PathWay #16 - Cover
15/7/08
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PathWay Winter 2008 - Issue #16
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Contents
Dr Debra Graves (Chairman)
Chief Executive, RCPA
Dr Tamsin Waterhouse
Deputy CEO, RCPA
Dr Edwina Duhig
Director of Anatomical Pathology QHPS
(Prince Charles Hospital)
Dr Sophie Otto
Trainees Advisory Committee, RCPA
PATHWAY
Winter 2008
Issue #16
Dr David Roche
New Zealand Representative, RCPA
Wayne Tregaskis
S2i Communications
PUBLISHER
Wayne Tregaskis
EXECUTIVE EDITOR
Dr Debra Graves
FEATURES
EDITOR
Dr Linda Calabresi
Testing, testing: The challenge of vitamin D testing
ART DIRECTOR
Jodi Webster
Disciplines in depth: Little patients – big rewards
ADVERTISING SALES DIRECTOR
Sue Butterworth
Paediatric pathology is a subspecialty characterised by unique
challenges and rewards
PUBLISHING CO-ORDINATOR
Andrea Plawutsky
In profile: A passion for puzzles
PathWay is published quarterly for the Royal College
Dr Susan Arbuckle’s love of a good whodunnit reflects this
paediatric anatomical pathologist’s passion for finding a
diagnosis
of Pathologists of Australasia (ABN 52 000 173 231)
8
Although becoming more common in Australia, testing for
Vitamin D deficiency remains controversial
13
18
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Hot topics: The vaccine revolution
22
Childhood survival is no longer a lottery thanks largely to
immunisation, but the battle against childhood infections is
not yet won
Diseases: When the defences are down
28
Although relatively rare, primary immunodeficiency disease is
often suspected in children who suffer repeated infections
The Royal College of Pathologists of Australasia
Tel: (02) 8356 5858
Email: rcpa@rcpa.edu.au
Movers and shakers: Finding what lies beneath
33
Forensic pathologist David Ranson is a leading proponent of the
routine use of CT scans in autopsies
S2i Communications Pty Ltd
Tel: (02) 9251 8222
Email: wayne@s2i.com.au
PathWay
Email: pathway@rcpa.edu.au
http://pathway.rcpa.edu.au
FOR FURTHER INFORMATION ON THE ROYAL COLLEGE OF
PATHOLOGISTS OF AUSTRALASIA OR ANY OF THE FEATURES
RCPA Update: Snapshot of Pathology Update 2008
36
Cutting edge: Childhood leukaemia
– a genetic success story
38
Pathology has had a major role in dramatically changing the
prognosis of acute lymphoblastic leukaemia in children
Foreign correspondence: Making a difference in Africa
44
Dr Andrew Field finds that a simple diagnostic technique can
dramatically improve pathology sevices in Africa’s poorer nations
IN THIS ISSUE OF PATHWAY CHECK OUT THE WEBSITE
www.rcpa.edu.au
PATHWAY_1
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REGULARS
From the CEO
4
RCPA CEO, Dr Debra Graves,
welcomes this 16th issue of Pathway
Under the microscope
LUCKY LIKEABLE LUKE
PAGE 55
6
News + views
6minutes news
42
Interesting news from around the
world
Finance finesse
48
LIFESTYLE
Financial advisor, Greg Lomax
discusses the nature and benefits of
self managed super funds
Conference calendar
63
Postscript
68
Dr Pam Rachootin finds the quest to
match the specialist to the patient can
sometimes prove challenging
SYDNEY’S SPECTACULAR
SURROUNDS
PAGE 52
Travel: Sydney's spectacular surrounds
- away from the madding crowd
52
Visitors to Sydney would be well advised to spend some time exploring
the sights outside the city’s periphery
Recipe for success: Lucky, likeable Luke
55
Luke Mangan is one of Australia’s best known most respected chefs
but the success hasn’t changed this modest man
Travel doc: 24 hours in Sydney
58
Five Sydney pathologists give their advice on what not to miss if you
only have a day to spend in this harbour city
The good grape: Gathering in the Hunter Valley
62
Ben Canaider investigates the unique offerings from the worldrenowned Hunter Valley wine region
Rearview: The battle against rejection
65
Dr George Biro looks back on the discoveries that relegated
haemolytic disease of the newborn to medical history
PATHWAY_3
from the CEO
Welcome
to the 16th Edition of PathWay
elcome to this special edition of
PathWay – ‘special’ because there
are two very important themes running
through this edition.
W
The first is the vital role of Paediatric
Pathology across all disciplines of
pathology and the part it plays in the
practice of medicine.
The second is to promote Sydney as a
conference destination, as it will be the
venue for an international conference on
Pathology, (Pathology Update 2009 in
conjunction with XXV WASPaLM) to be held
at Darling Harbour 13-15 March 2009.
We will also be sending this edition of
PathWay internationally (in addition to its
normal distribution across South East
Asia) to highlight what a great place
Australia is to visit and what a great
conference we will be hosting.
Paediatric Pathology as a career
opportunity is highlighted in our ‘Disciplines
in Depth’ story. Each of the seven separate
disciplines of pathology has paediatric
sub-specialties. Many people believe that
children are just like little adults; this is not
the case and there are many different
diseases and approaches to diagnosis and
management of paediatric conditions that
require special attention.
Children play a special role in society,
and as a consequence the community
always expects the highest level of care for
them; this is why paediatric pathology is
such a special specialty. PathWay talks with
Dr Susan Arbuckle, the Chairman of the
Children Hospital Westmead’s Division of
Diagnostic Services, and explores why she
finds the profession so rewarding.
In our ‘Cutting Edge’ story, we report the
latest developments in childhood leukaemia
and what pathology is doing to help improve
survival rates for children with this dreadful
disease. We also look at primary
immunodeficiency in children. While a
relatively rare disease, it is a vital one to have
accurately diagnosed so as to prevent severe
childhood illnesses that may result in death
or long term complications.
Sydney is a great conference
destination and our special feature on ‘24
4_PATHWAY
hours in Sydney’ has interviews with a
range of pathologists who give their insights
into great things to do in Sydney. We also
talk with Luke Mangan, chef at the sublime
Glass Restaurant in the Sydney Hilton. As
well as explore the delights of the Hunter
Valley, Blue Mountains and the South Coast.
The international basis of the
conference next year is particularly timely
as there has been much in the news of late
internationally about pathology.
The biggest item of concern for the
College has been the huge amount of
media surrounding the crisis in Pathology in
Canada (highlighted in our News section).
There are currently four provinces in
Canada where major reviews/inquiries are
being carried out because of medical
errors that have occurred, mainly in
cancer diagnoses. This is a serious issue
and the President of the Canadian
Association of Pathologist, Professor
Jagdish Butany puts the blame squarely
back on governments and health care
administrators for ignoring ten years’
worth of advice from the profession about
the severe workforce shortage of
pathologists and the serious absence of a
national quality framework for pathology.
Australia and New Zealand at least
have sound quality frameworks to help
protect the public, but the concerns over
serious workforce shortages are the same
for this side of the globe. Canada is a first
world country and its shortage is currently
at a level the College is predicting Australia
and New Zealand will be at in the next five
to 10 years, unless governments start to
act seriously and provide support for the
profession via appropriate funding for
training positions and other initiatives.
What is happening in Canada today will
happen in Australia unless something is
done about the workforce crisis.
Meanwhile in the US, the focus has
been on the competitive tendering process
for pathology, which was to be similar to
the destructive arrangements that have
been introduced in NZ in relation to
pathology.
In an unusual show of solidarity,
American Republicans and Democrats
reached an agreement in the House of
Representatives that will herald the end of
competitive tendering for pathology
laboratory contracts, if passed by the
Senate.
Working with government to achieve
good outcomes for patients and the
community has been a hallmark of the
RCPA (in partnership with the Australian
Association of Pathology Practices and the
National Coalition of Public Pathology) over
the last 20 years.
It was therefore disturbing that in the
last federal budget, the Rudd government
chose to ignore the very positive
achievements that both the profession and
government have achieved over these
years by unilaterally imposing a fee cut on
pathology.
This will have a direct impact on tests
involved in preventative medicine and also
seriously affect the delivery of health care in
rural areas.
The College has found this as unusual
as it is unacceptable with rural health and
preventative medicine being two crucial
government policies in relation to
fundamental healthcare.
At the time of going to press the
profession has only just secured a meeting
with the Health Minister, the Honourable
Nicola Roxon, to discuss this and other
issues. We hope that these discussions will
be productive, and be assured, we will
keep you fully informed.
We hope you enjoy this 16th edition of
PathWay.
Dr Debra Graves
CEO, RCPA
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under the microscope: news + views
New guidelines for dealing with
sudden death in the young
ew guidelines have been released
providing information on best autopsy
practices in cases of sudden unexpected
death in the young.
N
Developed by the Trans-Tasman
Response Against Sudden Death in the
Young (“TRAGADY”) the guidelines cover
a range of conditions that may cause
unexpected deaths in seemingly healthy
children, such as Prolonged QT
Syndrome.
health professionals from forensic
pathology, cardiology, sciences and
research from both Australia and New
Zealand.
President of the RCPA, Dr Bev
Rowbotham says “The objective of these
guidelines will be to provide answers to
grieving families.”
“The guidelines also provide
information for the surviving members of
According to the Chaiman of
TRAGADY, Associate Professor Jon
Skinner “This best practice document is a
critical first step in ultimately reducing
sudden death among young people in our
community.”
the families, including whether they
The guidelines, endorsed by the
RCPA, are the result of a collaboration of
www.rcpa.edu.au
TRAGADY - www.sads.com.au.
themselves are also carriers of these
inheritable cardiac conditions – to permit
treatment of these otherwise fatal
conditions.”
Pathology funding cuts
widely criticised
assive cuts in pathology funding
Spokesman for the group, RCPA CEO,
M
Dr Debra Graves, said the cuts would
budget brought a swift and united
mean pathology testing for a wide range
response from Australia’s three peak
of diseases such as diabetes, infertility,
pathology bodies.
HIV-AIDS, cholesterol, hepatitis C, viral
announced in the last Federal
Following the Rudd government’s
diseases such as glandular fever or Ross
announcement last May that more than
River fever would now become less
$180 million would be slashed from the
affordable. Cuts to fees for collection and
pathology budget over the next four
transport would affect patients living in
years, the Royal College of Pathologists of
regional and rural Australia in particular.
Australasia, the Australian Association of
Pathology Practices and the National
President of the RCPA, Dr Bev
Coalition of Public Pathology released a
Rowbotham, said that the College had
joint statement of condemnation. They
serious concerns that the profession had
criticised the move, saying it will
not been consulted as cuts in funding
potentially put the health of the Australian
could have unintended consequences for
public at risk, particularly those with
the quality of and access to pathology
chronic disease.
services.
6_PATHWAY
Coronial
morgue
closes
ydney’s Westmead Hospital will
no longer be conducting
coronial post-mortem examinations
because of a lack of pathologists.
S
Despite advertising
internationally, the Department of
Forensic Medicine has been unable
to recruit permanent forensic
pathologists to maintain the service,
NSW Health reports.
According to CEO of the RCPA,
Dr Debra Graves, the situation
represents only ‘the tip of the
iceberg’ in terms of the pathology
workforce shortage currently being
experienced Australia-wide.
“The closure of the coronial
morgue demonstrates that the
impending crisis, of which the RCPA
has been warning the government
repeatedly over the last five years, is
now a reality. There are an
insufficient number of pathologists
to provide the services the
community needs,” she says.
“The Government is not doing its
job in delivering a sufficient number
of training places,” Dr Graves adds.
There are 6000 coronial postmortem examinations undertaken in
NSW every year. Coronial services
that were conducted at Westmead
will now be performed by the
Department of Forensic Medicine at
Glebe, supported by the forensic
pathology centre in Newcastle.
Non-coronial post-mortem
examinations and mortuary facilities
would still be provided by
Westmead, according to a statement
issued by NSW Health.
Husband and
wife team
awarded
rs Jane Visvader and Geoff Lindeman,
D
researchers at Melbourne’s Walter and Eliza
Hall Institute and the Royal Melbourne Hospital,
have received the GlaxoSmithKline Award for
Research Excellence for their outstanding
contribution to breast cancer research.
The Award recognises their body of work which
has included their team’s discovery of a luminal
precursor breast cell which may be a target for
mutation in the majority of breast cancers, as well
as the demonstration that LMO4 and GATA-3 are
key regulators in breast tissue.
Canada’s pathology
service in crisis
As recipients of the Award the doctors will
receive an honorarium of $60,000 to further their
work.
rgent action is needed to repair Canada’s ailing hospital
U
laboratories that appear to be ‘unravelling at the seams’,
claims the president of the Canadian Association of
Pathologists, Dr Jagdish Butany.
In an editorial in the Canadian Medical Association Journal
(CMAJ 2008; 178: 1523-24) , Dr Butany says recent reports of
medical testing errors and misdiagnoses have eroded public
confidence in Canadian pathology services, and the
government urgently needed to address the growing problems
in overworked laboratories.
“The pathologist’s volume of work has increased and the
complexity of each case has multiplied,” he said. “Today,
extensive tissue sampling, exhaustive microscopic
examination and ancillary tests, many of which determine
therapy and predict outcome... as well as synoptic reporting
are essential.”
“All of these factors have overwhelmed the pathology
laboratory.”
The most significant challenge to the accuracy of cancer
and other medical tests is Canada’s lack of a national quality
assurance system, said Dr Butany. Such a glaring void
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exposes serious vulnerabilities as such a system oversees and
administers a wide variety of quality assurance initiatives,
strategies which have been proven to decrease error rates.
Local hospital administrations and provincial ministries of
health need to immediately fund quality assurance efforts in
the laboratory system, Dr Butany suggested, as well as paying
urgent attention to the serious human resource issues that are
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causing long-standing staffing problems across the country.
PATHWAY_7
testing testing
8_PATHWAY
The Challenge of
VITAMIN D TESTING
WHILE THE IMPLICATIONS AND PREVALENCE OF VITAMIN D DEFICIENCY SEEM TO BE
FREQUENTLY MAKING HEADLINES, THE PROBLEMS ASSOCIATED WITH TESTING FOR
THE VITAMIN ARE LESS WELL-KNOWN. TONY JAMES REPORTS.
ickets – a disease of bone growth and
development in children resulting from
vitamin D deficiency – conjures
Dickensian images of gloomy, 19th
Century northern Europe. To the surprise
of paediatricians and public health
authorities, there is a resurgence of rickets
in Australia and New Zealand. It is just
one element in what has been described
as a worldwide ‘epidemic’ of diseases
related to vitamin D deficiency.
R
The importance of vitamin D to bone
health in elderly people is well known, as
adequate levels can help prevent
osteoporosis by maintaining bone density,
reducing falls frequency, probably through
an effect on muscle strength, and
subsequent fracture rates. Growing
evidence suggests it also has an
important role in immune function, cell
growth and proliferation, with deficiency
linked to cancer and autoimmune disease.
Vitamins, the textbooks say, are
organic substances that cannot be
manufactured by the body but are needed
in small amounts for normal maintenance
and growth. ‘Vitamin’ D is an exception: it
is a steroid hormone predominantly
manufactured in the skin with only a small
proportion of total needs supplied by the
diet. The few nutritional sources include
oily fish (for example, salmon), liver, eggs,
and some fortified foods like margarine.
In the first step of a complex
metabolic pathway, sunlight converts 7dehydrocholesterol to vitamin D3 (also
called calciferol) in the skin. The liver
metabolises vitamin D3 to 25hydroxyvitamin D3, which circulates in the
blood bound to a carrier protein. Finally,
the kidney converts 25-hydroxyvitamin D3
to the biologically active form, 1,25dihydroxyvitamin D3 (calcitriol).
Calcitriol has an essential role in bone
growth and maintenance. It facilitates the
absorption of calcium and phosphate
from the small intestine, maintains
appropriate calcium balance throughout
the body, and promotes mineral
deposition in the skeleton.
Determining D deficiency
Dr Paul Glendenning, chemical
pathologist and endocrinologist at the
Royal Perth Hospital and clinical senior
lecturer in the Department of Medicine
and Pharmacology, University of Western
Australia, has a long term interest in
vitamin D physiology and the
consequences of deficiency. “Clinically,
we measure levels of 25-hydroxyvitamin D
(25OHD) to determine vitamin D status as
none of the other metabolites are strongly
associated with disease,” he says.
Increasing demand for vitamin D tests
has led to some challenges for pathology
laboratories. “We used to rely on laborious
but very accurate manual methods, but
have been forced to switch to automated
techniques to handle the volume of
requests,” Dr Glendenning says. “The
newer methods are usually adequate for
determining whether a patient has vitamin
D deficiency, but the results are not as
precise or accurate as in the past and
sometimes misleading. When an accurate
25 OHD level is critical for a diagnosis or
a clinical decision, laboratories may need
to resort to the older radioimmunoassay
or HPLC methods.” Similar analytical
problems exist when measuring a number
of other hormones including, for example,
testosterone.
The desirable lower limit for serum
25OHD is 50 nmol/L, but this threshold
has been debated.
Dr Glendenning states that American
authorities are campaigning to increase
the limit to 80 nmol/L, which would greatly
expand the number of people defined as
‘deficient’.
“The exact links between 25OHD
levels and bone pathology have not been
precisely defined, but there is good
evidence that it is beneficial to treat
patients once the level falls below the 50
nmol/L threshold,” he says.
Vitamin D toxicity is theoretically
possible, but extremely rare.
About half of women and one-third of
men older than 60 in Australia will suffer a
bone fracture due to osteoporosis. “Most
25OHD tests are in patients judged to be
at high risk of an osteoporosis-related
low-trauma fracture,” Dr Glendenning
says. “Their treating doctors often
measure calcium and parathyroid
hormone, but neglect to measure vitamin
D even though it is potentially more
important.”
