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:)ERSPECTIVES THROUGH THE MILLENNIUM

LIPITOR* Is an HMG-CoA reductase Inhibitor (stalin) . LIPITOR is indicated as an adjunct to diet for lhe reduction of elevated total cholesterol, LDL -C, triglyce rldes, and apolipoprotein Bin hypertipidemic rI and dyslipidemlc conditions I Oncluding pnmary hypercholesterolemia, combined [mixed] hyperlipidemia , dysbetallpoprotelnemla , hypertriglyceridemia, and familial hypercholesterolemia) when response to diet and other non-pharmacological measures alone has been inadequate. See prescribing information for complete warnings, precautions, dosing and administration. LIPITOR Is contraindicated during pregnancy and lactation. Lipid levels should be monitored pertodlcally and, ~ necessary,the dose of LIPITOR adjusted based on target lipid levels recommended by guidelines. Caution should be exercised In severely hypercholesterolemic patients who are also renally impaired, elderty, or are concomitantly being administered digoxinor CYP 3A4 inhibitors. Liver function tests should be performed before the Initiation of treatment, and periodically thereafter. Special attention should be paid to patients who develop elevated serum transaminase levels, and In these patients measurements should be repeated promptly and then performed more frequently. The effects of atorvastaijn induced changes In lipoprotein levels, Including reductlon In serum cholesterol, on cardiovascular morbidity, mortality,or total mortality have not been established.

Recent clinical data showed that LIPITOR actually gets patients to target with fewer titrations and fewer repeat visits than Przoco~ (simvastatin), PrPravachol®(pravastatin) or Prlescol®(fluvastatin).1¥ •

Exceptional LDL-C reductions of

•

Significantly better LDL-C and TC/HDL-C ratio reductions compared to Zocor or Pravachol at starting doses 3 •4 §t

(Type I Ia and lib) over the full dose range 2

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'TM Pfrzer l~el.lnd Pharmactutuls Pfizer CaNda Inc_, hctnsee

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•

Competitive price - LIPITOR costs less than Zocor or Pravachol at usual starting doses*

•

Less than 2% of patients discontinued therapy due to adverse experiences. Most common adverse effects were myalgia, headache, constipation, diarrhea, dyspepsia, flatulence and nausea 2

Y Results from a 54-week. randomiZed. open-label. ueat-to-target study w1th 336 patients enrolled Patients were ueated wnh LIPITOR 10 mg ln=1401. Lescol20 mg ln=581. Pravachol20 mg ln=721 or Zocor 10 mg ln=661 and uuated un111 LDL -C target was ach1eved Cholestyram1ne was added lor pat1en1s not reaching LOL-C target at max•mum dose pdJ 005 § Results at 16 weeks 1n a study of 177 hypercholesterolemic patients taking UPITOR 10 mg or Zocor 10 mg In a one-year, randormzed. double·bllnd study. The UPITOR group had LDL -C and TC reductions ol 37% and 29% and an HOL Cmease of 7%, while lhe Zocor group had LDL-C and TC reducllons of 30% and 24% respectrvely fp<O 051 and an HOL Cmease of 7%. t Results at 16 weeks 1n a sludy of 305 hyperdloleslerolemic patients laking UPITOR 10 mg or Pravadlol20 mg In a one-year. randomized. double blind s1udy The UPITOR group had LDL-C and TC reducllons of 35% and 5% and an HOL ·C 1ncrease of 6%, wh1le lhe Pravachol group had LDL -C and TC reductions of 23% and 17% respectiVely IP<O 051 and an HOL -C 1ncrease of 8% t Based on acqu1srt1on costs. excluding dlspenslng fees for a 30-day scnpt of lhe stalin at lhe usual starllng dose, LIPITOR (10 mg1 costs $48, and Zocor 110 mg) and Pravadlolj20 mg1 each cost $53 40 Adapted horn reference 5 Registered triidefml<s Zri:J:Jr- t.'e"ck Frosst. Pravachol - Bnstoi-Mye!s SqJ!t, Lescd' - N<war!Js

Mtmbu

OMJ Volume 71 Number 1

Spring 2001

Contents

Editorial Perspectives Through the Millennium Mason Ross, Editor-in-Chief

3

Feature Articles Anesthesiology: Continually seeking to provide improved comfort for patients John Fuller, Jamie McKishnie, Adrian Gelb Cardiac surgery - Past, present and future a London perspective F Neil McKenzie Emergency medicine: The newest specialty Rocco Gerace, Bill McCauley Epidemiology: Past, present and future Mark Speechley UWO family medicine at the millenium Thomas R. Freeman Hemato logy: Past, present, future Reinhard C. Lohman History of medicine Paul Potter Medical genetics in the new millennium Jack lung, Hubert So/tan

4

Neurology: from nihilism to the beginnings of hope.

Jose G. Merino, Vladimir Hachinski

27

Ophthalmology at the millenium: important recent developments in prevention and treatment of eye disease N R. Willis

31

Otorhinolaryngology in the year 2000 A look in both directions Erin D. Wright

34

A Tradition of Excellence -A Challenging Future Timothy C. Frewen

38

Physical medicine and rehabilitation in the 21st century Keith Sequeira, Keith Hayes

41

Psychiatry Emmanuel Persad, Praful Chandarana

43

A century of radiation oncology Gleen Bauman, Jerry Battista, Jake VanDyk

46

Radiology and imaging: Past, present and future.

Richard N Rankin

52

Sport Medicine P 1 Fowler

55

Urology as a specialty: From papyrus to palm pilots Joseph L. Chin, Hassan Razvi

57

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8

11

15

18

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Š 2001 UWOMJ UWOMJ is published biannually

Editorial Staff

Next Issue:

EDITORIAL BOARD

Surgery

COVER ART

Editor-in-Chief (middle) Senior Associate Editor Oeft) Junior Associate Editor (right)

Mason Ross Eric Wong Jason Ashley

Meds 2001 Meds 2002 Meds 2003

A native of London, Ontario, Scott Kish obtained his degree in Kinesiology from the University of Waterloo, where he specializes in anatomy and visual information processing. As a self-taught illustrator, Scott delivers a unique style of conceptualizing complex information pertaining to the human body to attract attention and increase comprehension. His work appears both locally and internationally with clients including doctors, lawyers, advertising agencies, etc.

HUMAN iNTERACTIVE INC. Medical Illustration & Graphics

DEPARTMENTAL EDITORS Ethics Sr. : Michael Lee-Poy, Meds 2003 Sr. : Kim Gilmour, Meds 2003 Jr. : Boris So, Meds 2004

Thinking on Your Feet Sr.: John Lee, Meds 2003 Jr.: Shashie Sade, Meds 2004

History of Medicine Sr.: Allison Suk, Meds 2003 Jr. : Chetna Tailor, Meds 2004

Vocabulary Sr. : Joe Chan, Meds 2002 Sr.: Heather Cockwell , Meds 2002 Jr. : Chris Chu, Meds 2003

Humour Sr. : Keir Peterson, Meds 2003 Jr.: Jessica Hopkins, Meds 2004

Zebra Files Sr: John Stein, Meds 2003 Jr: Chinedu Onochie, Meds 2004

Medical Myths Sr.: Heather Cox, Meds 2003 Jr. : Elizabeth Au-Yeung, Meds 2004

Senior Editors Allan Ve can, Meds, 2001 Ben Barankin, Meds, 2001 Dan Mendon9a, Meds 2001 Dav id Satin , Med , 200 I Helen Lewa ndowski, Meds, 200 1 Matt Crystal, Meds, 2001 Mahmoud haraf, Meds 2002 Mun if Bhimani, Meds 2002 Najib Safieddine, Meds 2002 Nyan Narine, Meds 2002

Medicine and the Law Sr. : Azadeh Moave ni , Meds 2003 Jr.: Birinder Singh , Meds 2004 Medicine on the Internet Sr. : Mark Baumgartner, Meds 2003 Jr. : Gabriel Chang, Meds 2004 Profiles Sr.: Naji Touma, Meds 2003 Jr.: Maryanne Rockx, Meds 2004

Poster Designer Eli zabeth Au- Yeung, Med 2004

Promotion and Prevention Sr. : Albina Veltman, Meds 2003 Jr.: Alan Kahn, Meds 2004

UWOMJ ADVISORY COUNCIL Dr. Colby, Microbiology Dr. Wexler, Ane thesiology Dr. Rieder, Ped iatrics

Dr. Silcox, Ob tetrics I Gynecology Dr. Nisker, Obstetrics I Gynecology Dr. Gupta, Card iology

ADVERTISING Ken mara

PRINTER Willow Printing Group Ltd .

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VWOMJ 71(1) 2001

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All editorial matter in UWOMJ represents the opinions of the authors and not necessari ly those of the editorial staff and advisory council. The editorial staff and advisory council assume no responsibility or liability for damages arising from any error or omission or from the use of any information or advice contained in UWOMJ. Canada Post - Publication Mail Agreement Number 1720198 POSTMASTER: Undeliverable copies, please return to address above.

Editorial

Perspectives Through the Millennium

Mason S. Ross Faculty of Medicine, Class of 2001 Editor-in-Chief, 2000-2001 UWO Medical Journal

Medicine is an evolving science and art. Change is rampant.

The twentieth century has been witness to an explosion of medical advances and will arguably be remembered most for its therapeutic achievements. With the development of antibiotics, infection does not carry the same death sentence it once did. With the discovery of insulin, diabetics have a chance for a longer, healthier life. The last hundred years have seen the creation of multiple vaccines, refinement of radiation and chemotherapy, and effective treatments for mental illness . Diagnostic abi lity has also advanced tremendously. From the discovery of X-Rays a little over one hundred years ago to today's CT scanners and MRI 's, medicine is providing pictures of the innermost regions of the human body that were unimaginable not long ago. The laboratory is increasingly able to confirm diagnostic suspicions with higher degrees of sensitivity and specificity. Medical technology is raising the bar. The dissecting microscope has enabled replantation of severed body parts, laparoscopic surgery has decreased operative morbidity, and cardiac surgeons are using robotics to push the boundaries of what is possible. We are on the frontier of bringing gene therapy and other forms of biotechnology from the bench to the bedside. Medicine has come far indeed, and the future has never held as much promise.

People have changed as well, both patients and doctors alike, and the landscape of practice has changed along with them.

Rapidly becoming extinct is the mentality of the paternalistic doctor and complacent patient. With increasing education and awareness, patients are taking an active role in their health care management. Multidisciplinary teams are becoming standard in

the hospital environment, and doctors are being called upon to lead these teams to achieve optimal health outcomes. Patient capacity is being ensured and realizing therapeutic decisions is a joint effort. However, with these changes come new challenges.

The information age is well upon us and it is not uncommon for patients to present with information obtained fresh from the Internet, often with preconceived ideas along with it. Alternative medicine has gained enormous popularity, and herbal remedies and holistic approaches are part of today 's reality. How traditional medicine deals with these issues on the front lines of health care will have implications for patient outcomes and how the public ultimately perceives the profession.

Currently, in London, Ontario, the word change has many connotations. Traveling the wards of the city hospitals, one might think the word is synonymous with much physician frustration.

Funding the system has become increasingly difficult and physicians have to do more with less. There have been many, and will continue to be, major challenges in the practice of medicine.

However, it should not be overlooked that the current state of medicine in Canada is still one of, if not the best in the world; for patients, and for doctors. This issue was created to celebrate the practice of medicine, both challenges and triumphs alike. The faculty within each department was asked to submit an article with the purpose of reflecting on their discipline 's past, the current state of practice, and outlook for the future. With this in mind, the editorial staff of the UWO Medical Journal welcomes you to this special commemorative edition - Perspectives Through the Millennium .

UWOMJ 71 (1) 2001

3

Features

Anesthesiology: Continually seeking to provide improved comfort for patients

Jamie McKishnie MD Assistant Professor, Department ofAnesthesia, Th e University of Western Ontario

John Fuller MD Assistant Professor, Department ofAnesthesia, The University of Western Ontario

Adrian Gelb MB, ChB Professor, Departm ent ofAnesthesia, The University of Western Ontario

The history of anesthesia spans just over a century and a half.

Although Morton was initially credited with the first demonstration of ether anesthesia at the Massachusetts General Hospital in Boston, it was in fact a medical practitioner in rural Georgia, Crawford Long, who in 1842 first employed an ether-soaked towel to produce anesthesia for a surgical procedure. This application, like many discoveries that were to follow, was sparked by the serendipitous observation of the effects (and side effects) of substances initially employed for recreational purposes, in this case, "ether frolics ". The local anesthetic properties of cocaine were first demonstrated by Carl Koller in 1884 and led to a profusion of local and regional anesthetic techniques being demonstrated by the turn of the century (spinal , epidural and various nerve blocks).

Although initially practiced by surgeons and their assistants, it was apparent by the early years of the 20th century that anesthesia was developing as a separate di sc ipline. Chloroform and later cyclopropane were added to the armamentarium. Anesthesia in the United Kingdom benefited from its endorsement by Queen Victoria who received "chl oroform a Ia reine" for labour pain.

Major advances in pharmacology did not occur until the World War II era, but these immediately had a major impact on anesthetic practice (pentothal, lidocaine) and improvements in 4

UWOMJ 71(1 ) 2001

general anesthesia in particular. Canada's significant contribution to this era was the first clinical use of the muscle relaxant "curare", demonstrated by Griffiths and Johnson in Montreal in 1943 . This set the stage for the introduction of the techniques of routine endotracheal intubation and mechanical ventilation. The momentum of anesthesia as a specialty increased in the 1950's with the introduction of succinylcholine, a rapid onset, short duration muscle relaxant, and halothane, the first inhalationa1 agent deliberately synthesized for anesthesia, based on its molecular structure.

The 1960's saw a profusion of advances in pharmacology and technology. Equipment for monitoring the well-being of patients emerged from the laboratory to practical application in the operating room. Examp les of this included electrocardiography and spirometry. Perhaps the most significant improvements came from better understanding of human physiology and how anesthesia altered these processes. The evolution from a specialty based on empiric application to that of a scientific understanding of physiology (especia lly cardiorespiratory) and pharmacology, was greatly accelerated during this period. The 1970's and 80's saw significant advances in several areas. New drugs were synthesized specifically for anesthesia with pharmacokinetic profiles suited to the perioperative period, as well as decreased toxic

effects. The monitoring of patients ' physiologic processes was improved greatly with the development of pulse oximetry and capnography. National and international societies developed standards for the manufacture and use of anesthesia equipment. All of the foregoing led to improvements in patient outcome and safety.

Subspecialty anesthesia began to emerge in areas such as obstetric, pediatric and cardiac anesthesia. Anesthesiologists also began to utilize their skills beyond the operating room. They were a major force behind the development of modern intensive care units and critical care medicine; the management of chronic pain was first given special attention by anesthesiologists.

Anesthesiologists also took the lead in the development and teaching of resuscitation and airway skills outside the operating room.

London and the University of Western Ontario were the sites of significant contributors to anesthesia development. M. Keeri Szanto was an internationally recognized pioneer in the development of the concept and application of patient controlled analgesia (PCA) for postoperative pain management. Equipment innovations came from W. Spoerel and J. Bain (the Bain circuit - a coaxial breathing circuit) and also H. Norry (the Norry valve - a pressure-limiting device in anesthesia breathing circuits). In basic science, original work on the effects of anesthesia on pulmonary physiology was carried out by R. Knill - work that is still recognized as ground breaking.

The practice of anesthesia is currently undergoing major evolutionary changes. The steadily improving knowledge and techniques available to anesthesiologists, supported by innovations in drugs and equipment, have led to the ability to safely anesthetize patients with much more serious underlying disease. This permits a wider variety of surgeries to improve and prolong the lives of patients previously deemed inoperable.

The continuing move to outpatient ambulatory surgery offers new roles and opportunities for anesthesiologists. They are rapidly developing a role as perioperative physicians. As a result, the practice of anesthesia is being altered to encompass a much less hospital based patient population.

While the demand for traditional surgeries increases, a variety of specialties are undertaking investigative and therapeutic procedures outside the operating room. These include surgery, radiology, dentistry, and a variety of internal medicine subspecialties utilizing invasive techniques. For reasons of patient comfort or need for immobility for practicalities of the techniques, anesthesiologists are thus increasingly requested to participate in these nontraditional settings. This is challenging anesthesiologists to develop techniques and equipment specifically suited to these environments.

In the 1990's the specialty of anesthesia initiated the concept of active management of acute pain. There are now anesthesia coordinated acute pain management teams in most hospitals, with London Health Sciences Centre-University Campus being one of the firsts . These teams utilize anesthesiologists ' expertise with various ways of administering different systemic analgesics as well as their growing expertise with continuous nerve conduction blocks. In a similar vein, anesthesiologists are improving and ' expanding their ability to manage labour pain. The ongoing development of less traumatic needles, such as the pencil-point

needle, have allowed the introduction of techniques such as combined spinal epidural analgesia which provides the opportunity to offer "walking epidurals", allowing parturients to remain ambulatory as well as very comfortable during labour and delivery.

In the 150 years since the first successful public demonstration of anesthesia there has been very little progress in how anesthesiologists assess depth of anesthesia. Then as now, clinicians use a combination of intimate knowledge of the pharmacokinetics and pharmacodynamics of anesthetic drugs together with signs of sympathetic stimulation in the patient. The difficulties in finding an objective measure are the challenges of amalgamating molecular biology, neurophysiology and philosophy. The key elements involve how to define consciousness (or unconsciousness in the case of anesthesia), where anatomically does it reside, how do we non-invasively measure it, and how do we pharmacologically manipulate it? Some progress has been made recently by applying interesting mathematical analysis models, such as chaos theory and entropy, to the interpretation of the EEG. Given the growing number of medicolegal suits for awareness during anesthesia, there is great impetus for the development of such technology, but such medicolegal issues also frighten potential developers. However, having an objective measure of the depth of anesthesia against which to titrate drugs will represent a huge leap forward .

The continuing understanding of receptor pharmacology will undoubtedly lead to more highly specific drugs in anesthesia practice. For example, most intravenous anesthetics act as fairly nonspecific GABA agonists. The development of transgenic mice resistant to some anesthetics will lead to a clearer understanding of the receptor subtypes responsible for anesthesia. This, in turn, will result in the development of more specific and appropriate drugs. The future will thus bring the anesthesiologist the ability to target specific receptors, allowing accurate titration of individual elements of anesthesia to each patient's requirements.

The pharmaceutical industry will develop the ability to formulate these new drugs to be rapidly metabolized. The agents will be administered by continuous intravenous infusion allowing rapid titration to changing patient requirements for individual agents during a procedure.

Anesthesiologists have already developed a variety of computer simulators for drug pharmacokinetics and pharmacodynamics. The sophistication of these computer models will improve dramatically. This will allow anesthesiologists to develop expertise with new agents before administering them to real patients.

Computer simulation of other aspects of anesthesia will also expand, allowing trainees and practicing physicians to experience and learn from some of the greatest anesthesia challenges in a life-like setting without risk to a live patient.

The developments described above will result in constantly improving knowledge and capabilities for anesthesiologists. This will allow the specialty to offer ever-improving analgesia for acute and chronic pain, and support patients' safe passage through ever-more sophisticated diagnostic and therapeutic procedures.

UWOMJ 71(1) 2001

5

Cardiac surgery - Past, present and future - a London perspective

Dr. F Neil McKenzie MB. ChB, MD, FRCS(Ed) ProfessOI; Department of Surge1y, Division of Cardiac Surgery, The University of Western Ontario

Although heart disease has afflicted humanity since the earliest recorded antiquity surgical approaches to the problem were begun only in the past 50 years and routinely successful surgery is even more recent than that. At the turn of the past century the heart was considered surgica lly inviolate and indeed the occasional forays denounced or suppressed. In 1929, a German urologist threaded a ureteric catheter via his antecubital vein into his heart and then went to the x-ray department and recorded the event. Thus began the era of cardiac catheterisation . With this information came the realization that simple cardiac anomalies such as atrial septal defects could be corrected if some means could be found of either stopping or taking over cardiac function during the procedure itself. Early pioneers in this fie ld included Charles Lindbergh who worked with Alexis Carrell , the first surgeon to win the Nobel Prize in Medicine in 1912, on a heart-lung machine. Their efforts in the 1930's were hampered by the lack of anticoagulants, antibiotics and biocompatible materials. The first successful use in a clinical case of heart-lung machines was in 1953 . The subsequent efforts by many teams to refine and extend this new technology created the specialty of cardiac surgery.

Surgeons of that era who were attracted to the specialty had all completed full general surgical training and had a particular interest in thoracic disease which at that time was largely the surgical treatment of pulmonary cancer and tuberculosis. Since tuberculosis was usually managed in a sanatorium, far from the smog-filled city, this was where many of the initial cardiac surgical units began at least in the UK and Commonwealth countries.

That too was the background of London 's first cardiac surgeon.

Dr. John Coles completed his general surgical training at the University of Western Ontario under Dr. Angus McLachlin in the mid-1950 's. He subsequently obtained further thoracic and car6

UWOMJ 7 1(1 ) 2001

diac surgical tramrng in England before returning to Victoria Hospital in London to establish cardiac surgery in July 1955 . The lni earliest operations were primarily associated with correction 01 ,JO palliation of congenital abnormalities and, while the mortalit; oo and morbidity was significant, overall results were vastly bette 1m than the natural history of the condition being treated. ·a In the early 1960's functional substitutes for heart valves became available and it became possible to offer cardiac surger) ~ to many individuals with rheumatic valvular heart disease. Witl ~· the availability of antibiotics, rheumatic disease leading to valv .· damage is now rare, and it is all too easy to forget the struggles of;• an earlier era. Mortality was high, operations were prolonged anc !r complications frequent. It was common before valve replacemer ~~ to recommend dental clearance supposedly to minimise the ris r.& of endocarditis. It was also usual at that time prior to renal trans ,11 plantation to recommend prior gastrectomy to minimise the risl iQ 1 of postoperative gastrointestinal hemorrhage. Both these notion: c seem bizarre today but reflect the state of the art at the time. B)•Gt the end of the 60 's routinely successfu l adult and pediatric surger)•!UJ was avai lable in London with around 150 pump cases being pen ~ formed annually. m There was dramatic expansion in the numbers of potentia cardiac surgical candidates in the early 1970's with the develo u ment of coronary artery surgery. Just as visualisation of the brain circulation led to efforts to correct the problems shown so too did r selective coronary artery visualisation allow surgeons to experi· ment with various solutions. Since the advent of coronary angiog· · raphy preceded these solutions by a number of years it is possible ~ to follow a large number of individuals in whom the anatomy 0 . their coronary disease was known but for whom there was very · . little effective treatment. The mortality outlook with coronary dis- ,I

ease was clearly shown to be related to the severity of narrowing of the coronary arteries, the number of disease coronary arteries and whether the left ventricular pump function was damaged or not. In addition, these investigations showed that there was not a good correlation between symptoms and severity of di sease. It is of course hard to imagine similar studies being performed today.

Coronary angiography is not risk-free and information would have been useful to only a small number of patients who had typical symptoms of myocardial ischemia but who did not have major coronary artery di sea e.

In the mid-60 's the notion that there should be a universityaffi liated hospital in London gradually took hold and a number of physicians pre-eminent in their field were attracted. Whether a second cardiac surgical unit should open in London was debated but ultimately the advice of Dr. Ramsay Gunton, at that time Chief of Medicine and subsequently Royal Coll ege Pres ident, among others wa accepted. The hospital opened in 1972 and cardiac surgical procedures began in 1974.

The main thrust at the cardiac w1its throughout the 1970's was coronary and valve surgery. Dr. Go ldbach who had received specific training in pediatric cardiac surgery continued Dr. Co les ' work in this area. In the late 1970's a new inununosuppressive "'!gent without the deadly side-effects seen in earlier drugs became ava ilable and a number of experimental studies were undertaken.

The drug, the product of a bacterial inoculum originally obtained in a Norwegian soil sample, was avai lable in microscopic ia~mounts initially. Over the course of severa l years sufficient eviJelence had accumulated to justify clinical trials and heart transl' •Jantation be.g an in 1981 followed shortly thereafter by heart/lung r nd lung transplantation. Similar efforts in the fields of liver and ~ jdney transplantation together with the development in London 1f a multi-organ transplant service promoted the development of e~milar programs elsewhere in Canada. f1 Steady advances on many fronts characterized the 1980's and tlllirly 90 's . Improvements in protection of the heart during sur1t;ery, in anesthesia , in postoperative care, in patient selection and )Preparation for surgery to name a few all contributed to an annur I increase in the number of procedures performed . While Dr. : oles looked after the cardiac surgical needs of London single~ ndedly during the first 15 years, by the late 90's the vo lume had ; 1creased to close to 2000 cases performed by eight surgeons. ;\ 1ore esoteric problems were tackled. Rhythm disturbances of the ~ eart comprise one example and for several years the expertise of h>r. Guiraudon and Dr. Klein and colleagues attracted to London r; significant number of patients (and gratifying financial support) ertho wished to have their abnormal and potentially lethal rhythm isturbances normalised. Interestmgly this surgical endeavour tiibruptly disappeared when the invasive cardiologist discovered 011at the same results could be achieved with a combination of adio frequency ablation and catheter-based technology.

0 d The pace of evolution towards a less invasive approach will !r1creasingly influence all surgical endeavours. The world 's first obotically assisted coronary artery bypass procedure was recent~y performed at London Health Sciences Centre by Dr. Boyd.

Nhile this methodology is presently in its infancy now further ,efinement is occurrillg constantly. The standard operations of my iurgical youth namely cholecystectomy is now routinely day sur-

gery performed tlu-ough small port while operations for peptic ulcer di sease have become a rarity. An entirely catheter-based percutaneous coronary artery bypass has been performed experimentally and the cardiac surgeon of the future wi ll likely be equally at home in an operating room or catheteri sation laboratory. Indeed, the distinction between the two areas may disappear.

The expanding fie ld of mol ecu lar biology is also likely to impact the cardiac surgeon markedly in the near future particularly in the areas of transplantation and ischemic heart disease. The pioneering spirit that led to the development of card iac surgery in London has provided a legacy which the community we serve will continue to enjoy today and in the future.

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UWOMJ 71 (1) 2001

7

Emergency medicine: The newest specialty

Rocco Gerace MD, FRCP(C) Professor & Chair, Division of Em ergency M edicine, Th e University of Western Ontario Site Chief, Department of Em ergency Medicine, London Health Sciences Centre - University Campus ProfessOI; Department of Pharma cology and Toxicology, The Uni versity of Western Ontario

It is about 11:30 pm and you are examining a young child with a fever and sore ear. The emergency nurse tells you that she has just received a call from the ambulance dispatcher that an elderly man has collapsed at a private home. The patient is not breathing and they are unable to feel a pulse. CPR is in progress and they will be arriving in about 4 minutes. After excusing yourself from your patient, you begin to prepare the cardiac room for the patient's arrival. As you do so, you refresh your memory about the resuscitation protocols you know so well and think about the many cardiac arrests which you dealt with during your emergency medicine residency. You certainly feel prepared to deal with the upcoming emergency.

This all too familiar scenario of a trained emergency physician dealing with a critically ill or dying patient has not been the norm for a long time. When one considers the history of medicine and the development of the various disciplines it is not often realized that emergency medicine is the newest free standing specia lty in a long line. It is hard to imagine that it was not once a discipline onto itself. This is indeed the case.

F~r many years, •IP!0 American College of physicians have been covering emergency Emergency ys1c1ans* departments treating Figure 1: Logo of ACEP patients who present themselves. However, it was not until the 70 's that the concept of emergency medicine being a distinct discipline with its own body of knowledge began to take hold. The first organized body of emergency physicians was the American College of Emergency Physicians was formed in 1969 to "improve emergency care by setting high standards for emergency medical education and practice" . One of the major objectives of the College was to achieve

1111

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UWOMJ 71(1 ) 2001

Ph . .

Bill McCauley MD, FRCP(C) Clinical Assistant Professor, Department of Medicine, Th e University ofWestern Ontario

specialty recognition for the specialty. In fact, the logo of ACEP is a square divided into 64 parts with one of the parts blank. This represented the body of specialties with emergency medicine as the missing specialty. This missing square had been placed over the ' i' in American. While the specialty has long been approved by the American Board of Medical Specialties (ABMS), the logo serves as a reminder of the history.

The approval in the US was not straightforward. The tradi· tiona! specialties were loathe to consider this upstart discipline as a specialty. It simp ly did not fit the traditional mode. It crossed many ofthe traditional qualifiers of specialties (eg related to body systems or anatomic regions) . It is for this reason that the first specialty board in emergency medicine was required to have sponsorship from the American Board of Internal Medicine; the ' American Board of Obstetrics and Gynecology· the American It Board of Pediatrics; the American Board of Psychiatry and 1 Neurology; and the American Board of Surgery. Members of each 1 of these boards sat on the founding American Board of Emergency Medicine. ABEM has long since achieved primary board status.

In Canada, the history was equally interesting. In the early 1970's, there were a number of physicians practising exclusively in the emergency department. It was recognized by these individuals that there was indeed a distinct body of knowledge known as emergency medicine. In fact, Western was one of the first academic units of emergency medicine, formed as a Division of the Department of Medicine in 1975 . The first residents in emergency medicine were accepted in 1976. At that time, there was no distinct program, but rather the residents were internal medicine residents who had chosen to focus there learning in emergency medicine. It was a 2 year program after which the resident would

complete an additional two years of internal medicine and be eligible for their exam. Similar hybrid programs sprung up across the country. However, there was still no formal recognition for the discipline in Canada.

It was in the late 70's that the Advanced Cardiac Life Support (ACLS) was introduced by the American Heart Association. This represented one of the first standards dedicated to the delivery of emergency care. The emergency physicians of the day embraced this program as participants and instructors to begin to promote standards associated with the practice of emergency physicians.

The establishment at the time was quite distressed at these upstarts daring to suggest that certain standards were necessary to work in the emergency department.

In the fall of 1978, in order further the goal of recognition, a meeting was arranged in Toronto of emergency physicians, from across the country, interested in promoting the specialty. It was at that meeting that the Canadian Association of Emergency Physicians (CAEP) was founded. Again, one of its founding objectives was the achievement of specialty recognition. With a founding executive, they immediately set about the task of travelling the country to recruit emergency physicians from every jurisdiction into the fledgling organization. They further carried out the task of beginning to lobby the certifying bodies, the Royal College ofPhysicians and Surgeons of Canada and the College of Family Physicians of Canada.

At about the same time, the certifying bodies had struck a working group to explore the feasibility of a joint process leading to some type of recognition in emergency medicine. It was assumed that candidates for recognition would be a certificant in one or other College and that there would be a prerequisite of training or experience to gain eligibility to the exam process.

There was concern within the emergency medicine community regarding the fate of the currently practising emergency physicians in that the vast majority of them did not hold certification in either body. Fortunately or not, there was not the degree of cordiality and trust between the two bodies which exists today. (In fact, at the present time, the two Colleges are in the process of conjointly creating a dual access specialty in palliative care).

While negotiations between the Colleges broke down, neither seemed inclined to give up ownership in the discipline. It was at this time (late 1982), that the Royal College Council approved emergency medicine as a primary specialty (ie no need for prior certification to achieve recognition), the last free standing specialty to be approved. There was a time limited practice eligible route created for physicians who had been engaged in the practice of emergency medicine for a period of five years. The first exam was held in the fall of 1983 with the first specialist certificates awarded in December of the same year.

Concurrently, the College of Family Physicians approved the creation of a Certificate of Special Competence in Emergency Medicine to be offered to Certificants of the College with a time limited access for those who were not certified. There first exam was in the Spring of 1983.

The recognition of the discipline was followed closely by the creation of residency programs and residency positions. There are currently 11 programs in emergency medicine nationally.

Unfortunately, the number of residency positions did not expand

to match the number of programs and currently, there are only 15 - 20 residents graduating per year from the Royal College Program.

Thus, although we are now approaching the 20 year mark as a speciality in Canada, this young speciality continues to struggle with defining its own identity. As the majority of patient care in emergency rooms across the country is still provided by family physicians who are working shifts in the Emergency Department, the concept of a specialist emergency physician is foreign to many members of the public and some members of the medical community. Many members of the public continue to think that anyone that works in the Emergency Department is doing so in additional to general practice or is doing so in a transitional way until they can find their own direction. It is certainly not uncommon for patients in the Emergency Department to ask of a specialist Emergency physician "so when will you be opening your own practice".

Similarly, the discipline occasionally struggles with respect to its identity as being distinct within the medical community.

Many specialities are very well defined. Cardiologists deal with the cardiovascular system. Pediatricians deal with problems with children. Emergency physicians, however, deal with all sorts of clinical scenarios. There are a few areas that tend to be, however, the domain of Emergency physicians. These are the areas that we can claim as "our own" in which Emergency Medicine is the most knowledgeable speciality with respect to these presentations.

These include acute cardiovascular resuscitation, including basic and advance cardiac life support, acute principles of trauma resuscitation, acute care of patients with toxicologic problems and prehospital care. Additional domains which are more specific to Emergency Medicine include environmental emergencies such as hypothermia, heat stroke, altitude illness, burns and inhalation injury, electrocution and acute radiation sickness. Emergency Medicine is also a truly multi-disciplinary field where team members including physicians, nurses, orderlies and social workers rely upon each other to fulfill their own important individual roles in the management in any given patient.

Still a relatively indistinct perception of this speciality provides difficulties for medical students with an interest in Emergency Medicine in choosing Emergency Medicine as a life long career. In Canada, there are currently two streams to certification in Emergency Medicine, one through the College of Family Physicians of Canada (CFPC) and the other through the Royal College of Physicians and Surgeons of Canada (RCPSC).

While often quoted that after ten years of clinical practice there is essentially little difference between the clinical aptitude of Royal College and Family Medicine trained Emergency physicians, the mandate of each program is essentially quite different. The program through CFPC is a one year program that follows a two year Family Medicine residency. The purpose of this program is generally to provide enhanced skills in Emergency Medicine for family physicians. While it is not specifically the intent of this program to train people to work full-time in Emergency Medicine, very often trainees coming out of the program choose to work full-time in Emergency Medicine over having a family practice with additional responsibilities in Emergency Medicine.

The Royal College Training Program, however, is a five year UWOMJ 71(1) 2001

9

program to which medical students are matched directly within the CaRMS match process. This program is dedicated to train specialist emergency physician with a career of Emergency Medicine in mind. Whi le not a specific mandate of the Royal College, many of the training programs across the country feel that they are training residents to be not only specialists in Emergency Medicine but academic Emergency physicians as well. The hope of many of these training programs is that the graduates of these programs will stay in academic centres where they can continue on with scholarly activity in Emergency Medicine.

Two routes to certification often provides confusion for medical students. For most medical students the main decision that should be made when considering the fie ld of Emergency Medicine is whether or not they want to pursue purely the clinical practice of Emergency Medicine or a practice in scholarly activity in Emergency Medicine. The CCFP/EM programs across the country provide excellent enhanced skills in Emergency Medicine that allow people to provide excellent clinical care in any centre in the country. If the student feels that she is likely to want to work in an academic centre then she is best advised to consider the Royal College Training Program. While Royal College certification is certain ly not necessary to work in an academic centre (indeed there are several leaders in the field of Emergency Medicine in Canada who hold CCFP/EM), one likely has greater flexibi lity in choice of work location with a FRCPC background.

There are several outstanding issues that currently are facing the Emergency Medicine specialty in Canada. Three main issues that are an ongoing struggle include the common route to certification, the development of scholarship in Emergency Medicine and the provision of Fellowship and sub-specialty opportunities within the discipline.

As mentioned earlier there are two routes to certification within Canada and this has created much discussion and debate regarding the development of a common route to certification . In the US , there is currently only one route to certification in Emergency Medicine through the America Board of Medical Specialities. ln Canada, there has historically been a bit of divisiveness between CCFP/EM physicians and Royal College trained physicians. Emergency Medicine national specialities 's society, CAEP is currently working with its membership as well as members from the CFPC and R PSC to look into the feasibility of the development of a single route to certification within Canada. While this may be a difficult road, it is genera lly felt to be one that is necessary to exp lore in order to strengthen and unify the discipline.

