Volume 1 number 1 - December 2008 - CRCHUM

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Vol. 1 - No 1 - December 2008
CRCHUM — Research Centre - Hospital Centre of the University of Montreal
Early treatment: the key to curing Hepatitis C
Without antiviral treatment, the Hepatitis C virus (HCV) reproduces itself in the liver
and causes damage that can lead to fibrosis, cirrhosis, and cancer of the liver. However,
if treatment is administered three to six months following HCV infection, the percentage
of cured patients goes from 50% to 80%. Indeed, the results of a study conducted by
Naglaa Shoukry in collaboration with Dr Julie Bruneau, researchers with the CRCHUM,
reveals that early treatment restores patients’ immune response. This has opened new
therapeutic horizons for maximizing treatment effectiveness.
By Louise Vadnais and Richard Ashby
Naglaa Shoukry is Director of the Viral Hepatitis
Research Group at the CRCHUM. Her research
centres on the immune response of patients infected with HCV. Specifically, she concentrates on
assessing the effects of treatment administered
during the initial acute phase of the infection. To
do so, however, requires that she be able to work
with patients in the early stages of infection, and
that is precisely where things get difficult. “The
immune response is difficult to study in humans,”
Shoukry notes, “largely because it is not easy to
make an early diagnosis since most people display
no signs of the disease during the first six months,
and for that reason do not visit a doctor.”
HCV is transmitted uniquely through blood exchanges. Many people with HCV contract the
virus through occupational or other forms of
exposure (nurses, doctors, ambulance workers,
police, contaminated tattoo needles, etc.). However, over 60% of people contract it through the
exchange of contaminated needles. Enter Dr Julie
Bruneau, a physician and clinical researcher at
the CRCHUM’s Saint-Luc Hospital site, whose
research focuses on disease transmission via
intravenous drug use. Dr Bruneau monitors a cohort of intravenous drug users who are regularly
tested for HCV, among other viruses. Given their
overlapping research interests, it was only natural that the two researchers would cross paths
and pave the way to a groundbreaking study.
A productive collaboration
Given the fact that it is unusual to have access to
a clinical cohort of human beings of this kind, a
fruitful collaborative effort was born. “Since the
disease does not manifest itself in the early
acute phase, treatment strategies at this stage
are almost impossible to evaluate.” But with Dr
Bruneau’s cohort, we succeeded in studying the
disease during its early acute phase and obtained results with direct implications for both
the patients and the therapeutic approach,”
notes Shoukry.
Their discussions led to the development of a
study of the immune response to HCV funded
by the Canadian Institutes of Health Research
and a study focused on the long-term followup of patients with HCV funded by the Fonds
de recherche en santé du Québec. Their applications were well received since the risk of
HCV infection is significant both in Canada and
abroad. Indeed, in Egypt, Shoukry’s country of
origin, 25% of the general population is infected with HCV.
From weak to strong
Twenty-five percent of patients completely
eliminate the virus because of their strong immune response. Among other patients, notes
Shoukry, this response is weak: “among the
latter group, some patients refused treatment
and because they were unable to recover, the
infection moved to the chronic phase.” Among
those who accepted treatment, the researchers
observed the immune response during the
acute phase of HCV, both during and after
treatment. These patients displayed a reconstitution of their immune response that was
identical to patients who spontaneously eliminate the virus. “At first, we didn’t understand
why early treatment was more effective,” says
Shoukry, “however, when we compared the
Naglaa Shoukry
data from the three groups, we saw that the reconstitution of the immune response was the key
element. The sooner treatment begins, the better
the immune response reconstitution and the
weaker the chance of relapse.” Moreover, Shoukry
predicts, when patients develop a good immune
response, they are more likely to avoid any future
infections by the virus, without treatment.
The advantages of early treatment
Since many intravenous drug users (IDUs) continue to exchange needles and therefore leave
themselves open to further exposure to HCV,
Shoukry plans to evaluate the rate of re-infection in
this cohort over the next two to three years. It is
her hope that this early treatment strategy will
increase resistance to subsequent infections and,
equally important, decrease the risk of infecting
other people, IDUs and the general population. General Practice in Crisis
The Dr. Welby myth made popular through the 1960s television series has fallen upon hard times.
