, 39,403-412.

WHAT ARE THE BENEFITS OF FES-ASSISTED WALKING? Popovic, M. R., Thrasher, T. A. (2004) "Neuroprostheses," In: Encyclopedia of Biomaterials and Biomedical Engineering [eds.:WnekGE, FES-assisted walking is effective for individuals with incomplete Bowlin GL], Marcel Dekker, N e w York, July 2004, pp. 1056-1065. spinal injuries, as it is a weight-bearing exercise that attempts to Postens, N. J., Hasler, J. P., Granat, M. H., & Maxwell, D. J. (2004). Functional electrical Stimulation to Augment Partial weight-Bearing prevent the atrophy of muscles, increase the range of motion, Supported Treadmill Training for Patients with Acute incomplete reduce spasticity, and slow the demineralization of bones in the Spinal Cord Injury: A Pilot Study. Arch Phys M e d Rehabil, 85, 604lower extremities (Bajd et al., 1999; CIGNA Health Care Coverage 610.

Position, 2005). M a n y walking neuroprostheses, such as the Taylor, P. N. (1999). Correction of Bilateral Dropped Foot Using the Odstock 2, WalkAid, and the Parastep have been developed to Odstock 2 Channel Stimulator. Proceedings of the 4th Annual Conassist patients in foot clearance during walking (Taylor, 1999; ference of the International FES Society, 257-260.

Wieler & Stein, 1999; Graupe & Kohn, 1998). Recent studies have Thrasher, T. A., Flett, H. M., Popovic, M. R. (2005). Gait training regimen noted that FES-assisted walking improves walking enduranceand for incomplete spinal cord injury using functional electrical stimulation. Spinal Cord, Oct 25; [Epub ahead of print] speed, the quality of gait, and lower-extremity muscle strength (Thrasher et al., 2005; Hesse et al., 2004; Postens et al., 2004). Wieler, M., Naaman, S., & Stein, R. B. (1999). Walkaid: An Improved Functional Electrical Stimulator for Correcting Foot-Drop. ProceedS o m e individuals enrolled in a FES-assisted walking program ings of the 1st Annual Conference of the International FES Society have reported psychosocial benefits, as well as improvements 101-104. in physical self-conception and a reduction in depression (Guest etal., 1997).

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The G a m m a Knife® Stereotactic Radiosurgery as an Alternative Surgical M e a n s

Sarah Mullen

W h i l e traditional, invasive neurosurgery has long been the most accepted method of rectifying brain abnormalities, stereotactic radiosurgery is becoming a more frequent, and arguably more efficient approach to treating certain cranial lesions. Despite its name, stereotactic radiosurgery is a non-invasive procedure that does not require opening the skull, which reduces hospitalization time and improves quality of life for patients (Lippitz, 2004). This alternative to conventional surgery focuses multiple high-energy radiation beams on a specific area of the brain in order to irradiate intracranial lesions with minimal destruction of any normal tissue.

The three forms of stereotactic radiosurgery currently in use include the charged Particle B e a m (or"Cyclotron"), the Linear Accelerator (commonly referred to as the LINAC system), and the G a m m a Knife®. The Particle B e a m unit is successful in treating unusually-shaped tumours, as well as those which reside outside of the cranial cavity, such as in the spine and base of the skull (John Hopkins Medicine, 2005). The LINAC system operates by transmitting x-ray photons to destroy cancer cells (Deinsberger & Tidstrand, 2005). The G a m m a Knife" is constructed in such a way that numerous, small high-energy g a m m a ray fields converge on a specific location, making it the most accurate form of stereotaxis. D u e to its extraordinary precision, the G a m m a Knife® is ideal for targeting small, intracranial tumours that m a y otherwise be inoperable. This surgical alternative can also be used in conjunction with conventional surgery, allowing for less complicated operations and resulting in fewer risks.

G a m m a Knife® surgery can be used to treat m a n y types of brain tumors, whether benign or malignant, primary or metastatic. A primary tumour refers to a growth located at the same site from which it originates, whereas a metastatic tumour develops from cancer cells that have spread from a different location within the body, such as from the breast or lung (Medline Plus Medical Dictionary, 2003). G a m m a Knife® surgery is also useful for treating arteriovenous malformations (AVMs), which are a m o n g the leading causes of stroke in young people.