As Emergency Medicine has traditiona lly been a clinically based speciality and has drawn to it physicians who are interested in clinical medicine, the development of scholarly and academic activity in Emergency Medicine has been somewhat slow to progress. Having said that, currently there are emergency physicians across Canada who hold advanced training in Biostatistics and Epidemiology, as well as Medical Education who are taking the specialty into the next century with a view to enhancing the academic output of the speciality. As the number of these specialists with enhanced academic training continues to 10

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increase, one can expect the volume and quality of scholarly activity in Emergency Medicine to improve dramatically.

Currently, there are no formal Fellowship opportunities for Canadian graduates of Emergency Medicine training programs within Canada. Many emergency physicians would consider doing enhanced training in some of the sub-specialities in Emergency Medicine such as Toxicology, Traumato logy, Pre-hospital Care/Emergency Medical Services and Disaster Planning.

While Fellowship opportunities in these areas do exist in the United States they have not yet been developed here in Canada.

Pediatric Emergency Medicine has recently become a recognized sub-speciality of the Royal College of Physicians and Surgeons of Canada. The development of Fellowship and sub-specialty training opportunities within the field will further promote and validate Emergency Medicine as a specialty in tbis country.

In summary, Emergency Medicine is an exciting field that has really only be around in Canada for seventeen years. Despite its use, it is a specialty that continues to attract energetic and enthusiastic physicians. It has and continues to establish itself as an important specialty in the field of medicine. The next twenty years should see Emergency Medicine permanently grounded as an important and recognized medical specialty.

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••

Epidemiology: Past, present and future

Mark Speechley PhD Associate Professol; Department of Epidemiology & Biostatistics, Th e Uni versity of Western Ontario

INTRODUCTION

While it is well known that the average quality of life in industrialized societies is much higher now than 50 or 100 years ago, it is Jess well appreciated how much of this increase can be traced directly or indirectly to knowledge gained using the epidemiologic method. For example, people are less likely to smoke tobacco, and more likely to engage in regular exercise and eat diets low in saturated fats and rich in fruits and vegetables, than at mid-century. Those receiving health care are more likely than past patients to receive a treatment that has been proven in randomized clinical trials to be efficacious. Employees are much less likely to face unhealthy exposures to chemicals, noise and injuries in the workplace, due in large measure to insights gained from occupational epidemiology. Children are much less likely to die or be disabled from communicable diseases thanks to the development of effective vaccines and the establishment of an effective public health infrastructure.

Much of this reduction in disease, and improvement in health, is the result of massive, population-level changes in basic human behaviours affecting what we eat and drink, where and how we live, the way we work, and how we approach the prevention and treatment of the most common diseases. Much of the scientific evidence supporting the health-enhancing effects of these behavioural changes was obtained through the development and application of epidemiologic methods. To illustrate this, I will put the history of epidemiology into broad eras, based on the leading health problems affecting society that most occupied epidemiologists at the time. Following that, I will sketch in necessarily brief form the extraordinary variety of health issues that now concern the discipline of epidemiology. Finally, I conclude with a discus-

sion of the challenges and the opportunities that face our discipline in the future .

EPIDEMIOLOGY: A BRIEF IDSTORY Epidemics of communicable disease: clSS0-1950

Elements of the epidemiologic perspective, such as the causal role of the environment in human health, can be traced to writings attributed to the giants of classical medicine, Hippocrates and Galen. But these early ideas would not evolve into the discipline of epidemiology for several centuries, when scientific thinking itself had developed enough to enable definitive tests of two longstanding and fundamentally different theories of epidemic disease spread. The miasma theory held that disease was spread by some quality of inspired air, such as odours caused by decomposing organic matter. It was supported by many, based on the observed relationship between unsanitary conditions and disease. The contagion theory stated that disease was spread from person to person, although the mechanisms were unknown.

Pasteur and the germ theory definitively proved miasma wrong by elucidating the microbial mechanism of communicable disease. Even before this, however, a brilliant series of observations and logical deductions of disease patterns in human populations revealed that some epidemic diseases could be spread by drinking water contaminated by sick people. This key period in the development of the epidemiologic method came in the 1850s with Dr. William Budd's investigations of typhoid fever, and Dr. John Snow's studies of cholera. Snow conducted a careful study of the neighborhood distribution of cholera cases in London, England.

Based on his results, he challenged the orthodoxy of the day by removing the handle from a public water pump, at once proving

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that cholera was a water-borne disease and saving countless Jives.'

The remainder of the 19th century saw repeated successes in the control of communicable diseases, often as epidemiologists and microbiologists collaborated on vaccine development and testing. This work eventually resulted in such triumphs as the global eradication of smallpox in 1980.2 Similarly, the application of epidemiologic methods in the polio field trials, which fifty years later are still the largest experiments ever conducted on human populations, gives hope that this once-epidemic disease will soon be eradicated.

From today's perspective we can trace the roots of the World Health Organization (W.H.O.) to communicable disease epidemiology and the science of public health.J This accumulated experience is needed now as society grapples with the very real threat of emerging and re-emerging infections. As we face this challenge we should remember that many of the major historical epidemic diseases were well in retreat before effective vaccines were developed for them or indeed before the responsible microorganism was even identified. Much of the reduction in these diseases is thought to be the result of improvements in sewage and garbage disposal, nutrition and shelter, and economic development that permitted a healthier standard ofliving in general. While research into new vaccines and antibiotics should be a high priority, the lesson learned from historical epidemiology is that effective disease control can begin with simple inexpensive interventions aimed at creating or promoting safe environments, nutritious diets, and healthy personal behaviours.

of epidemiologic principles and methods to problems encountered in clinical medicine' S continues to have a major influence on the teaching and practice of medicine. As a basic science of evidence-based care9,IO it provides clinicians with a formalized means of evaluating new diagnoses and of estimating the efficacy, effectiveness and efficiency of various clinical procedures, devices, substances, programs, and other treatment approaches.

THE PRESENT

A modem definition of epidemiology is ' the study of the distribution and determinants of health related states and events in specified populations and the application of the resulting knowledge to control health problems ' .s Many papers in the primary epidemiology literature are reports of etiologic studies of single diseases for which the causes are unknown and the opportunities for primary prevention therefore limited. But the suite of epidemiologic methods has proved itself to be extremely flexible, and is now applied to reproductive outcomes, intentional and unintentional injuries, and a range of other health issues." This flexibility, combined with the inherently multidisciplinary nature of the discipline due to the eclectic undergraduate preparation of its practitioners, means that epidemiologists are working on a wider variety of health problems than ever before. A selected survey of current epidemiologic research activity includes: 1.

2.

Chronic Diseases: 1940s - present

After World War II, epidemiologists further developed methods used to study infectious epidemics, and applied them to the leading causes of death in industrial societies--chronic conditions such as cardiovascular and neoplastic diseases.4 The development of the case-control design allowed epidemiologists to efficiently conduct the first controlled studies linking cigarette smoking and lung cancer. This design has since been extended to identify risk factors for other cancers and other chronic diseases, and to address non-etiologic questions of an evaluative nature.s It has proved itself to be a particularly efficient means of studying diseases that are rare or have a long latency period between exposure and disease expression.

Another methodological development was the cohort study, which can be applied retrospectively and prospectively. Many of our best estimates of the risks posed by workplace exposures to industrial processes, or to exposures sustained during military service, come from retrospective cohort studies. The best-known example of a prospective cohort study is probably the Framingham Heart Study, initiated by the U.S . Public Health Service in 1950.6 It and similar studies have contributed most of the population-based scientific knowledge we currently have about risk and protective effects of diets high in fat, physical exercise, smoking, alcohol consumption, and stress on the most common causes of disability and premature mortality.?

Clinical epidemiology: 1940s - present

The highly successful growth of population-based chronic disease epidemiology has been paralleled by similar advances in clinical epidemiology. This specialty, defined as 'the application 12

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3.

4.

5.

6.

Emerging and re-emerging infections.I2 Continued identification of infectious etiologies of chronic disease, and of increased susceptibility to infections posed by chronic illness, which is leading to a reappraisal of the infectious-chronic disease dichotomy.

Genetic epidemiology, 13 a quickly evolving area that complements laboratory-based study of the human genome with population-based investigations. Included are specialized studies, such as the genetic epidemiology of emerging infections.I4 Molecular epidemiology. While this term is sometimes used interchangeably with genetic epidemiology, molecular epidemiology can also be defined as the use of biological responses or biomarkers as surrogates of exposures or effects. Is For example, assay techniques can be applied to human tissue samples to reduce the error in exposure measurement, and improve the precision of risk estimates, over those that would be obtained purely by self-report.

Outcomes of interest to patients like quality of life and functional ability that go beyond crude measures of outcome such as survival, or markers of disease activity that are often only weakly related to how a patient feels or what s/he can do.

Psychiatric epidemiology, the population-based study of mental illness using epidemiologic methods.I6 Related areas include social epidemiology which is often concerned with socioeconomic differentials in health and illness. I?

An interesting current controversy in epidemiology concerns the benefits of individual versus population-level risk factor modification, and of focusing on specific diseases versus outcomes collectively related to measureable conditions such as poverty.I 8 A

recent paper by Leonard Symei9 illustrates the shortcomings of the individual-level specific-disease approach to improving population health status with reference to the Multiple Risk Factor Intervention Trial (MRFIT). The basic premise of MRFIT was that heart disease is multifactorial and caused by things like cigarette smoking, serum lipids, sedentary lifestyle, etc. Because these risk factors are thought to operate in a fashion that is at least additive, reducing individuals' risk factor counts (e.g. from three to two, from two to one, etc.) should reduce disease incidence at the population level. MRFIT was designed to provide experimental (randomized) reverse causal evidence of the role played by these exposures in fatal and non-fatal myocardial infarction outcomes.

While the MRFIT results were controversial, one thing is clear: they did not provide definitive proof that focusing on individual risk factors for specific diseases improves population health status. Syme identifies three main limitations to individual risk factor modification for specific diseases: i) after a half-century of trying, we can explain less than half of cardiovascular disease incidence with known risk factors (and cardiovascular disease is one of the best understood chronic diseases). Further research is unlikely to uncover one or two missed modifiable risk factors that would be powerful enough to account for the unexplained variation; ii) even highly motivated people at high risk for a disease are resistant to behavioural change. Men in the top 10% of the MRFIT risk gradient made "only modest changes" in their eating and smoking behaviour in spite of intensive intervention over a six year period; iii) new people can enter the at-risk population as quickly as people are removed. For example, for every middleaged person who is convinced to quit smoking, there may be two schoolchildren taking their first puffs on a cigarette. Thus, even a program that successfully changes the behaviours of individuals might have no net effect on the distribution of a risk factor at the population level. This is NOT(!) a reason to abandon effective individually targeted primary prevention programs, but it is a convincing argument for striving for more balance by developing effective population and community-level primary prevention interventions aimed at healthier environments, healthy policies, safe neighborhoods, and informed and empowered consumers.

On the education front, epidemiology is enjoying a renaissance in the modem medical school. As Du V Florey put it, "Over the past forty years epidemiology has grown from one of the waifs of the medical profession to a major subject which influences thinking and action in many aspects of health. The emergence of the key role of the epidemiologic method in clinical research has changed the once disdainful attitude of other disciplines to recognition of the need to acquire some of the epidemiologic skills."20

THE FUTURE Challenges One challenge faced by epidemiology is a growing anti-science sentiment that, of course, affects all disciplines that value carefully controlled observation, replication, and refutation. As health scientists, epidemiologists are empiricists who tend to believe most strongly in things they can count or see. But society seems to be in the grips of an anti-science movement that, in its

extreme, denies the validity of entities such as "disease". It is impossible to apply epidemiologic concepts such as reliable case definition or natural history to something that is believed to be a mere social construction.

Similarly, those who believe in currently unmeasureable qualities such as therapeutic energy fields given off by human hands, will be unconvinced by negative results from randomized comparisons to, say, placebo energy fields . Even a rigorous clinical trial that showed no detectable effect on any conceivable outcome would fail to convince those who reject science and its methods out of hand. Regrettably, too, principles of academic freedom and meritbased peer-review now face unprecedented interference by various corporate and other special interest groups .2 I,22 But at the same time, as a practical applied science devoted to improving the health of whole populations, epidemiology walks a tightrope between anti-scientific mysticism and sceptical pure empiricism. For example, millions of people report symptoms that form syndromes with names like fibromyalgia, chronic fatigue, environmental hypersensitivity, Gulf War, sick building, etc. The number of people affected, the consistency of clusters of symptoms, and the often high pre-morbid functioning of those affected severely strain the credibility of the view that the sufferers are malingerers or somaticizers seeking attention or secondary gain.

Unfortunately, even after exhaustive investigations using conventional clinical and laboratory paradigms, we remain far from a coherent biomedical disease model of these epidemic symptombased conditions.23 Sceptics (and, for different motivations, insurance companies) remain unconvinced that these are diseases, given the absence of consistent cellular or biochemical abnormalities. Epidemiologic methods can be applied to any condition for which there is a reliable case definition, but the overlap in symptoms among these syndromes, as well as considerable individual variability, makes this difficult.23 It is hoped that the continued epidemiologic study of these epidemic syndromes will aid the development of a coherent disease model, including etiology and natural history, that will in turn allow effective interventions in primary, secondary and tertiary prevention.

Another challenge increasingly faced by epidemiology is access to data. II In the past, epidemiologists were funded, usually by peer-review, for primary data collection. The resulting data were then stored, analyzed and interpreted in the apolitical and independent atmosphere of the university. It has become increasingly difficult, though, to fund some epidemiologic research such as large multi-year prospective cohort studies. Secondary and administrative data that cou ld be used by epidemiologists are now increasingly controlled by governments and private interests.

Academic epidemiologists and other qualified health researchers now have less access to health data than certain government employees. Paradoxically, legislation inspired by legitimate ethics and privacy concerns could have the unethical result of hampering the ability of epidemiology to quickly detect and report on new risks to human health.

Finally, epidemiology has emerged as perhaps the single most influential science in health care reform and health policy.

Epidemiologic knowledge and skills are increasingly relied upon in courts of law to estimate risks to human health posed by various activities and exposures. It Yet, in many ways the most diffi-

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cult challenge faced by epidemiologists is communicating the seemingly simple concept of risk.24 Our subject matter covers a huge possible range of exposures and outcomes, set amidst seemingly infinite combinations of confounding and effect-modifying variables, and so it is inevitable that not all studies of the same question will come to the same conclusion . Unfortunately, rather than publish reports of review articles, consensus conferences, or meta-analyses, many news media seize upon the most provocative, not to say least plausible, findings. The result is fallacious conclusions such as 'everything causes cancer' .

Most epidemiologists would probably agree that it is our responsibility as health scientists and as educators to continue to find ways of effectively communicating to the public, to legislators, policy makers and judges, the importance and the challenges involved in assessing causal risks to human health.24

OPPORTUNITIES Epidemiology is either the central science or a key contributor to several thriving and increasingly influential applied disciplines such as outcomes research , health services research, and population health. Because it has always been inherently multidisciplinary, epidemiology is a model for strategic funding initiatives intended to foster collaboration among previously separate disciplines and professions. And, the public is increasingly demanding answers to questions that epidemiology, in continued collaboration with biomedical, behavioural and social sciences, is ideally suited to answer.

For example, the continued introduction of complex novel molecules into the environment raises legitimate concerns about their independent and synergistic effects on human health. But people are more mobile - both occupationally and residentially than ever before and so traditional epidemiology based in a factory or community is more difficult to conduct due to losses to follow-up and other sources of bias. Computerized data permits the application of epidemiologic methods using record linkage to help accurately estimate risks among mobile populations.

Computerization of health information will also allow more study of the long-term effects of health care interventions.

Treatment histories linked across generations can provide large population-based samples that will allow both positive and negative effects of pharmaceuticals, surgical interventions and other treatments to be studied powerfully and more efficiently than relying exclusively on primary data collection designs. This will require the continued application of classical epidemiology, including record linkage, ways of maximizing follow-up rates, and statistically assessing and adjusting the effects of the many forms of bias that can so easily lead to incorrect conclusions.

It is especially promising that the combination of the statistical power and ability to control for confounding variables that comes from large epidemiologic samples, and the measurement precision that comes from innovations in the laboratory-based sciences, will resolve many of the controversies related to such exposures as pesticides, occupational fumes, ionizing and electromagnetic radiation, and biohazards. Research on information transfer and policy change will in tum allow the direct and hopefully timely application of epidemiologic knowledge to further improve population health status.

14

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ACKNOWLEDGEMENTS The author appreciates helpful suggestions on an earlier draft

by Drs. Kathy Nixon Speechley and Karen Campbell.

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Nakajime H. Epidemiology and the future of world health - the Robert Cruikshank Lecture. International Journal of Epidemiology 1991; 20(3) :589-594.

McKeown T. The role of medicine. London: Nuffeld Provincial Hospitals Trust, 1976.

Terris M. The Society for Epidemiologic Research and the future of epidemiology. Journal of Public Health Policy. 1993 (Summe1) :137-148.

Arm enian HK. (ed.) Applications of th e case-control method.

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Greenberg RS, Daniels SR, Flanders WD, Eley WW, Boring JR. Medical Epidemiology. 2nd ed. Norwalk, CT Appleton and Lange, 1996.

Sam et JM, Munoz A. Coh ort Studies. Epidemiologic Reviews 1998;20(1): 1-136.

Last JM. (ed.) A Dictionary of Epidemiology. 3rd ed. New York: Oxford University Press, 1995.

Sackett DL, Hay nes RB, Tugwell P Clinical Epidemiology: A basic science f or clinical medicine. Toronto: Little Brown, 1985.

Sackett DL, Richardson WS, Rosenberg W, Haynes RB. Evidence-based medicine: How to practice and teach EBM. New York: Churchill and Livingston e, 1997.

Nasca PC. Current problems that are likely to affect th e future of epidemiology. American Journal of Epidemiology. 1997; 146(11):907-911.

Levine MM, Thacker SB. (eds.) Em erging and Reemerging Infections.

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Khoury MJ, Risch N, Kelsey JL. (eds). Genetic Epidemiology.

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Abel L. Dessein AJ. Genetic epidemiology of infectious diseases in humans: design of population-based studies. Emerging Infectious Diseases. 4(4):593-603, 1998.

Albertini RJ. Biomarker responses in human populations: towards a worldwide map. Mutation Research. 428(1- 2) :21 7-26, 1999.

Anthony J C, Eaton WW, Henderson AS. (eds.) Psy chiatric Epidemiology. Epidemiologic Reviews 1995;17(1) :1-242.

Barnett E, Armstrong DL, Casp er ML. Evidence of increasing coronmy heart disease mortality among black men of lower social class. Annals of Epidemiology 1999;9:464-4 7.

Krieger N. Epidemiology and the web of causation: Has any one seen the spider? Social Science and Medicine 1994;39(7) :887-903.

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Du V Florey C. Teaching th e reluctant student. In Olsen J, Trichopolous D (eds.) Teaching epidemiology: What you should know and what you could do. Oxford: Oxford University Press, 1992:23-32.

Deyo Ra. Psaty BM, Simon G, Wagn er EH, Omenn GS. Th e messenger under attack - intimidation of researchers by special interest groups.

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UWO family medicine at the millenium

Thomas R. Freeman BSc(Hon), MD, MC!Sc, CCFP, FCFP Interim Chair and Associate Projess01; Department of Family Medicine, The University of Western Ontario

The largest gathering of family physicians from around the world was held in Dublin, Ireland in June, 1998 at the World Organization of National Colleges of Family Practice (WONCA) meeting. In this setting, Per Hjortdahl, one of the Norwegian organizers, in introducing a keynote speaker, described London, Ontario as the 'cradle of family medicine '. The story of the way in which The University of Western Ontario achieved this recognition, in a real way is the story of the re-emergence of family medicine as a distinct discipline in medicine, in the last half of the century.

In his book A Century of Medicine at Western 1 Dr. Murray Barr reports that as early as 1929 a general practitioner from Delhi, Ontario wrote to the then Dean of Medicine at UWO suggesting that generalists be invited to lecture to undergraduate medical students. However, almost 40 years would have to pass and the 'age of specialism' be in full bloom before that would occur.

At the time of the founding of the Western University Medical School in 1881 , medicine was reaching the end of a century described as the 'age of the general practitioner'2 because virtually all medical doctors in North America practiced medicine, surgery, apothecary and obstetrics. It was however, the beginning of the 'age of specialism' spurred on by discoveries in the new sciences of physiology and bacteriology and the curricular reforms recommended by Abraham Flexner. Flexner's comments on the proprietary Medical School in London, Ontario at the time are well known and won't be repeated here. The founding of the Johns Hopkins Medical School in 1889 was to provide the scientific basis for medical education and the model for the clinical method that has proven to be so influential.

Over the first half of the 20th century most of the major specialties emerged and medicine focused more on the incorporation

of new knowledge from the laboratory sciences and new technologies. As more medical graduates were attracted to the new specialties, fewer went into general practice and the numbers in this field declined after 1930. After the Second World War, with the acceleration of new technology that that conflict brought about, even the specialties in medicine began to divide into subspecialities. General practitioners virtually disappeared from medical faculties during this time. However, the President of the University, Dr. Edward Hall was influenced by the thinking of Dr. John Ryle, the Professor and Head of the Institute of Social Medicine at Oxford University) He became convinced that the medical school must have a department devoted to community medicine and prevention with an emphasis on environmental factors, industrial and social medicine, and the use of statistical and epidemiological techniques. Hall , canvassed his departmental chairs and found only one that was interested in taking on this responsibility. Dr. G. Edgar Hobbs, chair of psychiatry expressed interest and, after further training at the University of Michigan his department became Psychiatry and Clinical Preventive Medicine. Hobbs had the distinction of holding three professorships at various times: psychiatry, preventive medicine and the two combined. J The first woman PhD graduate in the faculty of medicine was Dr. Carol Buck who worked under Dr. Hobbs in Clinical Preventive Medicine. She received this degree in 1950 having completed her medical degree in 194 7. After further training at the University of London, Dr. Buck returned to Western and continued as an Assistant Professor.

Meanwhile, the age of specialism began to develop some weak spots and the time was propitious for a return of the generalist physician. It became recognized that a narrow focus on dis-

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eases, could not maximize health because the prevention of illness and the promotion of health and optimal functioning require a broader perspective than can be achieved by the disease specialist. Truly effective medical care must not stop with treatment of the disease alone, but must take into account the context of the patient. It is, of course, the case that diseases do not exist in isolation, especially when considered over time as is necessary with chronic diseases. While the disease specialist may provide the most appropriate care for specific diseases within the range of their competence, the primary care practitioner is best suited for providing comprehensive care over long periods of time.4 Specialism also interfered with the doctor-patient relationship because it tended to focus the doctor's interest too narrowly.

These factors made it desirable and necessary for the return of the generalist physician. The new generalist however, was not to consist simply of those who did not specialize, but was someone who was to have a well differentiated role and a defined set of skills.

Seminal in this development were two reports in the United States: The Graduate Education of Physicians (1966) and Meeting the Challenge of Family Practice ( 1966). Similar changes were taking place in all of the industrialized countries. In Canada, the College of Family Physicians was founded in 1954, with Dr. Victor Johnson, a general practitioner from Huron County as its first Executive Director.

It may seem at first a paradox that as a field of activity specializes, there occurs a greater need for generalism. The current ' information explosion' is an excellent example of the need for 'filters ' or organizers to help an individual to cope and turn information into meaningful knowledge. It falls to the generalist in medicine to help patients benefit from the tremendous amount of new information available.

Dr. Carol Buck, in her role as Chair of Community Medicine was able to entice a young general practitioner from Stratford-onAvon to UWO in 1967. Ian McWhinney was to play a seminal role in the development of family medicine not only locally, but nationally and internationally. He was the first Chair of Family Medicine in Canada as the Department of Community Medicine divided into Epidemiology ~nd Preventive Medicine which continued to be chaired by Dr. Buck, and a new department of Family Medicine. The 'pedigree ' of the Department of Family Medicine, then , locally derives from psychiatry, preventive medicine, community medicine and epidemiology, and strands of these disciplines remain evident and are reflected in the principles of the discipline.

Dr. McWhinney became known worldwide for his intellectual grasp of the issues in family medicine and hi s unmatched ability to articulate them. His A Textbook of Family Medicine2 is now in its second edition and has been translated into Japanese and Spanish . It is the primary textbook in family medicine in many medical schools around the world. His publications are extensive.

In 1998 his contributions to Canadian society were recognized when he was made a Member of the Order of Canada. In June, 2000 he was awarded an honourary doctorate by the University of Western Ontario.

As impressive as these achievements are, perhaps the most important has been his articulation of a new clinical method. The method used to arrive at an understanding of a person's ill health, 16

UWOMJ 71(1) 2001

is inextricably rooted in our explanatory models of illness. Since ancient times, these models, broadly speaking, have cycled between the ontological view which sees disease as something distinct and separate from the person suffering with it and the physiological or ecological or holistic model which sees ill health as an imbalance between the individual and the environment. In the ontological model, diseases have an existence of their own, but in the ecological model ' diseases ' are recognized as abstractions that are useful for naming clusters of signs an symptoms and it is not possible to separate the disease from the person and the environment. These two models have always been in a state of dynamic tension, with, at times one in ascendancy and, later, the other one dominants It must be emphasized that this type of distinction is an oversimplification and that at any given time, there are elements of both viewpoints present. It has always been the case that the best physicians utilize both approaches.

The clinical method associated with the ontological model emphasizes doing what is necessary to arrive at a correct diagnosis in the sense of naming the disease entity. This necessarily entails an objective search for the tell tale signs of pathology using examination skills, laboratory science and imaging techniques. Diagnosis is seen as a classification process and the accuracy of it is attested to by the pathologist. The ecological or holistic model recognizes the importance of the subjective experience of ill health, of communication between patient and doctor, and patient and environment, both social and physical. Diagnosis, then becomes a diagnosis of the whole person and there occurs a subtle shift from cause and cure to care, function, support and healing. These distinctions are neatly summarized in this quote from an Irish physician and colleague of James Joyce: "The village doctor was a great success . His success was due to his sympathy with his patients each of whom he treated as an individual with an idiosyncrasy of his own and worthy of special and separate consideration. It was as if, instead of giving every one massproduced medicine, he had moulded the portrait of each on his pill. He specialized in his patients . In this way he was a real specialist, in contradistinction to the town specialists who are identified with certain diseases or disasters . . ."6 While thi s may seem a digression, it has been one of the great contri butions of family medicine to medicine in general to bring these issues forward. Here at UWO, under the leadership of Dr. McWhinney, these concepts were articulated, and great strides made in the areas of research and education around them. The patient-centred clinical method ? did not begin at UWO, but work here made it possible to both study and teach it. It now forms the basis for the undergraduate medical curriculum at UWO and has been the basis for the national certification examination in family medicine for a number of years.

The Centre for Studies in Family Medicine was founded in 1986, and set about providing the research basis for the discipline.

Initially under the directorship of Dr. Martin Bass and presently Dr. Moira Stewart, it has established itself as the leading centre for research in family practice. Just as the discipline itself crosses many boundaries, so too, does the CSFM straddle traditional res~arch_ paradigms, blending the work of a number of disciplines (eptdemwlogy, social work, psychology, clinical medicine), using both quantitative and qualitative methods and liaising with com-

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munity family physicians through the Thames Valley Family Practice Research Unit. It strives to provide the scientific basis for understanding the individual response to and experience of ill health. Researchers in this unit have, collectively, published 250 papers, 7 books, and 5 videotapes in the past 10 years . In 199798, the Department of Family Medicine was conducting one-fifth of all family practice research in Canada. Other investigators, from around the world, are frequent visitors as it is recognized as the premier family medicine research centre in Canada and one of the best in the world.

Members of the department are recognized nationally as well as locally for their contributions to medical education. In 1976, the first graduate studies programme in family medicine in the world was established here. It remains the only such programme in Canada which trains family medicine educators to the Master's level and has recently explored new frontiers in going to a distance education format, making it accessible to many more practitioners around the world. To date, 62 individuals from 8 countries and 8 Canadian provinces have received a Masters degree in Family Medicine from UWO. A list of these graduates is a list of many of the most influential people in the discipline and illustrates the extent to which the work done in this department has been so influential nationally and internationally.

After Dr. McWhinney's retirement in 1987, Dr. Brian Hennen, returning from Dalhousie University where he had been the Head of Family Medicine, to become the Chair at UWO. Under his leadership, the department flourished with expansion f the post graduate programme and the development of a rural presence in the form of the Southwestern Ontario Rural Medicine unit. His interest and expertise in education was instrumental in advancing patient-centred concepts in the new curriculum. Dr. Hennen's dedication to the community and those in our society who are disadvantaged or otherwise marginalized served to emphasize family medicine's commitment to the society that it serves. He became the first individual in Canada from the discipline of family medicine to become a Dean of Medicine, taking that post at the University of Manitoba in July, 1999. The second family physician to achieve this distinction is Dr. Carol Herbert, the new Dean of Medicine and Dentistry at UWO. The future of the department of Family Medicine at UWO in the new millenium lies in building on its substantial strengths and history as it develops new opportunities. Extending service and education further into the community and region is a focus of not only the department, but also the whole Faculty of Medicine and Dentistry. The department will continue to lead the way in the development of new teaching strategies that recognize the importance of context in the training of medical practitioners. New alliances will be developed and existing ones strengthened, both within medicine (including the basic sciences), as well as with other disciplines (eg. Nursing, psychology etc.). Family practice will continue to bring a unique perspective to the discipline of medicine, one that advocates for a 'medicine of the person '. 8

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

Barr ML. A Century of Medicine at Western : a Centennial Hist01y of the Faculty of Medicine, University of Western Ontario. London, Ontario: The University of Western Ontario; 1977.

McWhinney JR. A Textbook of Family Medicine. 2nd ed. London: Oxford University Press; 1997.

Ryle JA . Changing Disciplines: Lectures on the History, Method and Motives of Social Pathology. London: Oxford University Press; 1948.

Star.field B. Prima~y Care: Balancing Health Needs, Services, and Technology. London: Oxford University Press; 1998.

Aronowitz RA . Making Sense of Illn ess: Science, Society, and Disease.

Cambridge: Cambridge University Press; 1998.

St. John Gogarty 0. Going Na tive. London: Constable and Co. Ltd. ; 1941.

Stewart MA eta/. Patient Cen tered Medicine: Transforming the Clinical Method. Thousand Oaks: Sage Publications; 1995.

Tournier P. A Place fo r You : Psychology and Religion. London: SCM Press Ltd. ; 1968.

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UWOMJ 71(1) 2001 17

Hematology: Past, present, future

Reinhard C. Lohman MD, FACP, FRCP(C) Chief and Cha ir, Division of Hematology, Department of Medicine, The University of Western Ontario

The transition from the 19th to the 20th century must have been as exciting as the turn to the 21 st century. The technology and science explosion of the later 1800s had opened new frontiers and opportunities never envisioned before. Medicine no longer was predominantly an art, but became a science. Empiricism and myths yielded to facts. The new technologies provided the tool s for new discoveries. This much could have been foreseen 100 years ago. What could not have been imagined is the direction and extent these new research tool s would carry the profess ion. Here is a short review of the course the science revolution took the specialty of Hematology.

THE HEMATOLOGISTS Hematology evolved in the third decade of the 20th century.

The defining event for Hematology was the ability to quantitate hemoglobin and other bl ood elements in the Laboratory. Since then, clini cal and laboratory hematology, stethoscope and mi croscope, have been close ly intertw ined: Th e visit to the "Lab" is part of the Hematol og ist's daily routine. It is to the credit of th e early London Hematologists, Dr. Walter Bruce Barton ( 1954, Vi ctori a Hospital) and Dr. David B. Meltzer (195 5, St. Joseph 's Hospital) th at they developed and maintained the Hematology Laboratori es and Blood Banks along with their clini ca l practi ce.

Sin ce then, laboratory and clini ca l hematology have been practi ced and administered together in London, almost unique in North Ameri ca. In the f irst decades of this century, Hematology was part of the general cli ni ca l practi ce and consisted large ly of observati ons and descri ptions since effecti ve treatment was not known. After establi shment of the specialty, the general hematol ogist would "rule the roost," but not for long: with a near ex plos ion of th erapeut ics in th e seco nd half of thi s century, 18

UWOMJ 71( 1) 2001

Hematology became a complex specialty and subspecialties evolved: Pediatric Hematology (in London, Dr. L. L. deVeber, 1961 ), Thrombosis I Hemostasis (Dr. R. K. Stuart, 1968, Dr. Martin J. Inwood, 1974), Blood Transfusion Medicine, Bone Marrow Transplantation (Dr. Anne M. Smith, 1989) and Medical Oncology. Medical Oncology, now a specialty of its own, evolved from Hematology because the first chemotherapeutic drugs (Nitrogen Mustard, 1943 and Aminopterine, the predecessor of Methotrexate, 1948), were first used in hematological malignancies . In London too, Medical Oncology was first practiced by Hematologists (Drs. W. B. Barton, D. B. Meltzer and D. F. White) and Hematologists have maintained a close link with Oncology and the Cancer Centre. Similar links existed and persist with the Red Cross I Canadian Blood Services Transfusion Service, London Centre, where London Hematologists served as medical directors (Drs. W. B. Barton, G . Chertkow, R . M. Barr).

THE EARLY HEMATOLOGY PATIENT

The type of Clinical Hematology practice changed with the diagnostic and therapeutic possibilities evolving over the course of the century. The diagnosis and treatment of iron deficiency was the domain of the Hematologists in the early days of the specialty. Less common, but more dramatic, were the megaloblastic anemias, diseases as devastating and lethal at the time as any acute leukemia and truly deserving of the name " pernicious." The di scovery of the causes of these anemias and identification and isol ation ofVitamin B 12, Intrinsic Factor and folate (Minot 1926, Castle 1931 ) were a triumph of scientific hematology. Since then, â&#x20AC;˘ it has been the dream and goal of Hematologi sts to find a "Vitamin" that converts malignant cells to orderly ce ll growth in stead of treating the leukemias and lymphomas by more or less

indiscriminate cell destruction (a glimmer of hope: the effect of Retinoids in the once-dreaded acute promyelocytic leukemias).

The so-called nutritional anemias are now largely managed by family physicians or general internists. The discovery and therapeutic availability of corticosteroids in the 1950s opened the way for treatment of immune disorders such as ITP, some hemolytic anemias and some hematological malignancies.

CYTOTOXIC CHEMOTHERAPY

Life became busy and exciting for the Hematologist with the dawning of the age of cytotoxic chemotherapy in the 1950s and 1960s and the development of blood banks, which provided hope for patients with formerly inevitably lethal diseases, especially the leukemias, myelomas and lymphomas. It was neither a miracle nor a breakthrough that heralded this development, but a painfully slow process with many doubters and many doubts along the way. London has its place in the history of chemotherapeutics by the discovery of the therapeutic effects of Vinblastine

by Drs. Robert Noble and 0 . H. Warwick in 1959. Dr. Warwick went on to become UWO Dean of Medicine and Vice President, Health Sciences, and Consultant at the London Cancer Clinic. He lives in retirement here in London.

However, what the 1960 hematologist did not dare to dream of became a reality a decade later: Hodgkin's disease and childhood acute leukemia became curable in increasing numbers followed to some degree by some non-Hodgkin 's lymphomas and adult leukemias. This created a certain chemotherapy euphoria amongst hematologists and oncologists : more drugs in higher doses would finish the job. New antibiotics, especially the cephalosporins, aminoglycocides, quinolones and macrolides would allow effective treatment for "neutropenic fever" that regularly followed bone marrow suppression; sterile "protective environment" and granulocyte transfusions were to prevent these often lethal events. Red cell and platelet transfusions bridged the time of the ominous bone marrow hypoplasia. Cytokines and bone marrow transplantation allowed escalation of "dose intensity" and pushed out the limits of ablative chemotherapy even further. However, by the turn of the millennium, the downside of this suppressive approach became evident: therapeutic limitations, cost, toxicity, long-term side effects, and secondary malignancies.