25OHD levels can fluctuate throughout
the year in response to varying sun
exposure, so a test at the end of winter
normally identifies the lowest level and is
most sensitive in identifying deficiency.
Topping up D supplies
Vitamin D supplementation, usually in the
form of calciferol (vitamin D3), is used
both to prevent and to treat deficiency.
The Pharmaceutical Benefits Scheme
regards calciferol as a nutritional
supplement rather than an essential
PATHWAY_9
>
Vitamin D deficiency
Only five or ten minutes’
IN AUSTRALIA
midday exposure of the
head, hands and arms is
required each day in
Vitamin D levels have been assessed in a number of population
groups, with the following proportions defined as having a
deficiency:
summer to generate
adequate vitamin D3 in the
Elderly men with hip fracture
63%
skin. In winter, the
Veiled Muslim women
68%
Elderly ambulant men with prostate cancer
34%
Healthy elderly men in southern Sydney
16%
Healthy ambulatory women in Geelong aged 20-39
20%
Older aged groups
53%
Men and women with psychiatric disorders
in south-eastern Queensland
23%
Pregnant women in south-eastern Australia
7%
requirement is about the
same for people living in
Darwin or Cairns, but
increases to about 30
minutes in the gentler
southern climate of Hobart.
Medical Journal of Australia 2005; 183: 53-54
medication, so consumers have to pay
the full cost.
“Only about half of patients with an
osteoporosis-related fracture probably need
supplementation, so a test can help them
decide whether it is worth the cost,” Dr
Glendenning says.
In a welcome innovation, vitamin D has
been incorporated in combinations with
risedronate and alendronate,
bisphosphonates used to treat established
osteoporosis.
A second 25OHD test after about
three months of supplementation will help
confirm whether there has been an
adequate response to supplementation.
“I’d like to see a more prescriptive
approach to vitamin D supplementation in
osteoporosis treatment guidelines,” he
says. “Most say that preventing or
10_PATHWAY
treating vitamin D deficiency should be
considered, but we need a more definitive
statement that it is essential to measure
25OHD in order to identify and correct
deficiency.”
screened. Adequate vitamin D levels are
probably an important factor in optimising
bone mineral density during adolescence,
but there is little evidence on whether
testing and supplementation is useful.
Other patients who may benefit from a
vitamin D measurement to guide
supplementation and other interventions
include pregnant women, especially those
who are darker-skinned or veiled.
Maternal deficiency can lead to fetal
abnormalities and increase the risk of
rickets in their babies, who might need
supplementation during their first 12
months.
Vitamin D deficiency contributes to
the risk of falls, perhaps through its
influence on muscle strength, in elderly
people already predisposed to fractures
because of low bone density.
Supplementation with 1000 IU/day has
been shown to reduce the risk of falls by
30% among elderly people in residential
care.
Patients treated with zoledronic acid
(a potent bisphosphonate used to treat
bone malignancy), and those taking
medications such as anticonvulsants that
can induce liver enzymes and reduce the
synthesis of 25OHD, also need to be
How does vitamin D deficiency (see
Box) occur in “a sunburnt country” like
Australia?
Only five or ten minutes’ midday
exposure of the head, hands and arms is
required each day in summer to generate
adequate vitamin D3 in the skin. In winter,
the requirement is about the same for
people living in Darwin or Cairns, but
increases to about 30 minutes in the
gentler southern climate of Hobart.
Risk factors for deficiency include
living in residential care or other
institutions, especially for people with
limited mobility, because of restricted time
spent outside. Sitting behind a sunny
window won’t work, as ultraviolet B
radiation does not penetrate glass. Older
people are inherently at higher risk as the
capacity of the skin to generate vitamin D
declines with age. Being dark-skinned
reduces ultraviolet B absorption by the
skin, and covering the skin for religious or
cultural reasons (for example, veiling)
reduces sun exposure.
Finding the Balance
The competing needs to provide adequate
sun exposure to manufacture vitamin D,
but also to prevent skin cancer, has
sparked a sometimes spirited debate
between cancer prevention and bone
health advocates, and concern about the
public being confused by contradictory
messages. A consensus may be reached
along the lines of: avoid high levels of sun
exposure, especially sunburn, but do not
avoid the sun completely.
In yet another contradiction, the
adequate vitamin D levels that are
generated by sun exposure seem to have
a general anti-cancer effect. “The
biologically active metabolite is a powerful
regulator of cell proliferation, and
potentially of tumour development and
expansion,” Dr Glendenning says. “We
now know that the ‘machinery’ of vitamin
D metabolism is found in many tissues,
and there are associations between the
incidence of some non-skin cancers and
latitude.”
A number of observational studies
have suggested that vitamin D
supplementation is associated with a
lower incidence of common cancers. In a
randomised clinical trial reported last year
(American Journal of Clinical Nutrition
2007; 85: 1586-1591), healthy
postmenopausal women were treated with
calcium alone, calcium plus
cholecalciferol, or placebo for four years,
primarily to determine the effect on
fracture rates. Cancer incidence was a
secondary outcome. Those receiving
vitamin D had a 60% lower incidence of
all types of cancer, and a 77% lower
incidence of cancers diagnosed after the
first 12 months of treatment.
Vitamin D also appears to be closely
involved in regulating normal immune
function, especially the development of
tolerance by T lymphocytes. Deficiency
has been linked with autoimmune
conditions such as type 1 diabetes,
multiple sclerosis and rheumatoid arthritis.
For example, one of the many perplexing
issues about the causes of multiple
sclerosis has been its higher prevalence at
higher latitudes – a finding consistent with
lower sun exposure and higher rates of
vitamin D deficiency.
Even in sunny Brisbane, children and
adolescents diagnosed with type 1
diabetes had lower serum 25OHD levels
than their healthy peers, and were more
than three times as likely to be vitamin D
deficient (Medical Journal of Australia
2007; 187: 59-60).
For Dr Glendenning, the central issue
about vitamin D is education – of the
medical profession about the need to
identify and treat deficiency, and of the
public about the need to maintain
adequate levels through sensible sun
exposure, diet and, if needed,
supplementation. For pathologists, the
priority is more accurate laboratory tests
and better reference standards to allow
optimal processing of the growing number
of tests.
PATHWAY_11
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after university just yet, but the Australian
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To find out more, call 13 19 01 or visit
university, you should apply to become an
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ADF Sponsored Undergraduate.
• Have all of your remaining tuition
fees paid.
12_PATHWAY
disciplines in depth
Little patients
– BIG REWARDS
HAVING ALREADY CONTRIBUTED SO MUCH TO MEDICINE, PAEDIATRIC PATHOLOGY CONTINUES
TO PLAY A KEY ROLE IN ADVANCING IN THE UNDERSTANDING, DIAGNOSIS AND MANAGEMENT
OF DISEASES OF CHILDHOOD. KATE WOODS REPORTS.
hen Dr Lilane Boccon-Gibod – president of the Paediatric
Pathology Society – was working in the early 70s, ultrasounds
during pregnancy were unheard of and pregnancy terminations were
“extremely rare”.
W
Most autopsies were performed on babies born with serious
malformations such as diaphragmatic hernia or hypoplastic left heart
complex, and surgical specimens were for conditions such as
meningomyelocoele where part of the spinal cord and membranes
1
protrude through the vertebral column.
How times have changed…
PathWay talks to seven Australian pathologists who – whether
referring to the latest research, diagnostic developments, new
therapies or future possibilities – all agree that now is “an exciting
time” to be involved in paediatric pathology.
ANATOMICAL PATHOLOGY
Dr Adrian Charles is a paediatric pathologist at Western Australia’s
King Edward Memorial and Princess Margaret Hospitals. He
suggests new technology and social shifts are responsible for the
growing – and exciting – emphasis being placed on perinatal
medicine in anatomical pathology.
“There is an increasing number of older women having babies
and the growing technological developments in foetal medicine;
ultrasounds, screening techniques and so on are increasing the
awareness of foetal disease.
“So what used to be described in neonates, we are now seeing
commonly at 18 weeks gestation or younger.”
As such, the effects of the placenta, disorders of foetal
development, and the causes of stillbirth, pregnancy loss and
prematurity are growing areas of research.
>
PATHWAY_13
“...difficult to diagnose tumours in
children are often sent
internationally to be reviewed by
“super-specialists” as part of the
tumour treatment protocol.
It means patients receive the best
diagnostic opinion possible,”
- Dr Adrian Charles.
Similarly, he adds, the emergence of
new working arrangements has improved
tissue sample diagnoses.
Instead of being reviewed by just one
person and staying in-house, difficult to
diagnose tumours in children are often
sent internationally to be reviewed by
“super-specialists” as part of the tumour
treatment protocol.
“It means patients receive the best
diagnostic opinion possible,” he says.
This process is also helping in the
recognition of unusual tumours as these
rare tumours are being reviewed by a
small group of specialised pathologists.
“For example, renal tumours were all
called Wilms’ tumours about 30-odd years
ago. Now we know there are quite a few
different types of tumours within this
group because super-specialists, when
reviewing them, realised that some
actually behaved a little differently and
had subtle histological differences.”
With much change having already
occurred over the past 10 years or so,
what can we expect to look forward to in
the future?
“The role of the anatomical pathologist
will still be as the reviewer of the initial
[stained tissue] slide. But I think there will
be growing integration of the advanced
molecular techniques, such as chip array
technology with selected tumours, that
will provide further information that can
then be used diagnostically by clinicians.
“Paediatric anatomical pathologists
are going to need to be conversant in
more than just the morphology they see
down the microscope. They will need to
be aware of these techniques and be key
in deciding when these are needed” he
predicts.
14_PATHWAY
CHEMICAL PATHOLOGY
“Paediatric chemical pathology is a very
fertile and rich goldmine of interesting
case material,” enthuses Dr James Doery,
a principal specialist in chemical
pathology at Monash Medical Centre.
“For example, we’ve recently found
the first case of sitosterolaemia in Victoria,
a serious disorder resulting in premature
vascular disease in children.”
“While probably an under-diagnosed
and under-appreciated condition, a case
like this gives pathologists the opportunity
to document it thoroughly, and educate
clinical colleagues.”
“[Also] the study of unusual conditions
such as sitosterolaemia leads to a much
deeper appreciation of normal
metabolism,” he adds.
Dr Doery says one of the more
challenging areas in paediatric chemical
pathology is neonatal metabolic postmortems, where the infants have physical
deformities, seizures or metabolic
derangements, or a combination of these,
and often with only hours or days to make
a definitive diagnosis.
“Mitochondrial disorders and
Congenital Disorders of Glycosylation
(CDG) [also known as carbohydrate
deficient glycoprotein syndromes] for
example are metabolic disorders which
have, only in recent years, been
understood at the detailed biochemical
level,” he says.
“A number of previously diverse
syndromes can now be understood to be
part of the spectrum of CDG whereby
many body organs and pathways can be
adversely affected depending which step
in glycosylation is defective.”
In the world of paediatric chemical
pathology, close collaboration with other
clinical colleagues such as paediatric
endocrinologists, is particularly important.
There also exists the option of doctors
undertaking joint Fellowships in these two
specialties. Such cooperation has made
other significant scientific and diagnostic
advances possible.
“A simple example is the development
of a standardised growth hormone
stimulation test using a motorised
treadmill.
“This has enabled us to exclude
growth hormone deficiency in over 90%
of children presenting with short stature…
replacing earlier tests... which were much
costlier in-patient procedures with
significant risks, cost and inconvenience.”
GENETICS
Professor John Christodoulou describes
genetics as “an area that is absolutely
mushrooming in terms of what is now
technically possible.”
Take chromosome analysis for
example, says the director of the Western
Sydney Genetics Program at the
Children’s Hospital at Westmead.
Previously, this process was very
labour-intensive, required a considerable
amount of operator expertise and was
associated with a resolution of only three
to five megabases. A megabase is a unit
of length of DNA fragment that contains a
million nucleotides.
But with the development of new DNA
technology pathologists can now drill
down to looking at structural
abnormalities as small as 100 kilobases,
each kilobase containing 1000
“Since 2001, five new
“There has been an
respiratory viruses that
increasing realisation that
affect children have been
children are not just small
discovered...”
adults, that they are quite
- Associate Professor
Michael Nissen
complex beings who have
different medical problems”
- Professor Roger Byard
nucleotides, a 50-fold increase in
resolution.
This has led to a significant increase in
the identification of abnormalities in
patients in whom there is a strong
suspicion that an abnormality is the
underlying cause for his or her problems.
“It is probably going to completely
reshape the way people think and test for
potential chromosomal abnormalities,” he
says.
The second area, while still in the
research stage, is the development of new
machinery that Professor Christodoulou
predicts could open up the field for high
throughput genetic analysis.
“These pieces of machinery enable an
individual to screen or sequence up to 10
million base pairs in a hit. And that
sequencing, depending on which
technology and platform you use, can
take place in the space of about 4.5
hours… which is huge.”
He suggests it may also be possible
one day to develop a sequencing chip
with the capacity to screen for the 10 or
so most common channel genes
associated with different disorders such
as epilepsy, gene-causing mental
retardation and so on.
“Again, while this is still very much in
the research arena, I would think in the
next three to five years it is going to be a
major contributor to the way we screen
for mutations in genes of interest.”
MICROBIOLOGY/
INFECTIOUS DISEASES
While much of the world focus on
infectious diseases over recent years, has
been on diseases such as the avian flu
and SARS, quietly but ever-so-effectively
significant advances are continuing to be
made in the world of paediatric
microbiology.
Since 2001, five new respiratory
viruses that affect children have been
discovered; the human metapneumovirus,
coronavirus NL63, coronavirus HKU1,
bocavirus and the WU and KI
polyomaviruses.
Pathology Queensland – says clinical
microbiologist Associate Professor
Michael Nissen – was involved in the
discovery of WU polyomavirus and was
the first laboratory in Australia to detect
the other four.
“Certainly the most significant
discovery was the human
metapneumovirus… mainly because the
number of cases we diagnose now is
quite high – at certain times of the year it
would almost be as much as respiratory
syncytial virus or influenza.”
He says the other significant
development in recent times has been the
advent of molecular diagnosis or the use
of polymerase chain reaction (PCR) a
technique that allows millions of copies of
a particular DNA sequence to be
produced very quickly.
This has opened the door for rapid
diagnosis of infectious diseases in
children, particularly the diagnosis of
herpes simplex encephalitis, and invasive
meningococcal and pneumococcal
disease.
“Culture is not required, so results can
be obtained within four hours from
receiver delivery,” says Dr Nissen, who is
also director of infectious diseases at the
Royal Children’s Hospital in Brisbane.
Furthermore, this technology has
improved diagnoses rates.
“When we first introduced
meningococcal PCR testing to Pathology
Queensland, we recorded a 25%
increase, which means potentially, we had
not been diagnosing or notifying public
health authorities of a quarter of cases.
This is significant, Dr Nissen says,
particularly with meningococcal disease
where it is important to identify contacts
that may be at risk of becoming infected
and giving them prophylactic antibiotics
where appropriate.
Despite these gains, he says
pathologists still face the challenge of not
being able to use PCR diagnosis for
conditions such as pneumonia, or for
problems such as anti-microbial
resistance.
“For significant infections such as
herpes or influenza, molecular markers
have been identified for anti-microbial or
anti-viral resistance, but those tests tend
to be confined to specialised laboratories.
But Dr Nissen is optimistic. “Once our
knowledge in this area increases however,
I have no doubt that problem will be
overcome.”
FORENSIC PATHOLOGY
According to Professor Roger Byard,
Marks Professor of Pathology at
University of Adelaide, paediatric forensic
pathology has only just started evolving
as a discipline.
PATHWAY_15
>
“... a "simple haematologist"
now needs to have a broad
knowledge of other clinical and
pathology disciplines and needs
to be able to cope with a high
degree of complexity in decision
making.”
- Dr Heather Tapp
“There has been an increasing
realisation that children are not just small
adults, that they are quite complex beings
who have different medical problems,
who have developmental problems, and
in whom inflicted trauma can be quite
different from adults.”
He says while SIDS and cases of
unexpected deaths have declined
dramatically in recent years, when they do
appear, they tend to be much more
complicated.
“We are getting more information
about family background, getting more
information about the circumstances of
death… and I think the more information
you have, the more complicated an
assessment is, which means cases are
taking a lot longer.”
Research is also contributing to the
amount of information on SIDS, with
investigations into “brain factors”, such as
whether abnormalities are present in the
neurotransmitters of SIDS babies’ brains–
showing some interesting findings.
“Trends seem to be emerging that
may soon allow us to identify subsets of
SIDS cases,” he says.
Professor Byard is also involved in
researching inflicted trauma, in particular
the dating of bruises and brain swelling in
children.
16_PATHWAY
“Some people believe that because
there is extensive brain swelling, a baby
must have been alive for some time [after
their injury]… whereas our study is
showing that in an animal model, cerebral
swelling occurs very quickly.”
And he is enthusiastic about future
discoveries.
“It’s spectacular what can be looked
at and is being studied”, he says.
But he warns, unless more people are
trained in pathology, particularly
paediatric forensic pathology, further
progress will be slowed.
“We may in fact be an endangered
species.”
HAEMATOLOGY
Another dedicated advocate for paediatric
pathology is haematologist, Dr Heather
Tapp from the Women’s and Children’s
Hospital in Adelaide.
She says one of the most exciting
areas of paediatric haematology/oncology
now is the ability to utilise characteristics
of both the child and the tumour, so as to
tailor make the treatment, ensuring
maximum effectiveness with minimal side
effects.
“Leukaemia and lymphoma treatment
programs, in particular, are becoming
increasingly risk adapted and stratified
according to host factors... and tumour
biology,” she says.
“We are now capable of tailoring
therapy to achieve the best possible
outcomes for patients with the least
possible toxicity.”
“… It is becoming far more
complicated but it is also very
fascinating.”