A V M s are arteries and veins that have tangled and can cause haemorrhage in the brain, as well as headaches and seizures.The G a m m a Knife® has proven to be a valuable substitute for invasive surgery, especially in cases where the lesion is e m b e d d e d deep within the brain, near or inside of vital regions (Kobayashi, Mori & Kida, 2003).

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INTRODUCTION TO GAMMA KNIFE® SURGERY

The fundamental principles of stereotactic radiosurgery include the selective irradiation of targeted tissue while sparing the surrounding normal brain tissue and without physically opening the skull. For each G a m m a Knife® treatment, ionizing g a m m a rays are emitted by 201 radioactive cobalt-60 sources with a c o m m o n focal point, and allows the radiation to converge simultaneously at the target (Papagiannis et al., 2005).The term " g a m m a ray" refers to the electromagnetic radiation emitted from the nucleus during a radioactive process (Figure 1).

Nuclear radiation is a result of the powerful strain between the opposing nuclear strong force and the electromagnetic forces, which are the two strongest basic forces. For this reason, the resulting g a m m a rays are very high-energy beams of radiation, with wavelengths of less than 1.0 x 10"12 m. With their extremely high energy level, g a m m a rays possess ionizing properties that can therefore be harnessed for this type of medical treatment (Nave, 2005).

While the radiation does not physically remove the brain abnormality, the emitted photons ionize the targeted tissue mass, triggering the production of free radicals. These inorganic ions are deleterious to the cellular and nuclear membranes of the target cells, as well as to their R N A and D N A molecules. W h e n the procedure is successful, the vital structures of the tumourous cells are destroyed, resulting in cell death and a gradual shrinkage in the volume of tissue until it is completely destroyed. The duration of the process depends on the type of tumour, as it generally requires only a few weeks with regard to metastases, but can take years with slow-growing benign tumours or AVMs. The dose of radiation absorbed by the treated tissue can define the rate of biological inactivation. This is measured in Gray units, where one Gray (Gy) is the absorption of one joule of radiation per kilogram of tissue mass (Guo et al., 2004).

GAMMA KNIFE® SURGERY: PROCEDURE

In order to begin treatment with the Gamma Knife®, a local anaesthetic is administered and an aluminium frame is attached to the patient's head, secured with sterile pins. This ensures that there is no head m o v e m e n t throughout the procedure, and that the highly focused g a m m a rays are appropriately guided to their

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precise location. With this frame in place, the patient is scanned using computed tomography (CT scan) or magnetic resonance imaging (MRI) technologies in order to determine the exact location of the lesion. The precise coordinates generated from the imaging studies unit are then relayed to the G a m m a Knife's® three-dimensional computer planning program.The image from this computer software allows the team of specialized medical professionals to focus the beams on the target area to within 0.3 m m accuracy, decide upon a dose, and calculate the radiation exposure times (Hayashi & Izawa, 2004). Upon completion of this planning, the patient enters the room containing the G a m m a Unit, which is composed of a moveable couch and 201 sources of cobalt-60 within a heavy shielded vault. The head frame is secured to a hemispherical helmet with 201 collimator parts that correspond to the radiation sources. To c o m m e n c e treatment, the vault doors open, and the couch advances until the cobalt source and collimators align (Figures 3 and 4). Throughout the treatment, the g a m m a rays delivered from the helmet's 201 sites converge at the precise coordinates determined during the planning stage. This arrangement ensures that the surrounding tissue receives minimal exposure, while the tumour receives m a x i m u m radiation due to the convergence of all of the beams (Dr. A. Kaufmann, 2006, personal communication) (Figure 4).

The positive effects of a G a m m a Knife® treatment are realized over time. Upon completion of the treatment, periodic imaging studies may be conducted, depending on the target (University of Maryland Medical Centre, 2004).