Many hematologists and oncologists now feel that ablative chemotherapy has reached its twilight and that new approaches are needed to make the cure of diseases, such as adult acute leukemia, disseminated lymphoma and plasmacytic myeloma. A phenomenon of the last two decades of the 20th century was the dramatic increase in the incidence ofnon-Hodgkin 's lymphomas, which is reaching near-epidemic proportions world-wide. The cause(s) remain speculative.

HEMOSTASIS AND THROMBOSIS

The 20th century was eventful for patients with bleeding disorders and their families. By mid-century, the basics of the coagulation system had been elucidated and soon ended the 5,000year-curse for patients suffering from bleeding diatheses. A breakthrough was the 1970 discovery by Judith Pool in California that coagulation factors , especially Factor VIII, could be concentrated by cryoprecipitation. This spelled the end of crippling joint

deformations and deaths from bleeding. Thanks to Dr. Martin Inwood 's efforts and organizational talents, London and St. Joseph's Hospital became a centre of excellence in coordinated Hemophilia care. The tragedies of transmission of diseases by pooled blood, especially Hepatitis B and C and HIV, were to follow. Recombinant technology finally ended this dreadful chapter of disease transmission.

On the other hand of the hemostatic spectrum are the patients with thromboembolism and thrombotic tendencies. Prevalence of obesity, smoking, oral contraceptives, malignancies and complex surgical procedures, especially hip replacement and cardiovascular prostheses, made thromboembolic disease a common problem and prompted intensive research. McMaster University in Hamilton became one of the world centres in thromboembolic research in the 1960s and 1970s. One of their shining lights, Dr. John G. Kelton, was a UWO product. He received worldwide recognition for his work on platelet immunology. Enormous strides have been made since thrombosis was treated with leeches in the first half of this century: Heparin and warfarin became the mainstay of anticoagulation for half a century, supplemented by platelet function inhibitors, such as ASA, for cardiac and stroke prophylaxis. London played a prominent role in the research of platelet function manipulation. The work of Dr. R. K. Stuart ( 1970) on ASA and Dr. Henry J. M. Barnett (1978) on stroke prophylaxis are milestones in thrombosis research. At the beginning of the third millennium, we are able to identify positively more than 60% of those patients who are likely to clot inappropriately. We can treat most patients with thromboembolism on an outpatient basis and use fractionated heparins and other anticoagulants in a more targeted way.

THE HEMATOLOGY LABORATORY

The microscope was more than 200 years old when the 20th century began, a century that would usher in unbelievable developments in microscopic optics, in the technique of specimen preparation, staining and interpretation. In the 1920s, microscopic bone marrow examination became feasible allowing an ex-vivo look into the factory of blood cells and many of its disorders. Yet as the century went on, the limits of the art and science of morphology became obvious: the microscope would produce beautiful pictures of cells, such as lymphocytes, but tell us little about their origin and functions . The origin of the Reed-Sternberg cell (Hodgkin's disease) would remain disputed for most of the century. The search for the elusive Astern cell, the mother of all cellular blood elements, remained a concept until the advent of cell marker technologies.

Towards the end of the 20th century, the definition of most Iymphoproliferative disorders depended on immune marker analysis, rather than morphologic pattern recognition. It was Dr. Diponkar Baneijee (now Princess Margaret Hospital, Toronto) who established in 1984 the first clinical flow cytometry unit in London at the then University Hospital. London subsequently achieved some worldwide recognition in Flow Cytometry through the work of Michael Keeney and Dr. Ian H. Chin-Yee on the definition of the stem cell. This technique is essential for the process of stem cell harvesting from the peripheral blood, via cytapheresis. Peripheral stem cell (auto-) transplantation proved to be superior to conventional bone marrow transplantation.

UWOMJ 71(1) 2001 19

The development of blood cell counting techniques in the laboratory borders on the miraculous. Older hematologists saw the elaborate and neat system of pipettes and counting chambers fade into history with some nostalgia. Thanks to the pioneer work of the Coulter Brothers in Chicago in the 1950s, the manual counting methods were replaced by a sophisticated array of automated solutions, dilutions, hydraulics, capillaries, laser beams, electric currents and computer integration which provided 12 and more counting parameters from microliters of blood within seconds with co-efficients of variation far less than 5%. Gone are the days where the physician dismissed inconvenient results as "lab errors." The establishment of quality controls and quality improvement in the laboratory is one of the great achievements of the 20th century. The establishment of the Laboratory Proficiency Testing Program of Ontario (LPTP) in 1974 promoted the quality in Ontario laboratories immensely. LPTP is now one of the leading proficiency testing programs in the world. London Hematologists and technologists have played a strong role in its development.

IMMUNOLOGY In the 1970s, a UWO Professor of Medicine remarked that he wished Immunology would go away- it didn 't. It has become part of the daily life of the Hematologist. The century of Immunology began for Hematology in 1902 with the discovery of blood groups

by Karl Landsteiner. In the evolving decades, more than 500 blood group antigens have been identified on the tiny red cell and its surface membrane. A relatively primitive red cell agglutination based technique led to the discovery and detection of these antigens and the corresponding antibodies and persists to this day in modified forms . A unique antibody to one of these antigens (the LW system) was first described in 1971 here in London by Dr. L. L. de Veber and Gertrude Clark of the then Victoria Hospital Blood Bank.

"Trude" Clark was the first Blood Banker in London. As a nurse, she co llected blood and separated the plasma for the WWII casualties; red cell storage became feasible only in 1947. Ms. Clark was subsequently certified as a Blood Bank technologist and was ChiefTechnologist of the then Victoria Hospital Blood Bank until she died in 1978. Blood transfusions with its triumphs and tragedies became a fact of hospital life. Ironically, the transfusion age became established before the advent of evidence-based medicine. Thus, there is no Level I evidence that blood transfusions save or prolong life; blood transfusions became an essential part of medi cal, surgical and gynecologica l practice before randomized contro l trials could prove its worth. Nowadays, modern hea lth protection branches wou ld not pennit entry of such powerfu l, but potentially harmful therapeuti cs into dai ly practice on an empiri ca l basis. In contrast, a great triumph of immunohemato logy, the conquest of Rh disease of the newborn by immunization was introduced in the 1960s by strictly scientif ic means- times had changed. Canada and the Winnipeg Rh Institute were recogn ized worldw ide for their Rh research. The Canadi an Rh immunization tri al of 1966-68 was one of the landmark studies on the prevention of Rh disease of the newborn.

It appears that Blood Transfus ion remains experi mental in its practice. Transfusion reactions, syphilis, hepatiti s B and C and HIV transmissions had to occur before they could be recognized 20

UWOMJ 71(1) 2001

and prevented. New threats appeared while the previous ones were being addressed: Creutzfeld-Jakob disease and HTLV are just two of the latest. We need to remember all the patients who suffered, so that others would be helped. The final chapter of the blood transfusion history will hopefully be written in the 21st century.

GENETICS In 1960, the discovery of the Philadelphia chromosome, a 922 translocation in patients with chronic myeloid leukemia, provided both, a first cytogenetics tumor marker and the first recognition of a new fusion gene that explained the uncontrolled growth of a cell line. The detection of many chromosomal abnormalities were to follow. An increasing number of leukemias and lymphomas are now being characterized by their cytogenetic defects , rather than their morphological or immunological appearance. In 1949, UWO Anatomy Professor, Murray Barr furthered our knowledge of the heterosome with the discovery of the "extra x" chromosome and its morphologic equivalent on the segmented neutrophil : The Barr Body. The development would soon shift from chromosomal analysis to gene mapping and diagnosis by polymerized chain reaction technology (PCR) . It is likely that in the third millennium many diseases, conditions and traits will be defined by their genetic makeup, rather than their clinical appearance. Which role gene manipulation will play in the therapy of conditions and diseases is for the 21st century to resolve.

By the end of the second millennium, Hematology in London had to adjust to dramatic changes; we were part of an extensive restructuring process. Expansion gave way to contraction, consolidation and relocation. The three Hematology services at South Street, St. Joseph's Health Centre and University Campus consolidated at the Westminster Site of the London Health Sciences Centre in 1997-1999. Those who participated in that difficult process benefited from the foresight of the founders of Hematology in London: these physicians created a tradition of cooperation and coordinated policies and technologies within London . In the 1970s and 1980s, the legendary "Blood Club" met monthly in the homes of the Hematologists to discuss scientific topics and enjoy some culinaries. The monthly combined Hematology Noon Rounds rotated through the three London hospitals with case presentations and discussions and united medical and techno logy staff of the three institutions. It created an "esprit de corps" and a forum of clinical and scientific exchange.

THE TWENTY-FIRST CENTURY One hundred years ago, the seeds for the electronics and informatics age were clearly in the ground. Yet, nobody could have predicted what fruit (and poisons) they would bear. The same appli es for Hematolo y in the Year 2000. However, some predictions and speculations are permitted. Here are some of the joys and problems for the Hematologist of 21st century, as I see them : Sophistication and knowledge base of the average Hematology patient will continue to increase and test the Hematologist's skill and patience.

Genetics will influence or replace much of our current diagnostic and therapeutic technology. This will alter the course of hemophilia, the hemoglobinopathies and some malignancies.

Non-invasive, transcutaneous point-of-care analyses and monitoring will replace much of our current Abloody@ laboratory system.

The causes and sources of the lymphoma epidemic will be uncovered and successfully contained.

Lymphomas, leukemias, and myelomas will be highly curable diseases by means other than cytoablative chemotherapy.

New environmental and aging related diseases, other than HIV and myelodysplasia, will appear and stimulate research.

The University will continue its transformation to a trade school. Industry will be the principal provider of science and development.

Synthetic/ recombinant blood products will replace the current blood transfusion system. Designer stem cell production will replace the current bone marrow transplant procedures.

There still will be a South Street Campus for patient care.

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ACKNOWLEDGEMENT London Hematologists, past and present, contributed essential information to this review. I am particularly grateful to Drs. deVeber, Stuart and Warwick for their historic papers.

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History of Medicine

Paul Potier MD, PhD Professor and Clwil~ Department of Hist01y of Medicine, The University of Western Ontario

Although medical writers since classical antiquity have regularly introduced their accounts of contemporary medicine with a history of progress down to their own time, it is only the twentieth century which has seen the establishment of History of Medicine as a full-time professional occupation. During the nineteenth century, many physician/historians- especially in France, Germany, Italy, and Great Britain- devoted a considerable amount of time and effort to the nascent discipline, producing many works of remarkable industry and sophistication. These include, besides editions and translations of classic medical texts, studies devoted to the conditions of health and disease in specific geographic areas, the medical theories and practices of various nonEuropean peoples, archeological finds uch as surgical instruments and healing temples , medical ideas as reflected in literary sources and popular beliefs, and individual di scoveries, per onalities, and schools of medicine. In the course of the century, some of these pioneer historians of medicine founded journals, set up courses for medical students, and authored general textbooks in the field .

In 1906, the University of Leipzig appointed Dr. Karl Sudhoff, a fifty-two year old general practitioner who had already published widely in the history of ancient and medieval medicine and surgery, as the first full-time Professor of the History of Medicine in Germany. It was from this Leipzig Institute that Sudhoff's successor, Dr. Henry E. Sigerist (1891-1957) emigrated in 1933. And together with his colleague Dr. Owsei Temkin, they founded the Institute for the History of Medicine at Johns Hopkins University in Baltimore, the medical school which, under the leadership of the Canadian William Osler (1849-1919) , had revolutionized American medical science and education at the turn of the century.

22

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In Canada, the first (unpaid) Professorship of History of Medicine was established at McGill University in 1905 . Its first incwnbent was Sir Andrew Macphail ( 1864-193 8), longtime editor of the quarterly Canadian literary periodical University Magazine, and founder of the Canadian Medical Association Journal in 1911. Macphail, a native of Prince Edward Island, was commissioned after his service in the Canadian Medical Corps to contribute the "Medical Services" volwne to the Official Hist01y of the Canadian Forces in the Great War (1914-19); the forthright criticisms he expressed in this carefully researched work did little to endear him to the military establishment.

At Western, Dr. J. W. Crane (1877-1959), one of the first three full-time professors appointed to the Medical Faculty in 1914, spent a considerable portion of his lecture time in Pharmacology talking about great medical men of the past, and instilling in his students certain precepts that he felt would prove helpful to them in their careers. Dr. Crane was also a prolific founder of clubs, including the Harvey Club of London, Ontario ( 1919) and the student Osler Society (1927), both of which still exist today. It is large ly to Dr. Crane's bibliophilic enthusiasm, expertise, and generosity that Western owes its present fine collection of historical medical books housed in the Special Collections section of the D. B. Weldon Library; the several thousand books he donated during his lifetime and bequeathed in his will form the nucleus to which the University and other donors have for many decades added.

A student of Dr. Crane, London native Dr. Lloyd G. Stevenson ( 1918-1988) spent the years fo llowing his graduation in 1944 writing Sir Frederick Banting (Toronto : Ryerson, 1946), an authoritative biography of the Canadian Nobel Prize wirmer for medicine in 1923 . Dr. Stevenson gave a series of lectures in

the history of medicine at Western in 1946-7, then going on to complete his Ph.D. at the Institute for the History of Medicine at Johns Hopkins under Professors Sigerist and Temkin. Dr. Stevenson returned to Western in 1950 as the John and Mary Markle Scholar in the History of Medicine, a position he held for four years. Eventually, after serving as Dean of Medicine at McGill University and Professor of the History of Medicine at Yale University, he finished his career as Director of the Johns Hopkins Institute.

At Western, in the meantime, the teaching of Medical History was continued on a somewhat irregular basis first by the retired Toronto physiologist Dr. Nonnan B. Taylor until 1956, then by Dr. L. F. G . Sennewald, a St. Thomas practitioner. From 1962 onward, it was propagated by a group of faculty volunteers including Dr. C. W. Gowdy of Pharmacology and Drs. R. G. E. Murray and C. F. Robin ow of Bacteriology and Immunology, and after 1967 by Professor R. A. Richardson, a historian of biology.

Beginning in 1974, a generous annual grant from Associated Medical Services - a Toronto medical insurance firm displaced by OHIP - allowed the establishment of the Hannah Chair for the History of Medicine, whose first occupant, Dr. Paul Potter, has taught a wide variety of students, besides carrying on research in several areas of medical history. The Hannah Chair was for several years associated with the Department of History of Science under the chairmanship of Professor F. L. Holmes, but now constitutes its own Department of the History of Medicine.

Generally, research in the history of medicine has expanded during the twentieth century beyond the textual, scientific, and biographical emphasis it had in the nineteenth century, to include elaborate studies on the profession and its institutions viewed in their social, political, and economic contexts. This institutional history of medicine has found a firm base at Western and its associated Colleges in the social science disciplines of History (Professors Ruth Brouwer, Peter Neary, and Maya Shatzmiller), Sociology (Professor Joseph Lelia), Anthropology (Professor Michael Spence), and Education (Professors R. D. Gidney and W. P. J. Millar). Within the Department of History of Medicine, itself, P. Potter and the McMaster Hannah Professor Dr. Charles G. Roland compiled An Annotated Bibliography of Canadian Medical Periodicals, 1826-1975 (Toronto : Clarke, Irwin, 1979), Dr. Helen Woolcock, a Hannah Post-doctoral Fellow (1983 -5 ), completed a monograph on the health conditions of Australian immigrant ships, Rights of Passage: Emigration to Australia in the Nineteenth Century (London : Tavistock, 1986), Dr. J. T. H. Connor, a Hannah Adjunct Professor, published a history of the London Health Association, A Heritage of Healing: the London Health Association and its Hospitals 1909-1987 (London, Ont. : L. H. A. , 1990), and Dr. Javed Siddiqi brought out hi s Oxford D.Phil. thesis, written while he was a Rhodes Scholar, as World Health and World Politics : the World Health Organization and the UN System (London: Hurst, 1995). Another area of concentration in the Department has been ancient medicine: P. Potter and Dr. Beate Gundert, both classicists trained in the Kiel school of the Hippocratic specialist Professor Hans Diller, have edited and translated texts of the important Greek physicians Hippocrates and Galen, as well as publishing articles on various aspects of the medicine these texts contain. Graduate seminars in this field have

benefited consistently by the participation of visiting scholars such as Hannah Visiting Professors Wesley D. Smith (University of Pennsylvania) in 1989-90 and Klaus-Dietrich Fischer (Mainz University) in 1991-2, and Hannah Post-doctoral Fellow Maury Hanson in 1988-90. Professor Smith devoted his sabbatical year to completing Hippocrates: Pseudepigraphic Writings (Leiden: Brill, 1990) and Dr. Hanson carried out much of the research at Western which led to the publication of Hippocrates: On Head Wounds (Berlin : Akademie Verlag, 1999). Another scholar active in textual research is cross-appointed to the Department, Professor Melitta Weiss Adamson, of the German Division of the Modern Languages Department in the Faculty of Arts, who studies medieval German and Latin cookbooks and pharmacopoeias

by Hildegard von Bingen and other writers. The biographical tradition in medical history is upheld by Dr. Murray L. Barr's biography of the biochemist Dr. J. B. Collip, the discoverer of parathormone in 1925 who became Western 's Dean of Medicine 194 7-61 , by F. L. Holmes ' study of a leading nineteenth century French biochemist, Claude Bernard and Animal Chemistry: th e Emergence of a Scientist (Cambridge, Mass .: Harvard, 1974), by P. Potter and Dr. Hubert Soltan's biography of M. L. Barr, and by J. Lelia's dramatic monologue on William Osler, Willie: a Dream (Montreal: McGill, 2000). In 1978, Western 's centennial was ce lebrated by the publication of M . L. Barr's A Century of Medicin e at Western , an immense store of detai ls on every aspect of the Medical Faculty's first hundred years, which in many cases res-

UWOMJ 71(1 ) 2001 23

cues from oblivion the lives of significant London individuals and their achievements.

Interdisciplinary ventures sponsored by the Department of History of Medicine have included a conference held in co-operation with the Department of Philosophy in 1994, which resulted in the recent publication by Professor John P. Wright (Hannah Visiting Professor 1992-3) and P. Potter, (eds.) of Psyche and Soma: Physicians and Metaphysicians on the Mind-Body Problem from Antiquity to Enlightenment (Oxford: Clarendon, 2000). Another forum for the exchange of ideas on health and medicine in their historical context has been the London Medical Historical Association, which was reactivated B Dr. Crane had formed a similar club in the 1920s - by Dr. Vladimir Hachinski and P. Potter in February, 1981 . This group, with a broad membership encompassing numerous Faculties and disciplines, meets monthly during the academic year in individuals' homes, and has proved a useful venue for lectures by prominent scholars visiting Western, who have included Professors W Bynum, W Coleman, J. Duffin, M. Grmek, F. Kudlien, R. Numbers, V Nutton, H. von Staden, and R. Wittern.

Western has also played a supportive role in the development of the Canadian Society for the History of Medicine, which was

founded in Quebec City in 1950. From 1990-5, J. T. H. Connor edited the national society's periodical (Canadian Bulletin of Medical History) from the Department, and P. Potter is presently serving as Secretary/Treasurer in a term which will extend from 1996 to 2002, an office which calls upon the Department's administrative capacities.

What does the future hold for the History of Medicine at Western? Recent endowment of the Hannah Chair, made possible by a capital donation of two million dollars by Associated Medical Services, would seem to guarantee a permanent professorship in our Faculty devoted to the discipline. The role these successive scholars are to play in pre-medical, medical, and graduate teaching will depend both on their individual training and inclinations, and on the general evolution of education in the years to come. With the rapid changes now taking place in both the technology of medicine and the provision of health care, the History of Medicine will continue to provide a useful point of reference for evaluating the present and planning the future from a knowledge of the past.

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S047C B3

Medical genetics in the new millennium

Jack Jung, MD, FRCPC, FCCMG Professor and Chief, Division of Medical Genetics, Department of Paediatrics Director, Medical Genetics Program of Southwestern Ontario, Children s Hospital of Western Ontario

Advances in DNA technology, super computers and rapid information transfer have all helped in accelerating the timetable for decoding the human genome. Although this project has been likened to the biological equivalent of the moon-shot, the most significant research is still ahead. The success of the Human Genome Project has laid the foundation for the greater challenges of interpreting this information into a better understanding of the biological basis of health and disease. To better appreciate the current status of medical genetics and possible future directions, it would be beneficial to review its historical evolution.

Soon after the "re-discovery" of Mendel 's laws of inheritance (1900), some physicians with foresight began to apply them to explain the origins and transmission of certain rare inherited diseases and disorders. The prescient work of Garrod as early as 1902 in England on alcaptonuria and later with other inborn errors of metabolism in the first decade of the 20th century was a good example. There were many others such as the early demonstration of autosomal inheritance for Huntington Disease in Canada by Hattie (1909).

At about the same time that Mendel 's Laws were first being applied to human diseases certain socially prominent persons and organizations, primarily in the United States, several European countries and Canada began to use the awakening of interest in genetic determinants to further their own aims. They utilized and expanded this new understanding of inheritance beyond the limits of science in an attempt to solve social ills such as poverty and criminality and to influence immigration policies. The Eugenic Movement, based more on sociopolitical ideologies than the new science of genetics, reached its maximum influence in the 1920's and 1930's. After 1945 the Movement declined rapidly when the world took stock of the barbarisms of World War II and recognized the racism that was part of it. Its decline was aided by an

Hubert So/tan MD, PhD, FCCMG Professor Emeritus, Department of Paediatrics, Th e University of Western Ontario

increasing scientific understanding of how genetic constitution really influenced the development of specific phenotypes and in general a better understanding of the interaction of heredity and environmental (social) factors.

The post World War II optimism in academic and medical circles recognized that future physicians should have some rudimentary education in current theory and in the medical applications of genetics, especially through genetic counselling. This recognition came about partly because it became painfully obvious that ignorance of basic genetic principles could lead to much harm when physicians counselled certain families with a heritage of genetic disease or parents of physically malformed or mentally handicapped children. Rudimentary brief "courses" in human or medical genetics were offered in most progressive medical schools. These were spurred on by the remarkable discoveries about the relationship of chromosomal anomalies to certain hitherto inexplicable syndromes in the 1950's and 1960's, Down Syndrome being the most common. Other stimuli to the development of medical genetics were the continued elucidation of a larger number of "inborn errors of metabolism" and the explosive interest in genetic prenatal diagnosis and screening.

Few would have predicted the impact of the discovery of so called restriction enzymes on the evolution of modem recombinant DNA technology. It has helped in identifying a large number of mutations responsible for human diseases. A common repetitive theme is the bridging of clinical information with research that emphasizes the importance of the "bedside to laboratory" approach. Clinical entities such as Huntington Disease, Duchenne muscular dystrophy and cystic fibrosis are relatively well delineated. Given their severity and how relatively common they are amongst genetic diseases, it was natural that they received the most concentrated early molecular research efforts.

UWOMJ 71 (1) 2001 25

Currently, the identification of mutations responsible for diseases is proceeding at a rapid pace. This has led to further descriptions of clusters of contiguous genes which when mutated, can result in complex syndromes. DiGeorge syndrome and velocardiofacial syndromes are examples of syndromes which can include clinical features such as congenital heart disease, thymic aplasia and unusual craniofacial and limb anomalies. These overlapping syndromic diagnoses have now been shown to be related to deletions involving a series of contiguous genes on chromosome 22. Loss of heterozygosity is a term describing the missing genetic information from one of a pair of homologous chromosomes due to these deletions. These situations can lead to a variability of clinical phenotype based on the size of the deleted segment. Some of the smaller sub-microscopic deletions, only visible with florescent in situ hybridization techniques, can give rise to just isolated characteristics of each syndrome. For example, a significant number of cases of isolated complex congenital heart disease are due to this mechanism.

The impact on clinical practice has also been significant. At a simple level , it has aided in the confirmation of many diagnoses. Mutational analysis has helped to avoid muscle biopsies or electrophysiological studies in neuromuscular diseases like Duchenne muscular dystrophy and myotonic dystrophy. It has also helped in presymptomatic or predisposition testing in areas such as the hereditary cancers.

In families with a strong history of colon cancer, verification of a gene specific mutation aids in identifying the at risk individuals who need careful surveillance. Individuals documented not to have the mutation are often relieved that their risks approximate those of the general population so that no extraordinary screening procedures (e.g., colonoscopy) need to be considered.

The combination of both clinical syndrome recognition and gene research will further our understanding of gene function and open the route for exploring treatment and prevention strategies. This same theme will recur with an increasing number of diseases, many of which are very rare but each offering us a fascinating insight into normal gene function and what can happen when it is disrupted.

The completion of the Human Genome Project (far ahead of schedule) has laid the raw data before us that will be the foundation for future advances in our understanding of the genetic determinants of health. Speculations regarding future possibilities are numerous but need to be balanced with some realistic expectations. Within the scope of thi s article, only a few possibilities will be discussed.

The promises of gene therapy are not yet reality for a wide variety of serious genetic conditions. The hypothetical concept is one of introducing a good gene to replace a faulty one. The problem remains how to insert genes into a target cell, retain its biological activity and avoid serious side effects. One of the early trials was for Severe Combined Immune Deficiency (SCID), sometimes referred to as the "Bubble Boy Disease" because of the young boy who was raised inside a plastic bubble to protect him from exposure to the viruses and bacteria. The problem was related to a deficiency of an enzyme called adenosine deaminase (ADA). The gene therapy trial did result in measurable increases in levels of ADA but it was of insufficient quantity to make any functional difference in the children treated. The positive news 26

UWOMJ 71(1) 2001

was that a pharmaceutical company developed an "orphan drug" to replace the enzyme so SCID became a treatable disease. Even given the early failures of gene therapeutic approaches to date, successes will undoubtedly occur in the future , especially given the research and development weight of large pharmaceutical and biotechnology companies.

Another trend will be the continued influence of the "G" economy which refers to the rubric of companies that are "genomic-based". Within the lay press, financial publications have increased the general public 's awareness of the companies involved in gene mapping or the development of genomic-based pharmaceuticals and therapies. The influence of the private sector in the recent (rudimentary) mapping of the human genome cannot be ignored and is surely representative of increasing research and development outside of traditional academic institutions. Although some will take issue with this profit motivated approach, the potential spin-offs are tremendous. One future direction, especially driven by the private sector, will be to apply genomic-based therapies to common diseases such as adult onset heart disease and cancers. Already, patients with coronary artery disease have received experimental gene therapy utilizing a growth factor (VEGF-2). Injected into the heart, VEGF-2 can trigger the growth of new blood vessels and decrease chest pain symptoms. Other possibilities applied to common adult ailments offer the potential for a preventative approach to the practice of medicine. If successful, one can only speculate on the effect on our lifespan.

Another area that will receive great attention will be cancer.

Advances in DNA arrays (computer chip-like devices) can quickly test for thousands of genes. In the case of T-cell lymphomas, one could quickly distinguish between the various genetic sub-types, each of which is known to respond best to different drugs . Likewise, a similar approach could be used to identify an individual 's unique pharmacogenetic profile that might include specific profiling of the liver enzymes known to metabolize certain drugs . This type of genetic characterization will also help in identifying the small percentage of people who might experience adverse reactions to medications.

Many diseases are a result of genetic predisposition and environmental factors. Increasing knowledge of a person's unique genetic trengths and liabilities should help to promote wiser lifestyle choices. With common conditions such as high blood pressure, an individualized approach could include identifying a person 's genetic predisposition, the environmental variables and the best treatment, be it pharmacological or related to environmental modification. This individualized or customized methodology will become more common as genotyping becomes easier.

This will then truly represent a patient centered (genotype and enviromnental) approach to the practice of medicine.

To briefly summarize, decoding the human genome promises many biotech miracles that will help in the diagnosis, treatment and prevention of a multitude of diseases. It has also started a much needed public debate regarding how we as a society wants to deal with an increasing number of legal and ethical issues. Of equal excitement, developmental biologists are primed to help explain more of the fundamental processes responsible for normal hun1an development. Brave new world or an exciting one? An optimist would choose the latter.

Neurology: from nihilism to the beginnings of hope

Jose G. Merino MD, MPhi/ Clinical Fellow, Dep artment of Clinical Neurological Sciences, Th e University of We tern Ontario

"Neurology had always been an entirely descriptive branch of medicin e. Once the clinician had figured out the precise location of the lesion (or lesions) in the brain or spinal cord -and the exactitude with which this localization could be accomplished, when you knew enough neuroanatomy, was the challenge of the field- there was nothing much to be don e for therapy because of so little understanding of how the structures really worked ...

"Th e making of a neurological diagnosis was itself l..'ind of a game. All you needed to play were three implements, a rubber hammer for eliciting reflexes over tendons and muscles, a pin for testing pain receptors, and a wisp of cotton (some neurologists carried around a feath er) for testing light touch. One's thumbnail served for scratching the soles of the f eet to see if the toes extended and spread; this reflex, the Babinski, was probably the most important single f eature of the neurological examination, signifying that damage had been don e to the long motor pathways and, always, real trouble."

Lewis Thomas, The youngest science. I TRADITIONAL NEUROLOGY

Neurology is rooted on clinical semiology, the study of the signs and symptoms of disease. Neurologists at the dawn of the twenty first century rely on the same tools Lewis Thomas used when he started his neurological training in 193 7. A detailed history and a thorough neurological examination allow the neurologist to localize a lesion in the nervous system with precision, to generate a differential diagnosis, and to formulate a treatment plan. Reliance on this clinical method has led neurologists to develop clinically useful and pathologically verified classifications of diseases based on syndromic characteristics .

Unfortunately, this precision in diagnosis and classification dis-

Vla dimir Hachinski MD, DSc, FRCP(C) Prof essor and Chail; Department of Clinical Neurological Sciences, Th e University of Western Ontario

ease has not been matched by the neurologist's ability to treat them. Interventions to ameliorate the symptoms of brain and nerve dysfunction have been used for decades but most illnesses have remained beyond relief or cure. The sense of therapeutic nihilism expressed by Lewis Thomas was captured by Labe Scheinberg when he summarized the task of the neurologist as "Adiagnose and Adios". A limited understanding of how the brain and nerves work has been the cause of the limited therapeutic options in neurology. During the last two decades, however, some of the secrets of the nervous system have begun to be unraveled, and there is now a greater, albeit far from complete, understanding of how the brain works. This new understanding brings with it a promise of effective interventions and a renewed sense of optimism in neurology.

NEUROLOGY IN THE NEW MILLENNIUM

Clinical neurology is changing. Advances in the laboratory have led to new ways of conceptualizing problems at the bedside.

A new classification of neurologic disease is emerging. The possibility of modifying the progression of neurologic disease is now a reality. New drugs and interventions challenge clinicians to adopt new ways of practicing neurology. Three areas deserve special attention: the growth of molecular neurology, advances in neuroimaging technologies, and new therapeutic possibilities.

Molecular Neurology

The growth of molecular biology has transformed medicine.

Its impact on neurology has been profound.2 This is not surprising.

Half of all human genes are expressed in the brain, about a third of all known genetic defects affect the nervous system, and about 300 genes that cause or contribute to neurological disease have

UWOMJ7 1(1)200 1 27

been identified (61 % of these are also present in drosophila!) .

Until recently the chapters of genetic diseases in neurology textbooks were limited to the metabolic diseases of childhood.

Nowadays most neurological illnesses are understood as having a genetic component. Our knowledge of the function of the nervous system in health and disease has expanded exponentially in the past decade, so has our awareness of the limits of our knowledge.

The impact of molecular biology is evident in the emerging terminology of clinical neurology. Until recently, a limited understanding of the cellular and molecular processes that produced dysfunction of the nervous system meant that neurologic diseases could only be classified based on their biochemical or clinical features. The therapeutic armamentarium of neurologists has been limited to agents that affect symptoms, not modify disease.

The language of neurology has been that of neuropathy, myopathy, movement disorders, ataxias, neurocutaneous disorders, paroxysmal disorders, cerebrovascular disease. A greater understanding of the molecular events that lead to disease have transformed neurological language to that of channelopathies, triplet disease disorders, mitochondrial dysfunction, prion agents. This emerging classification of diseases goes beyond symptoms; it addresses pathological processes and highlights possible therapies. For example, the channelopathies include diseases previously grouped under different syndromic classifications : Myopathies (hyper- and hypo- kalemic periodic paralyses, paramyotonia and myotonia congenita), disorders of the neuromuscular junction (congenital myasthenic syndrome), ataxias (episodic ataxia with myokimia (type 1) and with nystagmus (type 2), spinocerebellar ataxia type 6), paroxysmal disorders (familial hemiplegic migraine, hereditary epilepsies), movement disorders (hereditary hyperekplexia), and even cardiovascular disease (long QT syndrome). The understanding that this group of disorders with heterogeneous symptomatic manifestations have similar genetic defects that impair ionic transport through transmembrane channels has led to effective treatments based on pathophysiology. The discovery of the genetic mechanism of the triplet repeat disorders and mitochondrial diseases (also clinically heterogeneous groups) allows for effective diagnosis and genetic counseling and holds the promise of potential prophylactic and therapeutic interventions through gene therapy.

The recognition of allelic and locus heterogeneity has led to the identification of several new syndromes involving the central nervous system. Allelic and locus heterogeneity highlight the limitations of a classification of disease based on symptomatic characteristics. Allelic heterogeneity occurs when more than one clinical syndrome is caused by mutations of the same gene. For example, mutations of the gene on chromosome 17 that codes for the protein PMP-22 can lead to three different syndromes, each with different age of onset, clinical features, and prognosis:3 a duplication leads to Charcot-Marie-Tooth disease type 1 (CMT-1), a missense point mutation to hereditary neuropathy with liability to pressure palsies, and a deletion to Dejerine-Sottas disease. On the other hand, when the same clinical syndrome is caused by mutations of different genes, locus heterogeneity exists. The clinical syndrome CMT- 1 most often results from a duplication of the PMP-22 gene. However, it can also be the result of a missense point mutation of either the myelin protein zero (Po) gene on 28

UWOMJ 71 (1) 2001

chromosome 1, the early growth response gene on chromosome 10, or the connexin 32 gene on chromosome X .

Advances in molecular biology allow diagnosis by DNA analysis. DNA testing is available for hundreds of syndromes involving all clinical categories, from the ataxias to stroke.

Although most genetic tests are now limited to research laboratories it is expected that over the next few years they will become an important element of the neurological diagnostic armamentarium.

The identification of the abnormalities that underlie neurologic illnesses caused by single gene defects has made gene therapy a realistic possibility. Current application of this technique has been limited due to the difficulty of introducing the gene into the abnormal cells. This is an active field of research, and new vectors are being developed. Clinical trials with herpes-simplexthymidine kinase gene for the treatment of gliomas are underway; there have been some encouraging results.4 Its major applicability will be in single gene defects that affect a single organ.

Although there are hundreds of diseases caused by singlegene abnormalities, it is now clear that the more common neurological disorders arise from the interaction of environmental factors on a genetically susceptible nervous system. To effectively prevent or treat neurologic disease we will have to understand the gene responses induced by ischemia, hypoxia and oxidative stress that lead to cell damage in stroke, epilepsy, and the neurodegenerative disorders . For example, it is hypothesized that in some patients a brain insult (such as toxic injury or a prolonged febrile seizure) will lead to the development of hippocampal sclerosis (and epilepsy) only if genetic predisposition has rendered the hippocampus susceptible to injury.s No preventive intervention is possible until the nature of this environment-gene interaction is understood.

