University of Toronto Medical Journal, December 1999

92 Pages·1999·9.8 MB·English

by  Medical Society of the University of Toronto

UTMJ
University of Toronto Medical Journal
_Volume 77, Number 1/December, 1999_
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4 Editorial 28 NEWS AND VIEWS
5 Preface 55 MORNING REPORT
6 Leptin and Obesity: Is it All in the Mind? 60 CLINICOPATHOLOGICAL CORRELATION
Ehud Ur, Barbara Morash, Cindee Leopold, and Michael
Wilkinson
66 QUICK DIAGNOSIS
12 Acoustic Neuroma: Etiology, Presentation, and Treatment
74 TECHNOLOGY REVIEWS
Paul Kongkham
18 Antiglucocorticoid Treatment in Depression 76 BOOK REVIEWS
Michael Lewis
22 The Basics of Physician Compensation
Khristinn K. Leitch and Paul M. Walker
Canada's Oldest Medical Undergraduate
jrj Student-Run Publication
The University of Toronto Medical Journal (UTMJ)
&
Marks its 77th Year of Publication with the Announcement of the
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All review and original articles received for publication in the 77th UTMJ
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UTMJ
University of Toronto Medical Journal
Volume 77, Number 1/December, 1999
A s t it d e n t - r u n s c i e it t ifi c p u b 1 i c a t i o n . E s t a b l i s It e d in 1923
Table of Contents
4 Editorial Morning Report
55 Chest Pain: An Unusual Suspect
5 Preface Sharon J. Kular, Jordana B. Sacks, and Wayne L. Gold
Neuroendocrinology Clinicopathological Correlation
6 Leptin and Obesity: Is it All in the Mind? 60 Edema Everywhere
Ehud Ur, Barbara Morash, Cindee Leopold, and Jennifer L. Shin and Eni J. Keszthelyi
Michael Wilkinson
Quick Diagnosis
Neurosurgery 66 Surgery Rounds
72 Acoustic Neuroma: Etiology, Presentation, and Patrick S. Tawadros and Aric Storck
Treatment
Paul Kongkham Technology Reviews
74 Ultrasound Biomicroscopy: A Promising Candidate
Psychiatry for Monitoring Tumour Response to Therapy in
18 Antiglucocorticoid Treatment in Depression Cancer Patients
Michael Lewis Christopher Tam and Lana Tan
Health Policy Book Reviews
22 The Basics of Physician Compensation 76 Previously published in the UTMJ
Khristinn K. Leitch and Paul M. Walker
78 Nephrology
News and Views Reviewed by Dan Perri
28 In the Literature
Yvonne Chan and Stephen C. Juvet 80 Osteoporosis
Reviewed by Grant Chen
32 Prolific Scientist Profiles: Gairdner Awards
40th Anniversary: A Canadian Tradition 82 Bates' Guide to Physical Examination and
Susan Quesnel History Taking/Textbook of Physical Diagnosis,
History and Examination
36 Reversal of Fortune Reviewed by Stephanie Wiesenthal and Amy S.M. Tam
Allan K. Grill
84 Honour Due:
40 Law and Ethics in Medicine: The Story of Dr. Leonora Howard King
The Doctor's Duty of Confidentiality: Reviewed by Michael Klompas
Separating the Rule from the Exceptions
Bernard M. Dickens
44 Back to Basics:
Interpreting the Electrocardiogram
Stephen C. Juvet, Yvonne Chan and Robert W. Wald
52 Evidence-Based Medicine: A Primer on Medical Front cover illustration b\ Tedd\ Cameron
Division of Biomedical ( ommunications.
Statistics - P Values and Confidence Intervals
Department of Surgery, I’niversiry <>t Toronto.