Manitoba, making this still a relatively new form of surgical treatment for Canadian patients (WRHA, 2003). Despite its m a n y benefits, G a m m a Knife® surgery is associated with inherent risks, such as cerebral e d e m a (swelling of the brain), radionecrosis (the death of brain tissue), and cranial nerve palsy (loss of sensation or movement, due to injury of the cranial nerves) (Medline Plus Medical Dictionary, 2003). Studies have shown that conventional radiation therapy has induced secondary neoplasia in patients, or tumour formation, m a n y years after their treatment is completed (Ganz, 2002). Since g a m m a radiation ionizes matter, it is also capable of producing adverse physiological effects in cells, including mutations or cancer. Initially, treatment with the G a m m a Knife® can put patients with left temporal lobe epilepsy at a higher risk of seizures, but overall, the long-term effect includes a reduction in the occurrence of seizures (Ganz, 2002).

There m a y also be neuropsychological side effects for these patients, as studies indicate s o m e experience a significantly delayed verbal m e m o r y for up to two years following treatment with the G a m m a Knife®. (McDonald et al., 2004). In most cases, however, the risks associated with G a m m a Knife® treatment are lower than those associated with either open surgery or with leaving the disease untreated. While G a m m a Knife® surgery can offer therapeutic benefits in certain cases, these advantages must be weighed against the associated disadvantages for each individual patient before determining whether results will be more favourable with this non-invasive procedure or with conventional surgery.

ARTERIOVENOUS MALFORMATIONS

GAMMA KNIFE® SURGERY: PROS AND CONS

Although Gamma Knife® surgery is still evolving with regardAlthough to its 60% to 70% of patients with AVMs are treated with applications, it has been deemed successful at treating a variety conventional microsurgery, G a m m a Knife® treatment has of intracranial conditions. This technology was first developed in become an accepted alternative for all A V M s smaller than 3.5 1962 in Sweden and became widespread in the 1980s, with units c m in diameter. Certain patients are considered unsuitable located in a variety of countries. There are currently over 200 candidates for invasive surgery, such as in cases where the G a m m a Knife® units worldwide, and over 300 000 patients have abnormality lies in vital portions of the brain or is surgically been treated (Medical College of Georgia, 2005). Canada did not inaccessible (Kobayashi, Mori & Kida, 2003). Studies show, begin using the G a m m a Knife® technology until 2003, w h e n the however, that unlike conventional surgery, this form of first unit was installed at the Health Sciences Centre in Winnipeg, stereotactic radiosurgery does not protect the patient from the

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patients in the study had 3 or more metastatic brain tumours, and treatment with radiosurgery positively affected survival rates after diagnosis with the brain disease. (Jawahar et al., 2005). In terms of primary malignant brain tumours, the G a m m a Knife® is not typically used as a method oftreatmentasofyet. (Minnesota Department of Health, 2004).

TRIGEMINAL NEURALGIA

Figure 2: G a m m a Knife* Unit, composed of moveable couch and hemispherical helmet containing 201 cobalt-60 radiation sources (Indiana University School of Medicine, 2004).

risk of haemorrhage before the abnormality has been occluded.

Despite the fact that complications with G a m m a Knife® surgery include bleeding during the latency period after the surgery, the risks associated with traditional neurosurgery are still greater (Kaufmann, 2006, personal communication).

Trigeminal Neuralgia isadisorderof cranial nerveVfthetrigeminal nerve), causing attacks of intense pain on one side of the face where the branches of this nerve are distributed (John Hopkins Medicine, 2005). In recent years, G a m m a Knife® radiosurgery has become a widely used treatment for people unresponsive to other medical therapies for trigeminal neuralgia, and is also an alternative to more invasive surgical options. Increased experience with its use, along with advances in imaging, have underscored the importance of the G a m m a Knife® as a treatment option (John Hopkins Medicine, 2005). This method of treatment does pose s o m e disadvantages, however, for although it is perhaps the safest and easiest surgical treatment available for Trigeminal Neuralgia, it is also associated with a delay of a few weeks prior to pain relief, as well as with the lowest chances of permanent pain relief (John Hopkins Medicine, 2005).