She says these changes mean a
"simple haematologist" now needs to
have a broad knowledge of other clinical
and pathology disciplines and needs to
be able to cope with a high degree of
complexity in decision making.
However, the upside is the job
satisfaction that comes with achieving the
best possible outcomes for the children
with these conditions.
Dr Tapp suggests one of the other
significant advances to occur in
haematology in recent years is the
technological improvement. Not only has
this facilitated rapid access to results, but
it has also improved quality and safety.
She says transfusion medicine is an
example of this, with the introduction of
the Bloodsafe programme and nucleic
acid testing (NAT) for viruses.
“Although these initiatives do not
make blood 100% safe they reflect
significant improvements.”
IMMUNOPATHOLOGY
Professor Mimi Tang, a consultant
immunopathologist and paediatric allergist
at The Royal Children's Hospital in
Melbourne, says exciting changes are
occurring in immunopathology due to
which is particularly exciting for
Australia is getting recognition for the
paediatrics because it allows us to work
importance of the discipline.
with smaller volumes, and to expand the
Like so many other areas of pathology,
range of tests we can offer in a more
the significance of the contribution made
cost-efficient way.”
She says although the testing of
by paediatric pathology and paediatric
pathologists far outweighs the
clinicians’ “ever expanding”
allergic disease has not progressed
understanding of the immune system and
significantly in recent times, the
acknowledgment the discipline receives
the way it functions.
development of threshold cutoffs for
throughout the wider community and even
serum allergen-specific IgE assays has
within the medical profession as a whole.
As well as an increasing array of tests
available to evaluate immune function,
made life easier for a number of clinicians,
including genetic tests that identify the
not just immunopathologists.
mutational defects in immune deficiency
syndromes, there are now new technology
However with such an array of
developments already made and so many
“Above a certain threshold, you know
potential challenges set to be overcome,
the chance a child has clinical allergy, so
the enthusiasm of those currently
you can make the diagnosis without
practising paediatric pathology appears
proceeding to a challenge. This is
well founded and destined to rub off on
extremely helpful for GPs and
the next generation of would-be
beads that bind to different chemical
paediatricians who are managing simple,
specialists.
constituents , known as analytes.
primary level allergy problems.”
platforms for diagnosis.
One of the latest developments is
Luminex technology, an ELISA-based
assay that uses unique colour coded
“[Now] you have the opportunity to
assess various analytes in the one tube,
But she says one of the major
challenges for immunopathology in
1. Paediatric Pathology Society Newsletter,
February 2008
In the cool of Scandinavia, forensic crime
detection is a different kettle of fish
UNIT ONE
[VOLs 1-4]
FROM THE MAKERS
OF ‘THE EAGLE’, SUPERB
DANISH FORENSIC DRAMA
www.aztecinternational.com.au
PATHWAY_17
in profile
A passion for puzzles
PIECING TOGETHER
ANATOMICAL CLUES TO
REACH A DIAGNOSIS IS AT
THE HEART OF DR SUSAN
ARBUCKLE’S ENTHUSIASM
FOR HER JOB AS A
PAEDIATRIC PATHOLOGIST,
AS BRONWYN MCNULTY
FINDS OUT.
hen the weekend rolls around
anatomical pathologist, Dr Susan
Arbuckle can’t wait to pick up her book.
It’s not her only hobby. She also likes
going to the theatre and ballet, and
playing the piano.
W
But reading psychological thrillers is
this paediatric and perinatal pathologist’s
particular passion, one that she has to be
especially strict with herself about.
“I get to a point in a book where I
can’t put it down,” says the 55 year old,
Dr Arbuckle. “At 2am I say to myself, just
one more chapter… So I only read on the
weekends.”
Dr Arbuckle – chairman of the
Children’s Hospital Westmead’s division of
diagnostic services – says her love of
crime novels and psychological thrillers
reflects her days spent as a laboratory
detective, during which she is constantly
trying to piece puzzles together.
“It’s the solving of problems – I think.
That’s what I enjoy most about paediatric
and perinatal pathology,” she says. “It’s
like reading a detective novel and having
a whole lot of clues present, and you have
to try to come up with an answer.”
Dr Arbuckle’s ‘clues’ are the endless
array of pathology specimens ranging
from tumour biopsies to autopsies that
arrive in the laboratory awaiting her expert
diagnosis.
The days are usually long – averaging
12 hours, but Dr Arbuckle exudes
enthusiasm and dedication to her role in
improving the health of society’s youngest
members.
“It’s not difficult to maintain
enthusiasm for this job,” Dr Arbuckle
says. “The work is endlessly interesting.
18_PATHWAY
There’s a huge variety. We get an amazing
variety of material going through here. It’s
just a fascinating field.”
There’s little doubt that it was this
enthusiasm, added to her diligence and
expertise that saw her appointment to the
senior administrative role of director of
pathology at the Children’s Hospital,
Westmead, 12 years ago - the first
woman to hold the position.
But such success comes as no
surprise to those who work with Dr
Arbuckle.
Colleague and fellow crime novel
devotee, Dr Nicky Graf says “Susan’s a
great person to work with. She works
extremely hard and I have never seen
anyone advocate so well for other
people.”
Dr Graf who is also a perinatal and
paediatric pathologist, adds “She’s also
very knowledgeable. She spouts
syndrome names I have never heard of.”
But pathology wasn’t always a
passion for Dr Arbuckle.
As a young registrar, back in the 80s,
she started the physicians training
program at the Royal Brisbane Hospital,
thinking she might specialise in
haematology or oncology.
“I didn’t start out to be a pathologist,”
she says. “I was planning on going down
the clinical pathway.”
But after six months spent in
laboratory haematology and another six in
anatomical pathology, she decided
pathology was for her.
“I really enjoyed the anatomical
pathology. It was also a lifestyle choice:
the on-calls weren’t as rigid and
arduous,” says Dr Arbuckle.
>
“It’s the solving of problems – I think. That’s what I enjoy most
about paediatric and perinatal pathology,” she says. “It’s like
reading a detective novel and having a whole lot of clues present,
PHOTO CREDIT: LIZZY ADAMS
and you have to try to come up with an answer.”
“Sometimes it gets to me,” she admits. Having had
two miscarriages herself, Dr Arbuckle has empathy
with grieving parents.
According to Dr Arbuckle the field of paediatric and
perinatal pathology is a rapidly advancing one with
exciting new discoveries being made and new
technology and equipment being developed.
Time at Sydney’s Royal Prince Alfred
Hospital, as well as a short stint at
Sydney’s Camperdown Children’s Hospital
further refined her choice to paediatric
pathology.
In 1984 she flew to the United States
to do a fellowship in Paediatric Pathology
at the Children’s Hospital of Los Angeles.
“I enjoy the cases, and I enjoy the
clinicians involved with children. They are
a very caring group. One of the things that
strikes you [in paediatric medicine] is the
friendly atmosphere: you do feel a valued
part of the clinical team.”
After the US there were a hectic few
years where Dr Arbuckle combined
pathology tutoring at Sydney University
with looking after her young children
children, all born in just over four years.
She returned to the hospital system in
1990, starting at the Royal Hospital for
Women in Sydney, where her passion for
perinatal and placental pathology was
ignited.
“At the Royal Women’s you couldn’t
help but be interested in placental and
perinatal pathology,” she says.
Dr Arbuckle was appointed as staff
histopathologist to the Royal Alexandra
Hospital for Children in Camperdown in
1994, the hospital relocating to the
Children’s Hospital, Westmead a year
later.
20_PATHWAY
In 1996, when the hospital’s director
of pathology resigned, she was asked to
fill the position.
“That caused a bit of controversy at
the time, because I was a junior and had
only been here for a short time,” she says.
She went on to lobby for a Division of
Diagnostic Services at the hospital, which
was formed five years ago, of which she
is the current chairman.
In addition to her diagnostic work in
the laboratory, Dr Arbuckle has the
administrative duties that come with being
head of the department, which she
combines with teaching as well as
research.
Her main area of interest is perinatal
and placental pathology, particularly in
relation to foetal death.
“[Women] really need to know why it
happened, particularly with women being
older when they have their first baby
now,” she says.
“Once we get back the results the
parents will have a knowledge of what
happened with this pregnancy, and a
prediction of whether it will occur with the
next pregnancy.”
death can be found, but that’s not
necessarily a negative result.
“We might be able to say the baby is
normal, so at least they have some sort of
answer and can make some decisions
about their future.”
Over the course of a year Dr Arbuckle
and Dr Graf will perform about 300
autopsies between them. Dr Arbuckle also
sits on the perinatal working party, the
perinatal and maternal committee and the
birth defects committee for NSW Health.
An environment such as this poses
many challenges – not all of them
scientific.
She works closely with clinical
geneticists and cytogeneticists to make
sure she gets the appropriate tissue to
facilitate a diagnosis.
“Sometimes it gets to me,” she
admits. Having had two miscarriages
herself, Dr Arbuckle has empathy with
grieving parents.
It’s not always that straightforward, of
course. Sometimes no cause for the foetal
“I worried all through each pregnancy
that there might be something wrong,”
PHOTO CREDIT: LIZZY ADAMS
she says. “You realise that there’s this thin
line between something happening, and
something not happening,” she says. “We
always treat the baby with a huge amount
of respect and care.” All babies under 20
weeks gestation are cremated in a special
ceremony.
This sense of compassion, is also
apparent in other areas of Dr Arbuckle’s
work.
Recently she chaired a hospital group
on painful procedures.
“You really try to minimise pain for
different procedures,” she says. “Children
can develop needle phobias, or, if they are
always undergoing painful procedures,
that can have an impact on how they see
life.”
The committee implemented a host of
changes at the hospital: using local
anaesthetic cream before any blood is
taken; hiring a mural painter to decorate
treatment rooms; and developing “sensory
bags” to help distract children when
something is being done – a burns victim
having their daily dressing change, for
example.
According to Dr Arbuckle the field of
paediatric and perinatal pathology is a
rapidly advancing one with exciting new
discoveries being made and new
technology and equipment being
developed.
“It’s an exploding area, and every time
you turn around there’s been something
else added,” she says. “The sequencing
of the human genome made a big
impact.”
“For me, one of the interesting things
is that there’s a lot of information coming
out saying that the perinatal life has an
impact on later life.
“There are associations and
correlations with later outcomes. So, if
you can do something about growthrestricted foetuses you may improve the
life of these people in the long term, and
decrease the burden on society of
disease. It’s preventative medicine.”
And the most rewarding part of her
job?
“Finding an answer that’s going to
help someone.”
As satisfying as finding out who did it
in one of her detective novels?
“Coming to the conclusion on a baby
is actually far more satisfying,” Dr
Arbuckle says. “If you come up with an
answer and feel you are going to give the
family and the obstetrician something to
work on, there’s really nothing much more
satisfying than that.”
PATHWAY_21
hot topics
THE
vaccine revolution
IMMUNISATION HAS CHANGED THE
FACE OF INFECTIOUS DISEASES IN
CHILDREN. BUT, AS BIANCA NOGRADY
FINDS OUT, THERE ARE STILL
CHALLENGES TO BE MET IN THE
WORLD OF PAEDIATRIC
MICROBIOLOGY.
22_PATHWAY
>>>
eing a baby one hundred years ago was
a pretty dicey affair. Up to one in three
would not live to see their first birthday,
instead falling victim to any one of a long list
of diseases including smallpox, diphtheria,
measles, tetanus and whooping cough. Even
if they did successfully run the gauntlet of
these killers, they still had a lifetime of
fighting ahead of them. Something as simple
as a scratch could lead to an untreatable
and possibly fatal infection.
B
All that changed in 1796. A rural English
doctor called Edward Jenner discovered that
inoculating a person with material from a
cowpox lesion protected them against
subsequent smallpox infection, and the first
vaccine was born.
Since then, widespread immunisation
has lead to the complete eradication of
smallpox and, in the developed world,
almost relegated infectious diseases such as
polio, diphtheria, tetanus and measles to the
pages of medical history.
Immunisation has transformed paediatric
infectious disease management, according
to Dr Celia Cooper, director of microbiology
and infectious diseases at the Children’s,
Youth and Women’s Health Service in
Adelaide.
“Vaccination as a practice has been
demonstrated to be highly effective in
reducing the incidence of a whole number of
childhood diseases and they are diseases
that previously were very common and often
fatal,” Dr Cooper says. “In countries in the
world that don’t have effective vaccination
programs, these are still significant killers of
children.”
Immunisation in Australia
Immunisation really took off in Australia in
the 1920s with the introduction of the
tetanus, pertussis and diphtheria toxoid
vaccines, which were combined in 1953 to
form the first combination vaccine – DTPw.
Since then, childhood vaccines have been
introduced in Australia against polio,
measles, mumps, rubella, hepatitis A and B,
Haemophilus influenzae type B, chicken pox,
pneumococcal and meningococcal infection,
and, most recently, human papillomavirus
and rotavirus.
The childhood immunisation program in
Australia has been so effective that, as
microbiologist and infectious diseases
expert Professor Lyn Gilbert puts it,
“infectious disease is becoming a bit of a
bore”. But not entirely redundant.
Infectious diseases still claim young
lives, and while vaccines are effective, not
everyone gets them and they don’t protect
against everything.
Despite the existence of an effective
pertussis vaccine, pertussis, or whooping
cough – a throat infection caused by the
bacteria Bordetella pertussis - is still an
issue in Australia, says Professor Gilbert,
who is the Director of the Centre for
Infectious Diseases and Microbiology at
Sydney’s Westmead Hospital.
“Pertussis is still an ongoing problem but
patterns have changed, the age group has
increased,” Professor Gilbert says. “Children
are well protected so that most cases are
occurring now in adolescents and the
elderly.”
However this has the unwanted effect of
creating a potential reservoir of disease that
can then infect babies before they are fully
immunised at six months of age.
In NSW alone, regular epidemics of
pertussis have been occurring on an annual
basis, with up to 700 cases a month
reported in those peaks.
Professor Gilbert believes the solution
may lie in booster immunisations for schoolage children and the elderly, which may help
to eradicate this reservoir.
Respiratory infections such as pertussis
are still an area of concern in paediatric
medicine, says Dr Cooper. “Most of the
admissions with serious respiratory illness,
particularly children under the age of two,
would be respiratory syncytial virus (RSV),”
she says. In this age group, RSV can cause
bronchiolitis, which is inflammation of the
bronchioles of the lung, and lead to
pneumonia. It is highly contagious, and while
most children who contract it only
experience mild symptoms, in the very
young, and very old it can on rare occasions
be deadly. Unfortunately, no vaccine is yet
available, although clinical trials have been
conducted.
PATHWAY_23
>
“I think one of the important changes has also been … that
we’ve altered how we manufacture the vaccines to get a
better immune response,” says Dr Jelfs
The influenza challenge
Another paediatric respiratory bugbear is
influenza. “When we’ve been looking for it
in children, we realised that a lot of the
severe respiratory illness that brings
children into hospital start with flu and are
complicated by secondary pneumonia,”
Professor Gilbert says. A vaccine against
influenza is available but because of the
virus’ variability, a new vaccine must be
developed for each new strain that
emerges. But Professor Gilbert believes
there are arguments in favour of routine
child immunisation against influenza
annually.
“There are quite strong advocates for
routine childhood vaccination of
influenza,” Professor Gilbert says.
However, given the difficulties in
24_PATHWAY
developing vaccines against such a
readily adaptable pathogen, she
acknowledges the realities of producing
enough vaccine each year to vaccinate
not only all children but also the elderly.
“The cost of that is quite challenging.”
However, a trial is currently underway
to test the viability of such a proposal.
This year, the flu vaccine is available free
to all Western Australian children between
the ages of six months and five years, as
part of the study.
Gastrointestinal infections in children
have been dealt a major blow with the
recent introduction of the rotavirus
vaccine, but there are still other viruses
that have the potential to cause morbidity
among the vulnerable, including children.
Norovirus is a particular threat and there
are concerns it is becoming a leading
cause of gastrointestinal illness around
the world.
While more notorious for its role in
cruise ship outbreaks, Professor Gilbert
says norovirus has also been linked to
outbreaks in day care centres, yet there is
also no vaccine in sight.
Making a good vaccine better
Clinical microbiologist, Dr Janet Jelfs says
a lot of work is now focusing on improving
the vaccines we do have.
“I think one of the important changes
has also been … that we’ve altered how
we manufacture the vaccines to get a
better immune response,” says Dr Jelfs,
who is also a coordinator of the
immunisation handbook and immunisation
policy.
Antibiotic resistance
accines are most feted for simple prevention of disease, but
V
there is another bonus that is less recognised – a reduction in
the use of antibiotics. One area in which this is particularly
6ROLWRQ ,7
noticeable is infections caused by the bacteria Streptococcus
63((&+ 5(&2*1,7,21
pneumoniae, also known as pneumococcus, says Professor Lyn
' , * , 7$ / ' , & 7$7 , 2 1
Gilbert.
, 1 7 ( * 5 $7 , 2 1
“Particularly before the vaccine was introduced, there was an
increase in rates of antibiotic resistance and there are still problems
treating relatively minor pneumococcal infections such as otitis
6ROLWRQ,73DWKRORJ\5HSRUWLQJ
media, with antibiotics,” she says.
“One of the effects of the vaccine has been to reduce that
Ć'LJLWDO'LFWDWLRQ
problem, because the serotypes … that are in the vaccine are also
Ć5HDO7LPH6SHHFK5HFRJQLWLRQ
most likely to cause antibiotic resistance.”
Ć,QWHJUDWHVZLWKGHSDUWPHQWV\VWHP
But antibiotic resistance is rearing its ugly head in a particularly
Ć:RUNIORZ0DQDJHPHQW
frightening way with another pathogen Staphylococcus aureus, or
Ć%OXHWRRWKKHDGVHWIRUFXWXSURRPV
‘golden staph’.