Evette Weil
volume 77, number 1, December 1999 1
UTMJ
University of Toronto Medical Journal
Volume 77, Number 1/December, 1999
A s t u d e n t - r a n s c i e n t ifi c p u b I i c a t i on. E s t a b I i s bed in 192 3
UTMJ Staff
Editors-In-Chief Junior News and Views Editors Biomedical Communications
Raymo nd H. Kim, B.Sc. (MD/PhD2) Murray ).S. Beuerlein, M.Sc. (0T3) Eleanor Andrew, B.A., M.Sc.BMC (0T0)
Peter K. Stodand, M.Sc. (0T2) Martin C. Chang, Ph.D. (0T3) Teddy Cameron, B.F.A.(hon), M.Sc.BMC (0T0)
Roula Drossis, B.Sc.(hon), M.Sc.BMC (0T0)
Quick Diagnosis Editors
Senior Associate Editors Aric Storck, B.Soc.Sc. (0T2) Editorial Board
Omar Ghaffar, M.Sc. (0T2) Patrick S. Tawadros, B.Sc. (0T2) Manohar Bance, M.D.
Matthew Hebb, Ph.D. (0T2) Department of Otolaryngology
CPC Editors University of Toronto
Junior Associate Editors Eni ). Keszthelyi, M.Sc. (0T2)
Patricia Brubaker, Ph.D.
Michael A. Levesque, Ph.D. (0T3) Jennifer L. Shin, B.Sc. (0T2)
Department of Physiology
Kenji S. Miyata, Ph.D. (0T3)
University of Toronto
Andrea E. Waddell, B.Sc. (0T3) Morning Report Editors
Sharon ). kular, B.Sc. (0T2)
George Pink, Ph.D.
Managing Editors (ordana B. Sacks, B.Sc. (0T2)
Department of Health Administration
Alan W.L. Fung, B.Sc. (0T3)
University of Toronto
Mohammed Ali Warsi, M.Sc. (0T3) Senior Technology Review Editor
George Zogopoulos, Ph.D. (0T2) Victor X.D. Yang, M.A.Sc. (MD/PhD2) Robert Levitan, M.D.
Department of Psychiatry
Treasurer Junior Technology Review Editor University of Toronto
Jamie Newman, B.A. (0T2) Anand Govindarajan, B.Sc. (0T3)
Michael Angel, Ph.D. (0T0)
Yael Friedman, M.Sc. (0T3)
Art Director Book Review Editor
David Kaplan, M.Sc. (0T3)
Roula Drossis, B.Sc. (MSc. BMC, 0T0) Amy S.M. Tam, B.Sc. (0T2)
Andrew Schumacher, Ph.D. (0T1)
Senior News and Views Editors Chief Copy Editors
Yvonne Chan, M.Sc. (0T2) Tracy A. Chin, B.ArtsSc. (0T2) Faculty Advisory Board
Chair, Allan S. Detsky, M.D., Ph.D
Stephen C. Juvet, B.Sc. (0T2) Blaise Clarkson, M.A. (0T2)
Jay S. Keystone, M.D.
C. David Naylor, M.D., D.Phil.
News and Views Series Editors Copy Editors
Sharon E. Straus, M.D.
Incidence-Based Medicine: Philippe L. Bedard, B.ArtsSc. (0T3)
Evette Weil, B.A. (0T2) Christopher A.K.Y. Chong, B.Sc. (0T3)
Prolific Scientist Profile: Andrew S.P. Lim, B.Sc. (0T3) TESETTTING
Type & Graphics
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IMiv and Ethics in Medicine: Webmaster
Anna A. kulidjian, M.Sc. (0T2) Edward C.W. Leung, B.Sc. (0T2)
University of Toronto Medical Journal
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volume 77, number 1, December 1999 3
1 Editorial
A Letter to Our Patrons
Perusing through back-issues of the I "IM/, one comes across Create a living laboratory for medical scholarship in and
the most important page of the Journal, the list of patrons. The around the Journal, to provide firsthand experience in all
names on this page mean much more to us than the generous aspects of biomedical editing, review, and publishing that is
monetary contributions made by these individuals and institu¬ managed and upheld completely by students in the Faculty
tions. Rather, this page serves to remind us that our patrons of Medicine.
are keenly aware of the value and importance of maintaining
Develop a useful resource for teachers; to provide a forum
Canada’s oldest student-run publication. How can we be so
in which teacher and student can present their ideas and,
sure that our patrons feel this wav? Because, for the most part,
in doing so, promote a unique learning experience.
the names on this page have not changed. This support,
although greatly appreciated, has been mostly quiet in nature.