GAMMA KNIFE® SURGERY: CONCLUSION

BENIGN BRAIN TUMORS

The introduction of Gamma Knife® surgery into the Canadian healthcare system has successfully offered hope to patients w h o In many cases, complete surgical removal is the preferred method of treating benign tumours; however, G a m m a Knife® radiation are poor candidates for conventional surgery or w h o prefer a less is the treatment of choice in instances where patients are likely invasive treatment. Although use of G a m m a Knife® surgery has to experience surgical complications, or where the tumor is only been implemented within the last few decades, it has been located near a vital location of the brain. Success rates following very effective in treating c o m m o n neurosurgical diseases, and its treatment with the G a m m a Knife® of benign tumours are up to future remains very positive. A number of future applications are 90%, in which there is no further growth over a follow-up period currently being investigated, including treatments for Parkinson's Disease, epilepsy and other neurological disorders (Jawahar et of at least four years. (Minnesota Department of Health, 2004).

MALIGNANT BRAIN TUMORS Gamma Knife® surgery is highly effective in treating brain metastases 3 c m in diameter or smaller. Studies indicate a very low rate of associated morbidity, as well as very successful rates of local tumour control (Lippitz, 2004). This form of radiosurgery is also valuable in treating multiple metastases, as well as lesions that are resistant to traditional radiation therapy (Lippitz, 2004).

G a m m a Knife® radiation is especially useful in treating brain metastases due to melanoma and renal cancer. These lesions are particularly radio-resistant and therefore require the high doses which can be delivered with the G a m m a Knife® (Tarhini & Agarwala, 2004).There is still controversy, however, as to whether treatment of these lesions with G a m m a Knife® surgery increases survival rates in comparison to conventional radiation therapy (Kaufmann, 2006, personal communication). G a m m a Knife® surgery is n o w also used to treat individuals with multiple brain tumours. In one study involving patients with multiple newly diagnosed intracranial metastases from k n o w n primary cancer Figure 3: G a m m a Knife* approach: beams of g a m m a radiation are emitted from locations (the primary cancer being lung cancer in 6 6 % of the 201 cobalt-60 radiation sources, so that the surrounding tissue receives minimal exposure, and the rays converge on a precise targeted location. In this way, cases), the growth of tumours was arrested in 8 2 % of subjects the area within 0.1 m m accuracy of the coordinates is the only tissue receiving treated with the G a m m a Knife® (Jawahar et al., 2005). All of the m a x i m u m ionization from the radiation (Mayo Clinic, 2004). www.meducator.org

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Figure 4: The G a m m a Knife8 bombards the tumour with multiple beams of g a m m a radiation (BBC News Online, 1998).

Lippitz, B. (2004). G a m m a knife surgery improves the treatment of intracranial tumors. Lakartidningen, 30,101 (40), 3078-80.

MayoClinic Online. (2004). G a m m a knife radiosurgery: Neurosurgery without a scalpel. MayoClinic: Brain and Nervous System Centre.

Retrieved from http://www.mayoclinic.com.

McDonald, C.R. et al. (2004). Neuropsychological changes following g a m m a knife surgery in patients with left temporal lobe epilepsy: a review of 3 cases. Epilepsy Behave, 5(6), 949-57.

Medical College of Georgia. (2005). Southeast G a m m a Knife Centre.

Retrieved from http://www.mcg.edu/som/neurosurgery/ GKHistory.htm.

Medline Plus Medical Dictionary. (2003). U.S. National Library of Medicine. Retrieved from http://www.nlm.nih.gov/medlineplus/ mplusdictionary.html.

REFERENCES Minnesota Department of Health Online. (2004). Stereotactic Radiosurgery - Neurological Applications. Retrieved from http:// BBC News Online. (1998). Brain Tumor Surgery Without the Scalpel. www.health.state.mn.us/htac/srna.htm.

Retrieved from http://news.bbc.co.uk/ Nave, C.R. (2005). HyperPhysics: G a m m a Rays. Georgia State University.

Deinsberger, R., &Tidstrand, J. (2005). Linac radiosurgery as a tool in Dept. of Physics and Astronomy. Retrieved from http:// neurosurgery. Rev. Neurosurgery, 28(2), 79-88; discussion 89-90, hyperphysics.phy-astr.gsu.edu.

91.

Papagiannis P. et al. (2005). Three-dimensional dose verification of Ganz, J.C. (2002). G a m m a knife radiosurgery and its possible clinical application of g a m m a knife stereotactic radiosurgery relationship to malignancy: a review. J Neurosurg, 97 (5 Suppl), using polymer gel and MRI. Phys M e d Biol, 50(9), 1979-90.

644-52.