Methicillin-resistant Staphylococcus aureus (MRSA) was once
the scourge of hospitals only, but a new, community-acquired MRSA
Ć3KLOLSV'30IRUPRELOHGLFWDWLRQ
Ć5HTXHVW)RUPVFDQQLQJ
has emerged.
“It’s not common but people are beginning to see it more and
beginning to get concerned about it,” Professor Gilbert says.
Unfortunately, a vaccine is yet to be developed so in the
Ć'LJLWDO,PDJLQJ0DQDJHPHQW
Ć5HSRUW3ULRULW\0DQDJHPHQW
Ć7\SLQJ3RRODGPLQLVWUDWLRQ
meantime, the focus is on finding antibiotics that the pathogen has
not yet developed resistance to.
One technique is to use a conjugated
system – boosting a vaccine by including
a protein designed to enhance the body’s
immune response and increase the
protective effects of the vaccine. “The
older Haemophilus influenzae type b
vaccine was only a polysaccharide
vaccine so it wasn’t as efficacious in
young children, but by changing it using
conjugated system we can elicit a better
immune response,” says Dr Jelfs.
A similar approach has been taken
with the pneumococcus vaccine, which
has also been improved to cover multiple
serotypes of the bacteria.
Another approach is to make vaccines
more targeted by moving away from
‘whole cell’ vaccines to a more refined
product, as has happened with the
diphtheria/tetanus/pertussis vaccine.
“It used to be whole cell, which meant
getting all these other antigenic
components which we really didn’t need
in there,” Dr Jelfs says.
Refining the vaccine down to its
essential antigenic components reduces
the risk of adverse reactions.
But while vaccines have been
3DOPHU6WUHHW
:LQGVRU
%ULVEDQH4OG
3K
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spectacularly successful in reducing child
PDLODX#VROLWRQLWFRP
morbidity and mortality in the developed
ZZZVROLWRQLWFRP
world, there is a still much to be done in
developing nations. Many children don’t
:DWWOH6WUHHW
have access to simple, cheap and
8OWLPR
effective vaccines that have saved so
6\GQH\16:
many lives in the developed world, and
3K
there are still no effective vaccines for
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some of the biggest developing world
LQIR#VSHHFKVROXWLRQVFRPDX
killers: HIV, tuberculosis and malaria.
ZZZVSHHFKVROXWLRQVFRPDX
GPs NOTE: This article is available for
patients at http://pathway.rcpa.edu.au
PATHWAY_25
close up
Human embryo. View of a human
embryo at 7-8 weeks old, known as a
first trimester embryo under the age of
12 weeks. The embryo is attached to
the placenta and the mother's blood
circulation by an umbilical cord (upper
left), and is seen floating in an amniotic
sac filled with amniotic fluid. At upper
right is the remnant of the yolk sac. The
embryo's eye and limbs are visible, as
is its male sex. During the first trimester
the embryo develops a distinct human
appearance; in this early period, organ
differentiation overshadows growth and
all the major organs have been formed.
At this age the embryo is about 4
centimetres in length and less than 10
PHOTO CREDIT: DR G. MOSCOSO / SCIENCE PHOTO LIBRARY
grams in weight.
diseases
When the
defences
are down
PRIMARY IMMUNODEFICIENCY DISEASE IS A COMMONLY SUSPECTED THOUGH INFREQUENTLY
OCCURRING DISORDER. MATT JOHNSON INVESTIGATES WHAT HAPPENS WHEN THE BODY’S OWN
IMMUNE SYSTEM IS FAULTY.
f you want to know how hard your
immune system works, have a child.
Spend long periods with humans less
than five years of age and you start to
appreciate how many viruses and
germs your well-developed, healthy
immune system is capable of brushing
off without you even noticing.
I
But the immune system of children
lacks both the power and
sophistication of an adult: it hasn’t
been exposed to as many viruses and
catalogued them for future protection,
and the small degree of defence it
gains from the mother’s immune
system is generally lost by the end of
the second year.
It’s why as many as 14 viral
infections a year are considered normal
in young children who attend childcare.
Even children who stay at home are
expected to have between five and 10
infections a year.
These figures explain why one in
four GP consultations in Australia is for
28_PATHWAY
a child with a febrile illness. But for
many parents, especially first time
parents, this frequency of infections
makes them suspicious their child may
have a problem with their immune
system.
infections can cause permanent
The World Health Organisation
currently lists more than 70 different
types of Primary Immune Deficiency,
each with different symptoms
depending on how the immune system
is affected. The symptoms ranging
from mild to life-threatening but they all
have one thing in common: multiple
infections.
conditions.
Individuals with Primary Immune
Deficiency suffer recurrent infections of
the ear, sinuses, throat and lungs that
recover only slowly with treatment, and
often deteriorate into more serious
bacterial infections such as pneumonia
and meningitis. Recovery between
infections is rarely complete for
children with Primary Immune
Deficiency, and over time the chronic
damage to organs.
In the more severe forms of Primary
Immune Deficiency, germs which
usually only cause mild infections can
develop into life-threatening
Pathologist and physician Dr
Elizabeth Benson understands parent’s
concerns with children who seem to be
constantly ill but is quick to remind
them that Primary Immune Deficiencies
are in fact relatively rare.
“Parents who’s children have 10
viral illnesses a year start thinking
there’s definitely something’s wrong,
but that is not necessarily the case.”
But Dr Benson is also cautious in
dismissing every case, aware that the
condition is widely under-diagnosed.
“The problem with any rare disease
is that doctors don’t always go looking
for it, which means they won’t find it,”
she explained.
“Parents who’s children have
10 viral illnesses a year start
thinking there’s definitely
something’s wrong, but that is
not necessarily the case.”
Testing for the disorder has become
sophisticated and accurate over the
past decade but many doctors remain
reluctant to order the tests.
This is partly because the disease
is considered rare, and partly,
according to Dr Karl Baumgart,
Immunopathologist and Consultant
Physician in Clinical Immunology and
Allergy at the North Shore Medical
Centre in Sydney, because the nature
of immune diseases have become
increasingly confused.
“The word ‘immune’ has been
grabbed by the alternative medicine
world and it’s lead to confusion in
patients and to a mixed level of
enthusiasm in GPs for seeking the
most aggressive forms of assessment
and treatment.”
All of these factors have combined
to create an average delay of six years
between recognisable symptoms for
the most common form of Primary
Immune Deficiency and the diagnosis
of the disorder.
“It’s frustrating to see people come
along with symptoms that have been
neglected for long periods and have
subsequently suffered end-organ
damage that could have been
prevented,” says Dr Baumgart.
“People
fair share of
investigated
Deficiencies
he says.
who get more than their
infections should be
with Primary Immune
ruled out as the cause,”
“It’s very important to be diagnosed
because the treatment is now very
PATHWAY_29
>
All Primary Immune Deficiencies appear genetic in origin with a
mutated or faulty gene failing to instruct the body to create
essential elements of the immune system.
effective for some forms of this
The register, collated from doctors’
account for 3% and complement
disorder and that means people can
reports, quotes the 2006 prevalence
deficiencies just 1%.
lead a very long normal life.”
rate of Primary Immune Deficiency as
Antibodies are proteins found in the
blood and are the end product of a
complex immune reaction that starts
when a germ or other foreign object is
identified by a type of white blood cell
known as a “B cell”. B cells in turn
produce plasma cells that then create
antibodies which attach to the foreign
particles, marking them for destruction
by other immune cells.
The most serious inherited
immunodeficiencies are rarely
6-14 per 100,000 individuals.
Although it probably underestimates
misdiagnosed because they become
the true prevalence, this figure still
apparent almost immediately after birth
translates to only one in every 100 GPs
but, according to Dr Baumgart, the
coming across a patient with a
milder forms now being identified may
symptomatic Primary Immune
not reveal their long term effects until
Deficiency in their working lifetime.
patients reach their twenties and
thirties.
The actual rate of Primary Immune
Of all Primary Immune Deficiencies
in Australia, antibody deficiency is by
far the most common, capturing 81%
Deficiencies is gradually emerging since
of diagnosed cases. Severe combined
an Australian register of Primary Immune
immune deficiency (SCID) makes up
Deficiency was established in 1990.
just 7% while neutrophil defects
THE 10 WARNING SIGNS OF
PRIMARY IMMUNODEFICIENCY*
1.
EIGHT OR MORE NEW EAR INFECTIONS WITHIN A YEAR.
2.
TWO OR MORE SERIOUS SINUS INFECTIONS WITHIN A YEAR.
3.
TWO OR MORE MONTHS ON ANTIBIOTICS WITH LITTLE EFFECT.
4.
TWO OR MORE PNEUMONIAS WITHIN A YEAR.
5.
FAILURE OF AN INFANT TO GAIN WEIGHT OR GROW NORMALLY.
6.
RECURRENT DEEP ABSCESSES IN THE SKIN OR ORGANS.
7.
PERSISTENT THRUSH IN MOUTH OR ON SKIN, AFTER AGE ONE.
8.
NEED FOR INTRAVENOUS ANTIBIOTICS TO CLEAR INFECTIONS.
9.
TWO OR MORE DEEP-SEATED INFECTIONS SUCH AS MENINGITIS,
OSTEOMYELITIS, CELLULITIS, OR SEPSIS.
10. A FAMILY HISTORY OF PRIMARY IMMUNODEFICIENCY.
*Courtesy of The Jeffrey Modell Foundation and the American Red Cross.
30_PATHWAY
Antibodies are also known as
immunoglobulins, and the different
types, or classes, of immunoglobulins
play different roles in immune
defences. Immunoglobulin M (IgM) is
usually the first antibody to respond to
an invading pathogen, but it’s the far
more abundant Immunoglobulin G (IgG)
antibodies that coat germs so other
immune cells can engulf them that
contribute to the majority of the
antibody response.
Immunoglobulin A (IgA) is produced
and secreted in body fluids such as
tears, saliva, and mucus, where it
protects the entrances to the body –
the mouth, nose, lungs, and intestines.
Present in breast milk, IgA provides
protection against bacteria in the
intestines of newborns.
There are other types of white
blood cells that can be affected by
Primary Immune Deficiencies. “T cells”
not only control B cells but they can
also attack cells that have been
infected by viruses; while neutrophils
and monocytes contain potent
chemicals to destroy the germs they
engulf.
Finally, “the complement system” is
a series of more than 20 proteins found
in the blood that work together to
destroy bacteria and attract white
bloods cells to sites of infection.
Primary Immune Deficiency,
Selective IgA Deficiency may occur in
as many as one in every 300 people,
but this figure is only extrapolated from
blood donors because most people
with IgA deficiency never develop
significant symptoms.
At the other extreme, Severe
Combined Immune Deficiency (SCID)
and T cell deficiencies where a
multitude of the body’s immune
systems are damaged is far less
common but much more debilitating.
Where does it start?
How the disorder occurs and how
severe its effects will manifest is slowly
being discovered as scientists unravel
the genetic nature of the disorder.
All Primary Immune Deficiencies
appear genetic in origin with a mutated
or faulty gene failing to instruct the
body to create essential elements of
the immune system.
Some Primary Immune Deficiencies
are recessive, some are X-linked and at
least one is autosomal dominant. And
while many Primary Immune
Deficiencies can be traced to a single
gene, others cannot and some Primary
Immune Deficiencies have more than
one pattern of inheritance: Common
Variable Immunodeficiency (CVID) can
be inherited as recessive, dominant, or
X-linked or without any family pattern.
Even people who share the same
gene mutation can have different forms
of the disorder, underlining the
complexity and highly interactive
nature of the immune system.
“The immune system is a lot like a
high school,” explains Dr Baumgart “a
few bad kids in year 10 can disrupt the
function of the whole school but it’s
not the entire school that’s bad.”
A lack of understanding about the
complex cascades that occur during an
immune response is, according to Dr
Baumgart part of the problem in testing
patients for Primary Immune
Deficiencies.
“Measuring if the patient is antibody
deficient will capture most of the
disorders,” he says.
Testing for Primary Immune
Deficiencies is relatively straightforward
with just two blood tests – a full blood
count and immunoglobulins levels -detecting most immunodeficiencies
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cells looking for invaders. In
…because it’s not
just a test, it’s a patient.
some cases a trigger which
could include Primary Immune
Deficiency causes the body to
make T cells and antibodies
directed against its own cells
and organs. These T cells and
autoantibodies then attack
particular cells. Type I diabetes
and rheumatoid arthritis are
examples of autoimmune
disorders.
“They are quite simple tests,”
explained Professor Warwick Britton,
an Immunopathologist who is the
Bosch Professor at the University of
Sydney. “We basically look to see if all
the right immune cells present, in the
right numbers.”
In addition to total immunoglobulins
levels, the immunoglobulin test shows
levels of the different immunoglobulin
types (IgG, IgM, and IgA). “It’s vital
these test results are matched to age
and population,” explained Professor
Britton.
For example, maternal IgG, but not
IgA or IgM, cross the placenta and
maternal IgG levels reach their peak
within six months of age, so a normal
IgG in a 6-month-old infant does not
necessarily exclude an antibody defect.
Similarly, a low IgA is not uncommon in
children under six months of age and
some medications can cause low IgG,
IgM and IgA in children.
Genetic testing for the disorder is
available but is not currently covered
by Medicare. Largely unnecessary in
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>
PATHWAY_31
diagnosing the syndrome, it’s still
“The development of the Primary
marrow is a close biological match.
useful in determining if the mother is a
Immune Deficiency register has been
Bone marrow transplants work well for
carrier before she has more children.
fundamental in the growing use of IV
SCID, because children with SCID lack
gammaglobulin,” explained Professor
Treating Primary Immune
Deficiency
T cells that could attack the bone
Britton. “Before the register the Red
marrow graft and cause rejection, but
Cross knew more was being used but
even then the results are not
Once diagnosed, treatment for the
they didn’t know why, and the register
guaranteed.
most common form of Primary Immune
has been a central point for the
Deficiency, antibody deficiency, is now
planning and assessment of efficacy of
remarkably effective.
the treatment.”
Immunoglobulin-replacement
For the more severe forms of the
therapy uses immunoglobulins from
disease treatment options are still
thousands of donors pooled so each
being developed.
batch contains antibodies to many
different types of germs.
Administered intravenously in large
Injections of cytokines, gamma
interferon or growth factors such as
Granulocyte-macrophage colony-
doses every three to four weeks this
stimulating factor (GM-CSF) can boost
therapy can boost immunoglobulin
the development of white blood cells
levels to near normal, eliminate most
and they have injected hope into what
infections and allow an otherwise
was once a dismal prognosis.
normal life. If treatment begins early
For the most severe and life-
enough, it can even prevent long term
threatening immunodeficiencies, bone
organ damage and reduce the
marrow transplantation have long
development of auto-immune disorders
offered the only chance of a permanent
later in life.
cure, but they require a donor whose
32_PATHWAY
Treatments on the horizon include
cord blood transplants and gene
therapy which despite early promise
has failed to provide a lasting cure.
But new genes are constantly being
identified and, probably more
importantly, clinicians, pathologists and
immunologists are making headway in
untangling the intricate cascades and
pathways that control the immune
system. Within this understanding lie
the new treatments that will if not cure,
then at least control the disease.
GPs NOTE: This article is available for
patients at http://pathway.rcpa.edu.au
movers & shakers
PHOTO CREDIT: EAMON GALLAGHER
Finding what lies
beneath
FORENSIC PATHOLOGIST, DAVID RANSON HAS BEEN
ONE OF THE PIONEERS OF ROUTINE MORTUARY
BASED CT SCANNING. HERE HE TALKS TO JUSTINE
COSTIGAN ABOUT THE BENEFITS THIS ASSESSMENT
BRINGS TO FORENSIC INVESTIGATION.
few years ago the Victorian Institute
of Forensic Medicine (VIFM) received
an unusual delivery. The police brought
them a suitcase that had been discovered
in the course of a murder investigation.
They didn’t know what was inside but
were suspicious enough to ask the VIFM
to investigate. The ordinary looking
suitcase was duly delivered and it was
soon established that it contained a
human corpse. The body also contained
an unusual prosthetic implant, the clue the
police needed to quickly identify the body.
A
All of this was done without opening
the suitcase.
For anyone unfamiliar with forensic
medical technology, this scenario presents
PATHWAY_33
>
PHOTO CREDIT: EAMON GALLAGHER
an intriguing puzzle. What extraordinary
powers of detection were at play? Did the
suitcase have an odour? Did the weight
and feel of it indicate it might contain a
deceased adult male? Or was it just a
lucky guess based on years of
experience?
The answer to these questions is, of
course, none of the above. The VIFM
relied on a familiar and well-used piece of
everyday hospital equipment – a
computed tomography scanner, or CT
scanner, as it is commonly called – to
present the police with these basic facts.
Once the suitcase had been scanned
a computer image revealed its contents;
34_PATHWAY
not only did it show the body, complete
“The CT scan is really like taking a
with prosthetic, but it also indicated a
medical history,” says Dr Ranson. “When
possible cause of death, allowing the
you don’t have a personal history, or a
forensic team to carefully plan the next
complete medical history for the
step in the process, the autopsy itself.
deceased, a CT scan can show you
While the fundamentals of autopsies
evidence of previous surgery, for example.
have basically remained the same for
It gives you more information to work with
decades, if not centuries, new
and helps with planning the autopsy. It’s
technologies are helping forensic
an important filter.”
pathologists fine-tune the process.
“The more you know about the
VIFM Deputy Director, Dr David
deceased before you begin the autopsy
Ranson says that CT scanners help
the better,” says Dr Ranson. “Surgeons
pathologists plan their autopsies and in
approach their patients in the same way. It
some cases can do away with the need
allows you to focus your attention on the
for an autopsy at all.
areas that need it most.”
“The more you know about the deceased before you begin the
autopsy the better,” says Dr Ranson. “Surgeons approach their
patients in the same way. It allows you to focus your attention on
the areas that need it most.”