We, and our staff, strongly believe that no other medical jour¬
In order to understand why this was the case, we decided to
nal can match this vision with the same standard of excellence
meet many of you this past summer.
that the Journal has consistently showcased for the past 76 years.
Many of our patrons were very receptive to our scheduled
This 77th year of publication promises to build upon die Journal's
meetings. Praise, tributes, and compliments on the success of
legacy. Towards this end, we have assembled the largest staff in
the Journal were made. It was through our one-on-one meet¬
the Journal’s history and have developed a number of new series,
ings, however, that we discovered that the mandates of the
reflecting the interests of current medical students. Furthermore,
Journal might have been misinterpreted over the past years.
in an attempt to increase our readership and make communica¬
“Why should 1 subscribe to the lITMJ when there is a pletho¬
tion with the Journal easier, we have completely revamped our
ra of journals out there?” Or, “Why should I encourage my
website at www.utmj.org. Lastly, in order to encourage submis¬
students/residents to submit an article when it can go some¬
sions, we have established the l1TMJ Editors’ $1000 Award for
where else?” were common questions we were asked.
dae most deserving submission of the 77th volume.
Our answer to these questions required some introspection and
Finally, after completing our tour of meetings this past summer,
examination of the founding editor’s. Dr. Benjamin johnstone
it became clear to us that a number of patrons subscribe to the
(2T4), two goals: 1) to encourage writing and preparing papers
Journal as a means of supporting their alma mater. While we are
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indebted to this support, we challenge you as a conscientious
recent advances appearing in the current literature. Back in
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1922, it might have been a realistic goal to make the Journal a
a loud supporter of the l Al//; encourage your colleagues and
central, one-stop resource to read about recent innovations in
peers to subscribe; encourage your students to submit; and be
science and medicine. As the end of this century draws to a
proud that you are supporting a unique vehicle - a distinguished
close, we would challenge any medical journal to uphold this
University of Toronto tradition - that gives students the oppor¬
goal! Thus, we felt it was time to amend the founding goals of
tunity to synthesize and share their views with fellow students,
the Journal, while upholding their spirit. Our vision for the
colleagues, teachers, mentors, and clinicians.
l TMJ 1999-2000:
In keeping with Johnstone’s first objective, the Journal
Raymond H. Kim
serves to provide students with a foray into the world of
Peter k. Stotland
biomedical publishing; to provide a forum for original arti¬
Editors-in-Chief
cles, review articles, case reports, and general interest arti¬
cles about the science and humanities of medicine.
4 University of Toronto Medical Journal
Preface
Preface from the Editors
As this is the last issue of the century, we found it Review and Book Reviews offer insightful
fitdng to focus on the last scientific frontier: the opinions for the reader.
neurosciences. Ur et al. have thoroughly examined
the literature and ask: "Is leptin all in the mind?"; We encourage comments and queries about any¬
Kongkham writes a thorough account about the thing we publish. Inquiries may be directed to the
diagnosis and treatment of acoustic neuromas; and Editors at [email protected] or visit us
Lewis examines the role of antiglucocorticoid online at www.utmj.org.
treatment in depression.
Questions surrounding public policy, ethics, and We hope you enjoy Volume 77, Number 1.
the use of clinical trials are relevant in medicine
today. Compensation and physician benefits are
likely to be an emerging issue of discussion within
the next century and Leitch and Walker give
R.H.K. and P.K.S.
an informative overview of this subject. Dickens
discusses the time-honoured duty of physician-
patient confidentiality' in the new series, Law,
Ethics in Medicine, and Weil writes an overview of
basic statistical indices employed in all clinical tri¬
als in the new series, Evidence-Based Medicine.