Tarhini, A.,A., & Agarwala S.,S. (2004). Management of brain metastases Guo W.Y. et. al. (2004). Individuals' leukocyte D N A double-strand break in patients with melanoma. Curr Opin Oncol, 16(2), 161-6. repair as an indicator of radiosurgery responses for cerebral University of Maryland Medical Centre Online. (2004). G a m m a Knife arteriovenous malformations. J Radiat Res, 45(2), 269-74.

Centre -Treatment Process. Retrieved from http://www.umm.

Hayashi, M., & Izawa M. (2004). G a m m a knife surgery. Nippon Rinsho, edu/gammaknife/process.html.

62(4),677-88.

Winnipeg Regional Health Authority (WRHA). (2003). Canada's First Indiana University School of Medicine. (2004). G a m m a knife surgery. and Only State-of-the-Art G a m m a Knife Unveiled at Winnipeg's Dept. of Neurosurgery. Retrieved from http://www.iupui.

Health Sciences Centre. Retrieved from http://www.wrha.mb.ca/ edu/~neurosur/home.html. howcare/mdesk/news001 .php.

Jawahar, A. et al. (2005). Role of stereotactic radiosurgery as a primary treatment option in the management of newly diagnosed multiple (3-6) intracranial metastases. Surg Neurol, 64(3), 207-12.

Jawahar, A. et al. (2004). Stereotactic radiosurgery using the Leskell g a m m a knife: current trends and future directives. Front Biosci, 1(9), 932-8.

John Hopkins Medicine. (2005). Stereotactic Radiosurgery. Retrieved from http://www.hopkinsmedicine.org/radiosurgery/generalinfo/ aboutradiosurgery.cfm Kobayashi, T, Mori, Y., & Kida, Y. (2003). G a m m a Knife Radiosurgery.

Gan To Kagaku Ryoho, 30(13), 2043-9. al., 2004). As the G a m m a Knife® emerges as a primary m e t h o d of treatment for m a n y brain disorders, n e w possibilities for this technology will arise, widening the scope of patient care (Jawahar et al., 2004). Presently, however, the G a m m a Knife® improves the quality of life for m a n y patients with brain abnormalities (Hayashi & Izawa, 2004). By shortening hospitalization times, reducing post-operative side effects, eliminating the risks associated with anaesthesia, and removing the need for lengthy radiation therapy following intensive neurosurgery, it is no w o n d e r that the G a m m a Knife® is considered by m a n y patients to be a miracle treatment. |fl

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23

The Face of Autism

Sophie Kuziora

E a r l y childhood autism was first described by Dr. Leo Kanner 1994; Smalley, 1998; Williams & Hersh, 1998). Once thought to in 1943, yet there are m a n y reports of the existence of this be caused by neglectful or abusive parental behaviour, it is n o w disorder well before it was formally recognized (Olley, 1999; widely accepted that autism is a neurobiological disorder with Frith, 2003). As it is defined today, autism is estimated to affect 13 a strong genetic basis (Bettelheim, 1967; Volkmar, Chawarska & in 1000 children (Fombonne, 2005). According to the Diagnostic Klin, 2005; Baron-Cohen, 2004). As of yet, there has been no single and Statistical Manual of Mental Disorders IV (DSM-IV) and the environmental risk factor that has been shown to increase the risk World Health Organization (WHO), autism is classified as the of autism (Fombonne, 2003). As its onset typically occurs before most severe type of pervasive developmental disorder (PDD). It 3 years of age, autism and other PDDs can be diagnosed by 24 is characterized by a triad of behavioural abnormalities, namely, months. Unfortunately, early diagnosis does not always occur difficulty in social development and communication, as well as (Volkmar & Pauls, 2003). It is often years after parents have noticed repetitive or obsessive interests (APA, 1994; W H O , 1993; Baron- signs and have sought professional help that their child gets a Cohen, 2004). All three deficits must be present for a positive diagnosis. Factors such as the lack of availability and accessibility diagnosis of autism, while less severe or fewer deficits m a y result of appropriate tools and awareness of health care professionals in a positive diagnosis of another PDD. Here w e will explore the contribute to delays in intervention. This is problematic, as early life of a child affected by autism, including difficulties faced intervention for autism is most beneficial w h e n managed at an by the child and his or her family, and what can be done to help earlier stage (McGahan, 2001; Erba 2000). them. Furthermore, w e will investigate s o m e of the uncertainties and issues that d e m a n d further research.