Autopsies and children
ne of the most common responses from families when presented
with the possibility of an autopsy is that they “don’t want their loved
one to suffer any more.” Although this is an emotional rather than a
logical response, Dr Ranson and his colleagues at the VIFM understand
that what people are actually saying is that they cannot bear the thought
of their family member or friend being touched or cut open.
O
The mere thought of it causes them great anguish. And when the
deceased is a child, this suffering is often even greater.
While autopsies are often necessary in unexplained paediatric
deaths, Dr Ranson cites several examples where the use of a CT
scanner or a traditional x-ray as part of the standard pre-autopsy
medical history has enabled pathologists to provide coroners with
enough information to find a cause of death without ordering an
autopsy.
There are further benefits: CT scans
are a 3D representation of the body that
can be kept indefinitely and used in court;
they provide pre-autopsy information that
inform occupational health and safety
precautions; and it’s possible to see some
regions of the body much more easily on
Conversely, CT scans have also shown previously undetected
injuries, such as an internal haemorrhage, leading to suspicion of
assault.
Children, particularly infants, need to be prepared for autopsy
differently to adults. While the use of a CT scanner is extremely effective
in getting an overview of an adult body, babies’ bones are so fine that a
CT scanner sometimes cannot pick-up all the detail. In these cases, a
traditional x-ray is more effective in delivering a picture of the child’s
skeleton.
a scan that you can during autopsy.
Despite this long list of pluses, the
VIFM is one of only a few forensic medical
departments around the world that scans
every body that comes into their care as a
matter of course. Aside from the US
Military, which scans every returning
deceased soldier, the VIFM is one of the
few forensic institutes in the world to use
CT scanning as an automatic part of every
forensic death investigation.
Funded by the Victorian State
Government, the VIFM CT scanning
program was developed as a part of
planning for the 2006 Commonwealth
Games in Melbourne. Asked to come up
with strategies to respond to a major
disaster (such as a terrorist attack), the
automatic scanning of every body was
designed to facilitate quick identification
and to keep a record of every body that
came into the mortuary.
In practice for almost three years, the
VIFM now has a database of information
that is generating interest around the
world.
“When forensic pathologists have to
identify a body they usually refer to the
standard anatomical tables. However,
these tables are now very out of date. Not
only have people changed (size and
weight) but our society has changed too.
We live in a multicultural city and the
bodies coming into the mortuary may
have originally come from all over the
world,” says Dr Ranson.
A quiet revolution in the world of
forensic pathology, David Ranson believes
that mortuary based CT scanning will
inevitably become standard practice in all
forensic investigation. “The scanner offers
a higher standard in death investigation
and in some cases, can provide
information that a traditional autopsy can’t.
But it’s also providing us with research
data that will help us identify unknown
persons and solve missing persons cases.
The research currently underway is also
being used to assist with the examination
of mass graves in the aftermath of wars
and natural disasters.”
David Ranson is the Deputy Director of the
Victorian Institute of Forensic Medicine, a
clinical associate professor in the Department
of Forensic Medicine at Monash University and
the Director of the National Coroners’
Information System. He is a specialist in
forensic pathology and clinical forensic
medicine with a strong professional interest in
Medical Law.
PATHWAY_35
RCPA update
Snapshot of
Pathology Update 2008
14- 16 March 2008
PATHOLOGY UPDATE IS TRULY A UNIQUE CONFERENCE, WHICH BRINGS
TOGETHER EIGHT DIFFERENT DISCIPLINES OF PATHOLOGY OVER A THREE DAY
SCIENTIFIC MEETING, OFFERING SOMETHING FOR EVERYONE.
Cocktail Party
36_PATHWAY
Gala Dinner
Award Ceremony
PATHWAY_37
cutting edge
Childhood
leukaemia
– A GENETIC SUCCESS STORY
THE ADVANCES IN UNDERSTANDING, DIAGNOSING
AND TREATING ACUTE LYMPHOBLASTIC LEUKAEMIA
REPRESENT SOME OF THE BEST MODERN MEDICINE
HAS TO OFFER, AS ALEX WILDE REPORTS.
38_PATHWAY
ass murder is not only the stuff of
action movies. When the enemy is
leukaemia, traditional chemotherapy
indiscriminately attacks all newly-dividing
cells, whether leukaemic or not – with
severe side effects.
M
But it is now known that not all
patients with childhood leukaemia need
such aggressive treatment.
With survival rates for acute
lymphoblastic leukaemia currently
approaching 80% – up from a dismal 5%
in the 1940s – doctors have noticed
individual differences in the likelihood of
remission.
Overall about 20% of young patients
with this type of leukaemia fail to respond
to therapy and experience a relapse. But
researchers have found that this 20%
don’t always have the classic clinical
indicators of poor prognosis, such as a
high initial white blood cell count. Thanks
to recent advances in DNA technology,
pathologists can now analyse features of
the cancer and have identified particular
pathological markers that are associated
with a higher risk of relapse.
The upside of this, is that patients
without these markers generally have a
better chance of remission and therefore
can be given less intensive chemotherapy,
with the advantage of lower toxicity and
fewer side effects. The most intensive
treatment, including bone marrow
transplantation, is reserved for patients
with highest risk of relapse.
Identifying those at higher
risk of relapse
Dr Luciano Dalla-Pozza, paediatric
oncologist and senior staff specialist in
childhood cancer at the Children's
Hospital at Westmead says high risk
patients can be identified by various
means.
One marker of higher risk is how well
that patient initially responds to treatment.
Determining the response to treatment
involves measuring the concentration of
new leukaemic cells, known as blast cells,
in the blood in the seven days following
treatment with a single agent.
“If the level falls to under 1000 (1.0 x
9
10 per litre) within seven days then that
child has good risk disease, if it stays
above 1000 that child has high risk
disease.”
Another means of identifying those at
high risk of relapse is determining the
presence or absence of one or both of
two critical genetic mutations.
Having the Philadelphia chromosome
t(9;22) translocation or the t(4;11)
translocation in a leukaemia cell is a
stronger predictor for high risk of relapse,
Dr Dalla-Pozza says.
The Philadelphia chromosome –
named after its co-discoverer from
Philadelphia – occurs due to a fusion of
the ABL gene on chromosome 9 and a
gene known as the BCR gene, on
chromosome 22. This ‘new’ gene known
as a BCR-ABL produces an abnormal
fusion protein, which stimulates tyrosine
kinase activity, resulting in leukaemic
disease.
Another strong predictor of relapse is
the presence of a tiny number of cancer
cells that sometimes remain in the patient
during treatment or after treatment when
the patient is in remission.
PATHWAY_39
>
“There are a myriad of pathways to get to cancer but they all involve key genes, at least
100-200 key genes. So it is very unlikely you will get the precisely same pathway in the
development of leukaemia in one child to the next.”
“You take two children and give them chemotherapy and let’s say one loses her hair and
one doesn’t. There is something about the child that enables them to be resistant to that.
Known as minimum residual disease,
or MRD, laboratory tests, up until a
decade ago were not sensitive enough to
detect its presence.
containing sequences from ABL and BCR
But since the development of
polymerase chain reaction (PCR)
technology, minute levels of cancer cells
can be measured in tissue samples sometimes in concentrations as low as
one cancer cell in a million normal cells.
cytogenetics to PCR, but these
“Having minute amounts of leukaemia
carries a poor prognosis, yet the bone
marrow of these patients looks normal. So
the tests we would do by other means
would say that the child is in remission,”
Dr Dalla-Pozza says
and the DNA based techniques of PCR,”
she says.
“Sensitivity increases from
techniques are complementary. For
example FISH can show if another genetic
event such as deletion of ABL has
happened,” Dr Smith explains.
Detecting MRD in patients with acute
lymphoblastic leukaemia in remission has
profound prognostic importance says
clinical haematologist and oncologist
Professor Glenn Marshall.
“Survival curves go up by 5-10%
“The technology used [to detect MRD]
is based on the fact that leukaemia cells ..
arise from one cell, and [each] cell carries
a unique signature.”
every 5-10 yrs and that is because we’re
“So .. we take the leukaemia cells,
recognising that all those leukaemia cells
came from the same parent cell, so they
all have exactly the same signature,” Dr
Dalla-Pozza says.
treatment earlier,” says Professor
“We sequence the relevant part of the
.. gene to find a signature that is unique
for that leukaemia cell for that patient.”
conducting continual clinical research into
identifying patients who are at high risk of
relapse, and giving them stronger
Marshall, who is also director of the
Centre for Children’s Cancer and Blood
Disorders at Sydney Children’s Hospital.
“High risk patients did have a 30-40%
cure rate, which reached 60% in our last
study. But increasing intensity of
treatment increases toxicity… High risk
Techniques
Dr Ellie Smith, senior staff specialist in
cytogenetics at the Children’s Hospital,
Westmead, says a range of techniques
are employed by pathologists to identify
high risk markers.
“Techniques can include cytogenetics
with G banded chromosomes, molecular
cytogenetics (FISH) with probes
40_PATHWAY
patients now get a bone marrow
transplant even in first remission, [which
means] there is also a high risk of fatality.”
“It is important to continue to identify
new kinds of drugs that are directed
against particular molecular targets in
childhood acute lymphoblastic leukaemia
and that’s where we see the advances
coming in the next decade or so.”
Molecular assassins
Unselective anti-leukaemic agents
bombarding young developing bodies
take innocent casualties; typically cells
responsible for hair growth and cells that
replace the lining of the intestine are
destroyed along with the newly dividing
cancer cells.
Developing molecular-based targeted
therapies that fight specific cancer cells
while leaving normal cells unharmed is the
ultimate aim of cancer researchers. And it
is already a reality in chronic myeloid
leukaemia.
Chronic myeloid leukaemia was the
first malignant disease to be linked to
genetic abnormality. The first targeted
therapy was the tyrosine kinase inhibitor,
imatinib mesylate, (Glivec) which
specifically inhibits the activity of the
BCR-ABL protein.
The hunt is on to find the genetic
mutations involved in other similar
cancers. But while new technology has
enabled researchers to look at the activity
of thousands of genes at once, the
scientists are yet to confirm single genes
involved in acute lymphoblastic leukaemia
or acute myeloid leukaemia.
Dr David Joske, head of clinical
haematology Charles Gairdner Hospital in
Perth says researchers are closing in on
candidate groups of genes linked to acute
lymphoblastic leukaemia, but points out
the molecular pathways involved are
much more complex than those
associated with chronic myeloid
leukaemia.
G banded chromosomes in a child with ALL and a hyperdiploid karyotype (count 55,
additional chromosomes arrowed), associated with a favourable prognosis.
“In acute lymphoblastic leukaemia, we
have found abnormalities in genes of the
receptors of the bone marrow cells that
affect their growth. We have found
abnormalities in genes within the cell,
directly involved with cell growth, like
tyrosine kinase.
“There are probably genes that affect
the blood supply to the tumour cells even
within the bone marrow .. and there are
even some genes that probably alter the
bone marrow micro environment which do
or don’t permit the malignant cells to
grow.”
“There are several new classes of
chemo agents coming through and there
is a lot of work to be done in the coming
weeks and months to ascertain which are
going to be effective in the acute
leukaemias.”
The significance of
individual variation
Dr Dalla-Pozza predicts that advances in
the study of individual differences based
on genetic variation will eventually be
highly influential in helping pathologists
understand more about the behaviours of
cancers and patients’ likely response to
treatment.
“There are a myriad of pathways to
get to cancer but they all involve key
genes, at least 100-200 key genes. So it
is very unlikely you will get the precisely
same pathway in the development of
leukaemia in one child to the next.”
can do all these wonderful precise
assessments of sequences of genes, are
very important in providing you with
clues.”
But Dr Dalla-Pozza warns that
untangling which particular abnormalities
are relevant is going to take some time.
“There will be so many different spots,
if you take a gene and you find 20
“You take two children and give them
chemotherapy and let’s say one loses her
hair and one doesn’t. There is something
about the child that enables them to be
resistant to that.
different alleles or 20 different SNPs on
Each child has a set of polymorphisms
which explain we believe why they either
experience little toxicity or why they
experience a lot of toxicity; why they
might be at risk for heart disease later on
as a consequence of treatment; why their
body might eliminate the drug from their
body so quickly so that the cancer cell
isn’t exposed for long enough.”
usually only relevant in conjunction with
“Current single nucleotide
polymorphism [SNP] analyses, where you
pushing the cell into the cancer state,” he
them you might very well find two are
highly relevant, three are only relevant
70% of the time. And considering they are
differences in other genes, we still need to
be able to put them all together into some
sort of interpretable collage.”
“Ultimately I think proteomics will be
the next key area of development. We will
be able to define that certain proteins
were produced or that they cooperate in
says.
PATHWAY_41
No ties please we’re
British
ritain’s recent move to ban doctors
from wearing ties has drawn criticism
from doctors who say there’s scant
evidence that ties spread infections.
B
The National Health Service banned
doctors, including senior hospital
consultants, from wearing ties due to a
claim that they could spread hospital
superbugs such as MRSA.
Doctors' long-sleeved coats, jewellery
and even their wristwatches have also
been eliminated from hospitals as a
potential infection hazard.
However a US infection-control expert
claims to be very bemused by the move.
In a US newspaper, Dr. William
Schaffner, chair of the department of
preventive medicine at Vanderbilt
University in Nashville said "There is no
data showing that neckties transmit bugs.
Hands - that's where we ought to put our
focus."
“Anyone who touches a patient must
wash their hands before and after the
contact. Better yet, health professionals
should use a hand-hygiene foam or gel
that contains alcohol and kills up to 98%
of bacteria germs, as well as cold and flu
viruses.
"The trick is not to transmit
[pathogens] to patients and the
overwhelming consensus about how
doctors might transfer [them] is via their
hands," said Dr Schaffner.
Indians at higher risk of
atherosclerosis
atients from Indian backgrounds are more susceptible to the atherogenic effects of
cholesterol and diabetes while having no protection conferred by HDL, Australian
researchers have shown.
P
Using ultrasound to measure carotid intima-media thickness, researchers at the
George Institute for International Health in Sydney found that total cholesterol levels and
diabetes had much stronger associations with atherosclerosis in 300 south Asian Indian
patients compared to a sample of more than 1000 Caucasian Australians. The same
stronger associations with atherosclerosis were seen for diabetes.
The findings, published in the journal Atherosclerosis (199: 116-22), also show that
while higher HDL levels were associated with less atherosclerosis in Caucasian
Australians, the reverse was true for Indian subjects.
While there was no clear mechanism to explain the differences in atherosclerosis
risk, the explanation might lie in genetic predisposition, dietary factors such as folate or
recent trends towards a higher fat diet, the researchers said.
“There is a strong basis for expecting these differences to translate into worse risks
of major vascular events,” they said.
“These findings argue for specific and intensive strategies for the management of
lipids and glucose levels in South Asian Indians,” they conclude.
42_PATHWAY
Measles
resurgence
M
easles is resurgent this year
with outbreaks in NSW and
Queensland being attributed to
children and young people who have
missed out on MMR vaccine.
National figures show that while
there were only seven cases in 2007
– all among people exposed
overseas - there have already been
58 cases to July this year and many
infections appear to be locally
acquired.
"These latest cases do not
appear to be related which shows
the disease is circulating in the
community,” said Dr Jeremy
McAnulty, Director Communicable
Diseases for NSW Health.
He said a significant proportion
of measles cases this year were in
children who had not been
immunised, or had only received one
dose of the two-dose vaccine.
"We are seeing cases in infants
less than 12 months of age who are
not yet due for immunisation and
cases in young adults who have
missed out on the MMR vaccine.”
A Federal health department
spokeswoman said most measles
cases were localised clusters and
outbreaks in NSW and Queensland,
and secondary cases associated
with cases that acquired measles
outside of Australia.
Dr McAnulty urged parents to
ensure their children had the MMR
vaccine at 12 months of age and the
second dose at age four years.
“Adults up to 42 years of age
should also make sure they are
protected with two doses of MMR
vaccine, unless they are certain they
have had measles in the past,” he
said.
Bacteraemia less likely
than UTI in kid
ince the introduction of routine pneumococcal vaccination, young children
S
presenting with fever but no localising signs are most likely to have a UTI,
Sequential
therapy best
for H. pylori
according to US researchers.
While a UTI was always one of the differential diagnoses of fever of unknown
origin in children under three, pre-PCV7, occult bacteraemia was also a common
cause of fever.
However, on analysing all the paediatric blood cultures taken in the emergency
department of a major US hospital in the years pre- and post-PCV7, the researchers
found the vaccine had seen the frequency of occult bacteraemia drop dramatically.
“Bacteraemia with a pathogen has gone from 1 in every 14 children assessed to 1
in 275 children,” the researchers say in Archives of Diseases of Childhood Published
Online First: 6 June 2008.
According to the study, children with fever of unknown origin were just as likely to
have occult bacteraemia as a UTI prior to the introduction of the PCV7. In the years
after the vaccine however, a UTI was found to be the diagnosis 20 times more often
than occult bacteraemia.
“Based on our data, the emphasis in management of children with [fever without
localising signs] should be on diagnosing UTI,” the researchers say.
High risk of toothbrushing
eople are more at risk of bacteraemia from brushing teeth than from having a
P
tooth extracted, new research suggests.
The findings call into question the appropriateness of the routine use of
prophylactic antibiotics in at-risk patients, the US researchers said.
Published in the journal, Circulation (117: 3118-25), the randomised controlled trial
involved bacterial cultures being taken at various time points before, during and after
various interventions including toothbrushing and dental extraction with and without
antibiotic prophylaxis.
Unsurprisingly, they showed that antibiotic cover resulted in a significant reduction
in the incidence of positive cultures.
But although bacteraemia did not occur as frequently, for as long, or to the same
degree with toothbrushing as with dental extraction, a substantial proportion of
toothbrushing events (23%) were found to result in bacteraemia of infective
endocarditis-causing species of bacteria.