We are proud to continue our well-received
clinical sections: Clinicopathological Correlation
presents findings of edema, Morning Report is a
pain in the chest, and Quick Diagnosis takes
us into the O.R. In addition, we start a new
series, Back to Basics, and this issue reviews
the electrocardiogram. As always, Technology
volume 77, number 1, December 1999 5
Ncurc )endocrin( >]< )gy
Leptin and Obesity: Is it All in the Mind?
Ehud Ur, M B., B S \ , Barbara Morash, Ph.D. § , Clndee Leopold, B.Sc. § , and Michael Wilkinson, Ph.D.*4
Abstract However, its origins arc poorly understood. Heritability has
Obesity, defined as an increase in body fat, is a growing been estimated to be around 30%,’ and a number of rodent
problem in W estern societies. In Canada over 30% of the models exist for genetic obesity. The genes responsible for
population is obese. ()besity is associated with increases several of these genotypes have been cloned4-5-6 and a novel
in hypertension (high blood pressure), type 2 diabetes, physiological system based on the hormone leptin, and its
hyperlipidemia (high cholesterol), ischemic heart disease, receptors, has been identified. Human homologues arc known
and a number of other conditions. Factors that regulate for some of these mutations.7-8
food intake and energy expenditure are poorly under¬
stood. Leptin is a novel protein, produced by fat cells, Since its discovery in 1994, studies on leptin have generated
that acts on the brain in order to reduce food intake and over 2000 Medline citations and several reviews of this
increase energy expenditure. Until recently, leptin was expanding literature arc already available.7-,(l-11 The native pep¬
thought to be produced only by fat cells. We have dis¬ tide and several analogues arc undergoing phase II therapeutic
covered that the brain, and in particular the hypothala¬ efficacy trials in subjects with obesity and type 2 diabetes.12
mus, which is the part of the brain that controls appetite Leptin is secreted by adipocytes in response to feeding13 and
and weight, makes leptin itself. Most human obesity circulates as both free and bound lorms.14- 15 The free, pre¬
appears to involve the brain ignoring the high levels of sumably bioactive, form enters the brain and binds to specif¬
leptin in the blood, and we believe that this comes about ic receptors (OB-R; see below). Leptin plays a crucial role in
because the key regulator in the hypothalamus is locally- the regulation of body fat levels by co-ordinating metabolism,
derived leptin. ()ur findings may have important impli¬ feeding behaviour, energy balance and neuroendocrine
cations tor an understanding of the causes of obesity and response via actions mainly in the hypothalamus. Metabolic
may help improve treatments for this metabolic disease. factors which influence leptin secretion include adiposity,16
fasting1’ and caloric loading.18 There is a diurnal rhythm of
Introduction plasma leptin levels entrained to meal timing.19
Obesity is a growing problem in North America and in
W estern Europe. In Canada over 30% of the population are There are also important hormonal regulatory influences on
obese.1 Obesity' is associated with increases in hypertension, leptin production. Estradiol regulates leptin gene expression in
type 2 diabetes, hyperlipidemia, ischemic heart disease and a rat adipocytes.20-21 Serum leptin is reduced by testosterone in
number of other conditions.2 Obesity is a consequence of an women whereas estrogen increases it in men and women.22-23
increase in caloric intake compared to energy expenditure. Glucocorticoids stimulate leptin synthesis peripherally24 but
may contribute to leptin resistance and obesity centrally.25-26-27
Several recent reviews provide further details of leptin gene
* Departments <>t Obstetrics and Gynaecology, JPhvsiologv and Biophysics, and regulation.28-12-29
Division ot Kndocrinology, I'acuity of Medicine, Dalhousie University, Halifax,
Nova Scotia.