Defining exactly what a family doctor is in 2008 has become the source of a major identity crisis.
A case study directed by Dr Marie-Dominique Beaulieu, a CRCHUM researcher and herself a general
practitioner, draws an incontestable and at times stark portrait of front-line services in Canada: family
medicine is in urgent need of modernization. Published recently in Social Science & Medicine
(July 2008), the study takes an in-depth look at the situation and offers some ideas for the future.
By Louise Vadnais
Since the late 1990s, fewer medical school graduates are opting for family medicine practice.
As a result, patients everywhere are hard pressed
to find a family doctor and there is a shortage of
general practitioners in the health system. As Dr
Beaulieu, the Dr Sadok Besrour Family Medicine
Research Chair, notes “Whether we look at things
from within or from the outside, we can see that
the profession is under pressure. Everyone argues
for access to good front-line services and all agree
that family doctors are a key factor in ensuring
the health of the population. However, in reality,
medical students favour specialization.”
cians trained initially as generalists but whose
practice is limited because they have to divide
their time between the hospital, the emergency
department, or to maintaining home care services. However, there is still a consensus that
we need family physicians. “If this true,” argues
Beaulieu, “then we should stop specializing
them. If the system creates incentives in this
regard, then there is little point in trying to find
solutions.”
Modernizing general practice
If mini-specialization constitutes a real threat,
does the solution lie with generalists who are
good at everything and are always present and
The first of its kind in Canada, this study is based
available to help patients? This challenge has
on interviews with roughly 100 participants, fadiscouraged many young physicians who wind
mily doctors, specialists and residents at the end
up turning towards mini-specialization. “It
of their training period, and selected from four
amounts to trying to square the circle,” notes
faculties of medicine across Canada, including
Beaulieu, “which explains the urgent need to
Quebec. Two of these faculties are geared tomodernize family medicine practice. Since
wards family medicine and two focus on scien2001-02, Quebec responded by creating innotific research. However, the results of the study
vative Family Medical Groups (FMG). FMGs
reveal no differences in perception, regardless of
make it possible to integrate nurse practionplace or faculty mission. All agree that there are
ners into private medical practices that typisignificant issues in the field of family medicine
cally only include physicians. Moreover, they
and that steps need to be taken.
improve administrative support - administrative technician, secretariat, and
A double standard
IT support - to facilitate links with
the rest of the health network. In
While all concerned are unanimous in
short, it is an organizational stratheir belief in the importance of “true
All agree that
tegy that reduces the isolation of
generalists,” that is, that physicians
there are significant
family doctors. Beaulieu argues
are able to manage the majority of
issues in the field
that “It is important continue in
patients’ health problems, as Beaulieu
of family medicine
this vein and to work in greater
notes, the reality of the matter is
and that steps
collaboration with nurses, to insomewhat different: “Family doctors
crease the remuneration of family
need to be taken.
are proud of what they do, but they
doctors and to improve relations
are well aware that family medicine is
between family doctors and speless valued than specialization. Young
cialists.”
specialists feel abandoned.” As well,
family doctors from the previous generation find
it hard to abandon their role as omniscient phyRethinking the issues
sicians and to share their patient responsibilities
For Dr Beaulieu, there is no way around these
with other health professionals.
conclusions. It is now up to the various stakeFaculties of medicine themselves send a conflicholders–medical faculties, specialist federating message to their students: it’s good to be a
tions, the health system itself and all involved
generalist, but being a specialist is even better.
in trying to change it - to take matters in hand:
The result; only 36% of young physicians do what
“Our hope is that our results, which are based
they were trained to do. Indeed, there are an inon an analytic grid form by the sociology of
creasing number of “super-specialized” physiprofessions, will enable health sector actors
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and decision makers to have a better grasp of the
issues. It is important for them to step back and
think in new ways to with a view to opening up
new pathways for solutions.” To help them do so,
the results of this study have been transmitted to
faculties of medicine across Canada and to other
organizations implicated in shaping the professional health system. december 2 0 0 8
Dre Marie-Dominique Beaulieu
Understanding and treating Type 2 Diabetes
Marc Prentki, a CRCHUM researcher, is Director of the Montreal Diabetes Research Centre.