The issue of genetic defects causing or modifying genetic susceptibility to disease is illustrated by Alzheimer disease (AD).6 Several genetic mutations have been found to lead to early onset Alzheimer disease: mutations of the gene coding for the amyloid precursor protein on chromosome 21 , mutations of the Presenilin1 gene on chromosome 14, and mutations of the Presenilin-2 gene on chromosome 1. These mutations are transmitted in an autosomal dominant pattern and all lead to a clinical syndrome with differences in the age of onset and the rate of progression. Late-onset AD is not genetically transmitted, although the presence of a particular isoform (ÂŁ4) of apolipoprotein E (coded for by a gene on chromosome 19) has been found to increase the risk of developing the disease. This particular isoform of the APOE gene product also makes the brain more susceptible to develop cognitive impairment after stroke and head trauma. In these cases, understanding the gene-environment interaction will lead to effective preventive and therapeutic interventions.

The growth of molecular biology has also given us an increased understanding of the metabolic processes that are involved in cell damage and death in a variety of other diseases.

This knowledge has opened the possibility of new, more effective treatments.

Imaging Until twenty five years ago, neurologists could only image the nervous system indirectly through the introduction of sub-

stances (air, contrast material) into the peripheral vasculature or the subarachnoid space. The analyses of electrical activity at the cerebral cortex (electroencephalography) or along the nerves and in the muscles (electromyography/nerve conduction studies) were the only tests available to evaluate the physiology of the brain and peripheral nerves. The advent of computed tomography (CT) in the late 70s, and of magnetic resonance imaging (MRI) in the late 80s allowed physicians to directly visualize the structure of central nervous system. As a result of subsequent technological advances (functional MRI, diffusion weighted imaging (DWI), perfusion weighted imaging (PWI), magnetic resonance spectroscopy) physiologic processes (cerebral activation and tissue blood flow, water diffusion, metabolic makeup) in the brain can be visualized. Magnetic resonance angiography (MRA), Doppler and B mode carotid ultrasound (duplex ultrasound (DU)) and transcranial Doppler (TCD) provide non-invasive ways to evaluate the cervical and extracranial vasculature. The use of these technologies allows neuroscientists and clinical neurologists to study normal brain function and cerebral pathophysiology. Neuroimaging is now used to evaluate the impact of new treatments for multiple sclerosis and stroke.

An example of the way in which neuroimaging has altered the practice of neurology can be seen in the field of stroke.

Before the advent of CT, the location and etiology of a stroke could only be assumed from the history and clinical examination.

The differentiation between ischemic and hemorrhagic stroke could not be confirmed. Patients that are suspected of having an acute stroke can now be imaged in the emergency room within minutes of onset of symptoms. CT can rule out the presence of an intracranial hemorrhage determine the suitability for the use of intravenous thrombolytic agents and neuroprotective drugs.

DWI can ascertain the size of the infarct; PWI can identify tissue at risk. Evaluation of the vasculature with DU, TCD, and MRA can help determine the etiology of the stroke. The findings from a combination of studies allow treatment to be tailored to each particular patient.

N eurotherapeutics The therapeutic nihilism that has surrounded neurology is beginning to give way to hope. During the Decade of the Brain the therapeutic repertoire of neurologists expanded dramatically.

After decades of having fewer than eight traditional antiepileptic agents, the last ten years have witnessed the release of nine new anti-seizure medications (felbamate, gabapentin, lamotrigine, levetiracetam, fosphenytoin, oxcarbazepine, tiagabine, topiramate, and vigabatrin). Some of these have been effective for the most refractory patients. The treatment of Parkinson's disease is no longer limited to the use of anticholinergic agents, L-dopa, or bromocriptine. New dopamine agonists that may decrease the incidence of L-dopa related side effects are now available. The enzymatic degradation of dopamine can be retarded via inhibition of MAO-B (selegiline) or COMT (Tolcapone). The toxin produced by Clostridium botulinium has been used therapeutically to treat dystonias and other movement disorders. New drugs can retard, to a moderate degree, the progression of symptoms in neurodegenerative diseases. Riluzole (a glutamate inhibitor) can prolong life for 3 to 6 months in patients with amyotrophic later-

al sclerosis, and acetylcholinesterase inhibitors delay memory decline for few months in patients with Alzheimer disease. New agents can effectively abort migranous attacks. Novel antiplatelet agents, and combinations of some of these, are now routinely used in the secondary prevention of stroke. Intravenous immunoglobulin can accelerate the recovery from autoimmune mediated neuropathies. New treatments are not limited to those listed, interventions for almost every neurological condition have been developed. For the first time medications that modify the course of neurologic disease, and not just target symptoms,s such as P-interferon and glatiramer acetate, are available to treat multiple sclerosis. Gene therapy, neuroprotective agents, growth factors, and stem cells will become routine neurological treatments in the coming decade.

New interventions in the field of stroke have led to a redefinition of what a neurologist does and where she sees patients.

The approval of tissue plasminogen activator (tPA) has given neurologists the opportunity to restore blood flow to ischemic areas of the brain.9 Neurologists now work as members of acute stroke teams, and are becoming familiar with emergency medicine. The new proactive role of neurologists is reflected in the growth of a new specialty, interventional neurology. The pattern of neurologic practice will continue to evolve over the coming years .

THE CHALLENGE TO NEUROLOGY At the start of the new millennium the growth of the neurosciences has made clinical neurology the most exciting field in medicine. Neurologists now face the challenge of translating the discoveries of basic science into practical bedside treatments, including ways of rehabilitating the diseased nervous system.

Preventive neurology will have to be developed; its impact will not limited to stroke prevention but also to the prevention of neurodegeneration. Interdisciplinary research will become increasingly important.

These are times for tempered optimism in neurology. We must celebrate the advances that have been achieved while recognizing the limited nature of our knowledge. As neurologists we must make sure that our wisdom grows with our knowledge, so that we can address new ethical quandaries that arise from new scientific discoveries. We must resist the temptation of being blinded by the advances of technology and basic science to the detriment of the clinical method in neurology and the compassionate care of our patients.

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Neumann-Haefelin T, Moseley ME, Albers GW. New magnetic resonance imaging methods fo r cerebrovascular disease: Emerging clinical applications. Ann Neural 2000;47: 559-5 70.

In terferon -1 b is effective in relapsing- remitting multiple sclerosis. II. MRJ analysis results of a multicente1; randomi::ed, double-blind, placebo-controlled trial. UBC MSIMRJ Study Group and the IFN Multiple Sclerosis Study Group. Paty DW, Li DKB, University of British Columbia MSIMRI Study Group, JFN Mu ltiple Sclerosis Study Group.

Neurology 1993;43:662-667 NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Eng/J Med 1995;333: 1581-1587.

PLANNING FOR THE FUTURE OF HEALTH CARE IN OUR REGION Peterborough Regional Health Centre was officially launched January 11 , 1999 . Representing a new beginning for health care in Peterborough and the surrounding region, two sites currently support the Health Centre - the Hospital Drive Site (formerly Peterborough Civic H ospital) and the Rogers Street Site (formerly St. Joseph's H ealth Centre).

On June 19, 2000, the former M inister of Health and Long Term Care Elizabeth Witmer an nounced the go ahead for a new hospital.

Wo rki ng with our physicians, community and regional partners, PRHC will help develop and mai ntain a continuum of care which will serve to meet the needs of this growing communi ty well into the fu ture.

PETERBOROUGH REGIONAL HEALTH CENTRE Hospital Drive Site I Hospital Drive Peterborough, ON K9J 7C6 (705) 743-2121

Rogers Street Site 384 Rogers Street Peterborough, ON K9H 786 (705) 743-2121

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Begin your Career at the Rouge Valley Health System Rouge Valley

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The Rouge Val ley Health Sy tern offer today's career medical professional a wide variety of options for max imizing ru or her ski lls in an environment acutely ensiti ve to their needs.

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Whatever your specialty, you' ll fmd a home where your skills, contributions and input are highl y val ued !

The Rouge Valley Health System is made up of two full ervice, community based acute care ho pitals, Centenary Health Centre, serving east Toronto and Ajax and Pickering Health Centre, erving west Durham. Our two-health centre ite sy tern ha approximately 600 beds and serve one of Ontario's fastest growth areas with a population of over 400,000 people.

Health System

Centenary offers a full range of health services, such as Cardiac Services including catheterization, pacemaker implantation and cardiac rehabilitation- and has been put forward a the next cardiac surgery ite in Ontario. It i at o one of fi ve Regional Paediatric & Neonatal Centres in Metropolitan Toronto and is an integral prutner with the Hospital for Sick Children's Child Health Network. Centenary is undergoing exciting redevelopment with the creation of a new state of the art birthing centre, Level [l NICU and a recentl y approved MRI to enhance the diagno tic ervice to the communi ty by Summer 200 I. In June 1999, our Ajax & Pickering site completed a state-of-the-art upgrading to Diagnostic Services including a CT Scanner and specialized x- ray equipment such a gastric testing, ultrasound and re pirat01y te ting. The Ajax & Pickeri ng site has recentl y opened a brand new 20-bed Rehabilitation U nit to serve the population in West Durham. Trus new un it will allow for better and faster recovery for patients undergoing hip and knee replacements. The expansion of our Emergency Department and Outpatient Services is expected to begin in 2002.

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UWOMJ 71{1 ) 200 1

Ophthalmology at the millenium: important recent developments in prevention and treatment of eye disease

N R. Willis MSc, MD, FRCS(C) Projess01; Department of Ophthalmology, The University of Western Ontario

Ophthalmology has participated in many of the significant medical developments that we have experienced in recent decades of the last century. Three areas: management of cataract, prevention of ocular injuries, and the development and implementation of laser technology, will be reviewed to develop this premise.

MANAGEMENT OF CATARACT As we age, our ocular lens gradually loses its transparency.

When significant visual interference occurs, we employ the term, "cataract" to describe this change. As cataract develops, the clear black appearance of the pupil is lost, changing progressively from a translucent pale yellow colour to a foamy, whitish appearance in the pupil, when the cataract is said to have become "mature" or "ripe". The term "cataract" is derived from a Greek word meaning: "waterfall", likely in reference to the whitish foamy appearance of water as it descends over an incline.

The development of cataract has been feared over many centuries and early efforts at its management were quite primitive. In India and Africa, for many years, the lens has been intentionally dislocated out of the pupillary space in a maneuver known as "couching". The trauma of this surgery, combined with the loss of the focusing power of the lens resulted in a poor quality of life after surgery, although much more light entered the eye.

Hemorrhage and retinal detachment are frequent operative complications. The lens of the eye provides approximately 25% of the refractive strength of the globe and so its loss results in a permanently blurred image.

In North America and in Western Europe, a more sophisticated approach was taken to management of cataract using open surgical intervention. Initially this involved the removal of the opacified lens in its entirety (intracapsular extraction), a technique that was extensively employed in these areas until the mid

20th century. Following surgery by this approach, and the mandatory quiet interval of weeks to allow the large incision to heal , the patient was fitted with thick glasses in a spectacle frame to replace the lost focal power of the normal lens. While these glasses provided a relatively clear image of a stationary target when the patient was quiet and sendentary, they were a "disaster" to wear when either the patient or the subject of interest were moving, or worse still, when both were mobile. Although this technique resulted in some improvement in quality of life, it was far from an ideal outcome.

By the mid 1960's, several developments led to a remarkable improvement in surgical outcomes following cataract extraction.

The development of the operating microscope, which was embraced at the outset by ocular surgeons, allowed a much greater degree of precision in the surgical approach to the globe.

Parallel developments in needle and suture design and in operative instrumentation also followed . Furthermore, there was an increasing appreciation that removing the lens "en bloc" (by the intracapsular technique) destroyed the intraocular architecture and increased the risk of late postoperative complications, with retinal detachment being the most severe of all.

Increasing enthusiasm developed for an important modified technique that kept the posterior lens capsule intact and attached to the zonule following surgery. This approach, known as the extracapsular technique, has been widely accepted and it is now generally employed. However, the quality of visual improvement had not improved with the use of cataract spectacles and many of these patients, particularly those that had an active lifestyle prior to surgery, found themselves severely disabled after their operation. Thus, a search to eliminate the visual distortion and artifact associated with thick cataract spectacles began.

Following a short period of enthusiasm for the regular wear

UWOMJ 71(1) 2001 31

of contact lenses in cataract patients, attention focused on the development of an implantable lens that could be inserted directly into the eye at the time of surgery. Early key work in this area was done by Dr. Harold Ridley, a British military ophthalmologist who had managed several World War II fighter pilots whose plastic aircraft canopy had been shattered during combat resulting in intraocular injuries. Several of these pilots retained small intraocular fragments of the canopy plastic, a material known as Perspex CQ and, curiously, experienced very little adverse scarring and inflammation inside the eye. Ridley was astute enough to realize that this material might well be tolerated for long periods of time in the interior of the globe and this observation led to the development of the first intraocular lens implants (IOLs) more than 50 years ago. By contemporary standards, these were rather crude circular small plastic discs that were inserted into the pupillary space following intracapsular cataract surgery. While many of these dislodged, several remained in place with a highly successful visual outcome. Although Ridley was widely criticized by skeptical colleagues at the time, he continued to work in this area and his impetus has been critical to the subsequent development of contemporary intraocular lens implants.

As implant design improved, the material selected became more stable and the placement in the eye became more secure.

Early lenses were often fixated on the iris and were comprised of reactive materials, often with metal loops. These were unstable and often damaged the interior of the eye on movement. The second major phase of development related to anterior chamber intraocular lens implants that bridged the anterior segment of the eye from angle to angle, providing improved stability. However, the anterior location of these implants, the associated risk of glaucoma and the late corneal deterioration interfered with the widespread acceptance of this type of lens implant. Subsequent designs have led to placement of the implant at or immediately adjacent to its normal anatomic site. Thus, a wide variety of posterior chamber intraocular lens implants have been developed with rigid plastic optics and flexible supporting loops that rest in front of the lens capsule following extracapsular surgery and whose supporting loops wer lodged in the sulcus of the ciliary body. Sutures were still needed at this point to close the large operative incision and a significant period of restricted activity was required.

The latest development involves manufacturing IOLs from silicones and other polymers that have long-term transparency and yet are quite malleable so that they can be folded as they are inserted into the globe. Consequently, one is able to place an intraocular lens implant, often 7 mm in diameter, through a corneal incision of 3.5 mm or less. The foldable lens is the "state of the art" at the moment and is now inserted into the evacuated lens capsule which has a circular window cut in its front wall.

Ultrasonic emulsification of the cataractous lens material through a small external incision has facilitated this development. This surgical approach involving foldable lens and small corneal incisions is presently the most frequently performed operation in North America. Patients with cataracts undergoing this type of surgical management have rapid visual improvement and a shorter period of restricted activity postoperatively, which help facilitate a quicker return to normal activities.

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UWOMJ 71(1) 2001

PREVENTION OF OCULAR INJURIES Until midway through the last century, ocular injuries occurred frequently in sports and industry-related work. Encouraging developments in injury prevention, supported by Workers' Compensation Boards, were made initially in the industry. Flush fitting cover goggles for chemical workers, improved protective head-gear for welders, and improved industrial design of work areas have allied to significant reductions in work-related accident rates. Canadians have been, and remain, at the forefront of research and development in injury prevention efforts and management of the severely injured eye following industrial accidents.

A more troublesome problem has been that of eye injury occurring in sports, with the greatest offender being our national pastime of hockey. During the 1950's and 1960's, it became clear that our ocular injury rates in amateur and professional hockey players were much too high and that these injuries were frequently associated with serious permanent visual impairment. In order to confirm these impressions, a detailed Canada-wide survey was organized in 1975 by Dr. Thomas Pashby of Toronto under the auspices of the Canadian Ophthalmological Society. Pashby and colleagues confirmed the devastating impact of eye injury in competitive hockey and the numbing frequency with which this occurred in minor hockey players. Pashby subsequently persuaded the Brampton Minor Hockey Association in the winter of 1976 to be the first organized hockey association to use prototype face shields with the helmets that have recently become a mandatory requirement for minor hockey. This event marked the beginning of the campaign of athletic eye injury prevention spearheaded by Pashby and associates across the country. Blinding athletic eye injuries, which occurred with regularity more than 25 years ago, are now very unusual, occurring only among individuals who do not wear protectors. Commercial manufacturers of hockey equipment, notably the CCM and Cooper companies at the outset, strongly supported these developments even at a time when investment return was far from assured. Pashby has further worked with the Canadian Standards Association to develop appropriate standards for eye protectors and has expanded his efforts into other sports, notably the racquet sports, where injury rates were shown to be excessive. He has been properly recognized with the Order of Canada and was recently elected to the Canadian Sports Hall of Fame.

A recent severe ocular injury to a promising young NHL player has drawn the issue of eye protection in sports into focus once again. Most NHL players do not yet wear CSA approved eye protectors which, unfortunately, are viewed by some as admission of weakness. It is hoped that this situation will change soon, so that our best professional players can again serve as proper role models for our children .

DEVELOPMENT AND IMPLEMENTATION OF LASER TECHNOLOGY Ophthalmology was among the earliest areas in medicine to utilize the laser in regular clinical practice and has seen remarkable advances in the application of laser technology in the past three decades. One of the more notable advances in laser application is the management of diabetic retinopathy. The multi-center

co-ordinated clinical trial headed by the late Dr. Matthew Davis at the University of Wisconsin, showed convincingly that laser panretinal photocoagulation (the delivery of a series of intentional retinal laser burns according to a carefully prescribed protocol) retarded the growth of new blood vessels into the interior of the eye in patients with severe diabetic. This new laser application eliminated the requirement for pituitary ablation in these patients, a complicated technique with significant rates of operative mortality and morbidity and consistent deterioration in the quality of life thereafter.

Lasers are also regularly employed in ophthalmology to open clouding of the posterior lens capsule, which occurs in approximately 25% of patients following cataract surgery, and also to perform laser iridotomy in patients that are predisposed to angle closure glaucoma. Both of these laser treatments eliminate the need for open operative intervention in these conditions, converting in-patient procedures with risk of hemorrhage and infection to out-patient treatments with improved safety.

Age-related macular degeneration (ARMD) represents one of the major unsolved challenges to the specialty of ophthalmol ogy. And as the Canadian population ages, it will become a greater management problem. Although it involves only a minority of cases of ARMD, subretinal neovascularization in the macular can have devastating visual consequence, particularly if hem orrhage occurs from the fragile , newly formed vessels. A recent

multi-centred coordinated clinical trial has confirmed a new and effective therapy for this condition involving laser energy. In this treatment, a prescribed dose of a potentiating agent known as verteporphyrin (sold by its Canadian developers, QLT Phototherapeutics, as Visudyne) is injected intravenously.

Verteporphyrin concentrates rapidly in the abnorma l new vascular endothelial cells beneath the retina and predisposes them to damage when a laser of specified wavelength is delivered to the retina. This innovative approach to manage ARMD has resulted in significant increase in visual preservation in the treated group when compared with an age and disease-matched control group.

Of more recent vintage, and one where entrepreneurship and medicine intersect, is the application of the Excirner laser to reshape the contour of the cornea and correct various refractive errors. As is evident from the aggressive advertising programs in the public media, these techniques are becoming widely deployed, with several of the early trials of these devices undertaken in Canada.

In conclusion, ophthalmology has played a key role in constructive medical developments over the last century and is poised to continue that contribution in the future . Three examples have been cited to develop this thesis with significant reference made about the importance of Canadian contributions to developments in recent decades.

~.

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Hotel-Dieu Grace Hospital is a major tertiary care, 421 bed, regional hospital located in Windsor, Ontario. A Southern community surrounded by a world class waterfront with a rapidly growing vibrant community. The hospital is committed to supporting a patient / family-focused model of treatment by providing comprehensive high quality care. Hotel-Dieu Grace serves a regional population of approximately 350,000 residents, with 20,000 annual admissions and 50,000 E.R. visits.

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UWOMJ 71(1) 200 1 33

Otorhinolaryngology in the year 2000- A look in both directions

Erin D. Wright MD, CM, FRCS(C) Assistant Professor, Department of Otolary ngology, The University of Western Ontario

INTRODUCTION As we hurtl e along at the outset of thi s new millennium, it is a most opportune time to pause and refl ect upon both our past and our future . In medicine, and particularly in Otolaryngology, we have witnessed extraordmary changes in the past 200 years and can expect an accelerated rate of change and improvement in the coming years. This paper will attempt to examine the hi storica l t!vo lution of Otorhinolaryngology fro m the beginning of recorded rustory through to the present day. It will also attempt to provide an overview of the current state and scope of practice for today 's otolaryngologists and finally, attempt to provide some insight into future directions in possibilities for our specialty. Themes that wi ll be seen as major driving forces for innovation and change are an improved appreciation and understanding of anatomy and physio logy, as well as radical changes in technology.

HISTORICAL EVOLUTION-MEDICAL ADVANCES The most appropri ate name for our specialty, Otorhinolaryngo logy-Head and Neck Surgery, is rather long but is most accurate, reflecting the true scope of the specialty. Otorhinolary ngo logy (often simply Otolaryngology) has its origins in the three mai n areas of oto logy rhino logy, and laryngology. In the origin of the name, as we ll as the specialty itself, we see a rather interesting story through med ical and world hi story.

References to otolaryngology date back as far as 1550 B.C. when the Egypti ans made red lead and resin into a powder and used thi s with fresh olive oi l to treat a deaf ear. However, otolaryngology really began with Hippocrates in 430 B.C., who was the first to inspect the tympanic membrane. Subsequent to this,

34

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Aristotle dissected the ear and described the cochlea. In 131 A.D., Galen identified f ive pairs of cranial nerves and called the inner ear the labyrinth. Despite these significant advances in understanding, there still remained much work to be done in anatomy and physio logy. For instance, during tills same time, nasal secreti ons were thought to come from the brain via the cribriform pl ate.

The rather lengthy period through the Middle Ages, from approximately 500 to 1400 A.D. was one of stagnation. No significant advances were recorded during this time.

The 16th century brought a major reform in the study of anatomy. Vesalius advocated dissection of the human body and he made the first accurate description of the malleus and incus and al o described the oval and round window of the ear. Innovations with respect to the treatment of nasal polyps included use of a harpsichord wire and tube. Tracheostomy, a procedure that actually dates back to Galen was refined during the 16th century.

The 17th century brought a couple of interesting innovations as well. Joseph-Guichard Duvemey, the "Father of Otology", wrote the first treati se on otology. He described that the mastoid air ce ll s communi cate with the tympanic cavity as well as the function of the Eustachi an tube. He also di scovered that intracranial suppuration is di charged from the ear, not the brain. Also during this century, Nathaniel Highmore, after whom the maxillary antrum is nam ed, di scovered pus in the maxillary sinus wh ich was secondary to a tooth abscess . ' . The 18th-century saw further innovations with respect to otologic physiO logy and anatomy with de cription of the saccu le and utri cle by Antonio Scarpa . Scarpa also distingui shed between the fluid of the inner ear, thus essentially completing the anatomy of

the ear. During this century, in 1736, Jean-Louis Petit opened the mastoid process for the first time.

The development of medicine in general was accelerated in the 19th century by the discovery of anesthetics and bacteria. The development and use of antiseptics and electric light, as well as the advent of pathology also served to advance the profession. It was during this time that the first thyrotomy and laryngectomy were performed. A highly significant technological innovation was the use of endoscopy and direct laryngoscopy. Killian, the "Father of Endoscopy", adapted an esophagoscope for bronchoscopy in 1896, thus ushering in the endoscopic age.

The 20th-century saw a virtual explosion in the understanding in research of chronic ear disease and deafness. Adam Politzer, the "Father of Modem Otology", provided tremendous contribution in this regard. The first practical audiometer was developed in 1922. Also around this time Chevalier Jackson, arguably the most famous laryngologist and brochoesophagologist, adapted the endoscopes for laryngologic use. In 1957 Shea performed the first stapedectomy, thus revolutionizing the treatment of otosclerosis. Also deserving of mention is Prosper Meniere who recorded the famous case history of a girl suffering from vertigo that led to the recognition of the disease bearing his name.

HISTORICAL EVOLUTION-POLITICAL CHANGES During the 19th century, and indeed for a portion of the 20thcentury, the practice of otolaryngology was, in fact, a specialty known as Ophthalmology and Otolaryngology (EENT). This was reflected in the society governing the specialties in United States, which was known as the American Academy of Ophthalmology and Otolaryngology (AAOO).

In United States, the professional society governing these specialties was initially formed as the Western Society of Eye, Ear, Throat and Nose Surgeons. The Society incorporated inl896 and adopted the AAOO name in 1903. By the 1970s very few physicians were still practicing in both disciplines. This resulted in "the material rending of the Academy" (Pratt, 1996) occurring on January 1, 1979. This had been a long time coming and reflected the true state of practice. An additional change took place within the U.S . in 1980. At the annual business meeting the argument was made that the letters 'ENT' did not encompass the true scope of the specialty that included surgery of the salivary glands, thyroid, neck, and peripheral facial nerve, as well as head and neck oncology and facial plastic surgery. It was therefore proposed that the name of the governing body be changed to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). This name change was approved at the 1980 business meeting, although it did meet with some controversy as well as resistance from both General Surgeons and Plastic Surgeons.

The evolution of otolaryngology in Canada took a somewhat different course. Although the clinical practice did not differ significantly from the American experience, the political evolution was somewhat different. Otolaryngology, separately from ophthalmology, was one of the first specialties to be recognized by the Council of the Royal College of Physicians and Surgeons of Canada in 193 7. The first certification examinations and otolaryngology were held in 1946. It can therefore be seen that there

was never a combined certification for ' EENT ' in Canada.

Even the political representation of otolaryngology was separate from ophthalmology. With the formation of the Canadian Otolaryngological Society (COS) in 1945, the specialty now had an organization that aimed to enhance the confidence of members of the specialty " .. . in an atmosphere of mutual understanding and cooperation." (Baxter 1999) It is interesting to note that the early meetings of the society (in the '40s and ' 50s) were held back-tohack with those ofthe Canadian Ophthalmology Society, reflecting the dual interests of many of the membership at that time. The COS underwent a name change in 1983 when it became known as the Canadian Society of Otolaryngology-Head and Neck Surgery (CSO-HNS), again reflecting the scope of practice within the specialty. It is of some interest that this name change has never been recognized by the Canadian Royal College, which still refers to our specialty as Otolaryngology.

Worth noting in passing is the fact that in Nova Scotia, Alberta, and British Columbia the provincial societies were in fact combined Ophthalmological and Otolaryngological groups, separating off into separate entities beginning in the early '70s through the mid '70s.

Academic Otolaryngology has a rich history in Canada.

There has been Otolaryngology representation at virtually every medical school in Canada. Although the programs at Memorial University of Newfoundland, Queen's University, McMaster University, the University of Saskatchewan, and the University of Calgary do not have residency-training programs they are, by and large, involved in teaching of medical students, the provision of tertiary care, as well as clinical and basic science research.

Two of the earliest existing Departments of Otolaryngology were at McGill University and University of Toronto founded in 1905 and 1903 respectively. Here at the University of Western Ontario the Department of Otolaryngology was founded in 1957.

This occurred as the specialties of Ophthalmology and Otolaryngology split into two separate departments . The first Chair here at UWO was Dr. Robert Greenway who led the department until 1967. Dr. Greenway was followed as Chairman by Dr. Francis John Rounthwaite, who led the department until 1978.

Other Chairs of the department include Dr. Hans Heeneman ( 1978-1988), Dr. Ralph Ruby ( 1988-1991 ), and the current Chair, Dr. Howard Lampe (1991-present).

CURRENT STATE/SCOPE OF OTOLARYNGOLOGY In its current state, Otolaryngology has a remarkably varied scope. Simply put, otolaryngologists are the specialists of the head and neck, dealing with the medical and surgical management of problems above the clavicles . The obvious exceptions to this rule include the eyes and the brain. There are numerous subspecialties within Otolaryngology with residents receiving training in General Otolaryngology, Otology, Facial Plastic Surgery, Rhinology, Head and Neck Surgery, Laryngology, and Pediatric Otolaryngology. Most otolaryngologists working in the community will have a scope of practice that reflects, to varying degrees, all of these subspecialties.

General Otolaryngology is the most traditional practice and would include consultations in all areas of subspecialty training as well as, but not limited to, surgical procedures such as tonsilUWOMJ 7 1(1) 2001 35

lectomy, adenoidectomy, myringotomy and tubes, septoplasty, uvulopalatopharyngoplasty, and tympanoplasty, as well as basic sinus surgery and basic head and neck surgery.

Otology and neurootology is the subspecialty practice that deals with chronic ear problems, vestibular disturbances, cerebellopontine angle tumors, and facial nerve problems. The range of surgery can include more standard ear approaches and as well as paraneurosurgical approaches for CPA lesions. A particularly gratifying aspect of an otologist's practice is to restore hearing in a previously hearing impaired or deaf person. This can include the middle ear surgery (stapedectomy or tympanoplasty) as well as cochlear implantation.

Otolaryngologists have been performing facial plastic and reconstructive surgery for many years. One of the most exciting changes in the last 20 years, however, has been in the area of head and neck reconstruction. This can include everything from nasal reconstruction using a forehead flap to major oral cavity reconstruction using an osteomyocutaneous fibular free flap . The development of techniques that permit microvascular anastomosis has permitted this common use of free flap reconstruction following major ablative head and neck surgery. In recent years the practice of facial plastic surgery has become more formalized with the formation of the American Academy of Facial Plastic and Reconstructive Surgery. There also now exists formal fellowship training and certification in Facial Plastic and Reconstructive Surgery. The scope of practice of the facial plastic surgeon can include rhinoplasty, facial rejuvenation through blepharoplasty, brow lifts and facelifts, skin resurfacing, and hair restoration.

Technology has also had a significant impact on the subspecialty of Rhinology. Our ability to diagnose and treat chronic sinusitis has been greatly enhanced by the use of fiber-optic endoscopes, which have made surgery safer and allowed more complete exenteration of diseased mucosa. Improved understanding of the physiology of sinusitis has also led to the development of a more functional approach to the surgical management of si nusiti s with less emphasis on radical type surgery. The use of endoscopes has also permitted the development of techniques for endonasal orbital decompression and endonasal repair of cerebrospinal fluid fistulas as well as endoscopic approaches to pituitary tumors .

Otolaryngologists also lead the way in terms of head and neck surgery. Head and neck surgery encompasses both benign and malignant disease of the upper aero-d igestive tract and neck.

The scope of head and neck surgery can in clude everything from benign and malignant salivary gland neoplasms to the treatment of squamous carcinoma in the oral cavity and pharynx. As well , head and neck surgeons have considerable expertise in the treatment of thyroid and parathyroid disease. Head and neck surgery is the most visual aspect of Otolaryngology and is generally what attracts medical students to the specia lty.

The early specialists in Laryngology were also commonly experts in the area of bronchoscopy and esophagoscopy. Both bronchoscopy and esophagoscopy have diagnostic and therapeutic purposes, for examp le in the treatment of foreign bodies. The scope of a Laryngologist's practice can range from treatment of the professional voice to restoration of voice following vocal cord paralysis. Recent years have seen the development of complex and delicate laryngeal framework surgery as well as the use of

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UWOMJ 71(1) 2001

botulinum toxin for the treatment of spasmodic dysphonia. The development of micro laryngeal instruments and the use of an operating microscope have been significant technical advances in the practice of Laryngology.

While pediatrics makes up a large part of general Otolaryngology, in recent years there have been major advances in the management of serious pediatric head and neck problems.

One of the most significant advances has been in the management of pediatric airways. With the increased sophistication of neonatal intensive care, more children are surviving prolonged intubations and developing subglottic stenosis. The operation of laryngotracheoplasty helps to reconstruct the airways of these children.

The pediatric otolaryngologist also deals with craniofacial anomalies, airway emergencies and foreign bodies, as well as pediatric sinusitis. The scope is sufficiently complex that pediatric Otolaryngology training now encompasses a two-year postgraduate fellowship.

RESIDENCY TRAINING IN OTOLARYNGOLOGYHEAD AND NECK SURGERY There are currently 11 Canadian residency-training programs in Otolaryngology, graduating approximately 20 to 25 new specialists per year. Otolaryngology training is surgical with the first one or two years being spent in a core surgery program, depending on the particular residency-training program. What follows , is three or four years of formal Otolaryngology training. In addition to rigorous clinical training, Canadian residency training programs place a significant emphasis on resident research, with most training programs having a Resident Research Day each spring. There is also a national resident research competition held at the annual meeting of the Canadian Society of Otolaryngology.

All Otolaryngology residents are required to successfully complete the Principles of Surgery examination and are required to pass a certification examination at the completion of their training in order to receive certification from the Royal College of Physicians and Surgeons of Canada. Until recently, graduates of a Royal Co llege certified residency-training program were eligible for certification by the American Board of Otolaryngology.

Due to political reasons this eligibility is now being restricted, however, measures are being taken to reverse this situation.

Here at the University of Western Ontario the residencytraining program is two years of core surgery plus three years of Otolaryngology. The department provides community Otolaryngology services to the London/Middlesex County (population : 350,000) and tertiary care to southwestern Ontario (I ,400,000).

A LOOK TO THE FUTURE It can safely be aid that the 20th century was the golden age of Otolaryngology with remarkable improvements in technology and understanding of di sease. Revolutions in the treatment of hearing loss, sinusitis, head and neck cancer, and reconstructive surgery urely support thi s contention. We are however, on the cusp of the next explosion in innovation and discovery.

Recent advances have been made using molecular biological techniques to investigate the etiopathogenesis of head and neck tumors as well as the immunopathology of rhinosinusitis. It is

likely that this improved understanding will result in novel treatment modalities possibly including gene therapy and immune system modulation. For instance, since recent research strongly supports an inflammatory and not so much infectious etiology for chronic sinusiti s, therapeutic use of immunomodulatory cytokines may even make surgical treatment of chronic sinusitis obsolete. Another example of the use of molecular biological techniques is in the prevention of head neck cancer using derivatives of vitamin A. Future research will likely build on preliminary evidence suggesting that these compounds are capable, not only of preventing second primary tumors, but of reversing existing dysplasias.

Another area of anticipated advances is in the area of threedimensional imaging and its applicability to intraoperative surgical navigation. Adapted from neurosurgical uses, there currently exist two frameless stereotactic navigational systems for use in endoscopic sinus surgery that, while still in their infancy, permit real-time intraoperative visualization. Future investigation will continue to refine this technology and permit its application to neurootology and skull base surgery.

The treatment and restoration of hearing is another area that is likely to receive considerable attention and innovation in the future. While cochlear implantation has been a tremendous advance in our treatment of deaf, the future wi ll likely hold further technological refinement of this technology. However, a more exciting possibility will likely be derived from an improved

understanding of the function of the inner ear, specifically the cochlea. It would not be unreasonable to anticipate the development of techniques for hair cell (auditory receptor) regeneration and repair. This would allow a true cure for severe to profound hearing loss.

CONCLUSION This paper has attempted to provide a brief overview of our unique and varied specialty. The focus has been upon the evolution of Otolaryngology via an improved understanding of anatomy, physiology and pathophysiology as well as radical changes in technology. These areas of focus have and will likely continue to drive innovation and improvement through this new millennium.

REFERENCES 1.

2.

3.

4.

5.

Baxter J Th e HistOJ )I of Otolary ngology in Canada. Journal of Otolaryngology 1999; (Supplement) : 1-JJO He/idonis ES. Th e histoty of otolmy ngology fi"om ancient to modern times. Am J OtoiOJy ngol 1993; 14{6): 382-93.

Lucente, FE. Th e impact of otoiOJy ngology on world history. Trans A m Acad Ophthalmo/ Oto!OJy ngol 1973;77(6) : ORL424-8.

McFarland, GÂŁ. A brief history of otoiOJ)'ngology. Trans Am Acad Ophthalmol Oto/w y ngol 1974; 78(1) : ORLJ 5-20.

Pratt L et a/. A Cen/UJ)' of Excellence: A JOOth AnniverSOIJ' His!OJ)' of th e American Academy of OtoiOJ)'ngology-Head and Neck Swge1y and its Predecessor 01g anizations. 1996;Aiexandria, Virginia, AAO-HNS.