The researchers calculated that the potential for bacteraemia to occur from
toothbrushing alone was >200 times a year (based on twice daily brushing) compared
with an average of fewer than two dentist visits a year.
Toothbrushing may be a greater threat for individuals at risk of infective
endocarditis than dental extraction, they concluded.
While saying it is unfeasible to advocate antibiotic coverage for toothbrushing, the
study authors do suggest “there should be a greater focus on avoidance of dental
disease in patients at risk for distant site in general and for infective endocarditis in
atients with H. pylori are more
likely to be cured of the infection if
they are treated with antibiotics given
in sequence rather all together, says H.
pylori guru, Professor Barry Marshall.
P
In an editorial in the Annals of
Internal Medicine (148: 962-63),
Professor Marshall supports the
finding of a meta-analysis , in the
same journal that confirms the efficacy
of sequential therapy over and above
the more traditional triple combination
therapy. Triple therapy is now
associated with a 20% failure rate
largely due to clarithromycin
resistance, he notes.
Typically sequential therapy
involves an initial 5-day therapy with a
combination (for example pantoprazole
40mg with amoxicillin 1g twice daily)
followed by five days of two further
antibiotics plus a PPI (for example
clarithromycin 500mg, tinidazole
500mg, plus pantoprazole 40mg twice
daily).
Professor Marshall says
clarithromycin resistance is commonly
due to random mutations in the H.
pylori gene that prevent binding of the
antibiotic, rendering it ineffective.
Initial treatment with amoxicillin
significantly reduces the H. pylori
population (even eradicating it in 50%
of cases), meaning that it is much less
likely such resistance-causing genetic
mutations will be encountered when
the clarithromycin is introduced.
Also by combining two dissimilar
agents to eradicate the relatively small
residual population of H. pylori, high
cure rates are possible.
With the added advantages of
being cost-effective and not
associated with any additional sideeffects, Professor Marshall suggests,
the 10 day sequential regime is the
treatment of choice for eradicating H.
pylori.
particular.”
PATHWAY_43
foreign correspondence
Making a difference in Africa
TEACHING FINE NEEDLE
CYTOLOGY TO RESOURCEPOOR COLLEAGUES IN AFRICA
PROVES TO BE THE
PATHOLOGY EQUIVALENT OF
TEACHING A MAN TO FISH FOR
DR ANDREW FIELD, AS LOUISE
MARTIN-CHEW DISCOVERS.
ine needle cytology is a simple
F
procedure. A simple, quick,
inexpensive procedure that can enable
cytopathological diagnosis of a range of
aberrant lumps from lymphomas to breast
cysts
44_PATHWAY
Unlike much pathology, fine needle
cytology can be done without a laboratory
and requires little equipment (four jars,
needles, slides and a microscope).
It carries little risk of complications
and involves minimal trauma to the
patient.
However in order for it to be effective
the operator needs good training and
experience, a rare combination in many
countries in the world.
Since 2006, Sydney-based
cytopathologist Dr Andrew Field and his
Canadian colleague Dr Bill Geddie have
been sharing their expertise in the
technique with pathologists in African
countries.
The acquisition of skills in fine needle
cytology has the potential to significantly
improve diagnostic capabilities in these
medically resource-limited countries, and
already the efforts of Drs Field and
Geddie are proving worthwhile.
Dr Field learned the technique at the
birthplace of fine needle cytology, the
Karolinska Institute, Stockholm in 1989,
following his qualification as a
cytopathologist.
While taught to all students as part of
anatomical pathology training, fine needle
cytology is generally considered a superspecialty, with additional qualifications
available for those with a particular
interest in the technique.
The Royal College of Pathologists of
Australasia has only relatively recently
instituted a separate cytopathological
CASE STUDY 1:
Uganda
Opposite page:
Left: The crowded Mulago treatment rooms where the samples are stained
Top right: Rapid diagnosis of a stained slide using a basic microscope
Bottom right: Teaching staining techniques in Lagos
“
training program, a diploma first offered in
1996.
“There were four nurses all lined up in their
1960s style nursing kit and a large group of
surgeons, the registrar, and the hospital
administrator. The boy was brought in and he was
obviously very frightened. He had been on the ward
for two and a half weeks. They had tried to do a fine
needle, which had been unsuccessful, and then
incisional biopsy under local anaesthetic which had
been traumatic. “
The technique was discovered in the
1930s but not explored fully until Zajicek
and Franzen began to work with fine
needles and brought the technique to
international attention from about 1947 in
Stockholm.
Dr Field’s training was conducted by
the influential Torsten Lowhagen.
He notes, “The accuracy of a fine
needle aspiration to the breast [for
example] is about 95 per cent. However
fine needle cytology is very dependent on
who does it. You need an experienced
person to do it because getting the
material and making good smears with
that material is paramount.”
The procedure requires a very fine 2325 gauge needle. An alcohol wipe is used
on the skin and then the needle is
inserted through the skin into the lump.
Most commonly the technique is used
with lumps and lesions found in the
breast, thyroid or skin, but it may be used
just about anywhere.
Local anaesthetic is not usually
required and the whole procedure takes
only a minute or two.
Once the material is in the needle it is
expressed using a syringe and is smeared
onto a slide. There are
two ways of fixing that
smear: first in alcohol
and then with a
Papanicolai stain. It is
then air-dried, and fixed
in ethanol before
staining and washing.
The slide is examined
under the microscope,
and an immediate
cytological assessment
of the lump or lesion is
available.
This aspirant was on a 14 year old boy. There was
a large, tennis ball-sized mass on his neck.”
The test was conducted in a treatment room on
the ward, hot and jammed with about 45 people.
Clinically the mass should have been Burkitt's
lymphoma, which is endemic in the area. “However
the fine needle and the smear revealed this was a
classic case of Hodgkin's disease.”
“He has since had treatment and he’s doing ok.”
As Dr Field asserts,
“It’s a very powerful tool
which we use all the
time in breast and other
clinics in Australia. Here, not only can you
do a fine needle that way but if you have
ultrasound or CT scan available you can
take a longer needle and reach anywhere
in the body. It’s an absolutely routine
matter as a day patient.”
“I had delivered a lecture on what
cytopathology could do in that
environment, its ability to be an
enormously powerful tool because
expensive infrastructure is not required.
All you need to do is to train people how
to use it, and how to interpret the slides.”
Following an international pathology
meeting in 2006 at which Dr Field spoke
about the ability of cytopathology to
assist resource-limited countries, he was
approached by a pathologist who asked
him to conduct a fine needle aspiration
tutorial in Uganda.
Dr Field recruited his colleague Dr
Geddie to assist and they ran their
tutorial, first in Uganda for east African
registrants, then Lagos, and in Abuga
(capital of Nigeria). These were run in the
same very practical way that Drs Field
and Geddie had been taught at the
- Dr Andrew Field
PATHWAY_45
>
CASE STUDY 2:
Lagos
ecently, Dr Frances Fardoly in Lagos sent us
photos of a fine needle aspiration he’d done
on this five year old boy, and then a repeat fine
needle, Dr Field said.
R
The five year old boy presented with a 14 cm
mass destroying the right maxilla, the area that
forms the lower eye socket and upper jaw.
“It’s a huge mass and so far it has distorted
his teeth, caused his eye to be distorted and
pushed aside, and destroyed the bone of his
whole right cheek.”
“They did the aspiration thinking it was
Burkitt's lymphoma and that they could treat it,
probably with chemotherapy. The slides came by
courier from Uganda.”
After consultation with colleagues, it was
decided the mass was a cementifying fibroma or
something in that category, Dr Field said.
Karolinska Institute themselves, with
lectures, practical demonstrations (on
pieces of fruit) of the fine needle
technique and then demonstrations on
patients.
Registrants witnessed how to extract
the material, smear it on the slide, how to
stain, and how to interpret the results.
While conditions were rudimentary,
and they worked in tutorial rooms without
curtains or blinds (making showing slides
difficult), in very basic outpatient clinics
and crowded, unairconditioned
environments, the registrants were
inspired and excited by the results.
“Once you’ve done the demonstration
there is immediate enthusiasm. You are
able to handle the large number of
patients who have palpable lumps and
bumps who currently come in and are
seen by doctors and then may spend
Dr Field is hoping
eventually to bring some
African pathologists here to
Australia for further training
but he notes that in a
department you can only
have one or two people. By
running tutorials in Africa
many more may benefit. He
is also assisting his African
colleagues with diagnosis
via slides sent by courier
and digital photographs
transmitted by email.
Dr Field hopes that
expertise from Australia,
may one day help establish
a laboratory in Africa.
He says, “You need a
body of people - critical
mass - and we hope to
create that.”
“This is a very rare tumour that arises from
the root of the tooth before the tooth actually
becomes a tooth, and erupts.”
For the doctors in Lagos, the diagnosis
presented a difficult situation.
“The family is penniless. The tumour needs a
wide excision. Without treatment it will kill the
child, not by metastasising, but by preventing
him from eating.”
“He will need a re-section and operations to
rebuild his whole face, including bone grafts. He
will be going through this process for two or
three years.”
Images were sent to a colleague in London,
in the hope there might be an institute or charity,
which might help. Local people here in Australia
were also considered but the 32 hour flight to
reach here was considered too onerous for the
child.
The flight from Lagos to London is only five
or six hours and at this stage it is looking
promising that this option will eventuate.
- Dr Andrew Field
weeks on the ward in these countries
waiting, perhaps, for an incisional biopsy.”
“There is an empowerment of people,
pathologists and clinicians when you
teach them how to do fine needles. The
feedback we have had has been
incredibly positive.”
“What we’ve done and the success
we’ve had is only the tip of the iceberg.”
46_PATHWAY
Would you like to help?
Anyone interested in making a donation to Dr Andrew Field's work in teaching
cytopathology in Africa should contact Dr Field, Department of Anatomical
Pathology, St Vincent’s Hospital, Darlinghurst, 2010, ph. 02 8382 9211. Alternatively
cheques made out to St Vincents Hospital Pty Ltd can be mailed to him, with a
brief note stating that the funds should go towards the costs of the tutorials and
support of the Laboratories in Africa in the form of equipment and consumables.
27 minutes ± 4
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SMSFs had over $245 billion of assets
invested.
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What exactly is a self
managed super fund?
So what are the advantages
of a SMSF?
A self managed super fund is a small
superannuation fund with up to four
members who each must be in a position
to have a say in the manner in which their
super funds are invested. This is done
through their role as the Trustee of the
fund and is usually performed via a
company acting as the trustee with the
members of the fund as the Directors.
The following are the key advantages of a
SMSF structure:
•
A SMSF offers greater investment
control, choice and flexibility over
your superannuation benefits. The
mix of investments can be designed
to suit each member in line with their
investment strategy. It can also
provide access to gearing
opportunities through instalment
warrants where borrowing can now
be extended to direct property
investments.
•
The tax advantages that flow to a
SMSF via long term investments are
particularly evident when a member is
permitted to access their benefits on
reaching the age of 55. At that point
the benefits are treated differently
with the taxation rate reducing to zero
at that point. Consequently
investments bought when the
member was accumulating their
benefits remain in the same form
when the fund changes to its new
zero tax rate on pension
The SMSF must have a trust deed as
well as an investment strategy to reflect
the manner in which the fund will invest to
meet the objectives of the members.
The SMSF can invest in many
investments providing they are in sync
with the investment strategy and will
include:
•
Listed shares
•
Managed funds
•
Cash and term deposits
•
Direct property and indirect property
•
Instalment warrants
•
International shares
•
Exotic types of investments
commencement. This contrasts with
most public funds where the
investments accumulated in super
over the years are redeemed on
pension commencement with the
purchase of a new pension product
and tax is generally payable. However
in a SMSF the underlying assets do
not need to be sold when moving to
pension mode. Therefore any
subsequent sale of those assets after
the fund moves to pension mode
does not attract capital gains or
income tax in the fund. For example,
imagine the power of BHP shares
bought twenty years ago in a self
managed fund and today the member
decides to commence a pension in
his fund and sell them. There would
be no tax payable on the transaction!
•
Franking credits also offer significant
benefits to a SMSF. These belong to
the SMSF and benefit all the
members chiefly because they carry
tax credits of 30% attached to a
dividend whereas the tax payable in
the fund is only 15% on that
dividend. If the fund is in pension
mode then that member will not pay
tax on the dividend and the fund will
receive a full tax refund for the
franking credit. Whilst public funds
have these credits the members have
no control over the amount,
distribution or timing of these.
•
Tax deductible contributions to a
SMSF attract tax at 15% but this is
generally not paid until the fund
lodges its income tax return. This
There may also be additional costs if a
financial advisor is involved and provides
investment advice.
The responsibilities of the trustee are
significant but not too onerous especially
for those with good advisors and
experience in running their own business.
Details on the responsibilities for trustees
is available on the tax office website with
various fact sheets at
www.ato.gov.au/super.
contrasts with Public funds that
deduct the 15% tax on the day you
make the contribution. You therefore
have use of the money much longer
in an SMSF.
The costs of running a SMSF are
around $2000 for the establishment of the
trust deed and purchase of the trustee
company as your one off set up.
Annual running costs will be in the
vicinity of $3,000 which should cover your
accounting and audit costs. It can be
higher depending on the number of
different transactions and complexity of
the fund.
A SMSF is not for everyone and it
pays to speak to your advisor on what it
could mean for you. Of course the larger
public funds would have you believe that
the responsibility is enormous as they
certainly do not like to see this mass exit
to self managed super.
To make a SMSF worthwhile you really
need to have around $200,000 to
$250,000 in super already and be making
significant contributions annually.
Next issue we will be talking about
how much is enough in super for
retirement and strategies to calculate and
get you to that point.
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PATHWAY_49
Virtual Microscopy: digital images for tissue
pathology & blood film morphology
RCPA Quality Assurance Programs is
using high resolution digital microscopy
to enhance and expand external quality
assessment (EQA) programs.
The latest state of the art digital
scanning microscope is able to produce
high quality images suitable for
advanced cellular pathology analysis.
Objectives:
N
Provide virtual images for the
cellular disciplines of haematology,
cytopathology and microbiology
N
Establish an image library in
suitable formats for dissemination
as training sets for laboratories
and other educational institutions
N
Develop applications in education
and continuous professional
development (CPD) for
pathologists and medical
laboratory scientists
Advantages:
N
Provision of identical material to all
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which previously was not possible,
such as small biopsies and bone
marrow aspirates
Contact Details:
Dr Ian Gardner
Ph: 02 8356 5847
Email: iang@rcpa.edu.au
lP ia t hfWe
s
t
y
l
e
ay lifestyle
travel
52
recipe for success
55
travel doc
58
the good grape
62
rearview
65
postscript
68
PATHWAY_51
travel
Sydney’s
Spectacular
Surrounds
International visitors to Sydney
invariably comment on the physical
beauty of the city, epitomised by the
harbour image of the Opera House
framed by the Harbour Bridge and
city skyline.
But few realise the diversity and
stunning scenery of Sydney’s surrounds –
the Hunter Valley to the north, the Blue
Mountains to the west and Kiama, Jervis
Bay and the Shoalhaven to the south.
All within several hours drive of
Sydney, these regions have their own
unique charm and attractions.
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Hunter Valley
The Hunter Valley, best known as ‘wine
country’ for its more than 120 wineries, is
also home to some of the finest spas and
golf resorts in the State.
In among the lush green rolling hills
are award winning wines, with crisp
Semillon and rich Shiraz varietals
available for tasting at the cellar doors of
many of the vineyards. Some Hunter
vineyards have been owned by families
for generations – McGuigan, Taylor and
Tulloch – to name a few.
Wine, food and music events abound
in the Hunter, bringing together jazz or
opera in an open air environment,
complemented by local wines and food
prepared with locally grown produce. The
Tempus Two winery holds premium
outdoor events, and has played host to
acclaimed names as Sir Elton John, Rod
Stewart and the Beach Boys, as well as
Shakespeare’s much loved classic “The
Twelfth Night”.
During the day, the Hunter provides a
range of activities, even boasting three
championship golf courses including
Cypress Lakes. Some of the more
unusual activities for visitors include hot
air balloon rides, horse and carriage tours
of the vineyards, chocolate tasting, and
night-time wildlife spotting.
At the end of a long, active day, spa
options abound at resorts across the
region.
Blue Mountains
Situated only two hours west of Sydney,
the Blue Mountains offers a tempting
combination of spectacular natural
scenery and indulgent food and shopping.
With the fresh mountain air and the array
of local produce available, the Blue
Mountains is the perfect destination for a
day trip or short break from Sydney.
The lookout at Echo Point in
Katoomba affords breathtaking views
across the Jamison Valley of the famous
Three Sisters and Ruined Castle rock
formations.
From Echo Point, visitors can walk
Further west, Jenolan Caves offers
down the Giant Staircase and across the
visitors to the Blue Mountains an
valley floor where the Scenic Railway or
underground wonderland with guided
Cableway can take you back to the top of
tours of more than a dozen separate show
the steep escarpment. Those who don’t
wish to tackle the 896 steps of the Giant
Staircase can visit Scenic World, also in
Katoomba, and take a return trip to the
caves and adventure caves, as well as
lookouts and scenic bushwalks.
Accommodation options at Jenolan range
valley floor on the Scenic Railway,
from self-contained bush cabins or
Cableway or glass-bottomed Skyway.
camping to exclusive suites in Caves
The townships of Katoomba and
House, and visitors can choose to have a
Leura are well known for their antique and
picnic or barbecue by the river, or enjoy
arts and crafts shops, as well as their
hearty country-style fare or fine wine and
stylish selection of cafes and restaurants.
cheese in the guest house.
PATHWAY_53
>
South Coast
The South Coast of New South Wales
claims to have the whitest sand in the
world, the best oysters and the top
beaches. The unspoiled natural
playground of the South Coast is an allyear-round destination.