6 University of Toronto Medical Journal
Brain Leptin Receptors gested that leptin circulates in the form of a leptin-binding pro¬
The effects of leptin in the hypothalamus are mediated by spe¬ tein complex which is even less likely to enter the brain.14
cific receptors as well as a complex neurochemical signalling Indeed in rhesus monkeys, leptin reduces food intake only
system that includes melanocortins, cocaine and amphetamine- when administered centrally, suggesting that increases in circu¬
related transcript (CART), corticotropin releasing factor (CRF), lating leptin within the physiological range may not be suffi¬
galanin, neurotensin, neuropeptide Y (NPY), hypocrctins/orex- cient to acutely regulate food intake.34 33 The counter argument,
ins and steroid hormones A1-31-32- ki, as that a specific transport system for leptin may be located in
33-34
microvessels and choroid plexus,41-3 remains unproven.
Leptin receptors exist in the form of at least five splice vari¬
ants; a single long form with cell signaling characteristics and Nevertheless, even if transport of leptin into the brain does
four shorter forms, which may serve to transport the peptide exist, it does not explain why peripheral injection of high spe¬
across the blood-brain barrier (BBB)36- 3738 or as a circulating cific activity [l23I]- leptin fails to label brain regions outside the
binding protein.383 The rodent brain has been mapped with hypothalamus.49 It is conceivable that the labelling of leptin
specific probes for the long (OB-RA and short (OB-R ) with [l2T] might compromise binding and transport of the lep¬
mRNA splice variants.39-40-9 OB-R,, which is absent in the tin molecule, though this is unlikely in view of the binding
obese db/cib mouse, mediates the satiety effects of leptin experiments reported by Uotani et al?'A Radioiodinated leptin
whereas OB-R is localized to the choroid plexus and brain labelled both long-and short-form (OB-Rh and OB-R , respec¬
microvessels. The fa/fa (Zucker) rat mutation occurs in the tively) receptors stably expressed in Chinese hamster ovary
extracellular domain of the OB-R and results in defective cells. These receptors had k values in the nanomolar range
transport from the periphery.41 A soluble human leptin recep¬ and were able to internalize [l2A|-leptin via coated pits, con¬
tor has also been described.42 firming that P3I] - leptin binds normally to its cognate recep¬
tor. The authors also observed that the short form receptors
Elmquist et al. report an extensive distribution of OB-Rh (OB-R) were more efficient in mediating rapid internalization
mRNA in the rat hypothalamus.9 Other labelled sites, includ¬ and degradation of the [l2:il] leptin than were the long form
ing the thalamus, cerebellum and substantia nigra, imply that (OB-p receptors. The data suggest that OB-R located in
leptin may act on sensory7 and motor systems perhaps unrelat¬ brain micro vessels do not transport intact leptin into the brain,
ed to body weight regulation. Studies in the human brain also but rather ensure that the hormone is degraded before this
suggest a wide distribution of OB-R immunoreactivity, includ¬ occurs. Such an ‘enzymatic’ or ‘metabolic’ blood-brain barrier
ing hypothalamus, cerebellum and the nucleus basalis of has been postulated for neuroactive peptides.56- 57 OB-R in
Meynert.43 This latter observation is intriguing, given that microvessels could also be related to leptin’s action as an
patients with Alzheimer’s disease have low body weight despite angiogenic factor.38-59
adequate food intake.44
In summary, the available evidence supports our hypothesis
Why are Leptin Receptors Widely Distributed in Brain? that peripherally-derived leptin is not the ligand for those lep¬
Most studies on the eifects of leptin in the brain have been per¬ tin receptors located in extra-hypothalamic brain regions such
formed in the hypothalamus. Some, but not all, of the hypo¬ as cerebellum and central cortex. This leads to the additional hypoth¬
thalamus is located outside of the blood brain barrier (BBB). esis that leptin, or a leptin-like molecule, biosynthesiged in the brain, is