London Hospitals ... . . . CommiHed to providing the best health care system possible ur journey toward fully restructuring the London hospitals continues.

This year, we celebrate the recent integration of the former London and St. Thomas Psychiatric Hospitals into St. Joseph's Health Care, London; the integration of the Renal Dialysis

O

LONDON Health Sciences Centre

Program to new facilities at the Victoria Campus, London Health Sciences Centre, and the consolidation of Rheumatology at St. Joseph's.

Through the dedicated efforts of our physicians, staff and leadership, we are able to sustain our excellence in patient care, research and teaching, while we work through this complex and ongoing

(/jST OS~;~:n.

JHEALTH CARE LONDON

Building solutions for a healthier tommorrow UWOMJ 71 ( 1) 2001 37

A Tradition of Excellence- A Challenging Future

Timothy C. Frewen MD, FRCPC, FAAP Chief and Chair, Department of Paediatrics, Th e Universtiy of Western Ontario Paediatrician-in-Chief, Children s Hospital of Western Ontario, London Health Sciences Centre, St. Joseph s Health Care London

HISTORY OF PAEDIATRICS IN LONDON Paediatrics is concerned with the health of infants, children and adolescents, their growth and development, and their opportunity to achieve full potential as adults. Over a century ago, paediatrics emerged as a medical specialty in response to an increasing awareness that the health problems of children differ from those of adults and that the child's response to illness and stress varies with age. While the emphasis and scope of paediatrics continues to evolve, the truth of these claims remain valid.

In 1934, Paediatrics became recognized as a separate specialty, distinct from internal medicine within the Faculty of Medicine at the University of Western Ontario. In 1955, Dr. J.C. Rathbun was appointed Chair of Paediatrics at Western and the first "full time academic paediatrician" appointed to the Faculty of Medicine. Dr. Rathbun was an active researcher as well as clinician with a strong interest in metabolic disease. His tenure saw the paediatric department make fundamental contributions to the understanding of metabolic diseases and also participate in the first clinical trials in Canada with rhesus immunoglobulin.

Following the sudden death of Dr. Rathbun , Dr. J.E. Boone was named Chair of the department. Dr. Boone remained in this position until his retirement in 1992. During this nineteen-year period, the Department of Paediatrics developed as a regional child health care provider and expanded its paediatric subspecialty and consultative services. Accomplishments included the full accreditation by the Royal College of the postgraduate residency training program in paediatrics and the relocation of the Children's Hospital of Western Ontario, formerly the War Memorial Children's Hospital , to the Westminster site. This development included the establishment for the first time of separate critical care and emergency facilities and a freestanding institute to foster child health research named the Child Health Research

38

UWOMJ71(1) 2001

Institute. During 1992 to 1997, the department continued to develop under the leadership of Dr. Hurley. New programs in nephrology and an expansion of Western's nationally recognized program in clinical pharmacology were notable achievements.

The Department of Paediatrics fostered, together with the Department of Obstetrics and Gynecology, a new domain of medicine entitled neonatal perinatal care. Under the leadership of Dr. Graham Chance, the department established what is now the second largest neonatal facility in Ontario. This program boasted an innovative and dynamic perinatal outreach program that pioneered a regional network approach to neonatal and maternal health. Statistics Canada data demonstrates over 8 million Canadians or 26.1% of the population, are children and youth age 19 years or younger. The health status of this population should be of great concern to policy makers , health professionals and the general public since the future of Canada can be said to lie in the health and capacity of its children.

DETERMINANTS OF CHILD HEALTH It is well recognized that a variety offactors interact to determine the overall health and well being of children. Poverty is one important determinant that has been inextricably linked to the health of children and youth. Almost all facets of health are worse among impoverished children than among children from affluent families . The impact of the environment on child health has been less well studied. However, research demonstrates persistent harmful health effects to children exposed to low levels of environmental contaminants. The importance of early childhood education and development is being increasingly recognized. There is increasing data that childhood experiences impact significantly on subsequent health status.

Despite these insights and the acknowledgment that health is also a public good, the allocation of resources to the fostering of

lllld health remains problematic. It remains easier to get a coroary artery bypass graft than educational and preventative servic; for children. In our increasingly market based approach to ealth care, the needs of children who are neither voters or tax ayers, remain at risk unless advocates recognize the real health eeds of this group and the benefits of prevention and investment 1 the early years compared to disease treatment only.

:URRENT CHALLENGES TO INFANT, CHILDREN'S lEALTH Paediatricians in the developed world spend a significant ortion of their time treating the most seriously ill. It is beyond 1e scope of this article to discuss the role of the paediatrician in 1e developing world. However, many of the diseases we considr conquered in Western countries remain a serious challenge to hildren's health from a global perspective. Concerns related to quitable allocation of scarce resources for the promotion of .ealth referred to earlier remain a serious issue and require soluion. Estimates of chronic illness in children in the developed ;rorld are difficult to obtain but it is suggested that this populaion of children comprise up to I 0% of the childhood population. ~ffective response to the health challenges of this group of chillren requires a broad understanding not only of the special probems of infants children and adolescence, but also an undertanding of normal health and development and family health. As he health profile of Canadian children has shifted markedly in he past 50 years, so too has the focus of paediatrics. Paediatric are was once dominated by efforts to treat the effects of major nfectious diseases such as polio, diphtheria, scarlet fever, pneunonia, measles and pertussis. Today, widespread immunization tas virtually eliminated many of these diseases.

CHILDHOOD INJURIES Paediatri cians are involved in the struggle to reduce the incidence of childhood injury. Injuries are the leading cause of death among Canadian children and youth less than 20 years old. Of all deaths in this age group , 30.5% are attributable to injuries . For every injury related death , there are 40 hospitalizations and an estimated 670 emergency room visits for treatment of injuries.

Motor vehicle crashes are the leading cause of injury death in children older than 1 year of age. Paediatricians, including leaders at Western, are actively involved in reducing this incidence through their involvement in the Childhood Health Injury Reporting System (CHIRP) and other educational endeavours with community based agencies.

MENTAL HEALTH Suicide follows major trauma secondary to motor vehicle crashes as the second leading cause of injury death in both males and females aged 10 - 19 years. Suicide rates among aboriginal children in Canada are 3 to 4 times higher than the rate in the general population. While a number of factors far beyond the scope of this paper likely play a role in death secondary to suicide, the issue of adolescent health, especially adolescent mental health, has become increasingly important to paediatrics . Adolescents continue to face a constellation of problems including alcohol , tobacco and other drug abuse, school failure , delinquency, peer group violence, and unwanted pregnancy. Comprehensive programs based on the best science and guided by health care professionals such as child psychiatrists, adolescent mental health professionals and paediatricians are necessary to reduce this preventable yet tragic scourge on Canadian youth.

CHRONIC ILLNESSES <ETAL/NEWBORN HEALTH

Currently, many paediatricians are concerned with infant tealth including fetal health. In 1996, 4, 197 deaths occurred in ~anadians aged 0 - 19 years, with 2,051 or 48 .9% among those ess than 1 year of age. Of these 2,051 deaths , 948 or 46.2% were elated to perinatal conditions and 575 or 28% were attributed to ongenital anomalies. Many of these deaths are related to preterm 1irth and neural tube defects. Preterm birth remains an important 'et poorly understood condition accounting for the ~ajority of 1erinatal mortality and morbidity. Congenital anomalies or btrth lefects and their treatment remain a leading focus of paediatric are. Of all infant deaths, congenital anomalies remain one of the :>p 10 causes of potential years of life lost. Neural tu_be defe~ts re one important category of birth defects that result.m the fatlre of the neural tube to close during early embryoruc developlent. The importance of neural tube defects lies in both the disbility and death that arise as well as the opportu~tty to redu~e 1ese harmful effects through primary prevention. There ts 1creasingly strong evidence that multi-vitamin supple~ents conlining folic acid taken periconceptionally re~uce t_he nsk of ?eu11 tube defects. Paediatricians, through therr national specialty roup, support an active primary prevention strategy to reduce isability and death from this disease.

Paediatricians continue to play an essential role in the treatment of children with chronic illnesses. Australian studies suggest chronic illness accounts for up to 50% of the work performed by paediatricians outside of hospitals. Similar to adult medicine, the treatment of these illnesses including childhood cancer, juvenile diabetes, asthma, cystic fibrosis , and kidney, require paediatricians with additional training and expertise in specific domains of medical science. The complexity of these diseases and the advances in therapy over the years have substantively increased the need for not only general consulting paediatricians, but also subspecialists.

In 1996 - 97, Canada's population health survey reported asthma in 12.2% of children and youth less than 20 years of age in Canada. Although significant improvements have been achieved in the treatment of childhood cancer, oncologic disease represents the second leading cause of death after injury among Canadian children aged 1-14 years. The prevalence of juvenile diabetes in children is estimated at I 0 per 100,000 under 18 years of age and is the most common presentation in the 10- 12 year old age group.

Advances in care have also tended to increase the numbers of children in our community with chronic physical or medical conditions and special needs with prolonged dependence on medical devices. These children often referred to as " special needs" or "technology dependent children" and require the professional support of a number of caregivers coordinated by paediatricians.

UWOMJ 71(1) 2001 39

THE FUTURE OF PAEDIATRICS

REFERENCES

The challenge of physicians contemplating a career in paediatrics is to build on the successes of the past and support communities coming together to enrich the lives of young children and families . Currently, significant financial and political issues are hindering the establishment of comprehensive childcare and early childhood education programs including fami ly support initiatives in Canada. It is the task of future paediatricians to build on the advocacy of the past and continue to advance the needs of children. It is my own belief that at a time of diminishing resources, an even higher priority should be given to protect the development of children and youths. Increasingly, data demonstrates that the quality of care that a chi ld receives in the first 3 years of life is the single most important factor, excepting genetics, that influence that child 's future development, health, mental health and productivity.

Given the strong grounding paediatricians and physicians have in biomedical science and the recognition that health of children and youth influences not only well being in the present but also into the future, paediatricians need to continue to focus on perinatal health. Recent evidence suggests that the health impacts on a fetus as a result of an adverse pregnancy may continue on to adult life as increased risks for diseases like hypertension, coronary heart disease and diabetes. Further understanding of normal biological processes is fundamental in enabling us to treat and prevent abnormal disease processes in later life. Paediatricians therefore need to continue in the future as they have in the past to understand the processes of pregnancy, normal and abnormal formation of the embryo and fetus, term and pre term birth, and continue to foster newborn health.

One can only expect that the research methodologies currently available to our scientists including molecular biology and genetics, biochemical and histochemical techniques and the newly emerging area of functional genomics will help us to better develop a comprehensive framework for understanding mechanisms of both normal and abnormal growth and development including longer term cons~quences for ill health.

Paediatricians, in addition to continue investigating into the mechanisms of diseases afflicting childhood, must become even more voca l in their advocacy for children's needs. The literature as alluded to earlier clearly demonstrates low income status, educational level, employment, working conditions, and the biophysical environment such as air, water and soil quality, are key influences on health and well being. A large body of research also demonstrates that factors influencing the development of soc ial coping ski lls such as low self-esteem also influence personal hea lth . As a result of these insights and an increasing understanding of the psychosocial determinants of health and competence, paediatricians must remain active in advocating for children's needs. The challenge for paediatricians will be to make the transition from primary care giver to consultant and learn to effectively partner with other health care professionals, community agencies and schools to promote child well being. This transition will require future paediatricians to also extend their interest and understanding of the social sciences while maintaining their traditional commitment to compassionate care and respect for the young.

1.

40 UWOMJ 71(1) 2001

2.

3.

4.

5.

6.

Health Surveillance Update on Canada Children and Youth; Laboratory Centre for Disease Conh'oi Health Canada, Ottawa, Ontario 1999.

H ealth Canada Children: A Statistical Profile Second Edition, Canadian Institute of Child Health Ottawa, Ontario 1994.

Healthy Children 2000 National Health Promotion and Disease Prevention Objectives; US Department of Health and Human Services, Washington, D.C. , 1998.

Determinants of Health : Children and Youth. National Forum on Health , Health Canada, Sainte Foy, Quebec, 1998.

Feigin, RD. American Paediah'ic Society Presidential Address 1998: T¥hat i th e Future for Academic Pediatrics. Pediatric Research 1998; 44:958-963.

Kelly AF. Hewson PH. Factors Associated with Recurrent Hospitali::.ation in Chronically Ill Children and Adolescents. 1 Paedit1: Child Health 2000;36:13-1 8.

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Physical medicine and rehabilitation in the 21st century

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Keith Sequeira MD, FRCP(C) Assistant Professor, Department of Physical Medicin e and Rehabilitation, Th e University of Western Ontario

INTRODUCTION Physical Medicine and Rehabilitation (PM&R) or "physiatry" is a relatively new medical specialty having its origins in the 1930s I and becoming recognized by the Royal College of Physicians in 1947. It took its origin from two subspecialties: "Physical Medicine", the medical management of physical injuries or disease employing physical modalities (including electrotherapy) or therapeutic agents, and "Rehabilitation", the management of chronic disabling injury such as occurs from spinal cord injuries (SCI), acquired brain injury (ABI) and cerebrovascular disease. Much of the development of these two subspecialties took place during World War II as a consequence of the need to rehabilitate those injured in battle. Today, physiatrists, or specialists in PM&R, function independently in private practice or work in rehabilitation centres or hospitals, collaborating with colleagues in orthopaedics, the clinical neurosciences, and other specialties to provide medical input to a multi-disciplinary team of allied health professionals.

THE PAST Among the first developments in PM&R in Canada was the appointment in 1928 of William Gardiner to teach physiatry in the Toronto General Hospital. Later, Theodore Coffey (1905 -1 961 ), who worked in the Canadian Army overseas, pioneered the move to "active" rather than "passive" convalescence. Dr. Coffey served as the first Professor and Chair of the Department of Physical Medicine and Rehabilitation at UWO. He established a full curriculum course for undergraduate medical students in physical medicine and managed a busy clinical practice looking after the medical needs of disabled children and adults. Dr. Coffey's contribution is recognized through a book prize awarded

Keith C. Hayes PhD. Acting Chair, Department of Physical Medicin e & Rehabilitation, Th e University of Western Ontario Professor and Chair, Division of Rehabilitation and Geriatric Care, The Lawson Research Institute, St. Joseph s Health Care London

to the UWO undergraduate medical student with the best presentation on a physiatry-related topic. Dr. M.G. Peter Cameron, who succeeded Dr. Coffey as Chairman of PM&R in 1964, furthered the development of the specialty, and was instrumental in establishing the UWO programs of Occupational Therapy, Physical Therapy and Communicative Disorders.2 THE PRESENT Physiatry today embraces the medical management of patients suffering a wide spectrum of disease and disability including amputation, chronic pain, spinal cord injury (SCI), acute brain injury (ABI), stroke, musculoskeletal disability (hip fractures , ~pper lrmb trauma) and neuromuscular disease. This management rnvolves treatments aimed at remediating the medical problems associated with injury or diseases, or addressing the attendant functional limitation. The latter function is sometimes termed "disability management") This involves establishing causation providing medical treatment and direction for rehabilitation estab~ li~hing _the prognosis, and developing return to work str~tegies.

Disability management therefore requires evaluation of an individual's present functional capacity and capability to improve and return to their previous job with or without modifications or strategies.4 Modifications and strategies for return to work include altering the duration and frequency of an action, decreasing the amount ?f weight ~eing lifted, adapting the work environment to improve It ergonomically and allowing job rotations to decrease repetitiveness and prevent overuse syndromes. Further approaches include integration of work hardening to recondition individuals vocational counseling, and reeducation. Physiatrists thus play ~ integral role in the multidisciplinary approach needed for each patient to maximize function without compromising health.

UWOMJ 71(1) 2001 41

THE FUTURE

REFERENCES

Rehabilitation is a "growth industry". This is because of the advancement of medical knowledge and technology that has allowed more people to live to a greater age, to survive physically traumatic events and to live with inherited and acquired diseases with attendant disability. In this setting, the emphasis of physiatric practice will continue to be on improvement of function in patients whose capabilities have been compromised through di ease, injury or accident.

Although government and insurer will continue to attempt to fund treatment for individuals who require restoration of fimction , they wi ll do so with minimal costs. Prevention of disease will be at the vanguard of the endeavour to cut expenditures.

Education of individuals, family and clinicians are cruc ial factors in facilitating a successfu l di sease prevention approac h.

Physiatrists are well positioned to provide the holistic multidisciplinary approach needed to address thi s issue. Furthermore, evidenced-based policy and practice will be required. London has been at the North American forefront in providing the necessary research to allow for an evidenced-based approach to disease prevention and rehabilitation.

Innovative treatments, more sensitive and specific diagnostic techniques, improved assessment of pati ents and their clinica l outcomes, and evaluation of services are presently the foci for phys iatric research . At the University ofWestem Ontario (UWO), important progress has been made in many areas. These inc lude sh·oke rehabilitation with notabl e advances in the assessment and management of dysphagia and malnutritions.6, electrodiagnostic assessment of upper limb dysfunction7, management of chronic painS, and treatment of the consequences of spinal cord injury including autonomic dysreflexia9, urinary tract infectioni O and central conduction deficits. I I . I 2 These research activities are now conducted under the auspi ces of the Division of Rehabilitation and Geriatric Care ofThe Lawson Health Research Institute and invo lves collaboration with investigators fro m other institutions across the city and in other countri es .

1.

2.

http://www.aapmr.org Barr ML. A Century of M edicin e at Western. London: Th e University of Western Ontario; 1977.

3. Lacerte M. Disability prevention and management. Physical Medicine and Rehabilitation Clinics of North America 1993;4(1):1 1-25.

4. Lacerte M, Wright GR. Return to work determination. Physical Medicine & Rehabilitation: State of the Art Reviews 1992;6(2): 283-302.

5. Fin estone HM, Greene-Fin estone LS, Wi lson E, Teasel/ R W. Malnutrition and dysphag ia in stroke patients on the rehabilitation ward and at f ollowup: Prevalence and predictors. Archives Phys Med & Rehab 1995, 76(4):410-416.

6.

Teasel/ RW, McRae M, Heitzn er J. Bhardwaj A, Fines tone HM. The .fi'equency of videofluoroscopic modified barium swallow studies and pneumonia in sn·oke rehabilitation patients: A comparative study.

Archives Phys Med Rehabil 1999:80(3):294-298.

7. Miller TA , Pardo R, Yawors !.:i R. Clinical utility of reflex studies in assessing cervical radiculopathy. Muscle & Nerve 1999;22: 1075-1079.

8.

Teasel/ RW. Th e denial of chronic pain: A disturbing new management paradigm. Am J Phys Med Rehabil 1999; 78(1):83-84.

9. Arnold JMO, Delaney GA . Feng QP, Teasel/ R W. A lpha-adrenoceptor hyper-responsiveness in quadriplegic patients with autonomic dysreflexia. Clin Auton Res 1995:5:267-2 70.

10. Reid G, Potter P, Delaney G, H ieh J. Nicosia S, Hay es K. Ofloxacinfor the n·eatm ent of urinary n·act infection and biofilms in spinal cord injwy. In ! J Antimicrobial Agents 2000; 13(4):305-307 I 1. Hayes KC. 4-aminopy ridin e and spinal cord in} toy A review. J Restor Neural and New·osci 1994;6:259-270.

12. Potter PJ. Hayes KC, Segal JL, Hsieh JTC, Brunnemann SR, Delaney GA . Tierney D. Mason D. Randomi=ed double blind crossover n·ial of .fampridine-SR (s ustain ed release 4-aminopyridine) in patients with incomplete spinal cord injwy . J Neurotrauma 1998; 15:83 7-849.

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The Rehabilitation In stitute will enable program-based models of care and provide for a unique and enriched education and research environment. The new opportuniti es for undergraduate medi cal educat ion , affiliation with The Lawson Health Research Institute, collaboration with UWO PhD Program in Rehabilitation Sciences and the centralization of research foci in the areas of SCI, Stroke and Musculoskeletal-Pain Rehabilitation wi ll enabl e the UWO Departmen t of Physical Medicine & Rehabilitation to advance its position as the leader in academic physiatry in Canada as we move forward into the 2 1st century.

42

UWOMJ 71( 1) 200 1

ADV ISORS TO H EALTH CARE PROFESSIO:-.IALS P RACT ICE MANAGEMENT I ACCO L'NTI NG / T AX

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Barrie Neal Glenn Hardman

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Psychiatry

Emmanuel Persad MD Chief, Chair and Professor, Department of Psychiat1y, The University of Western Ontario

Psychiatry is the medical specialty charged with the care of those who suffer from disorders of the mind or emotions. Such a narrow definition, however, may not do justice to the emerging scope of the field of psychiatry. A recent description of the scope of this specialty stated that psychiatry is characterized "more by its interfaces than by its boundaries. It is the breadth of our knowledge that makes us unique".'

The evolution of modern psychiatry in the 20th century began with the work of Sigmund Freud and Emile Kraepelin. The former, as is well known, created an exclusive school of psychopathology based on his theories of the mind which came to be known as psychoanalysis. Freud's influence has extended beyond psychiatry and continues to this day to hold cultural dominance particularly in the western world in a variety of fields such as art, literature, politics, education and the law.

Kraepelin belonged to the German School of Psychiatry and, with his colleagues, postulated a brain dysfunction as a basis for psychiatric and emotional disorders. A reflection of this thinking was the designation by Kraepelin and his colleagues of a group of psychiatric disorders which they referred to as dementia praecox.

This group of disorders was reclassified as schizophrenia on the basis of the work of psychiatrists such as Bleuler who attempted to provide a bridge in conceptual thinking between the purely biological and predominantly psychosocial approaches in thinking about this major group of psychiatric disorders. However, most historians would view the influence of Kraepelin as being more significant and enduring in the evolution of modern psychiatry.

His additional contribution to psychiatry was the introduction of the first workable classification system of mental diseases. His work has continued to influence all subsequent classification systems of psychiatric disorders.

Praful Chandarana MD Associate Professor, Assistant Chair and Director of Postgraduate Education, Department of Psychiat1y, Th e University of Western Ontario Director, Consultation-Liaison Program, London Health Sciences Centre

Compared to other specialities of medicine, psychiatry has been more dependent on clinical observation. These observations form the basis for hypotheses regarding the nature of mental illness and its treatment. The field has also been characterized by the development of interventions based on empirical observations. The two noteworthy examples are the work of WagnerJauregg and Bini and Cerletti. The former introduced malaria therapy in an attempt to treat the symptoms of tertiary syphilis.

This work gained him the Nobel Prize in Medicine. Bini and Cerletti (1938) observed that epilepsy did not appear to co-exist with psychiatric disorders and that convulsions appeared to provide an ameliorative or protective function to patients with psychiatric disorders. This led to the introduction of electroconvulsive therapy, a treatment that has stood the test of time.

The introduction of Lithium (1949) for the treatment of psychotic disorders heralded a paradigm shift and as chlorpromazine became available (1952) for patients suffering from psychosis, the use of ECT became reserved largely for patients suffering from depression. As psychiatrists further explored the frontiers of psychopharmacology, drug therapy became grounded as additional armamentarium in the treatment of psychiatric illnesses.

This led to the next historical milestone in the development of psychiatry as large numbers of patients with severe mental illnesses were now able to leave hospitals and settle in the community. This deinstitutionalization of the mentally ill has continued since the 1960's to the present day.

As psychiatry evolved further, psychotherapy, often considered the centrepiece of the practice of psychiatry, came under significant challenge. The influence of psychoanalysis declined and evidence-based practice was emphasized. This development led to the refinement, not only of pharmacotherapy, but of other UWOMJ 71(1) 200 1 43

forms of therapies such as cognitive behavioural and interpersonal psychotherapy. Subsequent development saw the emergence of the biopsychosocial model introduced by George Engel in his seminal paper.2 He challenged the field of medicine to re-think its approach to medical disorders. Based on systems theory, the biopsychosocial model espoused the notion that illness and illness behaviour is multifactorial in origin and manifestation and the hypotheses of causation and therefore intervention can only be framed in the context of the affected individual 's total experiences . Ongoing tension exists, however, between neoKraepelinians who lean heavily towards a biomedical approach, viewed by some as overly reductionistic, and the biopsychosocial model which is advocated as the more holistic approach. To add to the complexity of this debate there are calls to consider social and cultural factors in the interpretation, causation and treatment of mental illness ) Furthermore, Lewis-Fernandez and Kleinman4, call for exploration of fo lk remedies in other cultures to link indigenous system of treatment to western nosologies and therapeutic modalities. They emphasize that "psychiatry can no more afford to be contextless than it can afford to be mindless or brainless."

The following quotation highlights a further challenge for the student of psychiatry: "The model of the psychiatrist who primarily provides office-based psychotherapy is outmoded. Rather, the psychiatrist must become a clinical expert in brain and behavioural sciences with mastery over an expanding array of diagnostic techniques and responsibility for directing integrated mu ltidisciplinary treatment and rehabilitative services. To ensure this expertise, students must receive a firm grounding in neuroscience, molecular genetics and brain imaging in addition to the traditional curriculum."5 While the debates on conceptual theories continue, the practice field has responded to the reform of the mental health system in several jurisdictions within Canada. Beginning in 1988, the Ministry of Health in Ontario, launched an initiative to reform the mental health system that espoused the principles that the most seriously mentally ill be assured of care and that institutional service delivery was to give路way to community-based care. This was partly driven by financial considerations and the assumption that community-based care is less expensive than institutional care.

The term community-based care has been used somewhat as a "catch-all" and may be construed as having several related but different meanings. In addition to presumptions that it may yield financial efficiency in service provision, discussions focusing on it are frequently directed through issues of accessibility and accountability in relation to psychiatric services. The mal-distribution of psychiatrists and the nature of their practices are often the centre of this discussion. Accessible services are required in under-serviced areas that may include inner cities, rural or small communities and remote regions. Services are also required for under-serviced special populations such as the severely mentally ill or in domains of practice such as Child or Geriatric Psychiatry.

A more recent initiative referred to as the "shared care model" proposes a close partnership between psychiatrists and family physicians to optimize the care of the mentally ill individual.

Finally, the recently introduced concept of a " life-span approach" 44

UWOMJ 71(1) 2001

should force us to study a more naturalistic evolution of mental illness during the course of an individual's life.

While the specialty has been supportive of this initiative and academic departments have improved and developed new curricula and training experiences to prepare residents, significant professional concerns remain. These include the inadequacy of available and planned community supports for those suffering from psychiatric disorders and concern that governments have seriously under-estimated the costs of community care.6 The practice of psychiatry and the training of residents in psychiatry continues to evolve to reflect current developments in the field which are occurring on a global scale. In 1993, the World Federation for Medical Education identified 12 principles to be incorporated into Undergraduate and Postgraduate education.?

These include the provision of medical education in relevant settings, basing curricular requirements on health needs of the population and emphasis on disease prevention and health promotion, the establishment of strategies to inculcate life-long learning, the identification of competencies expected of specialists, the requirement of supervisors to be trained in educational principles, the integration of science and clinical practice, the selection of entrants on the basis of non-cognitive as well as intellectual attributes, the co-ordination of medical education with the health care needs of the population, the achievement of balance in the production of different categories of medical practitioners and other health care professionals, multi-professional medical training and the provision of ongoing continuing medical education.

R. H. Cawley8 lists 7 themes that he believes will have an impact on the practice of psychiatry and on postgraduate training in psychiatry. He cites recent advances in the neurosciences, the emergence of the multiclisciplinary team, shared mental health care, a balance between embracing scientific achievement and maintaining awareness of a broad human experience, a lack of resolution and the role of psychoanalysis within psychiatry, the role of psychiatry in medicine and the role of management and audit in practice.

A major theme in the 1990's affecting all of medicine and certainly psychiatry, was an acknowledgment for the profession to demonstrate evidence for treatment outcome and accountability to society. This has been articulated in a Royal College of Physicians and Surgeons report entitled " Skills for the New Millennium."9 This report drew on the work of the Educating Future Physicians for Ontario (EFPO) project whose goal was to make medical education in Ontario more responsive to the evolving health care needs of the population. CanMeds 2000 stressed medicine's "solemn covenant to serve society" and the report went on to describe a list of competencies that will be expected of specialists in every field of medicine.

Psychiatry in the new millennium will reflect its "coming of age" as a major medical specialty and will probably lead the way for the rest of medicine in demonstrating the art of combining the profession 's societal obligations with the increasing demand for quality care from a well-informed population.

Garfinkel and Dorianio, in a recent article on Psychiatry in the New Millennium write, "While public expectations of professionals have generally fa llen, the role of the healer which is at the heart of psychiatric practice has remained high in public regard.

Psychiatry has also had to develop new relationships with an active consumer movement."

A central feature of psychiatry in the 21st century will be the pursuit of new knowledge capitalizing on the major discoveries in the last decade. These areas of research are summarized in six questions taken from an article by Ellen Frank and David Kupfer. II How does life experience alter gene expression in vulnerable individuals who manifest psychiatric disorders?

What are the neurobiological effects of psychotherapy?

This is in recognition that psychotherapy and other psychosocial interventions result in neurophysiological changes.

How does trauma lead to such a wide and complex range of symptoms and, as well, what are the protective factors which prevent the emergence of symptoms in individuals exposed to severe trauma?

Can we develop psychotropic medications which are free of adverse effects?

What is the connection between various physical illnesses and psychiatric disorders?

How does the aging process affect expression of psychiatric illness and its treatment?

The new millennium will see significant reduction in morbidity and mortality associated with psychiatric illnesses. This hope springs not so much from the improved treatments now becoming available but from attempts to prevent psychiatric illness before its occurrence or detect it and treat it before it becomes fully manifest. It is an established fact that many serious mental disorders, which usually begin in adolescence and early adulthood, are not diagnosed soon enough and that significant morbidity sets in when the illness is recognized months or years later. In keeping with this, the Department of Psychiatry at the University ofWestem Ontario has launched a major initiative for early detection and immediate intervention for patients suffering from psychosis.

In summary, psychiatry has progressed from its roots in psychoanalysis to an integrated biopsychosocial framework. Students entering this field will have many opportunities to become involved and contribute as psychiatry integrates the recent advances in neurosciences into its practice. The field of psychiatry offers tremendous variety and for students interested in research, opportunities abound as psychiatry continues to explore new frontiers.

REFERENCES 1.

2.

3.

4.

5.

Paris J. Canadian Psychiaf1y Across 5 Decades. Canadian Journal of Psychiany 2000;45:34-39.

Engel G. The Biopsychosocial Model and the Education of Health Professionals. Ann NY. Acad. Science 1978;3 10:I69-1 8I. Cooksey EC, Brown P International Journal of Health Services.

Baywood Publishing Inc. I998; 28(3) :525-554.

Cultural Psychiaf1y Theoretical. Clinical and Research Issues in the Psychiatric Clinics of North America. W.B. Saunders Company.

I995;18(3) :433-447.

Coyle, JT Th e Neuroscience Perspective and the Changing Role of the

Psychiatrist. Academic Psychiatry 1995; 202-212.

Leverette J, Persad, E. Postgraduate Education in Canada in Canadian Psychiatric Association 50th Anniversmy Book. Ed. Q. Rae-Grant. In Press.

7. Walton H. Presidential Address. Wo rld Forum on Medical Education.

Medical Education. 1995; 29:3-6.

8.

Cawley RH. Educating the Psychiatrist in th e 21st Cen tury. British Jou rnal of Psychiatry 1990;57:I 74-1 81.

9. CanMEDs 2000. Publication of the Royal College of Physicians and Surgeons.

10. Garfinkel P, Dorian B. Psychiatry in the New Millennium. Canadian Journal of Psychiahy 2000; 45:40-47.

11 . FrankE, Kupfer D.J. Peeking Through the Door to the 21st Century.

Arch. General Psychiatry 2000; 57:83-85.

6.

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UWOMJ 71(1) 200 1 45

A century of radiation oncology

Glenn Bauman MD, FRCP(C) Medical Director, Radiation Treatm ent Progarm Team, London Regional Cancer Centre Assistant Professor, Department of Oncology, The University of Western Ontario

Jerry Battista PhD, FCCPM, FAAPM Director of Physics Research and Education, London Regional Cancer Centre Professor and Head, Division of Radiation Oncology, The University of Western Ontario

Jake VanDyk MSc, FCCPM, DABMP, FAAPM Manage1; Radiation Treatment Planning and Deli very Support, London Regional Cancer Centre ProfessOI; Departments of Oncology, Medica l Biophysics, Diagnostic Radiology and Nuclear Medicine, Physics, Astronomy, The University of Western Ontario

INTRODUCTION The World Health Organization estimates that approximately nine million new cases of cancer are detected annually worldwide. By the year 2015 , thi s number will increase to fifteen million . Within our province, over 45000 people are diagnosed with cancer each year and over 23 000 peopl e will di e of cancer thi s year4 and about one in three peopl e can expect to be di agnosed with cancer at some time in their lifet ime. Approximately 50% of pati ents diagnosed with cancer will receive radiation as part of thei r treatment, either for curative intent (radi ca l radi otherapy) or for symptom control (palli ative radiotherapy).4 The early use of ionizing radiation in th e treatment of mali gnant di sease was large ly an empirica l discipline using un sophi sticated equipment. In the later half of thi s century, tremendous strides have been made in the more precise delivery of radiation as we ll as the integration of radiation with other treatments such as chemotherapy. Currently, ionizing radiation is delivered to targets of interest either by externa l radi ation sources (teletherapy) or by internal radiation (brachytherapy). In this review, we will trace the evolution of radi ation therapy in the treatment of ma lignant di sease through the 20th century and describe current trends

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that will drive the development of radiation therapy into the 21st century.

1895-1900: THE BIRTH OF A SPECIALTY X-rays were di scovered by Wilhelm Conrad Roentgen on November 8th, 1895 at his laboratory at the University of Wurzburg in Bavaria. At the time, Roentgen was investigating the properti es of electrica l discharges within a partially evacuated glass tube. During hi s experiments, he noted that a paper screen covered with barium platinocyanide fluoresced and that this fluore cence would take place even when solid objects were interposed between the tube and the paper "detector". The discovery that the so-ca ll ed unknown "X-rays" would illuminate bones on these flu orescent screens led to the almost immediate application of X-ray imaging in the medical field and by May 1896 the first medical radio logical journal appeared. I Less than 4 months later after Roentgen's discovery, Antoine Henri Becquerel , while ~x ploring the relation of fluorescent materials to X-ray productiOn, ~escr ibed the ability of uranium crystals to expose photographi c plates shielded with paper. Thus , a naturally occurring source of radiation was described and natural radioactivity was

thus discovered. By 1898, Pierre and Marie Curie had isolated 2 radioactive isotopes from uranium pitchblende: polonium and radium.

In addition to the possibility of radiographic imaging of the internal human body, the therapeutic usefulness of both X-rays and y-rays in the treatment of malignant disease was rapidly recognised. By 1906, a centre for radium therapy, the Biological Laboratory, in Paris was established and the first textbook of radium therapy publishedl. Unfortunately, the potentially harmful effects of X andy rays took longer to appreciate. As early as 1897 reports of radiation injury surfaced, but despite these early warnings, radioprotection standards and organizations to regulate exposure would not be developed until the 1920s. By that time the pioneers in the discovery of radiation and many of the early radiologists had their life foreshortened as " martyrs" of radiationinduced leukemia.

1900-1950: X-RAY CANNONS AND RADIUM BOMBS During the first half of this century, the application of radiation to the treatment of malignant disease was limited by the low energy and penetration capability of the radiation sources available and the rudimentary nature of radiation treatment planning and dosimetry.

Introduction of the Coolidge X-ray tube in 1913, allowed the production of a stable, reliable, reproducible source of X-rays.