Much of his research focuses on the etiology of Type 2 diabetes (T2D). He was the first researcher
to study “glucolipotoxicity,” a notion that led to major changes in our understanding of T2D and
that opened up new lines of investigation and the development of innovative treatments.
By Sylvie Gervais
T2D: a disease of epidemic
proportions
TD2 occurs when glycaemia (glucose levels in
the blood) exceeds acceptable levels due to insufficient insulin secretion by pancreatic beta
cells. It generally occurs among people 40 and
over and in particular, in those who are noticeably overweight because of poor eating habits
and lack of exercise. It can reduce life expectancy
by four to five years. The World Health Organization estimates that the number of diabetics in
the world will double by 2025. As such, TD2 is
on its way to taking on epidemic proportions and
to becoming one of the main causes of disability
and mortality.
What is glucolipotoxicity?
Glucolipotoxicity was initially a theoretical suggestion published by Prentki and his group in
Perspectives in Diabetes in 1996. As he puts it, “We
postulated that if glucose levels in the blood are a
bit too high and that circulating lipids are a bit too
numerous, a synergy is created that is very toxic
for body tissues, more so than for each surplus
considered individually.”
The main impact of this change of view, he emPrentki pursued his studies using pre-diabetic
phasizes, has been to focus research on various
and diabetic animals. Subsequent research has
molecules, enzymes or proteins related to the
revealed that glucose inhibits the degradation
metabolism of lipids as therapeutic targets in the
of lipids in beta cells and favours their storage.
treatment of T2D. Thus, most of the new drugs
“In the absence of glucose, lipids are burned
that have appeared in recent years act simultanewhereas in their presence, they join with the
ously on lipids and glucose. As such, they improve
glucose to create glycerolipids (esterified fat)
control over glycaemia by fostering the action of
that lodge in beta cells inducing their dysfuncinsulin and they modify lipid metabolism, thereby
tion. Prentki adds “this plays an instrumental
fostering their degradation and limit
role in how glucolipotoxicity works
their storage–with a concomitant reand therefore its role in T2D initiaduction of glucolipotoxicity.
tion and progression.”
Since then,
New approaches to
studying and treating T2D
“Before the introduction of the
concept of glucolipotoxicity,” says
Prentki, “T2D was considered a disease largely related to the metabolism of glucose. Since then, scientists have come to understand that
lipid metabolism plays a major and
probably causal role in the onset of
the disease.”
scientists have
come to understand that lipid
metabolism
plays a major
and probably
causal role in
the onset of
the disease.
Prentki’s current research in this area
is focused on understanding the mechanisms in beta cells that could be
inhibited or activated to protect them
against glucolipotoxicity. This line of
investigation is closely followed by
pharmaceutical companies interested
in developing new, more effective
drugs to combat T2D. The article caught the attention of researchers
throughout the world, who have since focused
on this phenomenon in various pathologies, including diabetes. For his part, Prentki wanted to
know whether glucolipotoxicity could explain the
progressive deterioration of pancreatic beta cells
at the origin of T2D. In light of the fact that glucolipotoxicity results from overeating, this phenomenon has become quite significant.
The hypothesis confirmed
and new avenues opened
To confirm their hypothesis, Prentki and his group
conducted in vitro research on isolated beta cells.
“We incubated them with different concentrations
of glucose, both in the presence and absence of
lipids,” explains Prentki. The results confirmed that
a simultaneous excess of glucose and lipids was
highly toxic for them. These excesses change how
they operate: insulin production is decreased,
their regeneration is inhibited, and the process
can lead to their death. Because of this research,
the study of glucolipotoxicity became a subject of
choice for both Prentki and other researchers in
the quest to understand the causes of T2D.
Marc Prentki
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What are the cancer risks associated
with our environment and lifestyle?
For the past 30 years, Jack Siemiatycki’s research has focussed on this question. His work has led
to the creation of databases able to shed light on the possible relationships between many cancers
and several hundred carcinogens present in our surroundings and related to our lifestyles.
us to definitively conclude whether a given agent
is carcinogenic or not. Why? “Because,” as
Siemiatycki points out, “in epidemiological research, a single research project, mine or anyone
else’s for that matter, cannot by itself determine
the extent to which a given agent is carcinogenic
or not.” The decision to identify a substance as
carcinogenic or not can be only be made “when
the same results are reproduced by other researchers from various countries.”