AUTISM AND DIAGNOSIS Since its official discovery, the understanding of autism has changed dramatically. Kanner originally reported no association The American Academy of Neurology recommends screening for of autism with other disorders, although more recent research autism in children that fail to meet developmental milestones. has shown a link between autism and disorders such as Fragile Validated screens include The Checklist for Autism in Toddlers, to X Syndrome, epilepsy, mental retardation, tuberous sclerosis be used for infants and toddlers (up to 18 months);The Screening and neurofibromatosis (Rutter, Bailey, Bolton & LeCouteur, Tool for Autism in Two-Year-Olds; and the Autism Screening Questionnaire, for children older than four years of age (Stone, Coonrod, Turner & Pozdol, 2004; Filipek et al., 2000). Autism is diagnosed by experienced clinicians using standardized diagnostic tools that focus on the symptoms of autism through observation of the child's behaviour rather than by examination of etiological factors. Instruments for diagnostic observation include the Childhood Autism Rating Scale, and the Autism Diagnostic Observation Schedule-Generic (ADOS-G) (Lord et al., 2000). Also useful are diagnostic parental interviews, which include the Gilliam Autism Rating Scale, The Parent Interview for Autism, The Pervasive Developmental Disorders Screening Test and the Autism Diagnostic Interview- Revised (Filipek, Accardo, Ashwal, Baranek, Cook, Dawson, et al., 2000). These systematic interview and observation schedules for diagnosis seek to find typical autistic signs and symptoms in a combination that would synergistically point to a PDD. Due to the symptoms exhibited by children with autism, a lack of social interest m a y be observed during their first year of life.

Impairment in social interaction includes minimal eye contact, a Figure 1: Interactive social behaviour, as seen here, m a y be absent in children with autism (Courtesy of Dr. Lonnie Zwaigenbaum). lack of social reciprocity, and reluctancy to form peer relationships (Volkmar & Pauls, 2003). Failure to respond to verbalizations or to one's name, as well as a tendency to be more interested in objects www.meducator.org

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24 "MEDUtiJOIt than in people may also be observed (Volkmar, Chawarska & Klin, 2005). Other behaviours in these young children include atypical eye contact and visual tracking, lack of visual attention, imitation, and reactivity (Zwaigenbaum et al, 2005). It has also been shown that impaired sensory-motor functioning, in the form of abnormal movement patterns, object manipulations, and postural adjustments, also have the potential to serve as an early marker of autism in infancy; however, signs of impairment usually become more evident as the autistic child grows older (Baranek, 1999).

Problems associated with communication involve a lack of language with no attempt to compensate for communication, or, if language is present, echolalia and persistent pragmatic difficulties (Volkmar & Pauls, 2003). This would include an absence of gestures and facial expressions. A child with autism is unlike a child w h o is hearing impaired, as those children will typically find alternate means of communicating their needs.

Other behaviours typically seen in young autistic children are abnormal preoccupations, interests or activities; difficulties with a change in routine; and stereotyped mannerisms (Volkmar & Pauls, 2003). One example might be an unusual interest in a certain object, like beads on a string or spinning the wheels of a toy truck. A child with autism m a y have elaborate rituals or routines that are followed meticulously, and may even possess obsessive tendencies. Autistic stereotypes include odd finger movements orfingerflicking, hand flapping, and body rocking or unusual posturing.

A "sensory phenomena" is often reported in children with autism. Although not necessary for a diagnosis, many autistic children seem to exhibit either a hyper or hyposensitivity to certain stimuli. This m a y result in either a heightened tolerance or sensitivity to pain, sound, smell, taste, or sight (Frith, 2003).