Early X-ray tubes could produce accelerating potentials of only 10 to 150 kilovolts (kV) and thus, X-rays could penetrate only the very superficial tissues; Coolidge tubes allowed the production of X-ray "cannons" with accelerating potentials up to 300kV and thus the treatment of deeper targets in the body. Van de Graaf generators subsequently allowed even higher accelerating potentials (up to 2 MV), however their large size (>50 feet high! for a megavo ltage machine) precluded their routine clinical use in a hospital setting. Commensurate with the evolution of radiation technology, the discipline of radiation dosimetry (measuring radiation dose accurately) evolved. By 1937, a standard unit of radiation exposure, the Roentgen was established and isodose curves (topographic lines of equivalent radiation dose) were routinely used to map radiation dose deposition in tissues. Establishment of these standards allowed easier comparison and reproducibility of treatment regimens on an internationally consistent scale.

The early development of isotope therapy using more penetrating g-rays rather than "man-made" x-rays arose largely in parallel with the developments in external beam radiotherapy.

Naturally harvested Radium-226 was the therapeutic isotope of choice during the first half of this century. "Systems" of radium application, either by surface mould (i .e. skin cancer), interstitial needles (i.e. tongue cancer) or intracavitary tubes (i .e. cervical cancer) were described by many practitioners including Alexander Graham Bell! Of these, the Manchester system, devised by Patterson and Parker was the most comprehensive and most extensively utilized system of precise dosage and layout of the Radium "seeds". In addition to such brachytherapy, the use of radium for external beam radiotherapy (the radium "bomb") as an alternative to X-ray tubes of limited maximum energy persisted through the first half of this century until replaced by sources produced artificially in nuclear reactors. At the same time , high

energy accelerators were being devised by physicists to increase the maximum energy of X-ray production to 10's of MeV Radiobiology, the study of the effects or radiation on living systems, was in its infancy in this era. Most radiobiologic efforts involved deciphering issues of dose and fractionation of treatment in a discipline where radiation schedu les had arisen empirically and along many different lines. Regaud was the first to demonstrate that a low dose of radiation over a protracted period cou ld preferentially sterilize germ cells within testicular tissue without injuring the surrounding parenchyma - the first demonstration of the benefit of dose fractionation (splitting up of the overall large tumouricidal radiation dose into small daily fractions) . I Clinically during this era, the use of radiation therapy in the treatment of malignant disease became well recogni zed as an alternative to surgery or as a salvage procedure when surgery had failed. In particular, the usefulness of radiation in the treatment of cutaneous , oropharyngeal and gynecological malignancies became well documented. The easy accessibility of these sites utilizing available technology (superficia l X-ray units and radium brachytherapy sources) accounts for the early success of radiation application in these malignancies. I Within Canada, in the first half of this century, provincial organizations for the provision of cancer services were established, largely because of the expense associated with radiation treatments. By 1923 , the first training program in radiology was established at the Toronto General Hospital and by 1946, therapeutic radiology had been establi shed as a separate discipline with a separate fellowship examination from Diagnostic Radiology. Within Ontario, the Ontario Cancer Treatment and Research Foundation (now Cancer Care Ontario) was established in 1946 and by 1950 Cancer Centres offering radiotherapy m Kingston, London and Toronto were established) 1950-2000: MEGAVOLTAGE ENERGY AND "MODERN" RADIOTHERAPY Whil e radium predominated as the therapeutic isotope of choice in the first half of the century, the 1940s saw the development of sustained nuclear fission by the Manhattan Project physicists and the availability of cyclotron particle accelerators.l From these efforts, new "des igner" radioactive isotopes could be generated. One in particular, Cobalt-60, held particular promise for use in teletherapy units, as had been suggested by Mayneord in the United Kingdom. In 1950, the only source of large quantities of Cobalt-60 was obtainable from the heavy water nuclear reactor at Chalk River, Ontario. A physicist, Harold Elford Johns, of the Saskatoon Cancer Clinic oversaw the construction of the first telecobalt unit and commissioning of this unit began in August 195 1. Subsequent commissioni ng of the unit resulted in the first clinical treatment by this unit in November 1951 at the Saskatoon Cancer Centre, but this was not the world 's firs t treatment of a patient with Cobalt-60 radiation. At the same time in Eastern Canada, the Eldorado Mining and Refining company, (a supplier of radium , later to become Atomic Energy of Canada Limited, AECL, and today re-incarnated as MDS-Nordion) also began construction of a telecobalt unit. The unit was purchased by the Ontario Cancer Treatment and Research Fmmdation in March 1950 and a Cobalt-60 source ordered from Chalk River in May UWOMJ 71(1) 2001 47

Figure 1: Radiation treatment using one of the original Cobalt-60 units. The plaster "vesf' carried set-up marks for the treatment beam placements. Beam trajectories and depths were set using the backpointer/caliper. The world 's first Cobalt treatments were delivered in London , Ontario (October 27, 1951) and in Saskatoon (November 8, 1951)[5]

1950. The unit was subsequently installed at the Ontario Institute for Radiotherapy at Victoria Hospital, London, Ontario on October 6, 1951. Rapid commissioning of the unit allowed it to "go clinical" on the 27th October, 1951. The first patient was treated with telecobalt therapy on this day in London by Dr. Ivan E. Smith at Victoria Hospital. (preceding the Saskatoon treatment by two weeks).3 By the end of 1959, there were over 46 models of telecobalt units available sold by 18 different companies. An illustration of a treatment on this cobalt unit is seen in Figure 1.

In parallel with the development oftelecobalt, improvements in microwave design (largely as the result of the war efforts to improve radar) led to the development of mega-voltage linear accelerators.l These machines were able to generate very high voltage potentials and produce therapeutic X-rays ofmegavoltage energies. The relatively compact size of these linear accelators (compared to Van de Graaf towers) allowed them to be mounted on rotating gantries so that treatments from multiple directions (cross firing techniques) could be easily performed and the high X-ray energy allowed tumors deep in the body to be treated. Later refinements would improve the ability to shape and perturb the intensity of radiation emitted by means of blocks and beam modifiers, such as wedges and compensators. Other reftnements to the linear accelerator would include multiple energy X-ray options as well as dual sources of either x-rays or electron beams.

By the 1990s, linear accelerators largely replaced Cobalt-60 within Radiotherapy Departments in the developed countries. Despite the competition from linear accelerators, however, the cost and reliability advantages to Cobalt-60 still make these units an attractive option for radiotherapy delivery ill developing countries and it is estimated that even within North American radiotherapy departments, up to I /3 of radiation treatments could be effectively delivered by a modernized Cobalt-60 teletherapy unit. Recent improvements in the technology of telecobalt units have been introduced and more are expected from manufacturers such as Canada's MDS-Nordion.

Clinically, before the introduction of the megavoltage treat48

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ment units, radiation dose to deep structures was limited largely by skin tolerance as orthovoltage and superficial machines had shallow penetration depth into tissue. The introduction of megavoltage machines provided the capacity to treat both superficial and deep seated, inaccessible tumors with radiation with significant sparing of the superficial tissues and skin due to a dose "build-up effect" at depth. Thus, the application of megavoltage radiation to the treatment of lung cancer, pelvic malignancies such as prostate cancer and abdominal malignancies became more prevalent over this period. Coupled with the improved ability to treat "deep" tumors was the ability to image these tumors with the introduction of axial imaging by computerized tomography (CT) in the 1970s.I Indeed CT scanners were suggested by Alan Cormack, a medical physicist who saw the need to correct radiotherapy dose distributions for the effects of variable tissue densities. With the introduction of CT, diagnostic imaging ability of clinicians increased enormously and the application of this cross-sectional imaging to three-dimensional (3D) radiotherapy treatment planning was also immediately apparent. Computerized treatment planning systems were rapidly introduced in Canada by J.R. Cunningham and systems able to calculate radiation dose deposition in large three dimensional CT data sets became commercially available. 2 More recently, the introduction of magnetic resonance imaging (MRI) and functional imaging through MRI spectroscopy and positron emission tomography (PET) also improved the ability to map tumour targets, and nearby tissues at risk. Incorporation of these modalities through digital image fusion with planning CT data sets and 3D dose distributions was developed.2 Improvements in imaging and computer technology also benefited the brachytherapy techniques . Computerized remote afterloading of radioactive sources allowed reduction of dose exposure to personnel performing the surgery and brachytherapy. Robotic afterloading also allowed computerized dose optimization prior to the placement of the radiation sources ill the treatment applicator. The use of transrectal ultrasound imaging and computerized dosimetry has greatly improved the efficacy of permanent prostate implants and this technique has recently undergone a renaissance usmg radioactive Iodine-125 or Palladium-103 seeds (mcidently produced in a nuclear reactor).

Within the latter half of the century, advances in radiation biology identified double-strand breaks in DNA as the specific lesion responsible for radiation-induced cellular death. This injury led to cell death during mitosis or programmed cell death (apoptosis) in response to the DNA double strand breaks.2 Mathematical models of radiation response allowed clinicians to explore variations in the schedules of radiation delivery and allowed the prediction of the probability of late effects for many tissues treated with various dose fractionation schemes. While classic radiobiology centred on cell death as the main outcome of mterest, in later years it became evident that radiation may also trigger changes ill growth factors , signal-transduction pathways and cell cycle kinetics that may mediate the cellular response to radiation. Like many fields of medicine, radiobiology at the end of the 20th century was rapidly becoming a much more molecular biology disciplme. 2 Clinically, the later half of this century saw the introduction of chemotherapy into the treatment of cancer patients. The inte-

gration of surgery, chemotherapy and radiation into the care of the cancer patient evolved over this time to reach the "multidisciplinary paradigm" currently employed. For example, early stage breast cancer patients who in past years may have been treated exclusively with mastectomy were now treated with breast conserving surgery (lumpectomy) and adjuvant whole breast radiation. Those with adverse prognostic factors (larger tumour, higher grade, involved lymph nodes) also received adjuvant systemic therapy with chemotherapy or hormonal therapy. As confirmed by randomized controlled trials, the combination of these treatments yielded significant improvements in survival and high rates of breast conservation without local recurrence compared to radical mastectomy alone.2 The multi-modality paradigm was also successfully applied to many disease sites such as prostate cancer, bladder cancer, soft tissue sarcoma, rectal and anal cancer and head and neck cancer.2 During this period, the trend towards evidence-based medicine was readily apparent in the oncology literature as the number of randomized trials reported in the literature has increased almost exponentially from 1970 to 1999.

Systematic reviews of evidence drove the development treatment guidelines such as the Cancer Care Ontario Provincial Guideline Initiative (http: / /hiru.mcmaster.ca/ccopgi/). Professionally, national organizations such as ASTRO (American Society for Therapeutic Radiology and Oncology) and CARO (Canadian Association for Radiation Oncologists) were created.3 The term "Radiation Oncologist" was adopted to reflect the broad based functioning of the physician in the care of the cancer patient, not just in the prescription of radiation dose. Along with these professional changes came recognition by licensing bodies, like the Royal College of Physicians and Surgeons, of Radiation Oncology as a unique specialty.3 Similar developments occurred in the evolution of the professions of radiation therapists (Associations of Medical Radiation Technologists) and of medical physicists (Colleges of Medical Physics) - professionals who complete the team in radiation oncology.

This manual registration of tumor volumes derived from diagnostic imaging onto the simulator radiographs/contours was both tedious and of limited accuracy. For most modern conventional radiation treatment planning, the acquisition of a fu ll 3D set of axial planning CT images through the vo lume of interest is required. Once the target and critical structures have been identified by the Radiati on Oncologist on the planning CT images, a radi ation physicist or radiation dosimetrist will design a plan to deliver a uniform radiation dose (usually homogenous within 5%) to the target while minimizing dose to any critical structures outside the target. Currently, most tumors are treated with a limited number (2 -6) of static fields, conformally shaped with a beam's eye view of the tumor with custom poured metal alloy (cerrobend) blocks or multileaf collimators [Figure 2]. The intensity of the beam across the field is typi ca lly uniform although simple beam modifiers ("wedges" or "compensators" that selectively attenuate portions of the radiation beam) may be placed in the field to ensure that the dose is homogeneously distributed throughout the PTV Most conventional radiation treatments are fractionated on a once daily basis, Monday to Friday over 5-6 weeks (25-30 treatments). Radiobiologic models suggest that altered fractionation

CURRENT CLINICAL PRACTICE A complete patient assessment should be taken by the Radiation Oncologist prior to radiation treatment including a history and physical and a review of all surgical procedures, pathology reports and diagnostic imaging.. Ideally the patient is assessed in a multidisciplinary team setting with surgical , pathologic, medical oncology and radiation oncology opinions on the best course of treatment for the patient. This approach is generally used in centralized Canadian cancer centres, including the London Regional Cancer Centre, but only in major academic centres in the United States.

Modem stereotactic conformal radiotherapy requires the reproducible,' accurate immobilization of the patient for both treatment planning and radiation delivery. Use of custom immobilization devices (masks, shells, foam cradles) combined with fiducial tattoos on the skin allow the precise alignment of patients on a daily basis for treatment. In the past, radiotherapy fields were designed by "simulation" with reference to bony anatomic landmarks using fluoroscopy and plain radiographs . Following simulation, manual acquisition of patient contours and delineation of the target volumes for computerized dosimetry was necessary.

Figure 2: A modern linear accelerator. The multi-leaf collimator in the treatment head allows beam shaping to conform to a target of any shape from multiple beam angles. Setup marks on the skin or immobilization device are aligned with fiducial lasers in the room to allow reproducible and precise patient position ing day to day.

UWOMJ 7 1(1)2001 49

(a) Figure 3: . . . (a) Radiotherapy utilizing a small number of simply shaped fl.elds to 1rrad1ate an irregularly shaped target. Good coverage of the target IS ach1eved but large volumes of surrounding normal tissue are inevitably irradiated.

schemes may enhance tumor control over conventional fractionation schemes while maintaining fewer normal tissue reactions.

Hyperfractionation involves delivering multiple, smaller fractions per day (2-3 times a day) over the same 5-6 weeks to a higher total dose. The smaller doses per fraction allow more sublethal damage repair by normal tissue and may permit modest total dose escalations of 15-20% over conventionally fractionated treatments.

Accelerated hyperfractionation involves delivering multiple fractions (2-3 times per day) of similar size to daily fractionation over a shorter period of time (3-4 weeks) with the intent of reducing tumor cell repopulation which may occur over a more protracted (5-6 week) course of radiation treatment. Randomized clinical trials have suggested a potential benefit to hyperfractionation or accelerated fractionation fo advanced head and neck cancers and advanced lung cancers. Radiation effects may also be enhanced by the addition of chemotherapy either before (neoadjuvant) or during (concurrent) radiation. Randomized clinical trials have demonstrated benefit to combined chemotherapy and radiation in diseases such as anal cancer, bladder cancer, cervical cancer, rectal cancer and lung cancer. The combined use of radiosensitizing chemotherapy and radiation is an area of extensive research.

Acute effects of radiation are usually a consequence of radiation injury to rapidly proliferating mucosal tumors in the radiation field . Thus, for example, mucositis, proctitis and cystitis can be a common side effect of radiation to the head and neck regions and pelvic regions, respectively. Other common side effects include epilation within radiation fields and fatigue . Late effects are a consequence of stem cell depletion in irradiated organs as well as obliterative vasculitis leadi ng to fibrosis and neovascularization . Current radiation prescriptions are des igned to create a manageable treatment with respect to acute toxicity and a low incidence of late toxicity.

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(b) Multiple moving beams (conformed) to the target in all dir~ctions produces . excellent target coverage with minimal irradiation of surrounding !issue. DynamiC modulation of beam intensity across the field shape can produce even more h1ghly focussed beams and normal tissue sparing.

2000 AND BEYOND A recent innovation is the availability of "inverse treatment planning" software whereby the radiation oncologist specifies the desired dose distribution (conforming to the PTV) as well as dose limits to organs at risk to be avoided. "Back" calculation (analogous to the image reconstruction algorithms used by CT scanners) then yields the appropriate beam delivery parameters (angle, shape, intensity profile) to produce the dose distribution desired in the patient. I The delivery of such "inversely planned" treatments may require the use of intensity modulation (IMRT, see below) to dynamically alter the intensity profile across the beam area .. This intensity modulation may be accomplished by the alteration offield shape "on the fly" by dynamic movement of multi-leaf collimator leaves (dynamic MLC) or the dynamic modulation of the slit aperture of an arced radiotherapy beam. Such treatments produce a very conformal dose deposition with a reasonable dose homogeneity of 20-30% (vs 5-l 0% for non-IMRT) throughout the PTV and a very rapid dose falloff outside of the PTV2 By more sophisticated modulation of the beam intensity across the PTV, very conformal complex dose distributions may be produced even for complex shaped (ie. convex or concave) tumors [Figure 3]. Ultimately, a form of treatment similar in geometry to spiral CT scanning, known as "tomotherapy" may allow the routine delivery of intensity modulated radiation treatments on a "slice-by slice" basis. Proposed "tomotherapy" units would carry the advantage of incorporating cross-sectional imaging for verification of patient positioning (and target volume positioning within the patient) day-to-day for treatment. Exit dose imaging during treatment would allow a verification of the three dimensional dose deposition within the patient, allowing more accurate quality assurance as well as iterative treatment modifications to correct for variances in daily treatment delivery due to

internal organ motion or patient set-up variances [Figure 4]. A clinical prototype of a tomotherapy is now under evaluation at the University ofWisconsin. Beta test units will probably be available for more widespread testing later in 200 I at the London Regional Cancer Centre and the Cross Cancer Institute in Edmonton.

For now the technical expertise needed to plan, deliver and verify the accuracy of intensity modulated radiotherapy restricts its use primarily to academic centres but the technology should become routinely available within the next 5 years. The routine introduction of intensity modulated radiotherapy into clinical practice will facilitate a new array of clinical trials exploring altered fractionation schemes and the manipulation of the therapeutic ratios with non-uniform irradiation. In particular, hypo-fractionated schemes (fewer fractions, larger dose per fraction) radiation schedules may be possible through highly conformal dose delivery.

Fewer fractions would mean less inconvenience to the patients and may have the potential to increase biologic effectiveness.

Highly conformal dose delivery requires more accurate tumor targeting, however. Availability of metabolic and functional imaging through positron emission tomography (PET), single photon emission tomography (SPECT) and MRI spectroscopy will improve our ability to detect tumor spread and relation to critical structures. Fusion of these modalities with CT radiation treatment planning data sets will allow a more accurate definition of the gross and clinical tumor volumes. As radiation treatment planning becomes more and more heavily image-guided and verified, the dividing line between therapeutic radiology and diagnostic radiology will begin to blur again and Radiation Oncologists will have to become more in touch with "their inner Diagnostic Radiology selfl" Introduction of novel agents such as monoclonal antibodies for tumour imaging, anti-angiogenesis agents, anti-invasion inhibitors as well as novel cyto-toxic agents and radio-protective agents will provide fuel for further clinical trials. Results from

these clinical trials will provide additional information for evidence-based treatment guidelines and ultimately, these guidelines may evolve into patient-tailored care paths that take into account a wide variety of factors other than the simple cancer staging factors used to date. Novel biologic predictors of tumor response (or normal tissue sensitivity to treatment) along with more traditional tumor staging parameters may help direct the care of the cancer patient. Finally, as more of the genetic changes underlying cancer are elucidated, improved preventive strategies and screening practices should help clinicians to detect and treat patients aggressively before overt cancer develops.

ACKNOWLEDGEMENT The authors would like to thank Peter Munro PhD for his helpful suggestions and figure with respect to the original cobalt-60 unit in London, Ontario.

CONCLUSIONS Radiation oncology, like every other medical discipline, is a work in progress. Technological multidisciplinary innovations in dose delivery and verification as well as improved integration with surgical and medical oncology promise to improve the outlook of cancer patients as we enter the 21st century.

REFERENCES 1.

2.

3.

4.

5.

Mould RF A Centtay of X-rays and Radioactivity in Medicine. Institute of Physics Publishing, Philadelphia, 1993.

Lichter AS, Lawrence TS. Recent Advances in Radiation Oncology. New England J Medicine 1995;332 (6) :371-3 79.

Hayer CRR. , Payne D, Ege GN Radiation Oncology in Canada 18951995. lnt J Radial Oneal Bioi Phys 1996;36(2) :987-496.

Shumak K. Cancer Care Ontario s Response to the 1999 Provincial Auditor s Report. http:www.cancercare.an.

Munro, P Cobalt-60: A Canadian Perspective. Part 3: London, Ontario and the "Peacetim e Bomb ". Canadian Medical Physics Newsletter 1999;45(3) :64-69.

Figure 4: Prototype of the Tomotherapy machine. A compact linear accelerator . mounted on a rotating ring gantry delivers beams 1n a sp1ral fashion wh1le a multileaf collimator dynamically alters the fan beam intensity throughout . CT detectors on the ring allows simultaneous patient-imaging for subsequent reconstruction of the dose delivered with in the patient and adapt1ve correct1on of dose vanances during daily treatments.

UWOMJ 7 1(1 ) 2001 51

Radiology and imaging: Past, present and future

Richard N. Rankin MB, ChB, FRCPC Chai1; Division of Radiology and Department of Diagnostic Radiology and Nuclear Medicine, The University of Western Ontario Chief, Department of Radiology, London Health Sciences Centre

X-actly So! The Roentgen Rays, The Roentgen Rays, What is this craze?

The town 's ablaze With the new phase OfX-rays ways.

I'm full of daze, Shock and amaze; For nowadays I hear they ' ll gaze Thro ' cloak and gown - and even stays, Those naughty, naughty Roentgen Rays .

From 'Electric Review ', April 1896.1

Only three months after the publi cation of an article in the Vienna Free Press on January 5th 1896, the power of the ' New Kind of Ray ' was recogni sed worldwide. And in typica l Victorian fas hion a prudish interpretation was put on the use of this most powerful tools' abili ty to penetrate the secrets of the body!

THE PAST X-rays were actuall y discovered by Professor Wi lhelm Konrad Roentgen on Friday November 8th 1895 while working in his physics laboratory at the University of Wurzburg on the properties of vacuum tubes . After typically meticulous checking and cross checking of hi s remarkabl e discovery he delivered his sem-

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inal paper, entitled "On a New Kind of Ray" , to the Wurzburg Physical and Medical Society on December 28th 1895. Roentgen named these new rays X-rays in a footnote to his paper. News of this discovery leaked to the Vienna Free Press, and from there on the rest, as they say, is history.2 Roentgen was awarded the f irst ever Nobel Prize in Physics in 190 l for his work, by this time Xrays were in use worldwide for medical and other purposes. A further ll Nobel prizes have si nce been awarded for work involving the investigation of the properties and uses of X-rays, a remarkable testament to the importance of his discovery) The speed of adoption of this new tool was astonishi ng when compared with the rate of adoption of medical discoveries today.

The new medical specialty of Radiology got its start not long after public knowledge of the power of this new technique became widespread. Soon professional societies were formed to promote this new profession, as an example the American Roentgen Ray Society was formed in 1900 and is still a major force in Radiological education in the U.S .. This was the first medical specialty to be fo unded on the basis of a tool to be used for diagnosis and treatn1ent. The first North American use of Xrays for medical diagnosis took pl ace at Dartmouth Co llege on February 3rd 1896, when a diagnosis of ulnar fracture was made.

In Canada the f irst use ofX-rays for this purpose was on February 7th 1896 at McGill University where Professor John Cox radiographed a patients leg and showed a bull et in the soft tissues. The bullet was removed the same day at operation and the pati ent later sued the person who had shot him, using the radiograph as evidence in court. This was the first recorded use of radiographs preoperatively to guide the surgeon, and the f irst use for medico-

legal purposes. X-ray diagnosis came to London in 1902 with the appointment of Dr George McNeil to Victoria Hospital.

Alexander Graham Bell was also involved in those early days of investigation of this new technique, and made two important observations. He devised a technique for stereoscopic radiography, noting that it should be possible to use this technique to see the skeleton in three dimensions. He also was amongst the first to suggest the possible use of x-rays to treat cancer, as discoveries were being made of the potentially harmful effects of x-ray exposure on tissues. Since those times radiography has changed little in principal, though many incremental advances have been made in x-ray techniques, equipment and recording devices to bring this tool to the advanced stage it is at today. Examples of the many important advances made abound, including the invention of flouroscopy, tomography, film, intensifying screens, grids and collimators, all of which have lead to safer and more productive radiography.

Until the latter part of the 20th century Radiology was confined to the use ofx-rays in diagnosis and treatment using film or one of its precursors as the recording medium. The rapid development of the specialty since then has depended on the technological revolution which spanned that century, producing such diverse additional imaging techniques as Nuclear Medicine, Ultrasound, Computerised Axial Tomography (CT), Magnetic Resonance Imaging (MRI) and Interventional Radiology. Most of these new techniques only came to the fore in the last 30 years of the century, Nuclear Medicine in the 1960's and 1970 's, Ultrasound in the 1970's, CT in the late 1970's, MRI in the 1980's and Interventional Radiology in the 1970's and 1980's. Most radiologists practising today have therefore had the excitement of seeing new and tremendously valuable techniques introduced into their specialty with a huge consequent growth in its importance to the whole field of medicine.

Just as the story of Professor Roentgen and his times is an illuminating insight into the development of our specialty, so is the story of the many subsequent inventors and scientists involved in bringing these newer techniques into the field of medical imaging. A short review of several of these people will help put Diagnostic Radiology and Nuclear Medicine today into its historical context.

Antoine Henri Becquerel: In March 1896 discovered radioactivity during his investigations of flourescence and phospheresence, studies initiated by Roentgens own discovery. He was awarded the 1903 Nobel Prize in Physics.4 Pierre and Marie Curie: This husband and wife pair worked in the Becqerel laboratory, and introduced the term 'radio-active'. After her husbands death Madamme Curie demonstrated that radiation is an atomic prop~rty of matter. They were awarded a Nobel Prize in Physics in 1903.5 The research of Becqerel and the Curies formed the groundwork for the later development ofNuclear Medicine. Interestingly Pierre Curie, working with his brother Jacques, in 1880 discovered and described the piezoelectric effect, later the key to the development of ultrasound.

Christian Andreas Doppler: In 1842 described the effect by which energy waves change frequency dependent on the velocity of the body from which they emanate.6 Called the Doppler effect, and central to the later development of Doppler ultrasound techniques, the effect was verified by comparing the notes of two identical musical instruments with perfect pitch being played simultaneously on a train station and a moving train.

John Julian Wild: Using developments in sonar prior to and during the years of the Second World War, Wild - a medical graduate and his partner Donald Neal - an engineer, developed A-mode ultrasound in 1949.7 Following Neals ' transfer to armed services work during the Korean War, Wild started working with John Reid- also an engineer. Together they developed B-mode ultrasound, publishing the first paper on B-mode imaging in Science Magazine in 1952.

From these beginnings diagnostic ultrasound has benefitted from the work of inumerable doctors and scientists to become the major investigative technique that it is today, though it was not until the late 1970's that it became a widespread technique in use in Radiology.

Godfrey Newbold Hounsfield: An engineer and the inventor of CT, he worked for EMI, an electronics firm best known at that time as a producer of music records. Given his own laboratories at their research facility in Hayes, England, and freedom to pursue his own research interests he took his interest in computers and pattern recognition to come up with the ideas and specifications for the first CT scanner. For this he was awarded a Nobel Prize in Medicine in 1979.8 1t is possible that the monies taken in from sales of records of such artists as the Beatles allowed this firm to fund such unusual research.

The first head CT came to London, Victoria Hospital in 1976 and the first body CT to University Hospital in 1977.

Raymond V. Damadian: He is credited with being the inventor of MRI. Nuclear magnetic resonance was discovered in the years prior to the Second World war, and came to scientific prominence in the early post war years as a means to investigate the chemical composition of materials. With training in Medicine and Physics, he was able to bring together diverse knowledge to design and patent MRI in 1972 while working at State Univeristy of New York.9 He is presently involved with the company he founded, Fonar Corporation, continuously developing the technique. The first MRI unit capable of human body imaging took its first scan in 1979 at Nottingham University, England. The first MRI in Canada opened for clinical work in 1984 at St Josephs Hospital, London.

Sven-Ivar Seldinger: In 1953, Dr Seldinger - a Swedish radiologist - first described his technique for percutaneous entry into a blood vessel.IO Still called the Seldinger technique, this was the start of clinical angiography and eventually of Interventional Radiology, though the idea of angiography (the visualisation of blood vessels by injection of a radio-opaque substance) had first occurred only a couple of years after Roentgens ' original discovery.

UWOMJ 71(1) 2001 53

Charles T. Dotter:

Chair of the Department of Radiology at Oregon Health Sciences University for 33 years, Dr Dotter pioneered angioplasty in 1964, and after this many other interventional procedures, and is widely considered the ' father ' of this new subspecialty of Radiology.II In Europe angioplasty was originally called ' Dottering', and as with most new techniques many other scientists were involved in development to the stage we know today.

THE PRESENT This brief review of the past and some of the most important people involved in the development of Radiology leads to some interesting observations. The fundamental scientific observations which lead to a new clinical technique may be made many years before that technique is developed. Large numbers of other investigators are involved in the interim, in investigation and extension of the original observations. Many, if not most, of the people who have invented or developed the techniques now in use are not radiologists. Indeed, the majority are scientists and engineers, and there are a number of non radiologist physicians. This history speaks very loudly to the wide applicability of radiologic techniques, their complexity and the need for radiology to work collegialy with other interests.

Radiology in a clinical and academic setting is now one of the major 'core ' specialties, its ' presence necessary for the practice of most other clinical specialties. The Department of Diagnostic Radiology and Nuclear Medicine at the University of Western Ontario has 42 radiologists, 9 Nuclear Medicine physicians and 21 Scientists, including Physicists, Engineers, Computer scientists and one Physiologist, on its staff at the time of writing this article, as well as several scientists and physicians in other specialties (biophysics, neurosciences, cardiology, psychiatry, oncology) with cross appointments to the academic department. As well many of its members are cross appointed to other basic science and clinical departments (biophysics, physiology, surgery, orthopedics, neurosciences). In a typical hospital setting the operating budget of the imaging departments is around 5% of the total operating budget of the institution, and the capital requirements are commensurately large. Across Canada at this time there are in excess of 100 jobs for radiologists available, and current manpower predictions of the Canadian Association of Radiologists indicate that within 5 years this may grow to 500.

The increasing need for imaging diagnosis and intervention, and the increasing complexity of each diagnostic imaging examination are the reasons for this situation.

The job opportunities for medical graduates in this setting are obviously very good, and the rewards of working closely with patients and other phsyicians are equally good. The opportunities for enlargment of the scope of both clinical and academic imaging are also bright, radiology worldwide is becoming a central part of undergraduate and postgraduate teaching, and the clinical position of imaging is assured. Only the intransigence of government in controlling numbers of physicians and health care expenditures prevents us from fully playing the role we should.

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THE FUTURE Is extremely bright!

Predicting the future is difficult, but it is clear that there are two things which will have a profound effect on the future of the specialties of Radiology and Nuclear Medicine: New imaging techniques and digitisation. Near infra-red spectroscopy, Electric Impedance Tomography, Acoustic Impedance Tomography and Micromagnetometry are all on the distant development horizon and may one day become techniques used in diagnosis of disease in tissues. Nuclear Medicine, Ultrasound, Flouroscopy, CT and MRI are all nowadays recorded digitally and transferred to film for reading and archival purposes. The technology for digital recording of standard radiographs has recently become commercially available, allowing us for the first time to dispense with film and record and archive all images in a digital format. The potential for this advance in this wired world of computers and networks is huge, including the ability to view examinations in a variety of ways not now done such as in 3-D and movie format. It will also lead to greater productivity of imaging departments and greater availability of imaging examinations and the reports produced from them by Radiologists and Nuclear Medicine physicians. There is no doubt that there is both opportunity and threat to these specialties in this continuing expansion and availability to all, however on balance there is clearly much benefit to be gained for patient care and an assurance that the imaging specialties will continue to have an increasing role in that care.

REFERENCES 1.

2.

http://www.xray.hmc.psu.edu/rcilss1/img0018jpg Aldrich JE, Lentle BC. editors. A New Kind of Ray. Van couvet; BC: The Canadian A sociation of Radiologists; 1995.

3. http://web. wn.netl- usrlrichter/web/nobelpri=e.html 4. http:l!wHI\o\(accesse.xcellence.org/AEIAEC/CC/historical_background.html 5. http://www. accesse.xcellence.org/AEIAECICC/radioactivity.hnnl 6. hllp:/lwww-groups.dcs.st-and.ac.ukl-history/Math emeticians/ Doppler.html 7. hllp://www.ob-ultrasound.net/histoty.hhnl 8. hllp:l/www.nobel.se/laureates/medicine-1979-2-autobio.hhnl 9. hllp:/lweb.mit.edu/inventlwwwlinventorsA-H/damadian.html 10. hllp://www.cookgroup.com/innovators. html 11 . hllp:/Avww.ohsu.edu/douerlhistol)'.hhnl

Sport Medicine

P J Fowler, MD FRCS(C) Professol; Orthopaedic Surgery Head, Section of Sport Medicine, The University of Western Ontario

SPORT MEDICINE IDSTORY The origins of Sport Medicine lie in 5th century BC Greece and Rome where physical education was a necessary aspect of youths' training and athletic contests first became a part of everyday life. It was not until in 1928 at the Olympics in St. Moritz, when a committee came together to plan the First International Congress of Sports Medicine, that the term itself was coined. In the 5th century, however, the care of athletes was primarily the responsibility of specialists. They were trainer-coaches and were considered to be experts on diet, physical therapy, and hygiene as well as on sport specific techniques. The first use of therapeutic exercise is credited to Herodicus, who is thought to have been one ofHippocrates' teachers. Until the 2nd century AD, when the first "team doctor", Galen, was appointed to the gladiators, the physician only became involved if there was an injury.

Whether or not there was good communication or rapport between the trainer-coaches and the team physician back then is a matter of speculation. What is clear however, is that from its beginnings, Sport Medicine has been multidisciplinary with the obligation not only to treat injuries but also to instruct and prepare athletes. Tills link with physical education has remained in place throughout its evolution.

many to assume that sport related problems are by default musculoskeletal and that Sport Medicine is an orthopaedic specialty.

There is much more to Sport Medicine than just musculoskeletal diagnosis and treatment. Illness or injury in sport can be caused by many factors - from environmental to physiological and psychological. Consequently, Sport Medicine can encompass an array of specialties - cardiology, orthopaedic surgery, biomechanics, traumatology, etc. For example, heat, cold or altitude during training and competition can alter performance or may even be life threatening. What about the female triad of disordered eating, menstrual and bone density problems, and the pregnant or the aging athlete? In addition, the management of dermato logical and endocrinological diseases and other such problems in the athlete demands expertise and sport specific knowledge.

The use of supplements, pharmacological or otherwise, and the topics of doping control and gender verification present complex ~oral , legal and health related difficulties. Then there are the particular problems associated with international sporting events, such as the effects of travel, acclimatization and the attempt to balance an athlete 's participation and his/her health. Much of tills represents new fields of study where extensive clinical and basic science research is burgeoning. Finally, prevention is an area of increasingly specialized knowledge, interest and expertise.

SPORT MEDICINE TODAY Sport Medicine has always been difficult to define because it is not a single specialty, but an area that involves health care professionals, researchers and educators from a wide variety of disciplines. Its function is not only curative and rehabilitative, but also preventative, wruch may actually be the most important one of all. Despite this wide scope, there has been a tendency for

THE FUTURE OF SPORT MEDICINE I believe that Sport Medicine will make its most significant fu~e contributions in the area of prevention. According to Dr. Davtd Janda, orthopaedic surgeon and director ofThe Institute for Preventative Medicine in Michigan, prevention is Sport M.ed~cine 's final fro~tier. The risk of injury will never be entirely ehmmated. But modtfications in training techniques, equipment,

UWOMJ 7 1(1) 2001 55

sports venues and rules based on outcomes of meaningful research have shown that it can be lowered. O ne rapidly advancing field with great potential for applications in prevention is the study of the body's neuromuscular adaptations. For example, a study of specific preseason neuromuscular training in soccer players demonstrated a significant decrease in the incidence of anterior cruciate ligament tears . In another investigation by Janda et al. , serious injuries in recreational softball were reduced by 98% when breakaway bases were used .