About an hour south of Sydney, the
town of Kiama is a charming seaside
holiday destination. Kiama boasts the
famous Blowhole, a rock formation at
the edge of the sea which sends
chimneys of water high into the air as
the waves surge through the hole in the
rocks and release their energy with a
spectacular show of the power of nature.
In what is considered the first truly
rural town south of Sydney, Berry is a
quaint village atmosphere that offers a
country experience in style. While the
town is renowned for its cafes, antique
and boutique shops, the gourmet delights
of local boutique wineries and restaurants
are also not to be missed.
A little further south, in the Shoalhaven
region, Jervis Bay is reputed to have the
clearest waters and whitest sands in the
world. Dolphins and whales are regular
sights in this area, and water sports such
as diving, fishing and sailing are popular.
Batemans Bay and its surrounds offer
galleries, arts and crafts, and historical
attractions. The town also acts as a
gateway to the nearby national park
attractions, including famous Pebbly
Beach where visitors are greeted by
kangaroos and native birds.
The towns and regions surrounding
Sydney cater for all tastes and budgets,
and are within easy reach for a day trip or
short getaway.
recipe for success
LUCKY, LIKEABLE
PHOTO CREDIT: LIZZY ADAMS
Luke
HIS CULINARY TALENTS HAVE
WON HIM WORLDWIDE
ACCLAIM, BUT THE MODEST
LUKE MANGAN TRIES TO
CONVINCE KATRINA LOBLEY ,
IT HAS OFTEN BEEN A CASE
OF GOOD LUCK. >>>
PATHWAY_55
luke
I
f there’s one dish on glass brasserie’s
menu that sums up Luke Mangan’s
philosophy on food, it’s no doubt “simply
prepared fish”.
enjoy eating it. You just can’t go into the
kitchen one day and start doing all these
things – I’ve been taught classic French,
that’s my background.”
“I really like to let the ingredients
speak for themselves and keep it simple,”
says the 38-year-old, whose 240-seat
restaurant, Glass inside the revamped
Sydney Hilton is in its third year. These
days, Mangan’s globetrotting life as a top
restaurateur includes looking after new
dining ventures in Japan and the United
States – last year he opened Salt Tokyo
and a few months later South Food +
Wine in San Francisco.
To help create glass’s French-inspired
menu, Mangan took his chefs on a tasting
tour around Lyons and Paris, which was
ambitious considering Mangan isn’t fluent
in French.
Keeping it simple might not grab
world headlines – these days many
column inches are devoted to temples of
molecular gastronomy combining unusual
ingredients with scientific techniques to
come up with dishes such as bacon and
egg ice-cream and snail porridge – but
this food trend isn’t at all Mangan’s style.
“It’s good and it’s different but it’s not
for me,” he says. “It’s something that I
don’t know much about although I do
56_PATHWAY
“My kitchen French is okay but that’s
about it – and they’re mostly swear
words,” he laughs.
This tasting trip, as well as Mangan’s
love of fresh Australian produce, inspired
main courses at glass such as barramundi
fillets from Humpty Doo in the Northern
Territory, poached in cabernet, with
Jerusalem artichoke puree, zucchini and
shimeji mushrooms.
Then there’s squab from Glenloth in
Victoria, accompanied by maple syrup
almond puree, sautéed asparagus
mushrooms, pea agnolotti and a lavender
sauce.
It’s hard to believe that this star chef
was once a badly behaved Melbourne
schoolboy - he was kicked out of school
at age 15 for throwing paper at a teacher.
Why was he so naughty? “I couldn’t really
sit still and wasn’t interested in school
work – they’d probably call it ADHD now,”
says Mangan.
“I still find it hard to sit behind a
desk.”
He developed a taste of cooking
through helping his mother in the kitchen
at home. Then he started helping one of
his brothers who was working as a chef.
“When I was 13 or 14, I used to go to
Brisbane where he used to work and I’d
wash dishes and get into a commercial
kitchen that way. I fell into it, I suppose.”
He settled down to learning his trade
from two of the best: Hermann Schneider
of Melbourne’s iconic Two Faces
restaurant, then Michel Roux at the threeMichelin-starred Waterside Inn in England.
Back in Australia, Mangan made a
splash when he was appointed head chef
at Sydney’s Restaurant CBD while only 24.
How did he achieve so much at such
a young age?
PHOTO CREDIT: LIZZY ADAMS
“Well, it’s probably a lot of luck and
being in the right place at the right time,”
Mangan says modestly. “I was like the
new kid on the block - doing modern
Australian food and bringing European
trends back and turning it around a bit for
the Australian palate. There were other
chefs doing that but I was young – right
place, right time. And when we opened
Salt [in Darlinghurst], the same sort of
“Along with luck, you’ve got to put in
the hard work, there’s no doubt about
that. There are plenty of ups and downs
along the way. I think a lot of people just
see my up side but there are downs in
there as well.”
The downs include bowing out of Salt
at Darlinghurst, which he owned from
1999 to 2005 – the eatery was named The
Sydney Morning Herald’s Best New
Restaurant in 2000.
glass
thing happened. I was doing a bit of a
twist with the food, with the Asian
influence and my love of Japanese
cuisine– that was the right place at the
right time again.”
But why did he succeed ahead of
other hot young chefs? “Well, cooking’s
not very hard – it’s commonsense, to be
honest,” he says. “The whole package of
a restaurant is commonsense. You’ve just
got to be determined to make it work and
take risks. I could have had a really bad
review for the first review of a restaurant
and that could have changed my career –
who knows? I just think I have been lucky.
He also closed Bistro Lulu and went
through a frustrating and expensive time
opening Moorish at Bondi.
“But look at what’s happened since
then - it’s all been quite good,” says
Mangan. Indeed, he has quite the life
these days. With experienced head chefs
running his three kitchens smoothly,
Mangan is free to work on developing
menus and playing mine host at glass. “I
like to get out on the floor and talk to
customers and have a bit of a laugh,” he
says. “We’ve got some good regulars who
come in – it’s a bit of fun.”
Despite his high profile, the tag of
celebrity chef doesn’t sit well with
Mangan. “I don’t see myself as a celebrity
chef – I just see myself as a chef who’s
been lucky and who’s trying to do
different things and promote Australian
produce overseas. I think a celebrity’s
someone who makes movies or
something like that.”
Nevertheless, he has rubbed
shoulders with a celebrity or two over the
years. In 2004, Mangan was invited to
Denmark to cook for Prince Frederik and
Mary Donaldson in the lead-up to the
royal nuptials.
“That was a great experience,” says
Mangan. “I also had the opportunity to
cook for Bill Clinton in New Zealand a few
years ago – I got a photo with him and all
that sort of stuff.”
But who was the biggest thrill for him?
“I think Richard Branson and Bill
Clinton were the two for me – and it was
nice looking at Uma Thurman when she
was eating at Salt a few years ago.”
PATHWAY_57
travel doc
24 hours
IN SYDNEY
>>>
SO YOU’RE IN SYDNEY AT A
CONFERENCE AND
TOMORROW’S A FREE DAY.
IT’S A BEAUTIFUL CITY BUT
WHERE DO YOU START, WHAT
SHOULD YOU DO?
>>>
TO POINT YOU IN THE RIGHT
DIRECTION PATHWAY ASKED
FIVE PATHOLOGISTS,
or chemical pathologist and Bondi
RESIDENTS OF THIS
F
MAGNIFICENT HARBOUR CITY
quintessential Sydney revolves around
FOR THEIR TIPS ON HOW TO
resident, Dr Peter Stewart, the
the beach.
He suggests you start the day early,
MAKE THE MOST OF YOUR
TIME TO REALLY ENJOY THE
SYDNEY EXPERIENCE.
58_PATHWAY
50_PATHWAY
going to South Head at the entrance to
the harbour to watch the sunrise over
the Pacific Ocean.
“It is truly spectacular!”
After that it’s a short drive to the
iconic Bondi Beach. Along the way,
don’t miss a marvellous photo
opportunity at Dudley Page Reserve on
Military Road where you are treated to
one of the best views of the city you
could possibly find.
On arrival at Bondi Beach, Dr
Stewart assures us you will be full of
energy and enthusiasm, all ready to
>>
>>>
tackle the Bondi to Bronte walk, a
After such an energetic start to the
For histo- and cytopathologist, Dr
picturesque 40-minute round trip along
morning, Dr Stewart suggests you then
Jeanne Tomlinson, visitors to Sydney
the cliff face and ocean.
indulge in a leisurely breakfast at one of
need to experience a little of everything –
the many coffee shops that are found
the culture, the scenery, the people – and,
Once back at Bondi it is time to catch
a few waves with a surf in the ocean.
Warm currents keep the water at a
pleasant temperature most of the year,
making surfing a feasible option for
visitors no matter what the season.
along the beachfront.
“What else can you do to beat such a
morning? Absolutely nothing!” he says.
But there’s so much more to see and
do, and the day has just begun.
of course great food and wine.
She suggests exploring the heart of
the city starting off at the Art Gallery of
NSW, where you can not only see many
fine examples of Australian art you can
also be treated to a particularly lovely
PATHWAY_59
>
>>>
view from the café terrace while enjoying
a coffee or lunch.
After the Gallery, Dr Tomlinson
suggests heading off, at an amiable pace
through the Botanical Gardens to the
world-renowned Sydney Opera House.
Guided tours of this architectural
masterpiece are conducted regularly
throughout the day, providing visitors the
opportunity to explore and understand the
building that for many epitomises Sydney.
Just metres from the Opera House, is
the Oyster Bar where Dr Tomlinson
suggests you might care to partake in a
cleansing glass of champagne. Looking
out towards the Harbour Bridge, it’s the
perfect vantage point to watch the ferries
go by, and it’s not bad for peoplewatching either.
Having appreciated the famous ‘coathanger’ from afar you might like to take a
closer look, says anatomical pathologist,
Dr Inny Busmanis.
The Harbour Bridge climb is an
experience not to be missed provided you
have a head for heights. Approached from
the Bridge’s southern aspect the climb
takes just over three hours by the time
you have included all the instruction time
and donned the grey coveralls (so you
don’t distract those commuters driving
underneath you). But the view from the
top makes it all worthwhile. From here you
can really appreciate the enormity and
magnificence of Sydney Harbour.
to the beachside suburb of Manly. The 30
minute journey will take you past many
beautiful bays and waterfront properties.
Once in Manly it’s an easy walk to the
beach where you can enjoy a stroll along
the famous Corso or take the promenade
south to the delightful Fairy Bower and on
to Shelly Beach.
You might also consider taking the
ferry to the nearby Taronga Zoo. As well
as being widely acknowledged as one of
the best zoos in the world, all
Sydneysiders know the giraffes have a
view that is second to none – looking
back up the harbour to the Bridge and
Opera House.
If you are a bit pressed for time but
still want the ferry experience, you can opt
for the quick ride north across the harbour
to Milsons Point, just near the Harbour
Bridge, says Dr Busmanis. There you will
find Luna Park and the North Sydney
Olympic Pool.
Ripples café, just on the harbourside
of the pool has a wonderful outlook under the Bridge to the Opera House, and
is another great option for a meal be it
breakfast, lunch or dinner, she suggests.
For those who like a little adrenalin
with their sight-seeing there is always a
high speed Jet Boat ride available from
Darling Harbour. It always adds to your
travel stories when you can throw in
you’ve done 270° spins in view of the
Opera House!
For many, the harbour is the essence
of Sydney and no visit to this city would
be complete without getting out on the
water and enjoying a view closer to the
‘Finding Nemo’ perspective.
But suppose you don’t have a
penchant for water. Suppose your tastes
run more toward the fruit of the vine.
Dr Busmanis suggests, in order to
savour such an experience, catch a ferry
It involves a little travelling, a two hour
drive north of Sydney in fact, but that will
60_PATHWAY
Forensic pathologist Dr Neil Langlois
has a suggestion for you.
put you in the heart of the Hunter Valley
wine growing district. An area consisting
of a wide range of wineries that will
provide tastings at their cellar door as well
as also often offering local produce for
sale. To maximise enjoyment and
minimise the risk of driving over the legal
blood alcohol limit, Dr Langlois suggests
opting for one of the many small group
tours that operate in the region. While
there is a myriad of accommodation
available up in the wine region for those
wanting to stay overnight, tours are also
available as day only options from Sydney
if you are sticking to your 24 hour time
limit arriving back home in the late
afternoon or evening.
After such an action-packed day, you
will no doubt be feeling a little weary.
Come evening, it’s time to relax over a
delicious meal accompanied by glass or
two of a very excellent Australian wine.
But where to go?
Here we can defer to haematologist,
Dr John Rasko who has a suggestion for
almost every palate and pocket.
“There are many superb restaurants
around the central business district of
Sydney. One of the best moderatelypriced restaurants with the most
magnificent view of the Harbour Bridge
and Luna Park is The Wharf Restaurant.
The owner, Tim Pak Poy is the son of a
distinguished pathologist from Adelaide
and one of Australia’s great chefs.
Located at the end of a wooden wharf
jutting into the harbour, the setting makes
you feel like you are sailing – but without
any waves!
Another wonderful, high-end
restaurant right at the water’s edge will
require a drive over the Harbour Bridge for
>>>
about 20 minutes to Balmoral. The
Bathers Pavilion has become a very
popular place for lunch and dinner with a
view to the North Head so large and small
sailing ships can be observed from the
safety of your restaurant table.
Continuing the theme of sea views,
few restaurants could claim a more Aussie
heritage than the Bondi Icebergs located
at Bondi Beach. The cuisine is decidedly
Italian, but the location is unquestionably
Sydney!
For some cheaper options head
towards King Street in Newtown, south of
the University of Sydney where there are
dozens of restaurants, at least two dozen
of which are Thai. Although a longstanding favourite remains Thai Pothong,
my current favourite is Chedi Restaurant,
which provides classical Thai cuisine with
a modern twist. The service is always
personal, the food is delivered promptly
and the price is very reasonable.”
So there you have it.
No excuses not to have the perfect
end to the perfect day in Sydney.
And all this in just one day! Imagine
what you could see if you had more time.
As most visitors to this beautiful city
agree, you’ll just have to come back….
The location of Guillaume at
Bennelong cradled underneath one of the
smaller sails of the Opera house would
alone make it a major attraction, but the
food never fails to impress. For some of
the freshest seafood cooked to perfection
try to squeeze yourself a place at Fish
Face in the inner-city suburb of
Darlinghurst. Although a little expensive in
light of the décor and service, the
restaurant has a real café buzz and
showcases the very best fish Sydney has
to offer, Dr Rasko says.
If you have a craving for casual
European fare matched with an extensive
selection of wine by the glass you could
do much worse than visiting Austrian
Sommelier Andreas at DeVine a few
blocks away from the Queen Victoria
building in the city centre.
If you can’t afford to hire a helicopter
to fly over the city to get your bearings,
you should definitely pay a visit to the
rotating Summit Restaurant and Orbit
Lounge Bar in the city centre atop
Australia Square Tower. The acclaimed
chef and restaurateur Michael Moore has
created a great experience for
international visitors and locals alike.
PATHWAY_61
the good grape
Gathering in the
Hunter Valley
BEN CANAIDER EXPLORES ONE
OF AUSTRALIA’S MOST
POPULAR WINE REGIONS, ,
LOOKING FOR WHAT IT IS THAT
MAKES THE HUNTER VALLEY
SO UNIQUE.
he Hunter Valley is perhaps Australia’s
most extraordinary wine region – and
for lots of reasons. Some good; some
odd, and some more to do with simple
convenience. The fact that it is less than a
two hour drive up the F3 from a little
village called Sydney is the convenient bit.
Sydneysiders have really taken the Hunter
as their own, and this has helped the
Hunter overcome all other adversities –
and there are a few.
T
It has soil which in the most part really
isn’t ideal for grape growing. It is a
distinctly warm wine region which doesn’t
generally auger well for fine wine
production; and when it rains it mostly
rains during ripening and vintage time,
causing all kinds of heck for grapes and
winemakers.
And yet despite this the Hunter makes
Australia’s greatest white wine style. No,
not chardonnay; but semillon. Hunter
Valley semillon is a unique and worldclass white wine – or wine, full stop –
wherever on the globe you might happen
upon two drinkers and a wine list.
Having said that, it also produces
some very good chardonnay in a more
refined Australian manner, such as Tyrrell’s
Vat 47; and an array of shiraz that run the
earthy and spicy and generous gamut of
the spectrum. Given that the region has
nearly 150 cellar doors and wineries it
isn’t hard for a wine tourist to stumble
across a likeable and good quality wine.
The fact that the Hunter’s wine history
goes back to 1825, and the fact that it
has a degree of wine-istocracy about it,
means that the pursuit of quality wine and
quality wine making is clear and present.
And there is more. That wine tourism now
62_PATHWAY
contributes so heavily to the region’s
bottom line also means there’s money
around to maintain that pursuit. Roughly
2.5 million wine tourists a year keep the
wheels of both wine quality and wine
sales spinning, despite those unsuitable
soils, warm climate, and bothersome
vintage rains…
The wealth of tourists makes for a
fairly diverse range of cellar doors,
restaurants, and accommodation. From
luxury hotels to more quaint bed and
breakfast, self-serviced vineyard cottages
and Greg Norman-designed golf links –
complete with self-contained apartments
– there’s an overnight stay or two to suit
every taste and budget. And with about
60 cafes and restaurants now operating it
is hard to go hungry. More of these
eateries are now offering not just the
bounty of the local vineyards, however.
Keep an eye peeled for the Hunter Valley
Smelly Cheese Shop and Binnoire Dairy.
There’s also good local stonefruits and
more and more olives.
But try not to let these add-ons
distract you too much from the real job at
hand – the wine.
For semillon you need to quickly
calibrate your palate with some
benchmarks – so go to Tyrrell’s and
McWilliam’s to try the former’s individual
vineyard examples and the latter’s Mount
Pleasant. These wineries offer semillons
with some bottle age, too, so you can get
a snapshot of what happens to this
remarkable wine style with good cellaring.