Since leptin is a large peptide (16 kDa) it is unlikely to pene¬ the ligand for non-hypothalamic OB-li. An analogous case has been
trate the BBB and it has been argued that leptin enters the brain made for a putative role for insulin in brain.6"-61 However, in
parenchyma via a specific transport system located in microves-
sels,45-37 or is transported into the intrathecal space.46 However,
attempts to localize peripherally injected [l2T] — leptin failed to
show central labelling except at the choroid plexus and the arcu¬
ate-median eminence region of the hypothalamus.47-48-49 These
data indicate that OB-R located at sites such as hippocampus,
substantia nigra and cerebellum, are unlikely to be accessible to
circulating leptin. This is consistent with experiments that
showed entry7 of large molecules into brain parenchyma only
(recurs at the circumventricular regions such as median emi¬
Leptin
nence.3(l- 31 Even at these sites peptides may well breach the
BBB, but penetrate only a short distance into the brain paren- Figure 1. Detection of leptin mRNA in neuronal and periph¬
cy7hma (i.e. from median eminence to arcuate nucleus). A sim¬ eral tissues by RT-PCR. Total RNA was reverse transcribed and PCR-
amplified (40 cycles) using primers spanning exons 2 and 3 of the leptin
ilar conclusion was reached by Herkcnham et al?1 in a detailed
cDNA A product of the expected size (217bp) was detected in various rat
study of c-fos expression following peripheral injection of 1L-1
tissues, as shown. No PCR product was detected in liver (lane 2) and in the
(see also Elmquist et al?'). In addition, Sinha et al have sug¬ ‘no RT' tubes in lane 8 (modified from Morash et al.67)
volume 77, number 1, December 1999 7
the case of leptin the hypothesis is of far greater significance brain, we used reverse transcriptase polymerase chain reaction
since the hypothalamus is considered to lx- the principal target (RT-PCR) with intron spanning primers directed at a 217 bp
tor leptin ot peripheral (adipoevte) origin. region spanning exons 2 and 3 ot the leptin transcript. A prod¬
uct of the expected size (217 bp) was detected in the follow¬
Does the Brain Express the Leptin Gene? ing rat tissues: tat, cerebral cortex, cerebellum, hypothalamus,
The cloning ot the leptin gene4 stimulated intensive studies on pineal gland, C6 glioblastoma cells, whole pituitary gland, pos
the signaling pathway that links adipose tissue and the hypo¬ terior pituitary and anterior pituitary (Figure 1), indicating that
thalamus. In til recently it was accepted that adipose tissue rep¬ these tissues express leptin mRNA. Leptin mRNA was unde¬
resented the onl\ source of leptin. However there is now ev i¬ tectable in liver and in hippocampus under the same condi¬
dence tor leptin gene expression in placenta, gastric epithelium, tions. Sequence analysis of the 217 bp amplicon from fat and
skeletal muscle, breast tissue and adrenal gland/’2-6:5-64-6S-M’ hypothalamus confirmed 100% homology with the corre¬
To establish whether leptin mRNA was expressed in the rat sponding region of the published sequence for leptin cDNA.
These observations differ from those previously reported in
A
E
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if
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Figure 2. Immunohistochemical detection of leptin in mouse brain. Coronal sections from fixed brain of adult female mice stained for lep¬
tin immunoreactivity using a polyclonal antibody (Santa Cruz; Y20, I 5000). Panel (A) shows leptln-ir in ependymal cells and tanycytes of the arcuate-medi¬
an eminence region, panel (B) illustrates leptm-immunoreactivity (leptm-ir) in laminae 2/3 of the ventral retrospleniai cortex; panel (C) shows multipolar cells
located in the suprachiasmatic nucleus (SCN), panel (D) illustrates dense nuclear staining in granule cells of dentate gyrus; panel (E) indicates tanycyte-hke
staining in dorsal hypothalamus. Control sections in panels a) - d) show that Immunolabeling was abolished in all regions by pre-adsorbmg the primary anti¬
body with the immunizing peptide.
* = third ventricle Magnifications are x 312, A, C, D, E and a, c, d; x 125, B and b.
University of Toronto Medical Journal