SPORT MEDICINE AT WESTERN The beginnings of Sport Medicine and physical education were humble at Western. Professor Jack Fairs, who currently coaches the squash team, taught exercise physiology to the first graduating class of the Honours Program in Physical and Health and Education in 1950. T he school's athletic trainer, Murray McNie, who was also the track coach, was a dedicated individual whose education and training was primarily " on-the-job". And in 1965, Dr Vince Callaghan, a general surgeon at St Joseph 's Hospital who had been the foo tball team's physician, retired and was replaced by Dr. J.C. Kennedy, an orthopaedic surgeon.

During the time of Professor Fairs and Murray McNie, injured foot ball players were assessed and received hydrotherapy in a whirlpool connected to a shower in the J.W. Little Stadium locker room. When the football season was over, the whirlpool was relocated in the men 's shower room and this , of course, excluded women from this particular treatment. Other student athletes were seen and treated in what is currently the men 's visitor dressing room in Thames Hall.

Mr. McNie retired in 1968 and David Wise, a certified therapist from Kent State, became head athletic therapist. During hj s service at Western he com pl eted his B.Sc. in physiotherapy and introduced the concept of student trainers . Currently, a network of student trainers, athletic therapists and physiotherapists admini ster to intercollegiate teams .

When ruscussing the development of Sport Medicine at Western it is important to recognize the vis ion and contributions of Dr. J. C. Kennedy. While watchjng his daughter Louise sw im at the 1968 O lympics in Mexico City, Dr. Kennedy concluded for a variety of reasons , that competing athletic teams from Canada should be accompanied by qualified and well organized medical care. This belief led him to be a founding fat her of the Canadia n Academy of Sport Medi cine. One of the primary mandates of thi s society was to provide expett care to Canad ia n athletes, and in 1972 he was appointed chief medical officer of the firs t " true" medical team at the Munich Olympics. Other countri es soon followed this example and assigned medical teams to Olympic athletes.

Dr. Kennedy 's vision was not limited to travelling Canadian athletes. At a time when Sport Medicine clinics were urtheard of in Can ada, he convinced Western 's administration to convert Room 20 in Thames Hall, known as the "combatives" room, into The Athletic Injuries Clinic that officially opened in 1972. The first Nautilus equipment in Canada was purchased fro m funds raised to outfit this clinic. Dr. Kennedy inspired and fostered an interest in research in Sport Medicine, for which The University of Western Ontario (UWO) and London have become known. For 56

UWOMJ 71(1) 2001

the past several decades, beginning with ills studies of the anatomy, pathophysiology and biomechanics of the knee, contributions from Western have been both prolific and significant.

Today at Western, a symbiosis between the new Faculty of Health Sciences and the Sport Medicine Clinic reflects the vital and dynamic state of Sport Medicine. Both areas have grown tremendously. The Faculty of Health Sciences now encompasses the schools of Physiotherapy and Kinesiology. Kinesiology has broadened to include many related resources such as The Centre for Activity and Aging, The Wieder Nutrition Laboratory and The Exercise and Pregnancy Laboratory. The Sport Medicine C linic is a multidisciplinary centre that provides primary care, imaging (ultrasound, x-ray), orthopaedics, physiotherapy, kinesiolgy and pedorthics for patients within and outside the UWO community.

Academically, residency and fellowship trainillg in the majority of these fields are offered. Graduate students in kinesiology and physiotherapy have the opportunity to plan and carry out research studies at the clinic under the guidance of the clinical staff and w ith the direct invo lvement and cooperation of patients.

Presently, there is a Master's thesis project in progress designed to determine if there is a familial predisposition to the anterior cruciate ligament rupture, one of the most common activity related knee injuries. Projects such as these are facilitated by the interaction of disciplines and are beneficial to all participants. Other research in progress includes a Medical Research Council funded randomized clinical trial studying the efficacy of arthroscopy in the treatment of osteoarthritis of the knee, and a prospective trial to evaluate the effectiveness of knee bracing following anterior cruciate ligam ent reconstruction.

Participation in all forms of physical activity at all levels is a huge part of everyday modern life and its benefits to health and quality of life are clear. Sport Medicine will continue to grow and develop so that these benefits can be fully and safely realized.

Urology as a specialty: From papyrus to palm pilots

Joseph L. Chin, MD, FRCS(C) Professor and Chair, Division of Urology, The University ofWestern Ontario

Although Urology was not officially recognized as a surgical sub-specialty until the late 1890's, Urologic disorders had been recognized since the dawn of civilization. Vesical stones from mummies dating back to 4800 BC have been discovered. The first urinary catheter was described over 3000 years BC. In the Book of the Dead, a quote from the Hieroglyphic Transcript translated into English as "I have not waded water" in reference to schistosomiasis infestation leading to hematuria. Bladder calculi, a "fluid from penis" (hematuria) and phallus had all been recorded on papyrus from 1500 BC Papyrus also depicted such conditions as hydrocele, urethral stricture, urinary retention, enuresis, incontinence, cystitis, and organic sexual disorders, again dating back to many centuries before the reign of Rameses II. Indeed, an earlier version of the Hippocratic Oath refers to "cutting for stones."

Although Hippocrates and Galen were responsible for studies in medieval universities, Theophilus (circa 7th Century AD) championed the specialty of urology, stating that Galen had not taught the subject of urology thoroughly enough. His publication "De Urinis" was a valiant and comprehensive attempt at defining the role of "Uroscopy" and documented the interpretation of the significance of different types of urine: "Such is Urine ... Urine is blood percolation." Isaac Israeli (850-950AD) published the Book of Urine, again emphasizing the diagnostic value of urine examination. In addition to lithotomy, one of the original urologic surgical procedures was circumcision. The "Memphis stone" was composed of carbonates of lime in an acid, which, in coming in contact with the moist prepuce, would release carbonic acid acting as a local anesthetic for the circumcision procedure.

Varicoceles were an intriguing entity for physicians throughout the centuries. Galen described it as a "cirsocele" (varix of the blood vessels). Celsus, a Roman encyclopedist, (25 -35A.D.)

Hassan Razvi, MD, FRCS(C) Assistant Professor and Program Director of the Residency Program, Division of Urology, The University of Western Ontario

described cauterizing a varicocele scrotally with a hot wire.

Leonardo Da Vinci had accurately depicted a varicocele in his drawings of urogenital anatomy and physiology. A well-publicized, infamous case of malpractice involved a well-known professor of surgery performing bilateral varicocelectomy on a patient who subsequently suffered testicular atrophy in both testes . The irate patient murdered his surgeon. Percival Potts (1713-1788) provided a comprehensive differential diagnosis of scrotal disorders including varicoceles, hydroceles, and hernias.

In particular he also described a disease which to this day bears his name as he related chimney-sweeps and scrotal cancer. In the 17th and 18th centuries, a relatively common urologic (albeit not medically indicated) procedure was castration as Castrati Operatic singers were very much in demand.

The philosophic and deductive manner of medical diagnoses and management planning gave way to more scientifically-oriented and "evidence-based" methods. As well, surgeons began to use organ-related diagnoses to formulate treatment planning.

Thus in the mid-1800 's, Urology as well as many other surgical specialties, enjoyed significant progress in their development. At this stage, urology benefited significantly from the discoveries in other medical disciplines (experimental physiology, microbiology, cellular diagnostic pathology and anesthesia). Previous limitations in surgery such as difficulty in pain control and sepsis had now been partially resolved with such discoveries as the concept of antisepsis (by Lister) and inhalation anesthetic agents.

There were further refinements in lithotrites and dilatation of urethral strictures in the 1820's. At this time, urology had a close association with venerealogy and syphilology. Archives in the libraries contained volumes of Journal of Cutaneous and Genitourinary Diseases and Journal of Syphilology, as well as UWOMJ 71(1 ) 2001 57

Maladies des Vois Urinaires et Maladies Veneriennes (1951 ).

Eventually the dermatologists and urologists parted ways, although the urologists continued to manage urethral strictures and prostate disorders .

One of the landmarks in the development ofUrologic surgery was the first planned nephrectomy in 1879 by Gustav Simon. This was made possible by better understanding of human anatomy, physiology, and disease processes. This opened the door for a variety of other renal procedures, both reconstructive and extirpative. Simultaneously another great landmark in defining the surgical sub-specialty of urology was the work by Nitze and an Austrian instrument maker, Leiter, who developed the first functional cystoscope. The incandescent lamp developed by Thomas Edison was incorporated. Numerous refinements ensued, most notably in illumination techniques. The discovery of retrograde pyelography techniques facilitated diagnostic procedures. The availability of cautery techniques transformed cystoscopy from diagnostic to therapeutic procedures such as transurethral fulguration of bladder tumors and eventually transurethral resection of the prostate. Transurethral prostatectomy had since become the surgical procedure the urologist is most closely identified with.

Urologic societies and associations were formed in France and Germany towards the beginning of the 20th century. The American Association of Genitourinary Surgeons was founded in 1887 and the American Urological Association was officially formed in 1902 as a distinct professional society from general surgery. Subspecialized areas of urology slowly emerged although the majority of urologists practiced all areas of urology, diagnosing and treating all disorders of the genito-urinary tract, with both endoscopic and open surgical means.

URO-ONCOLOGY The development of the subspecialty of uro-oncology paralleled the development of cancer treatment, as it became a more emerging problem. The first hospital in the world devoted to cancer management was an institution in Buffalo, New York. It was opened in 1875 by Roswell Park and still bears his name. Orooncology has since become prominent component of the practice for Urologists since prostate cancer, bladder cancer, and renal cancers are presently amongst the most common malignancies. In the late 1940's, Huggins and Hodges discovered hormone control of prostate cancer (Charles Huggins was a Canadian and the winner of the Nobel Prize). Contributions from the University of Western Ontario included the Noble Rat Experimental Model, the discovery of Vincristine, a chemotherapeutic agent, as well as pioneering efforts in radiotherapy. Cancer treatment became more efficacious, notably in chemotherapy for testicular cancer, and research efforts have turned towards earlier diagnosis as well as understanding the process of oncogenesis and metastasis. The discovery of prostate specific antigen in the 1980's was another landmark in uro-oncology, radically altering prostate cancer diagnosis, monitoring and treatment. For bladder cancer, cystectomy with urinary diversion (ileal conduit) , popularized by Bricker (1950's), was a significant milestone. Orthotopic urinary diversion has since become a common procedure in both sexes, improving quality of life for patients.

a

58

UWOMJ 71(1) 2001

RENAL TRANSPLANTATION Great strides were made in transplant immunology before the first renal transplant by Murray (another Nobel Laureate) in 1959. Improvement in vascular anastomotic tec~ques , suture material and more importantly immunosuppressive agents have drastically improved the survival rates of allograft and patients.

UROLITIDASIS & STONE SURGERY Stone surgery gained some notoriety when the King of the Belgiums required the service of a Urologic surgeon for cystolitholapexy. After the first planned "nephrectomy" by Simon of Heidelberg in 1869, renal preservation with nephrectomy (Heinike, 1879) instead of nephrectomy for renal s_tones became the standard practice. Great strides have been made m other forms of stone surgery including endoscopic stone removal and percutaneous stone procedures in the early 1980's. This was followed in quick succession by extra corporeal shock wave lithotripsy (ESWL: Chaussy, 1980). These developments , as well as improvements in endoscopic instruments (flexible and rigid), have changed the nature of stone surgery. Other significant advancements include the use of pulsed dye laser (1987) and the Holmium YAG laser (1990's) to fragment urinary calculi.

In the latter part of the 20th Century, Urology was a well defined surgical specialty with subspecialized areas such as urooncology, endourology, pediatric urology, renal transplantation, neuro-urology as well as the more recently defined areas of andrology, female urology or uro-gynecology. Laparoscopy was initially used as a diagnostic technique for undescended testes and subsequently gained therapeutic applicability in pelvic lymph node dissection (1998) nephrectomy, simple and radical adrenolectomy, live donor nephrectomy, as well as renal reconstructive procedures. Most recently radical prostatectomy as well as cystectomy and ileal conduit have also been attempted. Thus urology is currently a surgical specialty which encompasses many aspects of open endoscopic surgery as well as medical therapy and diagnostic problems. The complexity of many urologic patients necessitates vital linkages with other disciplines such as medicine, oncology, general surgery, rehabilitative medicine, pediatrics, intensive care, neurology, and others.

From a rich historic background, urology has evolved into a challenging and essential surgical specialty. As we enter the 21st Century several trends are evident. As with all other branches of medicine, computer technology and technologic innovations have a major impact on the practice of urology. Our specialty was one of the firsts to benefit from endoscopic technology, fibre optics, lasers, and various energy sources for stone treatment and for prostate and bladder therapy. Urologic researchers continue to be on the forefront for technologic advances in robotics and virtual reality systems and their applications to urology. Surgical procedures have become progressively "less invasive" as we have already witnessed the quintessential example of open stone surgery progressing on to percutaneous stone removal and endoscopic/intracorporeallithotripsy and finally extracorporeal shock wave lithotripsy with no incisions. Undoubtedly surgeries in other branches of urology will follow a similar trend.

On the research front, further advances in genetics and

molecular biology will facilitate accurate diagnosis at early stages of disease as with other specialties. Urology will benefit from results of the Human Genome Project and many urologic conditions can be diagnosed and possibly prevented. On the therapeutic front, genetic engineering and gene therapy which have already had preliminary research applications for prostate cancer, andrology and other areas, will be widely employed.

For some of the urologic conditions that we have already achieved satisfactory therapeutic outcome (e.g. testicular cancer), the future therapeutic challenges will be focused on minimizing the therapeutic burden while maintaining efficacy. For other conditions where current curative procedures often significantly adversely affect quality of life, efforts will be aimed at improving quality of life. Multidisciplinary approaches to treatment will continue to be an important aspect of management of urologic conditions. Urology will continue to flourish as a surgical specialty in the new age of palm pilots and beyond.

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Brief Presc ri bi ng Information

NORVASC• (amlod1pine besylatel Tablets 2.5, 5 and 10 mg Antthypertenstve-Anttangtnal Agent ACTION AND CLINICAL PHARMACOLOGY NORVASC (amlodtptne besylate) IS a calcmm 10n Influx mhtbttor (calc tum entry blocker or ca lctum ton antagomst) Amlod1pme IS a member of the dthydropyndtne class of calctum antagomsts INDICATIONS AND CLINICAL USE Hypertension

NORVASC (amlodtptne besylate) IS tndtcated '"the treatment of mtld-to -moderate essenttal hypertensiOn NORVASC should normally be used m those pattents m whom treatment wtth dtureucs or beta-blockers was found tneffecttve or has been associated wtth unacceptable adverse effects NORVASC can be tned as an tntttal agent'" those patients'" whom the use of dturetics and/or beta -blockers IS contra1nd1cated or 1n pat1ents w1th med1cal cond1t10ns m whtch these drugs frequently cause senous adverse effects Comb1nat1on of NORVASC w1th a dturet1c, a beta -blocking agent. or an ang10tensm convertmg enzyme 1nh1b1tor has been found to be compat1ble and showed add1t1ve ant1hypertens1ve effect Chronic Stable Angina NORVASC 1s md1cated for the management of chron1c stable angma (effort· assoc1ated ang1na) m pat1ents who rem am symptomatic despite adequate doses of beta -blockers and/or organ1c mtrates or who cannot tolerate those agents NORVASC may be tried 1n combmat10n w1th beta -blockers m chron1c stable angina, 1n pat1ents w1th normal ventncular function . When such concomitant therapy IS introduced, care must be taken to mon1tor blood pressure closely smce hypotens1on can occur from the comb1ned effects of the drugs CONTRAINOICATIONS ~ORVASC (amlodip1ne besylate) IS contramd1cated m pat1ents with hypersensitiVIty to the drug or other d1hydropynd1nes and m patients with severe hypotens1on !less than 90 mmHg systolic).

WARNINGS Increased Ang ina and/or Myocardial Infarction ~a rely, pat1ents, particularly those w1th severe obstruct1ve coronary artery d1sease. have developed documented mcreased frequency, durat1on and/or seventy of angma or acute myocardial1nfarct1on on startmg ca lc1um channel blocker therapy or at the t1me of dosage mcrease The mechan1sm of th1s effect has not been eluctdated Outflow ObsiTucti on (Aortic Stenosis) NORVASC should be used with cautiOn m a presence of f1xed left ventncular outflow obstructiOn (aortic stenos1s).

Use in Patients with Impaired Hepatic Fun ctio n There are no adequate studtes m pat1ents w1th hver dysfunction and dosage recommendations have not been established In a small number of patients w1th mild-to-moderate hepat1c 1mpatrment gtven s1ngle dose of 5 mg, amlod1pme half-life has been prolonged. NORVASC should, therefore, be administered w1th cautton in these pat1ents and careful momtoring should be performed A lower start1ng dose may be requ1red (see DOSAGE ANO ADMINISTRATION).

Beta-blocker Withdrawal NORVASC g1ves no protection aga1nst the dangers of abrupt beta -blocker Withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta -blocker PRECAUTIONS Use in Patients w ith Congestive Heart Failure Although generally calciUm channel blockers should only be used w1th cautiOn m patients w1th heart fa1lure, 1t has been observed that NORVASC had no overall deletenous effect on surv1val and cardiovascular morb1d1ty m both short-term and long-term clin1cal tnals m these pat1ents Wh1le a s1gmficant proportiOn of the patients m these stud1es had a h1story of 1schem1c heart d1sease, ang1na or hypertension, the studies were not des1gned to evaluate the treatment of angina or hypertensiOn 1n patients w1th concom1tant heart failure .

Hypotension NORVASC (amlod1pme besylate) may occa sionally precipitate symptomatiC hypotens1on. Careful mon1tonng of blood pressure IS recommended, espec1ally m pat1ents w1th a h1story of cerebrova scular 1nsuff1c1ency, and those takmg med1cat1ons known to lower blood pressure Periph eral Ed ema Mild-to-moderate penpheral edema was the most common adverse event m the chmcal tnals (see ADVERSE REACTIONS) The inc1dence of penpheral edema was dose-dependent and ranged m frequency from 3 0 to 10.8% m 5 to 10 mg dose range Care should be taken to d1fferenttate thts penpheral edema from the effects of mcreas1ng left ventncular dysfunction Use in Pregnan cy Although amlodipine was not teratogentc 1n the rat and rabb1t some dihydropyridine compounds have been found to be teratogeniC in an1mals. ln rats, amlod1pme has been shown to prolong both the gestalten penod and the durat1on of labor Th ere 1s no chn1cal expenence w1th NORVASC 1n pregnant women. NORVASC should be used dunng pregnancy only 1f the potenual benef1t outwe1gh s the potent1al nsk to the mother and fetu s.

Nursing Mothers It IS not known whether amlod1p1ne IS excreted 1n uman m1lk Smce amlod1pme safety m newborns has not been established, NORVASC should not be g1ven to nursmg mothers Use in Children The use of NORVASC 1s not recommended 1n ch1ldren s1nce safety and efficacy have not been established 1n that population Use in Elderly In elderly patients (~65 years) clearance of amlod1p1ne IS decreased w1th a resultmg mcrease m AUC In chmcal tnals the mc1dence of adverse reactions m elderly patients wa s approximately 6% htgher than that of younger popula~on (<65 years) Adverse react1ons 1nclude edema, mu scle cramps and d1zzmess NORVASC should be used cautiOusly m elderly pa~ents Dosage adtu stmentiS adviSable (see DOSAGE AND ADMINISTRATION) Intera ction with Grapefruit Juice Publ1shed data 1nd1cate that thro ugh tnh1b1t10n of the cyto chrome P450 system, grapefruit jwce can mcrease plasma levels and augment pharmacodynamiC effe cts of some d1hydropyndtne calciUm channel blockers Followtng oral adm1mstrat1on of 10 mg amlod1p1ne to 20 male volunteers, pharmacokmet1cs of amlod1pme were s1m1lar when amlod1pine wa s admm1stered w1th and wtthout grapefrUit JUICe. Drug Interactions As w1lh all drugs, care should be exerc1sed when treating pat1ents w1th multiple med1cat10ns. D1hydropynd1ne calc1um channel blockers undergo b1otransformat1on by lhe cytochrome P450 system, mamly v1a CYP 3A4 ISoenzyme. Co admmlstrattOn of amlod1pme w1th other drugs wh1ch follow the same route of b1otransformauon may result in altered bioava1lability of amlod1p1ne or th ese drugs. Dosages of Similarly metabolized drugs, particularly those of low therapeutiC ratiO, and espectally 1n pattents w1th renal and/or hepatiC 1mpa1rment, may requ1re adJUStment when startmg or stoppmg concomnantly adm1mstered amlod1pme to ma1ntam opumum therapeutic blood levels.

Drugs known to be tnh1b1tors of the cytochrome P450 system 1nclude: azote anttfungals, cimet1d1ne, cyclosponne, erythromycin, qu1n1d1ne. terfenad1ne, warfartn.

Drugs known to be 1nducers of the cytochrome P450 system mclude phenobarbital. phenytOin, nlampm Drugs known to be b1otransformed v1a P450 1nclude benzod1azep1nes, fleca1n1de, 1m1pram1ne, propafenone, theophylltne Amlod1pme has a low (rate of f~rst - passl hepatiC clearan ce and consequent high bioava11ab11ity, and thus. may be expected to have a low potent1al for clm1cally relevant effects assoc1ated w1th elevation of amlod1pine plasma levels when used concomitantly w1th drugs that compete for or tnh1b1t the cytochrome P450 system Cimetidine, Warfarin, Cyclosporin, Digoxin: Pharmacok1net1 c tnteract10n studtes w1th amlod1p1ne 1n healthy volunteers have 1nd1cated: • ci metidine d1d not alter the pharmacok1net1c s of amlod1p1ne • amlodip1ne d1d not change wa rfarin-induced prothrombin re spon se t1me.

• amlod1pme does not s1gmf1cantly alterthe pharmacok1nettc s of cyclosporin.

• amlodiptne did not change serum digoxi n levels or digoxi n renal clearance.

Anta ci ds Concomitant admims1rat10n of Maalox"' (magne siUm hydrox1de and alummum hydrox1del had no effect on the dispoSi tion of a Single 5 mg dose of amlod1pme m 24 sub1ects Beta -blo ckers: When beta -adrenerg1c receptor blockmg drugs are administered concomitantly with NORVASC, patients should be carefully monitored smce blood pressure lowermg effect of beta -blockers may be augmented by amlod1pme 's reductiOn m pertpheral va scular re s1stan ce Sildenafil: A single 100 mg dose of Sildenafii(VIAGRAIIn sub1ects w1th essential hypertenSion had no effect on AUC 1 or Cmax of amlodipine When sildenafil(lOO mgl was co-admm1 stered w1th amlod1pme, 5 or 10 mg m hypertenSive pat1ents, the mean add1t10nal reduction of sup1ne blood pre ssure was 8 mm Hg systolic and 7 mm Hg diastolic Special Studies: Effect of NORVASC on other agents

Atorvastatin: In healthy volunteers, co-admm1stration of mult1ple 10 mg doses of NORVASC w1th 80 mg of atorvastaun resulted m no significant change in the AUCt, Cmax or Tmax of atorvastatm.

ADVE RSE REACTIONS NORVASC (amlodipme besylate) has been adminiStered to 1,7 14 patients (805 hypertenSive and 909 ang1na patients) 1n controlled chn1cal tnals (vs placebo alone and with active comparative agents). Most adverse rea ct1ons reported dunng therapy were of mlld·to·moderate seventy.

Hypertens ion In the 805 hypertenstve patients treated with NORVASC 1n controlled clin1cal tnals, adverse effects were reported m 29 9% of patJents and requ1red discontmuatJon of therapy due to side effects in 1.9% of panents. The most common adverse reac~ons 1n controlled clin1cal trials were: edema (8.9%), and headache (8.3%1. The following adverse reactions were reponed wrth an 1nc1dence of ~.5% 1n the controlled clin1cal tnals program (n=805): Card iovascular. edema (8.9%1. palpitations 12.0%1. tachycardia (0.7%). postural dizzi ne ss (0.5%). Skin and App en dages: pruritus (0 7%). Musculoskeletal: muscle cra mp s (0.5%). Central and Peripheral Nervous Syslem: headache (8 3%1. d1wness (3.0%), parestheSia (0.5%1. Autonom ic Nervous System: llushing (3.1%), 1ncreased sweating (0.9%1. dry mouth (0.7%) Psychiatric: somnolence (1.4%). Gastrointestinal: nausea 12.4%1. abdommal pa1n (1.1%), dyspepSia (0 6%). constipation (0.5%1. General : fat1gue (4.1%). pain (0.5%).

Angina In the controlled climcal trials m 909 ang1na patients treated wrth NORVASC. adverse effects were reported in 30 5% of patients and reqwred d1scontJnuatton of therapy due to s1de effects m 0.6% of patients. The most common adverse reactiOns reported 1n controlled climca l trials we re: edema (9.9%) and headache 17.8%). The followmg adverse reactions occurred at an 1nc1dence of ~.5% 1n the controlled clime aI trials program (n:;:909): Cardiovascular. edema (9 9%1. palp1tat10ns (2.0%). postural diwness (0.6%). Skin and Appendages: rash (1 .0%1. pruntus (0.8%). Musculoskeletal: muscle cramps (1.0%). Central and Peripheral Nervous System: headache (7.8%1. d1wness (4.5%), parestheSia (1.0%). hypoestheSia (0.9%1. Autonomic Nervous System: llushing (1 9%1. Psychiatric: somnolence II 2%), msomma (0 9%), nervousness (0.7%1 Gastrointestinal: nausea (4.2%), abdommal pain (2.2%). dyspepSia (I 4%1. d1arrhea (1 1%). flatulence II 0%). constipation (0.9%). Respiratory System: dyspnea (1.1%1.

Special Senses: viSion abnormal(l3%l, tmnllus (0.6%). General: fatigue (4.8%). pam (1.0%), asthema (1.0%1.

NORVASC has been evaluated for safety m about 11 ,000 patients with hypertension and ang1na.

The followtng events occurred 1n <1% but >0.1% of pat1ents m compa rative ch n1 cal tnal s (double·bhnd comparative vs placebo or acttve agents, n :;: 2,615) or under conditions of open tnals or marketing experience whe re a causal relat1onshtp IS uncertain.

Card iovascular: arrhythmia (includmg ventncula r ta chycardia and atrial fibrilation), bradycardia, hypotension, penpheral1 schem1a, syncope, tachycardia, postural d1zzmess. postural hypotension, vasc ulitiS Central and Peripheral Nervous System: hypoesthes1a, penpheral neuropathy, tremor, vert1go Ga strointestinal: anorexia, const1pat10n, dysphagia, vom1tmg, g1ngtval hyperplas1a. General: allergic reaction, asthenia'. back pam, hot flushes, mala1se, ngors, we1ght gam. Musculoskel etal System: arthralgia, arthrosis, myalg1a. Psych iatric: sexual dysfunctiOn (male' and female). 1nsomma, nervousness, depreSSIOn, abnormal dreams, anx1ety, depersonalization Respiratory Syste m: ep1stax1 s Skin and Appendages: prurJtus 1, rash erythematous, rash maculopapular, erythema multlforme. Special Senses: con1uncbvms, d1plop1a, eye pa1n, tmnftus. Urinary System: mtcturitlon frequency, m1cturruon d1sorder, noctuna. Auto nomic Nervous System: dry mouth. sweating 1ncreased. Metabolic and Nutritional: hyperglycemia, th1rst Hemopoietic: leucopen1a, purpura. thrombocytopenta. trhese events occurred 1n less than 1% m placebo-c ontrolled tnals, but the mc1dence of these s1 de effects was between 1% and 2% 1n all multiple dose stud1es The foUow1ng events occurred 1n 50 1% of patients. card1ac failure. sk1n discoloration, urticaria, sk1n dryness, Stevens-Johnson syndrome, alopecia, twttchtng, atax1a, hypertonia, migra1ne, apathy, amnes1a, gastnt1s, pancreatJtts, 1ncreased appetite, cough1ng, rh1n1t1s, parosm1a, taste pervers1on, and xerophthal mia Isolated cases of ang1oedema have been reported. Ang1oedema may be accompan1ed by breath1ng difficulty. In postmarketlng expenence, 1aund1ce and hepatic enzyme elevations (mostly consistent w1th cholestasis or hepatitis) ~Ys~~~~~s;~';;'~"{~:~~~lhNt~ ~efq~~~~g~~~~z;"on have been reported 1n assoc1at1on w1th use of amlod1pme.

Symptoms Overdosage can cau se exce ss1ve penpheral vasodilatiOn w1th marked and probably prolonged hypotensiOn and posSibly a reflex ta chycardia. In humans, expenen ce w1th overdosage of NORVASC (amlodipme besylateiiS limited.

When amlod1p1ne was 1ngested at doses of 105-250 mg some pat1ents remamed normotenstve w1th or Without gastnc lavage while another pattent expenenced hypotens1on (90/50 mmHg) wh1ch normalized following plasma expansion A pat1ent who took 70 mg of amlod1p1ne w1th benzod1azepme developed shock whtch was refractory to treatment and d1ed In a 19 month-old ch1ld who mgested 30 mg of amlod1pme (about 2 mg/kg) there was no ev1dence of hypotens1on but tachycardia (180 bpm) was observed Ipecac was admtn1stered 3.5 hrs after mgestion and on subsequent observatiOn (overn1ghtl no sequelae were noted.

Trea tment Chmcally s1gn1f1cant hypotension due to overdosage requtres act1ve cardiovascular support 1ncluding frequent mon1tonng of card1ac and respiratory functton, elevation of extremities, and anent1on to c1rculattng flu1d volume and unne output. A vasoconstn ctor (such as noreptnephnne) may be helpful in restonng vascular tone and blood pressure. provtded that there IS no contramdlcatton to 1ts use. As NORVASC IS h1ghly protem bound, hemod1alys1s 1s not hkely to be of benefit Intravenous calcium gluconate may be benefic1al1n reversmg the effects of calc1um cha nnel blockade. Clearance of amlod1p1ne IS prolonged m elderly patients and in patients ~~~~";i'Ea~~~li~~~~~~~~~~~~~ amlod1pme absorption IS slow, gastric lavage may be worthwhile m some cases.

Dosage should be 1nd1v1duahzed dependtng on pat1ent's tolerance and respons1veness . For both hypertension and ang1na.the recommended 1n1!1al dose of NORVASC (amlod1pine be sylatel is 5 mg once daily. II necessary, dose. can be 1ncreased after 1-2 weeks to a maxtmum dose of 10 mg once daily.

Use m th e Elderly or in Patients wi th Impaired Ren al Fun ction The recommended lntttal dose m patients over 65 years of age or patients w1th tmpatred renal functiOn is 5 mg once. dallY: If re qu~red , mcreasmg 1n the dose should be done gradually and with ca ution (see PRECAUTIONS).

Use m Pati ents w1th lmp a ~r e d Hepatic Fun ction Do sage requ1rem.ents have not been established 1n pat1ents w1th tmpa1red hepatiC funct1on . When NORVASC IS used m these pa!lents. the dosage should be carefully and gradually ad1usted dependmg on pa!lent's tolerance ~~~~~~of";:~,:S iower startmg dose ol 2 5 mg once da1ly should be conSide red (see WARNINGS ).

Avai lability NORVASC IS available as wh1te octagonal tablets contam1ng amlod1pme besylate equ1valent to 2.5, 5 and 10 mg amlo_dlpme p~r tabl!t The:espec t1ve tablet strengths are debossed on one tablet fa ce as " NRV 2.5", "NRV 5" and NRV 10 w1th Pllzer on the oppoSite lace. The 5 mg tablet IS scored Supplied'" wh1te pla stic (h1gh denSity ~~6~~~1:ne) bonle s oiiOO tablets lor each strength Also the 5 mg and 10 mg are supplied m bonles of 250 tablets Store at15-30°C. Protect from light.

REFERENCES: ANGINA I NORVASC* Product Monograph, Pfizer Canada Inc . Apnl2000.

2. Purcell H, Waller DG, Fox K. TherapeutiC focus: calc 1um antagomsts 10 ca rdiova sc ular disease Br J Clin Pract 1989;43(101:369-79 .

3. Salerno SM and Zug1be FT. Calc1um channel antagoniSts. What do lhe second generat1on agents have to offer? Postgrad Mod 1994;95(1(:181 -90 4. Deanfteld JE et al. Aml od1pme reduces transtent myocard1al1schemia 1n patients with coronary artery disease: double-blind wcad1an anti-ISChemia program m Europe (CAPE trial!. JAm Coli Cardiol1994·24(6)·1460-7 5 Ezekow1tz MD et al Amlod1pme m chrome stable ang1na: results of a multicenter double · blt~d crossover tnal Am Heart J 1996;129131:527 -35.

6. van Kesteren HAM. A double-blind, comparative study ol amlodipine vs diluazem CR 1n the treatment ol stable ang1na. Poster presentatiOn, XVIIth Congress of the Europ ean Society of Cardiology Amsterdam Augu st23 1995 REFERENCES: HYPERTENSION ' ' ' I. NORVASC• Product Monograph, Pf1zer Canada Inc., April2000.

2. Hernandez-Hernandez A et al. The effects of m1ssmg a dose of enalapril versus amlodip 1ne on ambulatory bl?od pre ssure. Blood Pressure Monllormg 1996,1:121-6.

3 Luscher TF and Cosent1n~ F The class1f1cat10n of ca lctum antagontsts and thetr selectiOn 1n the treatment of hypertenSion - a reappraiSal. Drugs 1998,55141:509-17.

4. leenen FHH, Fourney A, Tanner J. Pe r s1sten~e of anti -hyperten sive effect after interruptiOn of therapy with long-actmg lamlod1p1nel vs short-actmg (dilllazem) calcium -antagoniSt Clin and Investigative MediC me 1994,17(4) Suppl. B 70 5. Hoegholm A eta/. Comparative effects of amlod1pme and felod ipine ER on office and ambulatory blood pressure m pat1en1s w1th m1ld to moderate hypertension. J Human Hypertens 1995;9(SuppiiO):S25 -S 28.

6. Ostergren J eta/. Effect of amlod1pme versus felod1p1ne extended release on 24-hour ambulatory blood pressure m hypertenSion. Am J Hypertens 1998;11:690-6.