INTENSIVE APPLIED BEHAVIOURAL ANALYSIS

Intensive Applied Behavioural Analysis (ABA) - widely used in Ontario - is based on a method developed by I.O. Lovaas. Children are subjected to the reinforcement-based, intensive, one-onone treatment for 20-40 hours per week over a span of two years (Lovaas, 1987). A B A is clearly beneficial to m a n y children with autism, and although there is evidence for its efficacy, controversy still exists with regards to its true benefit. Lovaas' study (1987) is methodologically stronger than m a n y studies looking for similar outcomes, despite s o m e major problems such as lack of randomization and limited outcome measures (Bryson, Rogers & Fombonne, 2003). Lovaas lacks the power to m a k e such strong claims such as the achievement of normal functioning, making many researchers hesitant to accept his results (Basset, Green & Kazanjian, 2000). In the face of these limitations, several problems arise. The challenge becomes providing effective intervention, while simultaneously obtaining useful information regarding the facets of treatment and program intensity (Miller & Zwaigenbaum, 2001). Sheinkopf and Siegal (1998) performed a study that observed the development of children and the impact of intensive behavioural treatment in a h o m e environment. The researchers found higher post-treatment IQ scores as well as decreased symptoms in those children w h o had received the treatment. However, all patients continued to meet criteria for autism and P D D (Sheinkopf & Siegal, 1998). From this evidence, it is clear that ABA is effective and beneficial, but cannot provide a complete solution.

TEACCH

The Treatment and Education of Autistic and Related Communication Handicapped Children Program (TEACCH) is a INTERVENTION & TREATMENT program that focuses on developing cognitive, academic, and prevocational skills in school-aged children (Ozonoff & Cathcart, Despite early claims of a cure (for example, Lovaas, 1987), autism 1998). Developed in 1966 at the University of North Carolina, the is a lifelong disability (Volkmar & Pauls, 2003). Because of links TEACCH program provides a structuralized environment for skill between autism and various neurological signs, it is widely acquisition. It aims to gradually help children gain independence accepted that autism is a neurological disorder, despite the fact and hone in on a child's strengths in areas such as visual-spatial that its etiology is still to be established. In the absence of a cure understanding and object manipulation (Schopler & Reichler, targeted at the basic etiology, treatment for autism is based 1971; Dawson & Osterling, 1997; Bryson, Rogers & F o m b o n n e on behavioural, developmental, and educational approaches. 2003). It utilizes parents as co-therapists to increase intervention However, in the absence of randomized controlled trials that time. In a study that compared children w h o received the utilize appropriate methodology to test the effects of these home-based treatment to children that did not, the former interventions, many questions still remain unanswered (Howlin, demonstrated significantly greater improvement in areas such 2005). It has become evident that no one treatment for autism as imitation, fine motor, gross motor, and cognitive performance, will be effective for all autistic children, thus treatments need and to a lesser extent, greater improvement in perception, and to be adapted for every individual's needs (Howlin, 1998). Early cognitive verbal skills (Ozonoff & Cathcart, 1998). Despite limited detection and intervention is of high priority forthe best outcome generalizations of the results due to design of such studies, from any treatment (Bryson, Rogers & Fombonne, 2003). Several these results outline the effectiveness of the T E A C C H treatment models for treatment are available and implemented, some of program for improving cognitive and developmental skills. which are described here.

As stated above, every intervention needs to be LEARNING EXPERIENCES...AN ALTERNATIVE PROGRAM FOR individualized and well planned to suit each child. However, PRESCHOOLERS AND PARENTS (LEAP) in general, a therapy that is consistently applied, and targets language and other areas of development will significantly aid in the child's development, language and cooperative skills The LEAP program was developed in 1984 by Hoyson, Jamieson and Strain, and is administered for about 15 hours'per week (Bryson, Rogers, & Fombonne, 2003).

(Dawson & Osterling, 1997). It incorporates a combination of several learning theories, with the primary focus being social

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Family physicians and primary health care providers need to become increasingly aware of the early warning signs of autism in order to provide optimal care for children w h o are at risk. Physicians, teachers, and other health professionals w h o suspect the presence of typical autistic tendencies should refer the child to a specialized assessment, with clinicians trained in the diagnosis of autism. It is through early diagnosis that the opportunity for intervention, a better outlook for the child, and ultimately, a happier family are m a d e possible. E9 A special thank you goes to Dr. Lonnie Zwaigenbaum for his time, support, guidance, and helpful discussions throughout the whole process of the preparation of this article.

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Rozga, 2004).

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Werner, E., Dawson, G., Osterling, J., & Dinno, N. (2000). Brief Report:

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