By Sylvie Gervais
“In almost every instance of
cancer,” explains Siemiatycki,
“there is an element of genetic
predisposition that acts in
concert with environmental
or lifestyle factors.” To encouraging prevention, Siemiatycki
chose to work on identifying the exogenous causes
of cancer, that is, those that
are independent of genetics
and upon which we can more
readily intervene. Holder
of the Guzzo EnvironmentCancer Research Chair and
the Canada Research Chair in
Environmental Epidemiology
and Population Health, he has
been conducting epidemiological studies of these factors
for the past 30 years.
Jack Siemiatycki
His work is largely focused on
potential carcinogens in the
workplace since, as he puts it,
“the majority of workplace agents are also found
in the environment or in consumer products,
though to a lesser degree and more difficult to
detect. As such, studying the workplace enables
us to detect risks where they are the most evident and discover what factors are relevant to the
general population.”
than the healthy subjects. A positive response
indicates that there is a correlation between
the risk factor and cancer, whereas a negative
response points in the opposite direction.
He has studied workplace exposure to nearly
300 agents that are potentially linked to 15 types
of cancer. These include: asbestos, diesel oil,
gasoline, several solvents and roughly 20 types
of organic and inorganic dust. Similarly, he has
collected data on non-workplace exposure to
several agents, including tobacco, home heating
appliances, cell phone radiofrequencies, atmospheric pollutants, etc.
While this system informs us about the possible relationships between various types
of cancer and several hundred agents in our
environment and lifestyles, it does not allow
Most of his field studies use a “case-control” approach. In this approach, patients with various
types of tumours (subjects) are interviewed regarding their exposure to a presumed carcinogen.
A similar line of questioning is used with healthy
people chosen from the general population (controls), who are then matched with the subjects
in terms of age and gender. Once the data are
collected, comparisons are made to determine
whether the subjects (patients) have had more
intense exposure to the presumed cancer risk
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For Siemiatycki, “this is one of the elements that
contribute to the originality of our approach;
rather than focussing on a narrow hypothesis,
we have set in place a system that enables us
to shed light on what the data reveal.”
e x celle n ce
Fortunately, there is an organization that reviews
all the scientific literature on potential carcinogens
— the International Agency for Research on
Cancer (IARC), part of the World Health Organization. Jack Siemiatycki sits on the IARC’s
Scientific Council. “The IARC,” says Siemiatycki,
“is responsible for cataloguing carcinogenic
agents and for drawing conclusions about the
carcinogenicity of any given agent or behaviour.
The results of these deliberations are published
in the IARC Monographs on the evolution of Carcinogenic Risks to Humans, in which potentially
carcinogenic agents are listed and classified by
degree of risk (demonstrated, probable, possible
or nil). National agencies generally refer to these
monographs to emit public health recommendations to their respective populations.
When asked about the concrete impact of his
work, Siemiatycki notes, “My objective is to contribute to available knowledge with the intent of
promoting a scientific consensus.” In the work
accomplished by the IARC over the past 30 years,
Siemiatycki’s research is the most frequently
cited epidemiologic research, largely because his
group provides relevant information for assessing such a wide range of potentially carcinogenic
agents. In short, his work is used in the way he
had hoped it would be. Mission accomplished for
him and his group.
i n n o vat i o n
tra n sfer
Research CRCHUM is published four times a year by the
CRCHUM — University of Montreal Hospital Centre’s Research Centre.
Editor: Richard Ashby
Design: Production multimédia CHUM
Photographs: Production multimédia CHUM
Contributors: Richard Ashby, Sylvie Gervais, Louise Vadnais
Free subscription (paper and/or PDF copy): [email protected]
Correspondence Research CRCHUM, Bureau d’aide à la recherche, Centre hospitalier de l’Université de Montréal
Hôtel-Dieu, Masson Pavilion, 8-113, 3850 St.Urbain St., Montreal, Quebec, Canada H2W 1T7
Legal deposit 2008
Bibliothèque nationale du Québec
National Library of Canada
Reproduction authorized with mention of the source.
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december 2 0 0 8
ISSN 1918-5936