7. Neaton JO era/. Treat~ent of m1ld hypertension study. JAMA 1993;270161:713-24.

8 Perna GP er al. Tol erability of amlod1pme - A meta-analySis. Clin Drug Invest 1997;13(Supplll:163-68 © 2000 Pfizer Canada Inc. Kirkland, Qu ebec H9J 2M5

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ZIPIIDR* ATOR!tLlSZA77N CALCIUM EFFICACY TO REACH TARGET THE FIRST TIME

" LIPITOR' (atorvaslatln calc1um) 10 mg, 20 mg and 40 mg tablets THERAPEUTIC CLASSIFICATION: Lipid Metabolism Regulator ACTIONS AND CLINICAL PHARMACOLOGY LIPITOR (atO<Vastaon calc1um) 1s a synthetiC lipld·lowenng agent It IS a se~I!Ve . compeO!JVe 1nh1bltor of 3-hydroxy-3methylgllJiaril-coenzyme A (HMG-CoA) reductase Th1s enzyme catalyzes the convers1011 of HMG-CoA to mevalonate, whiCh is an early and rate-lim1t1ng step 1n the biOSynthesiS of ct'olesterOI LIPITOR lowers plasma chOiestE!IOI and lipoprotein levels by 1nh1b10ng HMG-CoA redoctase and ct'olesterOI synthesiS n the liVE!! and by 1ncreas1ng the numbel of hepatiC Low Dens1ty L1poprote1n (LDL) receptors on the cell-surtace for enhanced uptake and catabolism of Low Density Lipoprotein (LDL) LIPITOR redoces LDL -Cholesterol (LDL-C) and the number of LDL par1Jcles LIPITOR also reduces Very Low Dens1ty Lipoprotein-ChOlesterol (VLDL-C), serum triglycendes (TG) and Intermediate Density Upoprote1ns ~DL), as well as the number of apolipoprote1n B (apo B) containing paniCles, but increases H1gh Dens1ty Lipoprotein-ChOlesterol (HDL·Q. Elevated serum chOlesterol due to elevated LDL -C 1s a maJOf nsk factor for the development of cardKJoiascular d1sease Elevated plasma TG 1s also a nsk factor for cardiOVascular disease, pan1cu1ar1y 1f due to 1ncreased IDL, or aSSCICI3ted with decreased HDL-C or Increased LDL ·C Alorvastatln IS rap1dly absorbed a"er oral adm1mstratJon, maJOmum plasma concentrat1011s occur w1th1n 1 to 2 hOurs Atorvastatln tablets are 95% to 99% b!CI3vallable compared to SOlutiOns Mean d1stnbutJon of atO<VaSiatln IS approximately 381 lltres Atorvastat10 1s 298% bound to plasma prote1ns At0<Vastat1n 1S extenswely metabolized by cytochrome P-450 3A4 to onhO- and para-hydroxylated derivatives and to variOus beta· oxidatiOn prodllC!S Appro~mately 70% of Clrculallng 1nh1bltory act1v1ty for HMG Co-A reductase 1s attr1buted to actwe metabolites Atorvastatln and rts metabolites are elim1nated by b1llary excretiOn Less than 2% of a dose of atorvas1a11n 1s recovered 1n urine follow1ng oral adm1mstra11on. Mean plasma elimination half-hie of atorvastatin 1n humans 1s approximately 14 hOurs, but the half-lne of 1nh1bltory ac!Mty for HMG-CoA redoctase IS 20 to 30 hOurs due to the contr1but10n ollongerIIVed active meta~rtes INDICATIONS ANO CLINICAL USE UPITOR (atO<VaSiatln cak:1um) 1s IndiCated as an adjunct to diet, at least equiValent to the Amencan Hean ASSCIC1atJon (AHA) Step 1 d1et, for the redoct1011 of elevated total chOlesterol, (total-C), LDL-C, TG and apot1poprote1n B (apo B) 1n hyperi1pJCiem1C and dyslipJCiemiC condltJonS, whlen response to diet and othel nonpharmacologiCal measures alone has been Inadequate, 1nctLXl1ng • Pnmary hyperdlolestelolem~a ITYPie Ita), • Combined (m~ed) hyperlipidemia (TYPif lib), 1nciLXl1ng familial combined hypert1Pldernl3, regardless ol whlethel cholesterOl or tnglycelldes are the lipid abnormality ol concern, • Dysbetallpoprote1nem~a (TYPif IIQ, • HYPifrtnglycendem~a (TYPif IV), • Fam1llal hypercholesterOlemia (hOmozygous arid heterOlYQOliS) For hOmozygous lamll131 hyperchOlesterolemia, LIPIIOR shOuld be used as an adjunct to treatments SllCh as LDL apheresis, or as monotherapy ~ soch treatments are not available.

In clinical tnals, LIPITOR (1 0 to 80 mg/day) s1gnnicantly 1mproved lipid profiles in pallents wrth a w1de vanety of hypert1pldem1C and dysllpldemiC cond1110ns. In 2 dose-response stud1es 1n m1ldly to moderately hYPifrlipidemic patients (FrednckSon Types lla and lib), LIPIIOR redl!Ced the levels ol total chOlesterol (29-45%), LDL-C (39-60%), apo B (32-50%), TG (19-37%), and 1ncreased hi!Jh deriSIIy l1poprote1n ct'olesterol (HDL-C) levels (5·9%) Comparable responses were achieVed 1n pallents ~th heterozygous familial hyperchOlesterolemia, non-familial forms of hyperchOlesterolemia, comb1ned hypertipldem~a, 1nciLXl1ng familial combined hyperi1Pldem1a and pallents ~th non-insulin dependent diabetes mellitus. In paoents ~ hypertri!Jiycendemla (TYPif IV), LIPITOR (10 to 80 mg da11y) redl!Ced IG (25 ·56%) and LDL-C levels (23 - 40%) ChytomiCroriS, whiCh character~e Types I and V, have not been measured 1n cliniCal stLXl1es 1n patients w1th hi!Jh IG levels (> t 1 mmoVL) In an op~en-label studly 1n pallents ~ dysbetalipoprote1nem1a (TYPif IIQ, LIPITOR (1 0 to 80 mg da11y) redl!Ced lotai-C (40-57%), TG (40·56%) and IDL·C + VLDL-C levels (34-58%) In an open label studly 1n patients w1th hOmozygous fam11ial hyperchOlesterolemia (FH) LIPITOR (10 to 80 mg da1ly) redl!Ced mean LDL -C levels (22%) In a p1lot study, LIPITOR 80 mg/day shOwed a mean LDL·C lowering ol 30% lor patients not on plasmapheresiS and of 31% for paOents whO continued plasmapheresiS A mean LDL -C lowenng ol 35% was Olbserved 1n receptor defectiVe patients and of 19% 1n receptor negative patients (see PHARMACOLOGY, Clinical SOLXl1es) For more derails on effiCaiCY results by pre-del1ned classifiCatiOn and poo~ data by FrednckSon types, see PHARMACOLOGY. CliniCal StLXl1es PriOr to 1nrt1<1nng therapy ~th LIPITOR, secondary causes shOuld be excluded for elevat1011s 1n plasma hp1d leve~ (e g poorly controlled diabetes mellitUS, hypothyroidism. nephrooc syndrome. dysprote1nem18S, obstructiVe liver disease, and alcohOhsm), and a hpld prof1le pertormed to measure total ct'olesterOI, LDL·C, HDL·C, and TG For pat1ents w1th TG <4 52 mmoVL (<400 mg/dl), LDL-C can be estllllated us1ng the fol~ng equat1on LDL-C (mmoVL) = totai-C • j(O 37 x (TG) + HDL·C)J LDL-C (mg/dL) = totai-C • ((0 2 x (TG) + HDL·C)J' For paOents w1th TG levels >4 52 mmoVL (>400 mg/dl), thiS equatiOn IS less accurate and LDL·C concentratiOns shOuld be measured directly or by ultracentrdugatiOn The Atorvastalln Versus Revascutanzat1011 Treatments (AVERT) study exam1ned the effect of 1ntens1vre hpid lowenng 1n paoonts with slable coronary anery d1sease and LDL -C at least 3 0 mmoVL 1n patients rei erred for pelCutaneous transfum1nal coronary angiQPiasty (PICA) Pahents WE!Ie randornlsed lor t 8 monthS to UPITOR 80 mg dally or to PICA ~ usual mediCal care whiCh could 1nclude hpid me1a~1sm regulators. The results of the AVERT study shOuld be consldlered as exploratory s1nce several hmllatiOils may affect 1ts desiQn and conduct In the mediCal-treated group w1th LIPITOR there was a trend for a redl!Ced 1ncidence ol 1schem1C events and lime to hrst ISChemiC event The results also suggest that 1ntenswe treatrnlent to target LDL·C levels w1th LIPIIOR IS additive and complementary to angiQPiaSty and would beneht pahents referred lor t111s procedure (see SELECTED BIBLIOGRAPHY) CONTRA/NO/CATIONS Hypersens,llvlly to any component ol th1s med~A~tion Acllve liVer d1sease or unexplained persistent elevat1ons of serum transam1nases exceeding 3 times the upper limit of normal (see WARNINGS) Pregnancy and lactatiOn (see PRECAUTIONS) WARNINGS nn c inetic Interaction The use of HMG-CoA redllCtase 1nh1bltors has been aSSCICiated ~th severe myopathy, 1nciLXl1ng rllabdomyolySIS, whiCh may be more lr~t when they are co-adm1mstered w1th drugs that 1nhlblt the cytochrome P-450 ~me systE!In. Atorvastat1n IS meta~~ed by cytochrome P-450 ISOform 3A4 and as SllCh may Interact ~th agents that 1nh1blt thiS enzyme. (See WARNINGS, Muscle effects and PRECAUTIONS. Drug lnteractiOilS and Cytochrome P-450- med~ated lnteractiOOIS) Hepatic Effects In clln~A~ I tr~als, perSIStent Increases 1n serum transam1nases greater than three 11mes the upper l1m1t ol normal occurred 1n <1% of patients whO received LIPITOR When the dosage ol LIPITOR was redoced, or when drug treatment was 1nterrupted or d1scontmued, serum transam1nase levels returned to pretreatment levels. The 1ncreases were generally not associated with jaundice or other clln1cal s1gns or symptoms. Most patients continued treatment w1th a redl!Ced dose of UPITOR without chn~A~I sequelae.

Liyer function tests shoukJ be pertormed belore the IO!ItatiOO ollreatrneot and oenodtcallv thereafter. Special aneniiOn should be paid to patients whO develop elevated serum transammase levels, and 1n these pat1ents measurements shOuld be repeated promptly and tlleO pertormed more frequently If Increases in alanine aminotransferase (All) or aspartate aminotransferase (ASl) show evidence of progression, particularly If they rise to greater than 3 Urnes the upper limn of nonnat and are persistent, the dosage should be reduced or the drug diKOnlinued.

Fnelfewakl. WT el al Cllfl Chern 1972. 18(6) 489·502

LIPITOR should be used w1th caution in patients who consume subslanll31 quantities of alcohOl aml/or have a past history of l~er disease. Active liver d1sease or unexpla1ned transaminase elevat1ons are contra1nd1cat1ons to the use ol LIPITOR; 1f soch a cond1tion shOuld develop durtng therapy, the drug should be d1sconunued.

Muscle Effects Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine pho~phokinase !CPK) values to greater than ten t1mes the upper limrt of normal, shOuld be cons1dered 1n any patient wrth diffuse myalg 1a, muscle tendemleSS or weakness, and/or marf<ed elevation of CPK Patients shOuld be advised to repon promptly unexplained muscle pam, tenderness or weakness, panK:ularly 1f accompanied by mala1se or fever. LIPIIOR therapy shOuld be d1scon11nued d marf<edly elevated CPK levels occur or myopathy IS d1agnc1Sed or suspected The nsk of myopathy and rllabdomyolySIS dunng treatment w1th HMG-CoA redoclase inhibitors .'s increased wrth concurrent adm~nlstratJon of cyclosponn, fibnc acid deriVatives, erythromycin, clarnhr~myc1n, mac1n (niCOtiniC acid), azote antdungals or nefazodone As there 1s no experience to date w1th the use of UPITOR gwen concurrently w1th these drugs, w1th the excepllon of pharmacoklnetc stud1es conducted in healthy subjects with erythromycin and clanthromycln, the benefns and risks of soch comb1ned tllerapy shOuld be carefully considered (see PRECAUTIONS, PharmacokmetiC lnteractJon Stud1es and Potenll31 Drug InteractionS). RhabdomyolySIS has been reponed in very rare cases w1th LIPITOR (see PRECAUTIONS, Drug InteractiOns).

RhabdomyolySIS with renal dysfunctiOn secondary to m1C1Qiob10una has also been reponed with HMG-CoA reductase 1nh1bltors UPITOR therapy shOuld be temporanly ~held or d1scon11nued 1n any pat1ent w1th an acute senous condi!JOn suggestiVe of a myopathy or hav1ng a nsk factor pred1spos1ng to the development of renal fa11ure secondary to rllabclomyotys 1s (soch as severe acute 1nfect1on. hypotensoo, majOr surgery, trauma, severe metaboliC, endocnne and e~trolyte disorders, and uncontrolled Seizures) PRECAUTIONS General The effects of atorvastaUn-induced changes in lipoprotein levels, including reduction of serum cholesterol on cardiovascular morbidity or mortality or total mortality have not been established.

Before 1nstrtu11ng therapy w1th UPITOR (atorvastatm calc1um), an anempt should be made to control elevated serum lipoprotein levels w1th appropriate d1et, exerc1se, and we1ght reductiOn 1n overwe1ght patients. and to treat other underly1ng mediA!I problems (see INDICATIONS AND CLINICAL USE) Pat~ents shOuld be advised to 1nform subsequent physiCians ol the pnor use of LIPIIOR or any othelllpid-lowenng agents Effect on the Lens Current long-term data from cliniCal tnals do not indiCate an adverse effect of atO<VaStalln on the human lens Effect on Ubiquinone tCoQ,ollevels SigndiCant decreases 1n Clrculallng ubiQUinone levels 1n pallents treated with atO<VaSia!ln and other statlns have been observed The cliniCal s1gnn1Car1Ce of a potenll31 long-term slabn·lndllCed defiCiency of ub1Qu1none has not been establiShed n has been reponed that a decrease 1n myc~Card~al ub1Qu1none levels could lead to 1mpaired card1ac lunct10111n patients With bordert1ne congestiVe hean failure (see SELECTED BIBLIOGRAPHY).

Effect on lipoprotein tal In some patients, tile beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concom ~t increase in Lp(a) levels. Until lurther experience is obtained, n is suggested, where feasible, that meaiSurements of serum Lp(a) be followed up in patients placed on atO<Vaslatin therapy (see SELECTED BIBLIOGRAPHY).

Hypersensitivity An apparent hypersensrtiVIIy syndrome has been reponed ~ other HMG·CoA redoclase 1nh1bltors whiCh has Included 1 or more of the fOIIow1ng features anaphylaxis, ari!JIOedE!Ina, lupus erythematous-like syndrom~e, polymyalg~a meumatiAI. vasculiiiS, purpura, thrombocytopenia, leukoplen~a, hemolyOC anem~a , posrtlve ANA, ESR 1ncrease, eos1noph111a, arthniiS, arthralgia, un!Cana, asthenia, photosens11Mty, fever, ch1lls, llush1ng, malaise, dysprlea, tooc epldlermal necrOiys1s, erythema mult1forme. 1nclud1ng SleveniS·Johnson syndrome. Although to date hypersensrtMty syndrome has not been descnbed as SllCh, LIPITOR shOuld be diSCOntinued If hYPifrsensiiiVIty is SuspleCted Use in Pregnancy LIPITOR is contraindicated during pregnancy (see CONTRAINDICATIONS).

Atherosclerosis Is a chronc process and diSCOntinuatiOn ol lipid-lowering drugs during pregnancy shOuld have llnte 1mpact on the outcome ol long-term tllerapy of pnmary hYPifrchOiesterolemia. Cholesterol and other products of cholesterol b1osynthes1s are essential components for fetal development ~ncludlng synthesis ol steroids and cell membranes). S1nce HMG-CoA redoctase 1nh1bltors decrease chOlesterol synthesis and possibly the synthes1s of other biOlogiCally achve substances deriVed from chOlesterol, they may cause harm to the fetus when adm1n1stered to pregnant women There are no data on the use of UPITOR dunng pregnancy LIPIIOR shOuld be adm1mstered to women of ch11dbeanng age only when such pat~ents are highly unlikely to concewe and have been 1nlormed of the potential hazards. ~the pat1ent becomes pregnant while taking UPIIOR. the drug shOuld be d1scont10ued and the pat~ent apprised of the potential riSk to the fetus

Nursing Mothers In rats, m1lk concentrat1011s ol atorvasta!ln are Similar to thOse 1n plasma ~ 1s not known whether this drug is excreted In human m1lk Because of the potential lor adverse reactiOns 1n nurs1ng 1nfants, women taking UPITOR shOuld not breast-feed (see CONTRAINDICAnONS) Pediatric Use Treatment exper~ence 1n a ped~atnc populat1011 IS limited to doses ol UPITOR up to 80 mg/day lor 1 year 10 8 patients w1th hOmozygous lam111a1 hYPifrChOiesterolem~a No chn~A~I or biochemiCal aboonmalities were reponed 1n these pat~ents G ri . s Treatment expenence 1n adu~s 70 years or oldler (N=221) w1th doses of UPIIOR up to 80 mg/day has demonstrated that the salety and effectiVeness ol atorvasta!ln 1n thiS populaoon was s,m,lar to that ol patients <70 years ol age.

PharmacokJne!lc evaluatiOn of atO<Vaslalln 1n sub1ects over the age ol 65 years IndiCates an 1ncreased AUG. As a precautionary measure. the lowest dose should be administered 10111ally (see PHARMACOLOGY, Human PharmacokJnetlcs; SELECTED BIBLIOGRAPHY).

Renal Insufficiency Plasma concentrations and LDL -C lowenng eff1cacy ol LIPITOR was shown to be similar in patients w1th moderate renal insuffciency compared w1th patients w1th normal renal function. However, s1nce several cases of rhabclomyolysls have been reponed 1n patients w1th a h1story of renal 1nsuff~lency of unknown severity, as a precautionary measure and pend1ng lunher expenence 1n renal diSease, the lowest dose (10 mg/day) of UPITOR shOuld be used 10 these patients S.mllar precaut1011s apply 1n pat~ents ~Ill severe renal InsuffiCiency jcreat1mne clearance <30 mUm1n (<0.5 mUsec)J, the lowest dosage shOuld be used and Implemented cautiOUSly (see WARNINGS, Muscle Effects; PRECAUTIONS, Drug lnteractiOils) Refer also to DOSAGE AND ADMINISTRATION End rin F ction HMG-CoA redoclase lnh,bltors 1ntertere ~th ct'olestE!IOI synthesiS and as soch mi!Jht theoretically blunt adrenal and/or Qorladal steroid prodllCOon CliniCal SOLXlleS With atorvastatln and other HMG-CoA redoctase Inhibitors have suggested that these agents do not redl!Ce plasma con1sol concentrat1011 or 1mpalr adrenal reserve and do not redllCe basal plasma testosterone concentrat1011 However, the effects of HMG-CoA reductase Inhibitors on male fenihty have not been studied in adequate numbels ol patients n1e effects, 11 any, on U1e pituitary-gonadal ruos in premenopausal women are unknown Patients treated with atorvastalin who develop clinical ev1dence ol endocrine dysfunction should be evaluated appropriately. Caution shOuld be exerc1sed il an HMG-CoA reductase 1nh1bitor or other agent used to lower chOlesterol levels 1s adm1mstered to patients receiv1ng other drugs (e.g. ketoconazole, SPironolactone or cimet1d1ne) that may decrease the levels of endogenous steroid hormones. annacokin ti f te tio Studies and te tlal D I t ra Pharmacoklnet1c 1nteract10n studies condocted ~th drugs 1n healthy subtects may not detect the poss1b1hty of a potential drug 1nteract10n 1n some patients due to dlffe~ences 1n underlying d1seases and use of concom1tant mediCatiOns (see also Genatnc Lise, Renal InsuffiCiency, Patients wrth Sevele HyperchOieste~olem~a) .

Concomitant Therapy with Other Lipid Metabolism Regulators: Combined drug therapy should be approached W1th caut1on as 1nformat10n from controlled studies Is llm1ted Bite Acid Sequestrants: Patl8!1ts Wlth m11d to moderate tMJercOO!estero!em!a LDL -C reductJon was greater l'ollen UPfTOR t 0 mg and colesbpol20 g were coadmtniS!ered (-45%) than l'ollen erther drug was admn11stered alone (-35% for UPfTOR and -22% for~ Pal!ents W!lh severe hyoerchoklstero!emla LDL-C reductiOn was s1m1lar (-53%) l'ollen UPfTOR 40 mg and colesllpol20 g were coadmlnlstered when compared to that w1th UPfTOR 80 mg alone. Plasma concentratkm of atorvastalln was lower (appr@mately 26%) when UPfTOR 40 mg plus coleshpol20 g were coadmlmstered compared with UPfTOR 40 mg alone.

However, the combtnat10n drug therapy was klss effect1ve in lowenng the tngi)'cendes than UPfTOR monotherapy 1n both types of hypercholesterolemiC patients (see PHARMACOLOGY, Climcal Studies) When LIPITOR is used concurrently with colestipol or any other resin, an Interval of at least two hours should be maintained between the two drugs, s1nce the absorption of UPITOR may be impaired by the restn.

Fibric Acid Derivatives (Gemfibrozil, Fenofibrate, Bezafibrate) and Niacin (Nicotinic Acid): Although there IS no experience wtlh the use of LIPITOR giVen concurrently w1th f1brc acid denvattves and niac~n, the beneftts and nsks of such combined therapy should be carefully considered. The risk of myopathy during treatment wtth other drugs in lhis class Is Increased wtth concurrent administration (see WARNINGS, Muscle Effects) Coumarin Anticoagulants: LIPITOR had no clinically stgntfteant effect on prothrombtn lime when admtmstered to pattents recetVtng chroniC wartann therapy (see SELECTED BIBLIOGRAPHY).

Digoxin: In healthy subjects, dtgoxln pharmacokinetiCS at steady-state were not slgmflcantly altered by coadmmtration of dtg@n 0 25 mg and UPITOR 10 mg datly However, diQOxin steady-state concentratiOns tncreased approximately 20% followlng coadmmtratJon of dtgaXJn 0 25 mg and UPITOR 80 mg datly (see Human PharmacokinetiCS) Pattents taking dtgox1n should be mon~ored appropnately Antihypertensive agents (amlodipine): In clinteal studtes, UPfTOR was used concomttantly wtth anbhypertenSIVe agents wtthout evidence to date of clinteally stgnntcant adverse tnteractiOns. In healthy subjects, atorvastalln pharrnacoklnel!cs were not altered by the coadmtntstratiOn of UPITOR 80 mg and amlodtptne 10 mg at steady state (see Human PharmacokinetiCS) Oral Contraceptives and Honmone Replacement Therapy: Coadmtmstral!on of UPfTOR wtth an oral contraceptive, containing 1 mg norethtndrone and 35~g ethinyl estradiol, increased plasma concentrations (AUG revels) of norethindrone and ethinyl estradiol by approxtmately 30% and 20%, respectively These tncreases should be considered l'ollen selecl!ng an oral contraceptiVe In clincal studtes, UPfTOR was used concomitantly W1th estrogen replacement therapy wrthout evdence to date of chnteally signnicant adverse Interactions Antacids: Admimstrat1an of aluminum and magnes1um based antacids, such as Maalo TC Suspension. wtth UPITOR decreased plasma concentratJons of UPfTOR by approx1mately 35% LDL -C reductiOn was not altered but the trtglycerldelowenng effect of UPITOR may be affected Cimetidine: AdmtmstratiOn of ctmettdlne with UPITOR dtd not a~er plasma concentratiOns or LDL-Clowenng effteacy of UPfTOR, however, the triglycende-iowenng effect of UPfTOR was reduced from 34% to 26% Cytochrome P-450-mediated Interactions: Atorvastahn IS metabolized by the cytochron11e P-450 tsoenzyme, GYP 3A4 Erythromyctn, a GYP 3A4 tnhtMor, 1ncreased atorvastabn plasma levels by 40% CoadmlniStratoo of GYP 3A4 nhlbrtors. such as grapefrutt ;ux:e, some macrolide anttbiOI!cs 0e erythromycin, clanthrornyctn), Immunosuppressants (cyclosponne), azole antifungal agents 0e =nazare. ketoconazole), or the antidepressant, nefazcldone, may have the potential to 1ncrease plasma concentrabons of HMG-CoA reductase tnhtbrtors, 1ncludtng UPfTOR (see SELECTED BIBLIOGRAPHY). CautiOn should thus be exerciSed Wlth concomitant use of these agents (see WARNINGS, PharrnacokJneoc lnteractoos, Muscle Effects: PRECAUTlONS, Renallnsuffictency and Endocnne funcbon, DOSAGE AND ADMINISTRATlON, SELECTED BIBLIOGRAPHY) In healthy subjects, coadm1n1strat10n of max1mum doses of both atorvastalln (80 mg) and tertenad1ne (120 mg), a GYP 3A4 substrate, was shown to produce a modest increase tn tertenadtne AUG. The OTc tnlerval remained unchanged However. stnce an tnteractiOn between these two drugs cannot be excluded in patients w1th pred1Spos1ng factors for arrhythmia, (e.g pre-extshng prolonged OT tnterval, severe coronary artery d1sease, hypokalemta). caut1on should be exercised when these agents are coadministered (see WARNINGS, Pharmacok~netic Interactions: DOSAGE AND ADMINISTRATlON) Antipyrine: Ant1pynne was used as a non-specifiC model for drugs metabolized by the mterosomal hepatiC enzyme system (cytochrome P-450 system) UPfTOR had no effect on the pharmacokinetiCS of anttpynne, thus 1nteract10ns with other drugs metaboliZed vl3 the same cytochrome 1sozymes are not expected Macrolide Antibiotics (azithromycin, clarithromycin, erythromycin): In hea~y adults, coadmtmstrabon of UPfTOR (1 0 mg 00) and azrthromyc1n (500 mg 00) did not stgndteantly alter the plasma concentrations of atorvastatln However, coadmtniStratJon of atorvastabn (10 mg 00) Wlth eryttvornyc1n (500 mg OlD) or clanthrornyc1n (500 mg BID), whiCh are both GYP 3A4 tnhtbnors, 1ncreased plasma concentratiOns of atorvasta!ln apprmomately 40% and 80%, respectiVely (see WARNINGS, Muscle Effects, Human Pharmacoklnebcs) Patients with Severe Hyoercholesterolemia: Htgher drug dosages (eO mg/day) requlfed tor some pabents w1th severe hyperchoklsterolem13 Oncludtng famtll31 hyperchoklsterolemi<l) are assocl<lted w1th 1ncreased plasma levels of atorvastalln Caution should be exercised in such patients who are also severely renally impaired, elderly, or are concomitantly being administered digoxin or CYP JA4 inhiMors (see WARNINGS, Pharmacokinetic Interactions, Muscle Effects; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).

Dru llaborato Te Interactions UPfTOR may elevate serum transam1nase and CPK levels (from skeletal muscle). In the d1fferent1al dl3gnosts of chest patn in a patient on therapy W1th UPfTOR, cardtac and noncardiac fracttons of these enzymes should be determtned.

ADVERSE REACTIONS UPfTOR ts generally well-tolerated Adverse reactJons have usually been mild and transtent In controlled cilnteal studtes (placebo-controlled and actiVe-controlled comparatiVe studtes w1th other lipld-lowenng agents) 1nvolvtng 2502 patients, <2% of patients were dtscontinued due to adverse expenences attributable Ia UPITOR. Of these 2502 patients, 1721 were treated for at least 6 m10nths and 1253 for 1 year or m10re Adverse expenences occumng at an tncldence ;;, t% tn patients partiCipating tn placebo-controlled chnteal studtes of UPfTOR and reponed to be possibly, probably or definrtely drug related are shown tn Table t below TABLE 1. Associated Adverse Events Reported in >1% of Patients in Placebo-Controlled Clinical Trials Placebo % (n 270) LIPITOR % (n 11 22 ) GASTROINTESTINAL Constipation Diarrhea Dyspepsta Flatulence Nausea NERVOUS SYSTEM Headache MISCELLANEOUS <I Patn 1 Myalgta <1 Asthenta The followtng addtbonal adverse events were reported tn chnteal tnals: not all events liSted below have been assocl3ted wtth a causal relatiOOShtp to UPITOR therapy Muscle cramps, myosrtts, myopathy, paresthesi<l, penpheral neuropathy, pancreatnts, hepatrtts, cholestahc ;aundtce. anorex1a, vorntttng, alopeci<l, prurrtus. rash, tmpotence. hypergl)'cemta, and hypoglycemia Post-mar1<elm exoenence Very rare reports severe myopathy with or W1thout rtlabdornyolysiS (see WARNINGS, Muscle EHects PRECAUTlONS Renallnsuff1CI8!1cy and Drug lnteractiOOS) Isolated reports thrornbocytopenta, arthralgl3 and allergiC reactJo~ 1nciud1ng urix:ana, angiOneurotiC edema, anaphylaxiS and bullous rashes Oncludtng erytherne mu~forme, Stevens-Johnson syndrome and tox1c eptderrnal necrolysts). These may have no causal relationship to atorvastatln Ophthalrnologtc observations see PRECAUTlONS. Laboratory Tests: Increases tn serum transam1nase levels have been noted tn clinteal trl<lls (see WARNINGS).

(AHA) Step 1 dtet] before rece1v1ng UPITOR. and should conttnue on thts dtet dunng treatment wtth LIPITOR If approprl3te. a program of wetght control and physteal exerciSe should be tmplemented Pnmarv Hypercholesterolemta and Comb1ned lMIXedl Hvoe!hptdem!a lnclu<ftna Famtilal Combined Hyped1p!dem~a The recommenlded dose of LIPfTOR IS 10 mg once a day The majarrty of pat1ents achteve and matntatn target cholesterol levels W1th UPfTOR 10 mg/day A stgntfteant therapeutiC response ts evdent W1lh1n two weeks, and the maxtmum response iS usually ach1eved w1th1n two to four weeks The response ts ma1nta1ned dunng chroniC therapy Oases can be giVen at any lime of the day, Wlth or W1thout food. and should preferably be gtVen tn the eventng Oases should be lndtv!dualized accordtng to baseline LDL-C and/or TG levels, the deslfed LDL-C and/or TG target (see the OetectJon and Management of Hypercholesteroleml3, Working Group on Hyperchoklsteroleml<l and other Oysltpldemtas [Canada] and/or the US Nalional Choklsterol EducatiOn Program [NCEP]). the goal of therapy and the pabent's response Adjustments of dosage, n necessary, should be made at tntervals of four weeks or more The recommended dcse range for most pattents ts 10 to 40 mg/day.The maxtmum dose Is eo mg/day, whiCh may be reqUired tn a mtnorrty of patients (see secllon below).

Lipid levels should be monitored periodically and, if necessary, the dose of LIPITOR adjusted based on target lipid levels recommended by guidelines.

The lollowtng reductions in total cholesterol and LDL-C revels have been observed tn two dcse-response studtes, and may serve as a guide to treatment of patients w1th m1ld to moderate hypercholesterolemta.

TABLE 2. Dose-Response In Patients With Mild to Moderate Hypercholesterolemia (Mean Percent Change from Baseline)' UPITOR Dose (mg/day) Lipid Parameter 40 eo 10 20 (N-23) (N-21) (N 22) (N-20) -29

-33

-37

-45

-39

-43

-50

-60

'Results are pooled from 2 dose-response stud1es.

'Mean baseline values.

Severe Dvslioidemias: In palients with severe dyslipldemi<ls, 1nclud1ng homozygous and heterozygous familtal hypercholesterolemia and dysbetahpoprote1nemia (Type IIQ, htgher dosages (up to eo mg/day) may be requlfed (see WARNINGS, Pharmacoklnette lnteracttons, Muscle Effects: PRECAUTlONS, Drug InteractiOns) Concomitant Therapy See PRECAUTIONS, Drug lnteracbons.

Dosage in Patients With Renal Insufficiency See PRECAUTIONS PHARMACEI/TICAL INFORMATION Drug Substance Proper Name Atorvastalin calctum Chemteal Name [R-(R" .R1]-2-(4-fluorophenyQ-B, o-dihydroxy-5-(1-methylethyQ-3-phenyl-4-[(phenytamtno) cartooyl]1!:J-pyrrole-1-heptanoc acid, calc1um salt (2. 1) tr1hydrate Emplfteal Formula (C33H, FN 20,)2Ca• 3H20 Molecular Wetght 1209.42 Structural Formula

Descnpt10n. Atorvastat1n calc1um 1s a whtte to off-white crystalline powder that IS practiCally tnsoluble tn aqueous solutiOns of pH 4 and below Atorvastalln calc1um 1s very sl~htly soluble 1n dtstilled water. pH 7 4 phosphate buffer and acetonttnle. slightly soluble tn ethanol, and freely soluble tn methanol Tablet Com osition: Each tablet contatns either 10 mg, 20 mg or 40 mg atorvastalln as the actiVe 1ngred1ent Each tablet also contatns the followtng non-medtetnaltngred,ents calc1um cartooate. candeillla wax. croscarmellose sodtum. hydroxypropyl cellulose, lactose miOnohydrate. magnestum stearate, miCrocrystalline cellulose, hydroxypropy methylcellulose, polyethylene glycol, talC, tltantum diOXIde, polysorbate eO and Stmethicone emulSIOn Stability and Storage Recommendations: Store at controlled room temperature 15 to 25'C AVAILABILITY OF DOSAGE FORMS LIPITOR (atorvastalln calcium) is avatlable tn dcsage strengths of 10 mg, 20 mg and 40 mg atorvastalln per tablet 10 mg:Whrte, elliptteal, film-coated tablet, coded "10" on one side and "PO 155" on the other Ava1lable tn bonkls of 90 tablets 20 mg: Wh1te, elhpllcal, film-coated tablet, coded "20" on one side and "PO 156" on the other Avatlable tn bottles of 90 tablets 40 mg: White, elhptteal, film-coated tablet. coded "40" on one side and "PO 157" on the other Available tn bottles of 90tablets References: t Smtth et at Cost ofTreallng to a Mod1fied European AtherosclerosiS Soc1ety LDL-C Target- Companson of Atorvastalin w1th Fluvastalln, Pravastattn and S1mvas1alin Ctm Drug Invest 1999 Mar,17(3).185-193 2. UPfTOR (atorvastattn calctum) Product Monograph, Pf~er Canada Inc .. June 2000 3. Benohn1 S, B1tollo Bon G. Campbell LM, Famter M, Langan J, Mahla G. Pauctullo P. Slrtor1 C. Egros F, Fayyad A, Nawrocki J The effteacy and safety of atorvastattn compared to pravastalln in patients w1th hypercholesterolemta. Arheroscterosts 1997,t 30 191-197 4. Dan A, Jerums G. Nicholson G, d'Emden M, Hamilton-Cra1g I, Tall1s G. Best J. West M, Sullivan D. Braes P. Black D Amulticenter, dcuble-bhnd, 1-year study cornpanng safety and eff1cacy ol atorvastalln versus stmvastalin 1n patl8!1ts wtth hypercholestero!emta Am J Card/01 1997,e039-44 5. OntariO Drug Beneftt Formulary, Apnl1999 For a copy of the Product Monograph or full Prescnb1ng InformatiOn, please contact·

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SYMPTOMS AND TREATMENT OF OVERDOSAGE There 15 no specnc treatment for atorvastatinoverdosage. Should an overdose _occur, the patient should be treated symptomatteally and supportive mteasures tnstrtuted as requtred Due to extenSIVe drug btndtng to plasma prote~ns, hemodl<liysiS IS not expected to stgMteantly enhance atorvastahn clearance

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OOSAGE AND ADMINISTRATION Pattents should be placed on a standard cholesterol-lowenng dtet [at least equivalent to the Amencan Heart Assocl3tton

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Long-acting BP control for mild-tomoderate hypertensives

Impressive tolerability after 4 years

• effectively control s BP at target levels for a full 24 hours and beyond 1•2t

• compared with antihypertensives from four different classes, more NORVASC* patients remained on therapy after 4 yea rsn

• intrinsically long half-life mai ntai ns plasma leve ls to redu ce BP up to 24 hours after a missed dose3•4t

• only 3% withdrawal rate among 12,83 1 patients in 16 clinical studies8

• shown to be more effective than felodipine at the sa me dose5•6

Th e most common adverse reactions incl ude edema (8.9%) and headache (8.3 %) .'

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t NORVASC* should always be prescribed as once-da il y therapy. ~ NORVASC* 5-10 mg o.d. (n= 103) versus fe lodipine ER 5-10 mg o.d. (n= l 03 ) after 8 weeks (p=0.036) 82% of NORVASC* patients reached target DBP of ::::90 mmHg versus 69% for fe lod ipine. :1: NORVASC* (n= 11 4), 83% of NORVASC* pati ents remained on therapy after 48 months.

NORVASC* is indica ted in the treatment of mild-to-moderate essential hypertension when diuretics or beta-blockers are unsuitable.

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Consu lt prescribing information for important safety information and drug interactions.

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