From the piercing, citric cut and thrust
of young semillon – that some people
reckon is like drinking battery acid – to the
more mellow, rounded, toasty and
honeyed flavours and smells you find in
the older bottle aged wines, both cellar
doors will help you rapidly come up to
speed on what the Hunter does best with
its white wine of choice. The other great
quality that Hunter semillon has, of
course, is its relatively low alcohol levels,
often closer to 10% than not. During a
new era of warmer weather and much
riper grapes (some of which produce wine
alcohol levels of 16% in red wines…) that
the semillons of the Hunter are so much
more moderately fuelled makes a
welcome change.
2008
Conference Calendar
AUGUST
31
Australian Health Informatics
Conference
31 August - 2 September 2008
Melbourne
www.hisa.org.au/hic08
SEPTEMBER 2008
5
RCPA Basic Pathological Sciences
Seminar 2008
5 - 6 September 2008
Sydney
222.rcpa.edu.au
8
19th Annual Gastrointestinal Surgical
Pathology
8 - 12 September 2008
Washington DC
Email: came@afip.osd.mil
12
Mercy and Austin Gynaecological
Pathology Symposium
12 - 13 September 2008
Melbourne
Email: nicholas.mulvany@austin.org.au
Besides Tyrrell’s and McWilliams’
visitors should also strongly consider
visiting Brokenwood and Bimbadgen
Estate, and also Allandale in Lovedale.
If your tastes lay closer to red
wine than semillon, however, you’ve
got shiraz to fall back on, so to speak.
Stylistic differences vary wildly,
however, which isn’t a bad thing as it
means all tastes can be catered for.
Brokenwood’s famous Graveyard
Shiraz is hard to beat for posh
powerful wine; or while at McWilliam’s
try their Old Hill and Old Paddock
versions, which are arguably more on
the graceful side.
I’m happy to admit to a great
liking for a small winery’s shiraz – at
Chateau Pato. This place only makes
a few hundred cases of wines a year,
and is only open by appointment, but
it is the sort of wine that you might
really fall for, and then you can call it
your own.
It just goes to show that even with
2.5 million visitors a year, there is still
something for you to secretly discover
in the Hunter Valley.
25
College of American Pathologists 08
25 - 28 September 2008
San Diego, USA
16
American Society of Clinical Pathology
16 - 19 October 2008
Baltimore MD, USA
http://www.ascp.org
19
XIII International Federation of Cervical
Pathology and Colposcopy
19 - 23 October 2008
Auckland, New Zealand
Email: hmc@xtra.co.nzhmc@xjtra.cko.nz2
26
Pathology Visions: Digital Pathology
Solutions Conference
26 - 28 October 2008
California, USA
http://www.aperio.com/pv/index.html
NOVEMBER 2008
7
American Society of Cytopathology
7 - 11 November 2008
Florida, USA
www.cytopathology.org/website
15
International Anatomical Pathology
Update
15 - 17 November 2008
Penang, Malaysia
www.hipohpathology.com.my
http://www.cap.org
OCTOBER 2008
3
Ontario Association of Pathologists,
70th Annual Meeting
3 - 5 October 2008
Ontario, Canada
www.ontariopathologists.org
6
The 19th International Symposium
on the Forensic Sciences
6 - 9 October 2008
Melbourne, Australia
Pathology Update 2009
in conjunction with XXV WASPalm
13-15 March 2009 - Sydney Australia
MARCH 2009
13
The XXV WASPaLM Congress in
conjunction with Pathology Update
13 - 15 March
Sydney, Australia
www.rcpa.edu.au/pathologyupdate
www.anzfss2008.org.au
12
XXVIIth Congress of the International
Academy of Pathology
12 - 17 October 2008
Athens, Greece
www.era.gr
SEPTEMBER 2009
13
22nd European Congress of Pathology
4 - 9 September 2009
Florence, Italy
222.ecp209.org
PATHWAY_63
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rearview
THE BATTLE AGAINST
REJECTION
DR GEORGE BIRO TAKES A
neonates who were jaundiced, anaemic,
These abnormalities included
bloated, brain-damaged, or even born
•
Stillbirths
•
Erythroblastosis foetalis (EF, also
called severe haemolytic anaemia)
•
Hydrops foetalis (heart failure from
anaemia)
•
Icterus gravis neonatorum (severe
jaundice)
•
Kernicterus (brain damage from toxic
levels of bile pigment)
LOOK AT HOW MEDICINE WON
dead. But they were at a loss to explain
THE WAR AGAINST RHESUS
the phenomenon.
In fact, it wasn’t until 1900 that the
INCOMPATIBILITY AND
Austrian-American Karl Landsteiner, the
HAEMOLYTIC DISEASE OF THE
father of blood science and immunology,
discovered the human ABO blood groups.
NEWBORN
ack in 1966, the eminent Dr Gus
Nossal, of Melbourne’s Walter and
Eliza Hall Institute told an international
conference “We do not often have the
privilege to be present at the beginning of
one of the revolutions of medicine.”
B
The revolution he was talking about
was the prevention of Rh haemolytic
disease of the newborn.
The story of haemolytic disease of the
newborn, the discovery of its cause and,
more importantly, finding how it could be
prevented is one of the great success
stories in medicine.
Around 400 BC, Greek physicians
noted a range of signs in particular
newborn infants. They described
The recognition that blood types had
to be compatible to avoid rejection
reactions was a major advance in the
safety of transfusions.
The Rh system and
pregnancy
While blood typing and its importance in
transfusion was well-accepted relatively
early in the twentieth century, the Rhesus
part of the equation and its importance in
These now associated abnormalities
came under the umbrella concept
haemolytic disease of the newborn.
In 1937, following studies with Rhesus
monkeys, Landsteiner and colleagues
discovered another blood antigen factor,
which they called Rhesus factor, which
also caused adverse reactions from
transfusions.
pregnancy had not yet been recognised.
Between 1928 and 1932, a key
advance was made. Researchers found a
collection of foetal abnormalities,
previously thought to be unrelated, were,
in fact, linked.
The importance of Rh factor
The Rhesus factor was found to occur
only in a minority of humans but its
importance was soon recognised as it
provided the explanation for the relatively
PATHWAY_65
common medical disorder known as
haemolytic disease of the newborn.
"The Rhesus blood type, present in
about 87% of the white population, is of
practical importance almost exclusively to
the persons who lack it," said Dr Louis
Diamond, one of the co-discoverers of a
simple test for Rh factor.
Using staining techniques of foetal
blood cells, researchers showed that
during labour and sometimes miscarriage
or abortion, foetal red cells could leak
across the placenta, into the mother’s
circulation.
If an Rh-negative woman is pregnant
for the first time and if she has an Rhpositive child whose cells leak into her
own bloodstream, she can develop
antibodies to these Rh-positive red blood
cells, after a period of days to weeks.
By the time such antibodies have
developed to any significant degree the
baby is usually delivered or the
pregnancy has ended, so the antibody
formation is of little consequence to that
first pregnancy.
But later, should the woman conceive
another Rh-positive child, the antibodies
can attack the foetus as though it was a
foreign disease.
WHO’S WHO IN
EARLY RESEARCH
ON RH FACTOR AND
HDN
t was Karl Landsteiner (pictured
above) and Alexander Wiener who
discovered the Rhesus blood system
around the end of the 1930s. About
85% of people of European stock
are Rh-positive.
I
In 1939, Philip Levine and Rufus
Stetson wrote their landmark paper
on a Mrs Seno (group O Rhnegative), who had an almost fatal
reaction after a transfusion from her
group O Rh-positive husband.
Levine later attributed this
reaction to Mrs Seno’s recent
stillbirth from Erythroblastosis
Foetalis, caused by antibodies she
had developed against the Rhpositive red cells of her foetus.
The antibodies destroy red blood cells
causing foetal anaemia, heart failure,
brain damage and even stillbirth.
The missing antibodies
In the 1940s, having discovered the
mechanism behind the development of
haemolytic disease of the newborn, the
researchers were puzzled to find that the
actual frequency of the disease was only
about a tenth of that predicted.
Almost one quarter of the Rh-negative
mothers found to have foetal Rh-positive
red cells in their bloodstream straight
after delivery did not go on to produce
antibodies.
When doctors reviewed these
mothers a short while later, the Rhpositive foetal red cells had mysteriously
gone!
While not everybody exposed to an
antigen produces an antibody, this
variability could not sufficiently explain
the phenomenon of the missing foetal
blood cells.
Finally, they found the answer: not in
the Rh system itself, but in the other
blood groups. Not only were these
66_PATHWAY
mothers Rh-negative when their infants
were Rh-positive, but they also had
different ABO groups.
The mother's intrinsic anti-A, anti-B,
or anti-AB antibodies destroyed the foetal
red blood cells because of their ABO
incompatibility, before the mother’s
immune system had time to produce anti
(D) antibodies.
Whereas anti-Rh (D) antibodies
develop only after antigen exposure, ABO
antibodies are present throughout life.
Fighting fire with fire
At last, someone wondered: "Why not
inject the mother (passively) with
antibodies to quickly destroy the Rhpositive foetal red cells before they can
trigger maternal antibodies?"
The injected antibodies themselves
would break down long before they could
affect any later Rh-positive child.
In 1961, a team at Liverpool (UK)
showed that anti-Rh (D) antibody, given
up to five days after injecting Rh-positive
red cells, would prevent immunisation
(sensitisation).
This was a major breakthrough.
In New York, the obstetrician Vince
Freda successfully injected anti-Rh (D)
antibody to unimmunised Rh-negative
women.
He achieved his aim: to quickly clear
them of any Rh-positive red cells, before
the latter could stimulate maternal
antibodies.
Where was the first dose of
actual immunoglobulin given?
Was it given by the British researchers at
Liverpool? Or the Americans in New
York?
Neither! Dr John Gorman, an
Australian graduate, working in New York
with Dr Vince Freda, on prevention of
HDN, came from a medical family. His
father, also John, was a physician in
Australia. Brother Frank, an
ophthalmologist, was studying in
England. Frank’s wife Kathryn was
pregnant and Rh-negative.
John senior was worried and
pressured his son John for a dose of the
immunoglobulin that had not then been
trialled, let alone released. Son John
bowed to his father’s wishes and broke all
the rules in airfreighting a vial to England.
After premature labour, on January 31,
1964, Kathryn became the first woman
known to be injected with
immunoglobulin. It was only some months
later that the formal trials, on both sides
of the Atlantic started.
Dr Eugene Hamilton: the
quiet achiever
But who first used anti-Rh (D) antibody on
a whole series of Rh-negative women?
It was Dr Eugene Hamilton, working
alone at St. Mary’s Hospital in St Louis,
Missouri. Starting in 1962, he had devised
a homemade vaccine. He used raw
plasma, drawn by plasmapheresis from
the blood of Rh-negative women who had
given birth to dead Rh-positive babies,
and who hence had high titres of anti (D).
To guard against transmitting infectious
disease, he used only a small, select
panel of donors, whose health was
carefully monitored.
He had injected 500 at risk Rhnegative women at delivery. Later, 74 of
these had returned to his hospital and
delivered 79 subsequent babies, who
were all well.
In 2008, the indications for giving antiRh (D) immunoglobulin include: Rhnegative mothers exposed to Rh-positive
blood from the foetus as a result of
foetomaternal bleeding, abdominal
trauma, amniocentesis, termination,
ectopic pregnancy, full-term delivery or
transfusion accident.
who agree to have repeated injections of
Rh-positive red cells. These donors are
•
women who have received Rh-
Treating a baby with HDN
What to do for an affected baby? Why not
replace the anaemic haemolysed Rhpositive blood with Rh-negative blood?
An exchange transfusion.
The first exchange transfusions in the
1940s had some dramatic successes.
Despite complications, exchange
transfusion, once or even repeatedly, after
delivery has saved many neonates from
death or morbidity. Later came in-utero
exchange transfusions. Any decision on
early induction or transfusion is based on
both the haemoglobin and bilirubin levels.
Phototherapy also helps less severe
cases.
Rh-negative men or postmenopausal
positive blood
•
Post menopausal women who have
become immunised by a pregnancy
The safety of these volunteers
depends on strict precautions against
infectious diseases. They are bled by a
machine that separates the immunised
donor's plasma and returns the rest. This
prevents anaemia and so allows more
frequent bleeding.
Combined with advances in
transfusion practice, anti-Rh (D)
immunoglobulin has greatly reduced the
incidence of both HDN and of transfusion
reactions.
Sources of anti-Rh (D)
immunoglobulin
Commonwealth Serum Laboratories (CSL)
derive the anti-Rh (D)immunoglobulin from
donor plasma. Originally, this plasma
came from women immunised by
pregnancy, but this supply became
inadequate as the prevention of HDN has
reduced the number of immunised
women!
Nowadays, the Australian Red Cross
Blood Service recruits Rh-negative donors
But some women are still becoming
immunised through failure to get antiRh(D)immunoglobulin after every
potentially immunising event. Just one
more reason for doctors and blood banks
to encourage suitable people, especially
the Rh-negative ones, to donate blood
regularly.
SUGGESTED READING: David Zimmerman, Rh:
the intimate history of a disease and its
conquest, Macmillan 1973; A free download
from The Virtual Museum of Transfusion
Medicine:http://www.bloodtransfusion.org/
PATHWAY_67
postscript
Pathological Horses for Courses
My first university
PAM RACHOOTIN
diploma is a Bachelor of
here is a secret ingredient for success
in medicine that I call QC. That’s
shorthand for Quirkiness Compatibility. I
agonise over QC to find the right
specialist for each patient. If I get the
match wrong… don’t ask.
T
Mrs Broken Heart can’t be referred to
any cardiologist — she needs one who
acknowledges the link between cardiac
disease and unrequited love. Mr Daring
Do requires an orthopaedic hero who has
scaled Everest, while Ms Swami will not
consider a surgeon without anatomical
expertise in mapping the body’s chakras.
Adolescent girls request referral to a
paediatrician who looks like their favourite
movie star. Mrs Mutual wants to book in
with a specialist who has the same
condition that she has. Frankly, it’s
surprising that any sane psychiatrist can
make a living.
Finding an available specialist when
your patient urgently needs one is hard
enough these days, but finding one with
maximum QC is nearly impossible. The
population is splitting into infinite degrees
of quirkiness. Unfortunately medical
specialist weirdos do not seem to be
evolving as quickly as the general public.
Thankfully one type of specialist does
not require QC — my good friends, the
pathologists. Their lack of direct patient
contact means no need to consider QC,
or so I thought.
Arts in Biology. From
reading the evidence
with her own eyes, Mrs
Grace has concluded
that I am trained in
science, which she
considers to be the
work of the devil. She
weighs up any advice
that I give her,
struggling to determine
whether it comes from my holy medical
side, or my depraved scientific side.
I have often watched in amazement as
an epic battle rages within her. Mrs Grace,
living up to her name, shows no outward
sign of distress, except a slight rhythmic
shifting from one buttock to the other and
a single bead of perspiration on her upper
so terribly wrong. Until they had their
theory, they probably weren’t bad people,
just rudderless — no beliefs. They got
influenced by everything they saw. They
tried to fit all the pieces together before
they understood what it was all supposed
to show. No, I won’t have any scientist
who works like that, and you shouldn’t
lip.
Recently Mrs Grace needed a
pathology workup for a new complaint.
She won’t have just any pathologist. She
insists on a high QC factor, although she
doesn’t call it this. Instead, she tells me
either.”
Before she left she made me agree
that I would find a pathologist who fitted
her requirements. She wanted written
evidence. She would wait for proof before
she submitted her blood sample.
that she doesn’t want a “scientist”, she
wants a believer.
I looked at her blankly as she
attempted to enlighten me.
“You know how God created
everything in the world?” she asked. “Well
Enter Amazing Grace. Mrs Grace is a
very strong believer, and the thing that she
believes most in is my corresponding lack
of faith (although I admit to the occasional
vision … of seeing “Divine Intervention”
scrawled across her medical file.)
scientists have a different explanation.
Mrs Grace is that one in a thousand
patients who actually reads the diplomas
that are hanging up in the surgery. Now,
when I began practising I found all of my
pre-medical diplomas (including my
certificate of dental excellence from Year
One) and had them framed. My hope was
to impress people with their sheer
number, if not their direct relevance.
Unfortunately, I have never made an effort
to re-decorate the room.
that shouldn’t be a problem. I’m sure that
68_PATHWAY
“That’s where the evolutionists went
They say that all life on earth was made
through evolution.”
“So, you want a pathologist who
believes in God, right?” I replied. “Well,
I could find several excellent practitioners
with a strong religious identification.”
Well, I like a good challenge…
Dear Pathologist,
I have an Adelaide patient, Mrs A Grace,
who requires some investigation by a
specialist in clinical chemistry. I hope that
you are able to take her case.
Her history is unremarkable, except for
the destruction of her home and near loss
of her family in Cyclone Tracy. To this
day, Mrs Grace morbidly fears any
association with the Northern Territory.
She has asked me to confirm that in
handling her work you and your lab will
not be involving any colleagues in the NT.
“No,” said Mrs Grace, “there’s more to
it than that. I want a pathologist who
believes, really believes, what you tell
them is wrong with me. I don’t want
someone who just goes off looking. That
kind of person will test for everything, and
just might find anything.
Dear Dr Rachootin,
I am in receipt of your letter re: Mrs A
Grace. I can assure you that, given our
strong belief in our excellent local
resources, we routinely reject the Darwin
option.
Pathology Update 2009
in conjunction with
hosted in association with
XXV WASPaLM World Congress
of Pathology and Laboratory Medicine
13 - 15 March 2009
The world of pathology meets down under
Sydney Convention and Exhibition Centre
Darling Harbour Sydney Australia
Conference Secretariat: Ms Eve Propper • email. evep@rcpa.edu.au • www.rcpa.edu.au